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1ab76019645a31da3b0448dcf00362c3

Many ESBL-producing E. coli had significantly lower susceptibility to gentamicin ( p ＜ 0.0001 ) and the quinolones nalidixic acid ( p＝0.004 ) and ciprofloxacin ( p ＜ 0.0001 ) than non-producers .

Antibiotic Susceptibilities and Genetic Characteristics of Extended-Spectrum Beta-Lactamase-Producing Escherichia coli Isolates from Stools of Pediatric Diarrhea Patients in Surabaya, Indonesia. The purpose of this study was to investigate extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli isolates from pediatric (aged 0 to 3 years) diarrhea patients in Surabaya, Indonesia, where this kind of survey is rare; our study included assessment of their antibiotic susceptibilities, as well as ESBL typing, multilocus sequence typing (MLST), and diarrheagenic E. coli (DEC)-typing. ESBL-producing E. coli were detected in 18.8% of all the samples. Many ESBL-producing E. coli had significantly lower susceptibility to gentamicin ( p ＜ 0.0001 ) and the quinolones nalidixic acid ( p＝0.004 ) and ciprofloxacin ( p ＜ 0.0001 ) than non-producers . In ESBL-producing E. coli, 84.0% of strains expressed CTX-M-15 alone or in combination with other ESBL types. MLST revealed that 24.0% of ESBL-producers had sequence type 617, all of which expressed the CTX-M-15 gene; we also detected expression of 3 DEC-related genes: 2 enteroaggregative E. coli genes and 1 enteropathogenic E. coli gene. In conclusion, CTX-M-15-type ESBL-producing E. coli ST617 appear to have spread to Indonesia.

https://pubmed.ncbi.nlm.nih.gov/28003592/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Antibiotic Susceptibilities and Genetic Characteristics of Extended-Spectrum Beta-Lactamase-Producing Escherichia coli Isolates from Stools of Pediatric Diarrhea Patients in Surabaya, Indonesia. The purpose of this study was to investigate extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli isolates from pediatric (aged 0 to 3 years) diarrhea patients in Surabaya, Indonesia, where this kind of survey is rare; our study included assessment of their antibiotic susceptibilities, as well as ESBL typing, multilocus sequence typing (MLST), and diarrheagenic E. coli (DEC)-typing. ESBL-producing E. coli were detected in 18.8% of all the samples. Many ESBL-producing E. coli had significantly lower susceptibility to gentamicin ( p ＜ 0.0001 ) and the quinolones nalidixic acid ( p＝0.004 ) and ciprofloxacin ( p ＜ 0.0001 ) than non-producers . In ESBL-producing E. coli, 84.0% of strains expressed CTX-M-15 alone or in combination with other ESBL types. MLST revealed that 24.0% of ESBL-producers had sequence type 617, all of which expressed the CTX-M-15 gene; we also detected expression of 3 DEC-related genes: 2 enteroaggregative E. coli genes and 1 enteropathogenic E. coli gene. In conclusion, CTX-M-15-type ESBL-producing E. coli ST617 appear to have spread to Indonesia. ### Response: gentamicin, nalidixic, ciprofloxacin

6d1750301095d2936cc280ebf081c991

The resistance of topotecan in MDR HL-60 cells was potently reversed by the addition of amlodipine .

Effect of stealthy liposomal topotecan plus amlodipine on the multidrug-resistant leukaemia cells in vitro and xenograft in mice. Multidrug resistance (MDR) is a major obstacle to successful cancer chemotherapy as the over-expressed MDR protein acts as an efflux pump, which leads to a reduction in the uptake of the anticancer agent by tumour cells. We combined topotecan and amlodipine together into the stealthy liposomes, in which amlodipine was applied as a MDR reversing agent to overcome the resistance. ### Materials And Methods Cytotoxicity, apoptosis and the signalling pathway assays were performed on human chronic myelogenous leukaemia K562, promyelocytic leukaemia HL-60 and MDR HL-60 cells, respectively. Pharmacokinetics and antitumour activity studies were performed on normal Kunming mice and female BALB/c nude mice with MDR HL-60 xenografts, respectively. ### results topotecan alone was effective in inhibiting the growth of non-resistant leukaemia cells, K562 and HL-60 cells but not the growth of MDR HL-60 cells. The resistance of topotecan in MDR HL-60 cells was potently reversed by the addition of amlodipine . Moreover, amlodipine enhanced the apoptosis-inducing effect of topotecan synergistically. Apoptosis was through activating caspases in a cascade: first, the initiator caspase 8 and then effectors caspase 3/7 (total activity of caspases 3 and 7) were activated. Being encapsulated into the stealthy liposomes with an acidic internal medium, topotecan existed dominantly in an active lactone species, which was reversibly changed from an inactive carboxylate form via a pH-dependent reaction. After administration of stealthy liposomes to mice, the blood exposure of the lactone form was evidently increased and extended. The antitumour effects in the MDR HL-60 xenografted tumour were stealthy liposomal topotecan (SLT) plus amlodipine > SLT > un-encapsulated topotecan > blank control. ### conclusions The enhanced antitumour activity in the MDR HL-60 cells by the SLT plus amlodipine could be owing to multiple reasons: (a) synergistic apoptosis inducing effect, (b) reversing MDR by amlodipine and (c) increasing the availability of active lactone of topotecan by the stealthy liposomes. The apoptosis induced by amlodipine is through caspase 8 and then the 3/7 signalling pathway.

https://pubmed.ncbi.nlm.nih.gov/16684125/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Effect of stealthy liposomal topotecan plus amlodipine on the multidrug-resistant leukaemia cells in vitro and xenograft in mice. Multidrug resistance (MDR) is a major obstacle to successful cancer chemotherapy as the over-expressed MDR protein acts as an efflux pump, which leads to a reduction in the uptake of the anticancer agent by tumour cells. We combined topotecan and amlodipine together into the stealthy liposomes, in which amlodipine was applied as a MDR reversing agent to overcome the resistance. ### Materials And Methods Cytotoxicity, apoptosis and the signalling pathway assays were performed on human chronic myelogenous leukaemia K562, promyelocytic leukaemia HL-60 and MDR HL-60 cells, respectively. Pharmacokinetics and antitumour activity studies were performed on normal Kunming mice and female BALB/c nude mice with MDR HL-60 xenografts, respectively. ### results topotecan alone was effective in inhibiting the growth of non-resistant leukaemia cells, K562 and HL-60 cells but not the growth of MDR HL-60 cells. The resistance of topotecan in MDR HL-60 cells was potently reversed by the addition of amlodipine . Moreover, amlodipine enhanced the apoptosis-inducing effect of topotecan synergistically. Apoptosis was through activating caspases in a cascade: first, the initiator caspase 8 and then effectors caspase 3/7 (total activity of caspases 3 and 7) were activated. Being encapsulated into the stealthy liposomes with an acidic internal medium, topotecan existed dominantly in an active lactone species, which was reversibly changed from an inactive carboxylate form via a pH-dependent reaction. After administration of stealthy liposomes to mice, the blood exposure of the lactone form was evidently increased and extended. The antitumour effects in the MDR HL-60 xenografted tumour were stealthy liposomal topotecan (SLT) plus amlodipine > SLT > un-encapsulated topotecan > blank control. ### conclusions The enhanced antitumour activity in the MDR HL-60 cells by the SLT plus amlodipine could be owing to multiple reasons: (a) synergistic apoptosis inducing effect, (b) reversing MDR by amlodipine and (c) increasing the availability of active lactone of topotecan by the stealthy liposomes. The apoptosis induced by amlodipine is through caspase 8 and then the 3/7 signalling pathway. ### Response: topotecan, amlodipine

afc15f1af9a6d595687c65bfe26bec27

In separate studies , the electrocardiogram ( ECG ) and cardiovascular effects of loratadine ( 30 and 100 mg/kg , i.v . ) , terfenadine ( 10 mg/kg , i.v . ) , promethazine ( 5 mg/kg , i.v . ) and diphenhydramine ( 20 mg/kg , i.v . ) were evaluated .

Antihistamine activity, central nervous system and cardiovascular profiles of histamine H1 antagonists: comparative studies with loratadine, terfenadine and sedating antihistamines in guinea-pigs. Sedation limits the clinical utility of classical H1 antihistamines, while newer antihistamines such as loratadine and terfenadine are non-sedating. However, clinical use of the terfenadine has been associated with rare but severe cardiac arrhythmias, in particular torsades de pointes. ### objective To establish a quantitative experimental model for assessing the sedating and cardiotoxicity potential of non-sedating and sedating antihistamines. ### methods Drugs were administered intravenously and the integrated amplitude of the cortical electroencephalogram (EEG) signal was recorded. The threshold dose that depressed EEG activity was compared with the dose required to inhibit by 50% the peripheral bronchospasm elicited by 10 micrograms/kg i.v., of histamine. In separate studies , the electrocardiogram ( ECG ) and cardiovascular effects of loratadine ( 30 and 100 mg/kg , i.v . ) , terfenadine ( 10 mg/kg , i.v . ) , promethazine ( 5 mg/kg , i.v . ) and diphenhydramine ( 20 mg/kg , i.v . ) were evaluated . ### results The sedating antihistamines, diphenhydramine and promethazine, depressed the integrated EEG at doses between 0.6 and 2.0 times their peripheral antihistamine doses. loratadine had no EEG depressant activity at 100 mg/kg, i.v., a dose more than 170 times its ED50 (0.58 mg/kg, i.v.) against histamine bronchospasm. We were unable to evaluate the EEG effects of terfenadine, because it produced cardiovascular collapse at 10 mg/kg, i.v. loratadine and promethazine did not produce adverse cardiovascular effects, nor did they alter normal ECG activity. diphenhydramine produced bradycardia followed by a transient hypertensive phase without affecting the QTc interval. In contrast, terfenadine elicited hypotension, bradycardia and significant arrhythmogenic activity, causing a prolongation of the QTc interval and a torsades de pointes--like ventricular arrhythmia. Pharmacokinetic studies after i.v. administration of loratadine (30 and 100 mg/kg) demonstrated plasma levels of loratadine and its major metabolite descarboethoxyloratadine to be several orders of magnitude greater than levels found in humans at the clinical dose of 10 mg. ### conclusion The CNS depressant effects of H1 antihistamines are promethazine approximately diphenhydramine >> loratadine = placebo. Of the non-sedating antihistamines, loratadine was devoid of adverse cardiovascular effects whereas terfenadine caused a pronounced disruption of the normal ECG, characterized by a torsades de pointes-like effect.

https://pubmed.ncbi.nlm.nih.gov/8556569/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Antihistamine activity, central nervous system and cardiovascular profiles of histamine H1 antagonists: comparative studies with loratadine, terfenadine and sedating antihistamines in guinea-pigs. Sedation limits the clinical utility of classical H1 antihistamines, while newer antihistamines such as loratadine and terfenadine are non-sedating. However, clinical use of the terfenadine has been associated with rare but severe cardiac arrhythmias, in particular torsades de pointes. ### objective To establish a quantitative experimental model for assessing the sedating and cardiotoxicity potential of non-sedating and sedating antihistamines. ### methods Drugs were administered intravenously and the integrated amplitude of the cortical electroencephalogram (EEG) signal was recorded. The threshold dose that depressed EEG activity was compared with the dose required to inhibit by 50% the peripheral bronchospasm elicited by 10 micrograms/kg i.v., of histamine. In separate studies , the electrocardiogram ( ECG ) and cardiovascular effects of loratadine ( 30 and 100 mg/kg , i.v . ) , terfenadine ( 10 mg/kg , i.v . ) , promethazine ( 5 mg/kg , i.v . ) and diphenhydramine ( 20 mg/kg , i.v . ) were evaluated . ### results The sedating antihistamines, diphenhydramine and promethazine, depressed the integrated EEG at doses between 0.6 and 2.0 times their peripheral antihistamine doses. loratadine had no EEG depressant activity at 100 mg/kg, i.v., a dose more than 170 times its ED50 (0.58 mg/kg, i.v.) against histamine bronchospasm. We were unable to evaluate the EEG effects of terfenadine, because it produced cardiovascular collapse at 10 mg/kg, i.v. loratadine and promethazine did not produce adverse cardiovascular effects, nor did they alter normal ECG activity. diphenhydramine produced bradycardia followed by a transient hypertensive phase without affecting the QTc interval. In contrast, terfenadine elicited hypotension, bradycardia and significant arrhythmogenic activity, causing a prolongation of the QTc interval and a torsades de pointes--like ventricular arrhythmia. Pharmacokinetic studies after i.v. administration of loratadine (30 and 100 mg/kg) demonstrated plasma levels of loratadine and its major metabolite descarboethoxyloratadine to be several orders of magnitude greater than levels found in humans at the clinical dose of 10 mg. ### conclusion The CNS depressant effects of H1 antihistamines are promethazine approximately diphenhydramine >> loratadine = placebo. Of the non-sedating antihistamines, loratadine was devoid of adverse cardiovascular effects whereas terfenadine caused a pronounced disruption of the normal ECG, characterized by a torsades de pointes-like effect. ### Response: loratadine, terfenadine, promethazine, diphenhydramine

2e896861e22edcf2d90edc62272567a9

[ Clinical evaluation of effects from neoadjuvant chemotherapy with epirubicin plus paclitaxel in cases of locally advanced breast cancer -- comparative study of treatment with 2 and 4 cycles ] .

[ Clinical evaluation of effects from neoadjuvant chemotherapy with epirubicin plus paclitaxel in cases of locally advanced breast cancer -- comparative study of treatment with 2 and 4 cycles ] . Neoadjuvant chemotherapy of epirubicin plus paclitaxel was administered to 75 patients (including a 2-cycle group of 39 patients and a 4-cycle group of 36 patients) with locally advanced breast cancer (35 cases of stage IIb, 28 of stage IIIa, 12 of stage IIIb) to compare efficacy and toxicity of 2 cycle and 4 cycle regimens. All patients were female. They were treated with epirubicin 60 mg/m2, on day 1, by i.v., followed by paclitaxel 150 mg/m2, by 3 hour continuous infusion on day 2 repeated every 3 weeks. Premedication with dexamethasone, ondansetron, diphenhydramine and cimetidine were administered to prevent gastroenteritic and allergic reactions before chemotherapy. Thirty-nine patients were given 2 cycles and thirty-six were given 4 cycles of this regimen. One of 39 patients had complete response, 28 had partial response and 10 had no change in the 2-cycle group. In addition, 21 of 36 patients had complete response (including 9 who had pathologic complete response), 13 had partial response and 2 had no change. The response rates were 74% (29/39) in the 2-cycle group and 94% (34/36) in the 4-cycle group. There were no progressive disease in these 2 groups. However a higher proportion of PR was observed in stage II patients than in stage III patients. Twelve of 36 patients underwent breast conserving surgery, as tumor size had become smaller and down-staging was realized after neoadjuvant chemotherapy. In addition, axillary lymph nodes were palpable in all 75 patients before neoadjuvant chemotherapy with the ET regimen. But 46% (18/39) in the 2-cycle group and 75% (27/36) in the 4-cycle group became impalpable. Conversely, major toxicities (including leukopenia and gastroenteric reactions) were similar in both groups, but myalgia, arthralgia, neurotoxicity and alopecia were more severe in the 4-cycle group than in the 2-cycle group. In the present study, neoadjuvant chemotherapy with a 4-cycle ET regimen was more effective than with a 2-cycle regimen in down staging locally advanced breast cancer. Although major toxicities were more severe in the 4-cycle group than in the 2-cycle group, the regimen was tolerable and safe.

https://pubmed.ncbi.nlm.nih.gov/14997752/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: [ Clinical evaluation of effects from neoadjuvant chemotherapy with epirubicin plus paclitaxel in cases of locally advanced breast cancer -- comparative study of treatment with 2 and 4 cycles ] . Neoadjuvant chemotherapy of epirubicin plus paclitaxel was administered to 75 patients (including a 2-cycle group of 39 patients and a 4-cycle group of 36 patients) with locally advanced breast cancer (35 cases of stage IIb, 28 of stage IIIa, 12 of stage IIIb) to compare efficacy and toxicity of 2 cycle and 4 cycle regimens. All patients were female. They were treated with epirubicin 60 mg/m2, on day 1, by i.v., followed by paclitaxel 150 mg/m2, by 3 hour continuous infusion on day 2 repeated every 3 weeks. Premedication with dexamethasone, ondansetron, diphenhydramine and cimetidine were administered to prevent gastroenteritic and allergic reactions before chemotherapy. Thirty-nine patients were given 2 cycles and thirty-six were given 4 cycles of this regimen. One of 39 patients had complete response, 28 had partial response and 10 had no change in the 2-cycle group. In addition, 21 of 36 patients had complete response (including 9 who had pathologic complete response), 13 had partial response and 2 had no change. The response rates were 74% (29/39) in the 2-cycle group and 94% (34/36) in the 4-cycle group. There were no progressive disease in these 2 groups. However a higher proportion of PR was observed in stage II patients than in stage III patients. Twelve of 36 patients underwent breast conserving surgery, as tumor size had become smaller and down-staging was realized after neoadjuvant chemotherapy. In addition, axillary lymph nodes were palpable in all 75 patients before neoadjuvant chemotherapy with the ET regimen. But 46% (18/39) in the 2-cycle group and 75% (27/36) in the 4-cycle group became impalpable. Conversely, major toxicities (including leukopenia and gastroenteric reactions) were similar in both groups, but myalgia, arthralgia, neurotoxicity and alopecia were more severe in the 4-cycle group than in the 2-cycle group. In the present study, neoadjuvant chemotherapy with a 4-cycle ET regimen was more effective than with a 2-cycle regimen in down staging locally advanced breast cancer. Although major toxicities were more severe in the 4-cycle group than in the 2-cycle group, the regimen was tolerable and safe. ### Response: epirubicin, paclitaxel

5933f7af6df7dcb19a1acf8b3630c4dd

When systemically active chemotherapy doses were reached , further dose escalation was discontinued , and a phase II dose-range was established ( pemetrexed 500 mg/m(2 ) and carboplatin AUC = 5 - 6 ) .

A phase I study of pemetrexed, carboplatin, and concurrent radiotherapy in patients with locally advanced or metastatic non-small cell lung or esophageal cancer. The primary objective of this phase I study was to determine the maximum tolerated dose for pemetrexed, alone and in combination with carboplatin, with concurrent radiotherapy. ### Experimental Design Patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) or esophageal cancer were treated every 21 days for two cycles. Regimen 1 was pemetrexed (200-600 mg/m(2)); regimen 2 was pemetrexed (500 mg/m(2)) with escalating carboplatin doses (AUC = 4-6). Both regimens included concurrent radiation (40-66 Gy; palliative-intent doses were lower). ### results Thirty patients (18 locally advanced and 12 metastatic with dominant local symptoms) were enrolled, with an Eastern Cooperative Oncology Group performance status of 0/1/2 (n = 8/21/1). All dose levels were tolerable for regimen 1 (n = 18: 15 NSCLC and 3 esophageal cancers) and regimen 2 (n = 12: all NSCLC). In regimen 1, one dose-limiting toxicity (grade 4 esophagitis/anorexia) occurred (500 mg/m(2)). Grade 3 neutropenia (3 of 18 patients) was the main hematologic toxicity. In regimen 2, one dose-limiting toxicity (grade 3 esophagitis) occurred (500 mg/m(2); AUC = 6); grade 3/4 leukopenia (4 of 12 patients) was the main hematologic toxicity. Four complete responses (2 pathology proven) and eight partial responses were observed. When systemically active chemotherapy doses were reached , further dose escalation was discontinued , and a phase II dose-range was established ( pemetrexed 500 mg/m(2 ) and carboplatin AUC = 5 - 6 ) . ### conclusions The combination of pemetrexed (500 mg/m(2)) and carboplatin (AUC = 5 or 6) with concurrent radiation is well tolerated, allows for the administration of systemically active chemotherapy doses, and shows signs of activity. To further determine efficacy, safety profile, and optimal dosing, the Cancer and Leukemia Group B study 30407 is currently evaluating this regimen in patients with unresectable stage III NSCLC.

https://pubmed.ncbi.nlm.nih.gov/17255273/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: A phase I study of pemetrexed, carboplatin, and concurrent radiotherapy in patients with locally advanced or metastatic non-small cell lung or esophageal cancer. The primary objective of this phase I study was to determine the maximum tolerated dose for pemetrexed, alone and in combination with carboplatin, with concurrent radiotherapy. ### Experimental Design Patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) or esophageal cancer were treated every 21 days for two cycles. Regimen 1 was pemetrexed (200-600 mg/m(2)); regimen 2 was pemetrexed (500 mg/m(2)) with escalating carboplatin doses (AUC = 4-6). Both regimens included concurrent radiation (40-66 Gy; palliative-intent doses were lower). ### results Thirty patients (18 locally advanced and 12 metastatic with dominant local symptoms) were enrolled, with an Eastern Cooperative Oncology Group performance status of 0/1/2 (n = 8/21/1). All dose levels were tolerable for regimen 1 (n = 18: 15 NSCLC and 3 esophageal cancers) and regimen 2 (n = 12: all NSCLC). In regimen 1, one dose-limiting toxicity (grade 4 esophagitis/anorexia) occurred (500 mg/m(2)). Grade 3 neutropenia (3 of 18 patients) was the main hematologic toxicity. In regimen 2, one dose-limiting toxicity (grade 3 esophagitis) occurred (500 mg/m(2); AUC = 6); grade 3/4 leukopenia (4 of 12 patients) was the main hematologic toxicity. Four complete responses (2 pathology proven) and eight partial responses were observed. When systemically active chemotherapy doses were reached , further dose escalation was discontinued , and a phase II dose-range was established ( pemetrexed 500 mg/m(2 ) and carboplatin AUC = 5 - 6 ) . ### conclusions The combination of pemetrexed (500 mg/m(2)) and carboplatin (AUC = 5 or 6) with concurrent radiation is well tolerated, allows for the administration of systemically active chemotherapy doses, and shows signs of activity. To further determine efficacy, safety profile, and optimal dosing, the Cancer and Leukemia Group B study 30407 is currently evaluating this regimen in patients with unresectable stage III NSCLC. ### Response: pemetrexed, carboplatin

ae5a3d41fe6197db7a7fa13e47a8af4f

Increased dose density is feasible : a pilot study of adjuvant epirubicin and cyclophosphamide followed by paclitaxel , at 10- or 11-day intervals with filgrastim support in women with breast cancer .

Increased dose density is feasible : a pilot study of adjuvant epirubicin and cyclophosphamide followed by paclitaxel , at 10- or 11-day intervals with filgrastim support in women with breast cancer . Because Cancer and Leukemia Group B 9741 trial showed a benefit for every 14-day administration of chemotherapy compared with every 21-day treatment, we hypothesized that even greater dose density would be more effective. We conducted a pilot trial to assess the feasibility of dose-dense chemotherapy consisting of a standard regime at 10- to 11-day intervals in the adjuvant/neoadjuvant setting. A 2-day window was allowed for scheduling logistics. ### Experimental Design Thirty-nine women with early-stage breast carcinoma were accrued from April 2004 to October 2004. Median age was 47 years (range, 26-67 years). Patients received therapy with 100 mg/m(2) epirubicin and 600 mg/m(2) cyclophosphamide (EC) q 10 to 11 days for four cycles followed by 175 mg/m(2) paclitaxel q 10 to 11 days for four cycles, all with filgrastim support (300 microg s.c. daily) from day 2 to 24 h before the next treatment. ### results Thirty-five (90%) patients completed all planned therapy. The median intertreatment interval was 10 days (range, 8-28 days). Cycles (80.7%) were delivered at no more than 10- to 11-day intervals. There were five dose reductions of 25% for grade 3 nonhematologic toxicity in five patients. Six (16%) patients developed febrile neutropenia defined as temperature >38 degrees C with absolute neutrophil count <1,000/microL. All febrile neutropenia was during therapy with EC. Other grade 3 toxicities included bone pain, hand and foot syndrome, neuropathy, mucositis, nausea, and vomiting. ### conclusions Therapy with EC for four cycles followed by paclitaxel for four cycles at 10- to 11-day intervals is feasible. The approximately 30% reduction in intertreatment interval compared with every 14-day treatment could increase the efficacy of adjuvant chemotherapy.

https://pubmed.ncbi.nlm.nih.gov/17200358/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Increased dose density is feasible : a pilot study of adjuvant epirubicin and cyclophosphamide followed by paclitaxel , at 10- or 11-day intervals with filgrastim support in women with breast cancer . Because Cancer and Leukemia Group B 9741 trial showed a benefit for every 14-day administration of chemotherapy compared with every 21-day treatment, we hypothesized that even greater dose density would be more effective. We conducted a pilot trial to assess the feasibility of dose-dense chemotherapy consisting of a standard regime at 10- to 11-day intervals in the adjuvant/neoadjuvant setting. A 2-day window was allowed for scheduling logistics. ### Experimental Design Thirty-nine women with early-stage breast carcinoma were accrued from April 2004 to October 2004. Median age was 47 years (range, 26-67 years). Patients received therapy with 100 mg/m(2) epirubicin and 600 mg/m(2) cyclophosphamide (EC) q 10 to 11 days for four cycles followed by 175 mg/m(2) paclitaxel q 10 to 11 days for four cycles, all with filgrastim support (300 microg s.c. daily) from day 2 to 24 h before the next treatment. ### results Thirty-five (90%) patients completed all planned therapy. The median intertreatment interval was 10 days (range, 8-28 days). Cycles (80.7%) were delivered at no more than 10- to 11-day intervals. There were five dose reductions of 25% for grade 3 nonhematologic toxicity in five patients. Six (16%) patients developed febrile neutropenia defined as temperature >38 degrees C with absolute neutrophil count <1,000/microL. All febrile neutropenia was during therapy with EC. Other grade 3 toxicities included bone pain, hand and foot syndrome, neuropathy, mucositis, nausea, and vomiting. ### conclusions Therapy with EC for four cycles followed by paclitaxel for four cycles at 10- to 11-day intervals is feasible. The approximately 30% reduction in intertreatment interval compared with every 14-day treatment could increase the efficacy of adjuvant chemotherapy. ### Response: epirubicin, cyclophosphamide, paclitaxel, filgrastim

520dc3a18b14a57a368bcd964095071e

Those who test positive are treated with combinations of the following agents : omeprazole , clarithromycin , amoxicillin , tetracycline , and metronidazole .

Pharmacist-managed Helicobacter pylori clinic. A pharmacist-managed Helicobacter pylori assessment clinic for ambulatory patients is described. The pharmacy service at a 400-bed Veterans Affairs Medical Center established a pharmacist-managed clinic to assess patients who were receiving long-term acid-suppressive medications (histamine H2-receptor antagonists, sucralfate, or omeprazole). Patients with active ulcer disease and those receiving ulcer prophylaxis are screened for the presence of H. pylori. Those who test positive are treated with combinations of the following agents : omeprazole , clarithromycin , amoxicillin , tetracycline , and metronidazole . The pharmacist also may adjust or discontinue acid-suppressive drug regimens. The pharmacist is responsible for ordering all appropriate laboratory tests, monitoring patients for adverse effects, collecting data on patient outcomes, and providing patient education. The clinic provides opportunities for pharmacists to study the clinical effectiveness and pharmacoeconomics of various regimens for treating H. pylori-associated disease and for pharmacy students and residents to interact with patients. As of fall 1994, 20 patients had been evaluated at the clinic: 12 tested positive for H. pylori and were treated with antimicrobials and all were pain-free without medication at the end of treatment. An H. pylori assessment clinic enabled pharmacists to assume a primary care role, document improvement in patient outcomes, and study the effectiveness of various antimicrobial regimens.

https://pubmed.ncbi.nlm.nih.gov/12879545/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Pharmacist-managed Helicobacter pylori clinic. A pharmacist-managed Helicobacter pylori assessment clinic for ambulatory patients is described. The pharmacy service at a 400-bed Veterans Affairs Medical Center established a pharmacist-managed clinic to assess patients who were receiving long-term acid-suppressive medications (histamine H2-receptor antagonists, sucralfate, or omeprazole). Patients with active ulcer disease and those receiving ulcer prophylaxis are screened for the presence of H. pylori. Those who test positive are treated with combinations of the following agents : omeprazole , clarithromycin , amoxicillin , tetracycline , and metronidazole . The pharmacist also may adjust or discontinue acid-suppressive drug regimens. The pharmacist is responsible for ordering all appropriate laboratory tests, monitoring patients for adverse effects, collecting data on patient outcomes, and providing patient education. The clinic provides opportunities for pharmacists to study the clinical effectiveness and pharmacoeconomics of various regimens for treating H. pylori-associated disease and for pharmacy students and residents to interact with patients. As of fall 1994, 20 patients had been evaluated at the clinic: 12 tested positive for H. pylori and were treated with antimicrobials and all were pain-free without medication at the end of treatment. An H. pylori assessment clinic enabled pharmacists to assume a primary care role, document improvement in patient outcomes, and study the effectiveness of various antimicrobial regimens. ### Response: omeprazole, clarithromycin, amoxicillin, tetracycline, metronidazole

2f4440a6312f23fd7a3100bd25f39c1e

Patients can be treatment-naïve for mCRPC or on first-line androgen receptor-targeted therapy for mCRPC ( ie , abiraterone or enzalutamide ) without evidence of progression at enrolment , and with no prior chemotherapy for mCRPC .

Intense Exercise for Survival among Men with Metastatic Castrate-Resistant Prostate Cancer (INTERVAL-GAP4): a multicentre, randomised, controlled phase III study protocol. Preliminary evidence supports the beneficial role of physical activity on prostate cancer outcomes. This phase III randomised controlled trial (RCT) is designed to determine if supervised high-intensity aerobic and resistance exercise increases overall survival (OS) in patients with metastatic castrate-resistant prostate cancer (mCRPC). ### Methods And Analysis Participants (n=866) must have histologically documented metastatic prostate cancer with evidence of progressive disease on androgen deprivation therapy (defined as mCRPC). Patients can be treatment-naïve for mCRPC or on first-line androgen receptor-targeted therapy for mCRPC ( ie , abiraterone or enzalutamide ) without evidence of progression at enrolment , and with no prior chemotherapy for mCRPC . Patients will receive psychosocial support and will be randomly assigned (1:1) to either supervised exercise (high-intensity aerobic and resistance training) or self-directed exercise (provision of guidelines), stratified by treatment status and site. Exercise prescriptions will be tailored to each participant's fitness and morbidities. The primary endpoint is OS. Secondary endpoints include time to disease progression, occurrence of a skeletal-related event or progression of pain, and degree of pain, opiate use, physical and emotional quality of life, and changes in metabolic biomarkers. An assessment of whether immune function, inflammation, dysregulation of insulin and energy metabolism, and androgen biomarkers are associated with OS will be performed, and whether they mediate the primary association between exercise and OS will also be investigated. This study will also establish a biobank for future biomarker discovery or validation. ### Ethics And Dissemination Validation of exercise as medicine and its mechanisms of action will create evidence to change clinical practice. Accordingly, outcomes of this RCT will be published in international, peer-reviewed journals, and presented at national and international conferences. Ethics approval was first obtained at Edith Cowan University (ID: 13236 NEWTON), with a further 10 investigator sites since receiving ethics approval, prior to activation. ### Trial Registration Number NCT02730338.

https://pubmed.ncbi.nlm.nih.gov/29764892/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Intense Exercise for Survival among Men with Metastatic Castrate-Resistant Prostate Cancer (INTERVAL-GAP4): a multicentre, randomised, controlled phase III study protocol. Preliminary evidence supports the beneficial role of physical activity on prostate cancer outcomes. This phase III randomised controlled trial (RCT) is designed to determine if supervised high-intensity aerobic and resistance exercise increases overall survival (OS) in patients with metastatic castrate-resistant prostate cancer (mCRPC). ### Methods And Analysis Participants (n=866) must have histologically documented metastatic prostate cancer with evidence of progressive disease on androgen deprivation therapy (defined as mCRPC). Patients can be treatment-naïve for mCRPC or on first-line androgen receptor-targeted therapy for mCRPC ( ie , abiraterone or enzalutamide ) without evidence of progression at enrolment , and with no prior chemotherapy for mCRPC . Patients will receive psychosocial support and will be randomly assigned (1:1) to either supervised exercise (high-intensity aerobic and resistance training) or self-directed exercise (provision of guidelines), stratified by treatment status and site. Exercise prescriptions will be tailored to each participant's fitness and morbidities. The primary endpoint is OS. Secondary endpoints include time to disease progression, occurrence of a skeletal-related event or progression of pain, and degree of pain, opiate use, physical and emotional quality of life, and changes in metabolic biomarkers. An assessment of whether immune function, inflammation, dysregulation of insulin and energy metabolism, and androgen biomarkers are associated with OS will be performed, and whether they mediate the primary association between exercise and OS will also be investigated. This study will also establish a biobank for future biomarker discovery or validation. ### Ethics And Dissemination Validation of exercise as medicine and its mechanisms of action will create evidence to change clinical practice. Accordingly, outcomes of this RCT will be published in international, peer-reviewed journals, and presented at national and international conferences. Ethics approval was first obtained at Edith Cowan University (ID: 13236 NEWTON), with a further 10 investigator sites since receiving ethics approval, prior to activation. ### Trial Registration Number NCT02730338. ### Response: abiraterone, enzalutamide

f99dcdd01f6107affbfbbd94efa2f838

CYP2D6 metabolizes other opioid analgesics , including tramadol , dihydrocodeine , oxycodone and hydrocodone , although they have been less systematically studied .

Response to hydrocodone, codeine and oxycodone in a CYP2D6 poor metabolizer. codeine is metabolized by the cytochrome P450 2D6 (CYP2D6) to morphine. codeine is a much weaker agonist at mu opioid receptors than morphine. Therefore, codeine analgesia is highly dependent on CYP2D6 activity. Large prospective studies in the clinical environment do not exist, but it appears reasonable to avoid codeine use in CYP2D6 poor metabolizers (PMs). CYP2D6 metabolizes other opioid analgesics , including tramadol , dihydrocodeine , oxycodone and hydrocodone , although they have been less systematically studied . It is unclear whether these other pro-drugs may be as completely dependent on CYP2D6 for their analgesia as codeine. We describe a patient identified as a CYP2D6 PM with a history of problems with opioid analgesics. The patient was an 85-year-old female Caucasian who had hip surgery. The patient had a long-standing intolerance to codeine. In her first admission, she couldn't tolerate the regimen of oxycodone combined with tramadol prns (as needed). She was genotyped as a CYP2D6 PM and after the information was provided to the treating physician in her second admission, she seemed to have a better response to hydrocodone. Large case-control naturalistic studies followed by randomized trials in patients taking opioid analgesics may be needed to definitively establish that CYP2D6 genotyping has clinical relevance in the use of several opioid analgesics.

https://pubmed.ncbi.nlm.nih.gov/16631290/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Response to hydrocodone, codeine and oxycodone in a CYP2D6 poor metabolizer. codeine is metabolized by the cytochrome P450 2D6 (CYP2D6) to morphine. codeine is a much weaker agonist at mu opioid receptors than morphine. Therefore, codeine analgesia is highly dependent on CYP2D6 activity. Large prospective studies in the clinical environment do not exist, but it appears reasonable to avoid codeine use in CYP2D6 poor metabolizers (PMs). CYP2D6 metabolizes other opioid analgesics , including tramadol , dihydrocodeine , oxycodone and hydrocodone , although they have been less systematically studied . It is unclear whether these other pro-drugs may be as completely dependent on CYP2D6 for their analgesia as codeine. We describe a patient identified as a CYP2D6 PM with a history of problems with opioid analgesics. The patient was an 85-year-old female Caucasian who had hip surgery. The patient had a long-standing intolerance to codeine. In her first admission, she couldn't tolerate the regimen of oxycodone combined with tramadol prns (as needed). She was genotyped as a CYP2D6 PM and after the information was provided to the treating physician in her second admission, she seemed to have a better response to hydrocodone. Large case-control naturalistic studies followed by randomized trials in patients taking opioid analgesics may be needed to definitively establish that CYP2D6 genotyping has clinical relevance in the use of several opioid analgesics. ### Response: tramadol, hydrocodone

84a375ec840963d68895d36ecd84f3c3

Atracurium or vecuronium was given for intubation .

Prediction of oculocardiac reflex in strabismus surgery using neural networks. Successfully predicting an oculocardiac reflex (OCR) is difficult to achieve despite various proposed maneuvers. The aim of this study was to test the models built up by neural networks to predict the occurrence of OCR during strabismus surgery in children. Premedication was not given. atropine 0.01 mg/kg was medicated just before induction. Induction was performed with fentanyl or ketorolac, followed by propofol. Atracurium or vecuronium was given for intubation . Anesthesia was maintained with O2-N2O with continuous propofol infusion. Chi-square test was performed for induction agents, gender, weight, muscle blockade, repaired muscle, number of repaired muscles, duration of operation to detect any association between the occurrence of OCR and to develop the model of neural networks. The multi-layer perceptron, radial basis function and Bayesian backpropagation network were tested. The occurrence of OCR was significantly associated with gender and repaired muscle (p < 0.05). Gender, repaired muscle and age were considered as input for the multi-layer perceptron, radial basis function and Bayesian backpropagation network. Three neural networks had predicted the same correction rate in the occurrence of OCR as being 87.5% overall among 16 patients' records tested. These models are conceptually different in predicting compared to conventional maneuvers, and have the advantage of testing individually and foretelling the propensity. By comparison neural networks use grouped experiential data and predict OCR by the learning rule. Neural networks require a relatively abundant number of experienced and homogenous patients' records to establish an accurate model. The multi-layer perceptron, radial basis function and Bayesian backpropagation modeling network may be an alternative way, and preferable to vagal tone maneuvers if the associated relationships to the occurrence of OCR are more clearly defined.

https://pubmed.ncbi.nlm.nih.gov/10412336/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Prediction of oculocardiac reflex in strabismus surgery using neural networks. Successfully predicting an oculocardiac reflex (OCR) is difficult to achieve despite various proposed maneuvers. The aim of this study was to test the models built up by neural networks to predict the occurrence of OCR during strabismus surgery in children. Premedication was not given. atropine 0.01 mg/kg was medicated just before induction. Induction was performed with fentanyl or ketorolac, followed by propofol. Atracurium or vecuronium was given for intubation . Anesthesia was maintained with O2-N2O with continuous propofol infusion. Chi-square test was performed for induction agents, gender, weight, muscle blockade, repaired muscle, number of repaired muscles, duration of operation to detect any association between the occurrence of OCR and to develop the model of neural networks. The multi-layer perceptron, radial basis function and Bayesian backpropagation network were tested. The occurrence of OCR was significantly associated with gender and repaired muscle (p < 0.05). Gender, repaired muscle and age were considered as input for the multi-layer perceptron, radial basis function and Bayesian backpropagation network. Three neural networks had predicted the same correction rate in the occurrence of OCR as being 87.5% overall among 16 patients' records tested. These models are conceptually different in predicting compared to conventional maneuvers, and have the advantage of testing individually and foretelling the propensity. By comparison neural networks use grouped experiential data and predict OCR by the learning rule. Neural networks require a relatively abundant number of experienced and homogenous patients' records to establish an accurate model. The multi-layer perceptron, radial basis function and Bayesian backpropagation modeling network may be an alternative way, and preferable to vagal tone maneuvers if the associated relationships to the occurrence of OCR are more clearly defined. ### Response: Atracurium, vecuronium

76b596dbb2298d1ba4668068b940f4c9

The data show that knockdown of Rad51 or BRCA2 greatly sensitizes cells to DSBs and the induction of cell death following temozolomide and nimustine ( ACNU ) .

Rad51 and BRCA2--New molecular targets for sensitizing glioma cells to alkylating anticancer drugs. First line chemotherapeutics for brain tumors (malignant gliomas) are alkylating agents such as temozolomide and nimustine. Despite growing knowledge of how these agents work, patients suffering from this malignancy still face a dismal prognosis. Alkylating agents target DNA, forming the killing lesion O(6)-alkylguanine, which is converted into DNA double-strand breaks (DSBs) that trigger apoptosis. Here we assessed whether inhibiting repair of DSBs by homologous recombination (HR) or non-homologous end joining (NHEJ) is a reasonable strategy for sensitizing glioma cells to alkylating agents. For down-regulation of HR in glioma cells, we used an interference RNA (iRNA) approach targeting Rad51 and BRCA2, and for NHEJ we employed the DNA-PK inhibitor NU7026. We also assessed whether inhibition of poly(ADP)ribosyltransferase (PARP) by olaparib would enhance the killing effect. The data show that knockdown of Rad51 or BRCA2 greatly sensitizes cells to DSBs and the induction of cell death following temozolomide and nimustine ( ACNU ) . It did not sensitize to ionizing radiation (IR). The expression of O(6)-methylguanine-DNA methyltransferase (MGMT) abolished all these effects, indicating that O(6)-alkylguanine induced by these drugs is the primary lesion responsible for the formation of DSBs and increased sensitivity of glioma cells following knockdown of Rad51 and BRCA2. Inhibition of DNA-PK only slightly sensitized to temozolomide whereas a significant effect was observed with IR. A triple strategy including siRNA and the PARP inhibitor olaparib further improved the killing effect of temozolomide. The data provides evidence that down-regulation of Rad51 or BRCA2 is a reasonable strategy for sensitizing glioma cells to killing by O(6)-alkylating anti-cancer drugs. The data also provide proof of principle that a triple strategy involving down-regulation of HR, PARP inhibition and MGMT depletion may greatly enhance the therapeutic effect of temozolomide.

https://pubmed.ncbi.nlm.nih.gov/22073281/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Rad51 and BRCA2--New molecular targets for sensitizing glioma cells to alkylating anticancer drugs. First line chemotherapeutics for brain tumors (malignant gliomas) are alkylating agents such as temozolomide and nimustine. Despite growing knowledge of how these agents work, patients suffering from this malignancy still face a dismal prognosis. Alkylating agents target DNA, forming the killing lesion O(6)-alkylguanine, which is converted into DNA double-strand breaks (DSBs) that trigger apoptosis. Here we assessed whether inhibiting repair of DSBs by homologous recombination (HR) or non-homologous end joining (NHEJ) is a reasonable strategy for sensitizing glioma cells to alkylating agents. For down-regulation of HR in glioma cells, we used an interference RNA (iRNA) approach targeting Rad51 and BRCA2, and for NHEJ we employed the DNA-PK inhibitor NU7026. We also assessed whether inhibition of poly(ADP)ribosyltransferase (PARP) by olaparib would enhance the killing effect. The data show that knockdown of Rad51 or BRCA2 greatly sensitizes cells to DSBs and the induction of cell death following temozolomide and nimustine ( ACNU ) . It did not sensitize to ionizing radiation (IR). The expression of O(6)-methylguanine-DNA methyltransferase (MGMT) abolished all these effects, indicating that O(6)-alkylguanine induced by these drugs is the primary lesion responsible for the formation of DSBs and increased sensitivity of glioma cells following knockdown of Rad51 and BRCA2. Inhibition of DNA-PK only slightly sensitized to temozolomide whereas a significant effect was observed with IR. A triple strategy including siRNA and the PARP inhibitor olaparib further improved the killing effect of temozolomide. The data provides evidence that down-regulation of Rad51 or BRCA2 is a reasonable strategy for sensitizing glioma cells to killing by O(6)-alkylating anti-cancer drugs. The data also provide proof of principle that a triple strategy involving down-regulation of HR, PARP inhibition and MGMT depletion may greatly enhance the therapeutic effect of temozolomide. ### Response: temozolomide, nimustine

be817a111debcf11e63cf8c34861fed7

The systemic treatment in both studies consisted of a four-drug-regimen ( VACA = vincristine , actinomycin D , cyclophosphamide , and adriamycin ; or VAIA = vincristine , actinomycin D , ifosfamide , and adriamycin ) and a total number of four courses , each lasting nine weeks , was recommended by the protocol .

Second malignancies after treatment for Ewing's sarcoma: a report of the CESS-studies. During recent years, more intensified systemic and local treatment regimens have increased the 5-year survival figures in localized Ewing's sarcoma to more than 60%. There is, however, concern about the risk of second malignancies (SM) in long-term survivors. We have analyzed the second malignancies in patients treated in the German Ewing's Sarcoma Studies CESS 81 and CESS 86. ### Materials And Methods From January 1981 through June 1991, 674 patients were registered in the two sequential multicentric Ewing's sarcoma trials CESS 81 (recruitment period 1981-1985) and CESS 86 (1986-1991). The systemic treatment in both studies consisted of a four-drug-regimen ( VACA = vincristine , actinomycin D , cyclophosphamide , and adriamycin ; or VAIA = vincristine , actinomycin D , ifosfamide , and adriamycin ) and a total number of four courses , each lasting nine weeks , was recommended by the protocol . Local therapy in curative patients was either complete surgery (n = 162), surgery plus postoperative radiotherapy with 36-46Gy (n = 274), or definitive radiotherapy with 46-60Gy (n = 212). The median follow-up at the time of this analysis was 5.1 years, the maximum follow-up 16.5 years. ### results The overall survival of all patients including metastatic patients was 55% after 5 years, 48% after 10 years, and 37% after 15 years. Eight out of 674 patients (1.2%) developed a SM. Five of these were acute myelogenic leukemias (n = 4) or MDS (n = 1), and three were sarcomas. The interval between diagnosis of Ewing's sarcoma and the diagnosis of the SM was 17-78 months for the four AMLs, 96 months for the MDS and 82-136 months for the three sarcomas. The cumulative risk of an SM was 0.7% after 5 years, 2.9% after 10 years, and 4.7% after 15 years. Out of five patients with AML/MDS, three died of rapid AML-progression, and two are living with disease. Local therapy (surgery vs. surgery plus postoperative irradiation vs. definitive radiotherapy) had no impact on the frequency of AML/MDS, but local therapy did influence the risk of secondary sarcomas. All three patients with secondary sarcomas had received radiotherapy; however, all three sarcomas were salvaged by subsequent treatment and are in clinical remission with a follow-up of 1 month, 4.3 years, and 7.5 years after the diagnosis of the secondary sarcoma. Thus far, SM contributed to less than 1 % (3/328) of all deaths in the CESS-studies. ### conclusions The risk of leukemia after treatment for Ewing's sarcoma is probably in the range of 2%. The risk of solid tumors also seems to be low within the first 10 years after treatment and remains in the range of 5 % after 15 years. In the CESS-studies, less than 1% of all deaths within the first 10 years after diagnosis were caused by SM. Effective salvage therapy for secondary sarcomas is feasible.

https://pubmed.ncbi.nlm.nih.gov/9788419/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Second malignancies after treatment for Ewing's sarcoma: a report of the CESS-studies. During recent years, more intensified systemic and local treatment regimens have increased the 5-year survival figures in localized Ewing's sarcoma to more than 60%. There is, however, concern about the risk of second malignancies (SM) in long-term survivors. We have analyzed the second malignancies in patients treated in the German Ewing's Sarcoma Studies CESS 81 and CESS 86. ### Materials And Methods From January 1981 through June 1991, 674 patients were registered in the two sequential multicentric Ewing's sarcoma trials CESS 81 (recruitment period 1981-1985) and CESS 86 (1986-1991). The systemic treatment in both studies consisted of a four-drug-regimen ( VACA = vincristine , actinomycin D , cyclophosphamide , and adriamycin ; or VAIA = vincristine , actinomycin D , ifosfamide , and adriamycin ) and a total number of four courses , each lasting nine weeks , was recommended by the protocol . Local therapy in curative patients was either complete surgery (n = 162), surgery plus postoperative radiotherapy with 36-46Gy (n = 274), or definitive radiotherapy with 46-60Gy (n = 212). The median follow-up at the time of this analysis was 5.1 years, the maximum follow-up 16.5 years. ### results The overall survival of all patients including metastatic patients was 55% after 5 years, 48% after 10 years, and 37% after 15 years. Eight out of 674 patients (1.2%) developed a SM. Five of these were acute myelogenic leukemias (n = 4) or MDS (n = 1), and three were sarcomas. The interval between diagnosis of Ewing's sarcoma and the diagnosis of the SM was 17-78 months for the four AMLs, 96 months for the MDS and 82-136 months for the three sarcomas. The cumulative risk of an SM was 0.7% after 5 years, 2.9% after 10 years, and 4.7% after 15 years. Out of five patients with AML/MDS, three died of rapid AML-progression, and two are living with disease. Local therapy (surgery vs. surgery plus postoperative irradiation vs. definitive radiotherapy) had no impact on the frequency of AML/MDS, but local therapy did influence the risk of secondary sarcomas. All three patients with secondary sarcomas had received radiotherapy; however, all three sarcomas were salvaged by subsequent treatment and are in clinical remission with a follow-up of 1 month, 4.3 years, and 7.5 years after the diagnosis of the secondary sarcoma. Thus far, SM contributed to less than 1 % (3/328) of all deaths in the CESS-studies. ### conclusions The risk of leukemia after treatment for Ewing's sarcoma is probably in the range of 2%. The risk of solid tumors also seems to be low within the first 10 years after treatment and remains in the range of 5 % after 15 years. In the CESS-studies, less than 1% of all deaths within the first 10 years after diagnosis were caused by SM. Effective salvage therapy for secondary sarcomas is feasible. ### Response: vincristine, actinomycin, cyclophosphamide, adriamycin, vincristine, actinomycin, ifosfamide, adriamycin

a3e9deca9aeff608f039be706f6f2666

Rationale , design , and baseline characteristics of a trial of prevention of cardiovascular and renal disease with fosinopril and pravastatin in nonhypertensive , nonhypercholesterolemic subjects with microalbuminuria ( the Prevention of REnal and Vascular ENdstage Disease Intervention Trial [ PREVEND IT ] ) .

Rationale , design , and baseline characteristics of a trial of prevention of cardiovascular and renal disease with fosinopril and pravastatin in nonhypertensive , nonhypercholesterolemic subjects with microalbuminuria ( the Prevention of REnal and Vascular ENdstage Disease Intervention Trial [ PREVEND IT ] ) . This study describes the rationale, design, and baseline characteristics of a trial to determine whether treatment with fosinopril 20 mg/day and/or pravastatin 40 mg/ day will prevent cardiovascular and renal disease in nonhypertensive (RR <160/100 mm Hg and not using antihypertensive medication) and nonhypercholesterolemic (total cholesterol <8.0 or <5.0 mmol/L in case of previous myocardial infarction and not using lipid lowering medication) men and women with persistent microalbuminuria (urinary albumin excretion >10 mg/L once in an early morning spot urine and 15 to 300 mg/24-hour at least once in two 24-hour urine collections). The Prevention of REnal and Vascular ENdstage Disease Intervention Trial is a single-center, double-blind, randomized, placebo-controlled trial with a 2 x 2 factorial design. The 864 randomized subjects will be monitored for a minimum of 4 years and a maximum of 5 years. The primary efficacy parameter is defined as the combined incidence of all-cause mortality or hospital admission for documented (1) nonfatal myocardial infarction, (2) myocardial ischemia, (3) heart failure, (4) peripheral vascular disease, (5) cerebrovascular accident and/or (6) end-stage renal disease.

https://pubmed.ncbi.nlm.nih.gov/10980214/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Rationale , design , and baseline characteristics of a trial of prevention of cardiovascular and renal disease with fosinopril and pravastatin in nonhypertensive , nonhypercholesterolemic subjects with microalbuminuria ( the Prevention of REnal and Vascular ENdstage Disease Intervention Trial [ PREVEND IT ] ) . This study describes the rationale, design, and baseline characteristics of a trial to determine whether treatment with fosinopril 20 mg/day and/or pravastatin 40 mg/ day will prevent cardiovascular and renal disease in nonhypertensive (RR <160/100 mm Hg and not using antihypertensive medication) and nonhypercholesterolemic (total cholesterol <8.0 or <5.0 mmol/L in case of previous myocardial infarction and not using lipid lowering medication) men and women with persistent microalbuminuria (urinary albumin excretion >10 mg/L once in an early morning spot urine and 15 to 300 mg/24-hour at least once in two 24-hour urine collections). The Prevention of REnal and Vascular ENdstage Disease Intervention Trial is a single-center, double-blind, randomized, placebo-controlled trial with a 2 x 2 factorial design. The 864 randomized subjects will be monitored for a minimum of 4 years and a maximum of 5 years. The primary efficacy parameter is defined as the combined incidence of all-cause mortality or hospital admission for documented (1) nonfatal myocardial infarction, (2) myocardial ischemia, (3) heart failure, (4) peripheral vascular disease, (5) cerebrovascular accident and/or (6) end-stage renal disease. ### Response: fosinopril, pravastatin

8aec468c4b89546f1205d002c2f46ab3

In the present study , rabbits prepared with chronic vascular cannulae were used to study the effects of nicotine administration on plasma corticosterone , catecholamine ( epinephrine , norepinephrine and dopamine ) and glucose responses to physical restraint stress .

Neuroendocrine responses to nicotine and stress: enhancement of peripheral stress responses by the administration of nicotine. Habitual smokers frequently report that when they are stressed smoking helps them to relax. One potential explanation for the reported stress ameliorating effect of smoking is that cigarette consumption (nicotine self-administration) may decrease the sympathetic autonomic nervous system activity which is associated with the stress response. In the present study , rabbits prepared with chronic vascular cannulae were used to study the effects of nicotine administration on plasma corticosterone , catecholamine ( epinephrine , norepinephrine and dopamine ) and glucose responses to physical restraint stress . nicotine (0.025, 0.05 or 0.10 mg nicotine base/kg body weight) was administered for 10 days prior to the "stress test" to allow for the development of habituation/tolerance to its acute toxic effects. Independent administration of nicotine, or the application of the physical restraint stressor, resulted in increases in the plasma concentrations of corticosterone, epinephrine, norepinephrine, and glucose. nicotine administration during restraint stress enhanced the increase in plasma corticosterone and epinephrine, as compared to the responses induced by either factor alone. The results suggest that the stress ameliorating effect of continued cigarette smoking, as reported by habitual smokers, is not due to a reduction in the activity of the peripheral sympathetic autonomic nervous system.

https://pubmed.ncbi.nlm.nih.gov/2505296/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Neuroendocrine responses to nicotine and stress: enhancement of peripheral stress responses by the administration of nicotine. Habitual smokers frequently report that when they are stressed smoking helps them to relax. One potential explanation for the reported stress ameliorating effect of smoking is that cigarette consumption (nicotine self-administration) may decrease the sympathetic autonomic nervous system activity which is associated with the stress response. In the present study , rabbits prepared with chronic vascular cannulae were used to study the effects of nicotine administration on plasma corticosterone , catecholamine ( epinephrine , norepinephrine and dopamine ) and glucose responses to physical restraint stress . nicotine (0.025, 0.05 or 0.10 mg nicotine base/kg body weight) was administered for 10 days prior to the "stress test" to allow for the development of habituation/tolerance to its acute toxic effects. Independent administration of nicotine, or the application of the physical restraint stressor, resulted in increases in the plasma concentrations of corticosterone, epinephrine, norepinephrine, and glucose. nicotine administration during restraint stress enhanced the increase in plasma corticosterone and epinephrine, as compared to the responses induced by either factor alone. The results suggest that the stress ameliorating effect of continued cigarette smoking, as reported by habitual smokers, is not due to a reduction in the activity of the peripheral sympathetic autonomic nervous system. ### Response: nicotine, epinephrine

2ff60aee3c52628cbf8ef1588d63a2cd

Phase III , randomized , double-blind , multicenter trial comparing orteronel ( TAK-700 ) plus prednisone with placebo plus prednisone in patients with metastatic castration-resistant prostate cancer that has progressed during or after docetaxel-based therapy : ELM-PC 5 .

Phase III , randomized , double-blind , multicenter trial comparing orteronel ( TAK-700 ) plus prednisone with placebo plus prednisone in patients with metastatic castration-resistant prostate cancer that has progressed during or after docetaxel-based therapy : ELM-PC 5 . Orteronel (tak-700) is an investigational, nonsteroidal, reversible, selective 17,20-lyase inhibitor. This study examined orteronel in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel therapy. ### Patients And Methods In our study, 1,099 men were randomly assigned in a 2:1 schedule to receive orteronel 400 mg plus prednisone 5 mg twice daily or placebo plus prednisone 5 mg twice daily, stratified by region (Europe, North America [NA], and non-Europe/NA) and Brief Pain Inventory-Short Form worst pain score. Primary end point was overall survival (OS). Key secondary end points (radiographic progression-free survival [rPFS], ≥ 50% decrease of prostate-specific antigen [PSA50], and pain response at 12 weeks) were to undergo statistical testing only if the primary end point analysis was significant. ### results The study was unblinded after crossing a prespecified OS futility boundary. The median OS was 17.0 months versus 15.2 months with orteronel-prednisone versus placebo-prednisone (hazard ratio [HR], 0.886; 95% CI, 0.739 to 1.062; P = .190). Improved rPFS was observed with orteronel-prednisone (median, 8.3 v 5.7 months; HR, 0.760; 95% CI, 0.653 to 0.885; P < .001). Orteronel-prednisone showed advantages over placebo-prednisone in PSA50 rate (25% v 10%, P < .001) and time to PSA progression (median, 5.5 v 2.9 months, P < .001) but not pain response rate (12% v 9%; P = .128). Adverse events (all grades) were generally more frequent with orteronel-prednisone, including nausea (42% v 26%), vomiting (36% v 17%), fatigue (29% v 23%), and increased amylase (14% v 2%). ### conclusion Our study did not meet the primary end point of OS. Longer rPFS and a higher PSA50 rate with orteronel-prednisone indicate antitumor activity.

https://pubmed.ncbi.nlm.nih.gov/25624429/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Phase III , randomized , double-blind , multicenter trial comparing orteronel ( TAK-700 ) plus prednisone with placebo plus prednisone in patients with metastatic castration-resistant prostate cancer that has progressed during or after docetaxel-based therapy : ELM-PC 5 . Orteronel (tak-700) is an investigational, nonsteroidal, reversible, selective 17,20-lyase inhibitor. This study examined orteronel in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel therapy. ### Patients And Methods In our study, 1,099 men were randomly assigned in a 2:1 schedule to receive orteronel 400 mg plus prednisone 5 mg twice daily or placebo plus prednisone 5 mg twice daily, stratified by region (Europe, North America [NA], and non-Europe/NA) and Brief Pain Inventory-Short Form worst pain score. Primary end point was overall survival (OS). Key secondary end points (radiographic progression-free survival [rPFS], ≥ 50% decrease of prostate-specific antigen [PSA50], and pain response at 12 weeks) were to undergo statistical testing only if the primary end point analysis was significant. ### results The study was unblinded after crossing a prespecified OS futility boundary. The median OS was 17.0 months versus 15.2 months with orteronel-prednisone versus placebo-prednisone (hazard ratio [HR], 0.886; 95% CI, 0.739 to 1.062; P = .190). Improved rPFS was observed with orteronel-prednisone (median, 8.3 v 5.7 months; HR, 0.760; 95% CI, 0.653 to 0.885; P < .001). Orteronel-prednisone showed advantages over placebo-prednisone in PSA50 rate (25% v 10%, P < .001) and time to PSA progression (median, 5.5 v 2.9 months, P < .001) but not pain response rate (12% v 9%; P = .128). Adverse events (all grades) were generally more frequent with orteronel-prednisone, including nausea (42% v 26%), vomiting (36% v 17%), fatigue (29% v 23%), and increased amylase (14% v 2%). ### conclusion Our study did not meet the primary end point of OS. Longer rPFS and a higher PSA50 rate with orteronel-prednisone indicate antitumor activity. ### Response: TAK-700, prednisone, prednisone

2696f2ed809244fe4362bf01ba2b9f1b

Five clinical trials with temozolomide or dacarbazine have been performed in metastatic colorectal cancer ( mCRC ) with selection based on methyl-specific PCR ( MSP ) testing with modest results .

Digital PCR assessment of MGMT promoter methylation coupled with reduced protein expression optimises prediction of response to alkylating agents in metastatic colorectal cancer patients. O(6)-methylguanine-DNA-methyltransferase (MGMT) is a repair protein, and its deficiency makes tumours more susceptible to the cytotoxic effect of alkylating agents. Five clinical trials with temozolomide or dacarbazine have been performed in metastatic colorectal cancer ( mCRC ) with selection based on methyl-specific PCR ( MSP ) testing with modest results . We hypothesised that mitigated results are consequences of unspecific patient selection and that alternative methodologies for MGMT testing such as immunohistochemistry (IHC) and digital polymerase chain reaction (PCR) could enhance patient enrolment. ### Patients And Methods Formalin-fixed paraffin embedded archival tumour tissue samples from four phase II studies of temozolomide or dacarbazine in MGMT MSP-positive mCRCs were analysed by IHC for MGMT protein expression and by methyl-BEAMing (MB) for percentage of promoter methylation. Pooled data were then retrospectively analysed according to objective response rate, progression-free survival (PFS) and overall survival (OS). ### results One hundred and five patients were included in the study. Twelve had achieved partial response (PR) (11.4%), 24 stable disease (SD; 22.9%) and 69 progressive disease (PD; 65.7%). Patients with PR/SD had lower IHC scores and higher MB levels than those with PD. MGMT expression by IHC was negatively and MB levels positively associated with PFS (p < 0.001 and 0.004, respectively), but not with OS. By combining both assays, IHC low/MB high patients displayed an 87% reduction in the hazard of progression (p < 0.001) and a 77% in the hazard for death (p = 0.001). ### conclusion In mCRC selected for MGMT deficiency by MSP, IHC and MB testing improve clinical outcome to alkylating agents. Their combination could enhance patient selection in this setting.

https://pubmed.ncbi.nlm.nih.gov/27997874/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Digital PCR assessment of MGMT promoter methylation coupled with reduced protein expression optimises prediction of response to alkylating agents in metastatic colorectal cancer patients. O(6)-methylguanine-DNA-methyltransferase (MGMT) is a repair protein, and its deficiency makes tumours more susceptible to the cytotoxic effect of alkylating agents. Five clinical trials with temozolomide or dacarbazine have been performed in metastatic colorectal cancer ( mCRC ) with selection based on methyl-specific PCR ( MSP ) testing with modest results . We hypothesised that mitigated results are consequences of unspecific patient selection and that alternative methodologies for MGMT testing such as immunohistochemistry (IHC) and digital polymerase chain reaction (PCR) could enhance patient enrolment. ### Patients And Methods Formalin-fixed paraffin embedded archival tumour tissue samples from four phase II studies of temozolomide or dacarbazine in MGMT MSP-positive mCRCs were analysed by IHC for MGMT protein expression and by methyl-BEAMing (MB) for percentage of promoter methylation. Pooled data were then retrospectively analysed according to objective response rate, progression-free survival (PFS) and overall survival (OS). ### results One hundred and five patients were included in the study. Twelve had achieved partial response (PR) (11.4%), 24 stable disease (SD; 22.9%) and 69 progressive disease (PD; 65.7%). Patients with PR/SD had lower IHC scores and higher MB levels than those with PD. MGMT expression by IHC was negatively and MB levels positively associated with PFS (p < 0.001 and 0.004, respectively), but not with OS. By combining both assays, IHC low/MB high patients displayed an 87% reduction in the hazard of progression (p < 0.001) and a 77% in the hazard for death (p = 0.001). ### conclusion In mCRC selected for MGMT deficiency by MSP, IHC and MB testing improve clinical outcome to alkylating agents. Their combination could enhance patient selection in this setting. ### Response: temozolomide, dacarbazine

4d616b8b6d114e89d6958f931fe85aaa

Heparin infusion , followed by oral warfarin , is indicated for symptomatic thromboembolic disease as well as for asymptomatic patients with substantial proximal deep venous thrombosis or large pulmonary emboli .

Therapy for postoperative thromboembolic disease: indications and treatment. Postarthroplasty patients develop venous thromboembolic disease because of venous stasis, hypercoaguability, and vessel wall injury. However, most venous thrombi are nonocclusive or small and elicit few symptoms; pulmonary emboli also tend to be asymptomatic. Noninvasive techniques to detect deep vein thrombosis do not appear to be reliable in this population, so venography may be required. Postoperative perfusion lung scans, with comparison to preoperative perfusion scans, are the best screen for asymptomatic pulmonary emboli. Heparin infusion , followed by oral warfarin , is indicated for symptomatic thromboembolic disease as well as for asymptomatic patients with substantial proximal deep venous thrombosis or large pulmonary emboli .

https://pubmed.ncbi.nlm.nih.gov/10147578/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Therapy for postoperative thromboembolic disease: indications and treatment. Postarthroplasty patients develop venous thromboembolic disease because of venous stasis, hypercoaguability, and vessel wall injury. However, most venous thrombi are nonocclusive or small and elicit few symptoms; pulmonary emboli also tend to be asymptomatic. Noninvasive techniques to detect deep vein thrombosis do not appear to be reliable in this population, so venography may be required. Postoperative perfusion lung scans, with comparison to preoperative perfusion scans, are the best screen for asymptomatic pulmonary emboli. Heparin infusion , followed by oral warfarin , is indicated for symptomatic thromboembolic disease as well as for asymptomatic patients with substantial proximal deep venous thrombosis or large pulmonary emboli . ### Response: Heparin, warfarin

251f5f7c9560eb8b5c97eec74bfe8344

Fluoxetine and paroxetine are potent inhibitors of CYP2D6 and administration of these SSRIs reduces the clinical benefit of an anticancer drug , such as tamoxifen , by decreasing the formation of active metabolites of this drug .

Metabolic drug interactions between antidepressants and anticancer drugs: focus on selective serotonin reuptake inhibitors and hypericum extract. Different antidepressant drugs are currently used for the treatment of depression in cancer patients, such as second-generation antidepressants and, recently, the extracts of Hypericum perforatum. These agents are susceptible to metabolically-based drug interactions with anticancer drugs. The aim of the present article is to provide an updated review of clinically relevant metabolic drug interactions between selected anticancer drugs and antidepressants, focusing on selective serotonin reuptake inhibitors (SSRIs) and Hypericum extract. SSRIs can cause pharmacokinetic interactions through their in vitro ability to inhibit one or more cytochrome P450 isoenzymes (CYPs). SSRIs differ in their potential for metabolic drug interactions with anticancer drugs. Fluoxetine and paroxetine are potent inhibitors of CYP2D6 and administration of these SSRIs reduces the clinical benefit of an anticancer drug , such as tamoxifen , by decreasing the formation of active metabolites of this drug . Women with breast cancer who receive paroxetine in combination with tamoxifen are at increased risk for death. Other SSRIs, including citalopram, escitalopram, are weak or negligible inhibitors of CYP2D6 and are less likely to interact with anticancer drugs, while sertraline causes significant inhibition of this isoform only at high doses. Hypericum extract, by inducing both the CYP3A4 and the P-glycoprotein (P-gp), can reduce the plasma concentrations of different antineoplastic agents such as imatinib, irinotecan and docetaxel, thus reducing the clinical efficacy of these drugs. Although these interactions are often predictable, the use of fluoxetine, paroxetine and Hypericum extract should be avoided in cancer patients.

https://pubmed.ncbi.nlm.nih.gov/21395523/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Metabolic drug interactions between antidepressants and anticancer drugs: focus on selective serotonin reuptake inhibitors and hypericum extract. Different antidepressant drugs are currently used for the treatment of depression in cancer patients, such as second-generation antidepressants and, recently, the extracts of Hypericum perforatum. These agents are susceptible to metabolically-based drug interactions with anticancer drugs. The aim of the present article is to provide an updated review of clinically relevant metabolic drug interactions between selected anticancer drugs and antidepressants, focusing on selective serotonin reuptake inhibitors (SSRIs) and Hypericum extract. SSRIs can cause pharmacokinetic interactions through their in vitro ability to inhibit one or more cytochrome P450 isoenzymes (CYPs). SSRIs differ in their potential for metabolic drug interactions with anticancer drugs. Fluoxetine and paroxetine are potent inhibitors of CYP2D6 and administration of these SSRIs reduces the clinical benefit of an anticancer drug , such as tamoxifen , by decreasing the formation of active metabolites of this drug . Women with breast cancer who receive paroxetine in combination with tamoxifen are at increased risk for death. Other SSRIs, including citalopram, escitalopram, are weak or negligible inhibitors of CYP2D6 and are less likely to interact with anticancer drugs, while sertraline causes significant inhibition of this isoform only at high doses. Hypericum extract, by inducing both the CYP3A4 and the P-glycoprotein (P-gp), can reduce the plasma concentrations of different antineoplastic agents such as imatinib, irinotecan and docetaxel, thus reducing the clinical efficacy of these drugs. Although these interactions are often predictable, the use of fluoxetine, paroxetine and Hypericum extract should be avoided in cancer patients. ### Response: Fluoxetine, paroxetine, tamoxifen

81dbb19a67ef1985983527cb474e4352

Epirubicin is an anthracyclin , analogous to doxorubicin , with a different toxicologic pattern .

A phase II study evaluating the cisplatin and epirubicin combination in patients with unresectable malignant pleural mesothelioma. Few chemotherapeutic agents have demonstrated their efficacy in malignant mesothelioma. The cisplatin plus doxorubicin combination has one of the highest response rates. Epirubicin is an anthracyclin , analogous to doxorubicin , with a different toxicologic pattern . As there are no data on the activity of the combination cisplatin plus epirubicin in malignant mesothelioma, the European Lung Cancer Working Party (ELCWP) designed a phase II study with response rate as primary objective. Sixty-nine eligible patients with malignant pleural mesothelioma were centrally registered. The majority of the patients were male (n=59), had a Karnofsky performance status of 80 or more (n=62) and presented with an epithelial histologic subtype (n=43). Median age was 62 years. In nine patients, metastases were documented at the initial work-up, mainly in bone, lung and skin. Three hundred and twenty-four cycles of chemotherapy were administered. The main toxicities were nausea and vomiting, neutropenia and alopecia. Among 63 assessable patients, response rate was 19.0% (95% confidence interval [CI] 9-29%). Median survival was 13.3 months. In multivariate analysis, poor prognostic factors for survival were neutrophil count and CALGB groups 4-6. In conclusion, cisplatin plus epirubicin appears as an effective regimen in malignant mesothelioma, with a favourable toxicity profile. However, it does not demonstrate superior activity to other active regimens in this disease.

https://pubmed.ncbi.nlm.nih.gov/16005104/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: A phase II study evaluating the cisplatin and epirubicin combination in patients with unresectable malignant pleural mesothelioma. Few chemotherapeutic agents have demonstrated their efficacy in malignant mesothelioma. The cisplatin plus doxorubicin combination has one of the highest response rates. Epirubicin is an anthracyclin , analogous to doxorubicin , with a different toxicologic pattern . As there are no data on the activity of the combination cisplatin plus epirubicin in malignant mesothelioma, the European Lung Cancer Working Party (ELCWP) designed a phase II study with response rate as primary objective. Sixty-nine eligible patients with malignant pleural mesothelioma were centrally registered. The majority of the patients were male (n=59), had a Karnofsky performance status of 80 or more (n=62) and presented with an epithelial histologic subtype (n=43). Median age was 62 years. In nine patients, metastases were documented at the initial work-up, mainly in bone, lung and skin. Three hundred and twenty-four cycles of chemotherapy were administered. The main toxicities were nausea and vomiting, neutropenia and alopecia. Among 63 assessable patients, response rate was 19.0% (95% confidence interval [CI] 9-29%). Median survival was 13.3 months. In multivariate analysis, poor prognostic factors for survival were neutrophil count and CALGB groups 4-6. In conclusion, cisplatin plus epirubicin appears as an effective regimen in malignant mesothelioma, with a favourable toxicity profile. However, it does not demonstrate superior activity to other active regimens in this disease. ### Response: Epirubicin, doxorubicin

6370dac70bb6f82f07d67292360f14ad

A total of 460 patients were randomized into four 10-day therapeutic schemes ( 115 patients per group ): ( i ) standard OCA , omeprazole , clarithromycin and amoxicillin ; ( ii ) triple OLA , omeprazole , levofloxacin and amoxicillin ; ( iii ) sequential OACM , omeprazole plus amoxicillin for 5 days , followed by omeprazole plus clarithromycin plus metronidazole for 5 days ; and ( iv ) modified sequential OALM , using levofloxacin instead of clarithromycin .

Clinical trial: clarithromycin vs. levofloxacin in first-line triple and sequential regimens for Helicobacter pylori eradication. Helicobacter pylori eradication rates with standard triple therapy have declined to unacceptable levels. ### aim To compare clarithromycin and levofloxacin in triple and sequential first-line regimens. ### methods A total of 460 patients were randomized into four 10-day therapeutic schemes ( 115 patients per group ): ( i ) standard OCA , omeprazole , clarithromycin and amoxicillin ; ( ii ) triple OLA , omeprazole , levofloxacin and amoxicillin ; ( iii ) sequential OACM , omeprazole plus amoxicillin for 5 days , followed by omeprazole plus clarithromycin plus metronidazole for 5 days ; and ( iv ) modified sequential OALM , using levofloxacin instead of clarithromycin . Eradication was confirmed by 13C-urea breath test. Adverse effects and compliance were assessed by a questionnaire. ### results Per protocol cure rates were: OCA (66%; 95% CI: 57-74%), OLA (82.6%; 75-89%), OACM (80.8%; 73-88%) and OALM (85.2%; 78-91%). Intention-to-treat cure rates were: OCA (64%; 55-73%), OLA (80.8%; 73-88%), OACM (76.5%; 69-85%) and OALM (82.5%; 75-89%). Eradication rates were lower with OCA than with all the other regimens (P < 0.05). No differences in compliance or adverse effects were demonstrated among treatments. ### conclusions levofloxacin-based and sequential therapy are superior to standard triple scheme as first-line regimens in a setting with high clarithromycin resistance. However, all of these therapies still have a 20% failure rate.

https://pubmed.ncbi.nlm.nih.gov/20180787/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Clinical trial: clarithromycin vs. levofloxacin in first-line triple and sequential regimens for Helicobacter pylori eradication. Helicobacter pylori eradication rates with standard triple therapy have declined to unacceptable levels. ### aim To compare clarithromycin and levofloxacin in triple and sequential first-line regimens. ### methods A total of 460 patients were randomized into four 10-day therapeutic schemes ( 115 patients per group ): ( i ) standard OCA , omeprazole , clarithromycin and amoxicillin ; ( ii ) triple OLA , omeprazole , levofloxacin and amoxicillin ; ( iii ) sequential OACM , omeprazole plus amoxicillin for 5 days , followed by omeprazole plus clarithromycin plus metronidazole for 5 days ; and ( iv ) modified sequential OALM , using levofloxacin instead of clarithromycin . Eradication was confirmed by 13C-urea breath test. Adverse effects and compliance were assessed by a questionnaire. ### results Per protocol cure rates were: OCA (66%; 95% CI: 57-74%), OLA (82.6%; 75-89%), OACM (80.8%; 73-88%) and OALM (85.2%; 78-91%). Intention-to-treat cure rates were: OCA (64%; 55-73%), OLA (80.8%; 73-88%), OACM (76.5%; 69-85%) and OALM (82.5%; 75-89%). Eradication rates were lower with OCA than with all the other regimens (P < 0.05). No differences in compliance or adverse effects were demonstrated among treatments. ### conclusions levofloxacin-based and sequential therapy are superior to standard triple scheme as first-line regimens in a setting with high clarithromycin resistance. However, all of these therapies still have a 20% failure rate. ### Response: omeprazole, clarithromycin, amoxicillin, omeprazole, levofloxacin, amoxicillin, omeprazole, amoxicillin, omeprazole, clarithromycin, metronidazole, levofloxacin, clarithromycin

1123d5ef9b6fdeb123b453991b3b6218

Captopril in combination with HYZ significantly reduced BP compared with controls but T replacement increased BP and coronary collagen deposition in spite of HYZ and captopril treatment .

Testosterone increases blood pressure and cardiovascular and renal pathology in spontaneously hypertensive rats. The objective of this paper was to test the hypothesis that testosterone (T) raises blood pressure (BP), which is associated with increased coronary adventitial collagen, whereas the hemodynamic force of BP increases the coronary media:lumen ratio. Five treatment groups of spontaneously hypertensive rat (SHR) were established (n = 8-10 per group): controls; hydralazine (HYZ); castration; castration + HYZ; and castration + HYZ + T + captopril. At 12 weeks of age, the castrate + HYZ group was divided so that the mean BP was the same in both groups (162 mmHg). Both groups continued to receive HYZ treatment; however one group received T implants. Also, at 12 weeks of age the castrate + HYZ + T + captopril group received T implants. BP in the HYZ group was reduced compared with controls (192 mmHg vs 218 mmHg, p < 0.01). Castration lowered BP to 170 mmHg (p < 0.01) compared with controls. However, T implants increased BP by 15 mmHg (p < 0.02) in the castrate + HYZ group and by 44 mmHg in the castrate + HYZ + captopril group (p < 0.01). Captopril in combination with HYZ significantly reduced BP compared with controls but T replacement increased BP and coronary collagen deposition in spite of HYZ and captopril treatment .

https://pubmed.ncbi.nlm.nih.gov/11055476/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Testosterone increases blood pressure and cardiovascular and renal pathology in spontaneously hypertensive rats. The objective of this paper was to test the hypothesis that testosterone (T) raises blood pressure (BP), which is associated with increased coronary adventitial collagen, whereas the hemodynamic force of BP increases the coronary media:lumen ratio. Five treatment groups of spontaneously hypertensive rat (SHR) were established (n = 8-10 per group): controls; hydralazine (HYZ); castration; castration + HYZ; and castration + HYZ + T + captopril. At 12 weeks of age, the castrate + HYZ group was divided so that the mean BP was the same in both groups (162 mmHg). Both groups continued to receive HYZ treatment; however one group received T implants. Also, at 12 weeks of age the castrate + HYZ + T + captopril group received T implants. BP in the HYZ group was reduced compared with controls (192 mmHg vs 218 mmHg, p < 0.01). Castration lowered BP to 170 mmHg (p < 0.01) compared with controls. However, T implants increased BP by 15 mmHg (p < 0.02) in the castrate + HYZ group and by 44 mmHg in the castrate + HYZ + captopril group (p < 0.01). Captopril in combination with HYZ significantly reduced BP compared with controls but T replacement increased BP and coronary collagen deposition in spite of HYZ and captopril treatment . ### Response: Captopril, HYZ, captopril

2f5b79becc8a6e69aaa31e1c49f396d2

Targeted therapy was administered to match the P1K3CA , c-MET , and SPARC and COX2 aberrations with sirolimus+ crizotinib and abraxane+ celecoxib .

Personalized comprehensive molecular profiling of high risk osteosarcoma: Implications and limitations for precision medicine. Despite advances in molecular medicine over recent decades, there has been little advancement in the treatment of osteosarcoma. We performed comprehensive molecular profiling in two cases of metastatic and chemotherapy-refractory osteosarcoma to guide molecularly targeted therapy. ### Patients And Methods Hybridization capture of >300 cancer-related genes plus introns from 28 genes often rearranged or altered in cancer was applied to >50 ng of DNA extracted from tumor samples from two patients with recurrent, metastatic osteosarcoma. The DNA from each sample was sequenced to high, uniform coverage. Immunohistochemical probes and morphoproteomics analysis were performed, in addition to fluorescence in situ hybridization. All analyses were performed in CLIA-certified laboratories. Molecularly targeted therapy based on the resulting profiles was offered to the patients. Biomedical analytics were performed using QIAGEN's Ingenuity® Pathway Analysis. ### results In Patient #1, comprehensive next-generation exome sequencing showed MET amplification, PIK3CA mutation, CCNE1 amplification, and PTPRD mutation. Immunohistochemistry-based morphoproteomic analysis revealed c-Met expression [(p)-c-Met (Tyr1234/1235)] and activation of mTOR/AKT pathway [IGF-1R (Tyr1165/1166), p-mTOR [Ser2448], p-Akt (Ser473)] and expression of SPARC and COX2. Targeted therapy was administered to match the P1K3CA , c-MET , and SPARC and COX2 aberrations with sirolimus+ crizotinib and abraxane+ celecoxib . In Patient #2, aberrations included NF2 loss in exons 2-16, PDGFRα amplification, and TP53 mutation. This patient was enrolled on a clinical trial combining targeted agents temsirolimus, sorafenib and bevacizumab, to match NF2, PDGFRα and TP53 aberrations. Both the patients did not benefit from matched therapy. ### conclusions Relapsed osteosarcoma is characterized by complex signaling and drug resistance pathways. Comprehensive molecular profiling holds great promise for tailoring personalized therapies for cancer. Methods for such profiling are evolving and need to be refined to better assist clinicians in making treatment decisions based on the large amount of data that results from this type of testing. Further research in this area is warranted.

https://pubmed.ncbi.nlm.nih.gov/26510912/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Personalized comprehensive molecular profiling of high risk osteosarcoma: Implications and limitations for precision medicine. Despite advances in molecular medicine over recent decades, there has been little advancement in the treatment of osteosarcoma. We performed comprehensive molecular profiling in two cases of metastatic and chemotherapy-refractory osteosarcoma to guide molecularly targeted therapy. ### Patients And Methods Hybridization capture of >300 cancer-related genes plus introns from 28 genes often rearranged or altered in cancer was applied to >50 ng of DNA extracted from tumor samples from two patients with recurrent, metastatic osteosarcoma. The DNA from each sample was sequenced to high, uniform coverage. Immunohistochemical probes and morphoproteomics analysis were performed, in addition to fluorescence in situ hybridization. All analyses were performed in CLIA-certified laboratories. Molecularly targeted therapy based on the resulting profiles was offered to the patients. Biomedical analytics were performed using QIAGEN's Ingenuity® Pathway Analysis. ### results In Patient #1, comprehensive next-generation exome sequencing showed MET amplification, PIK3CA mutation, CCNE1 amplification, and PTPRD mutation. Immunohistochemistry-based morphoproteomic analysis revealed c-Met expression [(p)-c-Met (Tyr1234/1235)] and activation of mTOR/AKT pathway [IGF-1R (Tyr1165/1166), p-mTOR [Ser2448], p-Akt (Ser473)] and expression of SPARC and COX2. Targeted therapy was administered to match the P1K3CA , c-MET , and SPARC and COX2 aberrations with sirolimus+ crizotinib and abraxane+ celecoxib . In Patient #2, aberrations included NF2 loss in exons 2-16, PDGFRα amplification, and TP53 mutation. This patient was enrolled on a clinical trial combining targeted agents temsirolimus, sorafenib and bevacizumab, to match NF2, PDGFRα and TP53 aberrations. Both the patients did not benefit from matched therapy. ### conclusions Relapsed osteosarcoma is characterized by complex signaling and drug resistance pathways. Comprehensive molecular profiling holds great promise for tailoring personalized therapies for cancer. Methods for such profiling are evolving and need to be refined to better assist clinicians in making treatment decisions based on the large amount of data that results from this type of testing. Further research in this area is warranted. ### Response: sirolimus+, crizotinib, abraxane+, celecoxib

6b6df6ff4095a8857ad554d4cf0c8f15

EURAMOS-1 results do not support the addition of ifosfamide and etoposide to postoperative chemotherapy in patients with poorly responding osteosarcoma because its administration was associated with increased toxicity without improving event-free survival .

Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial. We designed the EURAMOS-1 trial to investigate whether intensified postoperative chemotherapy for patients whose tumour showed a poor response to preoperative chemotherapy (≥10% viable tumour) improved event-free survival in patients with high-grade osteosarcoma. ### methods EURAMOS-1 was an open-label, international, phase 3 randomised, controlled trial. Consenting patients with newly diagnosed, resectable, high-grade osteosarcoma aged 40 years or younger were eligible for randomisation. Patients were randomly assigned (1:1) to receive either postoperative cisplatin, doxorubicin, and methotrexate (MAP) or MAP plus ifosfamide and etoposide (MAPIE) using concealed permuted blocks with three stratification factors: trial group; location of tumour (proximal femur or proximal humerus vs other limb vs axial skeleton); and presence of metastases (no vs yes or possible). The MAP regimen consisted of cisplatin 120 mg/m ### findings Between April 14, 2005, and June 30, 2011, 2260 patients were registered from 325 sites in 17 countries. 618 patients with poor response were randomly assigned; 310 to receive MAP and 308 to receive MAPIE. Median follow-up was 62·1 months (IQR 46·6-76·6); 62·3 months (IQR 46·9-77·1) for the MAP group and 61·1 months (IQR 46·5-75·3) for the MAPIE group. 307 event-free survival events were reported (153 in the MAP group vs 154 in the MAPIE group). 193 deaths were reported (101 in the MAP group vs 92 in the MAPIE group). Event-free survival did not differ between treatment groups (hazard ratio [HR] 0·98 [95% CI 0·78-1·23]); hazards were non-proportional (p=0·0003). The most common grade 3-4 adverse events were neutropenia (268 [89%] patients in MAP vs 268 [90%] in MAPIE), thrombocytopenia (231 [78% in MAP vs 248 [83%] in MAPIE), and febrile neutropenia without documented infection (149 [50%] in MAP vs 217 [73%] in MAPIE). MAPIE was associated with more frequent grade 4 non-haematological toxicity than MAP (35 [12%] of 301 in the MAP group vs 71 [24%] of 298 in the MAPIE group). Two patients died during postoperative therapy, one from infection (although their absolute neutrophil count was normal), which was definitely related to their MAP treatment (specifically doxorubicin and cisplatin), and one from left ventricular systolic dysfunction, which was probably related to MAPIE treatment (specifically doxorubicin). One suspected unexpected serious adverse reaction was reported in the MAP group: bone marrow infarction due to methotrexate. ### interpretation EURAMOS-1 results do not support the addition of ifosfamide and etoposide to postoperative chemotherapy in patients with poorly responding osteosarcoma because its administration was associated with increased toxicity without improving event-free survival . The results define standard of care for this population. New strategies are required to improve outcomes in this setting. ### funding UK Medical Research Council, National Cancer Institute, European Science Foundation, St Anna Kinderkrebsforschung, Fonds National de la Recherche Scientifique, Fonds voor Wetenschappelijk Onderzoek-Vlaanderen, Parents Organization, Danish Medical Research Council, Academy of Finland, Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, Federal Ministry of Education and Research, Semmelweis Foundation, ZonMw (Council for Medical Research), Research Council of Norway, Scandinavian Sarcoma Group, Swiss Paediatric Oncology Group, Cancer Research UK, National Institute for Health Research, University College London Hospitals, and Biomedical Research Centre.

https://pubmed.ncbi.nlm.nih.gov/27569442/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial. We designed the EURAMOS-1 trial to investigate whether intensified postoperative chemotherapy for patients whose tumour showed a poor response to preoperative chemotherapy (≥10% viable tumour) improved event-free survival in patients with high-grade osteosarcoma. ### methods EURAMOS-1 was an open-label, international, phase 3 randomised, controlled trial. Consenting patients with newly diagnosed, resectable, high-grade osteosarcoma aged 40 years or younger were eligible for randomisation. Patients were randomly assigned (1:1) to receive either postoperative cisplatin, doxorubicin, and methotrexate (MAP) or MAP plus ifosfamide and etoposide (MAPIE) using concealed permuted blocks with three stratification factors: trial group; location of tumour (proximal femur or proximal humerus vs other limb vs axial skeleton); and presence of metastases (no vs yes or possible). The MAP regimen consisted of cisplatin 120 mg/m ### findings Between April 14, 2005, and June 30, 2011, 2260 patients were registered from 325 sites in 17 countries. 618 patients with poor response were randomly assigned; 310 to receive MAP and 308 to receive MAPIE. Median follow-up was 62·1 months (IQR 46·6-76·6); 62·3 months (IQR 46·9-77·1) for the MAP group and 61·1 months (IQR 46·5-75·3) for the MAPIE group. 307 event-free survival events were reported (153 in the MAP group vs 154 in the MAPIE group). 193 deaths were reported (101 in the MAP group vs 92 in the MAPIE group). Event-free survival did not differ between treatment groups (hazard ratio [HR] 0·98 [95% CI 0·78-1·23]); hazards were non-proportional (p=0·0003). The most common grade 3-4 adverse events were neutropenia (268 [89%] patients in MAP vs 268 [90%] in MAPIE), thrombocytopenia (231 [78% in MAP vs 248 [83%] in MAPIE), and febrile neutropenia without documented infection (149 [50%] in MAP vs 217 [73%] in MAPIE). MAPIE was associated with more frequent grade 4 non-haematological toxicity than MAP (35 [12%] of 301 in the MAP group vs 71 [24%] of 298 in the MAPIE group). Two patients died during postoperative therapy, one from infection (although their absolute neutrophil count was normal), which was definitely related to their MAP treatment (specifically doxorubicin and cisplatin), and one from left ventricular systolic dysfunction, which was probably related to MAPIE treatment (specifically doxorubicin). One suspected unexpected serious adverse reaction was reported in the MAP group: bone marrow infarction due to methotrexate. ### interpretation EURAMOS-1 results do not support the addition of ifosfamide and etoposide to postoperative chemotherapy in patients with poorly responding osteosarcoma because its administration was associated with increased toxicity without improving event-free survival . The results define standard of care for this population. New strategies are required to improve outcomes in this setting. ### funding UK Medical Research Council, National Cancer Institute, European Science Foundation, St Anna Kinderkrebsforschung, Fonds National de la Recherche Scientifique, Fonds voor Wetenschappelijk Onderzoek-Vlaanderen, Parents Organization, Danish Medical Research Council, Academy of Finland, Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, Federal Ministry of Education and Research, Semmelweis Foundation, ZonMw (Council for Medical Research), Research Council of Norway, Scandinavian Sarcoma Group, Swiss Paediatric Oncology Group, Cancer Research UK, National Institute for Health Research, University College London Hospitals, and Biomedical Research Centre. ### Response: ifosfamide, etoposide, postoperative chemotherapy

10147e145cd0bdad159de619cec5c4f7

The focus of this study is to investigate , whether altered expression levels of potentially relevant microRNAs ( miRs ) in serum are associated with response to trastuzumab or lapatinib .

Changes in serum levels of miR-21, miR-210, and miR-373 in HER2-positive breast cancer patients undergoing neoadjuvant therapy: a translational research project within the Geparquinto trial. trastuzumab and lapatinib are established treatments for patients with HER2 (human epidermal growth factor receptor 2)-positive breast cancer with different mechanisms of action. The focus of this study is to investigate , whether altered expression levels of potentially relevant microRNAs ( miRs ) in serum are associated with response to trastuzumab or lapatinib . Circulating miR-21, miR-210, and miR-373 were quantified with TaqMan MicroRNA assays in serum of 127 HER2-postive breast cancer patients before and after neoadjuvant therapy and in 19 healthy controls. Patients received chemotherapy combined with either trastuzumab or lapatinib within the prospectively randomized Geparquinto trial. The association between miR levels and pathological response (pCR) to therapy and type of therapy was examined. Serum levels of miR-21 (p = 5.04e-08, p = 1.43e-10), miR-210 (p = 0.00151, p = 1.6e-05), and miR-373 (p = 7.87e-06, p = 1.75e-07) were significantly higher in patients before and after chemotherapy than in healthy women. Concentrations of miR-21 (p = 5.73e-08), miR-210 (p = 0.000724), and miR-373 (p = 0.00209) increased further after chemotherapy. A significant association of higher serum levels of miR-373 with advanced clinical tumor stage could be detected (p < 0.002). An association of miR-21 levels before (p = 0.0091) and after (p = 0.037) chemotherapy with overall survival of the patients could be detected, independent of type of anti-HER2 therapy. No association of circulating miRs with pCR was found. Our findings demonstrate a specific influence of neoadjuvant therapy on the serum levels of miR-21, miR-210, and miR-373 in breast cancer patients together with a prognostic value of miR-21.

https://pubmed.ncbi.nlm.nih.gov/25086636/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Changes in serum levels of miR-21, miR-210, and miR-373 in HER2-positive breast cancer patients undergoing neoadjuvant therapy: a translational research project within the Geparquinto trial. trastuzumab and lapatinib are established treatments for patients with HER2 (human epidermal growth factor receptor 2)-positive breast cancer with different mechanisms of action. The focus of this study is to investigate , whether altered expression levels of potentially relevant microRNAs ( miRs ) in serum are associated with response to trastuzumab or lapatinib . Circulating miR-21, miR-210, and miR-373 were quantified with TaqMan MicroRNA assays in serum of 127 HER2-postive breast cancer patients before and after neoadjuvant therapy and in 19 healthy controls. Patients received chemotherapy combined with either trastuzumab or lapatinib within the prospectively randomized Geparquinto trial. The association between miR levels and pathological response (pCR) to therapy and type of therapy was examined. Serum levels of miR-21 (p = 5.04e-08, p = 1.43e-10), miR-210 (p = 0.00151, p = 1.6e-05), and miR-373 (p = 7.87e-06, p = 1.75e-07) were significantly higher in patients before and after chemotherapy than in healthy women. Concentrations of miR-21 (p = 5.73e-08), miR-210 (p = 0.000724), and miR-373 (p = 0.00209) increased further after chemotherapy. A significant association of higher serum levels of miR-373 with advanced clinical tumor stage could be detected (p < 0.002). An association of miR-21 levels before (p = 0.0091) and after (p = 0.037) chemotherapy with overall survival of the patients could be detected, independent of type of anti-HER2 therapy. No association of circulating miRs with pCR was found. Our findings demonstrate a specific influence of neoadjuvant therapy on the serum levels of miR-21, miR-210, and miR-373 in breast cancer patients together with a prognostic value of miR-21. ### Response: trastuzumab, lapatinib

94f9dd27429e130f46f205da0891f4d4

These results suggest that the addition of intravenous ceftriaxone during the first 3 days of hospitalization does not improve the cost-efficacy of oral norfloxacin in the prevention of bacterial infections in cirrhotic patients with gastrointestinal bleeding and high risk of infection .

Parenteral antibiotic prophylaxis of bacterial infections does not improve cost-efficacy of oral norfloxacin in cirrhotic patients with gastrointestinal bleeding. Selective intestinal decontamination with norfloxacin is useful in the prevention of bacterial infections in cirrhotic patients with gastrointestinal bleeding. However, bleeding cirrhotic patients with ascites, encephalopathy, or shock are at high risk to develop bacterial infections in spite of prophylactic norfloxacin. The aim of this study was to assess whether the addition of intravenous ceftriaxone could improve the efficacy of prophylaxis with norfloxacin in these patients. ### methods Fifty-six cirrhotic patients with gastrointestinal hemorrhage and ascites, encephalopathy, or shock were randomized into two groups: Group 1 (n = 28) received oral norfloxacin 400 mg/12 h for 7 days, and group 2 (n = 28) received norfloxacin plus intravenous ceftriaxone 2 g daily during the first 3 days of admission. ### results Ten patients were excluded because of community-acquired infection, surgery, or death within the first 24 h. The incidence of bacterial infections during hospitalization was 18.1% in group 1 and 12.5% in group 2 (p = NS). The incidence of severe infections (spontaneous bacterial peritonitis, bacteremia, or pneumonia) was also similar in both groups: 9% in group 1 versus 8.3% in group 2 (p = NS). There were no statistical differences between the two groups with respect to duration of hospitalization or mortality. The cost of antibiotic therapy (including prophylaxis and treatment of infections) was significantly higher in group 2. ### conclusion These results suggest that the addition of intravenous ceftriaxone during the first 3 days of hospitalization does not improve the cost-efficacy of oral norfloxacin in the prevention of bacterial infections in cirrhotic patients with gastrointestinal bleeding and high risk of infection .

https://pubmed.ncbi.nlm.nih.gov/9860409/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Parenteral antibiotic prophylaxis of bacterial infections does not improve cost-efficacy of oral norfloxacin in cirrhotic patients with gastrointestinal bleeding. Selective intestinal decontamination with norfloxacin is useful in the prevention of bacterial infections in cirrhotic patients with gastrointestinal bleeding. However, bleeding cirrhotic patients with ascites, encephalopathy, or shock are at high risk to develop bacterial infections in spite of prophylactic norfloxacin. The aim of this study was to assess whether the addition of intravenous ceftriaxone could improve the efficacy of prophylaxis with norfloxacin in these patients. ### methods Fifty-six cirrhotic patients with gastrointestinal hemorrhage and ascites, encephalopathy, or shock were randomized into two groups: Group 1 (n = 28) received oral norfloxacin 400 mg/12 h for 7 days, and group 2 (n = 28) received norfloxacin plus intravenous ceftriaxone 2 g daily during the first 3 days of admission. ### results Ten patients were excluded because of community-acquired infection, surgery, or death within the first 24 h. The incidence of bacterial infections during hospitalization was 18.1% in group 1 and 12.5% in group 2 (p = NS). The incidence of severe infections (spontaneous bacterial peritonitis, bacteremia, or pneumonia) was also similar in both groups: 9% in group 1 versus 8.3% in group 2 (p = NS). There were no statistical differences between the two groups with respect to duration of hospitalization or mortality. The cost of antibiotic therapy (including prophylaxis and treatment of infections) was significantly higher in group 2. ### conclusion These results suggest that the addition of intravenous ceftriaxone during the first 3 days of hospitalization does not improve the cost-efficacy of oral norfloxacin in the prevention of bacterial infections in cirrhotic patients with gastrointestinal bleeding and high risk of infection . ### Response: ceftriaxone, norfloxacin

056c7e350cc7a5271279359bfcf3bc9d

However , clindamycin possesses only one of the two mechanisms of lincomycin action , which is bacteriostatic , against Escherichia coli .

Microbial kinetics of drug action against gram-positive and gram-negative organisms. III: Effect of lincomycin and clindamycin combinations on Staphylococcus aureus and Escherichia coli. The functional dependencies of apparent first-order generation rate constants kapp, of drug-affected cultures on drug concentrations indicate that lincomycin and clindamycin possess the same mechanism of action, which is bacteriostatic, against Staphylococcus aureus. clindamycin also possesses another mechanism of action, which is bactericidal, at high concentration levels. However , clindamycin possesses only one of the two mechanisms of lincomycin action , which is bacteriostatic , against Escherichia coli . The relative potency of action of a clindamycin-lincomycin combination against Staph. aureus is variable, and the effective ratio ranges between 5:1 and 9:1; the effective ratio against E. coli is fixed at 6:1 over a wide concentration range. This difference is attributed to differences in bioavailability and/or binding characteristics of the drugs for bioreceptors, as a consequence of structural modifications in the drug molecules, and to differences in modes of action in the respective organisms. Mixtures containing equipotent fractions of clindamycin and lincomycin show "equivalence" or "indifference" of effects on Staph. aureus. The combined action of the mixtures can be quantitatively predicted from the separate dose-response curves of either component drug alone. Therefore, it is concluded that clindamycin and lincomycin may bind to the same receptor site that is engaged in microbial protein synthesis to inhibit the generation of Staph. aureus. However, combinations of clindamycin and lincomycin are less active than the a priori equipotent concentration of either drug alone in their action against E. coli, demonstrating unequivocally an antagonism of effects. Furthermore, the degree of antagonism is dependent on the order of addition of the drugs, which is attributed to the possibility that clindamycin and lincomycin bind differently on active and allosteric loci of the same receptor site functionally engaged in protein synthesis in E. coli. A rational approach to the quantification and prediction of combined antibiotic action must, therefore, be based not only on the kinetics and mechanisms of action as well as on the dose-response relationship over a wide concentration range for the separate antibiotics but also on the strain and species of the test organism.

https://pubmed.ncbi.nlm.nih.gov/1102659/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Microbial kinetics of drug action against gram-positive and gram-negative organisms. III: Effect of lincomycin and clindamycin combinations on Staphylococcus aureus and Escherichia coli. The functional dependencies of apparent first-order generation rate constants kapp, of drug-affected cultures on drug concentrations indicate that lincomycin and clindamycin possess the same mechanism of action, which is bacteriostatic, against Staphylococcus aureus. clindamycin also possesses another mechanism of action, which is bactericidal, at high concentration levels. However , clindamycin possesses only one of the two mechanisms of lincomycin action , which is bacteriostatic , against Escherichia coli . The relative potency of action of a clindamycin-lincomycin combination against Staph. aureus is variable, and the effective ratio ranges between 5:1 and 9:1; the effective ratio against E. coli is fixed at 6:1 over a wide concentration range. This difference is attributed to differences in bioavailability and/or binding characteristics of the drugs for bioreceptors, as a consequence of structural modifications in the drug molecules, and to differences in modes of action in the respective organisms. Mixtures containing equipotent fractions of clindamycin and lincomycin show "equivalence" or "indifference" of effects on Staph. aureus. The combined action of the mixtures can be quantitatively predicted from the separate dose-response curves of either component drug alone. Therefore, it is concluded that clindamycin and lincomycin may bind to the same receptor site that is engaged in microbial protein synthesis to inhibit the generation of Staph. aureus. However, combinations of clindamycin and lincomycin are less active than the a priori equipotent concentration of either drug alone in their action against E. coli, demonstrating unequivocally an antagonism of effects. Furthermore, the degree of antagonism is dependent on the order of addition of the drugs, which is attributed to the possibility that clindamycin and lincomycin bind differently on active and allosteric loci of the same receptor site functionally engaged in protein synthesis in E. coli. A rational approach to the quantification and prediction of combined antibiotic action must, therefore, be based not only on the kinetics and mechanisms of action as well as on the dose-response relationship over a wide concentration range for the separate antibiotics but also on the strain and species of the test organism. ### Response: clindamycin, lincomycin

64f929edb877af3cddf0c724ad66a1ba

This study evaluated the response rate of the combination therapy of aprinocarsen , gemcitabine , and carboplatin in previously untreated patients with advanced non-small cell lung cancer ( NSCLC ) .

Phase II study of PKC-alpha antisense oligonucleotide aprinocarsen in combination with gemcitabine and carboplatin in patients with advanced non-small cell lung cancer. The antisense oligonucleotide aprinocarsen specifically inhibits the transcription of protein kinase C-alpha. This study evaluated the response rate of the combination therapy of aprinocarsen , gemcitabine , and carboplatin in previously untreated patients with advanced non-small cell lung cancer ( NSCLC ) . Secondary objectives included the measurement of time-to-event efficacy parameters and toxicity. Patients with stage IV or stage IIIB disease (N(3) and/or pleural/pericardial effusion) were treated with gemcitabine 1,250 mg/m(2) on days 1 and 8 and carboplatin AUC 5 on day 1 every 21 days. Aprinocarsen was administered as 2mg/kg/day continuous iv infusion on the first 14 days of each cycle, following the carboplatin treatment. A total of 36 patients received a median of 3 treatment cycles, with 10 patients completing 6 cycles. No complete response was observed, while partial response was seen in 25% of patients. Stable disease and progressive disease was observed in 36.1% and 22.2% of patients. The median overall survival was 8.3 months, and the median duration of progression-free survival was 5.7 months (95% CI, 3.2-7.1 months). Thrombocytopenia (78%) and neutropenia (50%) were the major grade 3/4 toxicities. Enrollment for this study was stopped and the study was terminated in March 2003 due to the results of a large phase III study, which suggested that aprinocarsen did not improve response or add survival benefit to chemotherapy in advanced NSCLC. The addition of aprinocarsen to gemcitabine+carboplatin therapy in patients with NSCLC showed moderate activity. However, this combination resulted in severe thrombocytopenia in the majority of patients.

https://pubmed.ncbi.nlm.nih.gov/16507327/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Phase II study of PKC-alpha antisense oligonucleotide aprinocarsen in combination with gemcitabine and carboplatin in patients with advanced non-small cell lung cancer. The antisense oligonucleotide aprinocarsen specifically inhibits the transcription of protein kinase C-alpha. This study evaluated the response rate of the combination therapy of aprinocarsen , gemcitabine , and carboplatin in previously untreated patients with advanced non-small cell lung cancer ( NSCLC ) . Secondary objectives included the measurement of time-to-event efficacy parameters and toxicity. Patients with stage IV or stage IIIB disease (N(3) and/or pleural/pericardial effusion) were treated with gemcitabine 1,250 mg/m(2) on days 1 and 8 and carboplatin AUC 5 on day 1 every 21 days. Aprinocarsen was administered as 2mg/kg/day continuous iv infusion on the first 14 days of each cycle, following the carboplatin treatment. A total of 36 patients received a median of 3 treatment cycles, with 10 patients completing 6 cycles. No complete response was observed, while partial response was seen in 25% of patients. Stable disease and progressive disease was observed in 36.1% and 22.2% of patients. The median overall survival was 8.3 months, and the median duration of progression-free survival was 5.7 months (95% CI, 3.2-7.1 months). Thrombocytopenia (78%) and neutropenia (50%) were the major grade 3/4 toxicities. Enrollment for this study was stopped and the study was terminated in March 2003 due to the results of a large phase III study, which suggested that aprinocarsen did not improve response or add survival benefit to chemotherapy in advanced NSCLC. The addition of aprinocarsen to gemcitabine+carboplatin therapy in patients with NSCLC showed moderate activity. However, this combination resulted in severe thrombocytopenia in the majority of patients. ### Response: aprinocarsen, gemcitabine, carboplatin

e227b7bceedb8122b04c7d13e3ee098c

All patients were treated by surgical debridement followed by a combination of antibiotics ; ( ceftazidime , amoxy-clavulanic acid , co-trimoxazole and doxycycline ) for six months except for one who died due to fulminant septicemia .

Burkholderia pseudomallei musculoskeletal infections (melioidosis) in India. Melioidosis, an infection due to gram negative Burkholderia pseudomallei, is an important cause of sepsis in east Asia especially Thailand and northern Australia. It usually causes abscesses in lung, liver, spleen, skeletal muscle and parotids especially in patients with diabetes, chronic renal failure and thalassemia. Musculoskeletal melioidosis is not common in India even though sporadic cases have been reported mostly involving soft tissues. During a two-year-period, we had five patients with musculoskeletal melioidosis. All patients presented with multifocal osteomyelitis, recurrent osteomyelitis or septic arthritis. One patient died early because of septicemia and multi-organ failure. All patients were diagnosed on the basis of positive pus culture. All patients were treated by surgical debridement followed by a combination of antibiotics ; ( ceftazidime , amoxy-clavulanic acid , co-trimoxazole and doxycycline ) for six months except for one who died due to fulminant septicemia . All other patients recovered completely with no recurrences. With increasing awareness and better diagnostic facilities, probably musculoskeletal melioidosis will be increasingly diagnosed in future.

https://pubmed.ncbi.nlm.nih.gov/20419012/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Burkholderia pseudomallei musculoskeletal infections (melioidosis) in India. Melioidosis, an infection due to gram negative Burkholderia pseudomallei, is an important cause of sepsis in east Asia especially Thailand and northern Australia. It usually causes abscesses in lung, liver, spleen, skeletal muscle and parotids especially in patients with diabetes, chronic renal failure and thalassemia. Musculoskeletal melioidosis is not common in India even though sporadic cases have been reported mostly involving soft tissues. During a two-year-period, we had five patients with musculoskeletal melioidosis. All patients presented with multifocal osteomyelitis, recurrent osteomyelitis or septic arthritis. One patient died early because of septicemia and multi-organ failure. All patients were diagnosed on the basis of positive pus culture. All patients were treated by surgical debridement followed by a combination of antibiotics ; ( ceftazidime , amoxy-clavulanic acid , co-trimoxazole and doxycycline ) for six months except for one who died due to fulminant septicemia . All other patients recovered completely with no recurrences. With increasing awareness and better diagnostic facilities, probably musculoskeletal melioidosis will be increasingly diagnosed in future. ### Response: ceftazidime, amoxy-clavulanic, co-trimoxazole, doxycycline

6d21b8fb44aec53cfdf566e8d7e95b68

To evaluate the eradication of Helicobacter pylori by therapy with a combination of 60 mg lansoprazole and 800 mg clarithromycin .

Dual therapy with lansoprazole and clarithromycin for eradication of Helicobacter pylori. To evaluate the eradication of Helicobacter pylori by therapy with a combination of 60 mg lansoprazole and 800 mg clarithromycin . ### Patients And Methods In an open therapeutic trial, 30 H. pylori-positive patients with active ulcer disease took 30 mg lansoprazole twice a day and 400 mg clarithromycin twice a day for the first 2 weeks, followed by 30 mg lansoprazole once a day for 4-6 weeks. Endoscopy was performed both before and at the end of therapy, and 4 weeks after the end of the therapy. H. pylori was detected by using a combination of smear, culture and tissue sections. ### results Complete pain relief occurred within 3 days in all patients and all ulcers were healed by the end of the therapy. The H. pylori clearance rate was 83.3% and the eradication rate was 73.3%. A minor side effect (metallic taste) was reported by only one patient (3.3%). ### conclusions Therapy with a combination of 60 mg lansoprazole and 800 mg clarithromycin is efficacious in the eradication of H. pylori and has the advantage of a low incidence of side effects and quick pain relief for patients with active ulcers.

https://pubmed.ncbi.nlm.nih.gov/8574739/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Dual therapy with lansoprazole and clarithromycin for eradication of Helicobacter pylori. To evaluate the eradication of Helicobacter pylori by therapy with a combination of 60 mg lansoprazole and 800 mg clarithromycin . ### Patients And Methods In an open therapeutic trial, 30 H. pylori-positive patients with active ulcer disease took 30 mg lansoprazole twice a day and 400 mg clarithromycin twice a day for the first 2 weeks, followed by 30 mg lansoprazole once a day for 4-6 weeks. Endoscopy was performed both before and at the end of therapy, and 4 weeks after the end of the therapy. H. pylori was detected by using a combination of smear, culture and tissue sections. ### results Complete pain relief occurred within 3 days in all patients and all ulcers were healed by the end of the therapy. The H. pylori clearance rate was 83.3% and the eradication rate was 73.3%. A minor side effect (metallic taste) was reported by only one patient (3.3%). ### conclusions Therapy with a combination of 60 mg lansoprazole and 800 mg clarithromycin is efficacious in the eradication of H. pylori and has the advantage of a low incidence of side effects and quick pain relief for patients with active ulcers. ### Response: lansoprazole, clarithromycin

91620a03f158f1956c52f44f1dcf437d

All patients were treated with vincristine , doxorubicin , cyclophosphamide and actinomycin-D , alternating with ifosfamide and etoposide every 3 weeks .

Extraskeletal Ewing's sarcoma family of tumors in adults: prognostic factors and clinical outcome. The aim of this study was to evaluate prognostic factors, survival rate and the efficacy of the treatment modalities used in patients with extraskeletal Ewing's sarcoma. ### methods Data of patients with extraskeletal Ewing's sarcoma followed up at our center between 1997 and 2010 were retrospectively analyzed. ### results The median age of 27 patients was 24 years (range, 16-54 years). The median follow-up was 31.8 months (range, 6-144 months). Tumor size was between 1.5 and 14 cm (median: 8 cm). Eighty-five percent of patients had localized disease at presentation and 15% had metastatic disease. Local therapy was surgery alone in 16% of patients, surgery combined with radiotherapy in 42% and radiotherapy alone in 27%. All patients were treated with vincristine , doxorubicin , cyclophosphamide and actinomycin-D , alternating with ifosfamide and etoposide every 3 weeks . In patients with localized disease at presentation, the 5-year event-free survival and overall survival were 59.7 and 64.5%, respectively. At univariate analysis, patients with tumor size ≥ 8 cm, high serum lactate dehydrogenase, metastasis at presentation, poor histological response to chemotherapy and positive surgical margin had significantly worse event-free survival. The significant predictors of worse overall survival at univariate analysis were tumor size 8 ≥ cm, high lactate dehydrogenase, metastasis at presentation, poor histological response to chemotherapy, radiotherapy only as local treatment and positive surgical margin. ### conclusions Prognostic factors were similar to primary osseous Ewing's sarcomas. Adequate surgical resection, aggressive chemotherapy (vincristine, doxorubicin, cyclophosphamide and actinomycin-D alternating with ifosfamide and etoposide) and radiotherapy if indicated are the recommended therapy for patients with extraskeletal Ewing's sarcoma.

https://pubmed.ncbi.nlm.nih.gov/22416252/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Extraskeletal Ewing's sarcoma family of tumors in adults: prognostic factors and clinical outcome. The aim of this study was to evaluate prognostic factors, survival rate and the efficacy of the treatment modalities used in patients with extraskeletal Ewing's sarcoma. ### methods Data of patients with extraskeletal Ewing's sarcoma followed up at our center between 1997 and 2010 were retrospectively analyzed. ### results The median age of 27 patients was 24 years (range, 16-54 years). The median follow-up was 31.8 months (range, 6-144 months). Tumor size was between 1.5 and 14 cm (median: 8 cm). Eighty-five percent of patients had localized disease at presentation and 15% had metastatic disease. Local therapy was surgery alone in 16% of patients, surgery combined with radiotherapy in 42% and radiotherapy alone in 27%. All patients were treated with vincristine , doxorubicin , cyclophosphamide and actinomycin-D , alternating with ifosfamide and etoposide every 3 weeks . In patients with localized disease at presentation, the 5-year event-free survival and overall survival were 59.7 and 64.5%, respectively. At univariate analysis, patients with tumor size ≥ 8 cm, high serum lactate dehydrogenase, metastasis at presentation, poor histological response to chemotherapy and positive surgical margin had significantly worse event-free survival. The significant predictors of worse overall survival at univariate analysis were tumor size 8 ≥ cm, high lactate dehydrogenase, metastasis at presentation, poor histological response to chemotherapy, radiotherapy only as local treatment and positive surgical margin. ### conclusions Prognostic factors were similar to primary osseous Ewing's sarcomas. Adequate surgical resection, aggressive chemotherapy (vincristine, doxorubicin, cyclophosphamide and actinomycin-D alternating with ifosfamide and etoposide) and radiotherapy if indicated are the recommended therapy for patients with extraskeletal Ewing's sarcoma. ### Response: vincristine, doxorubicin, cyclophosphamide, actinomycin-D, ifosfamide, etoposide

512ff22c22b6761f2530a2a9e49dbf3c

We identified 49 and 220 patients treated with sorafenib and sunitinib , respectively , as first-line therapy in the Asan Medical Centre from April 2005 to March 2011 .

Comparative efficacy of sunitinib versus sorafenib as first-line treatment for patients with metastatic renal cell carcinoma. This study investigated the efficacy and toxicity of sorafenib and sunitinib as primary treatment for patients with metastatic renal cell carcinoma (mRCC). ### methods We identified 49 and 220 patients treated with sorafenib and sunitinib , respectively , as first-line therapy in the Asan Medical Centre from April 2005 to March 2011 . ### results Disease control rates of 71 and 74% were achieved with sorafenib and sunitinib, respectively (p = 0.687). After a median follow-up of 27.6 months, progression-free survival (PFS) and overall survival (OS) were not significantly different between the sorafenib and the sunitinib group (PFS 8.6 vs. 9.9 months, respectively, p = 0.948, and OS 25.7 vs. 22.6 months, p = 0.774). Patients treated with sorafenib required dose reduction due to toxicities less frequently than those treated with sunitinib (37 vs. 54%, p = 0.034). Haematological toxicity of grade 3 or 4 was more common in the sunitinib group than in the sorafenib group (45 vs. 4%, p < 0.001). Multivariate analysis showed old age, Heng's risk group, and bone and liver metastases, but not the type of vascular endothelial growth factor tyrosine kinase inhibitor, were independent prognostic factors affecting OS. ### conclusion The results of this study indicate that sorafenib has comparable efficacy to sunitinib in the treatment of mRCC patients and fewer and less severe toxicities, but the number of patients included in the study was small.

https://pubmed.ncbi.nlm.nih.gov/23548259/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Comparative efficacy of sunitinib versus sorafenib as first-line treatment for patients with metastatic renal cell carcinoma. This study investigated the efficacy and toxicity of sorafenib and sunitinib as primary treatment for patients with metastatic renal cell carcinoma (mRCC). ### methods We identified 49 and 220 patients treated with sorafenib and sunitinib , respectively , as first-line therapy in the Asan Medical Centre from April 2005 to March 2011 . ### results Disease control rates of 71 and 74% were achieved with sorafenib and sunitinib, respectively (p = 0.687). After a median follow-up of 27.6 months, progression-free survival (PFS) and overall survival (OS) were not significantly different between the sorafenib and the sunitinib group (PFS 8.6 vs. 9.9 months, respectively, p = 0.948, and OS 25.7 vs. 22.6 months, p = 0.774). Patients treated with sorafenib required dose reduction due to toxicities less frequently than those treated with sunitinib (37 vs. 54%, p = 0.034). Haematological toxicity of grade 3 or 4 was more common in the sunitinib group than in the sorafenib group (45 vs. 4%, p < 0.001). Multivariate analysis showed old age, Heng's risk group, and bone and liver metastases, but not the type of vascular endothelial growth factor tyrosine kinase inhibitor, were independent prognostic factors affecting OS. ### conclusion The results of this study indicate that sorafenib has comparable efficacy to sunitinib in the treatment of mRCC patients and fewer and less severe toxicities, but the number of patients included in the study was small. ### Response: sorafenib, sunitinib

f14c3c8dadbef1d8912067d367d600b3

We studied the combination of pemetrexed , a multi-targeted antifolate , and cetuximab , an mAb against the epidermal growth factor receptor , with radiotherapy in poor prognosis head and neck cancer .

Phase I trial of pemetrexed in combination with cetuximab and concurrent radiotherapy in patients with head and neck cancer. We studied the combination of pemetrexed , a multi-targeted antifolate , and cetuximab , an mAb against the epidermal growth factor receptor , with radiotherapy in poor prognosis head and neck cancer . ### Patients And Methods Patients received pemetrexed on days 1, 22, and 43 on a dose-escalation scheme with starting level (0) 350 mg/m(2) (level -1, 200 mg/m(2); level +1, 500 mg/m(2)) with concurrent radiotherapy (2 Gy/day) and cetuximab in two separate cohorts, not previously irradiated (A) and previously irradiated (B), who received 70 and 60-66 Gy, respectively. Genetic polymorphisms of thymidylate synthase and methylenetetrahydrofolate reductase were evaluated. ### results Thirty-two patients were enrolled. The maximum tolerated dose of pemetrexed was 500 mg/m(2) in cohort A and 350 mg/m(2) in cohort B. Prophylactic antibiotics were required. In cohort A, two dose-limiting toxicities (DLTs) occurred (febrile neutropenia), one each at levels 0 and +1. In cohort B, two DLTs occurred at level +1 (febrile neutropenia; death from perforated duodenal ulcer and sepsis). Grade 3 mucositis was common. No association of gene polymorphisms with toxicity or efficacy was evident. ### conclusion The addition of pemetrexed 500 mg/m(2) to cetuximab and radiotherapy is recommended for further study in not previously irradiated patients.

https://pubmed.ncbi.nlm.nih.gov/21363880/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Phase I trial of pemetrexed in combination with cetuximab and concurrent radiotherapy in patients with head and neck cancer. We studied the combination of pemetrexed , a multi-targeted antifolate , and cetuximab , an mAb against the epidermal growth factor receptor , with radiotherapy in poor prognosis head and neck cancer . ### Patients And Methods Patients received pemetrexed on days 1, 22, and 43 on a dose-escalation scheme with starting level (0) 350 mg/m(2) (level -1, 200 mg/m(2); level +1, 500 mg/m(2)) with concurrent radiotherapy (2 Gy/day) and cetuximab in two separate cohorts, not previously irradiated (A) and previously irradiated (B), who received 70 and 60-66 Gy, respectively. Genetic polymorphisms of thymidylate synthase and methylenetetrahydrofolate reductase were evaluated. ### results Thirty-two patients were enrolled. The maximum tolerated dose of pemetrexed was 500 mg/m(2) in cohort A and 350 mg/m(2) in cohort B. Prophylactic antibiotics were required. In cohort A, two dose-limiting toxicities (DLTs) occurred (febrile neutropenia), one each at levels 0 and +1. In cohort B, two DLTs occurred at level +1 (febrile neutropenia; death from perforated duodenal ulcer and sepsis). Grade 3 mucositis was common. No association of gene polymorphisms with toxicity or efficacy was evident. ### conclusion The addition of pemetrexed 500 mg/m(2) to cetuximab and radiotherapy is recommended for further study in not previously irradiated patients. ### Response: pemetrexed, cetuximab

e0cba36b58781c2288d8448732651b68

Boosting darunavir with ritonavir instead of with cobicistat may be preferred if darunavir is to be combined with etravirine in clinical practice .

Pharmacokinetics of darunavir/cobicistat and etravirine alone and co-administered in HIV-infected patients. To determine the effect of etravirine on the pharmacokinetics of darunavir/cobicistat and vice versa. Safety and tolerability of this combination were also evaluated. ### methods Open-label, fixed-sequence trial in two cohorts of HIV-infected patients on therapy with darunavir/cobicistat 800/150 mg once daily (DRV cohort; n = 15) or etravirine 400 mg once daily (ETR cohort; n = 15). etravirine or darunavir/cobicistat were added on days 1-14 and 1-7 in participants in the DRV or ETR cohort, respectively. Full pharmacokinetic profiles were obtained on days 0 and 14 in the DRV cohort, and on days 0 and 7 in the ETR cohort. darunavir, cobicistat and etravirine pharmacokinetic parameters [AUC0-24, Cmax and trough concentrations in plasma (C24)] were calculated for each individual by non-compartmental analysis and were compared using linear mixed-effects models. Adverse events and HIV-1 RNA in plasma were monitored. ### results etravirine co-administration decreased cobicistat AUC0-24, Cmax and C24 by 30%, 14% and 66%, respectively. Although darunavir AUC0-24 and Cmax were unchanged by etravirine, darunavir C24 was 56% lower for darunavir/cobicistat co-administered with etravirine relative to darunavir/cobicistat alone. etravirine pharmacokinetics were unchanged by darunavir/cobicistat. Treatments were well tolerated, and HIV-1 RNA remained undetectable in all participants. ### conclusions Although etravirine pharmacokinetics was unchanged by darunavir/cobicistat, there was a significant decrease in cobicistat exposure and in darunavir C24 when darunavir/cobicistat was co-administered with etravirine. Boosting darunavir with ritonavir instead of with cobicistat may be preferred if darunavir is to be combined with etravirine in clinical practice .

https://pubmed.ncbi.nlm.nih.gov/29237008/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Pharmacokinetics of darunavir/cobicistat and etravirine alone and co-administered in HIV-infected patients. To determine the effect of etravirine on the pharmacokinetics of darunavir/cobicistat and vice versa. Safety and tolerability of this combination were also evaluated. ### methods Open-label, fixed-sequence trial in two cohorts of HIV-infected patients on therapy with darunavir/cobicistat 800/150 mg once daily (DRV cohort; n = 15) or etravirine 400 mg once daily (ETR cohort; n = 15). etravirine or darunavir/cobicistat were added on days 1-14 and 1-7 in participants in the DRV or ETR cohort, respectively. Full pharmacokinetic profiles were obtained on days 0 and 14 in the DRV cohort, and on days 0 and 7 in the ETR cohort. darunavir, cobicistat and etravirine pharmacokinetic parameters [AUC0-24, Cmax and trough concentrations in plasma (C24)] were calculated for each individual by non-compartmental analysis and were compared using linear mixed-effects models. Adverse events and HIV-1 RNA in plasma were monitored. ### results etravirine co-administration decreased cobicistat AUC0-24, Cmax and C24 by 30%, 14% and 66%, respectively. Although darunavir AUC0-24 and Cmax were unchanged by etravirine, darunavir C24 was 56% lower for darunavir/cobicistat co-administered with etravirine relative to darunavir/cobicistat alone. etravirine pharmacokinetics were unchanged by darunavir/cobicistat. Treatments were well tolerated, and HIV-1 RNA remained undetectable in all participants. ### conclusions Although etravirine pharmacokinetics was unchanged by darunavir/cobicistat, there was a significant decrease in cobicistat exposure and in darunavir C24 when darunavir/cobicistat was co-administered with etravirine. Boosting darunavir with ritonavir instead of with cobicistat may be preferred if darunavir is to be combined with etravirine in clinical practice . ### Response: darunavir, ritonavir, cobicistat, darunavir, etravirine

6281f828d97fd01753786d649998ee0f

Single-agent paclitaxel and vinorelbine are recommended treatments for advanced breast cancer ( ABC ) non-responsive to hormone therapy and without visceral crisis .

Randomized phase II study evaluating weekly oral vinorelbine versus weekly paclitaxel in estrogen receptor-positive, HER2-negative patients with advanced breast cancer (NorBreast-231 trial). Single-agent paclitaxel and vinorelbine are recommended treatments for advanced breast cancer ( ABC ) non-responsive to hormone therapy and without visceral crisis . This phase II trial compared first-line oral vinorelbine versus weekly paclitaxel for ABC. ### methods Eligible female patients had measurable locally recurrent/metastatic estrogen receptor-positive HER2-negative breast cancer and had received prior endocrine therapy (any setting) but no chemotherapy for ABC. Patients were stratified by prior taxane and visceral metastases and randomized to either oral vinorelbine 80 mg/m ### results The 131 randomized patients had received a median of 2 prior endocrine therapies; >70% had prior (neo)adjuvant chemotherapy and 79% visceral metastases. DCR was 75.8% (95% confidence interval: 63.6-85.5%) with vinorelbine and 75.4% (63.1-85.2%) with paclitaxel. The most common grade 3/4 adverse events were neutropenia (52%), fatigue (11%), and vomiting (5%) with vinorelbine, and neutropenia (17%), dyspnea (6%), hypertension (6%), and peripheral sensory neuropathy (5%) with paclitaxel. Grade 2 alopecia occurred in 2% of vinorelbine-treated and 34% of paclitaxel-treated patients. Neither arm showed relevant global health status changes. ### conclusion Oral vinorelbine and paclitaxel demonstrated similar DCRs (∼75%). Safety profiles differed and, together with administration route and convenience, may influence treatment choice (EudraCT number, 2012-003530-16).

https://pubmed.ncbi.nlm.nih.gov/30802822/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Randomized phase II study evaluating weekly oral vinorelbine versus weekly paclitaxel in estrogen receptor-positive, HER2-negative patients with advanced breast cancer (NorBreast-231 trial). Single-agent paclitaxel and vinorelbine are recommended treatments for advanced breast cancer ( ABC ) non-responsive to hormone therapy and without visceral crisis . This phase II trial compared first-line oral vinorelbine versus weekly paclitaxel for ABC. ### methods Eligible female patients had measurable locally recurrent/metastatic estrogen receptor-positive HER2-negative breast cancer and had received prior endocrine therapy (any setting) but no chemotherapy for ABC. Patients were stratified by prior taxane and visceral metastases and randomized to either oral vinorelbine 80 mg/m ### results The 131 randomized patients had received a median of 2 prior endocrine therapies; >70% had prior (neo)adjuvant chemotherapy and 79% visceral metastases. DCR was 75.8% (95% confidence interval: 63.6-85.5%) with vinorelbine and 75.4% (63.1-85.2%) with paclitaxel. The most common grade 3/4 adverse events were neutropenia (52%), fatigue (11%), and vomiting (5%) with vinorelbine, and neutropenia (17%), dyspnea (6%), hypertension (6%), and peripheral sensory neuropathy (5%) with paclitaxel. Grade 2 alopecia occurred in 2% of vinorelbine-treated and 34% of paclitaxel-treated patients. Neither arm showed relevant global health status changes. ### conclusion Oral vinorelbine and paclitaxel demonstrated similar DCRs (∼75%). Safety profiles differed and, together with administration route and convenience, may influence treatment choice (EudraCT number, 2012-003530-16). ### Response: paclitaxel, vinorelbine

f2c019857efd32ae3b64a68ef6a2ecd0

Nal-IRI with 5-fluorouracil ( 5-FU ) and leucovorin or gemcitabine plus cisplatin in advanced biliary tract cancer - the NIFE trial ( AIO-YMO HEP-0315 )

Nal-IRI with 5-fluorouracil ( 5-FU ) and leucovorin or gemcitabine plus cisplatin in advanced biliary tract cancer - the NIFE trial ( AIO-YMO HEP-0315 ) Biliary tract cancer (BTC) has a high mortality. Primary diagnosis is frequently delayed due to mostly unspecific symptoms, resulting in a high number of advanced cases at the time of diagnosis. Advanced BTCs are in principle chemotherapy sensitive as determined by improved disease control, survival and quality of life (QoL). However, median OS does not exceed 11.7 months with the current standard of care gemcitabine plus cisplatin. Thereby, novel drug formulations like nanoliposomal-irinotecan (nal-IRI) in combination with 5- fluorouracil (5-FU)/leucovorin may have the potential to improve therapeutic outcomes in this disease. ### methods NIFE is an interventional, prospective, randomized, controlled, open label, two-sided phase II study. Within the study, 2 × 46 patients with locally advanced, non-resectable or metastatic BTC are to be enrolled by two stage design of Simon. Data analysis will be done unconnected for both arms. Patients are allocated in two arms: Arm A (experimental intervention) nal-IRI mg/m ### discussion The NIFE trial evaluates the potential of a nanoliposomal-irinotecan/5-FU/leucovorin combination in the first line therapy of advanced BTCs and additionally offers a unique chance for translational research. ### Trial Registration Clinicaltrials.gov NCT03044587. Registration Date February 7th 2017.

https://pubmed.ncbi.nlm.nih.gov/31646981/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Nal-IRI with 5-fluorouracil ( 5-FU ) and leucovorin or gemcitabine plus cisplatin in advanced biliary tract cancer - the NIFE trial ( AIO-YMO HEP-0315 ) Biliary tract cancer (BTC) has a high mortality. Primary diagnosis is frequently delayed due to mostly unspecific symptoms, resulting in a high number of advanced cases at the time of diagnosis. Advanced BTCs are in principle chemotherapy sensitive as determined by improved disease control, survival and quality of life (QoL). However, median OS does not exceed 11.7 months with the current standard of care gemcitabine plus cisplatin. Thereby, novel drug formulations like nanoliposomal-irinotecan (nal-IRI) in combination with 5- fluorouracil (5-FU)/leucovorin may have the potential to improve therapeutic outcomes in this disease. ### methods NIFE is an interventional, prospective, randomized, controlled, open label, two-sided phase II study. Within the study, 2 × 46 patients with locally advanced, non-resectable or metastatic BTC are to be enrolled by two stage design of Simon. Data analysis will be done unconnected for both arms. Patients are allocated in two arms: Arm A (experimental intervention) nal-IRI mg/m ### discussion The NIFE trial evaluates the potential of a nanoliposomal-irinotecan/5-FU/leucovorin combination in the first line therapy of advanced BTCs and additionally offers a unique chance for translational research. ### Trial Registration Clinicaltrials.gov NCT03044587. Registration Date February 7th 2017. ### Response: 5-fluorouracil, leucovorin, gemcitabine, cisplatin

3d1b9b7ba6eec890228902c4011a7d7f

Ten patients were withdrawn from the terbutaline group because treatment was insufficiently effective , whereas only one dropped out of the budesonide group .

Comparison of a beta 2-agonist, terbutaline, with an inhaled corticosteroid, budesonide, in newly detected asthma. The presence of airway inflammation even in mild asthma points to the potential value of antiinflammatory therapy. We compared the effect of an inhaled corticosteroid, budesonide, with that of an inhaled beta 2-agonist, terbutaline, in the long-term treatment of newly detected asthma. ### methods We studied 103 patients (29 male and 74 female patients 15 to 64 years old) in whom asthma had appeared within the previous year. The patients were randomly assigned in blinded fashion to two treatment groups: one to receive 600 micrograms of inhaled budesonide twice a day, and the other to receive 375 micrograms of inhaled terbutaline twice a day. The study period was two years. ### results After six weeks of treatment, the patients treated with budesonide tolerated inhaled histamine better than the patients treated with terbutaline (a difference of one doubling dose step, P less than 0.001), and the difference was sustained. Patients' diaries kept during the first three months of the study and during the last month of the first and second years showed budesonide to be more effective than terbutaline in improving peak expiratory flow in the morning (average increase from the pretreatment value, 32.8 liters per minute for budesonide vs. 4.8 liters per minute for terbutaline; P less than 0.001) and in the evening (P less than 0.01). budesonide was also more effective in reducing the symptoms of asthma (P less than 0.01) and the use of supplemental beta 2-agonist medication (P less than 0.01). Ten patients were withdrawn from the terbutaline group because treatment was insufficiently effective , whereas only one dropped out of the budesonide group . The adverse reactions to both treatments were few and mild. ### conclusions Antiinflammatory therapy with inhaled budesonide is an effective first-line treatment for patients with newly detected, mild asthma, and it is superior to the use of terbutaline in such patients.

https://pubmed.ncbi.nlm.nih.gov/2062329/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Comparison of a beta 2-agonist, terbutaline, with an inhaled corticosteroid, budesonide, in newly detected asthma. The presence of airway inflammation even in mild asthma points to the potential value of antiinflammatory therapy. We compared the effect of an inhaled corticosteroid, budesonide, with that of an inhaled beta 2-agonist, terbutaline, in the long-term treatment of newly detected asthma. ### methods We studied 103 patients (29 male and 74 female patients 15 to 64 years old) in whom asthma had appeared within the previous year. The patients were randomly assigned in blinded fashion to two treatment groups: one to receive 600 micrograms of inhaled budesonide twice a day, and the other to receive 375 micrograms of inhaled terbutaline twice a day. The study period was two years. ### results After six weeks of treatment, the patients treated with budesonide tolerated inhaled histamine better than the patients treated with terbutaline (a difference of one doubling dose step, P less than 0.001), and the difference was sustained. Patients' diaries kept during the first three months of the study and during the last month of the first and second years showed budesonide to be more effective than terbutaline in improving peak expiratory flow in the morning (average increase from the pretreatment value, 32.8 liters per minute for budesonide vs. 4.8 liters per minute for terbutaline; P less than 0.001) and in the evening (P less than 0.01). budesonide was also more effective in reducing the symptoms of asthma (P less than 0.01) and the use of supplemental beta 2-agonist medication (P less than 0.01). Ten patients were withdrawn from the terbutaline group because treatment was insufficiently effective , whereas only one dropped out of the budesonide group . The adverse reactions to both treatments were few and mild. ### conclusions Antiinflammatory therapy with inhaled budesonide is an effective first-line treatment for patients with newly detected, mild asthma, and it is superior to the use of terbutaline in such patients. ### Response: terbutaline, budesonide

d2ab326fb295d3755d481670624d8d1a

We conducted a double-blind cross-over study in ten volunteers aged from 19 to 30 years , to compare the pain control effects of a single oral dose of two analgesic compounds ( drug A : propyphenazone mg 250 , ethylmorphine mg 5 , caffeine mg 5 ; drug B : dipyrone mg 500 , diphenhydramine mg 12.5 , adiphenine mg 5 , ethyl aminobenzoate mg 2.5 ) in an experimental pain model using stimulation of dental pulp .

[Electric stimulation of the dental pulp in the evaluation of the central effect of analgesics]. We conducted a double-blind cross-over study in ten volunteers aged from 19 to 30 years , to compare the pain control effects of a single oral dose of two analgesic compounds ( drug A : propyphenazone mg 250 , ethylmorphine mg 5 , caffeine mg 5 ; drug B : dipyrone mg 500 , diphenhydramine mg 12.5 , adiphenine mg 5 , ethyl aminobenzoate mg 2.5 ) in an experimental pain model using stimulation of dental pulp . Constant voltage stimuli were delivered through silver chloride electrodes placed in contact with the vestibular surface of the upper medial incisor. At the beginning of the session, the pain input was graded by asking the subject to identify the weakest stimulus perceived (threshold level) and the strongest stimulus endurable (tolerance level). The range between threshold and tolerance level was divided in nine steps plus a subliminal step. The ten steps were delivered randomly, and each series of steps was repeated eight times. The subjects were instructed to rate the pain sensation in an arbitrary scale of 5 degrees. The procedure was repeated at 60 min and 180 min after drug administration. Each subject received two tablets of drug A or drug B in two different sessions at weekly intervals. Statistical analysis of the procedures showed that neither drug A nor drug B significantly affected the pain threshold. Drug A significantly reduced the total pain score (P less than 0.01) and its action peaked 60 min after administration.(ABSTRACT TRUNCATED AT 250 WORDS)

https://pubmed.ncbi.nlm.nih.gov/1979494/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: [Electric stimulation of the dental pulp in the evaluation of the central effect of analgesics]. We conducted a double-blind cross-over study in ten volunteers aged from 19 to 30 years , to compare the pain control effects of a single oral dose of two analgesic compounds ( drug A : propyphenazone mg 250 , ethylmorphine mg 5 , caffeine mg 5 ; drug B : dipyrone mg 500 , diphenhydramine mg 12.5 , adiphenine mg 5 , ethyl aminobenzoate mg 2.5 ) in an experimental pain model using stimulation of dental pulp . Constant voltage stimuli were delivered through silver chloride electrodes placed in contact with the vestibular surface of the upper medial incisor. At the beginning of the session, the pain input was graded by asking the subject to identify the weakest stimulus perceived (threshold level) and the strongest stimulus endurable (tolerance level). The range between threshold and tolerance level was divided in nine steps plus a subliminal step. The ten steps were delivered randomly, and each series of steps was repeated eight times. The subjects were instructed to rate the pain sensation in an arbitrary scale of 5 degrees. The procedure was repeated at 60 min and 180 min after drug administration. Each subject received two tablets of drug A or drug B in two different sessions at weekly intervals. Statistical analysis of the procedures showed that neither drug A nor drug B significantly affected the pain threshold. Drug A significantly reduced the total pain score (P less than 0.01) and its action peaked 60 min after administration.(ABSTRACT TRUNCATED AT 250 WORDS) ### Response: propyphenazone, ethylmorphine, caffeine, dipyrone, diphenhydramine, adiphenine, aminobenzoate

dbd8e4b1986c862f4f6959bc01ba9a08

Forty-three mCRC patients who received cetuximab or panitumumab between April 2012 and December 2015 were the subjects of the present study .

Hypomagnesemia is a reliable predictor for efficacy of anti-EGFR monoclonal antibody used in combination with first-line chemotherapy for metastatic colorectal cancer. Anti-EGFR monoclonal antibody is effective for KRAS wild-type metastatic colorectal cancer (mCRC), but frequently causes several adverse reactions, including hypomagnesemia and skin disorders. The present study was designed to investigate the relationship between the incidence of adverse reactions and therapeutic effects in mCRC patients receiving anti-EGFR monoclonal antibody in combination with first-line chemotherapy. ### methods Forty-three mCRC patients who received cetuximab or panitumumab between April 2012 and December 2015 were the subjects of the present study . All patients were pretreated with oral minocycline in combination with skin treatment using moisturizer for prevention of skin rash. Hypomagnesemia and acneiform rash were graded according to the Common Terminology Criteria for Adverse Events, version 3.0. Overall response rate (ORR) and time to treatment failure (TTF) were compared between patients with and without these adverse events. ### results The incidence rates of hypomagnesemia and acneiform rash were 32.6 % (grade 1: 20.9 %, grade 2: 11.6 %) and 93.0 % (grade 1: 41.9 %, grade 2: 41.9 %, grade 3: 9.3 %), respectively. ORR was significantly higher in patients with hypomagnesemia than in those without it (71.4 vs 34.5 %, P = 0.048). Median TTF tended to be longer, though not significantly, in patients with hypomagnesemia than in those without it. However, no significant difference in both ORR and median TTF was observed between patients with and without acneiform rash. ### conclusion Hypomagnesemia may become a predicting factor for therapeutic effects of anti-EGFR monoclonal antibody in mCRC patients.

https://pubmed.ncbi.nlm.nih.gov/27106835/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Hypomagnesemia is a reliable predictor for efficacy of anti-EGFR monoclonal antibody used in combination with first-line chemotherapy for metastatic colorectal cancer. Anti-EGFR monoclonal antibody is effective for KRAS wild-type metastatic colorectal cancer (mCRC), but frequently causes several adverse reactions, including hypomagnesemia and skin disorders. The present study was designed to investigate the relationship between the incidence of adverse reactions and therapeutic effects in mCRC patients receiving anti-EGFR monoclonal antibody in combination with first-line chemotherapy. ### methods Forty-three mCRC patients who received cetuximab or panitumumab between April 2012 and December 2015 were the subjects of the present study . All patients were pretreated with oral minocycline in combination with skin treatment using moisturizer for prevention of skin rash. Hypomagnesemia and acneiform rash were graded according to the Common Terminology Criteria for Adverse Events, version 3.0. Overall response rate (ORR) and time to treatment failure (TTF) were compared between patients with and without these adverse events. ### results The incidence rates of hypomagnesemia and acneiform rash were 32.6 % (grade 1: 20.9 %, grade 2: 11.6 %) and 93.0 % (grade 1: 41.9 %, grade 2: 41.9 %, grade 3: 9.3 %), respectively. ORR was significantly higher in patients with hypomagnesemia than in those without it (71.4 vs 34.5 %, P = 0.048). Median TTF tended to be longer, though not significantly, in patients with hypomagnesemia than in those without it. However, no significant difference in both ORR and median TTF was observed between patients with and without acneiform rash. ### conclusion Hypomagnesemia may become a predicting factor for therapeutic effects of anti-EGFR monoclonal antibody in mCRC patients. ### Response: cetuximab, panitumumab

34d2058b1f46a61ed6efa1e0d2cc049f

Furthermore , 11 AML patients at primary diagnosis , including five AML patients with P-gp overexpression , who were treated with idarubicin , vepesid , and cytarabine V ( ara-C ) showed a complete remission .

Clinical importance of P-glycoprotein-related resistance in leukemia and myelodysplastic syndromes--first experience with their reversal. P-glycoprotein (P-gp) expression in mononuclear bone marrow cells was analyzed in 119 patients, including 60 with chronic myelogenous leukemia (CML), 48 with myelodysplastic syndromes (MDS), and 11 with acute myelogenous leukemia (AML). For P-gp measurement an immunocytological method using monoclonal antibodies C219, 4E3, and MRK 16 and the reverse transcription-polymerase chain reaction technique were applied. According to our results obtained in healthy volunteers using the immunocytological method, the limit for P-gp overexpression was set at > or = 10% P-gp-positive mononuclear bone marrow cells and at > or = 30% P-gp-positive mononuclear peripheral blood cells. All 42 CML patients in chronic phase had normal P-gp expression. P-gp overexpression was demonstrated in four of six patients in accelerated myelogenous blast cell phase and in four of 12 CML-BC patients. Of eight CML patients in blast crisis (BC) with normal P-gp expression, partial remission was achieved in three and minor response in five after prednisone/vindesine therapy. All four of the 12 CML-BC patients with P-gp overexpression did not respond to this therapy. Normal P-gp expression was seen in 41 (85.4%) of 48 untreated MDS patients. While P-gp overexpression did not develop during therapy in any of the myelodysplastic syndrome patients treated with low-dose ara-C alone, four of eight treated with low-dose ara-C plus GM-CSF and four of 11 treated with low-dose ara-C and IL-3 developed P-gp overexpression after therapy. Furthermore , 11 AML patients at primary diagnosis , including five AML patients with P-gp overexpression , who were treated with idarubicin , vepesid , and cytarabine V ( ara-C ) showed a complete remission . Additionally, one daunorubicin-cytarabine-pretreated refractory AML patient was treated with the oral form of the P-gp modulator drug dexniguldipine and achieved complete remission for a duration of 7 months. Our results suggest that in CML patients in BC, P-gp expression influences outcome after therapy. Further more, studies in a larger series of patients are necessary to prove the efficacy and toxicity of idarubicin/vepesid and cytardbine--or dexniguldipine-containing--therapy in relation to P-gp expression of AML patients.

https://pubmed.ncbi.nlm.nih.gov/7914749/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Clinical importance of P-glycoprotein-related resistance in leukemia and myelodysplastic syndromes--first experience with their reversal. P-glycoprotein (P-gp) expression in mononuclear bone marrow cells was analyzed in 119 patients, including 60 with chronic myelogenous leukemia (CML), 48 with myelodysplastic syndromes (MDS), and 11 with acute myelogenous leukemia (AML). For P-gp measurement an immunocytological method using monoclonal antibodies C219, 4E3, and MRK 16 and the reverse transcription-polymerase chain reaction technique were applied. According to our results obtained in healthy volunteers using the immunocytological method, the limit for P-gp overexpression was set at > or = 10% P-gp-positive mononuclear bone marrow cells and at > or = 30% P-gp-positive mononuclear peripheral blood cells. All 42 CML patients in chronic phase had normal P-gp expression. P-gp overexpression was demonstrated in four of six patients in accelerated myelogenous blast cell phase and in four of 12 CML-BC patients. Of eight CML patients in blast crisis (BC) with normal P-gp expression, partial remission was achieved in three and minor response in five after prednisone/vindesine therapy. All four of the 12 CML-BC patients with P-gp overexpression did not respond to this therapy. Normal P-gp expression was seen in 41 (85.4%) of 48 untreated MDS patients. While P-gp overexpression did not develop during therapy in any of the myelodysplastic syndrome patients treated with low-dose ara-C alone, four of eight treated with low-dose ara-C plus GM-CSF and four of 11 treated with low-dose ara-C and IL-3 developed P-gp overexpression after therapy. Furthermore , 11 AML patients at primary diagnosis , including five AML patients with P-gp overexpression , who were treated with idarubicin , vepesid , and cytarabine V ( ara-C ) showed a complete remission . Additionally, one daunorubicin-cytarabine-pretreated refractory AML patient was treated with the oral form of the P-gp modulator drug dexniguldipine and achieved complete remission for a duration of 7 months. Our results suggest that in CML patients in BC, P-gp expression influences outcome after therapy. Further more, studies in a larger series of patients are necessary to prove the efficacy and toxicity of idarubicin/vepesid and cytardbine--or dexniguldipine-containing--therapy in relation to P-gp expression of AML patients. ### Response: idarubicin, vepesid, cytarabine

26b52a93d8e856f6c5071f06c51f1393

Phase Ib Study of Bavituximab With Carboplatin and Pemetrexed in Chemotherapy-Naive Advanced Nonsquamous Non-Small-Cell Lung Cancer .

Phase Ib Study of Bavituximab With Carboplatin and Pemetrexed in Chemotherapy-Naive Advanced Nonsquamous Non-Small-Cell Lung Cancer . bavituximab is an immunomodulatory chimeric monoclonal antibody that inhibits phosphatidylserine signaling, which promotes innate and adaptive immune responses. In this phase Ib trial we evaluated the safety, tolerability, and preliminary antitumor activity of pemetrexed, carboplatin, bavituximab in advanced non-small-cell lung cancer (NSCLC). ### Patients And Methods Patients with advanced nonsquamous NSCLC and performance status 0 or 1 were treated with pemetrexed 500 mg/m ### results Between March 29, 2011 and December 30, 2013, 26 patients were enrolled. Three patients each were enrolled into dose escalation cohorts of bavituximab (0.3, 1, and 3 mg/kg). Therapy was well tolerated with no DLTs, and toxicities were consistent with those expected from pemetrexed/carboplatin. Overall response was 28%, with a median progression-free and overall survival of 4.8 months and 12.2 months, respectively. ### conclusion The combination of pemetrexed, carboplatin, bavituximab is well tolerated. However, with toxicities and preliminary efficacy signal similar to pemetrexed/carboplatin alone, further studies of bavituximab should focus on ways to enhance its immunomodulatory role.

https://pubmed.ncbi.nlm.nih.gov/29631965/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Phase Ib Study of Bavituximab With Carboplatin and Pemetrexed in Chemotherapy-Naive Advanced Nonsquamous Non-Small-Cell Lung Cancer . bavituximab is an immunomodulatory chimeric monoclonal antibody that inhibits phosphatidylserine signaling, which promotes innate and adaptive immune responses. In this phase Ib trial we evaluated the safety, tolerability, and preliminary antitumor activity of pemetrexed, carboplatin, bavituximab in advanced non-small-cell lung cancer (NSCLC). ### Patients And Methods Patients with advanced nonsquamous NSCLC and performance status 0 or 1 were treated with pemetrexed 500 mg/m ### results Between March 29, 2011 and December 30, 2013, 26 patients were enrolled. Three patients each were enrolled into dose escalation cohorts of bavituximab (0.3, 1, and 3 mg/kg). Therapy was well tolerated with no DLTs, and toxicities were consistent with those expected from pemetrexed/carboplatin. Overall response was 28%, with a median progression-free and overall survival of 4.8 months and 12.2 months, respectively. ### conclusion The combination of pemetrexed, carboplatin, bavituximab is well tolerated. However, with toxicities and preliminary efficacy signal similar to pemetrexed/carboplatin alone, further studies of bavituximab should focus on ways to enhance its immunomodulatory role. ### Response: Bavituximab, Carboplatin, Pemetrexed

d6601173b0972a426b9ca45a7a4f091c

In this multicenter study , the reliability of two nonradiometric , fully automated systems , the MB/BacT and BACTEC MGIT 960 systems , for testing the susceptibilities of 82 Mycobacterium tuberculosis strains to isoniazid , rifampin , ethambutol , and streptomycin was evaluated in comparison with the radiometric BACTEC 460 TB system .

Multicenter laboratory evaluation of the MB/BacT Mycobacterium detection system and the BACTEC MGIT 960 system in comparison with the BACTEC 460TB system for susceptibility testing of Mycobacterium tuberculosis. In this multicenter study , the reliability of two nonradiometric , fully automated systems , the MB/BacT and BACTEC MGIT 960 systems , for testing the susceptibilities of 82 Mycobacterium tuberculosis strains to isoniazid , rifampin , ethambutol , and streptomycin was evaluated in comparison with the radiometric BACTEC 460 TB system . The arbitration of discrepant results was done by the reanalysis of the strain, the determination of the MIC, and the molecular characterization of some resistance determinants. The overall level of agreement with BACTEC 460TB results was 96% with the MB/BacT test and 97.2% with the BACTEC MGIT 960 system. With both methods, the level of agreement with BACTEC 460TB results was 96.3% for isoniazid, 98.8% for rifampin, and 98.8% for ethambutol. The level of agreement for streptomycin was 90.2% with MB/BacT and 97.5% with BACTEC MGIT 960. Overall, there were 11 very major errors and 2 major errors with the MB/BacT method and 5 very major errors and 2 major errors with the BACTEC MGIT 960 system. In general, the MB/BacT and BACTEC MGIT 960 systems showed good performance for susceptibility testing with first-line antituberculosis drugs.

https://pubmed.ncbi.nlm.nih.gov/17442793/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Multicenter laboratory evaluation of the MB/BacT Mycobacterium detection system and the BACTEC MGIT 960 system in comparison with the BACTEC 460TB system for susceptibility testing of Mycobacterium tuberculosis. In this multicenter study , the reliability of two nonradiometric , fully automated systems , the MB/BacT and BACTEC MGIT 960 systems , for testing the susceptibilities of 82 Mycobacterium tuberculosis strains to isoniazid , rifampin , ethambutol , and streptomycin was evaluated in comparison with the radiometric BACTEC 460 TB system . The arbitration of discrepant results was done by the reanalysis of the strain, the determination of the MIC, and the molecular characterization of some resistance determinants. The overall level of agreement with BACTEC 460TB results was 96% with the MB/BacT test and 97.2% with the BACTEC MGIT 960 system. With both methods, the level of agreement with BACTEC 460TB results was 96.3% for isoniazid, 98.8% for rifampin, and 98.8% for ethambutol. The level of agreement for streptomycin was 90.2% with MB/BacT and 97.5% with BACTEC MGIT 960. Overall, there were 11 very major errors and 2 major errors with the MB/BacT method and 5 very major errors and 2 major errors with the BACTEC MGIT 960 system. In general, the MB/BacT and BACTEC MGIT 960 systems showed good performance for susceptibility testing with first-line antituberculosis drugs. ### Response: isoniazid, rifampin, ethambutol, streptomycin

6201ec7c59b896456b430a50bd41c74f

Most frequent first line therapy was Sunitinib ( 66 % ) , followed by Sorafenib ( 20 % ) and Pazopanib ( 10 % ) .

The impact of cytoreductive nephrectomy on survival outcomes in patients treated with tyrosine kinase inhibitors for metastatic renal cell carcinoma in a real-world cohort. Tyrosine kinase inhibitor therapy (TKI) has changed the treatment paradigm of metastatic renal cell carcinoma (mRCC). The recent CARMENA and SURTIME trials challenged the role of the cytoreductive nephrectomy (CN). ### objective To assess the impact of CN prior to TKI therapy in patients with mRCC in a real-world setting. ### methods Overall, 262 consecutive patients with mRCC were treated with CN plus TKI or TKI only at our institution between 2000 and 2016. Patients with prior immunotherapy or metastasectomy were excluded. Multiple imputation and inverse probability of treatment weighting (IPTW) were performed to account for missing values and imbalances between the treatment groups, respectively. Unadjusted and adjusted Kaplan-Meier estimates were used to determine differences in progression-free (PFS), overall (OS), and cancer-specific survival (CSS). ### results Overall, 104 (40%) patients received CN before TKI treatment. Most frequent first line therapy was Sunitinib ( 66 % ) , followed by Sorafenib ( 20 % ) and Pazopanib ( 10 % ) . After adjustment with IPTW, there was no difference in PFS, CSS, and OS (all P > 0.05) between the treatment groups. In subgroup analyses, CSS was improved when CN was performed in patients with sarcomatoid features and clear cell histology (P = 0.04 and P = 0.03) and PFS was improved in patients with clear cell histology when CN was performed [0.04]). CN did not improve OS in any subgroup analysis. ### conclusion The role of CN remains controversial. We found no difference in survival outcomes between patients treated with and without CN before TKI therapy. However, CN was associated with improved survival in specific patient subgroups. Tailored, individualized treatment is key to further improve oncological outcomes for mRCC.

https://pubmed.ncbi.nlm.nih.gov/32576526/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: The impact of cytoreductive nephrectomy on survival outcomes in patients treated with tyrosine kinase inhibitors for metastatic renal cell carcinoma in a real-world cohort. Tyrosine kinase inhibitor therapy (TKI) has changed the treatment paradigm of metastatic renal cell carcinoma (mRCC). The recent CARMENA and SURTIME trials challenged the role of the cytoreductive nephrectomy (CN). ### objective To assess the impact of CN prior to TKI therapy in patients with mRCC in a real-world setting. ### methods Overall, 262 consecutive patients with mRCC were treated with CN plus TKI or TKI only at our institution between 2000 and 2016. Patients with prior immunotherapy or metastasectomy were excluded. Multiple imputation and inverse probability of treatment weighting (IPTW) were performed to account for missing values and imbalances between the treatment groups, respectively. Unadjusted and adjusted Kaplan-Meier estimates were used to determine differences in progression-free (PFS), overall (OS), and cancer-specific survival (CSS). ### results Overall, 104 (40%) patients received CN before TKI treatment. Most frequent first line therapy was Sunitinib ( 66 % ) , followed by Sorafenib ( 20 % ) and Pazopanib ( 10 % ) . After adjustment with IPTW, there was no difference in PFS, CSS, and OS (all P > 0.05) between the treatment groups. In subgroup analyses, CSS was improved when CN was performed in patients with sarcomatoid features and clear cell histology (P = 0.04 and P = 0.03) and PFS was improved in patients with clear cell histology when CN was performed [0.04]). CN did not improve OS in any subgroup analysis. ### conclusion The role of CN remains controversial. We found no difference in survival outcomes between patients treated with and without CN before TKI therapy. However, CN was associated with improved survival in specific patient subgroups. Tailored, individualized treatment is key to further improve oncological outcomes for mRCC. ### Response: Sunitinib, Sorafenib, Pazopanib

cac8b6d7e0e9cff86690aeac01a51b77

Treatment of unresectable GISTs involves systemic chemotherapy with tyrosine kinase inhibitors , imatinib and sunitinib being first-line and second-line drugs .

A gastrointestinal stromal tumour with pulmonary metastases mimicking unilateral gynaecomastia. Gastrointestinal stromal tumours (GISTs) represent 1% of primary gastrointestinal cancers. These neoplasms most frequently metastasise to the liver and peritoneum and rarely to the lungs and bones. Treatment of unresectable GISTs involves systemic chemotherapy with tyrosine kinase inhibitors , imatinib and sunitinib being first-line and second-line drugs . We report the case of a 52-year-old man with GIST who developed a right-sided subareolar breast swelling and subsequently discovered to be an invasive metastatic pulmonary GIST. Given that gynaecomastia is a known adverse effect of imatinib and sunitinib, this case report illustrates the importance of including metastatic disease in the differential diagnosis of patients with GIST and with the new onset of soft tissue masses.

https://pubmed.ncbi.nlm.nih.gov/24343802/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: A gastrointestinal stromal tumour with pulmonary metastases mimicking unilateral gynaecomastia. Gastrointestinal stromal tumours (GISTs) represent 1% of primary gastrointestinal cancers. These neoplasms most frequently metastasise to the liver and peritoneum and rarely to the lungs and bones. Treatment of unresectable GISTs involves systemic chemotherapy with tyrosine kinase inhibitors , imatinib and sunitinib being first-line and second-line drugs . We report the case of a 52-year-old man with GIST who developed a right-sided subareolar breast swelling and subsequently discovered to be an invasive metastatic pulmonary GIST. Given that gynaecomastia is a known adverse effect of imatinib and sunitinib, this case report illustrates the importance of including metastatic disease in the differential diagnosis of patients with GIST and with the new onset of soft tissue masses. ### Response: imatinib, sunitinib

2bcb0a1c13e14733a47a2ce01f58095f

Such therapy has included weekly paclitaxel in combination with carboplatin/cisplatin plus topotecan , and carboplatin plus doxorubicin .

Role of weekly paclitaxel in the treatment of advanced ovarian cancer. Dose-dense weekly administration of paclitaxel has the potential advantage of allowing a larger percentage of cancer cells to enter the vulnerable phase of their cell cycle when cytotoxic paclitaxel concentrations are present. The lower doses and shorter infusion times used with weekly dosing should also minimize bone marrow suppression and other toxicities associated with standard paclitaxel 3-weekly administration. Clinical studies have confirmed that paclitaxel can be safely delivered on a weekly schedule as a 1-h infusion to patients with advanced ovarian cancer. Weekly administration of paclitaxel also appears to be better tolerated than 3-weekly administration. Single-agent weekly paclitaxel is associated with response rates of 20-65%. Combination therapy with weekly paclitaxel has mainly involved carboplatin and response rates with such regimens range from 60-88%. Triple-drug combination therapy has produced response rates of 42-67.5%. Such therapy has included weekly paclitaxel in combination with carboplatin/cisplatin plus topotecan , and carboplatin plus doxorubicin . In an attempt to avoid problems with high corticosteroid doses, dexamethasone doses of 10 and 8 mg have been used successfully in premedication regimens for weekly paclitaxel in ovarian cancer.

https://pubmed.ncbi.nlm.nih.gov/12505598/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Role of weekly paclitaxel in the treatment of advanced ovarian cancer. Dose-dense weekly administration of paclitaxel has the potential advantage of allowing a larger percentage of cancer cells to enter the vulnerable phase of their cell cycle when cytotoxic paclitaxel concentrations are present. The lower doses and shorter infusion times used with weekly dosing should also minimize bone marrow suppression and other toxicities associated with standard paclitaxel 3-weekly administration. Clinical studies have confirmed that paclitaxel can be safely delivered on a weekly schedule as a 1-h infusion to patients with advanced ovarian cancer. Weekly administration of paclitaxel also appears to be better tolerated than 3-weekly administration. Single-agent weekly paclitaxel is associated with response rates of 20-65%. Combination therapy with weekly paclitaxel has mainly involved carboplatin and response rates with such regimens range from 60-88%. Triple-drug combination therapy has produced response rates of 42-67.5%. Such therapy has included weekly paclitaxel in combination with carboplatin/cisplatin plus topotecan , and carboplatin plus doxorubicin . In an attempt to avoid problems with high corticosteroid doses, dexamethasone doses of 10 and 8 mg have been used successfully in premedication regimens for weekly paclitaxel in ovarian cancer. ### Response: paclitaxel, topotecan, carboplatin, doxorubicin, carboplatin/cisplatin

5b73032843858b59999366946c1e2aeb

This phase II study was performed to assess the efficacy and safety of the combination regimen of temozolomide and docetaxel in patients with advanced metastatic melanoma .

Temozolomide in combination with docetaxel in patients with advanced melanoma: a phase II study of the Hellenic Cooperative Oncology Group. temozolomide is a novel oral alkylating agent that is effective against melanoma. Moreover, temozolomide readily crosses the blood-brain barrier and may consequently be effective in patients with brain metastases. This phase II study was performed to assess the efficacy and safety of the combination regimen of temozolomide and docetaxel in patients with advanced metastatic melanoma . ### Patients And Methods Sixty-five patients with metastatic melanoma were enrolled. Treatment consisted of intravenous docetaxel (80 mg/m(2)) on day 1 and oral temozolomide (150 mg/m(2)) on days 1 to 5, every 4 weeks, for a maximum of six cycles. ### results Sixty-two patients were eligible for the efficacy and safety analysis. Seventeen patients (27%) achieved an objective response, including five complete (8%) and 12 partial responses (19%). Median response duration was 9.5 months. Among responders, median time to progression (TTP) was 11.2 months and median overall survival (OS) was 16 months. For all treated patients, the median TTP was 4 months and median OS was 11 months. Three (38%) of eight patients who presented with brain metastases had a partial response for 5, 6, and 12 months. Of 52 patients who did not have brain involvement at presentation, only four (8%) developed brain metastases at a median follow-up of 14 months. Myelosuppression was the primary toxicity. ### conclusion The combination of temozolomide and docetaxel was effective and well tolerated as first-line treatment for patients with advanced metastatic melanoma and demonstrated encouraging antitumor activity against brain metastases.

https://pubmed.ncbi.nlm.nih.gov/11786569/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Temozolomide in combination with docetaxel in patients with advanced melanoma: a phase II study of the Hellenic Cooperative Oncology Group. temozolomide is a novel oral alkylating agent that is effective against melanoma. Moreover, temozolomide readily crosses the blood-brain barrier and may consequently be effective in patients with brain metastases. This phase II study was performed to assess the efficacy and safety of the combination regimen of temozolomide and docetaxel in patients with advanced metastatic melanoma . ### Patients And Methods Sixty-five patients with metastatic melanoma were enrolled. Treatment consisted of intravenous docetaxel (80 mg/m(2)) on day 1 and oral temozolomide (150 mg/m(2)) on days 1 to 5, every 4 weeks, for a maximum of six cycles. ### results Sixty-two patients were eligible for the efficacy and safety analysis. Seventeen patients (27%) achieved an objective response, including five complete (8%) and 12 partial responses (19%). Median response duration was 9.5 months. Among responders, median time to progression (TTP) was 11.2 months and median overall survival (OS) was 16 months. For all treated patients, the median TTP was 4 months and median OS was 11 months. Three (38%) of eight patients who presented with brain metastases had a partial response for 5, 6, and 12 months. Of 52 patients who did not have brain involvement at presentation, only four (8%) developed brain metastases at a median follow-up of 14 months. Myelosuppression was the primary toxicity. ### conclusion The combination of temozolomide and docetaxel was effective and well tolerated as first-line treatment for patients with advanced metastatic melanoma and demonstrated encouraging antitumor activity against brain metastases. ### Response: temozolomide, docetaxel

0cad00d5e84694cb17717fc3f749e2aa

Addition of verapamil and tamoxifen to the initial chemotherapy of small cell lung cancer .

Addition of verapamil and tamoxifen to the initial chemotherapy of small cell lung cancer . Based on experimental observations that verapamil and tamoxifen reverse multiple drug resistance, the authors investigated the feasibility of combining both agents with the initial chemotherapy of extensive small cell lung cancer. Overall, in a consecutive series of 58 patients the most important toxicity was myelosuppression, and there was a 24% rate of severe infections. Therapeutic results included 24% complete and 34% partial response rates, median time to disease progression of 32 weeks, and median survival of 46 weeks. In three consecutive cohorts of patients the dose of either tamoxifen or verapamil were escalated by 25% and 33%, respectively. The cohort of patients receiving verapamil 360 mg/day and tamoxifen 100 mg/day (level 2) had slightly more toxicity but also more responses than the other groups. Therefore, the authors recommend that these doses be used in controlled trials to confirm the promising results of their study.

https://pubmed.ncbi.nlm.nih.gov/2164872/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Addition of verapamil and tamoxifen to the initial chemotherapy of small cell lung cancer . Based on experimental observations that verapamil and tamoxifen reverse multiple drug resistance, the authors investigated the feasibility of combining both agents with the initial chemotherapy of extensive small cell lung cancer. Overall, in a consecutive series of 58 patients the most important toxicity was myelosuppression, and there was a 24% rate of severe infections. Therapeutic results included 24% complete and 34% partial response rates, median time to disease progression of 32 weeks, and median survival of 46 weeks. In three consecutive cohorts of patients the dose of either tamoxifen or verapamil were escalated by 25% and 33%, respectively. The cohort of patients receiving verapamil 360 mg/day and tamoxifen 100 mg/day (level 2) had slightly more toxicity but also more responses than the other groups. Therefore, the authors recommend that these doses be used in controlled trials to confirm the promising results of their study. ### Response: verapamil, tamoxifen

86b8b2e11fa8569ee780430cc83fa446

In a scenario analysis comparing pembrolizumab with ipilimumab , the estimated ICER was USD8,904 .

Cost-effectiveness analysis of pembrolizumab compared to standard of care as first line treatment for patients with advanced melanoma in Hong Kong. pembrolizumab has been shown to improve overall survival (OS) and progression free survival (PFS) compared to ipilimumab in patients with ipilimumab-naïve advanced melanoma; however, there are no published data on the cost-effectiveness for pembrolizumab compared to standard-of-care treatments currently used in Hong Kong for advanced melanoma. ### methods A partitioned-survival model based on data from a recent randomized phase 3 study (KEYNOTE-006) and meta-analysis was used to derive time in PFS, OS, and post-progression survival for pembrolizumab and chemotherapy, such as dacarbazine (DTIC), temozolomide (TMZ), and the paclitaxel-carboplatin combination (PC). A combination of clinical trial data, published data, results of meta-analysis, and melanoma registry data was used to extrapolate PFS and OS curves. The base-case time horizon for the model was 30 years with costs and health outcomes discounted at a rate of 5% per year. Individual patient level data on utilities and frequencies of adverse events were obtained from the final analysis of KEYNOTE-006 (cut-off date: 3-Dec-15) for pembrolizumab. Cost data included drug acquisition, treatment administration, adverse event management, and clinical management of advanced melanoma. The distribution of patient weight from the Hong Kong population was applied to calculate the drug costs. Analyses were performed from a payer's perspective. The incremental cost effectiveness ratio (ICER) expressed as cost in US Dollars (USD) per quality-adjusted life years (QALYs) was the main outcome. ### results In base-case scenario, the ICER for pembrolizumab as a first-line treatment for advanced melanoma was USD49,232 compared to DTIC, with the ICER values lower than cost-effectiveness threshold in Hong Kong. Results comparing pembrolizumab to TMZ and to PC were similar to that when compared to DTIC. Probability sensitivity analyses showed that 99% of the simulated ICERs were below three times the Gross Domestic Product (GDP) per capita for Hong Kong (currently at $119,274//QALY threshold). In a scenario analysis comparing pembrolizumab with ipilimumab , the estimated ICER was USD8,904 . ### conclusions pembrolizumab is cost-effective relative to chemotherapy (DTIC, TMZ and PC), and highly-cost-effective compared to ipilimumab, for the first-line treatment of advanced melanoma in Hong Kong.

https://pubmed.ncbi.nlm.nih.gov/31969794/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Cost-effectiveness analysis of pembrolizumab compared to standard of care as first line treatment for patients with advanced melanoma in Hong Kong. pembrolizumab has been shown to improve overall survival (OS) and progression free survival (PFS) compared to ipilimumab in patients with ipilimumab-naïve advanced melanoma; however, there are no published data on the cost-effectiveness for pembrolizumab compared to standard-of-care treatments currently used in Hong Kong for advanced melanoma. ### methods A partitioned-survival model based on data from a recent randomized phase 3 study (KEYNOTE-006) and meta-analysis was used to derive time in PFS, OS, and post-progression survival for pembrolizumab and chemotherapy, such as dacarbazine (DTIC), temozolomide (TMZ), and the paclitaxel-carboplatin combination (PC). A combination of clinical trial data, published data, results of meta-analysis, and melanoma registry data was used to extrapolate PFS and OS curves. The base-case time horizon for the model was 30 years with costs and health outcomes discounted at a rate of 5% per year. Individual patient level data on utilities and frequencies of adverse events were obtained from the final analysis of KEYNOTE-006 (cut-off date: 3-Dec-15) for pembrolizumab. Cost data included drug acquisition, treatment administration, adverse event management, and clinical management of advanced melanoma. The distribution of patient weight from the Hong Kong population was applied to calculate the drug costs. Analyses were performed from a payer's perspective. The incremental cost effectiveness ratio (ICER) expressed as cost in US Dollars (USD) per quality-adjusted life years (QALYs) was the main outcome. ### results In base-case scenario, the ICER for pembrolizumab as a first-line treatment for advanced melanoma was USD49,232 compared to DTIC, with the ICER values lower than cost-effectiveness threshold in Hong Kong. Results comparing pembrolizumab to TMZ and to PC were similar to that when compared to DTIC. Probability sensitivity analyses showed that 99% of the simulated ICERs were below three times the Gross Domestic Product (GDP) per capita for Hong Kong (currently at $119,274//QALY threshold). In a scenario analysis comparing pembrolizumab with ipilimumab , the estimated ICER was USD8,904 . ### conclusions pembrolizumab is cost-effective relative to chemotherapy (DTIC, TMZ and PC), and highly-cost-effective compared to ipilimumab, for the first-line treatment of advanced melanoma in Hong Kong. ### Response: pembrolizumab, ipilimumab

0d17f81c5efb1b73b80eb287f32c69e0

Long-term cardiac outcomes of patients with HER2-positive breast cancer treated in the adjuvant lapatinib and/or trastuzumab Treatment Optimization Trial .

Long-term cardiac outcomes of patients with HER2-positive breast cancer treated in the adjuvant lapatinib and/or trastuzumab Treatment Optimization Trial . Cardiotoxicity is the most significant adverse event associated with trastuzumab (T), the main component of HER2-positive breast cancer (BC) treatment. Less is known about the cardiotoxicity of dual HER2 blockade with T plus lapatinib (L), although this regimen is used in the metastatic setting. ### methods This is a sub-analysis of the ALTTO trial comparing adjuvant treatment options for patients with early HER2-positive BC. Patients randomised to either T or concomitant T + L were eligible. Cardiac events (CEs) rates were compared according to treatment arm. ### results With 6.9 years of median follow-up (FU) and 4190 patients, CE were observed in 363 (8.6%): 166 (7.9%) of patient in T + L arm vs. 197 (9.3%) in T arm (OR = 0.85 [95% CI, 0.68-1.05]). During anti-HER2 treatment 270 CE (6.4%) occurred while 93 (2.2%) were during FU (median time to onset = 6.6 months [IQR = 3.4-11.7]). While 265 CEs were asymptomatic (73%), 94 were symptomatic (26%) and four were cardiac deaths (1%). Recovery was observed in 301 cases (83.8%). Identified cardiac risk factors were: baseline LVEF < 55% (vs > 64%, OR 3.1 [95% CI 1.54-6.25]), diabetes mellitus (OR 1.85 [95% CI 1.25-2.75]), BMI > 30 kg/m ### conclusions Dual HER2 blockade with T + L is a safe regimen from a cardiac perspective, but cardiac-focused history for proper patient selection is crucial. ### Trial Registration Number ClinicalTrials.gov Identifier: NCT00490139 (registration date: 22/06/2007); EudraCT Number: 2006-000562-36 (registration date: 04/05/2007); Sponsor Protocol Number: BIG2-06 /EGF106708/N063D.

https://pubmed.ncbi.nlm.nih.gov/32203207/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Long-term cardiac outcomes of patients with HER2-positive breast cancer treated in the adjuvant lapatinib and/or trastuzumab Treatment Optimization Trial . Cardiotoxicity is the most significant adverse event associated with trastuzumab (T), the main component of HER2-positive breast cancer (BC) treatment. Less is known about the cardiotoxicity of dual HER2 blockade with T plus lapatinib (L), although this regimen is used in the metastatic setting. ### methods This is a sub-analysis of the ALTTO trial comparing adjuvant treatment options for patients with early HER2-positive BC. Patients randomised to either T or concomitant T + L were eligible. Cardiac events (CEs) rates were compared according to treatment arm. ### results With 6.9 years of median follow-up (FU) and 4190 patients, CE were observed in 363 (8.6%): 166 (7.9%) of patient in T + L arm vs. 197 (9.3%) in T arm (OR = 0.85 [95% CI, 0.68-1.05]). During anti-HER2 treatment 270 CE (6.4%) occurred while 93 (2.2%) were during FU (median time to onset = 6.6 months [IQR = 3.4-11.7]). While 265 CEs were asymptomatic (73%), 94 were symptomatic (26%) and four were cardiac deaths (1%). Recovery was observed in 301 cases (83.8%). Identified cardiac risk factors were: baseline LVEF < 55% (vs > 64%, OR 3.1 [95% CI 1.54-6.25]), diabetes mellitus (OR 1.85 [95% CI 1.25-2.75]), BMI > 30 kg/m ### conclusions Dual HER2 blockade with T + L is a safe regimen from a cardiac perspective, but cardiac-focused history for proper patient selection is crucial. ### Trial Registration Number ClinicalTrials.gov Identifier: NCT00490139 (registration date: 22/06/2007); EudraCT Number: 2006-000562-36 (registration date: 04/05/2007); Sponsor Protocol Number: BIG2-06 /EGF106708/N063D. ### Response: lapatinib, trastuzumab

f2c24cda6984f8af1fd4c57784983b09

To determine the current status of ivermectin , abamectin and praziquantel combined , and fenbendazole resistance to Parascaris spp . in horses in Saudi Arabia .

A field study on the anthelmintic resistance of Parascaris spp. in Arab foals in the Riyadh region, Saudi Arabia. In the last decade, Parascaris spp. resistance to anthelmintics has been recorded in many countries. In Saudi Arabia, there are limited data available on Parascaris spp. resistance to anthelmintics. ### objective To determine the current status of ivermectin , abamectin and praziquantel combined , and fenbendazole resistance to Parascaris spp . in horses in Saudi Arabia . ### methods Three hundred and forty-one foals from eleven different farms were examined by faecal egg count (FEC). The foals were all Arab horses aged 17.2 ± 4.5 (SD) months. ivermectin (n = 46 foals), abamectin and praziquantel combined (n = 46), and fenbendazole (n = 46) were administered on day 0 and faeces were collected on day 14. The study comprised 41 untreated foals as controls. Animals that have FEC of ≥100 eggs per gram (EPG) were used to measure anthelmintic efficacy. Parascaris spp. populations were considered susceptible when faecal egg count reduction (FECR) was ≥95% associated with a lower 95% confidence limit (LCL) >90%, suspected resistant when FECR ≤90% or LCL <90% and resistant when FECR <90% and LCL <90%. ### results Prevalence of Parascaris spp. infection was 53% (179/341 horses). Anthelmintic resistance to Parascaris spp. were highest following fenbendazole (55% of farms and 65% of foals) and to a lower extent following ivermectin or the combination of abamectin and praziquantel which comprised 27% of farms (and 46% of foals) and 18% of farms (and 10% of foals), respectively. ### conclusion These data indicate that anthelmintics-resistant Parascaris spp. populations are present on horse farms in Saudi Arabia.

https://pubmed.ncbi.nlm.nih.gov/28537782/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: A field study on the anthelmintic resistance of Parascaris spp. in Arab foals in the Riyadh region, Saudi Arabia. In the last decade, Parascaris spp. resistance to anthelmintics has been recorded in many countries. In Saudi Arabia, there are limited data available on Parascaris spp. resistance to anthelmintics. ### objective To determine the current status of ivermectin , abamectin and praziquantel combined , and fenbendazole resistance to Parascaris spp . in horses in Saudi Arabia . ### methods Three hundred and forty-one foals from eleven different farms were examined by faecal egg count (FEC). The foals were all Arab horses aged 17.2 ± 4.5 (SD) months. ivermectin (n = 46 foals), abamectin and praziquantel combined (n = 46), and fenbendazole (n = 46) were administered on day 0 and faeces were collected on day 14. The study comprised 41 untreated foals as controls. Animals that have FEC of ≥100 eggs per gram (EPG) were used to measure anthelmintic efficacy. Parascaris spp. populations were considered susceptible when faecal egg count reduction (FECR) was ≥95% associated with a lower 95% confidence limit (LCL) >90%, suspected resistant when FECR ≤90% or LCL <90% and resistant when FECR <90% and LCL <90%. ### results Prevalence of Parascaris spp. infection was 53% (179/341 horses). Anthelmintic resistance to Parascaris spp. were highest following fenbendazole (55% of farms and 65% of foals) and to a lower extent following ivermectin or the combination of abamectin and praziquantel which comprised 27% of farms (and 46% of foals) and 18% of farms (and 10% of foals), respectively. ### conclusion These data indicate that anthelmintics-resistant Parascaris spp. populations are present on horse farms in Saudi Arabia. ### Response: ivermectin, abamectin, praziquantel, fenbendazole

65d4616fe9641bc48a437be91566e364

To determine the response rate ( RR ) and survival produced by carboplatin + gemcitabine therapy in patients with untreated extensive small cell lung cancer ( ESCLC ) .

Results of a Phase II study of carboplatin plus gemcitabine in patients with untreated extensive small cell lung cancer. To determine the response rate ( RR ) and survival produced by carboplatin + gemcitabine therapy in patients with untreated extensive small cell lung cancer ( ESCLC ) . ### Patients And Methods Treatment consisted of carboplatin (AUC = 5) on day 1 and gemcitabine (1100 mg/m(2)) on days 1 and 8 of each 21-day cycle for 4 planned cycles (additional cycles allowed as per treating physician). ECOG performance status 0/1/2 was 29, 58, and 13%. Median age was 66.5 years (range: 41.3-83.1), 94% were white, and 50.7% were female. ### results Between August 2000 and February 2002, 69 patients with ESCLC were enrolled. All 69 patients were included in the safety analysis, and 66 patients were evaluable for response. There were 2 CR (3.0%), 26 PR (39.5%), 23 SD (34.8%), and 15 PD (22.7%) resulting in a RR of 42.5%. The median survival was 9.2 months (range: <1-22.6), and the estimated 1-year survival was 33%. The median TTP was 3.9 months (range: <1-12.8), and the estimated 6-month progression free survival was 24%. The median duration of response was 3.8 months (range: 1.0-9.9). Out of 69 patients, 29, 3, and 16 received 4, 5, and 6 cycles of therapy, respectively. The major Grade 3, 4 toxicities included neutropenia (39.1%), thrombocytopenia (31.9%), anemia (13.0%), and fatigue (4.3%). ### conclusion This regimen resulted in survival data that was similar to other regimens for ESCLC and treatment appeared to be well tolerated. gemcitabine in combination with carboplatin or other active drugs in ESCLC may be worth further investigation.

https://pubmed.ncbi.nlm.nih.gov/15541823/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Results of a Phase II study of carboplatin plus gemcitabine in patients with untreated extensive small cell lung cancer. To determine the response rate ( RR ) and survival produced by carboplatin + gemcitabine therapy in patients with untreated extensive small cell lung cancer ( ESCLC ) . ### Patients And Methods Treatment consisted of carboplatin (AUC = 5) on day 1 and gemcitabine (1100 mg/m(2)) on days 1 and 8 of each 21-day cycle for 4 planned cycles (additional cycles allowed as per treating physician). ECOG performance status 0/1/2 was 29, 58, and 13%. Median age was 66.5 years (range: 41.3-83.1), 94% were white, and 50.7% were female. ### results Between August 2000 and February 2002, 69 patients with ESCLC were enrolled. All 69 patients were included in the safety analysis, and 66 patients were evaluable for response. There were 2 CR (3.0%), 26 PR (39.5%), 23 SD (34.8%), and 15 PD (22.7%) resulting in a RR of 42.5%. The median survival was 9.2 months (range: <1-22.6), and the estimated 1-year survival was 33%. The median TTP was 3.9 months (range: <1-12.8), and the estimated 6-month progression free survival was 24%. The median duration of response was 3.8 months (range: 1.0-9.9). Out of 69 patients, 29, 3, and 16 received 4, 5, and 6 cycles of therapy, respectively. The major Grade 3, 4 toxicities included neutropenia (39.1%), thrombocytopenia (31.9%), anemia (13.0%), and fatigue (4.3%). ### conclusion This regimen resulted in survival data that was similar to other regimens for ESCLC and treatment appeared to be well tolerated. gemcitabine in combination with carboplatin or other active drugs in ESCLC may be worth further investigation. ### Response: carboplatin, gemcitabine

fa9ec0fb6b4851232e80bbb0f13f1bab

The interaction of chloroquine and citalopram in vitro resulted in a synergistic response in the chloroquine-resistant strain but there was no interaction between the drugs in the chloroquine-sensitive strain -- a pattern found with other reversal agents .

Citalopram enhances the activity of chloroquine in resistant plasmodium in vitro and in vivo. citalopram, is an extremely potent inhibitor of neuronal serotonin reuptake. It is structurally unrelated to other antidepressants, but it contains the chemical features associated with reversal of drug resistance and exhibits minimal cardiotoxic side effects and fewer of the anticholinergic and adrenolytic side effects associated with other psychotropic agents. Sensitivity tests to citalopram alone and in combination with chloroquine were performed against chloroquine-resistant and chloroquine-sensitive strains of Plasmodium falciparum and Plasmodium chabaudi. citalopram alone showed intrinsic activity against the chloroquine-resistant strains of P. falciparum (IC50 = 1.51 +/- .6 microM) but only limited activity against the chloroquine-sensitive strain (IC50 = 33.27 +/- 5.87 microM) and no activity in vivo. The interaction of chloroquine and citalopram in vitro resulted in a synergistic response in the chloroquine-resistant strain but there was no interaction between the drugs in the chloroquine-sensitive strain -- a pattern found with other reversal agents . citalopram enhanced chloroquine susceptibility in both strains of P. chabaudi, however, the potentiating effect was seen at lower doses in the chloroquine-resistant strain. The results of this study suggest that citalopram may have potential as a chemosensitizer in Plasmodium infections on the basis of the low toxicity of citalopram at concentrations potentiating chloroquine activity both in vitro and in vivo.

https://pubmed.ncbi.nlm.nih.gov/9655857/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Citalopram enhances the activity of chloroquine in resistant plasmodium in vitro and in vivo. citalopram, is an extremely potent inhibitor of neuronal serotonin reuptake. It is structurally unrelated to other antidepressants, but it contains the chemical features associated with reversal of drug resistance and exhibits minimal cardiotoxic side effects and fewer of the anticholinergic and adrenolytic side effects associated with other psychotropic agents. Sensitivity tests to citalopram alone and in combination with chloroquine were performed against chloroquine-resistant and chloroquine-sensitive strains of Plasmodium falciparum and Plasmodium chabaudi. citalopram alone showed intrinsic activity against the chloroquine-resistant strains of P. falciparum (IC50 = 1.51 +/- .6 microM) but only limited activity against the chloroquine-sensitive strain (IC50 = 33.27 +/- 5.87 microM) and no activity in vivo. The interaction of chloroquine and citalopram in vitro resulted in a synergistic response in the chloroquine-resistant strain but there was no interaction between the drugs in the chloroquine-sensitive strain -- a pattern found with other reversal agents . citalopram enhanced chloroquine susceptibility in both strains of P. chabaudi, however, the potentiating effect was seen at lower doses in the chloroquine-resistant strain. The results of this study suggest that citalopram may have potential as a chemosensitizer in Plasmodium infections on the basis of the low toxicity of citalopram at concentrations potentiating chloroquine activity both in vitro and in vivo. ### Response: chloroquine, citalopram

dcd33444812f986d077de2eb9f79e65e

Interfacial Phenomenon Based Biocompatible Alginate-Chitosan Nanoparticles Containing Isoniazid and Pyrazinamide .

Interfacial Phenomenon Based Biocompatible Alginate-Chitosan Nanoparticles Containing Isoniazid and Pyrazinamide . Tuberculosis (TB) is one of the major health challenge in the world. The current treatment of TB needs daily administration of combined drug therapy for six or more months. Sometime non-adherence and less bioavailability from current therapy develops multidrug resistance, as a result, high dose requirement and subsequent intolerable toxicity are seen. Therefore, nanotechnology gained special attention as it has potential to improve patient compliance, bioavailability and reduction in dosing frequency. ### objective The aim of this study is to fabricate alginate-chitosan nanoparticles (AL-CS NPs) under appropriate conditions using ionic gelation method. The use of natural polymers in nanoparticle fabrication has a vast application due to their biodegradability, biocompatibility and nontoxic nature. Ionic gelation method involves the interaction between macromolecules with opposite charged ionizable groups forming polyelectrolyte complex. Hence, it is rational to formulate natural polymerbased sustained release nano-particulate matrix to improve patient adherence, reducing dose frequency and drug toxicity. ### method The formulations were based on 32 factorial designs. Nanoparticles of combined drug (isoniazid- INH and pyrazinamide-PYZ) were fabricated using natural polymer. Formulation process involved the use of pregelated sodium alginate followed by ionic gelation with chitosan. Pregelation of sodium alginate included calcium chloride. The effects of sodium alginate concentration and chitosan concentration on particle size, zeta potential, entrapment efficiency and in vitro drug release were studied. ### results Optimized Batch-3s showed particle size 539.7 ± 2.33 nm, zeta potential -26.4 ± 0.55 mV, and entrapment efficiency is 70.21 ± 0.24% and 73.45 ± 0.21% of INH and PYZ, respectively. Dissolution release study of Batch-3s in 7.4 pH phosphate buffer exhibited the initial burst of 5.04 ±0.45% and 19.68 ± 0.87% at 0.25 hrs followed by slow, sustained release of drug 74.53 ± 2.53 and 57.87 ± 2.04% at 10 hrs of INH and PYZ, respectively. ### conclusion It concluded that chitosan (CS) and sodium alginate (AL) concentration are rate-limiting factors in formulation development. Natural polymer based combined drug nano-particulate system could be an innovative and optimistic approach in the treatment of TB.

https://pubmed.ncbi.nlm.nih.gov/29938624/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Interfacial Phenomenon Based Biocompatible Alginate-Chitosan Nanoparticles Containing Isoniazid and Pyrazinamide . Tuberculosis (TB) is one of the major health challenge in the world. The current treatment of TB needs daily administration of combined drug therapy for six or more months. Sometime non-adherence and less bioavailability from current therapy develops multidrug resistance, as a result, high dose requirement and subsequent intolerable toxicity are seen. Therefore, nanotechnology gained special attention as it has potential to improve patient compliance, bioavailability and reduction in dosing frequency. ### objective The aim of this study is to fabricate alginate-chitosan nanoparticles (AL-CS NPs) under appropriate conditions using ionic gelation method. The use of natural polymers in nanoparticle fabrication has a vast application due to their biodegradability, biocompatibility and nontoxic nature. Ionic gelation method involves the interaction between macromolecules with opposite charged ionizable groups forming polyelectrolyte complex. Hence, it is rational to formulate natural polymerbased sustained release nano-particulate matrix to improve patient adherence, reducing dose frequency and drug toxicity. ### method The formulations were based on 32 factorial designs. Nanoparticles of combined drug (isoniazid- INH and pyrazinamide-PYZ) were fabricated using natural polymer. Formulation process involved the use of pregelated sodium alginate followed by ionic gelation with chitosan. Pregelation of sodium alginate included calcium chloride. The effects of sodium alginate concentration and chitosan concentration on particle size, zeta potential, entrapment efficiency and in vitro drug release were studied. ### results Optimized Batch-3s showed particle size 539.7 ± 2.33 nm, zeta potential -26.4 ± 0.55 mV, and entrapment efficiency is 70.21 ± 0.24% and 73.45 ± 0.21% of INH and PYZ, respectively. Dissolution release study of Batch-3s in 7.4 pH phosphate buffer exhibited the initial burst of 5.04 ±0.45% and 19.68 ± 0.87% at 0.25 hrs followed by slow, sustained release of drug 74.53 ± 2.53 and 57.87 ± 2.04% at 10 hrs of INH and PYZ, respectively. ### conclusion It concluded that chitosan (CS) and sodium alginate (AL) concentration are rate-limiting factors in formulation development. Natural polymer based combined drug nano-particulate system could be an innovative and optimistic approach in the treatment of TB. ### Response: Isoniazid, Pyrazinamide

576c8ac8cc0fa93c995c35b5e17b8c95

In a 27-day inpatient study , 10 methamphetamine-dependent individuals participated in a double-blind , placebo-controlled , cross-over design , with oral doses of topiramate ( 0 , 100 , and 200 mg ) administered as a pretreatment before intravenous doses of methamphetamine ( 0 , 15 , and 30 mg ) .

Kinetic and cardiovascular effects of acute topiramate dosing among non-treatment-seeking, methamphetamine-dependent individuals. Previously, we have shown that orally administered topiramate, a sulfamate-substituted fructopyranose derivative, appears to accentuate rather than diminish some aspects of methamphetamine-induced positive subjective mood and cognitive performance. One possible mechanism by which this might occur would be for topiramate to increase plasma methamphetamine level. Such an effect also would be expected to enhance methamphetamine-induced hemodynamic response. We, therefore, studied -- in the same experiment from which the previous findings originated -- the effects of topiramate on the kinetic profile and hemodynamic response to methamphetamine. In a 27-day inpatient study , 10 methamphetamine-dependent individuals participated in a double-blind , placebo-controlled , cross-over design , with oral doses of topiramate ( 0 , 100 , and 200 mg ) administered as a pretreatment before intravenous doses of methamphetamine ( 0 , 15 , and 30 mg ) . The 3x3 factorial combination of topiramate and methamphetamine resulted in a sequence of the nine treatments administered to each subject in an order determined by a 9x9 Latin Square design. methamphetamine alone was associated with prototypical increases in hemodynamic response that were not altered in the presence of topiramate. While there was no significant kinetic interaction between topiramate and methamphetamine, there was a non-significant trend for topiramate to increase plasma methamphetamine level. No significant adverse events were reported. The combination of topiramate and methamphetamine at pharmacologically relevant doses appears to be safe. Larger laboratory studies with chronic dosing regimens are needed to establish whether or not there is a kinetic interaction between topiramate and methamphetamine.

https://pubmed.ncbi.nlm.nih.gov/17184890/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Kinetic and cardiovascular effects of acute topiramate dosing among non-treatment-seeking, methamphetamine-dependent individuals. Previously, we have shown that orally administered topiramate, a sulfamate-substituted fructopyranose derivative, appears to accentuate rather than diminish some aspects of methamphetamine-induced positive subjective mood and cognitive performance. One possible mechanism by which this might occur would be for topiramate to increase plasma methamphetamine level. Such an effect also would be expected to enhance methamphetamine-induced hemodynamic response. We, therefore, studied -- in the same experiment from which the previous findings originated -- the effects of topiramate on the kinetic profile and hemodynamic response to methamphetamine. In a 27-day inpatient study , 10 methamphetamine-dependent individuals participated in a double-blind , placebo-controlled , cross-over design , with oral doses of topiramate ( 0 , 100 , and 200 mg ) administered as a pretreatment before intravenous doses of methamphetamine ( 0 , 15 , and 30 mg ) . The 3x3 factorial combination of topiramate and methamphetamine resulted in a sequence of the nine treatments administered to each subject in an order determined by a 9x9 Latin Square design. methamphetamine alone was associated with prototypical increases in hemodynamic response that were not altered in the presence of topiramate. While there was no significant kinetic interaction between topiramate and methamphetamine, there was a non-significant trend for topiramate to increase plasma methamphetamine level. No significant adverse events were reported. The combination of topiramate and methamphetamine at pharmacologically relevant doses appears to be safe. Larger laboratory studies with chronic dosing regimens are needed to establish whether or not there is a kinetic interaction between topiramate and methamphetamine. ### Response: topiramate, methamphetamine

6226da15ba7f4d73c2d17792fe9e79af

Synergism between penicillin , clindamycin , or metronidazole and gentamicin against species of the Bacteroides melaninogenicus and Bacteroides fragilis groups .

Synergism between penicillin , clindamycin , or metronidazole and gentamicin against species of the Bacteroides melaninogenicus and Bacteroides fragilis groups . Clinical isolates of the Bacteroides melaninogenicus and Bacteroides fragilis groups were tested for in vitro and in vivo susceptibility to penicillin, clindamycin, and metronidazole, used singly or in combination with gentamicin. The in vitro tests consisted of determinations of minimal inhibitory concentrations (MICs) carried out with or without constant amounts of gentamicin. When used alone, gentamicin had negligible effects on the bacteria but significantly reduced the MICs of penicillin, clindamycin, and metronidazole against 11, 10, and 3, of the 15 strains of the B. melaninogenicus group, respectively. The 15 strains of the B. fragilis group were all beta-lactamase producers and were highly resistant to penicillin or the combination of penicillin and gentamicin. However, gentamicin reduced the MICs of clindamycin and metronidazole against 1 and 7 strains of this group, respectively. The in vivo tests were carried out in mice and consisted of measurements of the effects of the antimicrobial agents on the sizes and bacterial content of abscesses induced by subcutaneous injection of bacterial suspensions. The results of the in vivo tests were generally consistent with those obtained in vitro with strains of the B. melaninogenicus group. Synergism between gentamicin and penicillin, clindamycin, or metronidazole was shown in 13, 10, and 3 strains of this group, respectively. In vivo synergism was not clearly demonstrated with the strains of the B. fragilis group, possibly because clindamycin and metronidazole used alone were highly efficacious. We suggest that the synergistic effect of gentamicin is due to its increased transport into the bacterial cell in the presence of penicillin and, possibly, other antimicrobial agents. The newly recognized in vitro and in vivo synergism between penicillin and other antimicrobial agents and an aminoglycoside in B. melaninogenicus may have clinical implications that deserve to be investigated.

https://pubmed.ncbi.nlm.nih.gov/6142680/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Synergism between penicillin , clindamycin , or metronidazole and gentamicin against species of the Bacteroides melaninogenicus and Bacteroides fragilis groups . Clinical isolates of the Bacteroides melaninogenicus and Bacteroides fragilis groups were tested for in vitro and in vivo susceptibility to penicillin, clindamycin, and metronidazole, used singly or in combination with gentamicin. The in vitro tests consisted of determinations of minimal inhibitory concentrations (MICs) carried out with or without constant amounts of gentamicin. When used alone, gentamicin had negligible effects on the bacteria but significantly reduced the MICs of penicillin, clindamycin, and metronidazole against 11, 10, and 3, of the 15 strains of the B. melaninogenicus group, respectively. The 15 strains of the B. fragilis group were all beta-lactamase producers and were highly resistant to penicillin or the combination of penicillin and gentamicin. However, gentamicin reduced the MICs of clindamycin and metronidazole against 1 and 7 strains of this group, respectively. The in vivo tests were carried out in mice and consisted of measurements of the effects of the antimicrobial agents on the sizes and bacterial content of abscesses induced by subcutaneous injection of bacterial suspensions. The results of the in vivo tests were generally consistent with those obtained in vitro with strains of the B. melaninogenicus group. Synergism between gentamicin and penicillin, clindamycin, or metronidazole was shown in 13, 10, and 3 strains of this group, respectively. In vivo synergism was not clearly demonstrated with the strains of the B. fragilis group, possibly because clindamycin and metronidazole used alone were highly efficacious. We suggest that the synergistic effect of gentamicin is due to its increased transport into the bacterial cell in the presence of penicillin and, possibly, other antimicrobial agents. The newly recognized in vitro and in vivo synergism between penicillin and other antimicrobial agents and an aminoglycoside in B. melaninogenicus may have clinical implications that deserve to be investigated. ### Response: penicillin, clindamycin, metronidazole, gentamicin

363c8fe1e1792237985df9fbfb8e1a58

Thirty-one animals were allocated randomly to three groups , all administered four boluses of 0.25 mg/kg rTPA every 10 min for 30 min , 17 mg/kg aspirin intravenously , and heparin ( as a 100 IU/kg bolus followed by infusion of 50 IU/kg heparin per h ) , hirudin ( as a 2 mg/kg bolus followed by infusion of 1 mg/kg hirudin per h ) , or Yagin ( as an 80 micrograms/kg bolus followed by infusion of 43 micrograms/kg Yagin per h ) .

Enhancement of recombinant tissue-type plasminogen activator thrombolysis with a selective factor Xa inhibitor derived from the leech Hirudo medicinalis: comparison with heparin and hirudin in a rabbit thrombosis model. To compare the efficacy of Yagin, a factor Xa inhibitor derived from the leech Hirudo medicinalis, with those of heparin and hirudin as adjuncts to recombinant tissue-type plasminogen activator (rTPA) thrombolysis in a rabbit thrombosis model. ### methods Thirty-one animals were allocated randomly to three groups , all administered four boluses of 0.25 mg/kg rTPA every 10 min for 30 min , 17 mg/kg aspirin intravenously , and heparin ( as a 100 IU/kg bolus followed by infusion of 50 IU/kg heparin per h ) , hirudin ( as a 2 mg/kg bolus followed by infusion of 1 mg/kg hirudin per h ) , or Yagin ( as an 80 micrograms/kg bolus followed by infusion of 43 micrograms/kg Yagin per h ) . ### results Administration of Yagin was associated with a significant acceleration of the reflow time, this time being 14.5 +/- 1.2 min with Yagin, 25.8 +/- 5.2 min with heparin (P < 0.0001, versus Yagin), and 28.7 +/- 16.0 min with hirudin (P = 0.012, versus Yagin). Overall patency did not differ significantly among the three groups. ### conclusions At the indicated single doses, inhibition of factor Xa by a relatively low concentration of Yagin was found to be superior than that with either heparin or hirudin for accelerating rTPA thrombolysis.

https://pubmed.ncbi.nlm.nih.gov/9116933/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Enhancement of recombinant tissue-type plasminogen activator thrombolysis with a selective factor Xa inhibitor derived from the leech Hirudo medicinalis: comparison with heparin and hirudin in a rabbit thrombosis model. To compare the efficacy of Yagin, a factor Xa inhibitor derived from the leech Hirudo medicinalis, with those of heparin and hirudin as adjuncts to recombinant tissue-type plasminogen activator (rTPA) thrombolysis in a rabbit thrombosis model. ### methods Thirty-one animals were allocated randomly to three groups , all administered four boluses of 0.25 mg/kg rTPA every 10 min for 30 min , 17 mg/kg aspirin intravenously , and heparin ( as a 100 IU/kg bolus followed by infusion of 50 IU/kg heparin per h ) , hirudin ( as a 2 mg/kg bolus followed by infusion of 1 mg/kg hirudin per h ) , or Yagin ( as an 80 micrograms/kg bolus followed by infusion of 43 micrograms/kg Yagin per h ) . ### results Administration of Yagin was associated with a significant acceleration of the reflow time, this time being 14.5 +/- 1.2 min with Yagin, 25.8 +/- 5.2 min with heparin (P < 0.0001, versus Yagin), and 28.7 +/- 16.0 min with hirudin (P = 0.012, versus Yagin). Overall patency did not differ significantly among the three groups. ### conclusions At the indicated single doses, inhibition of factor Xa by a relatively low concentration of Yagin was found to be superior than that with either heparin or hirudin for accelerating rTPA thrombolysis. ### Response: aspirin, heparin, heparin

bd1b614a9a5b0c1225075c98f84ca619

In vivo evofosfamide was tumor suppressive as a single agent and cooperated with paclitaxel to reduce mammary tumor growth .

Anticancer efficacy of the hypoxia-activated prodrug evofosfamide (TH-302) in osteolytic breast cancer murine models. Tumor hypoxia is a major cause of treatment failure for a variety of malignancies. However, hypoxia offers treatment opportunities, exemplified by the development of compounds that target hypoxic regions within tumors. evofosfamide (TH-302) is a prodrug created by the conjugation of 2-nitroimidazole to bromo-isophosphoramide mustard (Br-IPM). When evofosfamide is delivered to hypoxic regions, the DNA cross-linking effector, Br-IPM, is released. This study assessed the cytotoxic activity of evofosfamide in vitro and its antitumor activity against osteolytic breast cancer either alone or in combination with paclitaxel in vivo. A panel of human breast cancer cell lines were treated with evofosfamide under hypoxia and assessed for cell viability. Osteolytic MDA-MB-231-TXSA cells were transplanted into the mammary fat pad, or into tibiae of mice, allowed to establish and treated with evofosfamide, paclitaxel, or both. Tumor burden was monitored using bioluminescence, and cancer-induced bone destruction was measured using micro-CT. In vitro, evofosfamide was selectively cytotoxic under hypoxic conditions. In vivo evofosfamide was tumor suppressive as a single agent and cooperated with paclitaxel to reduce mammary tumor growth . Breast cancer cells transplanted into the tibiae of mice developed osteolytic lesions. In contrast, treatment with evofosfamide or paclitaxel resulted in a significant delay in tumor growth and an overall reduction in tumor burden in bone, whereas combined treatment resulted in a significantly greater reduction in tumor burden in the tibia of mice. evofosfamide cooperates with paclitaxel and exhibits potent tumor suppressive activity against breast cancer growth in the mammary gland and in bone.

https://pubmed.ncbi.nlm.nih.gov/26749324/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Anticancer efficacy of the hypoxia-activated prodrug evofosfamide (TH-302) in osteolytic breast cancer murine models. Tumor hypoxia is a major cause of treatment failure for a variety of malignancies. However, hypoxia offers treatment opportunities, exemplified by the development of compounds that target hypoxic regions within tumors. evofosfamide (TH-302) is a prodrug created by the conjugation of 2-nitroimidazole to bromo-isophosphoramide mustard (Br-IPM). When evofosfamide is delivered to hypoxic regions, the DNA cross-linking effector, Br-IPM, is released. This study assessed the cytotoxic activity of evofosfamide in vitro and its antitumor activity against osteolytic breast cancer either alone or in combination with paclitaxel in vivo. A panel of human breast cancer cell lines were treated with evofosfamide under hypoxia and assessed for cell viability. Osteolytic MDA-MB-231-TXSA cells were transplanted into the mammary fat pad, or into tibiae of mice, allowed to establish and treated with evofosfamide, paclitaxel, or both. Tumor burden was monitored using bioluminescence, and cancer-induced bone destruction was measured using micro-CT. In vitro, evofosfamide was selectively cytotoxic under hypoxic conditions. In vivo evofosfamide was tumor suppressive as a single agent and cooperated with paclitaxel to reduce mammary tumor growth . Breast cancer cells transplanted into the tibiae of mice developed osteolytic lesions. In contrast, treatment with evofosfamide or paclitaxel resulted in a significant delay in tumor growth and an overall reduction in tumor burden in bone, whereas combined treatment resulted in a significantly greater reduction in tumor burden in the tibia of mice. evofosfamide cooperates with paclitaxel and exhibits potent tumor suppressive activity against breast cancer growth in the mammary gland and in bone. ### Response: evofosfamide, paclitaxel

366808bdb989ebd4b56210b53fb3e265

Paclitaxel and vinorelbine are among the most active new agents in metastatic breast cancer .

Phase I/II study of paclitaxel and vinorelbine in metastatic breast cancer. Paclitaxel and vinorelbine are among the most active new agents in metastatic breast cancer . Both in vitro and in vivo studies have shown that the combined administration of these two microtubule-targeting agents is feasible and worthwhile. Based on the promising preclinical data, patients with metastatic breast cancer no longer amenable to conventional treatment were entered into a phase I/II study in which the vinorelbine dose was fixed at 30 mg/sqm and paclitaxel was started at 90 mg/sqm and then subsequently escalated by 30 mg/sqm per step. Cycles were repeated every 21 days. Hematopoietic growth factor support was provided from the 4th dose level onwards. Grade III neutropenia was observed only in 2 patients treated at the 5th dose level. Thrombocytopenia never reached grade 3. Neurotoxicity was considered dose-limiting, since grade 3 peripheral neuropathy occurred in all three patients treated at the 6th dose level. Other toxicities were mild. paclitaxel 210 mg/sqm and vinorelbine 30 mg/sqm was the selected combination for phase II. Overall response rate in 34 evaluable patients was 38% (95% confidence interval (C.I.), 22% to 54%). In particular, 3 complete responses (9%) and 10 partial responses (29%) were observed. The observed level of antitumor activity, with an overall response rate of 38% and a median duration of response of 12 months, is of interest, since the study was targeted only to anthracycline-pretreated patients, most of whom had adverse prognostic features. The evaluation of a combination of vinorelbine and paclitaxel as first-line therapy in metastatic breast cancer seems worthwhile and is currently undergoing.

https://pubmed.ncbi.nlm.nih.gov/9493980/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Phase I/II study of paclitaxel and vinorelbine in metastatic breast cancer. Paclitaxel and vinorelbine are among the most active new agents in metastatic breast cancer . Both in vitro and in vivo studies have shown that the combined administration of these two microtubule-targeting agents is feasible and worthwhile. Based on the promising preclinical data, patients with metastatic breast cancer no longer amenable to conventional treatment were entered into a phase I/II study in which the vinorelbine dose was fixed at 30 mg/sqm and paclitaxel was started at 90 mg/sqm and then subsequently escalated by 30 mg/sqm per step. Cycles were repeated every 21 days. Hematopoietic growth factor support was provided from the 4th dose level onwards. Grade III neutropenia was observed only in 2 patients treated at the 5th dose level. Thrombocytopenia never reached grade 3. Neurotoxicity was considered dose-limiting, since grade 3 peripheral neuropathy occurred in all three patients treated at the 6th dose level. Other toxicities were mild. paclitaxel 210 mg/sqm and vinorelbine 30 mg/sqm was the selected combination for phase II. Overall response rate in 34 evaluable patients was 38% (95% confidence interval (C.I.), 22% to 54%). In particular, 3 complete responses (9%) and 10 partial responses (29%) were observed. The observed level of antitumor activity, with an overall response rate of 38% and a median duration of response of 12 months, is of interest, since the study was targeted only to anthracycline-pretreated patients, most of whom had adverse prognostic features. The evaluation of a combination of vinorelbine and paclitaxel as first-line therapy in metastatic breast cancer seems worthwhile and is currently undergoing. ### Response: Paclitaxel, vinorelbine

5a93666939620e4a5416bd80da463252

Treatments included recombinant human leptin ( 10 - 100nM ) , recombinant human IL-6 ( 0.3 - 3nM ) , or recombinant human erythropoietin ( Epo ) ( 10mU/ml ) .

Leptin receptor JAK2/STAT3 signaling modulates expression of Frizzled receptors in articular chondrocytes. Differentiated articular chondrocytes express a functional bisoform of the leptin receptor (LRb); however, leptin-LRb signaling in these cells is poorly understood. We hypothesized that leptin-LRb signaling in articular chondrocytes functions to modulate canonical Wnt signaling events by altering the expression of Frizzled (FZD) receptors. ### methods Human chondrocyte cell lines and primary articular chondrocytes were grown in serum containing growth media for 24h, followed by a media change to Dulbecco's modified Eagle's medium (DMEM) containing 1% Nutridoma-SP to obtain a serum-deficient environment for 24h before treatment. Treatments included recombinant human leptin ( 10 - 100nM ) , recombinant human IL-6 ( 0.3 - 3nM ) , or recombinant human erythropoietin ( Epo ) ( 10mU/ml ) . Cells were harvested 30min-48h after treatment and whole cell lysates were analyzed using immunoblots or luciferase assays. ### results Treatment of cells with leptin resulted in activation of Janus kinase 2 (JAK2) and subsequent phosphorylation of specific tyrosine residues on LRb, followed by dose- and time-dependent increases in the expression of Frizzled-1 (FZD1) and Frizzled-7 (FZD7). leptin-mediated increases in the expression of FZD1 were blocked by pre-treatment with the protein synthesis inhibitor cycloheximide or the JAK2 inhibitor AG490. Experiments using a series of hybrid Epo extracellular domain-leptin intracellular domain receptors (ELR) harboring mutations of specific tyrosine residues in the cytoplasmic tail showed that increases in the expression of FZD1 were dependent on LRb-mediated phosphorylation of STAT3, but not ERK1/2 or STAT5. leptin pre-treatment of chondrocytes prior to Wnt3a stimulation resulted in an increased magnitude of canonical Wnt signaling. ### conclusion These experiments show that leptin-LRb signaling in articular chondrocytes modulates expression of canonical Wnt signaling receptors and suggests that direct cross-talk between these pathways is important in determining chondrocyte homeostasis.

https://pubmed.ncbi.nlm.nih.gov/20868760/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Leptin receptor JAK2/STAT3 signaling modulates expression of Frizzled receptors in articular chondrocytes. Differentiated articular chondrocytes express a functional bisoform of the leptin receptor (LRb); however, leptin-LRb signaling in these cells is poorly understood. We hypothesized that leptin-LRb signaling in articular chondrocytes functions to modulate canonical Wnt signaling events by altering the expression of Frizzled (FZD) receptors. ### methods Human chondrocyte cell lines and primary articular chondrocytes were grown in serum containing growth media for 24h, followed by a media change to Dulbecco's modified Eagle's medium (DMEM) containing 1% Nutridoma-SP to obtain a serum-deficient environment for 24h before treatment. Treatments included recombinant human leptin ( 10 - 100nM ) , recombinant human IL-6 ( 0.3 - 3nM ) , or recombinant human erythropoietin ( Epo ) ( 10mU/ml ) . Cells were harvested 30min-48h after treatment and whole cell lysates were analyzed using immunoblots or luciferase assays. ### results Treatment of cells with leptin resulted in activation of Janus kinase 2 (JAK2) and subsequent phosphorylation of specific tyrosine residues on LRb, followed by dose- and time-dependent increases in the expression of Frizzled-1 (FZD1) and Frizzled-7 (FZD7). leptin-mediated increases in the expression of FZD1 were blocked by pre-treatment with the protein synthesis inhibitor cycloheximide or the JAK2 inhibitor AG490. Experiments using a series of hybrid Epo extracellular domain-leptin intracellular domain receptors (ELR) harboring mutations of specific tyrosine residues in the cytoplasmic tail showed that increases in the expression of FZD1 were dependent on LRb-mediated phosphorylation of STAT3, but not ERK1/2 or STAT5. leptin pre-treatment of chondrocytes prior to Wnt3a stimulation resulted in an increased magnitude of canonical Wnt signaling. ### conclusion These experiments show that leptin-LRb signaling in articular chondrocytes modulates expression of canonical Wnt signaling receptors and suggests that direct cross-talk between these pathways is important in determining chondrocyte homeostasis. ### Response: leptin, erythropoietin

0cc39e9cd43eed735fbf93fa813da8a0

Lenalidomide is currently being tested in combination with both standard and novel agents , including bortezomib , for patients with relapsed/refractory multiple myeloma .

Management of the relapsed/refractory myeloma patient: strategies incorporating lenalidomide. The immunomodulatory drug (IMiD) lenalidomide is a more potent immunomodulator than thalidomide with respect to its effects on cytokine modulation and increased T-cell proliferation. Of all the IMiDs, clinical trial data are most mature for lenalidomide. In phase I studies, dose-limiting toxicities of lenalidomide were limited to myelosuppression and a response rate of 72% was seen in relapsed/refractory patients. Three phase II studies subsequently evaluated the efficacy of single-agent lenalidomide or lenalidomide in combination with dexamethasone. As a single agent for post-transplant salvage therapy, lenalidomide 25 mg every 3 weeks has shown response rates as high as 44%. For patients with relapsed/refractory multiple myeloma, the MM-007 study has shown that lenalidomide alone or in combination with dexamethasone provides response rates between 37% and 41%. In MM-007, median progression-free survival was 5.5 months at early analysis and the median overall survival has yet to be reached. Preliminary data for the single-arm, multicenter, open-label MM-014 study showed that median time to progression was 5.6 months. Response rates indicate that 70% of patients had stable disease or better as the best response to treatment. Two randomized, phase III trials (MM-009 and MM-010) evaluated lenalidomide with high-dose dexamethasone versus high-dose dexamethasone alone for the treatment of relapsed/refractory multiple myeloma. Both MM-009 and MM-010 provided remarkably similar response rates for patients receiving lenalidomide and dexamethasone. In both trials response rates with the combination were greater than twice the response rates seen with high-dose dexamethasone alone. Indeed, an independent Data Monitoring Committee determined that both trials exceeded the prespecified efficacy value of P<.0015, recommending that the trials be discontinued and that lenalidomide be offered to patients on the dexamethasone arm of the trial if clinically indicated. Toxicities observed in studies of lenalidomide alone were low; the incidence of peripheral neuropathy was significantly lower than those noted in trials using thalidomide. Thrombocytopenia was a significant grade 3 or 4 toxicity observed; however, it was manageable with dose reduction. In contrast with high-dose dexamethasone, deep vein thrombosis has emerged as an important toxicity. Lenalidomide is currently being tested in combination with both standard and novel agents , including bortezomib , for patients with relapsed/refractory multiple myeloma .

https://pubmed.ncbi.nlm.nih.gov/16344100/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Management of the relapsed/refractory myeloma patient: strategies incorporating lenalidomide. The immunomodulatory drug (IMiD) lenalidomide is a more potent immunomodulator than thalidomide with respect to its effects on cytokine modulation and increased T-cell proliferation. Of all the IMiDs, clinical trial data are most mature for lenalidomide. In phase I studies, dose-limiting toxicities of lenalidomide were limited to myelosuppression and a response rate of 72% was seen in relapsed/refractory patients. Three phase II studies subsequently evaluated the efficacy of single-agent lenalidomide or lenalidomide in combination with dexamethasone. As a single agent for post-transplant salvage therapy, lenalidomide 25 mg every 3 weeks has shown response rates as high as 44%. For patients with relapsed/refractory multiple myeloma, the MM-007 study has shown that lenalidomide alone or in combination with dexamethasone provides response rates between 37% and 41%. In MM-007, median progression-free survival was 5.5 months at early analysis and the median overall survival has yet to be reached. Preliminary data for the single-arm, multicenter, open-label MM-014 study showed that median time to progression was 5.6 months. Response rates indicate that 70% of patients had stable disease or better as the best response to treatment. Two randomized, phase III trials (MM-009 and MM-010) evaluated lenalidomide with high-dose dexamethasone versus high-dose dexamethasone alone for the treatment of relapsed/refractory multiple myeloma. Both MM-009 and MM-010 provided remarkably similar response rates for patients receiving lenalidomide and dexamethasone. In both trials response rates with the combination were greater than twice the response rates seen with high-dose dexamethasone alone. Indeed, an independent Data Monitoring Committee determined that both trials exceeded the prespecified efficacy value of P<.0015, recommending that the trials be discontinued and that lenalidomide be offered to patients on the dexamethasone arm of the trial if clinically indicated. Toxicities observed in studies of lenalidomide alone were low; the incidence of peripheral neuropathy was significantly lower than those noted in trials using thalidomide. Thrombocytopenia was a significant grade 3 or 4 toxicity observed; however, it was manageable with dose reduction. In contrast with high-dose dexamethasone, deep vein thrombosis has emerged as an important toxicity. Lenalidomide is currently being tested in combination with both standard and novel agents , including bortezomib , for patients with relapsed/refractory multiple myeloma . ### Response: Lenalidomide, bortezomib

edbe761e468cedddb1012894057a128a

[ Efficacy of fluvoxamine combined with extended-release methylphenidate on treatment-refractory obsessive-compulsive disorder ] .

[ Efficacy of fluvoxamine combined with extended-release methylphenidate on treatment-refractory obsessive-compulsive disorder ] . To observe the clinical efficacy of dopamine modulator methylphenidate (MPH) of extended-release formulations (MPH-ER) augmentation of ongoing fluvoxamine treatment in refractory obsessive-compulsive disorder (OCD) and its effects on patient's anxiety and sleep quality.
 Methods: A pilot randomized, placebo-controlled, and double-blind trial was conducted at an outpatient, single-center academic setting. Participants included 44 adults with serotonin reuptake inhibitor treatment-refractory OCD and they received a stable fluvoxamine pharmacotherapy with Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores higher than 20. The 44 patients were randomly assigned into a study group and a control group, with 22 patiencs in each group. fluvoxamine and MPH-ER were given to the study group, while fluvoxamine and placebo were given to the control group, with 8 weeks of the treatment course. Y-BOCS, Hamilton Anxiety Scale (HAMA) were used to assess the efficacy, Pittsburgh Sleep Quality Index (PSQI) was used to evaluate the sleep quality, and Treatment Emergent Symptom Scale (TESS) was used to evaluate the side effects. Data were analyzed in the intention-to-treat sample.
 Results: The improvement in the Y-BOCS total score, Y-BOCS obsession subscale score and HAMA score were more prominent in the study group than those in the control group (P<0.001). There was no significant difference in PSQI score and TESS score between the two groups. MPH-ER was well tolerated.
 Conclusion: fluvoxamine combined with MPH-ER is effective in the treatment of refractory obsessive-compulsive disorder. It can improve anxiety and has no adverse effect on sleep quality.

https://pubmed.ncbi.nlm.nih.gov/30643068/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: [ Efficacy of fluvoxamine combined with extended-release methylphenidate on treatment-refractory obsessive-compulsive disorder ] . To observe the clinical efficacy of dopamine modulator methylphenidate (MPH) of extended-release formulations (MPH-ER) augmentation of ongoing fluvoxamine treatment in refractory obsessive-compulsive disorder (OCD) and its effects on patient's anxiety and sleep quality.
 Methods: A pilot randomized, placebo-controlled, and double-blind trial was conducted at an outpatient, single-center academic setting. Participants included 44 adults with serotonin reuptake inhibitor treatment-refractory OCD and they received a stable fluvoxamine pharmacotherapy with Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores higher than 20. The 44 patients were randomly assigned into a study group and a control group, with 22 patiencs in each group. fluvoxamine and MPH-ER were given to the study group, while fluvoxamine and placebo were given to the control group, with 8 weeks of the treatment course. Y-BOCS, Hamilton Anxiety Scale (HAMA) were used to assess the efficacy, Pittsburgh Sleep Quality Index (PSQI) was used to evaluate the sleep quality, and Treatment Emergent Symptom Scale (TESS) was used to evaluate the side effects. Data were analyzed in the intention-to-treat sample.
 Results: The improvement in the Y-BOCS total score, Y-BOCS obsession subscale score and HAMA score were more prominent in the study group than those in the control group (P<0.001). There was no significant difference in PSQI score and TESS score between the two groups. MPH-ER was well tolerated.
 Conclusion: fluvoxamine combined with MPH-ER is effective in the treatment of refractory obsessive-compulsive disorder. It can improve anxiety and has no adverse effect on sleep quality. ### Response: fluvoxamine, methylphenidate

9b59233ac22acf3f6df19738ee0dccee

Analysis of HER Family ( HER1 - 4 ) Expression as a Biomarker in Combination Therapy with Pertuzumab , Trastuzumab and Docetaxel for Advanced HER2-positive Breast Cancer .

Analysis of HER Family ( HER1 - 4 ) Expression as a Biomarker in Combination Therapy with Pertuzumab , Trastuzumab and Docetaxel for Advanced HER2-positive Breast Cancer . Chemotherapy with trastuzumab, pertuzumab and docetaxel (TPD regimen) is now strongly recommended as a treatment option for first-line therapy for advanced human epidermal growth factor receptor (HER)2-positive breast cancer. In this study, we analyzed the expression of HER 1-4 proteins, and investigated whether or not their expression was predictive of the response of advanced HER2-positive breast cancer to chemotherapy with the TPD regimen. ### Patients And Methods The study consisted of 29 cases in which TPD regimen chemotherapy was carried out from September 2013 to November 2015. The expression levels of estrogen receptor (ER), progesterone receptor (PgR), Ki67, HER1, HER2, HER3 and HER4 were evaluated using immunostaining employing needle biopsy specimens. ### results The overall response rate (ORR) was significantly higher in the HER3-positive group than in the HER3-negative group (p=0.002). In prognostic analysis, the HER3-positive group showed a significant progression-free survival extension over the HER3-negative group (p=0.042, log-rank). In univariate analysis, objective response (p=0.004, hazard ratio(HR)=0.123) and positive HER3 expression (p=0.023, HR=0.279) significantly contributed to extension of progression-free survival interval. ### conclusion HER3 expression may be a useful factor for predicting the response of HER2-positive breast cancer to chemotherapy with the TPD regimen.

https://pubmed.ncbi.nlm.nih.gov/29599351/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Analysis of HER Family ( HER1 - 4 ) Expression as a Biomarker in Combination Therapy with Pertuzumab , Trastuzumab and Docetaxel for Advanced HER2-positive Breast Cancer . Chemotherapy with trastuzumab, pertuzumab and docetaxel (TPD regimen) is now strongly recommended as a treatment option for first-line therapy for advanced human epidermal growth factor receptor (HER)2-positive breast cancer. In this study, we analyzed the expression of HER 1-4 proteins, and investigated whether or not their expression was predictive of the response of advanced HER2-positive breast cancer to chemotherapy with the TPD regimen. ### Patients And Methods The study consisted of 29 cases in which TPD regimen chemotherapy was carried out from September 2013 to November 2015. The expression levels of estrogen receptor (ER), progesterone receptor (PgR), Ki67, HER1, HER2, HER3 and HER4 were evaluated using immunostaining employing needle biopsy specimens. ### results The overall response rate (ORR) was significantly higher in the HER3-positive group than in the HER3-negative group (p=0.002). In prognostic analysis, the HER3-positive group showed a significant progression-free survival extension over the HER3-negative group (p=0.042, log-rank). In univariate analysis, objective response (p=0.004, hazard ratio(HR)=0.123) and positive HER3 expression (p=0.023, HR=0.279) significantly contributed to extension of progression-free survival interval. ### conclusion HER3 expression may be a useful factor for predicting the response of HER2-positive breast cancer to chemotherapy with the TPD regimen. ### Response: Pertuzumab, Trastuzumab, Docetaxel

5ed89d28b16c808ded0f444bde90dc63

Hepatic arterial infusion of floxuridine and systemic administration of gemcitabine and oxaliplatin .

Assessment of Hepatic Arterial Infusion of Floxuridine in Combination With Systemic Gemcitabine and Oxaliplatin in Patients With Unresectable Intrahepatic Cholangiocarcinoma: A Phase 2 Clinical Trial. Unresectable intrahepatic cholangiocarcinoma (IHC) carries a poor prognosis, with a median overall survival (OS) of 11 months. Hepatic arterial infusion (HAI) of high-dose chemotherapy may have potential benefit in these patients. ### objective To evaluate clinical outcomes when HAI chemotherapy is combined with systemic chemotherapy in patients with unresectable IHC. ### Design Setting And Participants A single-institution, phase 2 clinical trial including 38 patients was conducted with HAI floxuridine plus systemic gemcitabine and oxaliplatin in patients with unresectable IHC at Memorial Sloan Kettering Cancer Center between May 20, 2013, and June 27, 2019. A confirmatory phase 1/2 study using the same therapy was conducted during the same time period at Washington University in St Louis. Patients with histologically confirmed, unresectable IHC were eligible. Resectable metastatic disease to regional lymph nodes and prior systemic therapy were permitted. Patients with distant metastatic disease were excluded. ### interventions Hepatic arterial infusion of floxuridine and systemic administration of gemcitabine and oxaliplatin . ### Main Outcomes And Measures The primary outcome was progression-free survival (PFS) of 80% at 6 months. ### results For the phase 2 clinical trial at Memorial Sloan Kettering Cancer Center, 42 patients with unresectable IHC were included and, of these, 38 patients were treated (13 [34%] men; median [range] age at diagnosis, 64 [39-81] years). The median follow-up was 30.5 months. Twenty-two patients (58%) achieved a partial radiographic response, and 32 patients (84%) achieved disease control at 6 months. Four patients had sufficient response to undergo resection, and 1 patient had a complete pathologic response. The median PFS was 11.8 months (1-sided 90% CI, 11.1) with a 6-month PFS rate of 84.1% (90% CI, 74.8%-infinity), thereby meeting the primary end point (6-month PFS rate, 80%). The median OS was 25.0 months (95% CI, 20.6-not reached), and the 1-year OS rate was 89.5% (95% CI, 80.2%-99.8%). Patients with resectable regional lymph nodes (18 [47%]) showed no difference in OS compared with patients with node-negative disease (24-month OS: lymph node negative: 60%; 95% CI, 40%-91% vs lymph node positive: 50%; 95% CI, 30%-83%; P = .66). Four patients (11%) had grade 4 toxic effects requiring removal from the study (1 portal hypertension, 2 gastroduodenal artery aneurysms, 1 infection in the pump pocket). Subgroup analysis showed significant improvement in survival in patients with IDH1/2 mutated tumors (2-year OS, 90%; 95% CI, 73%-99%) vs wild-type (2-year OS, 33%; 95% CI, 18%-63%) (P = .01). In the Washington University in St Louis confirmatory cohort, 9 patients (90%) achieved disease control at 6 months; the most common grade 3 toxic effect was elevated results of liver function tests, and median PFS was 12.8 months (1-sided 90% CI, 6.4). ### Conclusions And Relevance Hepatic arterial infusion plus systemic chemotherapy appears to be highly active and tolerable in patients with unresectable IHC; further evaluation is warranted.

https://pubmed.ncbi.nlm.nih.gov/31670750/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Assessment of Hepatic Arterial Infusion of Floxuridine in Combination With Systemic Gemcitabine and Oxaliplatin in Patients With Unresectable Intrahepatic Cholangiocarcinoma: A Phase 2 Clinical Trial. Unresectable intrahepatic cholangiocarcinoma (IHC) carries a poor prognosis, with a median overall survival (OS) of 11 months. Hepatic arterial infusion (HAI) of high-dose chemotherapy may have potential benefit in these patients. ### objective To evaluate clinical outcomes when HAI chemotherapy is combined with systemic chemotherapy in patients with unresectable IHC. ### Design Setting And Participants A single-institution, phase 2 clinical trial including 38 patients was conducted with HAI floxuridine plus systemic gemcitabine and oxaliplatin in patients with unresectable IHC at Memorial Sloan Kettering Cancer Center between May 20, 2013, and June 27, 2019. A confirmatory phase 1/2 study using the same therapy was conducted during the same time period at Washington University in St Louis. Patients with histologically confirmed, unresectable IHC were eligible. Resectable metastatic disease to regional lymph nodes and prior systemic therapy were permitted. Patients with distant metastatic disease were excluded. ### interventions Hepatic arterial infusion of floxuridine and systemic administration of gemcitabine and oxaliplatin . ### Main Outcomes And Measures The primary outcome was progression-free survival (PFS) of 80% at 6 months. ### results For the phase 2 clinical trial at Memorial Sloan Kettering Cancer Center, 42 patients with unresectable IHC were included and, of these, 38 patients were treated (13 [34%] men; median [range] age at diagnosis, 64 [39-81] years). The median follow-up was 30.5 months. Twenty-two patients (58%) achieved a partial radiographic response, and 32 patients (84%) achieved disease control at 6 months. Four patients had sufficient response to undergo resection, and 1 patient had a complete pathologic response. The median PFS was 11.8 months (1-sided 90% CI, 11.1) with a 6-month PFS rate of 84.1% (90% CI, 74.8%-infinity), thereby meeting the primary end point (6-month PFS rate, 80%). The median OS was 25.0 months (95% CI, 20.6-not reached), and the 1-year OS rate was 89.5% (95% CI, 80.2%-99.8%). Patients with resectable regional lymph nodes (18 [47%]) showed no difference in OS compared with patients with node-negative disease (24-month OS: lymph node negative: 60%; 95% CI, 40%-91% vs lymph node positive: 50%; 95% CI, 30%-83%; P = .66). Four patients (11%) had grade 4 toxic effects requiring removal from the study (1 portal hypertension, 2 gastroduodenal artery aneurysms, 1 infection in the pump pocket). Subgroup analysis showed significant improvement in survival in patients with IDH1/2 mutated tumors (2-year OS, 90%; 95% CI, 73%-99%) vs wild-type (2-year OS, 33%; 95% CI, 18%-63%) (P = .01). In the Washington University in St Louis confirmatory cohort, 9 patients (90%) achieved disease control at 6 months; the most common grade 3 toxic effect was elevated results of liver function tests, and median PFS was 12.8 months (1-sided 90% CI, 6.4). ### Conclusions And Relevance Hepatic arterial infusion plus systemic chemotherapy appears to be highly active and tolerable in patients with unresectable IHC; further evaluation is warranted. ### Response: floxuridine, gemcitabine, oxaliplatin

3ed64085bfe928c461f9c17f9f8f5ac1

Data from the New Zealand Intensive Medicines Monitoring Programme indicate that celecoxib 200 mg/day and rofecoxib 25 mg/day are/were the most commonly prescribed doses and that 6 % of patients had taken rofecoxib 50 mg/day for longer than recommended .

Cyclo-oxygenase-2 inhibitors: when should they be used in the elderly? Chronic pain in the elderly is frequently a result of arthritic disorders, particularly osteoarthritis. The cyclo-oxygenase (COX)-2 inhibitors are as effective as standard NSAIDs for the relief of pain and for improving function in elderly patients with osteoarthritis and rheumatoid arthritis. COX-2 inhibitors increase the risk of serious gastroduodenal adverse reactions but there is evidence that they carry a lower risk for these adverse effects than standard NSAIDs, except when there is concurrent aspirin use. Since gastroduodenal disorders are the most frequently reported serious adverse effects of NSAIDs and these disorders occur more frequently in the elderly, COX-2 inhibitors offer an alternative to standard NSAIDs in this age group. However, they are not appropriate for many patients with cardiovascular and renal disease. The adverse reaction profile of the COX-2 inhibitors has confirmed the role of the COX-2 enzyme in renal function, salt and water homeostasis and the vascular endothelium. Thus, like standard NSAIDs, COX-2 inhibitors can cause renal failure, hypertension and exacerbation of cardiac failure. Of note is that these disorders are dose related. Thus, there are good reasons to avoid high doses of COX-2 inhibitors in the elderly. Clinical trials indicate that daily doses of rofecoxib 12.5 mg, celecoxib 100-200 mg, valdecoxib 10mg and etoricoxib 60 mg are the minimum effective doses of these agents. Data from the New Zealand Intensive Medicines Monitoring Programme indicate that celecoxib 200 mg/day and rofecoxib 25 mg/day are/were the most commonly prescribed doses and that 6 % of patients had taken rofecoxib 50 mg/day for longer than recommended . Recent research indicates that COX-2 inhibitors have a thrombotic potential, especially in high doses and when use is prolonged, and this further limits the extent to which they can be used in the elderly. Important interactions with COX-2 inhibitors in the elderly include those with warfarin, which can result in loss of control of anticoagulation, and those with ACE inhibitors, angiotensin II type 1 receptor antagonists and diuretics, which can result in loss of control of blood pressure and cardiac failure and, in hypovolaemic conditions, renal failure. The clinical significance of an interaction between celecoxib and aspirin to reduce the antiplatelet effect of the latter drug is unknown. Preliminary information from spontaneous reporting systems indicates that there may be differences in the risk of cardiac failure and hypertension between standard NSAIDs and COX-2 inhibitors and between rofecoxib and celecoxib. More formal studies using equivalent doses are needed to test this observation. Use of COX-2 inhibitors may be considered in the elderly to reduce the risk of gastroduodenal complications associated with standard NSAIDs but only when consideration has first been given to use of less toxic medicines as alternatives or supplements, the appropriate dose of the COX-2 inhibitor or standard NSAID, the presence and possible impact of co-morbidities, and the implications of taking COX-2 inhibitors with any concomitant medications. Equally important is regular monitoring of the patient taking a COX-2 inhibitor for efficacy and adverse effects, and ensuring that the patient has a continuing need to keep taking the drug. Close attention also needs to be paid to intercurrent illnesses and new prescriptions that may reduce the safety of the COX-2 inhibitor. A standard NSAID plus a proton pump inhibitor may be equally effective as a COX-2 inhibitor in reducing the risk of gastroduodenal toxicity and if used the same prescribing advice applies. Current knowledge concerning the thrombotic potential of COX-2 inhibitors suggests that this combination, if tolerated, may be preferable to a COX-2 inhibitor, particularly where prolonged use is required. This knowledge also indicates that for patients with or at high risk of ischaemic heart disease or stroke, COX-2 inhibitors are contraindicated.

https://pubmed.ncbi.nlm.nih.gov/15813652/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Cyclo-oxygenase-2 inhibitors: when should they be used in the elderly? Chronic pain in the elderly is frequently a result of arthritic disorders, particularly osteoarthritis. The cyclo-oxygenase (COX)-2 inhibitors are as effective as standard NSAIDs for the relief of pain and for improving function in elderly patients with osteoarthritis and rheumatoid arthritis. COX-2 inhibitors increase the risk of serious gastroduodenal adverse reactions but there is evidence that they carry a lower risk for these adverse effects than standard NSAIDs, except when there is concurrent aspirin use. Since gastroduodenal disorders are the most frequently reported serious adverse effects of NSAIDs and these disorders occur more frequently in the elderly, COX-2 inhibitors offer an alternative to standard NSAIDs in this age group. However, they are not appropriate for many patients with cardiovascular and renal disease. The adverse reaction profile of the COX-2 inhibitors has confirmed the role of the COX-2 enzyme in renal function, salt and water homeostasis and the vascular endothelium. Thus, like standard NSAIDs, COX-2 inhibitors can cause renal failure, hypertension and exacerbation of cardiac failure. Of note is that these disorders are dose related. Thus, there are good reasons to avoid high doses of COX-2 inhibitors in the elderly. Clinical trials indicate that daily doses of rofecoxib 12.5 mg, celecoxib 100-200 mg, valdecoxib 10mg and etoricoxib 60 mg are the minimum effective doses of these agents. Data from the New Zealand Intensive Medicines Monitoring Programme indicate that celecoxib 200 mg/day and rofecoxib 25 mg/day are/were the most commonly prescribed doses and that 6 % of patients had taken rofecoxib 50 mg/day for longer than recommended . Recent research indicates that COX-2 inhibitors have a thrombotic potential, especially in high doses and when use is prolonged, and this further limits the extent to which they can be used in the elderly. Important interactions with COX-2 inhibitors in the elderly include those with warfarin, which can result in loss of control of anticoagulation, and those with ACE inhibitors, angiotensin II type 1 receptor antagonists and diuretics, which can result in loss of control of blood pressure and cardiac failure and, in hypovolaemic conditions, renal failure. The clinical significance of an interaction between celecoxib and aspirin to reduce the antiplatelet effect of the latter drug is unknown. Preliminary information from spontaneous reporting systems indicates that there may be differences in the risk of cardiac failure and hypertension between standard NSAIDs and COX-2 inhibitors and between rofecoxib and celecoxib. More formal studies using equivalent doses are needed to test this observation. Use of COX-2 inhibitors may be considered in the elderly to reduce the risk of gastroduodenal complications associated with standard NSAIDs but only when consideration has first been given to use of less toxic medicines as alternatives or supplements, the appropriate dose of the COX-2 inhibitor or standard NSAID, the presence and possible impact of co-morbidities, and the implications of taking COX-2 inhibitors with any concomitant medications. Equally important is regular monitoring of the patient taking a COX-2 inhibitor for efficacy and adverse effects, and ensuring that the patient has a continuing need to keep taking the drug. Close attention also needs to be paid to intercurrent illnesses and new prescriptions that may reduce the safety of the COX-2 inhibitor. A standard NSAID plus a proton pump inhibitor may be equally effective as a COX-2 inhibitor in reducing the risk of gastroduodenal toxicity and if used the same prescribing advice applies. Current knowledge concerning the thrombotic potential of COX-2 inhibitors suggests that this combination, if tolerated, may be preferable to a COX-2 inhibitor, particularly where prolonged use is required. This knowledge also indicates that for patients with or at high risk of ischaemic heart disease or stroke, COX-2 inhibitors are contraindicated. ### Response: celecoxib, rofecoxib, rofecoxib

22cc4576d56fdf21b9fcd4001d2e46f9

Chemoimmunotherapy with cyclophosphamide , doxorubicin , vincristine , and prednisolone combined with rituximab ( R-CHOP ) is currently the first-line therapy for diffuse large B-cell lymphoma ( DLBCL ) .

Efficacy and tolerability of rituximab and reduced-dose cyclophosphamide, doxorubicin, vincristine, and prednisolone therapy for elderly patient with diffuse large B-cell lymphoma. Chemoimmunotherapy with cyclophosphamide , doxorubicin , vincristine , and prednisolone combined with rituximab ( R-CHOP ) is currently the first-line therapy for diffuse large B-cell lymphoma ( DLBCL ) . However, management of elderly patients is challenging and often requires dose reductions or prolonged treatment intervals. We investigated the proper dose of R-CHOP for them. ### methods At our institute, for DLBCL patients aged 65-79 and ≥80 years, we had reduced CHOP dose to 5/6 and 7/12, respectively, and retrospectively evaluated the reduced-dose R-CHOP. ### results Although the median age in the standard, 5/6, and 7/12-dose groups was 57, 73, and 84 years, respectively (p < 0.001), the 3-year event-free survival (EFS) rate did not differ between the standard and 5/6-dose groups (60.2 and 56.7%); however, 7/12-dose group had significantly inferior survival (25.9%). When patients aged 60-80 were evaluated, no difference in EFS was observed between the standard and 5/6-dose groups using the same international prognostic index. The neutrophil nadir and the frequency of infection were comparable among the three dose groups. ### Discussion And Conclusions Reduced-dose R-CHOP chemotherapy is a promising treatment for elderly patients with DLBCL in terms of efficacy and toxicity.

https://pubmed.ncbi.nlm.nih.gov/30101679/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Efficacy and tolerability of rituximab and reduced-dose cyclophosphamide, doxorubicin, vincristine, and prednisolone therapy for elderly patient with diffuse large B-cell lymphoma. Chemoimmunotherapy with cyclophosphamide , doxorubicin , vincristine , and prednisolone combined with rituximab ( R-CHOP ) is currently the first-line therapy for diffuse large B-cell lymphoma ( DLBCL ) . However, management of elderly patients is challenging and often requires dose reductions or prolonged treatment intervals. We investigated the proper dose of R-CHOP for them. ### methods At our institute, for DLBCL patients aged 65-79 and ≥80 years, we had reduced CHOP dose to 5/6 and 7/12, respectively, and retrospectively evaluated the reduced-dose R-CHOP. ### results Although the median age in the standard, 5/6, and 7/12-dose groups was 57, 73, and 84 years, respectively (p < 0.001), the 3-year event-free survival (EFS) rate did not differ between the standard and 5/6-dose groups (60.2 and 56.7%); however, 7/12-dose group had significantly inferior survival (25.9%). When patients aged 60-80 were evaluated, no difference in EFS was observed between the standard and 5/6-dose groups using the same international prognostic index. The neutrophil nadir and the frequency of infection were comparable among the three dose groups. ### Discussion And Conclusions Reduced-dose R-CHOP chemotherapy is a promising treatment for elderly patients with DLBCL in terms of efficacy and toxicity. ### Response: cyclophosphamide, doxorubicin, vincristine, prednisolone, rituximab

f840117cf09b1a62ab954e23e6ccdf3a

The purpose of our study was to compare the survival of porcine lung allografts after induction with either cyclosporine A ( CsA ) or tacrolimus .

Tacrolimus versus cyclosporine induction therapy in pulmonary transplantation in miniature swine. tacrolimus has been shown to provide superior immunosuppression in various solid organ transplant settings. The purpose of our study was to compare the survival of porcine lung allografts after induction with either cyclosporine A ( CsA ) or tacrolimus . ### methods Single lung transplantation from MHC mismatched donors was performed in 10 minipigs. Immunosuppression included 1.5 mg/kg per day methylprednisolone and 1.0 mg/kg per day azathioprine. CsA (n=5) was adjusted to trough levels of 300-500 ng/ml, tacrolimus (n=5) was adjusted to 16-26 ng/ml. All immunosuppressive drugs were discontinued on postoperative day (POD) 28. Allograft survival was monitored by sequential chest radiographs, bronchoscopy and transbronchial biopsy histology. Peripheral blood leukocytes were scanned for donor chimerism and CD3, CD4, CD8 and CD25 expression. ### results The animals survived a 4-week course of immunosuppression without radiological or histological signs of rejection on POD 28. Median allograft survival in CsA-treated animals was 55+/-15 days and all animals rejected their grafts within 42 days after withdrawal of immunosuppression. In tacrolimus-treated animals, median survival was 152+/-65 days with the longest survivor being electively sacrificed on POD 390 (P=0.0064). The degree of donor leukocyte chimerism and the frequency of CD4+CD25+ T-cells were higher in the tacrolimus group, however, these differences were not statistically significant. ### conclusion The results of our study show that primary immunosuppression with tacrolimus is superior to cyclosporine after pulmonary allotransplantation in a large animal model.

https://pubmed.ncbi.nlm.nih.gov/16054825/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Tacrolimus versus cyclosporine induction therapy in pulmonary transplantation in miniature swine. tacrolimus has been shown to provide superior immunosuppression in various solid organ transplant settings. The purpose of our study was to compare the survival of porcine lung allografts after induction with either cyclosporine A ( CsA ) or tacrolimus . ### methods Single lung transplantation from MHC mismatched donors was performed in 10 minipigs. Immunosuppression included 1.5 mg/kg per day methylprednisolone and 1.0 mg/kg per day azathioprine. CsA (n=5) was adjusted to trough levels of 300-500 ng/ml, tacrolimus (n=5) was adjusted to 16-26 ng/ml. All immunosuppressive drugs were discontinued on postoperative day (POD) 28. Allograft survival was monitored by sequential chest radiographs, bronchoscopy and transbronchial biopsy histology. Peripheral blood leukocytes were scanned for donor chimerism and CD3, CD4, CD8 and CD25 expression. ### results The animals survived a 4-week course of immunosuppression without radiological or histological signs of rejection on POD 28. Median allograft survival in CsA-treated animals was 55+/-15 days and all animals rejected their grafts within 42 days after withdrawal of immunosuppression. In tacrolimus-treated animals, median survival was 152+/-65 days with the longest survivor being electively sacrificed on POD 390 (P=0.0064). The degree of donor leukocyte chimerism and the frequency of CD4+CD25+ T-cells were higher in the tacrolimus group, however, these differences were not statistically significant. ### conclusion The results of our study show that primary immunosuppression with tacrolimus is superior to cyclosporine after pulmonary allotransplantation in a large animal model. ### Response: cyclosporine, tacrolimus

69ce1c75c42d853e74eec788b249f146

Cystoid Macular Edema during Treatment with Paclitaxel and Bevacizumab in a Patient with Metastatic Breast Cancer : A Case Report and Literature Review .

Cystoid Macular Edema during Treatment with Paclitaxel and Bevacizumab in a Patient with Metastatic Breast Cancer : A Case Report and Literature Review . We present a case of a metastatic breast cancer patient with cystoid macular edema (CME) occurring during treatment with paclitaxel and bevacizumab. She had a history of neoadjuvant chemotherapy and partial mastectomy plus axillary lymph node dissection for stage IIB left-breast cancer. Twenty-four months later, she was diagnosed with multiple bone metastases and underwent chemotherapy with paclitaxel and bevacizumab. Thirty-three months after the initiation of the chemotherapy, she noticed bilateral blurred vision. The retinal thickening with macular edema was observed by optical coherence tomography, resulting in a diagnosis of CME. With cessation of paclitaxel and administrating ocular instillation of a nonsteroidal anti-inflammatory drug, her macular edema gradually reduced and disappeared in a month. While CME caused by chemotherapy is very rare, taxane may cause ocular adverse events such as CME. It is important to urge patients to consult an ophthalmologist promptly when they have visual complaints during taxane chemotherapy.

https://pubmed.ncbi.nlm.nih.gov/28868019/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Cystoid Macular Edema during Treatment with Paclitaxel and Bevacizumab in a Patient with Metastatic Breast Cancer : A Case Report and Literature Review . We present a case of a metastatic breast cancer patient with cystoid macular edema (CME) occurring during treatment with paclitaxel and bevacizumab. She had a history of neoadjuvant chemotherapy and partial mastectomy plus axillary lymph node dissection for stage IIB left-breast cancer. Twenty-four months later, she was diagnosed with multiple bone metastases and underwent chemotherapy with paclitaxel and bevacizumab. Thirty-three months after the initiation of the chemotherapy, she noticed bilateral blurred vision. The retinal thickening with macular edema was observed by optical coherence tomography, resulting in a diagnosis of CME. With cessation of paclitaxel and administrating ocular instillation of a nonsteroidal anti-inflammatory drug, her macular edema gradually reduced and disappeared in a month. While CME caused by chemotherapy is very rare, taxane may cause ocular adverse events such as CME. It is important to urge patients to consult an ophthalmologist promptly when they have visual complaints during taxane chemotherapy. ### Response: Paclitaxel, Bevacizumab

fb1cdc336bfa44facd7d223ab0910933

The results suggest that third-line chemotherapy with combined bevacizumab and S-1 is safe and may delay the progression of mCRC resistant to oxaliplatin and irinotecan with mutated KRAS .

A Phase II Study of Third-Line Combination Chemotherapy with Bevacizumab Plus S-1 for Metastatic Colorectal Cancer with Mutated KRAS (SAVIOR Study). No salvage treatment had been established for metastatic colorectal cancer (mCRC) with mutated KRAS before the emergence of the new drugs regorafenib and TAS-102. We performed a phase II study of third-line chemotherapy with combined bevacizumab and S-1 for mCRC. ### methods Subjects were mCRC patients with mutated KRAS who showed disease aggravation even after two regimens with oxaliplatin and irinotecan. bevacizumab was given intravenously every 2 weeks, and S-1 was administered orally on days 1-28 of a 42-day cycle. The primary endpoint was disease control rate (DCR). ### results In total, 31 subjects were enrolled between August 2009 and June 2011. Three subjects in whom antitumor effects could not be evaluated were excluded. The median follow-up period was 8.6 months. The DCR was 67.9%, the response rate 0%, median progression-free survival 3.7 months, and overall survival 8.6 months. In 30 subjects evaluated for safety, there was no treatment-related death. The most common adverse events were anorexia (grade ≥3, 20%), diarrhea (grade 3, 10%), and decreased hemoglobin (grade ≥3, 17%). ### conclusions The results suggest that third-line chemotherapy with combined bevacizumab and S-1 is safe and may delay the progression of mCRC resistant to oxaliplatin and irinotecan with mutated KRAS .

https://pubmed.ncbi.nlm.nih.gov/27229742/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: A Phase II Study of Third-Line Combination Chemotherapy with Bevacizumab Plus S-1 for Metastatic Colorectal Cancer with Mutated KRAS (SAVIOR Study). No salvage treatment had been established for metastatic colorectal cancer (mCRC) with mutated KRAS before the emergence of the new drugs regorafenib and TAS-102. We performed a phase II study of third-line chemotherapy with combined bevacizumab and S-1 for mCRC. ### methods Subjects were mCRC patients with mutated KRAS who showed disease aggravation even after two regimens with oxaliplatin and irinotecan. bevacizumab was given intravenously every 2 weeks, and S-1 was administered orally on days 1-28 of a 42-day cycle. The primary endpoint was disease control rate (DCR). ### results In total, 31 subjects were enrolled between August 2009 and June 2011. Three subjects in whom antitumor effects could not be evaluated were excluded. The median follow-up period was 8.6 months. The DCR was 67.9%, the response rate 0%, median progression-free survival 3.7 months, and overall survival 8.6 months. In 30 subjects evaluated for safety, there was no treatment-related death. The most common adverse events were anorexia (grade ≥3, 20%), diarrhea (grade 3, 10%), and decreased hemoglobin (grade ≥3, 17%). ### conclusions The results suggest that third-line chemotherapy with combined bevacizumab and S-1 is safe and may delay the progression of mCRC resistant to oxaliplatin and irinotecan with mutated KRAS . ### Response: bevacizumab, S-1, oxaliplatin, irinotecan

4aa4b4fdad3c2ed039c5ce33e2f3cef5

In accordance with their different pharmacological profiles , the three NLs iloperidone , clozapine , and haloperidol have different effects in this preclinical cognitive task .

Differential effects of iloperidone, clozapine, and haloperidol on working memory of rats in the delayed non-matching-to-position paradigm. Because cognitive function, particularly working memory (WM), is severely impaired in schizophrenia, evaluation of neuroleptic medication should include investigation of possible effects on cognition. iloperidone is a promising, novel atypical neuroleptic drug (NL), for which no cognitive data is presently available. ### objective To investigate whether the novel atypical NL iloperidone would affect performance of rats on a WM test, using a delayed non-matching-to-position (DNMTP) paradigm, and compare its effects with those of the atypical NL clozapine and the typical NL haloperidol. ### methods Male Lister Hooded rats trained to criterion in an operant DNMTP task (0-64 s delay intervals) were administered vehicle, iloperidone (0.03, 0.1 mg/kg, i.p.), clozapine (0.1, 0.3 mg/kg, s.c.), haloperidol (0.003, 0.01, 0.03 mg/kg, s.c.), or scopolamine (0.05 mg/kg, s.c.). Together with choice accuracy, the motor performance of the task was measured. ### results It was found that: (1) iloperidone significantly improved choice accuracy delay-dependently while impairing task performance; (2) the atypical NL clozapine had no effect on choice accuracy and parameters related to motor function, but significantly increased the number of uncompleted trials; (3) haloperidol did not affect choice accuracy except at the longest delay with the highest dose, but in contrast to clozapine it significantly impaired task performance. ### conclusion In accordance with their different pharmacological profiles , the three NLs iloperidone , clozapine , and haloperidol have different effects in this preclinical cognitive task . These results might provide important information for the development of NLs with beneficial effects on cognition.

https://pubmed.ncbi.nlm.nih.gov/12827343/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Differential effects of iloperidone, clozapine, and haloperidol on working memory of rats in the delayed non-matching-to-position paradigm. Because cognitive function, particularly working memory (WM), is severely impaired in schizophrenia, evaluation of neuroleptic medication should include investigation of possible effects on cognition. iloperidone is a promising, novel atypical neuroleptic drug (NL), for which no cognitive data is presently available. ### objective To investigate whether the novel atypical NL iloperidone would affect performance of rats on a WM test, using a delayed non-matching-to-position (DNMTP) paradigm, and compare its effects with those of the atypical NL clozapine and the typical NL haloperidol. ### methods Male Lister Hooded rats trained to criterion in an operant DNMTP task (0-64 s delay intervals) were administered vehicle, iloperidone (0.03, 0.1 mg/kg, i.p.), clozapine (0.1, 0.3 mg/kg, s.c.), haloperidol (0.003, 0.01, 0.03 mg/kg, s.c.), or scopolamine (0.05 mg/kg, s.c.). Together with choice accuracy, the motor performance of the task was measured. ### results It was found that: (1) iloperidone significantly improved choice accuracy delay-dependently while impairing task performance; (2) the atypical NL clozapine had no effect on choice accuracy and parameters related to motor function, but significantly increased the number of uncompleted trials; (3) haloperidol did not affect choice accuracy except at the longest delay with the highest dose, but in contrast to clozapine it significantly impaired task performance. ### conclusion In accordance with their different pharmacological profiles , the three NLs iloperidone , clozapine , and haloperidol have different effects in this preclinical cognitive task . These results might provide important information for the development of NLs with beneficial effects on cognition. ### Response: iloperidone, clozapine, haloperidol

38e0f18b20644a73a11a219785d8e7bf

In the comparison between rivaroxaban-based triple therapy and ticagrelor + aspirin , the RR was 1 and its 95 % CI remained within a post-hoc margin of ± 15 % .

New oral anticoagulants in acute coronary syndrome: is there any advantage over existing treatments? After an acute coronary syndrome, dual antiplatelet therapy with clopidogrel plus aspirin is still a standard of care, but several new approaches have been investigated. ### objectives The present study re-examined the studies published thus far on this topic to evaluate the effectiveness of dual antiplatelet therapy in comparison to some of these new approaches (mainly, ticagrelor + aspirin and dual therapy plus a new oral anticoagulant [NOAC]; i.e., "triple therapy"). ### Materials And Methods The clinical material was directly derived from that reported in recent meta-analyses. Our re-analysis relied on standard equivalence methods in which interpretation is based on Relative Risks (RRs) along with their 95% Confidence Intervals (CI). The equivalence margins employed in our statistical testing were directly derived from those reported in randomized studies. ### results The equivalence margins were initially set at RR ranging from 0.775 to 1.29. According to these margins, triple therapy based on any NOAC proved to be superior to dual therapy alone, but at the same time demonstrated its equivalence with dual therapy. The results for apixaban-based triple therapy were inconclusive (not superior, not not-inferior, not equivalent and, of course, not inferior to the controls). Those for rivaroxaban-based triple therapy showed that this combination treatment was superior to dual therapy alone and failed to meet the criterion of equivalence. In the comparison between rivaroxaban-based triple therapy and ticagrelor + aspirin , the RR was 1 and its 95 % CI remained within a post-hoc margin of ± 15 % . ### conclusions Even if one considers the most effective NOAC in combination with clopidogrel + ticagrelor, this triple therapy is not more effective than ticagrelor + aspirin. On the other hand, the increased risk of bleeding with triple regimens is well demonstrated. We therefore conclude that these triple regimens did not play any important roles in the patients experiencing an acute coronary syndrome.

https://pubmed.ncbi.nlm.nih.gov/25177676/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: New oral anticoagulants in acute coronary syndrome: is there any advantage over existing treatments? After an acute coronary syndrome, dual antiplatelet therapy with clopidogrel plus aspirin is still a standard of care, but several new approaches have been investigated. ### objectives The present study re-examined the studies published thus far on this topic to evaluate the effectiveness of dual antiplatelet therapy in comparison to some of these new approaches (mainly, ticagrelor + aspirin and dual therapy plus a new oral anticoagulant [NOAC]; i.e., "triple therapy"). ### Materials And Methods The clinical material was directly derived from that reported in recent meta-analyses. Our re-analysis relied on standard equivalence methods in which interpretation is based on Relative Risks (RRs) along with their 95% Confidence Intervals (CI). The equivalence margins employed in our statistical testing were directly derived from those reported in randomized studies. ### results The equivalence margins were initially set at RR ranging from 0.775 to 1.29. According to these margins, triple therapy based on any NOAC proved to be superior to dual therapy alone, but at the same time demonstrated its equivalence with dual therapy. The results for apixaban-based triple therapy were inconclusive (not superior, not not-inferior, not equivalent and, of course, not inferior to the controls). Those for rivaroxaban-based triple therapy showed that this combination treatment was superior to dual therapy alone and failed to meet the criterion of equivalence. In the comparison between rivaroxaban-based triple therapy and ticagrelor + aspirin , the RR was 1 and its 95 % CI remained within a post-hoc margin of ± 15 % . ### conclusions Even if one considers the most effective NOAC in combination with clopidogrel + ticagrelor, this triple therapy is not more effective than ticagrelor + aspirin. On the other hand, the increased risk of bleeding with triple regimens is well demonstrated. We therefore conclude that these triple regimens did not play any important roles in the patients experiencing an acute coronary syndrome. ### Response: ticagrelor, aspirin

ffeb8dccbb9425bef2c952f8290978d5

The incidence of cross-resistance between indinavir , nelfinavir , ritonavir and saquinavir was high ( 60 - 90 % ) .

Analysis of HIV cross-resistance to protease inhibitors using a rapid single-cycle recombinant virus assay for patients failing on combination therapies. To assess the patterns of HIV phenotypic cross-resistance to protease inhibitors (PI) in patients experiencing viral load rebound on combination therapy including a PI. ### methods Phenotypic analysis of sensitivity to indinavir, nelfinavir, saquinavir, ritonavir and amprenavir was carried out using a single-cycle recombinant virus assay. Viral protease was sequenced by automated dideoxynucleotide chain termination. ### results Of the 108 patients studied, 68 had received indinavir, 50 ritonavir, 25 saquinavir and eight nelfinavir. The majority (71%) had received only one PI. The incidence of cross-resistance between indinavir , nelfinavir , ritonavir and saquinavir was high ( 60 - 90 % ) . Cross-resistance to amprenavir was less frequent (37-40%). However there was some correlation between levels of sensitivity to amprenavir and indinavir (r2 = 0.34; P < 0.01). Conversely, the correlation between levels of sensitivity to indinavir and saquinavir was poor (r2 = 0.25), particularly for patients who had not received saquinavir. The degree of cross-resistance correlated with the level of resistance and with the total number of mutations in the protease gene (P < 0.05, chi square test) but could not be significantly correlated to any one particular mutation or combination of mutations. Mutation 184V was significantly associated with cross-resistance to amprenavir, with no mutations at codon 50 observed, while mutations associated with cross-resistance to saquinavir differed according to the treatment received. ### conclusions These results suggest that, although the total number of protease mutations correlates with the degree of cross-resistance, the specific mechanisms accounting for primary resistance and for cross-resistance may be different.

https://pubmed.ncbi.nlm.nih.gov/10546858/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Analysis of HIV cross-resistance to protease inhibitors using a rapid single-cycle recombinant virus assay for patients failing on combination therapies. To assess the patterns of HIV phenotypic cross-resistance to protease inhibitors (PI) in patients experiencing viral load rebound on combination therapy including a PI. ### methods Phenotypic analysis of sensitivity to indinavir, nelfinavir, saquinavir, ritonavir and amprenavir was carried out using a single-cycle recombinant virus assay. Viral protease was sequenced by automated dideoxynucleotide chain termination. ### results Of the 108 patients studied, 68 had received indinavir, 50 ritonavir, 25 saquinavir and eight nelfinavir. The majority (71%) had received only one PI. The incidence of cross-resistance between indinavir , nelfinavir , ritonavir and saquinavir was high ( 60 - 90 % ) . Cross-resistance to amprenavir was less frequent (37-40%). However there was some correlation between levels of sensitivity to amprenavir and indinavir (r2 = 0.34; P < 0.01). Conversely, the correlation between levels of sensitivity to indinavir and saquinavir was poor (r2 = 0.25), particularly for patients who had not received saquinavir. The degree of cross-resistance correlated with the level of resistance and with the total number of mutations in the protease gene (P < 0.05, chi square test) but could not be significantly correlated to any one particular mutation or combination of mutations. Mutation 184V was significantly associated with cross-resistance to amprenavir, with no mutations at codon 50 observed, while mutations associated with cross-resistance to saquinavir differed according to the treatment received. ### conclusions These results suggest that, although the total number of protease mutations correlates with the degree of cross-resistance, the specific mechanisms accounting for primary resistance and for cross-resistance may be different. ### Response: indinavir, nelfinavir, ritonavir, saquinavir

bd9e3e4a321fffdb4c4e9ccdaf754cc3

Maintenance Treatment With Low-Dose Mercaptopurine in Combination With Allopurinol in Children With Acute Lymphoblastic Leukemia and Mercaptopurine-Induced Pancreatitis .

Maintenance Treatment With Low-Dose Mercaptopurine in Combination With Allopurinol in Children With Acute Lymphoblastic Leukemia and Mercaptopurine-Induced Pancreatitis . mercaptopurine (6-mercaptopurine, 6MP) is a mainstay of curative therapy in childhood acute lymphoblastic leukemia (ALL), and contributes to its 90% overall survival rate. We present two patients with ALL who suffered with severe pancreatitis secondary to 6MP. Through the use of allopurinol in conjunction with reduced dose 6MP, we were able to continue 6MP without further pancreatitis. This report contributes to the small body of literature on 6MP associated pancreatitis in childhood ALL and describes a novel approach to continued use of 6MP during therapy.

https://pubmed.ncbi.nlm.nih.gov/26878433/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Maintenance Treatment With Low-Dose Mercaptopurine in Combination With Allopurinol in Children With Acute Lymphoblastic Leukemia and Mercaptopurine-Induced Pancreatitis . mercaptopurine (6-mercaptopurine, 6MP) is a mainstay of curative therapy in childhood acute lymphoblastic leukemia (ALL), and contributes to its 90% overall survival rate. We present two patients with ALL who suffered with severe pancreatitis secondary to 6MP. Through the use of allopurinol in conjunction with reduced dose 6MP, we were able to continue 6MP without further pancreatitis. This report contributes to the small body of literature on 6MP associated pancreatitis in childhood ALL and describes a novel approach to continued use of 6MP during therapy. ### Response: Mercaptopurine, Allopurinol

a43b30fbecc655bb6b300d1ce1cb8cf2

The aim of this study was to assess the predictive and prognostic value of clinical response to second line treatment ( with capecitabine or with a two-drug regimen including irinotecan ) and to analyze its relation to selected clinical and pathological variables with respect to time to disease progression .

Second-Line Chemotherapy of Advanced Colorectal Cancer: Predictive and Prognostic Factors. Colorectal cancer progression presents a significant clinical problem. After its dissemination, the foundation of its treatment comprises of palliative chemotherapy. ### objectives The aim of this study was to assess the predictive and prognostic value of clinical response to second line treatment ( with capecitabine or with a two-drug regimen including irinotecan ) and to analyze its relation to selected clinical and pathological variables with respect to time to disease progression . ### Material And Methods The retrospective analysis of 164 patients with advanced colorectal cancer treated in 2001- -2008 included chosen clinical, pathological and follow-up data. ### results Response to second-line chemotherapy was observed in 34 out of 164 patients: In 18/82 in the irinotecan group (22%) and in 16/82 in the capecitabine group (19.5%). The mean survival time to progression following the second line of treatment amounted to 5.85 and 6.2 months respectively. Statistically, a higher number of patients in good condition of 0 to 1 was documented in the group responding to treatment. Significant correlation was documented between primary stage of the disease and time to progression in patients treated with capecitabine (p = 0.0258). The recurrence of the disease was observed in 44/45 patients following operation with radical intention but with an insufficient number of excised lymph nodes. A significantly longer time to progression was observed in women treated with capecitabine. In logistic regression, lack of treatment response was found to be an independent factor affecting the time to disease progression. Patients who did not respond to the second line of treatment demonstrated a significantly shorter time to disease progression than patients who responded to it and they showed a significantly higher number of patients with leucopenia during treatment. ### conclusions Clinical response to treatment in both treated groups is of significant importance for the probability of local recurrence of the disease, preservation of a good patient's condition and the higher level of leukocytes during treatment.

https://pubmed.ncbi.nlm.nih.gov/27629847/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Second-Line Chemotherapy of Advanced Colorectal Cancer: Predictive and Prognostic Factors. Colorectal cancer progression presents a significant clinical problem. After its dissemination, the foundation of its treatment comprises of palliative chemotherapy. ### objectives The aim of this study was to assess the predictive and prognostic value of clinical response to second line treatment ( with capecitabine or with a two-drug regimen including irinotecan ) and to analyze its relation to selected clinical and pathological variables with respect to time to disease progression . ### Material And Methods The retrospective analysis of 164 patients with advanced colorectal cancer treated in 2001- -2008 included chosen clinical, pathological and follow-up data. ### results Response to second-line chemotherapy was observed in 34 out of 164 patients: In 18/82 in the irinotecan group (22%) and in 16/82 in the capecitabine group (19.5%). The mean survival time to progression following the second line of treatment amounted to 5.85 and 6.2 months respectively. Statistically, a higher number of patients in good condition of 0 to 1 was documented in the group responding to treatment. Significant correlation was documented between primary stage of the disease and time to progression in patients treated with capecitabine (p = 0.0258). The recurrence of the disease was observed in 44/45 patients following operation with radical intention but with an insufficient number of excised lymph nodes. A significantly longer time to progression was observed in women treated with capecitabine. In logistic regression, lack of treatment response was found to be an independent factor affecting the time to disease progression. Patients who did not respond to the second line of treatment demonstrated a significantly shorter time to disease progression than patients who responded to it and they showed a significantly higher number of patients with leucopenia during treatment. ### conclusions Clinical response to treatment in both treated groups is of significant importance for the probability of local recurrence of the disease, preservation of a good patient's condition and the higher level of leukocytes during treatment. ### Response: capecitabine, irinotecan

2e00802dc163aa6e6be87ebdb2ca208f

An 8-week , randomized , parallel-group , double-blind international trial comparing the once-daily single-pill combination of telmisartan 80 mg and amlodipine 10 mg ( T/A ; n = 352 ) with once-daily amlodipine 10 mg ( A ; n = 354 ) in patients with type 2 diabetes mellitus and stage 1 or 2 hypertension ( systolic BP [ SBP ] > 150 mm Hg ) .

Single-pill combination of telmisartan/amlodipine versus amlodipine monotherapy in diabetic hypertensive patients: an 8-week randomized, parallel-group, double-blind trial. Hypertensive patients with diabetes often require combination therapy to achieve a blood pressure (BP) goal, and evidence suggests that time to BP goal is crucial to decrease cardiovascular risk. ### objective The aim of the study was to investigate whether the single-pill combination of telmisartan and amlodipine was superior to amlodipine alone as initial antihypertensive therapy in patients with diabetes and hypertension. ### methods An 8-week , randomized , parallel-group , double-blind international trial comparing the once-daily single-pill combination of telmisartan 80 mg and amlodipine 10 mg ( T/A ; n = 352 ) with once-daily amlodipine 10 mg ( A ; n = 354 ) in patients with type 2 diabetes mellitus and stage 1 or 2 hypertension ( systolic BP [ SBP ] > 150 mm Hg ) . ### results Patient demographics were similar between treatment groups, with an mean (SD) age of 60.5 (10.1) years; 51.7% were male, the mean (SD) body mass index was 32.0 (6.1) and the mean (SD) duration of hypertension was 8.8 (7.9) years. After 8 weeks (primary end point) as well as after 1, 2, and 4 weeks (key secondary end points), significantly greater decreases in the in-clinic mean seated trough cuff SBP with T/A versus A were achieved (-29.0 mm Hg vs -22.9 mm Hg at 8 weeks; P < 0.0001). After 8 weeks, 71.4% versus 53.8% of patients achieved the BP goal (<140/90 mm Hg) with T/A versus A, with mean SBPs of 131.9 and 137.9 mm Hg, respectively. Similar results were observed in the obese (metabolic syndrome) subpopulation. The more stringent goal (<130/80 mm Hg) was achieved by 36.4% and 17.9% patients in the T/A and A groups, respectively. The most common adverse events were peripheral edema, headache, and dizziness. ### conclusions In this selected population of patients with diabetes and hypertension, T/A provided prompt and greater BP decreases compared with A monotherapy, with the majority of patients achieving the BP goal (<140/90 mm Hg).

https://pubmed.ncbi.nlm.nih.gov/22386829/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Single-pill combination of telmisartan/amlodipine versus amlodipine monotherapy in diabetic hypertensive patients: an 8-week randomized, parallel-group, double-blind trial. Hypertensive patients with diabetes often require combination therapy to achieve a blood pressure (BP) goal, and evidence suggests that time to BP goal is crucial to decrease cardiovascular risk. ### objective The aim of the study was to investigate whether the single-pill combination of telmisartan and amlodipine was superior to amlodipine alone as initial antihypertensive therapy in patients with diabetes and hypertension. ### methods An 8-week , randomized , parallel-group , double-blind international trial comparing the once-daily single-pill combination of telmisartan 80 mg and amlodipine 10 mg ( T/A ; n = 352 ) with once-daily amlodipine 10 mg ( A ; n = 354 ) in patients with type 2 diabetes mellitus and stage 1 or 2 hypertension ( systolic BP [ SBP ] > 150 mm Hg ) . ### results Patient demographics were similar between treatment groups, with an mean (SD) age of 60.5 (10.1) years; 51.7% were male, the mean (SD) body mass index was 32.0 (6.1) and the mean (SD) duration of hypertension was 8.8 (7.9) years. After 8 weeks (primary end point) as well as after 1, 2, and 4 weeks (key secondary end points), significantly greater decreases in the in-clinic mean seated trough cuff SBP with T/A versus A were achieved (-29.0 mm Hg vs -22.9 mm Hg at 8 weeks; P < 0.0001). After 8 weeks, 71.4% versus 53.8% of patients achieved the BP goal (<140/90 mm Hg) with T/A versus A, with mean SBPs of 131.9 and 137.9 mm Hg, respectively. Similar results were observed in the obese (metabolic syndrome) subpopulation. The more stringent goal (<130/80 mm Hg) was achieved by 36.4% and 17.9% patients in the T/A and A groups, respectively. The most common adverse events were peripheral edema, headache, and dizziness. ### conclusions In this selected population of patients with diabetes and hypertension, T/A provided prompt and greater BP decreases compared with A monotherapy, with the majority of patients achieving the BP goal (<140/90 mm Hg). ### Response: telmisartan, amlodipine, amlodipine

63e916e263ec45ae78e3b37282fa746f

Pharmacokinetic studies evaluating the concurrent use of tenofovir and didanosine have been performed in healthy volunteers .

Effect of tenofovir on didanosine absorption in patients with HIV. To evaluate the pharmacokinetic interaction between tenofovir and didanosine when used in combination as a highly active antiretroviral therapy regimen. ### Data Sources Literature retrieval was accessed through MEDLINE (1966-January 2003) using the terms tenofovir and didanosine. Abstracts from recent meetings, including the International AIDS Society, Interscience Conference on Antimicrobial Agents and Chemotherapy, and the Infectious Diseases Society of America, were reviewed for relevant abstracts and poster presentations. ### Data Synthesis Pharmacokinetic studies evaluating the concurrent use of tenofovir and didanosine have been performed in healthy volunteers . tenofovir 300 mg administered concurrently with 400 mg didanosine results in a 48-64% increase in the didanosine maximum plasma concentration and AUC with no significant alterations in the tenofovir pharmacokinetic parameters. tenofovir 300 mg and didanosine 250 mg has been compared with didanosine 400 mg alone. The results demonstrated equivalent didanosine AUCs. ### conclusions When used concurrently, tenofovir significantly increases the maximum plasma concentration and the AUC of didanosine. Additional data in HIV-infected patients are needed to determine the long-term toxicities of this combination therapy. didanosine dose reduction should be considered when these 2 agents are used concurrently.

https://pubmed.ncbi.nlm.nih.gov/12921517/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Effect of tenofovir on didanosine absorption in patients with HIV. To evaluate the pharmacokinetic interaction between tenofovir and didanosine when used in combination as a highly active antiretroviral therapy regimen. ### Data Sources Literature retrieval was accessed through MEDLINE (1966-January 2003) using the terms tenofovir and didanosine. Abstracts from recent meetings, including the International AIDS Society, Interscience Conference on Antimicrobial Agents and Chemotherapy, and the Infectious Diseases Society of America, were reviewed for relevant abstracts and poster presentations. ### Data Synthesis Pharmacokinetic studies evaluating the concurrent use of tenofovir and didanosine have been performed in healthy volunteers . tenofovir 300 mg administered concurrently with 400 mg didanosine results in a 48-64% increase in the didanosine maximum plasma concentration and AUC with no significant alterations in the tenofovir pharmacokinetic parameters. tenofovir 300 mg and didanosine 250 mg has been compared with didanosine 400 mg alone. The results demonstrated equivalent didanosine AUCs. ### conclusions When used concurrently, tenofovir significantly increases the maximum plasma concentration and the AUC of didanosine. Additional data in HIV-infected patients are needed to determine the long-term toxicities of this combination therapy. didanosine dose reduction should be considered when these 2 agents are used concurrently. ### Response: tenofovir, didanosine

14e658c0964fbb5b76fbaf6250621d8a

This comparative phase III trial of mitoxantrone+vinorelbine ( MV ) versus 5-fluorouracil+cyclophosphamide+either doxorubicin or epirubicin ( FAC/FEC ) in the treatment of metastatic breast cancer was conducted to determine whether MV would produce equivalent efficacy , while resulting in an improved tolerance in relation to alopecia and nausea/vomiting .

Results of a phase III prospective, randomised trial, comparing mitoxantrone and vinorelbine (MV) in combination with standard FAC/FEC in front-line therapy of metastatic breast cancer. This comparative phase III trial of mitoxantrone+vinorelbine ( MV ) versus 5-fluorouracil+cyclophosphamide+either doxorubicin or epirubicin ( FAC/FEC ) in the treatment of metastatic breast cancer was conducted to determine whether MV would produce equivalent efficacy , while resulting in an improved tolerance in relation to alopecia and nausea/vomiting . This multicentre study recruited and randomised 281 patients with metastatic breast cancer; 280 were evaluable for response survival and toxicity (138 received FAC/FEC, 142 received MV). Patient characteristics were matched in each arm and stratification for prior exposure to adjuvant therapy was made prospectively. The overall response rate (ORR) was equivalent in the two arms (33.3% for FAC/FEC versus 34.5% for MV), but MV was more effective in patients who had received prior adjuvant therapy (13% (95% confidence interval (CI) 3-23) for FAC/FEC versus 33% (95% CI 20-47) for MV P=0.025) with a better progression-free survival (PFS) (5 months (range 1-18 months) versus 8 months (range 1-27 months); P=0.0007 for FAC/FEC versus MV, respectively) while FAC/FEC was more effective in previously untreated patients (ORR 43% (95% CI 33-53) versus 35% (95% CI 25-45), P=0.26; PFS 9 months (range 0-29 months) versus 6 months (range 0-26 months) P=0.014). Toxicity was monitored through the initial six cycles of therapy; febrile neutropenia and delayed haematological recovery was more frequent for MV (P=0.001), while nausea/vomiting of grades 3-4 was greater for FAC/FEC (P=0.031), as was alopecia (P=0.0001), cardiotoxicity was the same for the two regimens. MV represents a chemotherapy combination with equivalent efficacy to standard FAC/FEC and improved results for patients who have previously received adjuvant chemotherapy. Toxicity must be balanced to allow for increased haematological suppression and risk of febrile neutropenia with MV compared with a higher risk of subjectively unpleasant side-effects such as nausea/vomiting and alopecia with FAC/FEC.

https://pubmed.ncbi.nlm.nih.gov/11378344/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Results of a phase III prospective, randomised trial, comparing mitoxantrone and vinorelbine (MV) in combination with standard FAC/FEC in front-line therapy of metastatic breast cancer. This comparative phase III trial of mitoxantrone+vinorelbine ( MV ) versus 5-fluorouracil+cyclophosphamide+either doxorubicin or epirubicin ( FAC/FEC ) in the treatment of metastatic breast cancer was conducted to determine whether MV would produce equivalent efficacy , while resulting in an improved tolerance in relation to alopecia and nausea/vomiting . This multicentre study recruited and randomised 281 patients with metastatic breast cancer; 280 were evaluable for response survival and toxicity (138 received FAC/FEC, 142 received MV). Patient characteristics were matched in each arm and stratification for prior exposure to adjuvant therapy was made prospectively. The overall response rate (ORR) was equivalent in the two arms (33.3% for FAC/FEC versus 34.5% for MV), but MV was more effective in patients who had received prior adjuvant therapy (13% (95% confidence interval (CI) 3-23) for FAC/FEC versus 33% (95% CI 20-47) for MV P=0.025) with a better progression-free survival (PFS) (5 months (range 1-18 months) versus 8 months (range 1-27 months); P=0.0007 for FAC/FEC versus MV, respectively) while FAC/FEC was more effective in previously untreated patients (ORR 43% (95% CI 33-53) versus 35% (95% CI 25-45), P=0.26; PFS 9 months (range 0-29 months) versus 6 months (range 0-26 months) P=0.014). Toxicity was monitored through the initial six cycles of therapy; febrile neutropenia and delayed haematological recovery was more frequent for MV (P=0.001), while nausea/vomiting of grades 3-4 was greater for FAC/FEC (P=0.031), as was alopecia (P=0.0001), cardiotoxicity was the same for the two regimens. MV represents a chemotherapy combination with equivalent efficacy to standard FAC/FEC and improved results for patients who have previously received adjuvant chemotherapy. Toxicity must be balanced to allow for increased haematological suppression and risk of febrile neutropenia with MV compared with a higher risk of subjectively unpleasant side-effects such as nausea/vomiting and alopecia with FAC/FEC. ### Response: doxorubicin, epirubicin

a4a0e2aa03eb1a3c7b02ab4d991eca20

Overnight urinary oxytocin and vasopressin levels were obtained from 62 healthy males ( age range : 18 - 26 years ) to compare with trait measures of trust and aggressive behavior .

Oxytocin, vasopressin and trust: Associations with aggressive behavior in healthy young males. oxytocin enhances trust during social interactions and reduces the tendency for social betrayal. Animal studies have revealed that oxytocin is also an important factor in the establishment and regulation of aggression, for which social interaction is a critical precondition. In humans, however, the effects of oxytocin appear more nuanced and influenced by social context and personality traits. Moreover, the pro-social effects of oxytocin are not mirrored by vasopressin, despite their high chemical similarity. Rather, vasopressin has been associated with an increase of aggressive responses. Therefore, we sought to investigate the association of oxytocin and vasopressin with trust and aggressive behavior. Overnight urinary oxytocin and vasopressin levels were obtained from 62 healthy males ( age range : 18 - 26 years ) to compare with trait measures of trust and aggressive behavior . We found a significant interaction of oxytocin and trust on aggression in which low trait measures of trust, in combination with low levels of oxytocin, were associated with a history of aggressive behavior. Notably, we found no significant associations for vasopressin. Although both oxytocin and vasopressin have been shown to be important in the emergence of violent behavior, our study suggests that oxytocin may be particularly modified by affiliative behaviors. These findings provide insights into the neuropsychological influences of oxytocin, and highlights the potential for clinical translation regarding the treatment of patients who exhibit recurrent aggressive behavior.

https://pubmed.ncbi.nlm.nih.gov/30802507/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Oxytocin, vasopressin and trust: Associations with aggressive behavior in healthy young males. oxytocin enhances trust during social interactions and reduces the tendency for social betrayal. Animal studies have revealed that oxytocin is also an important factor in the establishment and regulation of aggression, for which social interaction is a critical precondition. In humans, however, the effects of oxytocin appear more nuanced and influenced by social context and personality traits. Moreover, the pro-social effects of oxytocin are not mirrored by vasopressin, despite their high chemical similarity. Rather, vasopressin has been associated with an increase of aggressive responses. Therefore, we sought to investigate the association of oxytocin and vasopressin with trust and aggressive behavior. Overnight urinary oxytocin and vasopressin levels were obtained from 62 healthy males ( age range : 18 - 26 years ) to compare with trait measures of trust and aggressive behavior . We found a significant interaction of oxytocin and trust on aggression in which low trait measures of trust, in combination with low levels of oxytocin, were associated with a history of aggressive behavior. Notably, we found no significant associations for vasopressin. Although both oxytocin and vasopressin have been shown to be important in the emergence of violent behavior, our study suggests that oxytocin may be particularly modified by affiliative behaviors. These findings provide insights into the neuropsychological influences of oxytocin, and highlights the potential for clinical translation regarding the treatment of patients who exhibit recurrent aggressive behavior. ### Response: oxytocin, vasopressin

a852ffe5eeabb1b66257d24e56fa70bf

Additionally , the combined effect of Lapatinib together with Herceptin or Cetuximab on cell-mediated cytotoxicity was evaluated .

Lapatinib inhibits receptor phosphorylation and cell growth and enhances antibody-dependent cellular cytotoxicity of EGFR- and HER2-overexpressing esophageal cancer cell lines. lapatinib is a dual tyrosine kinase inhibitor of the EGFR and HER2 tyrosine kinase domains. EGFR is expressed in 33.3% and HER2 in 30.3% of esophageal squamous cell carcinomas (ESCCs). To explore the potential utility of lapatinib for therapy of ESCC patients, we evaluated the effect of lapatinib on a panel of ESCC cell lines. EGFR and HER2 expression by the cell lines was established, and the effects of lapatinib on inhibition of the phosphorylation of HER2, antiproliferative effect, apoptosis-inducing activity and accumulation of HER2 and EGFR on cell surface were evaluated. Additionally , the combined effect of Lapatinib together with Herceptin or Cetuximab on cell-mediated cytotoxicity was evaluated . lapatinib inhibited HER2 phosphorylation in HER2-overexpressing, HER2 gene amplification positive ESCC cell line. lapatinib also inhibited cell proliferation, induced apoptosis and caused the surface accumulation of HER2 and EGFR in ESCC cell lines. Addition of lapatinib increased Herceptin-mediated antibody-dependent cell-mediated cytotoxicity by 15-25% with three ESCC target cell lines. Similarly, cetuximab-mediated antibody-dependent cell-mediated cytotoxicity also increased by 15-30% in two ESCC cell lines on addition of lapatinib. Cumulatively, the data indicate that lapatinib has activity in EGFR- and/or HER2-expressing ESCC cells, and the combination therapy of lapatinib and cetuximab/Herceptin is a promising strategy in ESCC.

https://pubmed.ncbi.nlm.nih.gov/21207425/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Lapatinib inhibits receptor phosphorylation and cell growth and enhances antibody-dependent cellular cytotoxicity of EGFR- and HER2-overexpressing esophageal cancer cell lines. lapatinib is a dual tyrosine kinase inhibitor of the EGFR and HER2 tyrosine kinase domains. EGFR is expressed in 33.3% and HER2 in 30.3% of esophageal squamous cell carcinomas (ESCCs). To explore the potential utility of lapatinib for therapy of ESCC patients, we evaluated the effect of lapatinib on a panel of ESCC cell lines. EGFR and HER2 expression by the cell lines was established, and the effects of lapatinib on inhibition of the phosphorylation of HER2, antiproliferative effect, apoptosis-inducing activity and accumulation of HER2 and EGFR on cell surface were evaluated. Additionally , the combined effect of Lapatinib together with Herceptin or Cetuximab on cell-mediated cytotoxicity was evaluated . lapatinib inhibited HER2 phosphorylation in HER2-overexpressing, HER2 gene amplification positive ESCC cell line. lapatinib also inhibited cell proliferation, induced apoptosis and caused the surface accumulation of HER2 and EGFR in ESCC cell lines. Addition of lapatinib increased Herceptin-mediated antibody-dependent cell-mediated cytotoxicity by 15-25% with three ESCC target cell lines. Similarly, cetuximab-mediated antibody-dependent cell-mediated cytotoxicity also increased by 15-30% in two ESCC cell lines on addition of lapatinib. Cumulatively, the data indicate that lapatinib has activity in EGFR- and/or HER2-expressing ESCC cells, and the combination therapy of lapatinib and cetuximab/Herceptin is a promising strategy in ESCC. ### Response: Lapatinib, Herceptin, Cetuximab

aa87c9c97af30d5f0c6ba4db662cd97d

In a case-control study , we compared 52 consecutive patients undergoing isolated CABG on aspirin and clopidogrel 75mg/d versus 50 controls on aspirin monotherapy .

Preoperative platelet aggregation predicts perioperative blood loss and rethoracotomy for bleeding in patients receiving dual antiplatelet treatment prior to coronary surgery. Patients scheduled for coronary artery bypass graft surgery (CABG) are commonly treated with clopidogrel. We sought to assess the relation between preoperative platelet aggregation and bleeds in CABG patients on clopidogrel. ### Material And Methods In a case-control study , we compared 52 consecutive patients undergoing isolated CABG on aspirin and clopidogrel 75mg/d versus 50 controls on aspirin monotherapy . Platelet aggregation induced by 10μmol/l adenosine di-phosphate (ADP) in platelet-rich plasma was measured in subjects on clopidogrel within 5days prior to surgery. ADP-induced aggregation of ≥50% was used to define subjects with satisfactory inhibition of platelet reactivity. ### results In 29 patients with preoperative ADP-induced aggregation ≥50%, compared with 23 subjects with aggregation <50%, lower chest-tube drainage volumes (after 6h, p=0.002; and 12h, p=0.001) and fewer rethoracotomies were observed (p=0.03). The former group was characterized with lower transfusion rates of packed red blood cells (p=0.009), platelet concentrate (p=0.04) and fresh frozen plasma (p=0.001). Patients with ADP-induced aggregation ≥50% did not differ from untreated controls regarding the postoperative drainage, transfusions and rethoracotomy. The incidence of thromboembolic events and death during perioperative period were similar in all groups. Multivariate logistic regression identified ADP-induced aggregation <50% as the only independent predictor of rethoracotomy (OR=2.94 [1.12-7.75], p=0.029). ### conclusions Patients on aspirin and clopidogrel <5days before CABG who had preoperative ADP-induced platelet aggregation ≥50% have bleeding risk similar to those receiving aspirin monotherapy. Reduced platelet reactivity to ADP can predict postoperative bleeding in CABG patients on dual antiplatelet therapy.

https://pubmed.ncbi.nlm.nih.gov/26003782/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Preoperative platelet aggregation predicts perioperative blood loss and rethoracotomy for bleeding in patients receiving dual antiplatelet treatment prior to coronary surgery. Patients scheduled for coronary artery bypass graft surgery (CABG) are commonly treated with clopidogrel. We sought to assess the relation between preoperative platelet aggregation and bleeds in CABG patients on clopidogrel. ### Material And Methods In a case-control study , we compared 52 consecutive patients undergoing isolated CABG on aspirin and clopidogrel 75mg/d versus 50 controls on aspirin monotherapy . Platelet aggregation induced by 10μmol/l adenosine di-phosphate (ADP) in platelet-rich plasma was measured in subjects on clopidogrel within 5days prior to surgery. ADP-induced aggregation of ≥50% was used to define subjects with satisfactory inhibition of platelet reactivity. ### results In 29 patients with preoperative ADP-induced aggregation ≥50%, compared with 23 subjects with aggregation <50%, lower chest-tube drainage volumes (after 6h, p=0.002; and 12h, p=0.001) and fewer rethoracotomies were observed (p=0.03). The former group was characterized with lower transfusion rates of packed red blood cells (p=0.009), platelet concentrate (p=0.04) and fresh frozen plasma (p=0.001). Patients with ADP-induced aggregation ≥50% did not differ from untreated controls regarding the postoperative drainage, transfusions and rethoracotomy. The incidence of thromboembolic events and death during perioperative period were similar in all groups. Multivariate logistic regression identified ADP-induced aggregation <50% as the only independent predictor of rethoracotomy (OR=2.94 [1.12-7.75], p=0.029). ### conclusions Patients on aspirin and clopidogrel <5days before CABG who had preoperative ADP-induced platelet aggregation ≥50% have bleeding risk similar to those receiving aspirin monotherapy. Reduced platelet reactivity to ADP can predict postoperative bleeding in CABG patients on dual antiplatelet therapy. ### Response: aspirin, clopidogrel, aspirin

53063ff66fc71e61d0f3a62bb493d9fe

The MBCs were 1 to 2 tubes higher than the broth dilution MICs for levofloxacin , 1 to 3 tubes higher than the broth dilution MICs for ofloxacin , 1 to 3 tubes higher than the broth dilution MICs for erythromycin , and the same as the broth dilution MICs for rifampin .

Inhibitory and bactericidal activities of levofloxacin, ofloxacin, erythromycin, and rifampin used singly and in combination against Legionella pneumophila. The susceptibilities of 56 Legionella pneumophila isolates (43 clinical and 15 environmental isolates) to levofloxacin, ofloxacin, erythromycin, and rifampin were studied with buffered charcoal yeast extract (BCYE) agar (inoculum, 10(4) CFU per spot), and the susceptibilities of five isolates were studied with buffered yeast extract (BYE) broth (inoculum, 10(5) CFU/ml). The MICs inhibiting 90% of strains tested on BCYE agar were 0.125, 0.25, 1.0, and < or = 0.004 micrograms/ml for levofloxacin, ofloxacin, erythromycin, and rifampin, respectively. The MICs by the BYE broth dilution method were 1 to 3, 2, 1 to 2, and 1 tube lower than those by the agar dilution method for levofloxacin, ofloxacin, erythromycin, and rifampin, respectively. The MBCs were 1 to 2 tubes higher than the broth dilution MICs for levofloxacin , 1 to 3 tubes higher than the broth dilution MICs for ofloxacin , 1 to 3 tubes higher than the broth dilution MICs for erythromycin , and the same as the broth dilution MICs for rifampin . In kinetic time-kill curve studies, at drug concentrations of 1.0 and 2.0 times the MIC, the most active drugs were levofloxacin and rifampin. At 72 h, concentrations of levofloxacin and rifampin of 2.0 times the MIC demonstrated a bactericidal effect against L. pneumophila. In contrast, at concentrations of 1.0 and 2.0 times the MICs regrowth was observed with ofloxacin and only a gradual decrease in the numbers of CFU per milliliter was observed with erythromycin. Only a minor inhibitory effect was observed with 0.25 or 0.5 time the MICs of all drugs at 24 to 48 h, with regrowth occurring at 72 h. In contrast to erythromycin or ofloxacin plus rifampin at 0.25 time the MICs, only levofloxacin plus rifampin demonstrated synergy. Thus, levofloxacin demonstrated the best inhibitory and bactericidal effects against L. pneumophila when it was studied alone or in a combination with rifampin.

https://pubmed.ncbi.nlm.nih.gov/7486896/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Inhibitory and bactericidal activities of levofloxacin, ofloxacin, erythromycin, and rifampin used singly and in combination against Legionella pneumophila. The susceptibilities of 56 Legionella pneumophila isolates (43 clinical and 15 environmental isolates) to levofloxacin, ofloxacin, erythromycin, and rifampin were studied with buffered charcoal yeast extract (BCYE) agar (inoculum, 10(4) CFU per spot), and the susceptibilities of five isolates were studied with buffered yeast extract (BYE) broth (inoculum, 10(5) CFU/ml). The MICs inhibiting 90% of strains tested on BCYE agar were 0.125, 0.25, 1.0, and < or = 0.004 micrograms/ml for levofloxacin, ofloxacin, erythromycin, and rifampin, respectively. The MICs by the BYE broth dilution method were 1 to 3, 2, 1 to 2, and 1 tube lower than those by the agar dilution method for levofloxacin, ofloxacin, erythromycin, and rifampin, respectively. The MBCs were 1 to 2 tubes higher than the broth dilution MICs for levofloxacin , 1 to 3 tubes higher than the broth dilution MICs for ofloxacin , 1 to 3 tubes higher than the broth dilution MICs for erythromycin , and the same as the broth dilution MICs for rifampin . In kinetic time-kill curve studies, at drug concentrations of 1.0 and 2.0 times the MIC, the most active drugs were levofloxacin and rifampin. At 72 h, concentrations of levofloxacin and rifampin of 2.0 times the MIC demonstrated a bactericidal effect against L. pneumophila. In contrast, at concentrations of 1.0 and 2.0 times the MICs regrowth was observed with ofloxacin and only a gradual decrease in the numbers of CFU per milliliter was observed with erythromycin. Only a minor inhibitory effect was observed with 0.25 or 0.5 time the MICs of all drugs at 24 to 48 h, with regrowth occurring at 72 h. In contrast to erythromycin or ofloxacin plus rifampin at 0.25 time the MICs, only levofloxacin plus rifampin demonstrated synergy. Thus, levofloxacin demonstrated the best inhibitory and bactericidal effects against L. pneumophila when it was studied alone or in a combination with rifampin. ### Response: levofloxacin, erythromycin, rifampin

e7607395b589a9d6a885823a4bdd8d74

Ketanserin ( a 5-HT2 antagonist , 10 mumol/L ) and tropisetron ( a 5-HT3 antagonist , 1 mumol/L ) had no effect .

Ketotifen modulates noncholinergic contraction in guinea pig airways in vitro by a prejunctional nonhistamine receptor. In guinea pig airways, electrical field stimulation (50 V, 0.5 msec, 8 Hz for 20 seconds) produces a rapid contraction, which is followed by a long-lasting contraction, at least in the lower part of the trachea and in the bronchi. The latter contraction is due to the release of neuropeptides from airway sensory nerves. ketotifen fumarate has been demonstrated to inhibit the noncholinergic contraction in guinea pig airways in vitro, but no attempt has been made to identify the receptor type. Therefore we have performed an in vitro study to investigate which receptor is responsible for the inhibitory effects of ketotifen on noncholinergic contraction in guinea pig airways. ketotifen (3 to 100 mumol/L) produced a concentration-dependent inhibition of the noncholinergic contraction, with a maximum inhibition of 74% +/- 7% at 8 Hz stimulation (p < 0.001; n = 5). Pretreatment of the tissues with either cimetidine (10 mumol/L) or thioperamide (10 mumol/L) or phentolamine (10 mumol/L) did not prevent the inhibitory effect of ketotifen (10 mumol/L). cetirizine (10 mumol/L), on the other hand, produced no inhibition of the noncholinergic contraction at all. Metitepine (0.1 mumol/L) and methysergide (1 mumol/L), both 5-HT1 antagonists, attenuated the inhibitory effect of ketotifen (10 mumol/L). Ketanserin ( a 5-HT2 antagonist , 10 mumol/L ) and tropisetron ( a 5-HT3 antagonist , 1 mumol/L ) had no effect . Ketoifen (100 mumol/L) did not affect the cumulative dose-response relationship to exogenous substance P (0.01 mumol/L to 10 mmol/L).(ABSTRACT TRUNCATED AT 250 WORDS)

https://pubmed.ncbi.nlm.nih.gov/8064073/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Ketotifen modulates noncholinergic contraction in guinea pig airways in vitro by a prejunctional nonhistamine receptor. In guinea pig airways, electrical field stimulation (50 V, 0.5 msec, 8 Hz for 20 seconds) produces a rapid contraction, which is followed by a long-lasting contraction, at least in the lower part of the trachea and in the bronchi. The latter contraction is due to the release of neuropeptides from airway sensory nerves. ketotifen fumarate has been demonstrated to inhibit the noncholinergic contraction in guinea pig airways in vitro, but no attempt has been made to identify the receptor type. Therefore we have performed an in vitro study to investigate which receptor is responsible for the inhibitory effects of ketotifen on noncholinergic contraction in guinea pig airways. ketotifen (3 to 100 mumol/L) produced a concentration-dependent inhibition of the noncholinergic contraction, with a maximum inhibition of 74% +/- 7% at 8 Hz stimulation (p < 0.001; n = 5). Pretreatment of the tissues with either cimetidine (10 mumol/L) or thioperamide (10 mumol/L) or phentolamine (10 mumol/L) did not prevent the inhibitory effect of ketotifen (10 mumol/L). cetirizine (10 mumol/L), on the other hand, produced no inhibition of the noncholinergic contraction at all. Metitepine (0.1 mumol/L) and methysergide (1 mumol/L), both 5-HT1 antagonists, attenuated the inhibitory effect of ketotifen (10 mumol/L). Ketanserin ( a 5-HT2 antagonist , 10 mumol/L ) and tropisetron ( a 5-HT3 antagonist , 1 mumol/L ) had no effect . Ketoifen (100 mumol/L) did not affect the cumulative dose-response relationship to exogenous substance P (0.01 mumol/L to 10 mmol/L).(ABSTRACT TRUNCATED AT 250 WORDS) ### Response: Ketanserin, tropisetron

6f5e628682c1f970cc1c941f78c757f9

This three-phase study was designed to determine if a pharmacokinetic drug-drug interaction exists between zidovudine and oxazepam .

Pharmacokinetics of zidovudine alone and in combination with oxazepam in the HIV infected patient. This three-phase study was designed to determine if a pharmacokinetic drug-drug interaction exists between zidovudine and oxazepam . Six individuals infected with human immunodeficiency virus (HIV) and receiving zidovudine at 500 mg daily, with normal renal and hepatic function, were enrolled. During phase I, zidovudine pharmacokinetics were studied after steady-state oral administration (100 mg every 4 h) and after a single dose (70 mg) of intravenous zidovudine. Phase II consisted of a single oral dose (30 mg) of oxazepam followed by a 48-h blood sampling period. Phase III began with 48 h of concomitant zidovudine, 100 mg orally every 4 h, and oxazepam, 15 mg orally every 8 h, followed by concomitant dosing of intravenous zidovudine and oral oxazepam. zidovudine concentrations were determined by radioimmunoassay. oxazepam concentrations were determined with use of a fluorescence polarization immunoassay. The calculated bioavailability was 0.61 for zidovudine alone and 0.75 when administered in combination with oxazepam (p = 0.16). Plasma half-life for oral zidovudine alone and in combination with oxazepam was 1.17 h versus 0.99 h, respectively (p = 0.25), and 1.38 h versus 1.15 h (p = 0.38) for intravenous zidovudine during single and combination therapy, respectively. Total body clearance of zidovudine was not significantly altered by oxazepam (93 L/h vs. 109 L/h, p = 0.16). The mean pharmacokinetic parameters determined for a single 30-mg dose of oxazepam for oral clearance, apparent volume of distribution, and plasma half-life were 9.8 L/h, 65.7 L, and 5.1 h, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

https://pubmed.ncbi.nlm.nih.gov/8417175/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Pharmacokinetics of zidovudine alone and in combination with oxazepam in the HIV infected patient. This three-phase study was designed to determine if a pharmacokinetic drug-drug interaction exists between zidovudine and oxazepam . Six individuals infected with human immunodeficiency virus (HIV) and receiving zidovudine at 500 mg daily, with normal renal and hepatic function, were enrolled. During phase I, zidovudine pharmacokinetics were studied after steady-state oral administration (100 mg every 4 h) and after a single dose (70 mg) of intravenous zidovudine. Phase II consisted of a single oral dose (30 mg) of oxazepam followed by a 48-h blood sampling period. Phase III began with 48 h of concomitant zidovudine, 100 mg orally every 4 h, and oxazepam, 15 mg orally every 8 h, followed by concomitant dosing of intravenous zidovudine and oral oxazepam. zidovudine concentrations were determined by radioimmunoassay. oxazepam concentrations were determined with use of a fluorescence polarization immunoassay. The calculated bioavailability was 0.61 for zidovudine alone and 0.75 when administered in combination with oxazepam (p = 0.16). Plasma half-life for oral zidovudine alone and in combination with oxazepam was 1.17 h versus 0.99 h, respectively (p = 0.25), and 1.38 h versus 1.15 h (p = 0.38) for intravenous zidovudine during single and combination therapy, respectively. Total body clearance of zidovudine was not significantly altered by oxazepam (93 L/h vs. 109 L/h, p = 0.16). The mean pharmacokinetic parameters determined for a single 30-mg dose of oxazepam for oral clearance, apparent volume of distribution, and plasma half-life were 9.8 L/h, 65.7 L, and 5.1 h, respectively.(ABSTRACT TRUNCATED AT 250 WORDS) ### Response: zidovudine, oxazepam

5fb6d683308d65ef5c0f0d786b1bd4cf

Patients with apical CFTR protein showed higher residual chloride secretion than those without ( amiloride to isoprenaline value of 4.59 and 0.56 mV , respectively , p = 0.01 ) .

Correlation between nasal potential difference measurements, genotype and clinical condition in patients with cystic fibrosis. In cystic fibrosis (CF), the clinical condition of patients correlates poorly with genotype. One possible explanation is that clinical status is influenced by net preserved chloride secretion rather than the CF mutation. We tested the relationships between residual chloride secretion, as measured by nasal potential difference (PD) and the type of mutation (genotypes expressing apical cystic fibrosis transmembrane conductance regulator (CFTR) protein versus those that do not) and clinical status. Twenty two CF patients (mean age 25.7 yrs, 11 females and 11 males, mean forced expiratory volume in one second (FEV1) 53.1% of predicted) with defined genotypes were recruited. Nasal PD was measured using a standard protocol involving the perfusion of the nasal epithelium with a sodium channel blocker (amiloride), followed by a solution of low chloride and finally with isoprenaline. Patients with apical CFTR protein showed higher residual chloride secretion than those without ( amiloride to isoprenaline value of 4.59 and 0.56 mV , respectively , p = 0.01 ) . There was no correlation between mutation type and clinical condition. When these patients were recategorized as "high" (> 10 mV amiloride to isoprenaline response) or "low" (10 mV or less) chloride secretors, we found that the former group had a significantly higher FEV1 (67.7 versus 48.3% pred) and a better pulmonary radiological score (4.14 versus 7.07, by Northern scoring system). These results suggest that some cystic fibrosis patients, regardless of genotype, have an ability to secrete chloride when stimulated with chloride secretatagogues, and this is correlated with a better lung function. These results also have implications for the use of potential difference measurements in novel cystic fibrosis transmembrane conductance regulator replacement trials.

https://pubmed.ncbi.nlm.nih.gov/9311495/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Correlation between nasal potential difference measurements, genotype and clinical condition in patients with cystic fibrosis. In cystic fibrosis (CF), the clinical condition of patients correlates poorly with genotype. One possible explanation is that clinical status is influenced by net preserved chloride secretion rather than the CF mutation. We tested the relationships between residual chloride secretion, as measured by nasal potential difference (PD) and the type of mutation (genotypes expressing apical cystic fibrosis transmembrane conductance regulator (CFTR) protein versus those that do not) and clinical status. Twenty two CF patients (mean age 25.7 yrs, 11 females and 11 males, mean forced expiratory volume in one second (FEV1) 53.1% of predicted) with defined genotypes were recruited. Nasal PD was measured using a standard protocol involving the perfusion of the nasal epithelium with a sodium channel blocker (amiloride), followed by a solution of low chloride and finally with isoprenaline. Patients with apical CFTR protein showed higher residual chloride secretion than those without ( amiloride to isoprenaline value of 4.59 and 0.56 mV , respectively , p = 0.01 ) . There was no correlation between mutation type and clinical condition. When these patients were recategorized as "high" (> 10 mV amiloride to isoprenaline response) or "low" (10 mV or less) chloride secretors, we found that the former group had a significantly higher FEV1 (67.7 versus 48.3% pred) and a better pulmonary radiological score (4.14 versus 7.07, by Northern scoring system). These results suggest that some cystic fibrosis patients, regardless of genotype, have an ability to secrete chloride when stimulated with chloride secretatagogues, and this is correlated with a better lung function. These results also have implications for the use of potential difference measurements in novel cystic fibrosis transmembrane conductance regulator replacement trials. ### Response: amiloride, isoprenaline

74c0e16ee5db2c1c5de0863213b10cdd

African American men were more likely to receive ketoconazole than abiraterone , enzalutamide , or docetaxel ( AME , 2.8 % ; 95 % CI , 0.7%-4.9 % ) .

Factors influencing treatment of veterans with advanced prostate cancer. Treatments for metastatic castration-resistant prostate cancer (CRPC) differ in toxicity, administration, and evidence. In this study, clinical and nonclinical factors associated with the first-line treatment for CRPC in a national delivery system were evaluated. ### methods National electronic laboratory and clinical data from the Veterans Health Administration were used to identify patients with CRPC (ie, rising prostate-specific antigen [PSA] on androgen deprivation) who received abiraterone, enzalutamide, docetaxel, or ketoconazole from 2010 through 2017. It was determined whether clinical (eg, PSA) and nonclinical factors (eg, race, facility) were associated with the first-line treatment selection using multilevel, multinomial logistic regression. The average marginal effects (AMEs) were calculated of patient, disease, and facility characteristics on ketoconazole versus more appropriate CRPC therapy. ### results There were 4998 patients identified with CRPC who received first-line ketoconazole, docetaxel, abiraterone, or enzalutamide. After adjustment, increasing age was associated with receipt of abiraterone (adjusted odds ratio [aOR], 1.07; 95% credible interval [CrI], 1.06-1.09) or enzalutamide (aOR, 1.10; 95% CrI, 1.08-1.11) versus docetaxel. Greater preexisting comorbidity was associated with enzalutamide versus abiraterone (aOR, 1.53; 95% CrI, 1.23-1.91). Patients with higher PSA values at the start of treatment were more likely to receive docetaxel than oral agents and less likely to receive ketoconazole than other oral agents. African American men were more likely to receive ketoconazole than abiraterone , enzalutamide , or docetaxel ( AME , 2.8 % ; 95 % CI , 0.7%-4.9 % ) . This effect was attenuated when adjusting for facility characteristics (AME, 1.9%; 95% CI, -0.4% to 4.1%). ### conclusions Clinical factors had an expected effect on the first-line treatment selection. Race may be associated with the receipt of a guideline-discordant first-line treatment.

https://pubmed.ncbi.nlm.nih.gov/33764537/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Factors influencing treatment of veterans with advanced prostate cancer. Treatments for metastatic castration-resistant prostate cancer (CRPC) differ in toxicity, administration, and evidence. In this study, clinical and nonclinical factors associated with the first-line treatment for CRPC in a national delivery system were evaluated. ### methods National electronic laboratory and clinical data from the Veterans Health Administration were used to identify patients with CRPC (ie, rising prostate-specific antigen [PSA] on androgen deprivation) who received abiraterone, enzalutamide, docetaxel, or ketoconazole from 2010 through 2017. It was determined whether clinical (eg, PSA) and nonclinical factors (eg, race, facility) were associated with the first-line treatment selection using multilevel, multinomial logistic regression. The average marginal effects (AMEs) were calculated of patient, disease, and facility characteristics on ketoconazole versus more appropriate CRPC therapy. ### results There were 4998 patients identified with CRPC who received first-line ketoconazole, docetaxel, abiraterone, or enzalutamide. After adjustment, increasing age was associated with receipt of abiraterone (adjusted odds ratio [aOR], 1.07; 95% credible interval [CrI], 1.06-1.09) or enzalutamide (aOR, 1.10; 95% CrI, 1.08-1.11) versus docetaxel. Greater preexisting comorbidity was associated with enzalutamide versus abiraterone (aOR, 1.53; 95% CrI, 1.23-1.91). Patients with higher PSA values at the start of treatment were more likely to receive docetaxel than oral agents and less likely to receive ketoconazole than other oral agents. African American men were more likely to receive ketoconazole than abiraterone , enzalutamide , or docetaxel ( AME , 2.8 % ; 95 % CI , 0.7%-4.9 % ) . This effect was attenuated when adjusting for facility characteristics (AME, 1.9%; 95% CI, -0.4% to 4.1%). ### conclusions Clinical factors had an expected effect on the first-line treatment selection. Race may be associated with the receipt of a guideline-discordant first-line treatment. ### Response: ketoconazole, abiraterone, enzalutamide, docetaxel

5fb2877fd458b4bee2e72b3106d5a0a8

These observations are important in the development of vorinostat , and may have clinical implications on other cancer and noncancer drugs that are UGT2B17 substrates such as exemestane and ibuprofen .

Impact of UDP-gluconoryltransferase 2B17 genotype on vorinostat metabolism and clinical outcomes in Asian women with breast cancer. vorinostat, a histone deacetylase inhibitor being actively evaluated in solid tumors, is metabolized by UGT2B17. UGT2B17 null genotype (UGT2B17*2) has been shown in vitro to reduce UGT2B17 activity. This variant is common in Asians but rare in Caucasians, and we studied its impact on vorinostat pharmacokinetics and pharmacodynamics in a clinical study in Asian patients with metastatic breast cancer. ### methods Eligible patients received 400 mg of vorinostat monotherapy daily in a lead-in phase I followed by a phase II study. Patients were genotyped for UGT2B17*2, which was correlated with vorinostat pharmacokinetics and clinical outcomes. ### results Twenty-six patients were treated with no complete response, one partial response, six stable disease lasting for 12 weeks or more, and 19 progressive disease. Sixteen patients (62%) were UGT2B17*2 homozygotes and had significantly lower mean area under the curve ratio of vorinostat-O-glucuronide/vorinostat (1.84 vs. 2.51 on day 1, P=0.02; 1.63 vs. 2.38 on day 15, P=0.028), and trended toward having higher vorinostat area under the curve (399.02 vs. 318.40, P=0.188), more serious adverse events (31 vs. 0%, P=0.121), higher clinical benefit rate (40 vs. 10%, P=0.179), and longer median progression-free survival (3.0 vs. 1.5 months, P=0.087) than patients with at least one wild-type allele. ### conclusion UGT2B17*2 genotype reduces vorinostat glucuronidation and may increase vorinostat efficacy and toxicity. These observations are important in the development of vorinostat , and may have clinical implications on other cancer and noncancer drugs that are UGT2B17 substrates such as exemestane and ibuprofen .

https://pubmed.ncbi.nlm.nih.gov/21849928/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Impact of UDP-gluconoryltransferase 2B17 genotype on vorinostat metabolism and clinical outcomes in Asian women with breast cancer. vorinostat, a histone deacetylase inhibitor being actively evaluated in solid tumors, is metabolized by UGT2B17. UGT2B17 null genotype (UGT2B17*2) has been shown in vitro to reduce UGT2B17 activity. This variant is common in Asians but rare in Caucasians, and we studied its impact on vorinostat pharmacokinetics and pharmacodynamics in a clinical study in Asian patients with metastatic breast cancer. ### methods Eligible patients received 400 mg of vorinostat monotherapy daily in a lead-in phase I followed by a phase II study. Patients were genotyped for UGT2B17*2, which was correlated with vorinostat pharmacokinetics and clinical outcomes. ### results Twenty-six patients were treated with no complete response, one partial response, six stable disease lasting for 12 weeks or more, and 19 progressive disease. Sixteen patients (62%) were UGT2B17*2 homozygotes and had significantly lower mean area under the curve ratio of vorinostat-O-glucuronide/vorinostat (1.84 vs. 2.51 on day 1, P=0.02; 1.63 vs. 2.38 on day 15, P=0.028), and trended toward having higher vorinostat area under the curve (399.02 vs. 318.40, P=0.188), more serious adverse events (31 vs. 0%, P=0.121), higher clinical benefit rate (40 vs. 10%, P=0.179), and longer median progression-free survival (3.0 vs. 1.5 months, P=0.087) than patients with at least one wild-type allele. ### conclusion UGT2B17*2 genotype reduces vorinostat glucuronidation and may increase vorinostat efficacy and toxicity. These observations are important in the development of vorinostat , and may have clinical implications on other cancer and noncancer drugs that are UGT2B17 substrates such as exemestane and ibuprofen . ### Response: vorinostat, exemestane, ibuprofen

bb7ddd4997f0951a2d47cc6d0d000cc5

Additional results from MTT cell viability assays demonstrated that H1975 cell proliferation was not significantly decreased after Wnt inhibition by XAV939 , but combination treatment with everolimus ( mTOR inhibitor ) and erlotinib resulted in synergistic cell growth inhibition .

Mechanism of Resistance and Novel Targets Mediating Resistance to EGFR and c-Met Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer. Tyrosine kinase inhibitors (TKIs) against EGFR and c-Met are initially effective when administered individually or in combination to non-small cell lung cancer (NSCLC) patients. However, the overall efficacies of TKIs are limited due to the development of drug resistance. Therefore, it is important to elucidate mechanisms of EGFR and c-Met TKI resistance in order to develop more effective therapies. Model NSCLC cell lines H1975 and H2170 were used to study the similarities and differences in mechanisms of EGFR/c-Met TKI resistance. H1975 cells are positive for the T790M EGFR mutation, which confers resistance to current EGFR TKI therapies, while H2170 cells are EGFR wild-type. Previously, H2170 cells were made resistant to the EGFR TKI erlotinib and the c-Met TKI SU11274 by exposure to progressively increasing concentrations of TKIs. In H2170 and H1975 TKI-resistant cells, key Wnt and mTOR proteins were found to be differentially modulated. Wnt signaling transducer, active β-catenin was upregulated in TKI-resistant H2170 cells when compared to parental cells. GATA-6, a transcriptional activator of Wnt, was also found to be upregulated in resistant H2170 cells. In H2170 erlotinib resistant cells, upregulation of inactive GSK3β (p-GSK3β) was observed, indicating activation of Wnt and mTOR pathways which are otherwise inhibited by its active form. However, in H1975 cells, Wnt modulators such as active β-catenin, GATA-6 and p-GSK3β were downregulated. Additional results from MTT cell viability assays demonstrated that H1975 cell proliferation was not significantly decreased after Wnt inhibition by XAV939 , but combination treatment with everolimus ( mTOR inhibitor ) and erlotinib resulted in synergistic cell growth inhibition . Thus, in H2170 cells and H1975 cells, simultaneous inhibition of key Wnt or mTOR pathway proteins in addition to EGFR and c-Met may be a promising strategy for overcoming EGFR and c-Met TKI resistance in NSCLC patients.

https://pubmed.ncbi.nlm.nih.gov/26301867/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Mechanism of Resistance and Novel Targets Mediating Resistance to EGFR and c-Met Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer. Tyrosine kinase inhibitors (TKIs) against EGFR and c-Met are initially effective when administered individually or in combination to non-small cell lung cancer (NSCLC) patients. However, the overall efficacies of TKIs are limited due to the development of drug resistance. Therefore, it is important to elucidate mechanisms of EGFR and c-Met TKI resistance in order to develop more effective therapies. Model NSCLC cell lines H1975 and H2170 were used to study the similarities and differences in mechanisms of EGFR/c-Met TKI resistance. H1975 cells are positive for the T790M EGFR mutation, which confers resistance to current EGFR TKI therapies, while H2170 cells are EGFR wild-type. Previously, H2170 cells were made resistant to the EGFR TKI erlotinib and the c-Met TKI SU11274 by exposure to progressively increasing concentrations of TKIs. In H2170 and H1975 TKI-resistant cells, key Wnt and mTOR proteins were found to be differentially modulated. Wnt signaling transducer, active β-catenin was upregulated in TKI-resistant H2170 cells when compared to parental cells. GATA-6, a transcriptional activator of Wnt, was also found to be upregulated in resistant H2170 cells. In H2170 erlotinib resistant cells, upregulation of inactive GSK3β (p-GSK3β) was observed, indicating activation of Wnt and mTOR pathways which are otherwise inhibited by its active form. However, in H1975 cells, Wnt modulators such as active β-catenin, GATA-6 and p-GSK3β were downregulated. Additional results from MTT cell viability assays demonstrated that H1975 cell proliferation was not significantly decreased after Wnt inhibition by XAV939 , but combination treatment with everolimus ( mTOR inhibitor ) and erlotinib resulted in synergistic cell growth inhibition . Thus, in H2170 cells and H1975 cells, simultaneous inhibition of key Wnt or mTOR pathway proteins in addition to EGFR and c-Met may be a promising strategy for overcoming EGFR and c-Met TKI resistance in NSCLC patients. ### Response: XAV939, everolimus, erlotinib

a07c1da8ac6e880d708e348dee854111

The addition of dexmedetomidine to bupivacaine 0.5 % in EUS-CPN demonstrated beneficial effects as regards the degree and duration of pain relieve with negligible effect on the patient survival .

Value of Adding Dexmedetomidine in Endoscopic Ultrasound-Guided Celiac Plexus Neurolysis for Treatment of Pancreatic Cancer-Associated Pain. Abdominal and back pain is present in up to 80% of patients with pancreatic cancer and represents a significant cause of morbidity. Celiac plexus neurolysis (CPN) demonstrated good results in relief of pain of upper abdominal malignancy. Dexmedetomidine is alpha-2 adrenoceptor highly selective agonist approved for procedural sedation use. ### Patients And Methods Fifty patients divided in two groups with locally advanced pancreatic cancer-associated abdominal pain underwent endoscopic ultrasound (EUS)-guided CPN using bupivacaine 0.5% alone with alcohol for the first group and bupivacaine 0.5% plus dexmedetomidine in the second. Patients scored their pain according to the Numeric Rating Scale (NRS-11) before, 2, 4, 6, 8, 12, 16, and 24 week after the procedure. ### results The study has included 50 patient in two groups. There was no significant difference between the two groups as regards medical, laboratory, or tumor characters. The median pain score decreases from 8.32 ± 0.75 before the procedure to 3.75 ± 3.72 24 week after the procedure in group 1 and from 8.08 ± 0.86 before to 1.67 ± 2.3 24 week after the procedure in group 2. However, there was no significant difference between the two groups in the median pain score during the first 4 weeks. There was no statistically significant difference between the two groups as regards the median survival time. ### conclusion The addition of dexmedetomidine to bupivacaine 0.5 % in EUS-CPN demonstrated beneficial effects as regards the degree and duration of pain relieve with negligible effect on the patient survival .

https://pubmed.ncbi.nlm.nih.gov/32621112/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Value of Adding Dexmedetomidine in Endoscopic Ultrasound-Guided Celiac Plexus Neurolysis for Treatment of Pancreatic Cancer-Associated Pain. Abdominal and back pain is present in up to 80% of patients with pancreatic cancer and represents a significant cause of morbidity. Celiac plexus neurolysis (CPN) demonstrated good results in relief of pain of upper abdominal malignancy. Dexmedetomidine is alpha-2 adrenoceptor highly selective agonist approved for procedural sedation use. ### Patients And Methods Fifty patients divided in two groups with locally advanced pancreatic cancer-associated abdominal pain underwent endoscopic ultrasound (EUS)-guided CPN using bupivacaine 0.5% alone with alcohol for the first group and bupivacaine 0.5% plus dexmedetomidine in the second. Patients scored their pain according to the Numeric Rating Scale (NRS-11) before, 2, 4, 6, 8, 12, 16, and 24 week after the procedure. ### results The study has included 50 patient in two groups. There was no significant difference between the two groups as regards medical, laboratory, or tumor characters. The median pain score decreases from 8.32 ± 0.75 before the procedure to 3.75 ± 3.72 24 week after the procedure in group 1 and from 8.08 ± 0.86 before to 1.67 ± 2.3 24 week after the procedure in group 2. However, there was no significant difference between the two groups in the median pain score during the first 4 weeks. There was no statistically significant difference between the two groups as regards the median survival time. ### conclusion The addition of dexmedetomidine to bupivacaine 0.5 % in EUS-CPN demonstrated beneficial effects as regards the degree and duration of pain relieve with negligible effect on the patient survival . ### Response: dexmedetomidine, bupivacaine

ee28ea04905713e9b380ad3cbd796d56

The incidence of carcinoma , confirmed microscopically , was : control 14/20 ( 70 % ) ; high-dose gefitinib , 7/20 ( 35 % ) ; low-dose gefitinib , 7/20 ( 35 % ) ; high-dose meloxicam 7/21 ( 33 % ) ; and low-dose meloxicam , 12/20 ( 60 % ) .

Chemopreventive effects of cyclooxygenase-2 inhibitor and epidermal growth factor-receptor kinase inhibitor on rat urinary bladder carcinogenesis. To examine the chemopreventive effects of a selective cyclooxygenase (COX)-2 inhibitor, meloxicam, and a selective epidermal growth factor (EGF)-receptor tyrosine kinase inhibitor, gefitinib (as a single agent) on a carcinogen-induced rodent bladder carcinogenesis model. ### Materials And Methods The study comprised 103 male Fisher-344 rats (8 weeks old); after initial carcinogen treatment for 8 weeks with 0.05%N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in drinking water, the rats were divided into five groups, i.e. group 1, control (vehicle only); group 2, gefitinib high-dose (15 mg/kg by gavage once daily); group 3, gefitinib low-dose (5 mg/kg); group 4, meloxicam high-dose (1.8 mg/kg by gavage once daily); and group 5, meloxicam low-dose (0.6 mg/kg). Twelve weeks later the rats were killed; after fixing the bladder in 10% formalin, the number and size of hyperplasia and carcinoma foci were recorded microscopically in sections stained with haematoxylin and eosin, submitted entirely as multiple strips. ### results The incidence of carcinoma , confirmed microscopically , was : control 14/20 ( 70 % ) ; high-dose gefitinib , 7/20 ( 35 % ) ; low-dose gefitinib , 7/20 ( 35 % ) ; high-dose meloxicam 7/21 ( 33 % ) ; and low-dose meloxicam , 12/20 ( 60 % ) . The mean numbers of carcinomas per bladder in groups 1-5 were 1.2, 0.5, 0.4, 0.5 and 1.1, respectively. The incidence and the mean number of carcinomas per bladder were significantly lower in the treatment groups (P < 0.05) than in the control group, except in the low-dose meloxicam group. There were no significant adverse effects. ### conclusion Both meloxicam and gefitinib have inhibitory effects on rat bladder carcinogenesis with no significant adverse effects. A combination of these drugs would be worth studying for their synergistic effects.

https://pubmed.ncbi.nlm.nih.gov/16469040/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Chemopreventive effects of cyclooxygenase-2 inhibitor and epidermal growth factor-receptor kinase inhibitor on rat urinary bladder carcinogenesis. To examine the chemopreventive effects of a selective cyclooxygenase (COX)-2 inhibitor, meloxicam, and a selective epidermal growth factor (EGF)-receptor tyrosine kinase inhibitor, gefitinib (as a single agent) on a carcinogen-induced rodent bladder carcinogenesis model. ### Materials And Methods The study comprised 103 male Fisher-344 rats (8 weeks old); after initial carcinogen treatment for 8 weeks with 0.05%N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in drinking water, the rats were divided into five groups, i.e. group 1, control (vehicle only); group 2, gefitinib high-dose (15 mg/kg by gavage once daily); group 3, gefitinib low-dose (5 mg/kg); group 4, meloxicam high-dose (1.8 mg/kg by gavage once daily); and group 5, meloxicam low-dose (0.6 mg/kg). Twelve weeks later the rats were killed; after fixing the bladder in 10% formalin, the number and size of hyperplasia and carcinoma foci were recorded microscopically in sections stained with haematoxylin and eosin, submitted entirely as multiple strips. ### results The incidence of carcinoma , confirmed microscopically , was : control 14/20 ( 70 % ) ; high-dose gefitinib , 7/20 ( 35 % ) ; low-dose gefitinib , 7/20 ( 35 % ) ; high-dose meloxicam 7/21 ( 33 % ) ; and low-dose meloxicam , 12/20 ( 60 % ) . The mean numbers of carcinomas per bladder in groups 1-5 were 1.2, 0.5, 0.4, 0.5 and 1.1, respectively. The incidence and the mean number of carcinomas per bladder were significantly lower in the treatment groups (P < 0.05) than in the control group, except in the low-dose meloxicam group. There were no significant adverse effects. ### conclusion Both meloxicam and gefitinib have inhibitory effects on rat bladder carcinogenesis with no significant adverse effects. A combination of these drugs would be worth studying for their synergistic effects. ### Response: gefitinib, gefitinib, meloxicam, meloxicam

94de76aa894156859854546a83ca433f

Patients with incurable cancer causing chronic pain rated above 6/10 on a numerical scale while receiving high-dose opioid therapy ( more than 200 mg/d of oral morphine equivalent ) and/or exhibiting severe opioid-related adverse events received intrathecal infusions of ziconotide combined with morphine , ropivacaine , and clonidine .

Ziconotide adverse events in patients with cancer pain: a multicenter observational study of a slow titration, multidrug protocol. Ziconotide is a new analgesic agent administered intrathecally. It is challenging to use and can induce several and sometimes serious adverse events. A low initial dosage followed by slow titration may reduce serious adverse events. ### objective To determine whether a low starting dosage of ziconotide, followed by slow titration, decreases the incidence of major adverse events associated with ziconotide when used for intractable cancer pain. ### Study Design Observational cohort study. ### setting Three French cancer centers. ### methods Patients with incurable cancer causing chronic pain rated above 6/10 on a numerical scale while receiving high-dose opioid therapy ( more than 200 mg/d of oral morphine equivalent ) and/or exhibiting severe opioid-related adverse events received intrathecal infusions of ziconotide combined with morphine , ropivacaine , and clonidine . ### results Seventy-seven patients were included. Adverse events were recorded in 57% of them; moderate adverse events occurred in 51%. Adverse events required treatment discontinuation in 7 (9%) including 5 (6%) for whom a causal role for ziconotide was highly likely; among them 4 (5%) were serious. All patients experienced a significant and lasting decrease in pain intensity (by 48%) in response to intrathecal analgesic therapy that included ziconotide. ### limitations Limitations include the nonrandomized, observational nature of the study. Determining the relative contributions of each drug to adverse events was difficult, and some of the adverse events manifested as clinical symptoms of a subjective nature. ### conclusions The rates of minor and moderate adverse events were consistent with previous reports. However, the rate of serious adverse events was substantially lower. Our study confirms the efficacy of intrathecal analgesia with ziconotide for relieving refractory cancer pain. These results indicate that multimodal intrathecal analgesia in patients with cancer pain should include ziconotide from the outset in order to provide time for subsequent slow titration.

https://pubmed.ncbi.nlm.nih.gov/22996851/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Ziconotide adverse events in patients with cancer pain: a multicenter observational study of a slow titration, multidrug protocol. Ziconotide is a new analgesic agent administered intrathecally. It is challenging to use and can induce several and sometimes serious adverse events. A low initial dosage followed by slow titration may reduce serious adverse events. ### objective To determine whether a low starting dosage of ziconotide, followed by slow titration, decreases the incidence of major adverse events associated with ziconotide when used for intractable cancer pain. ### Study Design Observational cohort study. ### setting Three French cancer centers. ### methods Patients with incurable cancer causing chronic pain rated above 6/10 on a numerical scale while receiving high-dose opioid therapy ( more than 200 mg/d of oral morphine equivalent ) and/or exhibiting severe opioid-related adverse events received intrathecal infusions of ziconotide combined with morphine , ropivacaine , and clonidine . ### results Seventy-seven patients were included. Adverse events were recorded in 57% of them; moderate adverse events occurred in 51%. Adverse events required treatment discontinuation in 7 (9%) including 5 (6%) for whom a causal role for ziconotide was highly likely; among them 4 (5%) were serious. All patients experienced a significant and lasting decrease in pain intensity (by 48%) in response to intrathecal analgesic therapy that included ziconotide. ### limitations Limitations include the nonrandomized, observational nature of the study. Determining the relative contributions of each drug to adverse events was difficult, and some of the adverse events manifested as clinical symptoms of a subjective nature. ### conclusions The rates of minor and moderate adverse events were consistent with previous reports. However, the rate of serious adverse events was substantially lower. Our study confirms the efficacy of intrathecal analgesia with ziconotide for relieving refractory cancer pain. These results indicate that multimodal intrathecal analgesia in patients with cancer pain should include ziconotide from the outset in order to provide time for subsequent slow titration. ### Response: ziconotide, morphine, ropivacaine, clonidine

68c9547776b2824a3e90e1f59b9b4366

Both adalimumab and etanercept were more effective than methotrexate in slowing radiographic joint damage .

A systematic review of the effectiveness of adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis in adults and an economic evaluation of their cost-effectiveness. This report reviews the clinical effectiveness and cost-effectiveness of adalimumab, etanercept and infliximab, agents that inhibit tumour necrosis factor-alpha (TNF-alpha), when used in the treatment of rheumatoid arthritis (RA) in adults. ### Data Sources Electronic databases were searched up to February 2005. ### Review Methods Systematic reviews of the literature on effectiveness and cost-effectiveness were undertaken and industry submissions to the National Institute for Health and Clinical Excellence (NICE) were reviewed. Meta-analyses of effectiveness data were also undertaken for each agent. The Birmingham Rheumatoid Arthritis Model (BRAM), a simulation model, was further developed and used to produce an incremental cost-effectiveness analysis. ### results Twenty-nine randomised controlled trials (RCTs), most of high quality, were included. The only head-to-head comparisons were against methotrexate. For patients with short disease duration (<or=3 years) who were naïve to methotrexate, adalimumab was marginally less and etanercept was marginally more effective than methotrexate in reducing symptoms of RA. etanercept was better tolerated than methotrexate. Both adalimumab and etanercept were more effective than methotrexate in slowing radiographic joint damage . etanercept was also marginally more effective and better tolerated than methotrexate in patients with longer disease durations who had not failed methotrexate treatment. infliximab is only licensed for use with methotrexate. All three agents, either alone (where so licensed) or in combination with ongoing disease-modifying antirheumatic drugs (DMARDs), were effective in reducing the symptoms and signs of RA in patients with established disease. At the licensed dose, the numbers needed to treat (NNTs) (95% CI) required to produce an American College for Rheumatology (ACR) response compared with placebo were: ACR20: adalimumab 3.6 (3.1 to 4.2), etanercept 2.1 (1.9 to 2.4), infliximab 3.2 (2.7 to 4.0); ACR50: adalimumab 4.2 (3.7 to 5.0), etanercept 3.1 (2.7 to 3.6), infliximab 5.0 (3.8 to 6.7); and ACR70: adalimumab 7.7 (5.9 to 11.1), etanercept 7.7 (6.3 to 10.0), infliximab 11.1 (7.7 to 20.0). In patients who were naïve to methotrexate, or who had not previously failed methotrexate treatment, a TNF inhibitor combined with methotrexate was significantly more effective than methotrexate alone. infliximab combined with methotrexate had an increased risk of serious infections. All ten published economic evaluations met standard criteria for quality, but the incremental cost-effectiveness ratios (ICERs) ranged from being within established thresholds to being very high because of varying assumptions and parameters. All three sponsors who submitted economic models made assumptions favourable to their product. BRAM incorporates improvements in quality of life and mortality, but assumes no effect of TNF inhibitors on joint replacement. For use in accordance with current NICE guidance as the third DMARD in a sequence of DMARDs, the base-case ICER was around pound30,000 per quality-adjusted life-year (QALY) in early RA and pound50,000 per QALY in late RA. Sensitivity analyses showed that the results were sensitive to the estimates of Health Assessment Questionnaire (HAQ) progression while on TNF inhibitors and the effectiveness of DMARDs, but not to changes in mortality ratios per unit HAQ. TNF inhibitors are most cost-effective when used last. The ICER for etanercept used last is pound24,000 per QALY, substantially lower than for adalimumab ( pound30,000 per QALY) or infliximab ( pound38,000 per QALY). First line use as monotherapy generates ICERs around pound50,000 per QALY for adalimumab and etanercept. Using the combination of methotrexate and a TNF inhibitor as first line treatment generates much higher ICERs, as it precludes subsequent use of methotrexate, which is cheap. The ICERs for sequential use are of the same order as using the TNF inhibitor alone. ### conclusions adalimumab, etanercept and infliximab are effective treatments compared with placebo for RA patients who are not well controlled by conventional DMARDs, improving control of symptoms, improving physical function, and slowing radiographic changes in joints. The combination of a TNF inhibitor with methotrexate was more effective than methotrexate alone in early RA, although the clinical relevance of this additional benefit is yet to be established, particularly in view of the well-established effectiveness of MTX alone. An increased risk of serious infection cannot be ruled out for the combination of methotrexate with adalimumab or infliximab. The results of the economic evaluation based on BRAM are consistent with the observations from the review of clinical effectiveness, including the ranking of treatments. TNF inhibitors are most cost-effective when used as last active therapy. In this analysis, other things being equal, etanercept may be the TNF inhibitor of choice, although this may also depend on patient preference as to route of administration. The next most cost-effective use of TNF inhibitors is third line, as recommended in the 2002 NICE guidance. Direct comparative RCTs of TNF inhibitors against each other and against other DMARDs, and sequential use in patients who have failed a previous TNF inhibitor, are needed. Longer term studies of the quality of life in patients with RA and the impact of DMARDs on this are needed, as are longer studies that directly assess effects on joint replacement, other morbidity and mortality.

https://pubmed.ncbi.nlm.nih.gov/17049139/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: A systematic review of the effectiveness of adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis in adults and an economic evaluation of their cost-effectiveness. This report reviews the clinical effectiveness and cost-effectiveness of adalimumab, etanercept and infliximab, agents that inhibit tumour necrosis factor-alpha (TNF-alpha), when used in the treatment of rheumatoid arthritis (RA) in adults. ### Data Sources Electronic databases were searched up to February 2005. ### Review Methods Systematic reviews of the literature on effectiveness and cost-effectiveness were undertaken and industry submissions to the National Institute for Health and Clinical Excellence (NICE) were reviewed. Meta-analyses of effectiveness data were also undertaken for each agent. The Birmingham Rheumatoid Arthritis Model (BRAM), a simulation model, was further developed and used to produce an incremental cost-effectiveness analysis. ### results Twenty-nine randomised controlled trials (RCTs), most of high quality, were included. The only head-to-head comparisons were against methotrexate. For patients with short disease duration (<or=3 years) who were naïve to methotrexate, adalimumab was marginally less and etanercept was marginally more effective than methotrexate in reducing symptoms of RA. etanercept was better tolerated than methotrexate. Both adalimumab and etanercept were more effective than methotrexate in slowing radiographic joint damage . etanercept was also marginally more effective and better tolerated than methotrexate in patients with longer disease durations who had not failed methotrexate treatment. infliximab is only licensed for use with methotrexate. All three agents, either alone (where so licensed) or in combination with ongoing disease-modifying antirheumatic drugs (DMARDs), were effective in reducing the symptoms and signs of RA in patients with established disease. At the licensed dose, the numbers needed to treat (NNTs) (95% CI) required to produce an American College for Rheumatology (ACR) response compared with placebo were: ACR20: adalimumab 3.6 (3.1 to 4.2), etanercept 2.1 (1.9 to 2.4), infliximab 3.2 (2.7 to 4.0); ACR50: adalimumab 4.2 (3.7 to 5.0), etanercept 3.1 (2.7 to 3.6), infliximab 5.0 (3.8 to 6.7); and ACR70: adalimumab 7.7 (5.9 to 11.1), etanercept 7.7 (6.3 to 10.0), infliximab 11.1 (7.7 to 20.0). In patients who were naïve to methotrexate, or who had not previously failed methotrexate treatment, a TNF inhibitor combined with methotrexate was significantly more effective than methotrexate alone. infliximab combined with methotrexate had an increased risk of serious infections. All ten published economic evaluations met standard criteria for quality, but the incremental cost-effectiveness ratios (ICERs) ranged from being within established thresholds to being very high because of varying assumptions and parameters. All three sponsors who submitted economic models made assumptions favourable to their product. BRAM incorporates improvements in quality of life and mortality, but assumes no effect of TNF inhibitors on joint replacement. For use in accordance with current NICE guidance as the third DMARD in a sequence of DMARDs, the base-case ICER was around pound30,000 per quality-adjusted life-year (QALY) in early RA and pound50,000 per QALY in late RA. Sensitivity analyses showed that the results were sensitive to the estimates of Health Assessment Questionnaire (HAQ) progression while on TNF inhibitors and the effectiveness of DMARDs, but not to changes in mortality ratios per unit HAQ. TNF inhibitors are most cost-effective when used last. The ICER for etanercept used last is pound24,000 per QALY, substantially lower than for adalimumab ( pound30,000 per QALY) or infliximab ( pound38,000 per QALY). First line use as monotherapy generates ICERs around pound50,000 per QALY for adalimumab and etanercept. Using the combination of methotrexate and a TNF inhibitor as first line treatment generates much higher ICERs, as it precludes subsequent use of methotrexate, which is cheap. The ICERs for sequential use are of the same order as using the TNF inhibitor alone. ### conclusions adalimumab, etanercept and infliximab are effective treatments compared with placebo for RA patients who are not well controlled by conventional DMARDs, improving control of symptoms, improving physical function, and slowing radiographic changes in joints. The combination of a TNF inhibitor with methotrexate was more effective than methotrexate alone in early RA, although the clinical relevance of this additional benefit is yet to be established, particularly in view of the well-established effectiveness of MTX alone. An increased risk of serious infection cannot be ruled out for the combination of methotrexate with adalimumab or infliximab. The results of the economic evaluation based on BRAM are consistent with the observations from the review of clinical effectiveness, including the ranking of treatments. TNF inhibitors are most cost-effective when used as last active therapy. In this analysis, other things being equal, etanercept may be the TNF inhibitor of choice, although this may also depend on patient preference as to route of administration. The next most cost-effective use of TNF inhibitors is third line, as recommended in the 2002 NICE guidance. Direct comparative RCTs of TNF inhibitors against each other and against other DMARDs, and sequential use in patients who have failed a previous TNF inhibitor, are needed. Longer term studies of the quality of life in patients with RA and the impact of DMARDs on this are needed, as are longer studies that directly assess effects on joint replacement, other morbidity and mortality. ### Response: adalimumab, etanercept, methotrexate

5386d10522b4ceab39a95e1adbc57b27

Combination chemotherapy with gemcitabine ( Gem ) , doxorubicin ( Dox ) , and paclitaxel ( Pac ) ( GAT ) has been considered attractive as first-line treatment in metastatic breast cancer .

Evaluation of a gemcitabine-doxorubicin-paclitaxel combination schedule through flow cytometry assessment of apoptosis extent induced in human breast cancer cell lines. Combination chemotherapy with gemcitabine ( Gem ) , doxorubicin ( Dox ) , and paclitaxel ( Pac ) ( GAT ) has been considered attractive as first-line treatment in metastatic breast cancer . We compared the potential of various schedules of GAT to induce apoptosis on MDA-MB-231, MCF7, and T47D human breast cancer cell lines. The extent of apoptotic induction was analyzed by flow cytometry with 7-aminoactinomycin D (7AAD) staining. Differences between various schedules in terms of apoptotic induction were statistically significant (P < 0.05). The most effective apoptotic induction regimen was achieved by the sequence: Dox for 16 h followed by Pac + Gem. Schedules employing a 16-h interval between drug administrations induced higher levels of apoptosis in human breast cancer cell lines compared with schedules using a 4-h interval. The therapeutic efficacy of the experimental results shown in this paper has been clinically corroborated in a phase II trial in metastatic breast cancer patients.

https://pubmed.ncbi.nlm.nih.gov/12036452/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Evaluation of a gemcitabine-doxorubicin-paclitaxel combination schedule through flow cytometry assessment of apoptosis extent induced in human breast cancer cell lines. Combination chemotherapy with gemcitabine ( Gem ) , doxorubicin ( Dox ) , and paclitaxel ( Pac ) ( GAT ) has been considered attractive as first-line treatment in metastatic breast cancer . We compared the potential of various schedules of GAT to induce apoptosis on MDA-MB-231, MCF7, and T47D human breast cancer cell lines. The extent of apoptotic induction was analyzed by flow cytometry with 7-aminoactinomycin D (7AAD) staining. Differences between various schedules in terms of apoptotic induction were statistically significant (P < 0.05). The most effective apoptotic induction regimen was achieved by the sequence: Dox for 16 h followed by Pac + Gem. Schedules employing a 16-h interval between drug administrations induced higher levels of apoptosis in human breast cancer cell lines compared with schedules using a 4-h interval. The therapeutic efficacy of the experimental results shown in this paper has been clinically corroborated in a phase II trial in metastatic breast cancer patients. ### Response: gemcitabine, doxorubicin, paclitaxel

e9da5f1b64d56f794f15c5887995e662

Anti-cancer agents like adriamycin , mitomycin-C , bleomycin , and etoposide express their cell-killing activity partly through oxygen radicals .

Overcoming of cross-resistance to the cell-killing activity of oxygen radicals in VCR-resistant hematologic cell lines with cyclosporin-A. Anti-cancer agents like adriamycin , mitomycin-C , bleomycin , and etoposide express their cell-killing activity partly through oxygen radicals . Since vincristine (VCR)-resistant cells show cross-resistance to oxygen radicals, this study was designed to study whether the combined effects of oxygen radicals derived from hypoxanthine-xanthine oxidase plus enhancers of anti-cancer drugs such as verapamil (Ver), dipyridamole (Dip), and cyclosporin-A (Cy-A) overcome the cross-resistance for oxygen radicals in VCR-resistant human leukemia/lymphoma cell lines. We found that 3 micrograms/mL Cy-A enhances the cidal effect of oxygen radicals on two of five types of wild type and two of five VCR-resistant cell lines and it could overcome the cross-resistance to oxygen radicals in VCR-resistant cells. Neither Ver nor Dip showed any effect on the cidal activity of oxygen radicals. Thus, it was suggested that Cy-A works with different mechanisms from those of Ver or Dip, and Cy-A may be useful in reducing the doses of anti-neoplastic agents that exert their activity via oxygen radicals in the clinical treatment.

https://pubmed.ncbi.nlm.nih.gov/9673368/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Overcoming of cross-resistance to the cell-killing activity of oxygen radicals in VCR-resistant hematologic cell lines with cyclosporin-A. Anti-cancer agents like adriamycin , mitomycin-C , bleomycin , and etoposide express their cell-killing activity partly through oxygen radicals . Since vincristine (VCR)-resistant cells show cross-resistance to oxygen radicals, this study was designed to study whether the combined effects of oxygen radicals derived from hypoxanthine-xanthine oxidase plus enhancers of anti-cancer drugs such as verapamil (Ver), dipyridamole (Dip), and cyclosporin-A (Cy-A) overcome the cross-resistance for oxygen radicals in VCR-resistant human leukemia/lymphoma cell lines. We found that 3 micrograms/mL Cy-A enhances the cidal effect of oxygen radicals on two of five types of wild type and two of five VCR-resistant cell lines and it could overcome the cross-resistance to oxygen radicals in VCR-resistant cells. Neither Ver nor Dip showed any effect on the cidal activity of oxygen radicals. Thus, it was suggested that Cy-A works with different mechanisms from those of Ver or Dip, and Cy-A may be useful in reducing the doses of anti-neoplastic agents that exert their activity via oxygen radicals in the clinical treatment. ### Response: adriamycin, mitomycin-C, bleomycin, etoposide

5f1a3d2c3e4b6683bc6cb633081ad7a6

The efficacy and safety of isepamicin compared with amikacin in the treatment of intra-abdominal infections .

The efficacy and safety of isepamicin compared with amikacin in the treatment of intra-abdominal infections . This multicentre, randomised, open-label, parallel group study compared the efficacy and safety of isepamicin (15 mg/kg once daily) and amikacin (7.5 mg/kg twice daily) when given intravenously in combination with metronidazole to 267 hospitalised adults with intra-abdominal infections. Clinical cure or improvement was achieved in 96.3% (130/135) evaluable patients (efficacy population) in the isepamicin group and 94.3% (66/70) patients in the amikacin group. Bacteriological elimination occurred in 93.3% (126/135) evaluable isepamicin patients and 95.7% (67/170) amikacin patients. there was not statistically significant differences between the groups. Adverse events were reported by 9% of patients in the isepamicin group (16/178) and 10% of patients in the amikacin group (9/89). Events considered to be related to treatment occurred in 6% of patients in both groups. The most frequent adverse events were diarrhoea, nausea and vomiting. Renal problems caused three patients (2 isepamicin, 1 amikacin) to withdraw from the study. Ototoxicity (detected by audiometric testing) occurred in one patient (treated with isepamicin). In conclusion, isepamicin at a dose of 15 mg/kg once daily was shown to be as effective as amikacin (7.5 mg/kg twice daily) in the treatment of intra-abdominal infections in hospitalised adults also treated with metronidazole. Both treatments were well tolerated.

https://pubmed.ncbi.nlm.nih.gov/8622103/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: The efficacy and safety of isepamicin compared with amikacin in the treatment of intra-abdominal infections . This multicentre, randomised, open-label, parallel group study compared the efficacy and safety of isepamicin (15 mg/kg once daily) and amikacin (7.5 mg/kg twice daily) when given intravenously in combination with metronidazole to 267 hospitalised adults with intra-abdominal infections. Clinical cure or improvement was achieved in 96.3% (130/135) evaluable patients (efficacy population) in the isepamicin group and 94.3% (66/70) patients in the amikacin group. Bacteriological elimination occurred in 93.3% (126/135) evaluable isepamicin patients and 95.7% (67/170) amikacin patients. there was not statistically significant differences between the groups. Adverse events were reported by 9% of patients in the isepamicin group (16/178) and 10% of patients in the amikacin group (9/89). Events considered to be related to treatment occurred in 6% of patients in both groups. The most frequent adverse events were diarrhoea, nausea and vomiting. Renal problems caused three patients (2 isepamicin, 1 amikacin) to withdraw from the study. Ototoxicity (detected by audiometric testing) occurred in one patient (treated with isepamicin). In conclusion, isepamicin at a dose of 15 mg/kg once daily was shown to be as effective as amikacin (7.5 mg/kg twice daily) in the treatment of intra-abdominal infections in hospitalised adults also treated with metronidazole. Both treatments were well tolerated. ### Response: isepamicin, amikacin

796ef671b82d8b62f17e74d857fe5411

Imipenem was compared with nafcillin and with penicillin plus gentamicin in the therapy of experimental endocarditis induced in rabbits by Staph . aureus and Str . faecalis , respectively .

Imipenem therapy of experimental Staphylococcus aureus and Streptococcus faecalis endocarditis. imipenem was very active in vitro against 36 Staphylococcus aureus isolates from cases of infective endocarditis; the MBC90 was 0.06 mg/l (four- to eight-fold more active than nafcillin). The in-vitro activity of imipenem against 22 Streptococcus faecalis isolates from proven endocarditis cases was similar to that of penicillin G (MBC90 = 8 mg/l). Imipenem was compared with nafcillin and with penicillin plus gentamicin in the therapy of experimental endocarditis induced in rabbits by Staph . aureus and Str . faecalis , respectively . The dosages were chosen to simulate closely serum antibiotic concentrations found in humans receiving standard parenteral regimens. imipenem was more rapidly bactericidal than nafcillin in experimental staphylococcal endocarditis. The mean +/- S.D. Staph. aureus concentrations within aortic valve vegetations (log10 cfu/g) after 5 days of therapy were as follows: imipenem = 1.39 +/- 0.61 versus nafcillin 2.39 +/- 0.36 (P less than 0.02). Both the imipenem and nafcillin regimens resulted in 'sterile' vegetations in congruent to 50% of rabbits with experimental staphylococcal endocarditis after 5 days of therapy (P greater than 0.05). imipenem was also equivalent to penicillin plus gentamicin in the therapy of experimental enterococcal endocarditis for 5 days, as assessed by the mean cfu/g vegetation and the percentage of vegetations rendered sterile. However, 7 days of therapy cured experimental enterococcal endocarditis in 72% of rabbits receiving penicillin plus gentamicin versus 20% for imipenem alone (P less than 0.05). imipenem deserves further evaluation in the therapy of infective endocarditis, both in experimental animal models of infection and in humans. This agent may prove useful in the therapy of staphylococcal endocarditis in a variety of difficult clinical situations. Therapy of enterococcal endocarditis with imipenem alone is not advisable, pending further data.

https://pubmed.ncbi.nlm.nih.gov/6421794/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Imipenem therapy of experimental Staphylococcus aureus and Streptococcus faecalis endocarditis. imipenem was very active in vitro against 36 Staphylococcus aureus isolates from cases of infective endocarditis; the MBC90 was 0.06 mg/l (four- to eight-fold more active than nafcillin). The in-vitro activity of imipenem against 22 Streptococcus faecalis isolates from proven endocarditis cases was similar to that of penicillin G (MBC90 = 8 mg/l). Imipenem was compared with nafcillin and with penicillin plus gentamicin in the therapy of experimental endocarditis induced in rabbits by Staph . aureus and Str . faecalis , respectively . The dosages were chosen to simulate closely serum antibiotic concentrations found in humans receiving standard parenteral regimens. imipenem was more rapidly bactericidal than nafcillin in experimental staphylococcal endocarditis. The mean +/- S.D. Staph. aureus concentrations within aortic valve vegetations (log10 cfu/g) after 5 days of therapy were as follows: imipenem = 1.39 +/- 0.61 versus nafcillin 2.39 +/- 0.36 (P less than 0.02). Both the imipenem and nafcillin regimens resulted in 'sterile' vegetations in congruent to 50% of rabbits with experimental staphylococcal endocarditis after 5 days of therapy (P greater than 0.05). imipenem was also equivalent to penicillin plus gentamicin in the therapy of experimental enterococcal endocarditis for 5 days, as assessed by the mean cfu/g vegetation and the percentage of vegetations rendered sterile. However, 7 days of therapy cured experimental enterococcal endocarditis in 72% of rabbits receiving penicillin plus gentamicin versus 20% for imipenem alone (P less than 0.05). imipenem deserves further evaluation in the therapy of infective endocarditis, both in experimental animal models of infection and in humans. This agent may prove useful in the therapy of staphylococcal endocarditis in a variety of difficult clinical situations. Therapy of enterococcal endocarditis with imipenem alone is not advisable, pending further data. ### Response: Imipenem, nafcillin, penicillin, gentamicin

2ffc3bc4a2d4cef091142559f41db561

The total dose of paclitaxel ( 175 - 200 mg/m2 ) ; cisplatin ( 75 mg/m2 ) ; and etoposide ( 175 - 200 mg/m2 ) was divided into five daily doses administered over 3 h with cycles repeated at 21 - 28 days .

Paclitaxel, cisplatin, etoposide combination chemotherapy: a multifractionated bolus dose schedule for non-small cell lung cancer. In this phase II study, paclitaxel was added to the combination of cisplatin and etoposide (TPE regimen), in 37 patients with advanced non-small cell lung cancer, using a multifractionated dosing schedule. The total dose of paclitaxel ( 175 - 200 mg/m2 ) ; cisplatin ( 75 mg/m2 ) ; and etoposide ( 175 - 200 mg/m2 ) was divided into five daily doses administered over 3 h with cycles repeated at 21 - 28 days . 15 patients had stage III A or B disease and 22 stage IV disease. 32 patients were evaluable for toxicity and 37 for response. Neutropenia was the most prominent toxicity. Grade 3 or grade 4 neutropenia was observed in 12 (38%) and 9 (25%) of the patients, respectively and 11 patients required hospitalisation. 3 patients died secondary to chemotherapy related sepsis. Diarrhoea (grade 3, 3 patients; grade 4, 2 patients) was the only other significant non-haematological acute toxicity. The optimal dose rate for this multifractionated regimen was paclitaxel 35 or 40 mg/m2/fraction; cisplatin 15 mg/m2/fraction; etoposide 35 or 40 mg/m2/fraction. Responses were observed in 28 of 37 evaluable patients (3 complete response; 25 partial responses [76%]. 22 patients are alive; 8 with stage III B disease received radiation or surgery (3 had minimal or no tumour in the pathology specimen). TPE is a highly active regimen for non-small cell lung cancer and multifractionated dose scheduling is a feasible and well tolerated system.

https://pubmed.ncbi.nlm.nih.gov/9713270/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Paclitaxel, cisplatin, etoposide combination chemotherapy: a multifractionated bolus dose schedule for non-small cell lung cancer. In this phase II study, paclitaxel was added to the combination of cisplatin and etoposide (TPE regimen), in 37 patients with advanced non-small cell lung cancer, using a multifractionated dosing schedule. The total dose of paclitaxel ( 175 - 200 mg/m2 ) ; cisplatin ( 75 mg/m2 ) ; and etoposide ( 175 - 200 mg/m2 ) was divided into five daily doses administered over 3 h with cycles repeated at 21 - 28 days . 15 patients had stage III A or B disease and 22 stage IV disease. 32 patients were evaluable for toxicity and 37 for response. Neutropenia was the most prominent toxicity. Grade 3 or grade 4 neutropenia was observed in 12 (38%) and 9 (25%) of the patients, respectively and 11 patients required hospitalisation. 3 patients died secondary to chemotherapy related sepsis. Diarrhoea (grade 3, 3 patients; grade 4, 2 patients) was the only other significant non-haematological acute toxicity. The optimal dose rate for this multifractionated regimen was paclitaxel 35 or 40 mg/m2/fraction; cisplatin 15 mg/m2/fraction; etoposide 35 or 40 mg/m2/fraction. Responses were observed in 28 of 37 evaluable patients (3 complete response; 25 partial responses [76%]. 22 patients are alive; 8 with stage III B disease received radiation or surgery (3 had minimal or no tumour in the pathology specimen). TPE is a highly active regimen for non-small cell lung cancer and multifractionated dose scheduling is a feasible and well tolerated system. ### Response: paclitaxel, cisplatin, etoposide

d3d3065094bd69c0fc64085832f1d55a

In this phase 3 trial , we randomly assigned ( in a 1:1:1 ratio ) patients with advanced renal cell carcinoma and no previous systemic therapy to receive lenvatinib ( 20 mg orally once daily ) plus pembrolizumab ( 200 mg intravenously once every 3 weeks ) , lenvatinib ( 18 mg orally once daily ) plus everolimus ( 5 mg orally once daily ) , or sunitinib ( 50 mg orally once daily , alternating 4 weeks receiving treatment and 2 weeks without treatment ) .

Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. lenvatinib in combination with pembrolizumab or everolimus has activity against advanced renal cell carcinoma. The efficacy of these regimens as compared with that of sunitinib is unclear. ### methods In this phase 3 trial , we randomly assigned ( in a 1:1:1 ratio ) patients with advanced renal cell carcinoma and no previous systemic therapy to receive lenvatinib ( 20 mg orally once daily ) plus pembrolizumab ( 200 mg intravenously once every 3 weeks ) , lenvatinib ( 18 mg orally once daily ) plus everolimus ( 5 mg orally once daily ) , or sunitinib ( 50 mg orally once daily , alternating 4 weeks receiving treatment and 2 weeks without treatment ) . The primary end point was progression-free survival, as assessed by an independent review committee in accordance with Response Evaluation Criteria in Solid Tumors, version 1.1. Overall survival and safety were also evaluated. ### results A total of 1069 patients were randomly assigned to receive lenvatinib plus pembrolizumab (355 patients), lenvatinib plus everolimus (357), or sunitinib (357). Progression-free survival was longer with lenvatinib plus pembrolizumab than with sunitinib (median, 23.9 vs. 9.2 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.32 to 0.49; P<0.001) and was longer with lenvatinib plus everolimus than with sunitinib (median, 14.7 vs. 9.2 months; hazard ratio, 0.65; 95% CI, 0.53 to 0.80; P<0.001). Overall survival was longer with lenvatinib plus pembrolizumab than with sunitinib (hazard ratio for death, 0.66; 95% CI, 0.49 to 0.88; P = 0.005) but was not longer with lenvatinib plus everolimus than with sunitinib (hazard ratio, 1.15; 95% CI, 0.88 to 1.50; P = 0.30). Grade 3 or higher adverse events emerged or worsened during treatment in 82.4% of the patients who received lenvatinib plus pembrolizumab, 83.1% of those who received lenvatinib plus everolimus, and 71.8% of those who received sunitinib. Grade 3 or higher adverse events occurring in at least 10% of the patients in any group included hypertension, diarrhea, and elevated lipase levels. ### conclusions lenvatinib plus pembrolizumab was associated with significantly longer progression-free survival and overall survival than sunitinib. (Funded by Eisai and Merck Sharp and Dohme; CLEAR ClinicalTrials.gov number, NCT02811861.).

https://pubmed.ncbi.nlm.nih.gov/33616314/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. lenvatinib in combination with pembrolizumab or everolimus has activity against advanced renal cell carcinoma. The efficacy of these regimens as compared with that of sunitinib is unclear. ### methods In this phase 3 trial , we randomly assigned ( in a 1:1:1 ratio ) patients with advanced renal cell carcinoma and no previous systemic therapy to receive lenvatinib ( 20 mg orally once daily ) plus pembrolizumab ( 200 mg intravenously once every 3 weeks ) , lenvatinib ( 18 mg orally once daily ) plus everolimus ( 5 mg orally once daily ) , or sunitinib ( 50 mg orally once daily , alternating 4 weeks receiving treatment and 2 weeks without treatment ) . The primary end point was progression-free survival, as assessed by an independent review committee in accordance with Response Evaluation Criteria in Solid Tumors, version 1.1. Overall survival and safety were also evaluated. ### results A total of 1069 patients were randomly assigned to receive lenvatinib plus pembrolizumab (355 patients), lenvatinib plus everolimus (357), or sunitinib (357). Progression-free survival was longer with lenvatinib plus pembrolizumab than with sunitinib (median, 23.9 vs. 9.2 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.32 to 0.49; P<0.001) and was longer with lenvatinib plus everolimus than with sunitinib (median, 14.7 vs. 9.2 months; hazard ratio, 0.65; 95% CI, 0.53 to 0.80; P<0.001). Overall survival was longer with lenvatinib plus pembrolizumab than with sunitinib (hazard ratio for death, 0.66; 95% CI, 0.49 to 0.88; P = 0.005) but was not longer with lenvatinib plus everolimus than with sunitinib (hazard ratio, 1.15; 95% CI, 0.88 to 1.50; P = 0.30). Grade 3 or higher adverse events emerged or worsened during treatment in 82.4% of the patients who received lenvatinib plus pembrolizumab, 83.1% of those who received lenvatinib plus everolimus, and 71.8% of those who received sunitinib. Grade 3 or higher adverse events occurring in at least 10% of the patients in any group included hypertension, diarrhea, and elevated lipase levels. ### conclusions lenvatinib plus pembrolizumab was associated with significantly longer progression-free survival and overall survival than sunitinib. (Funded by Eisai and Merck Sharp and Dohme; CLEAR ClinicalTrials.gov number, NCT02811861.). ### Response: lenvatinib, pembrolizumab, lenvatinib, everolimus, sunitinib

6f0476440606d257ae4a2266a30878d1

Only chemotherapy by intravenous administration of 2 courses of 120 - 150 mg ACNU ( 1.7 - 2.2 mg/kg ) and 4 mg vincristine ( 0.06 mg/kg ) with intrathecal administration of methotrexate was given at this time .

A long surviving case of recurrent medulloblastoma displaying effectiveness of ACNU/vincristine chemotherapy. A favorable case of recurrent medulloblastoma, in which 19 years has elapsed with combination therapy due to surgery, radiation and chemotherapy since the initial operation, is reported. The case was a male of age 12 who was admitted due to medulloblastoma of the classical type. Tumor recurrences were observed 3 times within 7 years after the initial operation and radiation treatment. At the 3rd recurrence, a large tumor was found in the cerebellar vermis and left cerebellar hemisphere on CT with CSF dissemination and a high NSE level in the CSF (62 ng/ml). Only chemotherapy by intravenous administration of 2 courses of 120 - 150 mg ACNU ( 1.7 - 2.2 mg/kg ) and 4 mg vincristine ( 0.06 mg/kg ) with intrathecal administration of methotrexate was given at this time . The tumor image and gait disturbance with radicular pain disappeared completely and the NSE level in the CSF improved to within the normal range (5.4 ng/ml). The patient continues in complete remission, with a Karnovsky performance status of 100% at 4 years after the 3rd recurrence. We report full details of this case in which active treatments consisting mainly of chemotherapy proved to be effective for recurrent medulloblastoma, even though its prognosis is generally very unfavorable.

https://pubmed.ncbi.nlm.nih.gov/8057133/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: A long surviving case of recurrent medulloblastoma displaying effectiveness of ACNU/vincristine chemotherapy. A favorable case of recurrent medulloblastoma, in which 19 years has elapsed with combination therapy due to surgery, radiation and chemotherapy since the initial operation, is reported. The case was a male of age 12 who was admitted due to medulloblastoma of the classical type. Tumor recurrences were observed 3 times within 7 years after the initial operation and radiation treatment. At the 3rd recurrence, a large tumor was found in the cerebellar vermis and left cerebellar hemisphere on CT with CSF dissemination and a high NSE level in the CSF (62 ng/ml). Only chemotherapy by intravenous administration of 2 courses of 120 - 150 mg ACNU ( 1.7 - 2.2 mg/kg ) and 4 mg vincristine ( 0.06 mg/kg ) with intrathecal administration of methotrexate was given at this time . The tumor image and gait disturbance with radicular pain disappeared completely and the NSE level in the CSF improved to within the normal range (5.4 ng/ml). The patient continues in complete remission, with a Karnovsky performance status of 100% at 4 years after the 3rd recurrence. We report full details of this case in which active treatments consisting mainly of chemotherapy proved to be effective for recurrent medulloblastoma, even though its prognosis is generally very unfavorable. ### Response: ACNU, vincristine, methotrexate

fac270cf9d9f839bc49728d2d4f38fc7

In first-line treatment of intermediate- to poor-risk patients , the CheckMate 214 study demonstrated a significant survival advantage for nivolumab and ipilimumab versus sunitinib .

A Cost-Effectiveness Analysis of Nivolumab and Ipilimumab Versus Sunitinib in First-Line Intermediate- to Poor-Risk Advanced Renal Cell Carcinoma. The treatment paradigm of advanced renal cell carcinoma (RCC) has changed rapidly in recent years. In first-line treatment of intermediate- to poor-risk patients , the CheckMate 214 study demonstrated a significant survival advantage for nivolumab and ipilimumab versus sunitinib . The high cost of combined immune-modulating agents warrants an understanding of the combination's value by considering both efficacy and cost. The objective of this study was to estimate the cost-effectiveness of nivolumab and ipilimumab compared with sunitinib for first-line treatment of intermediate- to poor-risk advanced RCC from the U.S. payer perspective. ### Materials And Methods A Markov model was developed to compare the costs and effectiveness of nivolumab and ipilimumab with those of sunitinib in the first-line treatment of intermediate- to poor-risk advanced RCC. Health outcomes were measured in life-years and quality-adjusted life-years (QALYs). Drug costs were based on Medicare reimbursement rates in 2017. We extrapolated survival beyond the trial closure using Weibull distribution. Model robustness was addressed in univariable and probabilistic sensitivity analyses. ### results The total mean cost per-patient of nivolumab and ipilimumab versus sunitinib was $292,308 and $169,287, respectfully. nivolumab and ipilimumab generated a gain of 0.978 QALYs over sunitinib. The incremental cost-effectiveness ratio (ICER) for nivolumab and ipilimumab was $125,739/QALY versus sunitinib. ### conclusion Our analysis established that the base case ICER in the model for nivolumab and ipilimumab versus sunitinib is below what some would consider the upper limit of the theoretical willingness-to-pay threshold in the U.S. ($150,000/QALY) and is thus estimated to be cost-effective. ### Implications For Practice This article assessed the cost-effectiveness of nivolumab and ipilimumab versus sunitinib for treatment of patients with intermediate- to poor-risk metastatic kidney cancer, from the U.S. payer perspective. It would cost $125,739 to gain 1 quality-adjusted life-year with nivolumab and ipilimumab versus sunitinib in these patients.

https://pubmed.ncbi.nlm.nih.gov/30710066/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: A Cost-Effectiveness Analysis of Nivolumab and Ipilimumab Versus Sunitinib in First-Line Intermediate- to Poor-Risk Advanced Renal Cell Carcinoma. The treatment paradigm of advanced renal cell carcinoma (RCC) has changed rapidly in recent years. In first-line treatment of intermediate- to poor-risk patients , the CheckMate 214 study demonstrated a significant survival advantage for nivolumab and ipilimumab versus sunitinib . The high cost of combined immune-modulating agents warrants an understanding of the combination's value by considering both efficacy and cost. The objective of this study was to estimate the cost-effectiveness of nivolumab and ipilimumab compared with sunitinib for first-line treatment of intermediate- to poor-risk advanced RCC from the U.S. payer perspective. ### Materials And Methods A Markov model was developed to compare the costs and effectiveness of nivolumab and ipilimumab with those of sunitinib in the first-line treatment of intermediate- to poor-risk advanced RCC. Health outcomes were measured in life-years and quality-adjusted life-years (QALYs). Drug costs were based on Medicare reimbursement rates in 2017. We extrapolated survival beyond the trial closure using Weibull distribution. Model robustness was addressed in univariable and probabilistic sensitivity analyses. ### results The total mean cost per-patient of nivolumab and ipilimumab versus sunitinib was $292,308 and $169,287, respectfully. nivolumab and ipilimumab generated a gain of 0.978 QALYs over sunitinib. The incremental cost-effectiveness ratio (ICER) for nivolumab and ipilimumab was $125,739/QALY versus sunitinib. ### conclusion Our analysis established that the base case ICER in the model for nivolumab and ipilimumab versus sunitinib is below what some would consider the upper limit of the theoretical willingness-to-pay threshold in the U.S. ($150,000/QALY) and is thus estimated to be cost-effective. ### Implications For Practice This article assessed the cost-effectiveness of nivolumab and ipilimumab versus sunitinib for treatment of patients with intermediate- to poor-risk metastatic kidney cancer, from the U.S. payer perspective. It would cost $125,739 to gain 1 quality-adjusted life-year with nivolumab and ipilimumab versus sunitinib in these patients. ### Response: nivolumab, ipilimumab, sunitinib

b050c4f05066a38a88314ba7a6cf1d3a

In addition , docetaxel has a longer retention time in tumor cells than paclitaxel because of greater uptake and slower efflux .

Preclinical pharmacology of the taxanes: implications of the differences. Taxanes are one of the most powerful classes of compounds among all chemotherapeutic drugs. Only 30 years separate the isolation of the first taxane from the results of direct clinical comparisons in metastatic breast, ovarian, and lung cancer between the two taxanes available in routine clinical practice. These results suggest a more favorable benefit-to-risk ratio for docetaxel compared to paclitaxel when these drugs are used as single agents or in combination with other chemotherapeutic agents in an every-3-week dosing regimen. Pharmacological data support the difference between the taxanes, likely explaining the clinical results. Considering the molecular pharmacology of the two drugs, docetaxel appears to bind to beta-tubulin with greater affinity and has a wider cell cycle activity than paclitaxel. docetaxel also appears to have direct antitumoral activity via an apoptotic effect mediated by bcl-2 phosphorylation. In addition , docetaxel has a longer retention time in tumor cells than paclitaxel because of greater uptake and slower efflux . Pharmacokinetics and pharmacodynamics of the taxanes show both agents to be extensively metabolized in the liver, and paclitaxel has a nonlinear pharmacokinetic behavior while docetaxel has linear pharmacokinetics. These differences explain the more simple treatment schedule and favorable results for docetaxel as a single agent and in combination therapy. Last, but not least, there is a pharmacokinetic interaction between paclitaxel and the anthracyclines, an active class of compounds commonly used in the treatment of breast cancer. This pharmacokinetic interaction is associated with greater cardio- and myelotoxicities, which are sequence dependent. These pharmacological data likely explain the different clinical development strategies for the two molecules as well as the different clinical results from individual trials and direct comparisons.

https://pubmed.ncbi.nlm.nih.gov/15161985/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Preclinical pharmacology of the taxanes: implications of the differences. Taxanes are one of the most powerful classes of compounds among all chemotherapeutic drugs. Only 30 years separate the isolation of the first taxane from the results of direct clinical comparisons in metastatic breast, ovarian, and lung cancer between the two taxanes available in routine clinical practice. These results suggest a more favorable benefit-to-risk ratio for docetaxel compared to paclitaxel when these drugs are used as single agents or in combination with other chemotherapeutic agents in an every-3-week dosing regimen. Pharmacological data support the difference between the taxanes, likely explaining the clinical results. Considering the molecular pharmacology of the two drugs, docetaxel appears to bind to beta-tubulin with greater affinity and has a wider cell cycle activity than paclitaxel. docetaxel also appears to have direct antitumoral activity via an apoptotic effect mediated by bcl-2 phosphorylation. In addition , docetaxel has a longer retention time in tumor cells than paclitaxel because of greater uptake and slower efflux . Pharmacokinetics and pharmacodynamics of the taxanes show both agents to be extensively metabolized in the liver, and paclitaxel has a nonlinear pharmacokinetic behavior while docetaxel has linear pharmacokinetics. These differences explain the more simple treatment schedule and favorable results for docetaxel as a single agent and in combination therapy. Last, but not least, there is a pharmacokinetic interaction between paclitaxel and the anthracyclines, an active class of compounds commonly used in the treatment of breast cancer. This pharmacokinetic interaction is associated with greater cardio- and myelotoxicities, which are sequence dependent. These pharmacological data likely explain the different clinical development strategies for the two molecules as well as the different clinical results from individual trials and direct comparisons. ### Response: docetaxel, paclitaxel

0cf78118eeb04f8f121db21b6dd8b17a

The total sample size was 103 , consisting of 31 , 23 , and 19 patients in olanzapine , risperidone , and clozapine groups , respectively and 30 controls .

Comparative study of sexual dysfunction and serum prolactin level associated with olanzapine, risperidone, and clozapine in patients with remitted schizophrenia. Sexual dysfunctions have been a major side effect of the second generation anti-psychotic drugs which often affects treatment compliance in patients with schizophrenia. There is no/few systematic review or research addressing sexual dysfunction and their effect on serum prolactin level among different atypical antipsychotics in India. ### aims To determine and compare the frequency of sexual dysfunction associated with olanzapine, risperidone, and clozapine and their effect on serum prolactin level in remitted patients with schizophrenia. ### Settings And Design Cross-sectional hospital-based study. Recruitment by purposive sampling. Estimation of serum prolactin was done using enzyme-linked immunosorbent assay technique. ### Materials And Methods The total sample size was 103 , consisting of 31 , 23 , and 19 patients in olanzapine , risperidone , and clozapine groups , respectively and 30 controls . A Brief Psychiatric Rating Scale, Udvalg for Kliniske Undersogelser (UKU) Side Effect Rating Scale and Sexual Functioning Questionnaire were administered. Analysis of variance was used to compare clinical variables. Chi-square test was used to identify the frequency of sexual dysfunction. Kruskal-Wallis test was used to compare UKU side effect, sexual dysfunction, and blood parameters across the study groups. ### Results And Conclusion Eighty-six percentage reported sexual dysfunction in one or more domains of sexual functioning in risperidone group as compared to 48.3% in olanzapine and 31% in clozapine groups, respectively. Prolactin level elevation was statistically significant in risperidone group followed by clozapine and olanzapine groups, respectively.

https://pubmed.ncbi.nlm.nih.gov/26816428/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Comparative study of sexual dysfunction and serum prolactin level associated with olanzapine, risperidone, and clozapine in patients with remitted schizophrenia. Sexual dysfunctions have been a major side effect of the second generation anti-psychotic drugs which often affects treatment compliance in patients with schizophrenia. There is no/few systematic review or research addressing sexual dysfunction and their effect on serum prolactin level among different atypical antipsychotics in India. ### aims To determine and compare the frequency of sexual dysfunction associated with olanzapine, risperidone, and clozapine and their effect on serum prolactin level in remitted patients with schizophrenia. ### Settings And Design Cross-sectional hospital-based study. Recruitment by purposive sampling. Estimation of serum prolactin was done using enzyme-linked immunosorbent assay technique. ### Materials And Methods The total sample size was 103 , consisting of 31 , 23 , and 19 patients in olanzapine , risperidone , and clozapine groups , respectively and 30 controls . A Brief Psychiatric Rating Scale, Udvalg for Kliniske Undersogelser (UKU) Side Effect Rating Scale and Sexual Functioning Questionnaire were administered. Analysis of variance was used to compare clinical variables. Chi-square test was used to identify the frequency of sexual dysfunction. Kruskal-Wallis test was used to compare UKU side effect, sexual dysfunction, and blood parameters across the study groups. ### Results And Conclusion Eighty-six percentage reported sexual dysfunction in one or more domains of sexual functioning in risperidone group as compared to 48.3% in olanzapine and 31% in clozapine groups, respectively. Prolactin level elevation was statistically significant in risperidone group followed by clozapine and olanzapine groups, respectively. ### Response: olanzapine, risperidone, clozapine

3602ecfca299c3ee0a85bc8259f20cae

The relative analgesic potency ratios were 0.65 ( 0.56 - 0.76 ) for ropivacaine : bupivacaine , 0.80 ( 0.70 - 0.92 ) for ropivacaine : levobupivacaine , and 0.81 ( 0.69 - 0.94 ) for levobupivacaine : bupivacaine .

Minimum local analgesic doses of ropivacaine, levobupivacaine, and bupivacaine for intrathecal labor analgesia. Doses for intrathecal opioid-local anesthetic mixtures have been arbitrarily chosen. The aim of this study was to compare the analgesic efficacies of intrathecal ropivacaine, levobupivacaine, and bupivacaine for labor analgesia and to determine the analgesic potency ratios for these three drugs. For this purpose, the authors used the up-down sequential allocation model, which estimates the minimum local analgesic dose for intrathecal local anesthetic. ### methods Ninety-seven nulliparous term parturients in spontaneous labor, requesting combined spinal-epidural analgesia, were randomly allocated to one of three groups to receive 0.25% spinal ropivacaine, levobupivacaine, or bupivacaine. The initial dose of the local anesthetic drug was chosen to be 2.5 mg, and the testing interval was set at 0.25 mg. The subsequent doses were determined by the response of the previous parturient. Efficacy was accepted if the visual analog pain score decreased to 10 mm or less on a 100-mm scale within 30 min. The minimum local analgesic dose was calculated using the method of Dixon and Massey. ### results The intrathecal minimum local analgesic dose was 3.64 mg (95% confidence interval, 3.33-3.96 mg) for ropivacaine, 2.94 (2.73-3.16) mg for levobupivacaine, and 2.37 (2.17-2.58) mg for bupivacaine. The relative analgesic potency ratios were 0.65 ( 0.56 - 0.76 ) for ropivacaine : bupivacaine , 0.80 ( 0.70 - 0.92 ) for ropivacaine : levobupivacaine , and 0.81 ( 0.69 - 0.94 ) for levobupivacaine : bupivacaine . There were significant trends (P bupivacaine and levobupivacaine. ### conclusions This study suggests a potency hierarchy of spinal bupivacaine > levobupivacaine > ropivacaine.

https://pubmed.ncbi.nlm.nih.gov/15731605/

### Instruction: Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds that can co-occur for the mentioned treatment ### Input: Minimum local analgesic doses of ropivacaine, levobupivacaine, and bupivacaine for intrathecal labor analgesia. Doses for intrathecal opioid-local anesthetic mixtures have been arbitrarily chosen. The aim of this study was to compare the analgesic efficacies of intrathecal ropivacaine, levobupivacaine, and bupivacaine for labor analgesia and to determine the analgesic potency ratios for these three drugs. For this purpose, the authors used the up-down sequential allocation model, which estimates the minimum local analgesic dose for intrathecal local anesthetic. ### methods Ninety-seven nulliparous term parturients in spontaneous labor, requesting combined spinal-epidural analgesia, were randomly allocated to one of three groups to receive 0.25% spinal ropivacaine, levobupivacaine, or bupivacaine. The initial dose of the local anesthetic drug was chosen to be 2.5 mg, and the testing interval was set at 0.25 mg. The subsequent doses were determined by the response of the previous parturient. Efficacy was accepted if the visual analog pain score decreased to 10 mm or less on a 100-mm scale within 30 min. The minimum local analgesic dose was calculated using the method of Dixon and Massey. ### results The intrathecal minimum local analgesic dose was 3.64 mg (95% confidence interval, 3.33-3.96 mg) for ropivacaine, 2.94 (2.73-3.16) mg for levobupivacaine, and 2.37 (2.17-2.58) mg for bupivacaine. The relative analgesic potency ratios were 0.65 ( 0.56 - 0.76 ) for ropivacaine : bupivacaine , 0.80 ( 0.70 - 0.92 ) for ropivacaine : levobupivacaine , and 0.81 ( 0.69 - 0.94 ) for levobupivacaine : bupivacaine . There were significant trends (P bupivacaine and levobupivacaine. ### conclusions This study suggests a potency hierarchy of spinal bupivacaine > levobupivacaine > ropivacaine. ### Response: ropivacaine, bupivacaine, ropivacaine, levobupivacaine, levobupivacaine, bupivacaine