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0e92133c9b682a28ac91ea5d2c6fcb9d

Lapatinib ( LPT ) could sensitize human epidermal growth factor receptor-2 ( HER-2 ) positive breast cancer to paclitaxel ( PTX ) and induce synergetic action with PTX in preclinical test and phase II/III trial .

A novel combined micellar system of lapatinib and Paclitaxel with enhanced antineoplastic effect against human epidermal growth factor receptor-2 positive breast tumor in vitro. Lapatinib ( LPT ) could sensitize human epidermal growth factor receptor-2 ( HER-2 ) positive breast cancer to paclitaxel ( PTX ) and induce synergetic action with PTX in preclinical test and phase II/III trial . In this study, LPT-conjugated poly (ethylene glycol) (PEG) and poly (lactic acid) (PLA) (LPT-PEG-PLA) was first synthesized and confirmed with ¹H Nuclear Magnetic Resonance and Matrix-Assisted Laser Desorption/ Ionization Time of Flight Mass Spectrometry, which was used for the preparation of a novel PEG-PLA combined micelles of LPT and PTX (PPM-LP). The obtained PPM-LP exhibited uniform, spherical shape with a size of 25.80 ± 0.47 nm and zeta potential of -3.17 ± 0.15 mv. PTX existed in molecular or amorphous forms in the micelles and superficial LPT could better delay PTX release. The cytotoxicity of PPM-LP with LPT conjugation against SKBr-3 cells (HER-2 positive) was found to be significantly increasing as compared with PPM-PTX, whereas there was no significant difference against MDA-MB-231 cells (HER-2 negative). PPM-LP could escape from endosomes and be distributed into cytoplasm and led to cell arrest in G2/M and G1/S phases simultaneously. Results of nucleus staining and flow cytometry confirmed that LPT could remarkably increase antineoplastic effect of PTX against SKBr-3 cells. All these results demonstrated that PPM-LP may be a promising drug delivery system for HER-2 positive breast cancer.

https://pubmed.ncbi.nlm.nih.gov/25421492/

### 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 novel combined micellar system of lapatinib and Paclitaxel with enhanced antineoplastic effect against human epidermal growth factor receptor-2 positive breast tumor in vitro. Lapatinib ( LPT ) could sensitize human epidermal growth factor receptor-2 ( HER-2 ) positive breast cancer to paclitaxel ( PTX ) and induce synergetic action with PTX in preclinical test and phase II/III trial . In this study, LPT-conjugated poly (ethylene glycol) (PEG) and poly (lactic acid) (PLA) (LPT-PEG-PLA) was first synthesized and confirmed with ¹H Nuclear Magnetic Resonance and Matrix-Assisted Laser Desorption/ Ionization Time of Flight Mass Spectrometry, which was used for the preparation of a novel PEG-PLA combined micelles of LPT and PTX (PPM-LP). The obtained PPM-LP exhibited uniform, spherical shape with a size of 25.80 ± 0.47 nm and zeta potential of -3.17 ± 0.15 mv. PTX existed in molecular or amorphous forms in the micelles and superficial LPT could better delay PTX release. The cytotoxicity of PPM-LP with LPT conjugation against SKBr-3 cells (HER-2 positive) was found to be significantly increasing as compared with PPM-PTX, whereas there was no significant difference against MDA-MB-231 cells (HER-2 negative). PPM-LP could escape from endosomes and be distributed into cytoplasm and led to cell arrest in G2/M and G1/S phases simultaneously. Results of nucleus staining and flow cytometry confirmed that LPT could remarkably increase antineoplastic effect of PTX against SKBr-3 cells. All these results demonstrated that PPM-LP may be a promising drug delivery system for HER-2 positive breast cancer. ### Response: Lapatinib, paclitaxel

32a61c25a4ad01c272675f512c603206

Two of nine patients received 15 mg/kg bevacizumab IV , 90 mg/m(2 ) irinotecan orally for five consecutive days , 100 mg/m(2)/day temozolomide IV for 5 days , and 1.5 mg/m(2 ) vincristine IV , each administered every 21 days .

Response to bevacizumab, irinotecan, and temozolomide in children with relapsed medulloblastoma: a multi-institutional experience. Chemotherapy for relapsed medulloblastoma has been inadequate, and most patients succumb to disease. ### methods We retrospectively reviewed nine cases of relapsed medulloblastoma treated with bevacizumab, irinotecan, ± temozolomide. Patients received one to three prior therapeutic regimens. Five patients received 10 mg/kg bevacizumab and 125-150 mg/m(2) irinotecan IV every 2 weeks, with temozolomide, starting at a median dose of 150 mg/m(2) orally for 5 days monthly. Two patients received bevacizumab and irinotecan, but not temozolomide, due to provider preference. Two of nine patients received 15 mg/kg bevacizumab IV , 90 mg/m(2 ) irinotecan orally for five consecutive days , 100 mg/m(2)/day temozolomide IV for 5 days , and 1.5 mg/m(2 ) vincristine IV , each administered every 21 days . ### results Median time to progression was 11 months. Median overall survival was 13 months. Objective tumor response at 3 months was 67 %, including six patients with partial response (PR) and three patients with stable disease (SD). At 6 months, objective response was 55 %, with two patients with PR and three with complete response. Additionally, one patient had SD and three had PD. Two patients remain alive and progression free at 15 and 55 months; another is alive with disease at 20 months. Toxicities included two patients with grade III neutropenia, two with grade III thrombocytopenia, one with grade III elevation of liver function tests, and one patient with grade III diarrhea. ### conclusions The combination of bevacizumab and irinotecan, with or without temozolomide, produces objective responses with minimal toxicity in children with recurrent medulloblastoma. Prospective clinical trials are needed to evaluate the efficacy of this strategy.

https://pubmed.ncbi.nlm.nih.gov/23296323/

### 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 bevacizumab, irinotecan, and temozolomide in children with relapsed medulloblastoma: a multi-institutional experience. Chemotherapy for relapsed medulloblastoma has been inadequate, and most patients succumb to disease. ### methods We retrospectively reviewed nine cases of relapsed medulloblastoma treated with bevacizumab, irinotecan, ± temozolomide. Patients received one to three prior therapeutic regimens. Five patients received 10 mg/kg bevacizumab and 125-150 mg/m(2) irinotecan IV every 2 weeks, with temozolomide, starting at a median dose of 150 mg/m(2) orally for 5 days monthly. Two patients received bevacizumab and irinotecan, but not temozolomide, due to provider preference. Two of nine patients received 15 mg/kg bevacizumab IV , 90 mg/m(2 ) irinotecan orally for five consecutive days , 100 mg/m(2)/day temozolomide IV for 5 days , and 1.5 mg/m(2 ) vincristine IV , each administered every 21 days . ### results Median time to progression was 11 months. Median overall survival was 13 months. Objective tumor response at 3 months was 67 %, including six patients with partial response (PR) and three patients with stable disease (SD). At 6 months, objective response was 55 %, with two patients with PR and three with complete response. Additionally, one patient had SD and three had PD. Two patients remain alive and progression free at 15 and 55 months; another is alive with disease at 20 months. Toxicities included two patients with grade III neutropenia, two with grade III thrombocytopenia, one with grade III elevation of liver function tests, and one patient with grade III diarrhea. ### conclusions The combination of bevacizumab and irinotecan, with or without temozolomide, produces objective responses with minimal toxicity in children with recurrent medulloblastoma. Prospective clinical trials are needed to evaluate the efficacy of this strategy. ### Response: bevacizumab, irinotecan, temozolomide, vincristine

8153038603c4967e7f15cff9488531d3

These findings may help clinicians identify patients for whom acamprosate and naltrexone may be most beneficial .

Baseline trajectories of drinking moderate acamprosate and naltrexone effects in the COMBINE study. The COMBINE study evaluated the effects of acamprosate, naltrexone, and the Combined Behavioral Intervention (CBI). In secondary analyses, our goals were to identify trajectories of any drinking prior to randomization, to characterize subjects in these trajectories, and to assess whether prerandomization trajectories predict drinking outcomes and moderate treatment response. ### methods We analyzed daily indicators of any drinking in 90 days prior to randomization using a trajectory-based approach. General linear models and generalized logistic regression assessed main and interactive effects of prerandomization drinking trajectories and treatment on summary drinking measures during active treatment. ### results We identified five trajectories of any drinking prior to randomization: "T1: frequent drinkers", "T2: very frequent drinkers", "T3: nearly daily drinkers", "T4: consistent daily drinkers", and "T5: daily drinkers stopping early". During treatment, "T3: nearly daily drinkers" and "T4: consistent daily drinkers" had significantly worse drinking outcomes than "T1: frequent drinkers", while "T5: daily drinkers stopping early" had comparable drinking outcomes to "T1: frequent drinkers". acamprosate significantly increased the chance of abstinence from heavy drinking for the "T2: very frequent drinking" trajectory but decreased the chance of abstinence from heavy drinking for "T5: daily drinkers stopping early". naltrexone differentially improved rates of continuous abstinence for very frequent drinkers. ### conclusions acamprosate benefited very frequent drinkers and contrary to expectations was associated with poorer response compared to placebo for consistent daily drinkers who had longer durations of pretreatment abstinence (e.g., ≥14 days). Baseline drinking trajectories also moderated naltrexone effects. These findings may help clinicians identify patients for whom acamprosate and naltrexone may be most beneficial .

https://pubmed.ncbi.nlm.nih.gov/21143249/

### 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: Baseline trajectories of drinking moderate acamprosate and naltrexone effects in the COMBINE study. The COMBINE study evaluated the effects of acamprosate, naltrexone, and the Combined Behavioral Intervention (CBI). In secondary analyses, our goals were to identify trajectories of any drinking prior to randomization, to characterize subjects in these trajectories, and to assess whether prerandomization trajectories predict drinking outcomes and moderate treatment response. ### methods We analyzed daily indicators of any drinking in 90 days prior to randomization using a trajectory-based approach. General linear models and generalized logistic regression assessed main and interactive effects of prerandomization drinking trajectories and treatment on summary drinking measures during active treatment. ### results We identified five trajectories of any drinking prior to randomization: "T1: frequent drinkers", "T2: very frequent drinkers", "T3: nearly daily drinkers", "T4: consistent daily drinkers", and "T5: daily drinkers stopping early". During treatment, "T3: nearly daily drinkers" and "T4: consistent daily drinkers" had significantly worse drinking outcomes than "T1: frequent drinkers", while "T5: daily drinkers stopping early" had comparable drinking outcomes to "T1: frequent drinkers". acamprosate significantly increased the chance of abstinence from heavy drinking for the "T2: very frequent drinking" trajectory but decreased the chance of abstinence from heavy drinking for "T5: daily drinkers stopping early". naltrexone differentially improved rates of continuous abstinence for very frequent drinkers. ### conclusions acamprosate benefited very frequent drinkers and contrary to expectations was associated with poorer response compared to placebo for consistent daily drinkers who had longer durations of pretreatment abstinence (e.g., ≥14 days). Baseline drinking trajectories also moderated naltrexone effects. These findings may help clinicians identify patients for whom acamprosate and naltrexone may be most beneficial . ### Response: acamprosate, naltrexone

26cdeb8104e8e3213f01593e3d4ec34a

From August 2002 to August 2004 , 42 patients with metastatic breast cancer were recruited for treatment with pegylated liposomal doxorubicin 40 mg/m(2 ) intravenously ( i.v . ) on day 1 and vinorelbine 30 mg/m(2 ) i.v . on days 1 and 15 every 4 weeks .

Multicenter phase II study of pegylated liposomal doxorubicin in combination with vinorelbine as first-line treatment in elderly patients with metastatic breast cancer. This multicenter phase II trial was conducted to analyze the clinical activity and toxicity of the combination of pegylated liposomal doxorubicin and vinorelbine as first-line treatment in elderly patients with metastatic breast cancer. ### Patients And Methods From August 2002 to August 2004 , 42 patients with metastatic breast cancer were recruited for treatment with pegylated liposomal doxorubicin 40 mg/m(2 ) intravenously ( i.v . ) on day 1 and vinorelbine 30 mg/m(2 ) i.v . on days 1 and 15 every 4 weeks . ### results The median age of the patients in this trial was 68 years (range 60-82). 40% of patients had 2 or more sites of metastasis, 33 (78%) had predominantly visceral metastasis, and 7 (16%) mostly bone metastasis. Just 2 (5%) patients had only lymphogenous or soft tissue metastasis. All patients had an ECOG performance status of 0-1, but 70% of the patients had relevant comorbidities. In an intention-to-treat analysis, the overall clinical response rate was 36%, the complete response rate was 2%, and the rate of partial remissions was 34%; stable disease occurred in 30%, and progressive disease was observed in 36%. Median duration of response was 10 months. Median time to progression was 4 months, and median overall survival time was 24 months. ### conclusion The combination of pegylated liposomal doxorubicin and vinorelbine is an active and well tolerated regimen in elderly patients with metastatic breast cancer in first-line treatment.

https://pubmed.ncbi.nlm.nih.gov/19209014/

### 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 phase II study of pegylated liposomal doxorubicin in combination with vinorelbine as first-line treatment in elderly patients with metastatic breast cancer. This multicenter phase II trial was conducted to analyze the clinical activity and toxicity of the combination of pegylated liposomal doxorubicin and vinorelbine as first-line treatment in elderly patients with metastatic breast cancer. ### Patients And Methods From August 2002 to August 2004 , 42 patients with metastatic breast cancer were recruited for treatment with pegylated liposomal doxorubicin 40 mg/m(2 ) intravenously ( i.v . ) on day 1 and vinorelbine 30 mg/m(2 ) i.v . on days 1 and 15 every 4 weeks . ### results The median age of the patients in this trial was 68 years (range 60-82). 40% of patients had 2 or more sites of metastasis, 33 (78%) had predominantly visceral metastasis, and 7 (16%) mostly bone metastasis. Just 2 (5%) patients had only lymphogenous or soft tissue metastasis. All patients had an ECOG performance status of 0-1, but 70% of the patients had relevant comorbidities. In an intention-to-treat analysis, the overall clinical response rate was 36%, the complete response rate was 2%, and the rate of partial remissions was 34%; stable disease occurred in 30%, and progressive disease was observed in 36%. Median duration of response was 10 months. Median time to progression was 4 months, and median overall survival time was 24 months. ### conclusion The combination of pegylated liposomal doxorubicin and vinorelbine is an active and well tolerated regimen in elderly patients with metastatic breast cancer in first-line treatment. ### Response: doxorubicin, vinorelbine

3bc93c0827679996e6c214c767d3824d

The aim of the present study was to investigate the combined effects of simvastatin and exemestane on MCF-7 human breast cancer cells .

Synergistic effects of combined treatment with simvastatin and exemestane on MCF-7 human breast cancer cells. Breast cancer is associated with high levels of incidence, morbidity and mortality; therefore, the identification of effective chemopreventive strategies is crucial. It is important for clinicians to be able to identify the populations at risk who would benefit from chemoprevention, and the interventions that are effective and safe. The aim of the present study was to investigate the combined effects of simvastatin and exemestane on MCF-7 human breast cancer cells . The anti-proliferative effects of simvastatin and exemestane, alone and in combination, on the growth of MCF-7 human breast cancer cells were assessed by MTT assay. The synergism between the two drugs was determined in vitro using the combination index (CI) analysis. Cell cycle distribution and apoptosis were analyzed by flow cytometry, and alterations to the signaling pathway in MCF-7 cells were examined by immunoblotting following treatment with various regimens. The results of the MTT assay indicated that the combined treatment of simvastatin and exemestane significantly decreased the viability of MCF-7 estrogen receptor-positive (ER+) human breast cancer cells, as compared with those that were treated with the individual drugs (CI<1). In addition, coadministration of exemestane and simvastatin was shown to result in marked inhibition of tumor cell proliferation, significant cell cycle arrest at G0/G1 phase and induction of apoptosis, as compared with that of the control and individual drug-treated cells. Furthermore, the results of the present study indicated that these synergistic effects may be associated with the B-cell lymphoma 2 (Bcl-2)/Bcl-2-associated X protein apoptotic pathway and the mitogen-activated protein kinase/mammalian target of rapamycin/p70S6 kinase growth pathway. The combination of exemestane and simvastatin generated synergistic effects on MCF-7 ER+ breast cancer cells, indicating that the combination of these drugs may be a potential therapeutic strategy for the treatment of hormone-dependent breast cancer. The combination of the two inhibitors markedly increased the efficacy, as compared with the single-agent treatment, suggesting that combination treatment could become a highly effective approach for breast cancer. The results of the present study suggested that this combination of drugs has therapeutic potential, and requires further mechanistic and biomarker investigations in clinical trials.

https://pubmed.ncbi.nlm.nih.gov/25738757/

### 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: Synergistic effects of combined treatment with simvastatin and exemestane on MCF-7 human breast cancer cells. Breast cancer is associated with high levels of incidence, morbidity and mortality; therefore, the identification of effective chemopreventive strategies is crucial. It is important for clinicians to be able to identify the populations at risk who would benefit from chemoprevention, and the interventions that are effective and safe. The aim of the present study was to investigate the combined effects of simvastatin and exemestane on MCF-7 human breast cancer cells . The anti-proliferative effects of simvastatin and exemestane, alone and in combination, on the growth of MCF-7 human breast cancer cells were assessed by MTT assay. The synergism between the two drugs was determined in vitro using the combination index (CI) analysis. Cell cycle distribution and apoptosis were analyzed by flow cytometry, and alterations to the signaling pathway in MCF-7 cells were examined by immunoblotting following treatment with various regimens. The results of the MTT assay indicated that the combined treatment of simvastatin and exemestane significantly decreased the viability of MCF-7 estrogen receptor-positive (ER+) human breast cancer cells, as compared with those that were treated with the individual drugs (CI<1). In addition, coadministration of exemestane and simvastatin was shown to result in marked inhibition of tumor cell proliferation, significant cell cycle arrest at G0/G1 phase and induction of apoptosis, as compared with that of the control and individual drug-treated cells. Furthermore, the results of the present study indicated that these synergistic effects may be associated with the B-cell lymphoma 2 (Bcl-2)/Bcl-2-associated X protein apoptotic pathway and the mitogen-activated protein kinase/mammalian target of rapamycin/p70S6 kinase growth pathway. The combination of exemestane and simvastatin generated synergistic effects on MCF-7 ER+ breast cancer cells, indicating that the combination of these drugs may be a potential therapeutic strategy for the treatment of hormone-dependent breast cancer. The combination of the two inhibitors markedly increased the efficacy, as compared with the single-agent treatment, suggesting that combination treatment could become a highly effective approach for breast cancer. The results of the present study suggested that this combination of drugs has therapeutic potential, and requires further mechanistic and biomarker investigations in clinical trials. ### Response: simvastatin, exemestane

65bcf2e8ba4bd0911cf6a8ed3352e2e9

Synergy of Omeprazole and Praziquantel In Vitro Treatment against Schistosoma mansoni Adult Worms .

Synergy of Omeprazole and Praziquantel In Vitro Treatment against Schistosoma mansoni Adult Worms . Treatment and morbidity control of schistosomiasis relies on a single drug, praziquantel (PZQ), and the selection of resistant worms under repeated treatment is a concern. Therefore, there is a pressing need to understand the molecular effects of PZQ on schistosomes and to investigate alternative or synergistic drugs against schistosomiasis. ### methodology We used a custom-designed Schistosoma mansoni expression microarray to explore the effects of sublethal doses of PZQ on large-scale gene expression of adult paired males and females and unpaired mature females. We also assessed the efficacy of PZQ, omeprazole (OMP) or their combination against S. mansoni adult worms with a survival in vitro assay. ### Principal Findings We identified sets of genes that were affected by PZQ in paired and unpaired mature females, however with opposite gene expression patterns (up-regulated in paired and down-regulated in unpaired mature females), indicating that PZQ effects are heavily influenced by the mating status. We also identified genes that were similarly affected by PZQ in males and females. Functional analyses of gene interaction networks were performed with parasite genes that were differentially expressed upon PZQ treatment, searching for proteins encoded by these genes whose human homologs are targets of different drugs used for other diseases. Based on these results, OMP, a widely prescribed proton pump inhibitor known to target the ATP1A2 gene product, was chosen and tested. Sublethal doses of PZQ combined with OMP significantly increased worm mortality in vitro when compared with PZQ or OMP alone, thus evidencing a synergistic effect. ### conclusions Functional analysis of gene interaction networks is an important approach that can point to possible novel synergistic drug candidates. We demonstrated the potential of this strategy by showing that PZQ in combination with OMP displayed increased efficiency against S. mansoni adult worms in vitro when compared with either drug alone.

https://pubmed.ncbi.nlm.nih.gov/26402251/

### 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: Synergy of Omeprazole and Praziquantel In Vitro Treatment against Schistosoma mansoni Adult Worms . Treatment and morbidity control of schistosomiasis relies on a single drug, praziquantel (PZQ), and the selection of resistant worms under repeated treatment is a concern. Therefore, there is a pressing need to understand the molecular effects of PZQ on schistosomes and to investigate alternative or synergistic drugs against schistosomiasis. ### methodology We used a custom-designed Schistosoma mansoni expression microarray to explore the effects of sublethal doses of PZQ on large-scale gene expression of adult paired males and females and unpaired mature females. We also assessed the efficacy of PZQ, omeprazole (OMP) or their combination against S. mansoni adult worms with a survival in vitro assay. ### Principal Findings We identified sets of genes that were affected by PZQ in paired and unpaired mature females, however with opposite gene expression patterns (up-regulated in paired and down-regulated in unpaired mature females), indicating that PZQ effects are heavily influenced by the mating status. We also identified genes that were similarly affected by PZQ in males and females. Functional analyses of gene interaction networks were performed with parasite genes that were differentially expressed upon PZQ treatment, searching for proteins encoded by these genes whose human homologs are targets of different drugs used for other diseases. Based on these results, OMP, a widely prescribed proton pump inhibitor known to target the ATP1A2 gene product, was chosen and tested. Sublethal doses of PZQ combined with OMP significantly increased worm mortality in vitro when compared with PZQ or OMP alone, thus evidencing a synergistic effect. ### conclusions Functional analysis of gene interaction networks is an important approach that can point to possible novel synergistic drug candidates. We demonstrated the potential of this strategy by showing that PZQ in combination with OMP displayed increased efficiency against S. mansoni adult worms in vitro when compared with either drug alone. ### Response: Omeprazole, Praziquantel

1ed70d4deb51eaba9be4d2bdbada5d16

Inclusion criteria were proven infection with evidence of a bacterial strain of PA resistant to all β-lactams and treated with the association of at least aztreonam plus cefepime .

Use of aztreonam in association with cefepime for the treatment of nosocomial infections due to multidrug-resistant strains of Pseudomonas aeruginosa to β-lactams in ICU patients: A pilot study. Resistance to all β-lactams is emerging among Pseudomonas aeruginosa (PA) clinical isolates. aztreonam and cefepime act synergistically in vitro against AmpC overproducing PA isolates. The objective of this study was to evaluate the clinical efficacy of this treatment in ICU patients infected with multidrug-resistant PA. ### Material And Methods Retrospective study (2 years, 2 ICUs) in a tertiary university hospital. Inclusion criteria were proven infection with evidence of a bacterial strain of PA resistant to all β-lactams and treated with the association of at least aztreonam plus cefepime . Treatment was considered effective for pneumonia using CPIS scores at the end of treatment and for other infections, using the SOFA score and signs of infection improvement at the end of treatment. Infectious episodes were classified as cure or failure. ### results Thirteen patients were included (10 nosocomial pneumonia, 3 nosocomial intra-abdominal infections). The median [25th-75th percentiles] admission SAPS2 score was 54 [51-69] and the median SOFA score at the beginning of infection was 7 [4-8]. The median CPIS scores for pneumonia at the beginning and end of treatment were 9 [7-10.5] and 2 [0.75-5.5]. The duration of treatment with the combination of aztreonam plus cefepime was 14 days [9.5-16]. Nine episodes were classified as cures and 4 as failures, indicating a clinical efficacy of 69.2%. Overall mortality was 38.5%. ### discussion These data suggest that the association of cefepime plus aztreonam could be an attractive alternative in the treatment of infections with multidrug-resistant PA to all β-lactams with a clinical efficacy rate of 69%.

https://pubmed.ncbi.nlm.nih.gov/26004874/

### 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: Use of aztreonam in association with cefepime for the treatment of nosocomial infections due to multidrug-resistant strains of Pseudomonas aeruginosa to β-lactams in ICU patients: A pilot study. Resistance to all β-lactams is emerging among Pseudomonas aeruginosa (PA) clinical isolates. aztreonam and cefepime act synergistically in vitro against AmpC overproducing PA isolates. The objective of this study was to evaluate the clinical efficacy of this treatment in ICU patients infected with multidrug-resistant PA. ### Material And Methods Retrospective study (2 years, 2 ICUs) in a tertiary university hospital. Inclusion criteria were proven infection with evidence of a bacterial strain of PA resistant to all β-lactams and treated with the association of at least aztreonam plus cefepime . Treatment was considered effective for pneumonia using CPIS scores at the end of treatment and for other infections, using the SOFA score and signs of infection improvement at the end of treatment. Infectious episodes were classified as cure or failure. ### results Thirteen patients were included (10 nosocomial pneumonia, 3 nosocomial intra-abdominal infections). The median [25th-75th percentiles] admission SAPS2 score was 54 [51-69] and the median SOFA score at the beginning of infection was 7 [4-8]. The median CPIS scores for pneumonia at the beginning and end of treatment were 9 [7-10.5] and 2 [0.75-5.5]. The duration of treatment with the combination of aztreonam plus cefepime was 14 days [9.5-16]. Nine episodes were classified as cures and 4 as failures, indicating a clinical efficacy of 69.2%. Overall mortality was 38.5%. ### discussion These data suggest that the association of cefepime plus aztreonam could be an attractive alternative in the treatment of infections with multidrug-resistant PA to all β-lactams with a clinical efficacy rate of 69%. ### Response: aztreonam, cefepime

92445f629c7c8fa9a5f669f9895c4ca4

Comparison of the additive effects of nipradilol and carteolol to latanoprost in open-angle glaucoma .

Comparison of the additive effects of nipradilol and carteolol to latanoprost in open-angle glaucoma . To compare the effects of nipradilol and carteolol on intraocular pressure (IOP) when added to latanoprost treatment for glaucoma patients. ### methods Fifty patients with primary open-angle glaucoma were treated with latanoprost 0.005% once daily for 3 months. Then they were assigned to one of two groups randomly. One group received nipradilol 0.25% twice daily (nipradilol preceding group; n = 25), and the other carteolol hydrochloride 2% twice daily (carteolol preceding group; n = 25), for 3 months in addition to latanoprost. Then, nipradilol and carteolol were switched, and the subjects were treated for 3 more months. One eye was selected randomly for analysis. ### results In the nipradilol preceding group, IOP was 21.4 +/- 2.3 mmHg (mean +/- SD) at baseline, and 16.8 +/- 1.9 mmHg at the end of latanoprost monotherapy (P < 0.01). The addition of nipradilol decreased IOP to 15.8 +/- 1.7 mmHg, and the change to carteolol, to 15.3 +/- 2.0 mmHg. In the carteolol preceding group, IOP was 21.2 +/- 2.0 mmHg at baseline, and 17.0 +/- 2.1 mmHg at the end of latanoprost monotherapy (P < 0.01). The addition of carteolol decreased IOP to 15.4 +/- 1.8 mmHg, and the change to nipradilol, to 16.3 +/- 1.9 mmHg. Additional IOP reduction was greater with carteolol than with nipradilol (cross-over analysis of variance; P = 0.0005). ### conclusions Both nipradilol and carteolol have additive effects when used in combination with latanoprost. carteolol, however, may have a more potent effect than nipradilol.

https://pubmed.ncbi.nlm.nih.gov/16453185/

### 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 the additive effects of nipradilol and carteolol to latanoprost in open-angle glaucoma . To compare the effects of nipradilol and carteolol on intraocular pressure (IOP) when added to latanoprost treatment for glaucoma patients. ### methods Fifty patients with primary open-angle glaucoma were treated with latanoprost 0.005% once daily for 3 months. Then they were assigned to one of two groups randomly. One group received nipradilol 0.25% twice daily (nipradilol preceding group; n = 25), and the other carteolol hydrochloride 2% twice daily (carteolol preceding group; n = 25), for 3 months in addition to latanoprost. Then, nipradilol and carteolol were switched, and the subjects were treated for 3 more months. One eye was selected randomly for analysis. ### results In the nipradilol preceding group, IOP was 21.4 +/- 2.3 mmHg (mean +/- SD) at baseline, and 16.8 +/- 1.9 mmHg at the end of latanoprost monotherapy (P < 0.01). The addition of nipradilol decreased IOP to 15.8 +/- 1.7 mmHg, and the change to carteolol, to 15.3 +/- 2.0 mmHg. In the carteolol preceding group, IOP was 21.2 +/- 2.0 mmHg at baseline, and 17.0 +/- 2.1 mmHg at the end of latanoprost monotherapy (P < 0.01). The addition of carteolol decreased IOP to 15.4 +/- 1.8 mmHg, and the change to nipradilol, to 16.3 +/- 1.9 mmHg. Additional IOP reduction was greater with carteolol than with nipradilol (cross-over analysis of variance; P = 0.0005). ### conclusions Both nipradilol and carteolol have additive effects when used in combination with latanoprost. carteolol, however, may have a more potent effect than nipradilol. ### Response: nipradilol, carteolol, latanoprost

c02a93b4a7110fb9bc0dc35cbaf0cd6e

The poly(ADP-ribose ) polymerase ( PARP ) inhibitor olaparib has recently received approval from the Food and Drug Administration ( FDA ) and European Medicines Agency ( EMA ) , with a second agent ( rucaparib ) likely to be approved in the near future .

Clinical Application of Poly(ADP-Ribose) Polymerase Inhibitors in High-Grade Serous Ovarian Cancer. : High-grade serous ovarian cancer is characterized by genomic instability, with one half of all tumors displaying defects in the important DNA repair pathway of homologous recombination. Given the action of poly(ADP-ribose) polymerase (PARP) inhibitors in targeting tumors with deficiencies in this repair pathway by loss of BRCA1/2, ovarian tumors could be an attractive population for clinical application of this therapy. PARP inhibitors have moved into clinical practice in the past few years, with approval from the Food and Drug Administration (FDA) and European Medicines Agency (EMA) within the past 2 years. The U.S. FDA approval of olaparib applies to fourth line treatment in germline BRCA-mutant ovarian cancer, and European EMA approval to olaparib maintenance in both germline and somatic BRCA-mutant platinum-sensitive ovarian cancer. In order to widen the ovarian cancer patient population that would benefit from PARP inhibitors, predictive biomarkers based on a clear understanding of the mechanism of action are required. Additionally, a better understanding of the toxicity profile is needed if PARP inhibitors are to be used in the curative, rather than the palliative, setting. We reviewed the development of PARP inhibitors in phase I-III clinical trials, including combination trials of PARP inhibitors and chemotherapy/antiangiogenics, the approval for these agents, the mechanisms of resistance, and the outstanding issues, including the development of biomarkers and the rate of long-term hematologic toxicities with these agents. ### Implications For Practice The poly(ADP-ribose ) polymerase ( PARP ) inhibitor olaparib has recently received approval from the Food and Drug Administration ( FDA ) and European Medicines Agency ( EMA ) , with a second agent ( rucaparib ) likely to be approved in the near future . However, the patient population with potential benefit from PARP inhibitors is likely wider than that of germline BRCA mutation-associated disease, and biomarkers are in development to enable the selection of patients with the potential for clinical benefit from these agents. Questions remain regarding the toxicities of PARP inhibitors, limiting the use of these agents in the prophylactic or adjuvant setting until more information is available. The indications for olaparib as indicated by the FDA and EMA are reviewed.

https://pubmed.ncbi.nlm.nih.gov/27022037/

### 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 Application of Poly(ADP-Ribose) Polymerase Inhibitors in High-Grade Serous Ovarian Cancer. : High-grade serous ovarian cancer is characterized by genomic instability, with one half of all tumors displaying defects in the important DNA repair pathway of homologous recombination. Given the action of poly(ADP-ribose) polymerase (PARP) inhibitors in targeting tumors with deficiencies in this repair pathway by loss of BRCA1/2, ovarian tumors could be an attractive population for clinical application of this therapy. PARP inhibitors have moved into clinical practice in the past few years, with approval from the Food and Drug Administration (FDA) and European Medicines Agency (EMA) within the past 2 years. The U.S. FDA approval of olaparib applies to fourth line treatment in germline BRCA-mutant ovarian cancer, and European EMA approval to olaparib maintenance in both germline and somatic BRCA-mutant platinum-sensitive ovarian cancer. In order to widen the ovarian cancer patient population that would benefit from PARP inhibitors, predictive biomarkers based on a clear understanding of the mechanism of action are required. Additionally, a better understanding of the toxicity profile is needed if PARP inhibitors are to be used in the curative, rather than the palliative, setting. We reviewed the development of PARP inhibitors in phase I-III clinical trials, including combination trials of PARP inhibitors and chemotherapy/antiangiogenics, the approval for these agents, the mechanisms of resistance, and the outstanding issues, including the development of biomarkers and the rate of long-term hematologic toxicities with these agents. ### Implications For Practice The poly(ADP-ribose ) polymerase ( PARP ) inhibitor olaparib has recently received approval from the Food and Drug Administration ( FDA ) and European Medicines Agency ( EMA ) , with a second agent ( rucaparib ) likely to be approved in the near future . However, the patient population with potential benefit from PARP inhibitors is likely wider than that of germline BRCA mutation-associated disease, and biomarkers are in development to enable the selection of patients with the potential for clinical benefit from these agents. Questions remain regarding the toxicities of PARP inhibitors, limiting the use of these agents in the prophylactic or adjuvant setting until more information is available. The indications for olaparib as indicated by the FDA and EMA are reviewed. ### Response: olaparib, rucaparib

d2cc5f8f48a70aafe4eb86abc0c90963

Fluvoxamine is a fairly potent inhibitor of CYP2C19 and it has the potential for causing drug-drug interactions with substrates for CYP2C19 such as imipramine , clomipramine , amitriptyline and diazepam .

Fluvoxamine inhibits the CYP2C19-catalysed metabolism of proguanil in vitro. The potent CYP1A2 inhibitor fluvoxamine has recently been shown also to be an effective inhibitor of the CYP2C19-mediated metabolism of the antimalarial drug proguanil in vivo. The purpose of the present study was to confirm this interaction in vitro. ### methods A high-performance liquid chromatography (HPLC) method was developed to assay 4-chlorophenylbiguanide (4-CPBG) and cycloguanil formed from proguanil by microsomes prepared from human liver. The limit of detection was 0.08 nmol mg-'. h-I. ### results The formation of 4-CPBG and cycloguanil could be described by one-enzyme kinetics, indicating that the formation of the two metabolites is almost exclusively catalysed by a single enzyme, i.e. CYP2C19 within the concentration range used, or that the contribution of an alternative low-affinity enzyme, probably CYP3A4, is very low. This notion was confirmed by the lack of potent inhibition by four CYP3A4 inhibitors: ketoconazole, bromocriptine, midazolam and dihydroergotamine. fluvoxamine was a very effective inhibitor of the oxidation of proguanil, displaying Ki values of 0.69 micromol x l(-1) for the inhibition of cycloguanil formation and 4.7 micromol x l(-1) for the inhibition of 4-CPBG formation. As expected, the CYP2C19 substrate omeprazole inhibited the formation of both metabolites with an IC50 of 10 micromol x l(-1). Norfluoxetine and sulfaphenazole inhibited proguanil oxidation with Ki values of 7.3-16 micromol x l(-1), suggesting that the two compounds are moderate inhibitors of CYP2C19. ### conclusions Fluvoxamine is a fairly potent inhibitor of CYP2C19 and it has the potential for causing drug-drug interactions with substrates for CYP2C19 such as imipramine , clomipramine , amitriptyline and diazepam . The combination of fluvoxamine and proguanil can not be recommended.

https://pubmed.ncbi.nlm.nih.gov/9923577/

### 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: Fluvoxamine inhibits the CYP2C19-catalysed metabolism of proguanil in vitro. The potent CYP1A2 inhibitor fluvoxamine has recently been shown also to be an effective inhibitor of the CYP2C19-mediated metabolism of the antimalarial drug proguanil in vivo. The purpose of the present study was to confirm this interaction in vitro. ### methods A high-performance liquid chromatography (HPLC) method was developed to assay 4-chlorophenylbiguanide (4-CPBG) and cycloguanil formed from proguanil by microsomes prepared from human liver. The limit of detection was 0.08 nmol mg-'. h-I. ### results The formation of 4-CPBG and cycloguanil could be described by one-enzyme kinetics, indicating that the formation of the two metabolites is almost exclusively catalysed by a single enzyme, i.e. CYP2C19 within the concentration range used, or that the contribution of an alternative low-affinity enzyme, probably CYP3A4, is very low. This notion was confirmed by the lack of potent inhibition by four CYP3A4 inhibitors: ketoconazole, bromocriptine, midazolam and dihydroergotamine. fluvoxamine was a very effective inhibitor of the oxidation of proguanil, displaying Ki values of 0.69 micromol x l(-1) for the inhibition of cycloguanil formation and 4.7 micromol x l(-1) for the inhibition of 4-CPBG formation. As expected, the CYP2C19 substrate omeprazole inhibited the formation of both metabolites with an IC50 of 10 micromol x l(-1). Norfluoxetine and sulfaphenazole inhibited proguanil oxidation with Ki values of 7.3-16 micromol x l(-1), suggesting that the two compounds are moderate inhibitors of CYP2C19. ### conclusions Fluvoxamine is a fairly potent inhibitor of CYP2C19 and it has the potential for causing drug-drug interactions with substrates for CYP2C19 such as imipramine , clomipramine , amitriptyline and diazepam . The combination of fluvoxamine and proguanil can not be recommended. ### Response: Fluvoxamine, imipramine, clomipramine, amitriptyline, diazepam

8d5eb6f039e442f59bb27170b6806920

We have compared amphotericin B , flucytosine , ketoconazole and fluconazole susceptibilities of 40 clinical isolates of Candida albicans by broth microdilution in two different media : RPMI 1640 ( RPMI ) and the same medium supplemented with 18 g of glucose per L ( RPMI-2 % glucose ) .

Defining conditions for microbroth antifungal susceptibility tests: influence of RPMI and RPMI-2% glucose on the selection of endpoint criteria. We have compared amphotericin B , flucytosine , ketoconazole and fluconazole susceptibilities of 40 clinical isolates of Candida albicans by broth microdilution in two different media : RPMI 1640 ( RPMI ) and the same medium supplemented with 18 g of glucose per L ( RPMI-2 % glucose ) . Preparation of media, drugs and inocula, as well as incubation temperature, followed the recommendations of the National Committee for Clinical Laboratory Standards (Villanova, PA, USA) antifungal agent working group for broth macrodilution tests with antifungal agents. Microtitre plates were agitated for 5 min before spectrophotometric readings were performed with an automatic plate reader. MIC endpoints were defined in three different ways: (i) MIC-100% for amphotericin B and flucytosine; (ii) MIC-80% for azole-drugs and also for flucytosine; (iii) IC1/2 for azole-drugs. The MIC endpoints were compared between the two different media in order to ascertain which was the best criterion. For amphotericin B, 100% of strains had a maximum difference of a twofold dilution in both media. For flucytosine, MIC values were very similar in both media, irrespective of the MIC endpoint chosen, MIC-100% or MIC-80%. For azole-drugs the (MIC-80%)50 and (MIC-80%)90 in RPMI were higher than those in RPMI-2% glucose. However, (IC1/2)50 and (IC1/2)90 were identical in both media as well as (MIC-80%)50 and (MIC-80%)90 in RPMI-2% glucose, The limited growth of yeasts in RPMI precludes the selection of an azole-MIC-80% endpoint, although the MIC determination was performed with an objective turbidimetric method (spectrophotometric reading plus mathematical MIC calculation). The use of RPMI-2% glucose produces the same MIC whatever methods was used, IC1/2 or MIC-80%. However, some minor discrepancies can be expected between IC1/2 and MIC-80% when strains with higher "trailing effect" are being tested. Therefore, we recommended IC1/2 in RPMI-2% glucose as the method of choice for MIC calculation, until more studies correlating in-vitro results with clinical outcome have been performed.

https://pubmed.ncbi.nlm.nih.gov/7559186/

### 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: Defining conditions for microbroth antifungal susceptibility tests: influence of RPMI and RPMI-2% glucose on the selection of endpoint criteria. We have compared amphotericin B , flucytosine , ketoconazole and fluconazole susceptibilities of 40 clinical isolates of Candida albicans by broth microdilution in two different media : RPMI 1640 ( RPMI ) and the same medium supplemented with 18 g of glucose per L ( RPMI-2 % glucose ) . Preparation of media, drugs and inocula, as well as incubation temperature, followed the recommendations of the National Committee for Clinical Laboratory Standards (Villanova, PA, USA) antifungal agent working group for broth macrodilution tests with antifungal agents. Microtitre plates were agitated for 5 min before spectrophotometric readings were performed with an automatic plate reader. MIC endpoints were defined in three different ways: (i) MIC-100% for amphotericin B and flucytosine; (ii) MIC-80% for azole-drugs and also for flucytosine; (iii) IC1/2 for azole-drugs. The MIC endpoints were compared between the two different media in order to ascertain which was the best criterion. For amphotericin B, 100% of strains had a maximum difference of a twofold dilution in both media. For flucytosine, MIC values were very similar in both media, irrespective of the MIC endpoint chosen, MIC-100% or MIC-80%. For azole-drugs the (MIC-80%)50 and (MIC-80%)90 in RPMI were higher than those in RPMI-2% glucose. However, (IC1/2)50 and (IC1/2)90 were identical in both media as well as (MIC-80%)50 and (MIC-80%)90 in RPMI-2% glucose, The limited growth of yeasts in RPMI precludes the selection of an azole-MIC-80% endpoint, although the MIC determination was performed with an objective turbidimetric method (spectrophotometric reading plus mathematical MIC calculation). The use of RPMI-2% glucose produces the same MIC whatever methods was used, IC1/2 or MIC-80%. However, some minor discrepancies can be expected between IC1/2 and MIC-80% when strains with higher "trailing effect" are being tested. Therefore, we recommended IC1/2 in RPMI-2% glucose as the method of choice for MIC calculation, until more studies correlating in-vitro results with clinical outcome have been performed. ### Response: amphotericin, flucytosine, ketoconazole, fluconazole

a0ac50dcdd622cfc2511df4110f4c9c2

Over the past decade , paclitaxel , docetaxel , vinorelbine , gemcitabine , irinotecan , and topotecan have been introduced into the clinic .

Is cisplatin required for the treatment of non-small-cell lung cancer? Experience and preliminary results of a phase I/II trial with topotecan and vinorelbine. Platinum-based chemotherapy is considered standard treatment for advanced non-small-cell lung cancer (NSCLC). However, toxicity of most platinum-based regimens is substantial and requires close monitoring and supportive care. Over the past decade , paclitaxel , docetaxel , vinorelbine , gemcitabine , irinotecan , and topotecan have been introduced into the clinic . These newer agents have shown promising activity against NSCLC with a favorable toxicity profile as single agents. For patients with metastatic NSCLC, palliation is the main goal of therapy. Therefore, treatment should be easy to administer on an outpatient basis. We explored a novel combination therapy avoiding platinum. Patients with recurrent or metastatic NSCLC were treated with intravenous (i.v.) topotecan (0.5-1.0 mg/m(2)/day x 5) and i.v. vinorelbine (20-30 mg/m(2)/day on day 1 and day 5) in 21-day cycles. Dose-limiting toxicity (DLT) was defined separately with or without the addition of granulocyte colony-stimulating factor (G-CSF) support. Twenty-nine patients have been enrolled to date. At i.v. topotecan doses of 0.75-1.0 mg/m(2)/day and i.v. vinorelbine of 25 mg/m(2)/day, neutropenia was frequent but of short duration (<7 days). The DLT of i.v. topotecan (0.85 mg/m(2)) in the absence of G-CSF support was based on myelosuppression with neutropenic fever. With the addition of G-CSF, a DLT has not been reached. Nonhematologic toxicities included mild to moderate fatigue and constipation. An overall clinical response rate of 42% was achieved, with responses noted at all dose levels. At a short median follow-up of 15 months, the median survival for all patients is 13 months. In conclusion, the combination regimen of topotecan and vinorelbine is feasible for outpatient administration and is well tolerated with less toxicity than platinum-based regimens. Preliminary response data demonstrate good tumor activity, suggesting that this regimen could make an excellent palliative treatment for advanced NSCLC.

https://pubmed.ncbi.nlm.nih.gov/11598413/

### 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: Is cisplatin required for the treatment of non-small-cell lung cancer? Experience and preliminary results of a phase I/II trial with topotecan and vinorelbine. Platinum-based chemotherapy is considered standard treatment for advanced non-small-cell lung cancer (NSCLC). However, toxicity of most platinum-based regimens is substantial and requires close monitoring and supportive care. Over the past decade , paclitaxel , docetaxel , vinorelbine , gemcitabine , irinotecan , and topotecan have been introduced into the clinic . These newer agents have shown promising activity against NSCLC with a favorable toxicity profile as single agents. For patients with metastatic NSCLC, palliation is the main goal of therapy. Therefore, treatment should be easy to administer on an outpatient basis. We explored a novel combination therapy avoiding platinum. Patients with recurrent or metastatic NSCLC were treated with intravenous (i.v.) topotecan (0.5-1.0 mg/m(2)/day x 5) and i.v. vinorelbine (20-30 mg/m(2)/day on day 1 and day 5) in 21-day cycles. Dose-limiting toxicity (DLT) was defined separately with or without the addition of granulocyte colony-stimulating factor (G-CSF) support. Twenty-nine patients have been enrolled to date. At i.v. topotecan doses of 0.75-1.0 mg/m(2)/day and i.v. vinorelbine of 25 mg/m(2)/day, neutropenia was frequent but of short duration (<7 days). The DLT of i.v. topotecan (0.85 mg/m(2)) in the absence of G-CSF support was based on myelosuppression with neutropenic fever. With the addition of G-CSF, a DLT has not been reached. Nonhematologic toxicities included mild to moderate fatigue and constipation. An overall clinical response rate of 42% was achieved, with responses noted at all dose levels. At a short median follow-up of 15 months, the median survival for all patients is 13 months. In conclusion, the combination regimen of topotecan and vinorelbine is feasible for outpatient administration and is well tolerated with less toxicity than platinum-based regimens. Preliminary response data demonstrate good tumor activity, suggesting that this regimen could make an excellent palliative treatment for advanced NSCLC. ### Response: paclitaxel, docetaxel, vinorelbine, gemcitabine, irinotecan, topotecan

85cf1d136acd78cbd2c0e0e7ba8af4a6

Alternatively , it may be that the adverse effects of pindolol and propranolol are due to the simultaneous blockade of both beta 1- and beta 2-adrenoceptors .

Central propranolol and pindolol, but not atenolol nor metoprolol, inhibit sexual behavior in male rats. Are the anti-sexual effects of propranolol and pindolol due to actions within the brain? To answer this, these agents were administered directly into the brain ventricular system (ICV). Additionally, atenolol and metoprolol were evaluated to see whether differential delivery to the brain contributed to the observed lack of effect of systemically administered beta 1-adrenoceptor antagonists. ICV administration of pindolol (45 or 90 micrograms) was followed by a suppression of copulation. At 45 micrograms, inhibition was limited to performance aspects of copulation, whereas at 90 micrograms, decrements in motivational and performance aspects of copulation were evident. ICV administration of propranolol also suppressed copulatory behavior. At 45 micrograms, no significant effects were observed, whereas at 90 micrograms decrements in motivational and performance aspects of copulation were evident. In contrast, ICV administration of the beta 1-adrenoceptor antagonists, atenolol and metoprolol, was not associated with any major modifications in copulatory behavior. We suggest that the inhibitory effects of propranolol and pindolol may involve interactions with 5-HT1A receptors in the CNS. Alternatively , it may be that the adverse effects of pindolol and propranolol are due to the simultaneous blockade of both beta 1- and beta 2-adrenoceptors .

https://pubmed.ncbi.nlm.nih.gov/8838601/

### 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: Central propranolol and pindolol, but not atenolol nor metoprolol, inhibit sexual behavior in male rats. Are the anti-sexual effects of propranolol and pindolol due to actions within the brain? To answer this, these agents were administered directly into the brain ventricular system (ICV). Additionally, atenolol and metoprolol were evaluated to see whether differential delivery to the brain contributed to the observed lack of effect of systemically administered beta 1-adrenoceptor antagonists. ICV administration of pindolol (45 or 90 micrograms) was followed by a suppression of copulation. At 45 micrograms, inhibition was limited to performance aspects of copulation, whereas at 90 micrograms, decrements in motivational and performance aspects of copulation were evident. ICV administration of propranolol also suppressed copulatory behavior. At 45 micrograms, no significant effects were observed, whereas at 90 micrograms decrements in motivational and performance aspects of copulation were evident. In contrast, ICV administration of the beta 1-adrenoceptor antagonists, atenolol and metoprolol, was not associated with any major modifications in copulatory behavior. We suggest that the inhibitory effects of propranolol and pindolol may involve interactions with 5-HT1A receptors in the CNS. Alternatively , it may be that the adverse effects of pindolol and propranolol are due to the simultaneous blockade of both beta 1- and beta 2-adrenoceptors . ### Response: pindolol, propranolol

33b4a24c32bbaeaa9098849bae7fd55c

The combinations of irinotecan and mitomycin C or oxaliplatin have given very good results with high objective response rates and good tolerance .

[Irinotecan in combination for colon cancer]. As a single agent, irinotecan has demonstrated efficacy in metastatic 5FU resistant colorectal metastatic cancer. Chemotherapy with fluorouracil (5FU) plus leucovorin remains a standard in the treatment of patients with metastatic colorectal cancer. It seemed logical to test the combination of this reference treatment and the new agent. The first trials gave rather disappointing results, suggesting an inhibition of the metabolism of irinotecan into SN38 when 5FU was present in the circulation. More recent studies have given totally different results with a very good tolerance and strong efficacy of the combination of weekly folinic acid + 5FU and irinotecan or LV5FU2 (the so-called de Gramont regimen) and irinotecan. The results were so good that these new schedules are currently developed as first line regimen. Another way to combine 5FU, folinic acid and irinotecan is to alternate a cycle of 5FU, folinic acid and a cycle of irinotecan. Such an alternated schedule has given encouraging results with an objective response rate greater than 30% and a long median survival time (more than 16 months). It is also very easy to combine irinotecan with other drug which have demonstrated activity in the treatment of colorectal cancer. The combinations of irinotecan and mitomycin C or oxaliplatin have given very good results with high objective response rates and good tolerance . irinotecan plays now an important part in the treatment of metastatic colorectal cancer. This part becomes larger due to the results of the combination trials already presented which have shown strong efficacy and good tolerance.

https://pubmed.ncbi.nlm.nih.gov/9932084/

### 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: [Irinotecan in combination for colon cancer]. As a single agent, irinotecan has demonstrated efficacy in metastatic 5FU resistant colorectal metastatic cancer. Chemotherapy with fluorouracil (5FU) plus leucovorin remains a standard in the treatment of patients with metastatic colorectal cancer. It seemed logical to test the combination of this reference treatment and the new agent. The first trials gave rather disappointing results, suggesting an inhibition of the metabolism of irinotecan into SN38 when 5FU was present in the circulation. More recent studies have given totally different results with a very good tolerance and strong efficacy of the combination of weekly folinic acid + 5FU and irinotecan or LV5FU2 (the so-called de Gramont regimen) and irinotecan. The results were so good that these new schedules are currently developed as first line regimen. Another way to combine 5FU, folinic acid and irinotecan is to alternate a cycle of 5FU, folinic acid and a cycle of irinotecan. Such an alternated schedule has given encouraging results with an objective response rate greater than 30% and a long median survival time (more than 16 months). It is also very easy to combine irinotecan with other drug which have demonstrated activity in the treatment of colorectal cancer. The combinations of irinotecan and mitomycin C or oxaliplatin have given very good results with high objective response rates and good tolerance . irinotecan plays now an important part in the treatment of metastatic colorectal cancer. This part becomes larger due to the results of the combination trials already presented which have shown strong efficacy and good tolerance. ### Response: irinotecan, mitomycin, oxaliplatin

b3ba634638d733010cbe6ea8555c17d1

The NHB of strategy A was 31.6 QALMs versus strategy C when palbociclib was included in strategy C ; similarly , strategy A had a NHB of 13.8 QALMs versus strategy C when pertuzumab was included in strategy C. Monte-Carlo simulation demonstrated that the main factor influencing NHB of strategy A over strategy C was the cost of systemic therapy .

Liver Resection for Breast Cancer Liver Metastases: A Cost-utility Analysis. To estimate the cost-effectiveness of liver resection followed by adjuvant systemic therapy relative to systemic therapy alone for patients with breast cancer liver metastasis. ### background Data on cost-effectiveness of liver resection for advanced breast cancer with liver metastasis are lacking. ### methods A decision-analytic Markov model was constructed to evaluate the cost-effectiveness of liver resection followed by postoperative conventional systemic therapy (strategy A) versus conventional therapy alone (strategy B) versus newer targeted therapy alone (strategy C). The implications of using different chemotherapeutic regimens based on estrogen receptor and human epidermal growth factor receptor 2 status was also assessed. Outcomes included quality-adjusted life months (QALMs), incremental cost-effectiveness ratio, and net health benefit (NHB). ### results NHB of strategy A was 10.9 QALMs compared with strategy B when letrozole was used as systemic therapy, whereas it was only 0.3 QALMs when docetaxel + trastuzumab was used as a systemic therapy. The addition of newer biological agents (strategy C) significantly decreased the cost-effectiveness of strategy B (conventional systemic therapy alone). The NHB of strategy A was 31.6 QALMs versus strategy C when palbociclib was included in strategy C ; similarly , strategy A had a NHB of 13.8 QALMs versus strategy C when pertuzumab was included in strategy C. Monte-Carlo simulation demonstrated that the main factor influencing NHB of strategy A over strategy C was the cost of systemic therapy . ### conclusions Liver resection in patients with breast cancer liver metastasis proved to be cost-effective when compared with systemic therapy alone, particularly in estrogen receptor-positive tumors or when newer agents were used.

https://pubmed.ncbi.nlm.nih.gov/28266967/

### 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: Liver Resection for Breast Cancer Liver Metastases: A Cost-utility Analysis. To estimate the cost-effectiveness of liver resection followed by adjuvant systemic therapy relative to systemic therapy alone for patients with breast cancer liver metastasis. ### background Data on cost-effectiveness of liver resection for advanced breast cancer with liver metastasis are lacking. ### methods A decision-analytic Markov model was constructed to evaluate the cost-effectiveness of liver resection followed by postoperative conventional systemic therapy (strategy A) versus conventional therapy alone (strategy B) versus newer targeted therapy alone (strategy C). The implications of using different chemotherapeutic regimens based on estrogen receptor and human epidermal growth factor receptor 2 status was also assessed. Outcomes included quality-adjusted life months (QALMs), incremental cost-effectiveness ratio, and net health benefit (NHB). ### results NHB of strategy A was 10.9 QALMs compared with strategy B when letrozole was used as systemic therapy, whereas it was only 0.3 QALMs when docetaxel + trastuzumab was used as a systemic therapy. The addition of newer biological agents (strategy C) significantly decreased the cost-effectiveness of strategy B (conventional systemic therapy alone). The NHB of strategy A was 31.6 QALMs versus strategy C when palbociclib was included in strategy C ; similarly , strategy A had a NHB of 13.8 QALMs versus strategy C when pertuzumab was included in strategy C. Monte-Carlo simulation demonstrated that the main factor influencing NHB of strategy A over strategy C was the cost of systemic therapy . ### conclusions Liver resection in patients with breast cancer liver metastasis proved to be cost-effective when compared with systemic therapy alone, particularly in estrogen receptor-positive tumors or when newer agents were used. ### Response: palbociclib, pertuzumab

02016864b7b05842923fc562653e6d26

In the second study 12 patients with small cell undifferentiated cancers were treated with carboplatin , etoposide and ifosfamide .

Effects of interleukin-3 on myelosuppression induced by chemotherapy for ovarian cancer and small cell undifferentiated tumours. Two clinical studies were undertaken to study the toxicity profile and effects of interleukin-3 (rhIL-3) on chemotherapy-induced myelosuppression. Fifteen patients with recurrent ovarian carcinoma were treated with high dose carboplatin (800 mg m-2). All patients received 5.0 micrograms/kg/d rhIL-3 subcutaneously but timing and duration of rhIL-3 treatment differed. Constitutional symptoms were the major toxicity and in addition to the carboplatin-induced nausea and vomiting the combination was poorly tolerated. In 5/15 patients receiving high dose carboplatin rhIL-3 administration was discontinued due to nephrotoxicity (2 x), hypotension, severe malaise and bone pain. In this study, rhIL-3 ameliorated chemotherapy-induced neutropenia as well as thrombocytopenia and reduced the requirement for platelet transfusions in the second cycle of chemotherapy. However, rhIL-3 failed to prevent cumulative platelet toxicity. In the second study 12 patients with small cell undifferentiated cancers were treated with carboplatin , etoposide and ifosfamide . Three dose levels of rhIL-3 were explored (0.125, 5.0 and 7.5 micrograms/kg/d). In this study, toxicity of the treatment was mild, however, no beneficial haematologic effects of rhIL-3 could be demonstrated. In conclusion, the haematological effects of rhIL-3 were modest and dependent on the chemotherapeutic regimen, timing and duration of rhIL-3 treatment (in relation to the expected nadir). In general rhIL-3-induced toxicity was mild, but combination with high dose carboplatin could be hazardous if rhIL-3 is initiated at 24 h after the cytostatic agent.

https://pubmed.ncbi.nlm.nih.gov/7692922/

### 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: Effects of interleukin-3 on myelosuppression induced by chemotherapy for ovarian cancer and small cell undifferentiated tumours. Two clinical studies were undertaken to study the toxicity profile and effects of interleukin-3 (rhIL-3) on chemotherapy-induced myelosuppression. Fifteen patients with recurrent ovarian carcinoma were treated with high dose carboplatin (800 mg m-2). All patients received 5.0 micrograms/kg/d rhIL-3 subcutaneously but timing and duration of rhIL-3 treatment differed. Constitutional symptoms were the major toxicity and in addition to the carboplatin-induced nausea and vomiting the combination was poorly tolerated. In 5/15 patients receiving high dose carboplatin rhIL-3 administration was discontinued due to nephrotoxicity (2 x), hypotension, severe malaise and bone pain. In this study, rhIL-3 ameliorated chemotherapy-induced neutropenia as well as thrombocytopenia and reduced the requirement for platelet transfusions in the second cycle of chemotherapy. However, rhIL-3 failed to prevent cumulative platelet toxicity. In the second study 12 patients with small cell undifferentiated cancers were treated with carboplatin , etoposide and ifosfamide . Three dose levels of rhIL-3 were explored (0.125, 5.0 and 7.5 micrograms/kg/d). In this study, toxicity of the treatment was mild, however, no beneficial haematologic effects of rhIL-3 could be demonstrated. In conclusion, the haematological effects of rhIL-3 were modest and dependent on the chemotherapeutic regimen, timing and duration of rhIL-3 treatment (in relation to the expected nadir). In general rhIL-3-induced toxicity was mild, but combination with high dose carboplatin could be hazardous if rhIL-3 is initiated at 24 h after the cytostatic agent. ### Response: carboplatin, etoposide, ifosfamide

cbb38295f9bb8e6d792b8d943d1ea03e

3 . Systemic ( i.v . ) pretreatment with furosemide ( 2 - 10 mg kg-1 ) increased urine volume and dose-dependently inhibited the pressor response to i.c.v . clonidine ( 10 micrograms ) , and a long-lasting depressor response to clonidine was observed .

Furosemide inhibits the centrally-mediated pressor response to clonidine in conscious, normotensive rats. 1. The effect of furosemide on the pressor response induced by intracerebroventricular (i.c.v.) injection of clonidine was investigated in freely moving, normotensive rats with chronically implanted arterial catheters. 2. When injected i.c.v., clonidine at doses of 5 and 10 micrograms produced a dose-dependent pressor response and a decrease in heart rate. No depressor response was induced by clonidine. 3 . Systemic ( i.v . ) pretreatment with furosemide ( 2 - 10 mg kg-1 ) increased urine volume and dose-dependently inhibited the pressor response to i.c.v . clonidine ( 10 micrograms ) , and a long-lasting depressor response to clonidine was observed . However, furosemide treatment did not alter the bradycardia produced in response to clonidine. 4. The systemic treatment with furosemide (10 mg kg-1, i.v.) had no effect on the pressor response to i.v. noradrenaline. 5. These results suggest that reduction of body fluid volume inhibits the centrally-mediated pressor response to clonidine and leads to the hypotensive effect. We also suggest that combined treatment with a diuretic increases the hypotensive efficacy of clonidine.

https://pubmed.ncbi.nlm.nih.gov/1797326/

### 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: Furosemide inhibits the centrally-mediated pressor response to clonidine in conscious, normotensive rats. 1. The effect of furosemide on the pressor response induced by intracerebroventricular (i.c.v.) injection of clonidine was investigated in freely moving, normotensive rats with chronically implanted arterial catheters. 2. When injected i.c.v., clonidine at doses of 5 and 10 micrograms produced a dose-dependent pressor response and a decrease in heart rate. No depressor response was induced by clonidine. 3 . Systemic ( i.v . ) pretreatment with furosemide ( 2 - 10 mg kg-1 ) increased urine volume and dose-dependently inhibited the pressor response to i.c.v . clonidine ( 10 micrograms ) , and a long-lasting depressor response to clonidine was observed . However, furosemide treatment did not alter the bradycardia produced in response to clonidine. 4. The systemic treatment with furosemide (10 mg kg-1, i.v.) had no effect on the pressor response to i.v. noradrenaline. 5. These results suggest that reduction of body fluid volume inhibits the centrally-mediated pressor response to clonidine and leads to the hypotensive effect. We also suggest that combined treatment with a diuretic increases the hypotensive efficacy of clonidine. ### Response: furosemide, clonidine, clonidine

f76833b73a044ef61bb52a3c0dacafb8

Nine studies connected to the network for the PFS analysis in which necitumumab in combination with gemcitabine and cisplatin was associated with the lowest HR .

First-line treatment of patients with advanced or metastatic squamous non-small cell lung cancer: systematic review and network meta-analysis. The objectives of this systematic review and meta-analysis were to compare the survival, toxicity, and quality of life of patients treated with necitumumab in combination with gemcitabine and cisplatin. These agents were investigated in published randomized controlled trials (RCTs) of patients with squamous non-small cell lung cancer (NSCLC) in the first-line setting. ### methods The systematic review was executed on January 27, 2015, and updated on August 21, 2016, using a pre-specified search strategy. Searches were conducted using PubMed, Medline, and EMBASE, with supplemental searches using the Evidence Based Medicine Reviews and ClinicalTrials.gov to identify RCTs published in English from 1995-2016 and reporting at least one of the primary outcomes [overall survival (OS), progression-free survival (PFS), toxicity, or quality of life] in patients who received first-line treatment for advanced or metastatic squamous NSCLC. Study quality and risk of bias were assessed using the Physiotherapy Evidence Database (PEDro) scale and Cochrane risk of bias tool, respectively. A Baysian network meta-analysis was performed on the primary outcomes. Hazard ratios (HRs) were evaluated for the primary analysis; secondary analyses were conducted using median OS data. Planned sensitivity analyses were conducted including reanalysis using a Frequentist approach and limiting analyses to subsets based on clinical and demographic covariates. ### results The systematic literature review resulted in identification of 4,016 unique publications; 40 publications (35 unique trials) were eligible for inclusion. Eight studies connected to a common network for the OS analysis using HR data. The majority of studies were not limited to squamous NSCLC, thus analyzable data were limited to a subset of data within the published trials. carboplatin + S-1 and necitumumab in combination with gemcitabine and cisplatin were associated with lower HRs for OS versus all other comparators. Nine studies connected to the network for the PFS analysis in which necitumumab in combination with gemcitabine and cisplatin was associated with the lowest HR . Data were not available to analyze toxicity or quality of life. ### conclusions Although the results suggest that carboplatin + S-1 and necitumumab in combination with gemcitabine and cisplatin may have value in terms of OS versus other comparators, the results should be interpreted with caution due to the limited number of studies (with few focused exclusively on squamous NSCLC) and wide credible intervals.

https://pubmed.ncbi.nlm.nih.gov/30746213/

### 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: First-line treatment of patients with advanced or metastatic squamous non-small cell lung cancer: systematic review and network meta-analysis. The objectives of this systematic review and meta-analysis were to compare the survival, toxicity, and quality of life of patients treated with necitumumab in combination with gemcitabine and cisplatin. These agents were investigated in published randomized controlled trials (RCTs) of patients with squamous non-small cell lung cancer (NSCLC) in the first-line setting. ### methods The systematic review was executed on January 27, 2015, and updated on August 21, 2016, using a pre-specified search strategy. Searches were conducted using PubMed, Medline, and EMBASE, with supplemental searches using the Evidence Based Medicine Reviews and ClinicalTrials.gov to identify RCTs published in English from 1995-2016 and reporting at least one of the primary outcomes [overall survival (OS), progression-free survival (PFS), toxicity, or quality of life] in patients who received first-line treatment for advanced or metastatic squamous NSCLC. Study quality and risk of bias were assessed using the Physiotherapy Evidence Database (PEDro) scale and Cochrane risk of bias tool, respectively. A Baysian network meta-analysis was performed on the primary outcomes. Hazard ratios (HRs) were evaluated for the primary analysis; secondary analyses were conducted using median OS data. Planned sensitivity analyses were conducted including reanalysis using a Frequentist approach and limiting analyses to subsets based on clinical and demographic covariates. ### results The systematic literature review resulted in identification of 4,016 unique publications; 40 publications (35 unique trials) were eligible for inclusion. Eight studies connected to a common network for the OS analysis using HR data. The majority of studies were not limited to squamous NSCLC, thus analyzable data were limited to a subset of data within the published trials. carboplatin + S-1 and necitumumab in combination with gemcitabine and cisplatin were associated with lower HRs for OS versus all other comparators. Nine studies connected to the network for the PFS analysis in which necitumumab in combination with gemcitabine and cisplatin was associated with the lowest HR . Data were not available to analyze toxicity or quality of life. ### conclusions Although the results suggest that carboplatin + S-1 and necitumumab in combination with gemcitabine and cisplatin may have value in terms of OS versus other comparators, the results should be interpreted with caution due to the limited number of studies (with few focused exclusively on squamous NSCLC) and wide credible intervals. ### Response: necitumumab, gemcitabine, cisplatin

aeff9357c8822f550a9039fff2c8eab1

To evaluate the efficacy and toxicities of gemcitabine combined with ifosfamide and anthracycline chemotherapy for recurrent platinum resistant ovarian epithelial cancer .

[Gemcitabine based combination chemotherapy, a new salvage regimen for recurrent platinum resistant epithelial ovarian cancer]. To evaluate the efficacy and toxicities of gemcitabine combined with ifosfamide and anthracycline chemotherapy for recurrent platinum resistant ovarian epithelial cancer . ### methods gemcitabine 800 mg/m(2) (day 1, 8), ifosfamide 1.5 g/m(2) (day 1 - 3), adriamycin 40 mg/m(2) or epirubicin 60 mg/m(2) (day 1) or mitoxantrone 10 mg/m(2) (day 1, 8) were used in recurrent platinum resistant/refractory ovarian cancer patients, the cycle was repeated at interval of 21 to 28 days. ### results A total of 60 patients received 172 cycles combined chemotherapy. There were no one cases complete response, while partial response 22 (37%, 22/60), stable 23 (38%, 23/60) and progression 15 (25%, 15/60) were observed, with clinical benefit rate 75% (45/60). The median time of progression-free survival was 7 months, and the median overall survival time was 20 months. The main side effect was hematologic toxicity with leukopenia rate of 82% (49/60), among which III-IV accounted for 31% (15/49). Digestive reaction was all in I-II, accounted for 42% (25/60). ### conclusion The regimen of gemcitabine combined with ifosfamide and anthracycline is feasible, tolerable and effective in patients with recurrent platinum resistant/refractory epithelial ovarian cancer.

https://pubmed.ncbi.nlm.nih.gov/21211276/

### 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: [Gemcitabine based combination chemotherapy, a new salvage regimen for recurrent platinum resistant epithelial ovarian cancer]. To evaluate the efficacy and toxicities of gemcitabine combined with ifosfamide and anthracycline chemotherapy for recurrent platinum resistant ovarian epithelial cancer . ### methods gemcitabine 800 mg/m(2) (day 1, 8), ifosfamide 1.5 g/m(2) (day 1 - 3), adriamycin 40 mg/m(2) or epirubicin 60 mg/m(2) (day 1) or mitoxantrone 10 mg/m(2) (day 1, 8) were used in recurrent platinum resistant/refractory ovarian cancer patients, the cycle was repeated at interval of 21 to 28 days. ### results A total of 60 patients received 172 cycles combined chemotherapy. There were no one cases complete response, while partial response 22 (37%, 22/60), stable 23 (38%, 23/60) and progression 15 (25%, 15/60) were observed, with clinical benefit rate 75% (45/60). The median time of progression-free survival was 7 months, and the median overall survival time was 20 months. The main side effect was hematologic toxicity with leukopenia rate of 82% (49/60), among which III-IV accounted for 31% (15/49). Digestive reaction was all in I-II, accounted for 42% (25/60). ### conclusion The regimen of gemcitabine combined with ifosfamide and anthracycline is feasible, tolerable and effective in patients with recurrent platinum resistant/refractory epithelial ovarian cancer. ### Response: gemcitabine, ifosfamide, anthracycline

cc21758921b269913859dccc84fcc675

Combination of erlotinib and sorafenib , synergistic in GSC11 , induced apoptosis and autophagic cell death associated with suppressed Akt and ERK signaling pathways and decreased nuclear PKM2 and β-catenin in vitro , and tended to improve survival of nude mice bearing GSC11 brain tumor .

Suppression of RAF/MEK or PI3K synergizes cytotoxicity of receptor tyrosine kinase inhibitors in glioma tumor-initiating cells. The majority of glioblastomas have aberrant receptor tyrosine kinase (RTK)/RAS/phosphoinositide 3 kinase (PI3K) signaling pathways and malignant glioma cells are thought to be addicted to these signaling pathways for their survival and proliferation. However, recent studies suggest that monotherapies or inappropriate combination therapies using the molecular targeted drugs have limited efficacy possibly because of tumor heterogeneities, signaling redundancy and crosstalk in intracellular signaling network, indicating necessity of rationale and methods for efficient personalized combination treatments. Here, we evaluated the growth of colonies obtained from glioma tumor-initiating cells (GICs) derived from glioma sphere culture (GSC) in agarose and examined the effects of combination treatments on GICs using targeted drugs that affect the signaling pathways to which most glioma cells are addicted. ### methods Human GICs were cultured in agarose and treated with inhibitors of RTKs, non-receptor kinases or transcription factors. The colony number and volume were analyzed using a colony counter, and Chou-Talalay combination indices were evaluated. Autophagy and apoptosis were also analyzed. Phosphorylation of proteins was evaluated by reverse phase protein array and immunoblotting. ### results Increases of colony number and volume in agarose correlated with the Gompertz function. GICs showed diverse drug sensitivity, but inhibitions of RTK and RAF/MEK or PI3K by combinations such as EGFR inhibitor and MEK inhibitor, sorafenib and U0126, erlotinib and BKM120, and EGFR inhibitor and sorafenib showed synergy in different subtypes of GICs. Combination of erlotinib and sorafenib , synergistic in GSC11 , induced apoptosis and autophagic cell death associated with suppressed Akt and ERK signaling pathways and decreased nuclear PKM2 and β-catenin in vitro , and tended to improve survival of nude mice bearing GSC11 brain tumor . Reverse phase protein array analysis of the synergistic treatment indicated involvement of not only MEK and PI3K signaling pathways but also others associated with glucose metabolism, fatty acid metabolism, gene transcription, histone methylation, iron transport, stress response, cell cycle, and apoptosis. ### conclusion Inhibiting RTK and RAF/MEK or PI3K could induce synergistic cytotoxicity but personalization is necessary. Examining colonies in agarose initiated by GICs from each patient may be useful for drug sensitivity testing in personalized cancer therapy.

https://pubmed.ncbi.nlm.nih.gov/26861698/

### 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: Suppression of RAF/MEK or PI3K synergizes cytotoxicity of receptor tyrosine kinase inhibitors in glioma tumor-initiating cells. The majority of glioblastomas have aberrant receptor tyrosine kinase (RTK)/RAS/phosphoinositide 3 kinase (PI3K) signaling pathways and malignant glioma cells are thought to be addicted to these signaling pathways for their survival and proliferation. However, recent studies suggest that monotherapies or inappropriate combination therapies using the molecular targeted drugs have limited efficacy possibly because of tumor heterogeneities, signaling redundancy and crosstalk in intracellular signaling network, indicating necessity of rationale and methods for efficient personalized combination treatments. Here, we evaluated the growth of colonies obtained from glioma tumor-initiating cells (GICs) derived from glioma sphere culture (GSC) in agarose and examined the effects of combination treatments on GICs using targeted drugs that affect the signaling pathways to which most glioma cells are addicted. ### methods Human GICs were cultured in agarose and treated with inhibitors of RTKs, non-receptor kinases or transcription factors. The colony number and volume were analyzed using a colony counter, and Chou-Talalay combination indices were evaluated. Autophagy and apoptosis were also analyzed. Phosphorylation of proteins was evaluated by reverse phase protein array and immunoblotting. ### results Increases of colony number and volume in agarose correlated with the Gompertz function. GICs showed diverse drug sensitivity, but inhibitions of RTK and RAF/MEK or PI3K by combinations such as EGFR inhibitor and MEK inhibitor, sorafenib and U0126, erlotinib and BKM120, and EGFR inhibitor and sorafenib showed synergy in different subtypes of GICs. Combination of erlotinib and sorafenib , synergistic in GSC11 , induced apoptosis and autophagic cell death associated with suppressed Akt and ERK signaling pathways and decreased nuclear PKM2 and β-catenin in vitro , and tended to improve survival of nude mice bearing GSC11 brain tumor . Reverse phase protein array analysis of the synergistic treatment indicated involvement of not only MEK and PI3K signaling pathways but also others associated with glucose metabolism, fatty acid metabolism, gene transcription, histone methylation, iron transport, stress response, cell cycle, and apoptosis. ### conclusion Inhibiting RTK and RAF/MEK or PI3K could induce synergistic cytotoxicity but personalization is necessary. Examining colonies in agarose initiated by GICs from each patient may be useful for drug sensitivity testing in personalized cancer therapy. ### Response: erlotinib, sorafenib

285ff522dbf828beae54331363e1aa59

In the first trial , paclitaxel and doxorubicin were alternated every 3 weeks in doses of 200 mg/m2 and 75 mg/m2 , respectively , for patients who had received no more than one prior chemotherapeutic regimen .

Paclitaxel (Taxol)/doxorubicin combinations in advanced breast cancer: the Eastern Cooperative Oncology Group experience. paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), the first taxane to enter routine clinical practice, has aroused considerable interest due to its novel mechanism of action and its significant activity in metastatic breast cancer. Given this activity, it seemed logical to attempt to combine paclitaxel with doxorubicin, the other most active single agent in metastatic breast cancer. The Eastern Cooperative Oncology Group performed two trials investigating paclitaxel/doxorubicin combinations in patients with advanced breast cancer in an attempt to identify a tolerable dose and schedule of the combination. In the first trial , paclitaxel and doxorubicin were alternated every 3 weeks in doses of 200 mg/m2 and 75 mg/m2 , respectively , for patients who had received no more than one prior chemotherapeutic regimen . Therapy was well tolerated in this setting. At these doses, paclitaxel induced more granulocytopenia and less thrombocytopenia than did doxorubicin. Objective responses (complete and partial responses) were seen in seven of 12 patients; two other patients had improved disease (relief of pain in bony metastases). A second limited-institution Eastern Cooperative Oncology Group trial evaluated paclitaxel and doxorubicin given in combination. In this phase I trial, doxorubicin was given as an intravenous push and paclitaxel as a 24-hour continuous infusion. The sequence of drug administration (D-->P or P-->D) was alternated both between and within patients, so that we might evaluate the effect of administration schedule on toxicity. Therapy was begun at an initial paclitaxel dose of 150 mg/m2 and an initial doxorubicin dose of 50 mg/m2 in six patients, with a subsequent six patients receiving 175 and 60 mg/m2, respectively, of paclitaxel and doxorubicin. In addition, patients received granulocyte colony-stimulating factor 5 micrograms/kg/d. While therapy at the initial dose level was well tolerated, dose-limiting mucositis was seen at the second dose level, although only when paclitaxel preceded doxorubicin. This suggests that sequence of drug administration in paclitaxel-based regimens may play an important role as a determinant of toxicity and (perhaps) efficacy, a finding similar to that seen when paclitaxel and cisplatin were combined in patients with ovarian cancer. Based on this study, we identified the sequence of doxorubicin (50 mg/m2) followed by paclitaxel (150 mg/m2) to be the maximum tolerated dose. This combination is currently being compared with paclitaxel alone and doxorubicin alone in patients with advanced breast cancer in an intergroup trial led by the Eastern Cooperative Oncology Group.

https://pubmed.ncbi.nlm.nih.gov/7939756/

### 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 (Taxol)/doxorubicin combinations in advanced breast cancer: the Eastern Cooperative Oncology Group experience. paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), the first taxane to enter routine clinical practice, has aroused considerable interest due to its novel mechanism of action and its significant activity in metastatic breast cancer. Given this activity, it seemed logical to attempt to combine paclitaxel with doxorubicin, the other most active single agent in metastatic breast cancer. The Eastern Cooperative Oncology Group performed two trials investigating paclitaxel/doxorubicin combinations in patients with advanced breast cancer in an attempt to identify a tolerable dose and schedule of the combination. In the first trial , paclitaxel and doxorubicin were alternated every 3 weeks in doses of 200 mg/m2 and 75 mg/m2 , respectively , for patients who had received no more than one prior chemotherapeutic regimen . Therapy was well tolerated in this setting. At these doses, paclitaxel induced more granulocytopenia and less thrombocytopenia than did doxorubicin. Objective responses (complete and partial responses) were seen in seven of 12 patients; two other patients had improved disease (relief of pain in bony metastases). A second limited-institution Eastern Cooperative Oncology Group trial evaluated paclitaxel and doxorubicin given in combination. In this phase I trial, doxorubicin was given as an intravenous push and paclitaxel as a 24-hour continuous infusion. The sequence of drug administration (D-->P or P-->D) was alternated both between and within patients, so that we might evaluate the effect of administration schedule on toxicity. Therapy was begun at an initial paclitaxel dose of 150 mg/m2 and an initial doxorubicin dose of 50 mg/m2 in six patients, with a subsequent six patients receiving 175 and 60 mg/m2, respectively, of paclitaxel and doxorubicin. In addition, patients received granulocyte colony-stimulating factor 5 micrograms/kg/d. While therapy at the initial dose level was well tolerated, dose-limiting mucositis was seen at the second dose level, although only when paclitaxel preceded doxorubicin. This suggests that sequence of drug administration in paclitaxel-based regimens may play an important role as a determinant of toxicity and (perhaps) efficacy, a finding similar to that seen when paclitaxel and cisplatin were combined in patients with ovarian cancer. Based on this study, we identified the sequence of doxorubicin (50 mg/m2) followed by paclitaxel (150 mg/m2) to be the maximum tolerated dose. This combination is currently being compared with paclitaxel alone and doxorubicin alone in patients with advanced breast cancer in an intergroup trial led by the Eastern Cooperative Oncology Group. ### Response: paclitaxel, doxorubicin

d94638045c3e1a5a7b55e25f7b2727bb

Thirty-one patients with histologically proven small cell lung cancer were treated with cyclophosphamide 1 g m-2 and etoposide ( VP16 - 213 ) 125 mg m-2 both intravenously on day 1 followed by etoposide 250 mg m-2 orally on days 2 - 3 for a maximum of six courses at 3 weekly intervals .

Combination cyclophosphamide and etoposide in treatment of small cell lung cancer. Thirty-one patients with histologically proven small cell lung cancer were treated with cyclophosphamide 1 g m-2 and etoposide ( VP16 - 213 ) 125 mg m-2 both intravenously on day 1 followed by etoposide 250 mg m-2 orally on days 2 - 3 for a maximum of six courses at 3 weekly intervals . Fourteen patients had limited and 17 patients had extensive disease. Twenty-five patients were evaluable for response. Objective response was observed in 18 patients (58%) with 6 (19%) complete and 12 (39%) partial responses. Median survival of the entire group of patients was 30 weeks. There was significant survival benefit among the responders (P less than 0.005) when compared with non-responders. One patient (3.3%) developed grade 4 while 60% of patients developed grade 1-2 haematological toxicity. Other side effects were relatively mild. We conclude that combination cyclophosphamide and etoposide was active in small cell lung cancer and relatively well tolerated.

https://pubmed.ncbi.nlm.nih.gov/2160034/

### 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: Combination cyclophosphamide and etoposide in treatment of small cell lung cancer. Thirty-one patients with histologically proven small cell lung cancer were treated with cyclophosphamide 1 g m-2 and etoposide ( VP16 - 213 ) 125 mg m-2 both intravenously on day 1 followed by etoposide 250 mg m-2 orally on days 2 - 3 for a maximum of six courses at 3 weekly intervals . Fourteen patients had limited and 17 patients had extensive disease. Twenty-five patients were evaluable for response. Objective response was observed in 18 patients (58%) with 6 (19%) complete and 12 (39%) partial responses. Median survival of the entire group of patients was 30 weeks. There was significant survival benefit among the responders (P less than 0.005) when compared with non-responders. One patient (3.3%) developed grade 4 while 60% of patients developed grade 1-2 haematological toxicity. Other side effects were relatively mild. We conclude that combination cyclophosphamide and etoposide was active in small cell lung cancer and relatively well tolerated. ### Response: cyclophosphamide, etoposide, etoposide

a4208d3dba815399d8e4010b689a8027

Pemetrexed plus carboplatin followed by pemetrexed , docetaxel , atezolizumab and S-1 were performed in sequence .

Dacomitinib as a retreatment for advanced non-small cell lung cancer patient with an uncommon EGFR mutation. In non-small cell lung cancer (NSCLC), uncommon epidermal growth factor receptor (EGFR) mutations are mutations other than Ex19 deletion and Ex21 L858R, which are common mutations highly sensitive to EGFR-tyrosine kinase inhibitors. afatinib, a second-generation EGFR-tyrosine kinase inhibitor, has been shown to be effective in patients with uncommon mutations. dacomitinib, another second-generation EGFR-tyrosine kinase inhibitor, has not previously been shown to be effective in patients with uncommon mutations. Here, we report the efficacy of dacomitinib for uncommon EGFR mutations in a 71-year-old woman diagnosed with metastatic lung adenocarcinoma with uncommon EGFR mutation (Ex18 G719A). afatinib was administered as the first-line treatment, and a remarkable antitumor effect was observed. However, the tumor grew after 14 months. Pemetrexed plus carboplatin followed by pemetrexed , docetaxel , atezolizumab and S-1 were performed in sequence . Although approximately four years had passed since the start of treatment, her physical condition was good. The patient started dacomitinib as the sixth-line treatment. Lesions were markedly reduced and treatment with dacomitinib was continued for 7.8 months. dacomitinib is a possible treatment option for NSCLC with uncommon mutations.

https://pubmed.ncbi.nlm.nih.gov/33651475/

### 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: Dacomitinib as a retreatment for advanced non-small cell lung cancer patient with an uncommon EGFR mutation. In non-small cell lung cancer (NSCLC), uncommon epidermal growth factor receptor (EGFR) mutations are mutations other than Ex19 deletion and Ex21 L858R, which are common mutations highly sensitive to EGFR-tyrosine kinase inhibitors. afatinib, a second-generation EGFR-tyrosine kinase inhibitor, has been shown to be effective in patients with uncommon mutations. dacomitinib, another second-generation EGFR-tyrosine kinase inhibitor, has not previously been shown to be effective in patients with uncommon mutations. Here, we report the efficacy of dacomitinib for uncommon EGFR mutations in a 71-year-old woman diagnosed with metastatic lung adenocarcinoma with uncommon EGFR mutation (Ex18 G719A). afatinib was administered as the first-line treatment, and a remarkable antitumor effect was observed. However, the tumor grew after 14 months. Pemetrexed plus carboplatin followed by pemetrexed , docetaxel , atezolizumab and S-1 were performed in sequence . Although approximately four years had passed since the start of treatment, her physical condition was good. The patient started dacomitinib as the sixth-line treatment. Lesions were markedly reduced and treatment with dacomitinib was continued for 7.8 months. dacomitinib is a possible treatment option for NSCLC with uncommon mutations. ### Response: Pemetrexed, carboplatin, pemetrexed, docetaxel, atezolizumab

710177e4ab5628b7cf2962ce9a4347ee

The initial response ( IR ) was sustained for a mean ( s.d . ) of 309 ( 244 ) days with vildagliptin versus 270 ( 223 ) days for glimepiride ( p < 0.001 ) ( IR = nadir HbA1c where change from baseline > or = 0.5 % or HbA1c < or = 6.5 % within the first six months of treatment .

Vildagliptin add-on to metformin produces similar efficacy and reduced hypoglycaemic risk compared with glimepiride, with no weight gain: results from a 2-year study. To show that vildagliptin added to metformin is non-inferior to glimepiride in reducing HbA1c levels from baseline over 2 years. ### methods A randomized, double-blind, active-comparator study of patients with type 2 diabetes mellitus inadequately controlled (HbA1c 6.5-8.5%) by metformin monotherapy. Patients received vildagliptin (50 mg twice daily) or glimepiride (up to 6 mg/day) added to metformin. ### results In all, 3118 patients were randomized (vildagliptin, n = 1562; glimepiride, n = 1556). From similar baseline values (7.3%), after 2 years adjusted mean (s.e.) change in HbA1c was comparable between vildagliptin and glimepiride treatment: -0.1% (0.0%) and -0.1% (0.0%), respectively. The primary objective of non-inferiority was met. A similar proportion of patients reached HbA1c <7% (36.9 and 38.3%, respectively), but with vildagliptin more patients reached this target without hypoglycaemia (36.0% vs. 28.8%; p = 0.004). The initial response ( IR ) was sustained for a mean ( s.d . ) of 309 ( 244 ) days with vildagliptin versus 270 ( 223 ) days for glimepiride ( p < 0.001 ) ( IR = nadir HbA1c where change from baseline > or = 0.5 % or HbA1c < or = 6.5 % within the first six months of treatment . After IR was detected, sustained response = time between nadir and an increase of >0.3% above IR). Independent of disease duration, age was a predictor of effect sustainability. Fewer patients experienced hypoglycaemia with vildagliptin (2.3% vs. 18.2% with glimepiride) with a 14-fold difference in the number of hypoglycaemic events (59 vs. 838). vildagliptin had a beneficial effect on body weight [mean (s.e.) change from baseline -0.3 (0.1) kg; between-group difference -1.5 kg; p < 0.001]. Overall, both treatments were well tolerated and displayed similar safety profiles. ### conclusions vildagliptin add-on has similar efficacy to glimepiride after 2 years' treatment, with markedly reduced hypoglycaemia risk and no weight gain.

https://pubmed.ncbi.nlm.nih.gov/20649630/

### 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: Vildagliptin add-on to metformin produces similar efficacy and reduced hypoglycaemic risk compared with glimepiride, with no weight gain: results from a 2-year study. To show that vildagliptin added to metformin is non-inferior to glimepiride in reducing HbA1c levels from baseline over 2 years. ### methods A randomized, double-blind, active-comparator study of patients with type 2 diabetes mellitus inadequately controlled (HbA1c 6.5-8.5%) by metformin monotherapy. Patients received vildagliptin (50 mg twice daily) or glimepiride (up to 6 mg/day) added to metformin. ### results In all, 3118 patients were randomized (vildagliptin, n = 1562; glimepiride, n = 1556). From similar baseline values (7.3%), after 2 years adjusted mean (s.e.) change in HbA1c was comparable between vildagliptin and glimepiride treatment: -0.1% (0.0%) and -0.1% (0.0%), respectively. The primary objective of non-inferiority was met. A similar proportion of patients reached HbA1c <7% (36.9 and 38.3%, respectively), but with vildagliptin more patients reached this target without hypoglycaemia (36.0% vs. 28.8%; p = 0.004). The initial response ( IR ) was sustained for a mean ( s.d . ) of 309 ( 244 ) days with vildagliptin versus 270 ( 223 ) days for glimepiride ( p < 0.001 ) ( IR = nadir HbA1c where change from baseline > or = 0.5 % or HbA1c < or = 6.5 % within the first six months of treatment . After IR was detected, sustained response = time between nadir and an increase of >0.3% above IR). Independent of disease duration, age was a predictor of effect sustainability. Fewer patients experienced hypoglycaemia with vildagliptin (2.3% vs. 18.2% with glimepiride) with a 14-fold difference in the number of hypoglycaemic events (59 vs. 838). vildagliptin had a beneficial effect on body weight [mean (s.e.) change from baseline -0.3 (0.1) kg; between-group difference -1.5 kg; p < 0.001]. Overall, both treatments were well tolerated and displayed similar safety profiles. ### conclusions vildagliptin add-on has similar efficacy to glimepiride after 2 years' treatment, with markedly reduced hypoglycaemia risk and no weight gain. ### Response: vildagliptin, glimepiride

9e4a4ac0b5d6f5c60c5f0d73fcc3b766

The aim of this phase I study was to determine the maximum tolerated dose of a 3-h infusion of paclitaxel , combined with carboplatin at a fixed AUC of 7 mg ml-1 min every 4 weeks for up to six cycles and to evaluate any possible pharmacokinetic interaction .

A clinical and pharmacokinetic study of the combination of carboplatin and paclitaxel for epithelial ovarian cancer. The aim of this phase I study was to determine the maximum tolerated dose of a 3-h infusion of paclitaxel , combined with carboplatin at a fixed AUC of 7 mg ml-1 min every 4 weeks for up to six cycles and to evaluate any possible pharmacokinetic interaction . Twelve chemonaive patients with ovarian cancer were treated with paclitaxel followed by a 30-min infusion of carboplatin. paclitaxel dose was escalated from 150 mg m-2 to 225 mg m-2 in cohorts of three patients. carboplatin dose was based on renal function. Pharmacokinetic studies were performed in nine patients (at least two at each dose level). A total of 66 courses were evaluable for assessment. Grade 3 or 4 neutropenia was seen in 70% of the courses, however hospitalization was not required. Grade 3 or 4 thrombocytopenia occurred in 24% of the courses. Alopecia, myalgia and peripheral neuropathy were common but rarely severe. The pharmacokinetics of paclitaxel was non-linear and did not appear to be influenced by co-administration of carboplatin. The AUC of carboplatin was 7.0 +/- 1.4 mg ml-1 min, indicating that there was no pharmacokinetic interaction. The combination of carboplatin and paclitaxel may be administered as first-line treatment for advanced ovarian cancer. Although myelosuppression is the dose-limiting toxicity of the component drugs, the severity of thrombocytopenia was less than anticipated. The results of this study, with only a small number of patients, need to be confirmed in future investigations.

https://pubmed.ncbi.nlm.nih.gov/9010040/

### 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 clinical and pharmacokinetic study of the combination of carboplatin and paclitaxel for epithelial ovarian cancer. The aim of this phase I study was to determine the maximum tolerated dose of a 3-h infusion of paclitaxel , combined with carboplatin at a fixed AUC of 7 mg ml-1 min every 4 weeks for up to six cycles and to evaluate any possible pharmacokinetic interaction . Twelve chemonaive patients with ovarian cancer were treated with paclitaxel followed by a 30-min infusion of carboplatin. paclitaxel dose was escalated from 150 mg m-2 to 225 mg m-2 in cohorts of three patients. carboplatin dose was based on renal function. Pharmacokinetic studies were performed in nine patients (at least two at each dose level). A total of 66 courses were evaluable for assessment. Grade 3 or 4 neutropenia was seen in 70% of the courses, however hospitalization was not required. Grade 3 or 4 thrombocytopenia occurred in 24% of the courses. Alopecia, myalgia and peripheral neuropathy were common but rarely severe. The pharmacokinetics of paclitaxel was non-linear and did not appear to be influenced by co-administration of carboplatin. The AUC of carboplatin was 7.0 +/- 1.4 mg ml-1 min, indicating that there was no pharmacokinetic interaction. The combination of carboplatin and paclitaxel may be administered as first-line treatment for advanced ovarian cancer. Although myelosuppression is the dose-limiting toxicity of the component drugs, the severity of thrombocytopenia was less than anticipated. The results of this study, with only a small number of patients, need to be confirmed in future investigations. ### Response: paclitaxel, carboplatin

d95a9f0bb64d0b88c37b7f2b8fa950f2

Efficacy of tramadol in combination with doxepin or venlafaxine in inhibition of nociceptive process in the rat model of neuropathic pain : an isobolographic analysis .

Efficacy of tramadol in combination with doxepin or venlafaxine in inhibition of nociceptive process in the rat model of neuropathic pain : an isobolographic analysis . Neuropathic pain constitutes a serious therapeutic problem. In most cases polytherapy is necessary. tramadol and antidepressants have common mechanisms of action and are frequently used together in clinical practice, thus interaction between them is very important. In the present study isobolographic analysis for equivalent doses of drugs was applied to examine the nature of interaction between tramadol and doxepin or venlafaxine in a neuropathic pain model in rats. Allodynia and hyperalgesia were assessed after intraperitoneal administration of each drug alone or in combination. Dose response curves were obtained and ED(50) doses were calculated. All drugs were effective in reducing thermal hyperalgesia and mechanical allodynia, however doxepin was more effective than venlafaxine. Combined administration of tramadol and doxepin demonstrated synergistic action in reducing thermal hyperalgesia and additive action in reducing mechanical allodynia. Combined administration of tramadol and venlafaxine showed additive action in reducing hyperalgesia and allodynia. Moreover, combined administration of tramadol and doxepin was more effective than combined administration of tramadol and venlafaxine. The experiments demonstrated that the nature of interaction between tramadol and doxepin is synergistic, which is not the case for tramadol and venlafaxine, what provides a valuable information referring to clinical practice, rationalizing administration of such drug combination.

https://pubmed.ncbi.nlm.nih.gov/20065499/

### 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 tramadol in combination with doxepin or venlafaxine in inhibition of nociceptive process in the rat model of neuropathic pain : an isobolographic analysis . Neuropathic pain constitutes a serious therapeutic problem. In most cases polytherapy is necessary. tramadol and antidepressants have common mechanisms of action and are frequently used together in clinical practice, thus interaction between them is very important. In the present study isobolographic analysis for equivalent doses of drugs was applied to examine the nature of interaction between tramadol and doxepin or venlafaxine in a neuropathic pain model in rats. Allodynia and hyperalgesia were assessed after intraperitoneal administration of each drug alone or in combination. Dose response curves were obtained and ED(50) doses were calculated. All drugs were effective in reducing thermal hyperalgesia and mechanical allodynia, however doxepin was more effective than venlafaxine. Combined administration of tramadol and doxepin demonstrated synergistic action in reducing thermal hyperalgesia and additive action in reducing mechanical allodynia. Combined administration of tramadol and venlafaxine showed additive action in reducing hyperalgesia and allodynia. Moreover, combined administration of tramadol and doxepin was more effective than combined administration of tramadol and venlafaxine. The experiments demonstrated that the nature of interaction between tramadol and doxepin is synergistic, which is not the case for tramadol and venlafaxine, what provides a valuable information referring to clinical practice, rationalizing administration of such drug combination. ### Response: tramadol, doxepin, venlafaxine

4b31d5b4682f2cb6d4de9cd5ecdc3527

All those treated with mefloquine plus artemether survived and their parasite clearance time and fever clearance time were significantly shorter than those of patients receiving quinine .

The effect of mefloquine-artemether compared with quinine on patients with complicated falciparum malaria. 30 pairs of patients with complicated Plasmodium falciparum malaria (with anaemia, hyperpyrexia, jaundice or more than 5% of erythrocytes parasitized) were studied. Patients with cerebral signs and symptoms were excluded. One group of patients was treated with oral mefloquine (750 mg) and artemether (600 mg by injection, 200 mg initially and 100 mg every 12 h). The second group of patients was treated with quinine (10 mg/kg orally every 8 h for 7 d). All patients were admitted to hospital for 7 d and examined subsequently on days 14, 21 and 28. All those treated with mefloquine plus artemether survived and their parasite clearance time and fever clearance time were significantly shorter than those of patients receiving quinine . 2 patients treated with quinine died. There was no recrudescence in any patient of either group.

https://pubmed.ncbi.nlm.nih.gov/3075350/

### 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 effect of mefloquine-artemether compared with quinine on patients with complicated falciparum malaria. 30 pairs of patients with complicated Plasmodium falciparum malaria (with anaemia, hyperpyrexia, jaundice or more than 5% of erythrocytes parasitized) were studied. Patients with cerebral signs and symptoms were excluded. One group of patients was treated with oral mefloquine (750 mg) and artemether (600 mg by injection, 200 mg initially and 100 mg every 12 h). The second group of patients was treated with quinine (10 mg/kg orally every 8 h for 7 d). All patients were admitted to hospital for 7 d and examined subsequently on days 14, 21 and 28. All those treated with mefloquine plus artemether survived and their parasite clearance time and fever clearance time were significantly shorter than those of patients receiving quinine . 2 patients treated with quinine died. There was no recrudescence in any patient of either group. ### Response: mefloquine, artemether, quinine

070556e0b7ed1a722df98cba5e44277b

Currently available adrenal steroidogenesis inhibitors , including ketoconazole , metyrapone , etomidate , and mitotane , have variable efficacy and significant side effects , and none are approved by the US Food and Drug Administration for CS .

Updates on the role of adrenal steroidogenesis inhibitors in Cushing's syndrome: a focus on novel therapies. Endogenous Cushing's syndrome (CS) is a rare disease that results from exposure to high levels of cortisol; Cushing's disease (CD) is the most frequent form of CS. Patients with CS suffer from a variety of comorbidities that increase the risk of mortality. Surgical resection of the disease-causing lesion is generally the first-line treatment of CS. However, some patients may not be eligible for surgery due to comorbidities, and approximately 25 % of patients, especially those with CD, have recurrent disease. For these patients, adrenal steroidogenesis inhibitors may control cortisol elevation and subsequent symptomatology. CS is rare overall, and clinical studies of adrenal steroidogenesis inhibitors are often small and, in many cases, data are limited regarding the efficacy and safety of these treatments. Our aim was to better characterize the profiles of efficacy and safety of currently available adrenal steroidogenesis inhibitors, including drugs currently in development. ### methods We performed a systematic review of the literature regarding adrenal steroidogenesis inhibitors, focusing on novel drugs. ### results Currently available adrenal steroidogenesis inhibitors , including ketoconazole , metyrapone , etomidate , and mitotane , have variable efficacy and significant side effects , and none are approved by the US Food and Drug Administration for CS . Therefore, there is a clear need for novel, prospectively studied agents that have greater efficacy and a low rate of adverse side effects. Efficacy and safety data of current and emerging adrenal steroidogenesis inhibitors, including osilodrostat (LCI699) and levoketoconazole (COR-003), show promising results that will have to be confirmed in larger-scale phase 3 studies (currently ongoing). ### conclusions The management of CS, and particularly CD, remains challenging. Adrenal steroidogenesis inhibitors can be of major interest to control the hypercortisolism at any time point, either before or after surgery, as discussed in this review.

https://pubmed.ncbi.nlm.nih.gov/27600150/

### 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: Updates on the role of adrenal steroidogenesis inhibitors in Cushing's syndrome: a focus on novel therapies. Endogenous Cushing's syndrome (CS) is a rare disease that results from exposure to high levels of cortisol; Cushing's disease (CD) is the most frequent form of CS. Patients with CS suffer from a variety of comorbidities that increase the risk of mortality. Surgical resection of the disease-causing lesion is generally the first-line treatment of CS. However, some patients may not be eligible for surgery due to comorbidities, and approximately 25 % of patients, especially those with CD, have recurrent disease. For these patients, adrenal steroidogenesis inhibitors may control cortisol elevation and subsequent symptomatology. CS is rare overall, and clinical studies of adrenal steroidogenesis inhibitors are often small and, in many cases, data are limited regarding the efficacy and safety of these treatments. Our aim was to better characterize the profiles of efficacy and safety of currently available adrenal steroidogenesis inhibitors, including drugs currently in development. ### methods We performed a systematic review of the literature regarding adrenal steroidogenesis inhibitors, focusing on novel drugs. ### results Currently available adrenal steroidogenesis inhibitors , including ketoconazole , metyrapone , etomidate , and mitotane , have variable efficacy and significant side effects , and none are approved by the US Food and Drug Administration for CS . Therefore, there is a clear need for novel, prospectively studied agents that have greater efficacy and a low rate of adverse side effects. Efficacy and safety data of current and emerging adrenal steroidogenesis inhibitors, including osilodrostat (LCI699) and levoketoconazole (COR-003), show promising results that will have to be confirmed in larger-scale phase 3 studies (currently ongoing). ### conclusions The management of CS, and particularly CD, remains challenging. Adrenal steroidogenesis inhibitors can be of major interest to control the hypercortisolism at any time point, either before or after surgery, as discussed in this review. ### Response: ketoconazole, metyrapone, etomidate, mitotane

38e86e2ea081339e207960ade6df585f

The differential effects of haloperidol and methamphetamine on time estimation in the rat .

The differential effects of haloperidol and methamphetamine on time estimation in the rat . Forty rats were trained to make a left lever response if a signal (white noise) was 2.5s and to make a right lever response if the signal was 6.3s. When seven intermediate signal durations, to which responses were not reinforced, were randomly interspersed the probability of a right-lever ('long') response increased as a function of signal duration. methamphetamine shifted this psychometric function leftward and decreased its slope: haloperidol also decreased the slope but shifted the function rightward. A combination of haloperidol and methamphetamine led to a function similar to the saline control function. The leftward shift probably reflects an increase in the speed of an internal clock, and the rightward shift probably reflects a decrease in its speed. Since methamphetamine releases several catecholamines, including dopamine, and haloperidol blocks dopamine receptors, it is plausible that the horizontal location of the psychometric function (the speed of the clock) is related to the effective level of dopamine.

https://pubmed.ncbi.nlm.nih.gov/6403957/

### 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 differential effects of haloperidol and methamphetamine on time estimation in the rat . Forty rats were trained to make a left lever response if a signal (white noise) was 2.5s and to make a right lever response if the signal was 6.3s. When seven intermediate signal durations, to which responses were not reinforced, were randomly interspersed the probability of a right-lever ('long') response increased as a function of signal duration. methamphetamine shifted this psychometric function leftward and decreased its slope: haloperidol also decreased the slope but shifted the function rightward. A combination of haloperidol and methamphetamine led to a function similar to the saline control function. The leftward shift probably reflects an increase in the speed of an internal clock, and the rightward shift probably reflects a decrease in its speed. Since methamphetamine releases several catecholamines, including dopamine, and haloperidol blocks dopamine receptors, it is plausible that the horizontal location of the psychometric function (the speed of the clock) is related to the effective level of dopamine. ### Response: haloperidol, methamphetamine

e1cbaee16f90b5f5cd216566c4f3348a

In the present study , we evaluated the efficacy and safety of the weekly combination of etoposide , leucovorin ( LV ) and 5-fluorouracil ( 5-FU ) when administered as second-line chemotherapy in patients with relapsed/refractory advanced colorectal cancer ( ACC ) , previously treated with weekly LV+5-FU .

Etoposide, leucovorin (LV) and 5-fluorouracil (5-FU) in 5-FU+LV pre-treated patients with advanced colorectal cancer. In the present study , we evaluated the efficacy and safety of the weekly combination of etoposide , leucovorin ( LV ) and 5-fluorouracil ( 5-FU ) when administered as second-line chemotherapy in patients with relapsed/refractory advanced colorectal cancer ( ACC ) , previously treated with weekly LV+5-FU . etoposide was administered at 3 different dose levels (DLs), in 3 groups of 20 patients each (total: 60); DL-I: etoposide 80 mg/m2, DL-II: etoposide 120 mg/m2, and DL-III: etoposide 180 mg/m2, in 45 min i.v. infusion, and followed in all levels by LV 100 mg/m2 i.v. over 1 hour and 5-FU 500 mg/m2 i.v. bolus. Treatment was administered weekly until disease progression or unacceptable toxicity. No patients at DL-I responded, while 2 patients at DL-II and 3 at DL-III had a partial response (PR). Stable disease (SD) rates were as follows; at DL-I: 2, DL-II: 8 and DL-III: 9. More patients in DL-I progressed (n = 19) compared to DL-II (n=10) and DL-II (n = 8) (p < 0.0007). Time to progression was for DL-I, -II, -III: 17, 15, and 14 weeks, respectively. Median survival was DL-I, -II, -III: 30, 30, and 32.5 weeks, respectively. Toxicity consisted mainly of neutropenia, diarrhea and mucositis at all DLs, and was significantly more severe in DL-III. No difference was noted in responses between DL-II and DL-III. The authors conclude that the combination of etoposide with LV+5-FU has limited activity when administered after failure of weekly LV+5-FU in patients with ACC and should not be recommended for further evaluation.

https://pubmed.ncbi.nlm.nih.gov/12420860/

### 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: Etoposide, leucovorin (LV) and 5-fluorouracil (5-FU) in 5-FU+LV pre-treated patients with advanced colorectal cancer. In the present study , we evaluated the efficacy and safety of the weekly combination of etoposide , leucovorin ( LV ) and 5-fluorouracil ( 5-FU ) when administered as second-line chemotherapy in patients with relapsed/refractory advanced colorectal cancer ( ACC ) , previously treated with weekly LV+5-FU . etoposide was administered at 3 different dose levels (DLs), in 3 groups of 20 patients each (total: 60); DL-I: etoposide 80 mg/m2, DL-II: etoposide 120 mg/m2, and DL-III: etoposide 180 mg/m2, in 45 min i.v. infusion, and followed in all levels by LV 100 mg/m2 i.v. over 1 hour and 5-FU 500 mg/m2 i.v. bolus. Treatment was administered weekly until disease progression or unacceptable toxicity. No patients at DL-I responded, while 2 patients at DL-II and 3 at DL-III had a partial response (PR). Stable disease (SD) rates were as follows; at DL-I: 2, DL-II: 8 and DL-III: 9. More patients in DL-I progressed (n = 19) compared to DL-II (n=10) and DL-II (n = 8) (p < 0.0007). Time to progression was for DL-I, -II, -III: 17, 15, and 14 weeks, respectively. Median survival was DL-I, -II, -III: 30, 30, and 32.5 weeks, respectively. Toxicity consisted mainly of neutropenia, diarrhea and mucositis at all DLs, and was significantly more severe in DL-III. No difference was noted in responses between DL-II and DL-III. The authors conclude that the combination of etoposide with LV+5-FU has limited activity when administered after failure of weekly LV+5-FU in patients with ACC and should not be recommended for further evaluation. ### Response: etoposide, leucovorin, 5-fluorouracil

e6ec9d1de8b404c19da2279ecaa39e05

Diazoxide , nifedipine and 2-deoxy glucose suppressed ( p < 0.05 ) glucose stimulated insulin secretion in AtT20HI-GLUT2-GK-6 cells .

Cellular characterization of pituitary adenoma cell line (AtT20 cell) transfected with insulin, glucose transporter type 2 (GLUT2) and glucokinase genes: insulin secretion in response to physiological concentrations of glucose. We investigated the mechanisms of insulin secretion by transfecting into a pituitary adenoma cell line (AtT20) a combination of genes encoding human insulin (HI), glucose transporter type 2 (GLUT2) and glucokinase (GK), followed by studying the characteristics of these cells. In static incubation, a cell line transfected with insulin gene alone (AtT20HI) secreted mature human insulin but this was not in a glucose-dependent manner. Other cell lines transfected with insulin and GLUT2 genes (AtT20HI-GLUT2-3) or with insulin and GK genes (AtT20HI-GK-1) secreted insulin in response to glucose concentrations of only less than 1 mmol/l. In contrast, cell lines transfected with insulin, GLUT2 and GK genes (AtT20HI-GLUT2-GK-6, AtT20HI-GLUT2-GK-7 and AtT20HI-GLUT2-GK-10) showed a glucose-dependent insulin secretion up to 25 mmol/l glucose. Glucose utilization and oxidation were increased in AtT20HI-GLUT2-GK cell lines but not in AtT20HI, AtT20HI-GLUT2-3 and AtT20HI-GK-1 cells at physiological glucose concentrations, compared with AtT20 cells. Diazoxide , nifedipine and 2-deoxy glucose suppressed ( p < 0.05 ) glucose stimulated insulin secretion in AtT20HI-GLUT2-GK-6 cells . Glibenclamide, KCl or corticotropin releasing factor (CRF) stimulated (p < 0.05) insulin secretion both in AtT20HI and AtT20HI-GLUT2-GK-6 cells. Insulin secretion stimulated by glibenclamide, KCl or CRF was further enhanced by the addition of 25 mmol/l glucose in AtT20HI-GLUT2-GK-6 cells but not in AtT20HI cells. In perifusion experiments, a stepwise increase in glucose concentration from 5 to 25 mmol/l stimulated insulin secretion in AtT20HI-GLUT2-GK cell lines but the response lacked a clear first phase of insulin secretion. Our results suggest that both GLUT2 and glucokinase are necessary for the glucose stimulated insulin secretion in at least rodent cell lines, and that other element(s) are necessary for a biphasic insulin secretion typically observed in beta cells.

https://pubmed.ncbi.nlm.nih.gov/9867217/

### 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: Cellular characterization of pituitary adenoma cell line (AtT20 cell) transfected with insulin, glucose transporter type 2 (GLUT2) and glucokinase genes: insulin secretion in response to physiological concentrations of glucose. We investigated the mechanisms of insulin secretion by transfecting into a pituitary adenoma cell line (AtT20) a combination of genes encoding human insulin (HI), glucose transporter type 2 (GLUT2) and glucokinase (GK), followed by studying the characteristics of these cells. In static incubation, a cell line transfected with insulin gene alone (AtT20HI) secreted mature human insulin but this was not in a glucose-dependent manner. Other cell lines transfected with insulin and GLUT2 genes (AtT20HI-GLUT2-3) or with insulin and GK genes (AtT20HI-GK-1) secreted insulin in response to glucose concentrations of only less than 1 mmol/l. In contrast, cell lines transfected with insulin, GLUT2 and GK genes (AtT20HI-GLUT2-GK-6, AtT20HI-GLUT2-GK-7 and AtT20HI-GLUT2-GK-10) showed a glucose-dependent insulin secretion up to 25 mmol/l glucose. Glucose utilization and oxidation were increased in AtT20HI-GLUT2-GK cell lines but not in AtT20HI, AtT20HI-GLUT2-3 and AtT20HI-GK-1 cells at physiological glucose concentrations, compared with AtT20 cells. Diazoxide , nifedipine and 2-deoxy glucose suppressed ( p < 0.05 ) glucose stimulated insulin secretion in AtT20HI-GLUT2-GK-6 cells . Glibenclamide, KCl or corticotropin releasing factor (CRF) stimulated (p < 0.05) insulin secretion both in AtT20HI and AtT20HI-GLUT2-GK-6 cells. Insulin secretion stimulated by glibenclamide, KCl or CRF was further enhanced by the addition of 25 mmol/l glucose in AtT20HI-GLUT2-GK-6 cells but not in AtT20HI cells. In perifusion experiments, a stepwise increase in glucose concentration from 5 to 25 mmol/l stimulated insulin secretion in AtT20HI-GLUT2-GK cell lines but the response lacked a clear first phase of insulin secretion. Our results suggest that both GLUT2 and glucokinase are necessary for the glucose stimulated insulin secretion in at least rodent cell lines, and that other element(s) are necessary for a biphasic insulin secretion typically observed in beta cells. ### Response: Diazoxide, nifedipine, 2-deoxy glucose

56767edbaaf4aa1833e32ccf779a6d71

Reducing the duration of medication use postoperatively may also minimize the possible side effects of ketorolac and codeine , which could develop with extended periods of use .

Evaluation of ketorolac (Toradol) with varying amounts of codeine for postoperative extraction pain control. This study analyzes the combination of oral ketorolac 10 mg with varying amounts of codeine phosphate, and the postoperative pain relief that developed from these combinations. Five groups of patients were administered the codeine/ketorolac combinations. Variations of the combinations were analyzed to ascertain if an optimal analgesic ratio existed. All controllable variables involved with the surgical procedure were held constant to allow for better evaluation of postoperative pain. Results obtained from 67 patients indicated that the best pain relief was achieved with a combination of 10 mg ketorolac and 15 mg codeine phosphate. codeine alone provided adequate analgesia, but the addition of ketorolac reduced the patients' perceived side effects. The presence of codeine in the analgesic combination was also shown to reduce the number of days that the patient required the medication postoperatively. Reducing the duration of medication use postoperatively may also minimize the possible side effects of ketorolac and codeine , which could develop with extended periods of use .

https://pubmed.ncbi.nlm.nih.gov/12190134/

### 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 ketorolac (Toradol) with varying amounts of codeine for postoperative extraction pain control. This study analyzes the combination of oral ketorolac 10 mg with varying amounts of codeine phosphate, and the postoperative pain relief that developed from these combinations. Five groups of patients were administered the codeine/ketorolac combinations. Variations of the combinations were analyzed to ascertain if an optimal analgesic ratio existed. All controllable variables involved with the surgical procedure were held constant to allow for better evaluation of postoperative pain. Results obtained from 67 patients indicated that the best pain relief was achieved with a combination of 10 mg ketorolac and 15 mg codeine phosphate. codeine alone provided adequate analgesia, but the addition of ketorolac reduced the patients' perceived side effects. The presence of codeine in the analgesic combination was also shown to reduce the number of days that the patient required the medication postoperatively. Reducing the duration of medication use postoperatively may also minimize the possible side effects of ketorolac and codeine , which could develop with extended periods of use . ### Response: ketorolac, codeine

d5f7976596eb3d6b0af16a3cf786c912

Lenalidomide plus dexamethasone is a reference treatment for relapsed multiple myeloma .

Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. Lenalidomide plus dexamethasone is a reference treatment for relapsed multiple myeloma . The combination of the proteasome inhibitor carfilzomib with lenalidomide and dexamethasone has shown efficacy in a phase 1 and 2 study in relapsed multiple myeloma. ### methods We randomly assigned 792 patients with relapsed multiple myeloma to carfilzomib with lenalidomide and dexamethasone (carfilzomib group) or lenalidomide and dexamethasone alone (control group). The primary end point was progression-free survival. ### results Progression-free survival was significantly improved with carfilzomib (median, 26.3 months, vs. 17.6 months in the control group; hazard ratio for progression or death, 0.69; 95% confidence interval [CI], 0.57 to 0.83; P=0.0001). The median overall survival was not reached in either group at the interim analysis. The Kaplan-Meier 24-month overall survival rates were 73.3% and 65.0% in the carfilzomib and control groups, respectively (hazard ratio for death, 0.79; 95% CI, 0.63 to 0.99; P=0.04). The rates of overall response (partial response or better) were 87.1% and 66.7% in the carfilzomib and control groups, respectively (P<0.001; 31.8% and 9.3% of patients in the respective groups had a complete response or better; 14.1% and 4.3% had a stringent complete response). Adverse events of grade 3 or higher were reported in 83.7% and 80.7% of patients in the carfilzomib and control groups, respectively; 15.3% and 17.7% of patients discontinued treatment owing to adverse events. Patients in the carfilzomib group reported superior health-related quality of life. ### conclusions In patients with relapsed multiple myeloma, the addition of carfilzomib to lenalidomide and dexamethasone resulted in significantly improved progression-free survival at the interim analysis and had a favorable risk-benefit profile. (Funded by Onyx Pharmaceuticals; ClinicalTrials.gov number, NCT01080391.).

https://pubmed.ncbi.nlm.nih.gov/25482145/

### 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: Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. Lenalidomide plus dexamethasone is a reference treatment for relapsed multiple myeloma . The combination of the proteasome inhibitor carfilzomib with lenalidomide and dexamethasone has shown efficacy in a phase 1 and 2 study in relapsed multiple myeloma. ### methods We randomly assigned 792 patients with relapsed multiple myeloma to carfilzomib with lenalidomide and dexamethasone (carfilzomib group) or lenalidomide and dexamethasone alone (control group). The primary end point was progression-free survival. ### results Progression-free survival was significantly improved with carfilzomib (median, 26.3 months, vs. 17.6 months in the control group; hazard ratio for progression or death, 0.69; 95% confidence interval [CI], 0.57 to 0.83; P=0.0001). The median overall survival was not reached in either group at the interim analysis. The Kaplan-Meier 24-month overall survival rates were 73.3% and 65.0% in the carfilzomib and control groups, respectively (hazard ratio for death, 0.79; 95% CI, 0.63 to 0.99; P=0.04). The rates of overall response (partial response or better) were 87.1% and 66.7% in the carfilzomib and control groups, respectively (P<0.001; 31.8% and 9.3% of patients in the respective groups had a complete response or better; 14.1% and 4.3% had a stringent complete response). Adverse events of grade 3 or higher were reported in 83.7% and 80.7% of patients in the carfilzomib and control groups, respectively; 15.3% and 17.7% of patients discontinued treatment owing to adverse events. Patients in the carfilzomib group reported superior health-related quality of life. ### conclusions In patients with relapsed multiple myeloma, the addition of carfilzomib to lenalidomide and dexamethasone resulted in significantly improved progression-free survival at the interim analysis and had a favorable risk-benefit profile. (Funded by Onyx Pharmaceuticals; ClinicalTrials.gov number, NCT01080391.). ### Response: Lenalidomide, dexamethasone

8c077eeed55f1a34d9df0058007d72b1

Following definitive treatment , patients were randomized to either cyclophosphamide 1 g/m2 intravenously every 3 weeks for 2 years , estramustine phosphate 600 mg/m2 orally daily for 2 years or to observation only .

Adjuvant therapy for clinical localized prostate cancer treated with surgery or irradiation. Because of efficacy demonstrated with chemotherapy in patients with metastatic disease, the National Prostate Cancer Project in 1978 initiated two protocols evaluating adjuvant therapy following surgery (Protocol 900) and irradiation (Protocol 1000) for patients with localized disease at high risk for relapse. ### methods All patients underwent staging pelvic lymph node dissection. Following definitive treatment , patients were randomized to either cyclophosphamide 1 g/m2 intravenously every 3 weeks for 2 years , estramustine phosphate 600 mg/m2 orally daily for 2 years or to observation only . Accession closed in 1985 and included 184 patients in Protocol 900 (170 evaluable) and 253 in Protocol 1000 (233 evaluable). ### results Nodal involvement was identified in 198 patients (49% of total): 29% in Protocol 900 and 63% in protocol 1000. Median progression-free survival (PFS) and survival have been greater for patients in Protocol 900 regardless of adjuvant, reflecting their lower pathologic stage. Median PFS is significantly greater for patients in Protocol 1000 receiving estramustine (52.2 months) compared to cyclophosphamide (35.0 months). Median PFS for patients with nodal involvement in Protocol 1000 receiving estramustine is increased (43.5 months) compared to no treatment (21.5 months). Patients with limited nodal involvement in Protocol 1000 have a longer median PFS (45.6 months) compared to patients with extensive disease (23.6 months). But in the latter group patients receiving estramustine experienced a significantly longer median PFS (43.5 months) compared to cyclophosphamide (29.1 months) or no adjuvant (13.5 months). Increased PFS with estramustine adjuvant was also noted in stage C patients (only Protocol 900) and in those with high-grade (grade 3) tumors (both protocols). ### conclusions With now over 10 years mean follow-up for this series of patients, we conclude that adjuvant estramustine is beneficial for prostate cancer patients receiving definitive irradiation. This benefit is particularly noted in those patients with extensive nodal involvement (N+, D-1).

https://pubmed.ncbi.nlm.nih.gov/8791049/

### 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: Adjuvant therapy for clinical localized prostate cancer treated with surgery or irradiation. Because of efficacy demonstrated with chemotherapy in patients with metastatic disease, the National Prostate Cancer Project in 1978 initiated two protocols evaluating adjuvant therapy following surgery (Protocol 900) and irradiation (Protocol 1000) for patients with localized disease at high risk for relapse. ### methods All patients underwent staging pelvic lymph node dissection. Following definitive treatment , patients were randomized to either cyclophosphamide 1 g/m2 intravenously every 3 weeks for 2 years , estramustine phosphate 600 mg/m2 orally daily for 2 years or to observation only . Accession closed in 1985 and included 184 patients in Protocol 900 (170 evaluable) and 253 in Protocol 1000 (233 evaluable). ### results Nodal involvement was identified in 198 patients (49% of total): 29% in Protocol 900 and 63% in protocol 1000. Median progression-free survival (PFS) and survival have been greater for patients in Protocol 900 regardless of adjuvant, reflecting their lower pathologic stage. Median PFS is significantly greater for patients in Protocol 1000 receiving estramustine (52.2 months) compared to cyclophosphamide (35.0 months). Median PFS for patients with nodal involvement in Protocol 1000 receiving estramustine is increased (43.5 months) compared to no treatment (21.5 months). Patients with limited nodal involvement in Protocol 1000 have a longer median PFS (45.6 months) compared to patients with extensive disease (23.6 months). But in the latter group patients receiving estramustine experienced a significantly longer median PFS (43.5 months) compared to cyclophosphamide (29.1 months) or no adjuvant (13.5 months). Increased PFS with estramustine adjuvant was also noted in stage C patients (only Protocol 900) and in those with high-grade (grade 3) tumors (both protocols). ### conclusions With now over 10 years mean follow-up for this series of patients, we conclude that adjuvant estramustine is beneficial for prostate cancer patients receiving definitive irradiation. This benefit is particularly noted in those patients with extensive nodal involvement (N+, D-1). ### Response: cyclophosphamide, estramustine

0e3638fb7225dbfb492b6e28afaefb04

The authors report on anemia observed during preoperative paclitaxel and carboplatin chemotherapy in patients with advanced head and neck carcinoma and discuss how the use of recombinant human erythropoietin ( r-HuEPO ) ameliorates this anemia , reducing the need for subsequent packed red blood cell ( PRBC ) transfusions .

Erythropoietin reduces anemia and transfusions after chemotherapy with paclitaxel and carboplatin. The authors report on anemia observed during preoperative paclitaxel and carboplatin chemotherapy in patients with advanced head and neck carcinoma and discuss how the use of recombinant human erythropoietin ( r-HuEPO ) ameliorates this anemia , reducing the need for subsequent packed red blood cell ( PRBC ) transfusions . ### methods Response to r-HuEPO was defined as reduced hemoglobin fall during preoperative chemotherapy and reduced transfusion requirements during surgery. Thirty-six patients with advanced head and neck carcinoma were evaluable after treatment with preoperative chemotherapy using paclitaxel and carboplatin. Group 1 was comprised of 14 patients who empirically received r-HuEPO at a dose of 150 U/kg 3 times per week for 3 weeks; in patients deemed nonresponders, the dose was increased to 300 U/kg and 450 U/kg in the subsequent courses. Group 2 was comprised of 22 patients who did not receive r-HuEPO. ### results During preoperative chemotherapy, the mean hemoglobin fall was 0.5 g/dL in Group 1 (P = 0.40). In Group 2 there was a statistically significant mean hemoglobin fall of 3.3 g/dL (P < 0.0001). There was also a nonstatistically significant trend toward fewer PRBC transfusions: none of 14 patients (0%) in Group 1 versus 4 of 22 patients (18%) in Group 2 (P = 0.141). ### conclusions A significant fall in hemoglobin and an increase in the need for transfusions were observed in head and neck carcinoma patients receiving carboplatin and paclitaxel chemotherapy prior to surgery. Empiric r-HuEPO therapy appeared to prevent anemia and reduced the need for PRBC transfusions.

https://pubmed.ncbi.nlm.nih.gov/9118049/

### 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: Erythropoietin reduces anemia and transfusions after chemotherapy with paclitaxel and carboplatin. The authors report on anemia observed during preoperative paclitaxel and carboplatin chemotherapy in patients with advanced head and neck carcinoma and discuss how the use of recombinant human erythropoietin ( r-HuEPO ) ameliorates this anemia , reducing the need for subsequent packed red blood cell ( PRBC ) transfusions . ### methods Response to r-HuEPO was defined as reduced hemoglobin fall during preoperative chemotherapy and reduced transfusion requirements during surgery. Thirty-six patients with advanced head and neck carcinoma were evaluable after treatment with preoperative chemotherapy using paclitaxel and carboplatin. Group 1 was comprised of 14 patients who empirically received r-HuEPO at a dose of 150 U/kg 3 times per week for 3 weeks; in patients deemed nonresponders, the dose was increased to 300 U/kg and 450 U/kg in the subsequent courses. Group 2 was comprised of 22 patients who did not receive r-HuEPO. ### results During preoperative chemotherapy, the mean hemoglobin fall was 0.5 g/dL in Group 1 (P = 0.40). In Group 2 there was a statistically significant mean hemoglobin fall of 3.3 g/dL (P < 0.0001). There was also a nonstatistically significant trend toward fewer PRBC transfusions: none of 14 patients (0%) in Group 1 versus 4 of 22 patients (18%) in Group 2 (P = 0.141). ### conclusions A significant fall in hemoglobin and an increase in the need for transfusions were observed in head and neck carcinoma patients receiving carboplatin and paclitaxel chemotherapy prior to surgery. Empiric r-HuEPO therapy appeared to prevent anemia and reduced the need for PRBC transfusions. ### Response: paclitaxel, carboplatin, erythropoietin

31a0bb182139720ca8b79d8e68089d7e

Combination therapy with fluconazole and flucytosine in the murine model of cryptococcal meningitis .

Combination therapy with fluconazole and flucytosine in the murine model of cryptococcal meningitis . This study elucidates the role of combined fluconazole and flucytosine as therapy for cryptococcosis in the murine model of meningitis. Three strains of Cryptococcus neoformans for which the range of fluconazole MICs was wide--2 microg/ml (susceptible strain), 8 microg/ml (moderately susceptible strain), and 32 microg/ml (resistant strain)--were used for infection. One day postinfection, the mice were randomized into eight treatment groups: placebo; flucytosine (40 mg/kg of body weight/day); fluconazole at 3 mg/kg/day (low dosage), 10 mg/kg/day (moderate dosage), or 20 mg/kg/day (high dosage); and combined flucytosine and fluconazole at low, moderate, or high doses of fluconazole. Three major findings were demonstrated: (i) correlation between the MICs for the isolates and the in vivo effectiveness of fluconazole as assessed by the reduction in cryptococcal brain burden, (ii) a dose-response curve (a higher dose of fluconazole was significantly more efficacious than a lower dose [P < 0.001]), and (iii) synergism between fluconazole and flucytosine (therapy with a combination of fluconazole and flucytosine was superior to therapy with either agent alone [P < 0.01]).

https://pubmed.ncbi.nlm.nih.gov/9145879/

### 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: Combination therapy with fluconazole and flucytosine in the murine model of cryptococcal meningitis . This study elucidates the role of combined fluconazole and flucytosine as therapy for cryptococcosis in the murine model of meningitis. Three strains of Cryptococcus neoformans for which the range of fluconazole MICs was wide--2 microg/ml (susceptible strain), 8 microg/ml (moderately susceptible strain), and 32 microg/ml (resistant strain)--were used for infection. One day postinfection, the mice were randomized into eight treatment groups: placebo; flucytosine (40 mg/kg of body weight/day); fluconazole at 3 mg/kg/day (low dosage), 10 mg/kg/day (moderate dosage), or 20 mg/kg/day (high dosage); and combined flucytosine and fluconazole at low, moderate, or high doses of fluconazole. Three major findings were demonstrated: (i) correlation between the MICs for the isolates and the in vivo effectiveness of fluconazole as assessed by the reduction in cryptococcal brain burden, (ii) a dose-response curve (a higher dose of fluconazole was significantly more efficacious than a lower dose [P < 0.001]), and (iii) synergism between fluconazole and flucytosine (therapy with a combination of fluconazole and flucytosine was superior to therapy with either agent alone [P < 0.01]). ### Response: fluconazole, flucytosine

a4eaf1e008a043a0608e1e0a1e0bf452

The consumption of meropenem or doripenem was calculated using the Anatomic Therapeutic Chemical classification and defined daily doses methodology .

Correlation between the consumption of meropenem or doripenem and meropenem susceptibility of Pseudomonas aeruginosa in a university hospital in Japan. The appropriate use of carbapenems is essential in order to prevent resistance in Pseudomonas aeruginosa. We investigated the correlation between the consumption of meropenem or doripenem and the susceptibility of P. aeruginosa to meropenem in a Japanese university hospital from 2004 to 2009. The susceptibility data of P. aeruginosa and the annual consumption of meropenem or doripenem were analyzed. The consumption of meropenem or doripenem was calculated using the Anatomic Therapeutic Chemical classification and defined daily doses methodology . meropenem consumption decreased and doripenem consumption increased and throughout the entire investigation period, total consumption of meropenem plus doripenem was stable. Although the annual number of isolated P. aeruginosa has not changed, the annual number of isolated multidrug resistant P. aeruginosa decreased by measures against nosocomial infection. The rate of meropenem resistant P. aeruginosa decreased in a time-dependent manner. meropenem consumption was positively correlated with the meropenem resistance rate among P. aeruginosa (r = 0.9455, p<0.01). The total consumption of meropenem and doripenem was not correlated with the meropenem resistance rate (r = -0.6601, p>0.1). These results suggested that even if the total consumption of meropenem plus doripenem was not changed, meropenem susceptibility among P. aeruginosa improved by the decrease of meropenem consumption. Although meropenem and doripenem have been suggested to show cross-resistance with each other, the reduction of meropenem consumption might be effective for preventing an increase of meropenem-resistant P. aeruginosa.

https://pubmed.ncbi.nlm.nih.gov/22687536/

### 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 the consumption of meropenem or doripenem and meropenem susceptibility of Pseudomonas aeruginosa in a university hospital in Japan. The appropriate use of carbapenems is essential in order to prevent resistance in Pseudomonas aeruginosa. We investigated the correlation between the consumption of meropenem or doripenem and the susceptibility of P. aeruginosa to meropenem in a Japanese university hospital from 2004 to 2009. The susceptibility data of P. aeruginosa and the annual consumption of meropenem or doripenem were analyzed. The consumption of meropenem or doripenem was calculated using the Anatomic Therapeutic Chemical classification and defined daily doses methodology . meropenem consumption decreased and doripenem consumption increased and throughout the entire investigation period, total consumption of meropenem plus doripenem was stable. Although the annual number of isolated P. aeruginosa has not changed, the annual number of isolated multidrug resistant P. aeruginosa decreased by measures against nosocomial infection. The rate of meropenem resistant P. aeruginosa decreased in a time-dependent manner. meropenem consumption was positively correlated with the meropenem resistance rate among P. aeruginosa (r = 0.9455, p<0.01). The total consumption of meropenem and doripenem was not correlated with the meropenem resistance rate (r = -0.6601, p>0.1). These results suggested that even if the total consumption of meropenem plus doripenem was not changed, meropenem susceptibility among P. aeruginosa improved by the decrease of meropenem consumption. Although meropenem and doripenem have been suggested to show cross-resistance with each other, the reduction of meropenem consumption might be effective for preventing an increase of meropenem-resistant P. aeruginosa. ### Response: meropenem, doripenem

22debd462be9d02dd7750eb8021920c8

After successful phase II studies , recent phase III trials established combinations of chlorambucil with anti-CD20 antibodies such as rituximab , ofatumumab and obinutuzumab as a valuable treatment option for these patients .

Past, present and future role of chlorambucil in the treatment of chronic lymphocytic leukemia. For many decades, chlorambucil was the standard of care for chronic lymphocytic leukemia (CLL), but meanwhile has been replaced by purine analog-based chemoimmunotherapy. Monotherapy with the alkylator only retained significance in the treatment of older patients unfit for standard treatment. After successful phase II studies , recent phase III trials established combinations of chlorambucil with anti-CD20 antibodies such as rituximab , ofatumumab and obinutuzumab as a valuable treatment option for these patients . Today, chlorambucil therefore should be used as a chemotherapy backbone for antibody-based chemoimmunotherapy in this patient population rather than as monotherapy. Starting from the past role of chlorambucil in CLL treatment, we here review the most recent efforts to elaborate chlorambucil-based chemoimmunotherapy in CLL and discuss clinically relevant questions that arise from this approach.

https://pubmed.ncbi.nlm.nih.gov/25219593/

### 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: Past, present and future role of chlorambucil in the treatment of chronic lymphocytic leukemia. For many decades, chlorambucil was the standard of care for chronic lymphocytic leukemia (CLL), but meanwhile has been replaced by purine analog-based chemoimmunotherapy. Monotherapy with the alkylator only retained significance in the treatment of older patients unfit for standard treatment. After successful phase II studies , recent phase III trials established combinations of chlorambucil with anti-CD20 antibodies such as rituximab , ofatumumab and obinutuzumab as a valuable treatment option for these patients . Today, chlorambucil therefore should be used as a chemotherapy backbone for antibody-based chemoimmunotherapy in this patient population rather than as monotherapy. Starting from the past role of chlorambucil in CLL treatment, we here review the most recent efforts to elaborate chlorambucil-based chemoimmunotherapy in CLL and discuss clinically relevant questions that arise from this approach. ### Response: chlorambucil, rituximab, ofatumumab, obinutuzumab

188b16b8466b9036888f9feac1266c4b

Unorthodox antibiotic combinations including ciprofloxacin against high-level gentamicin resistant enterococci .

Unorthodox antibiotic combinations including ciprofloxacin against high-level gentamicin resistant enterococci . Development of high-level gentamicin resistance among enterococci represents a serious therapeutic problem as it precludes synergy between aminoglycosides and cell-wall active agents. As part of a search for active antibiotic combinations against enterococci with high-level gentamicin resistance, we tested by the time kill curve method the efficacy of ciprofloxacin combined with ampicillin, trimethoprim-sulphamethoxazole, vancomycin or teicoplanin against ten isolates of Enterococcus faecium, three of Enterococcus casseliflavus and 13 of Enterococcus faecalis that exhibited a MIC of gentamicin > or = 2000 mg/L. Most of the E. faecium were also resistant to ampicillin and to ciprofloxacin. The combination of ciprofloxacin with ampicillin was bactericidal against five of seven E. faecium strains that exhibited a ciprofloxacin MIC < or = 4 mg/L, but was inactive against the three E. faecium that were highly resistant to ciprofloxacin. This combination was also bactericidal against the E. casseliflavus and all the E. faecalis strains. The combination of ciprofloxacin with trimethoprim-sulphamethoxazole was bactericidal against five of the seven E. faecium and seven of the nine E. faecalis strains with a ciprofloxacin MIC < or = 4 mg/L. No bactericidal activity of this combination was seen against the enterococci that were highly resistant to either ciprofloxacin or to trimethoprim-sulphamethoxazole. The combination of ciprofloxacin with glycopeptides was inactive against E. faecium and E. casseliflavus and against E. faecalis, it was either ineffective or antagonistic; in only one case it was bactericidal. Five strains of E. faecium were resistant to all antibiotic combinations tested.

https://pubmed.ncbi.nlm.nih.gov/8722538/

### 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: Unorthodox antibiotic combinations including ciprofloxacin against high-level gentamicin resistant enterococci . Development of high-level gentamicin resistance among enterococci represents a serious therapeutic problem as it precludes synergy between aminoglycosides and cell-wall active agents. As part of a search for active antibiotic combinations against enterococci with high-level gentamicin resistance, we tested by the time kill curve method the efficacy of ciprofloxacin combined with ampicillin, trimethoprim-sulphamethoxazole, vancomycin or teicoplanin against ten isolates of Enterococcus faecium, three of Enterococcus casseliflavus and 13 of Enterococcus faecalis that exhibited a MIC of gentamicin > or = 2000 mg/L. Most of the E. faecium were also resistant to ampicillin and to ciprofloxacin. The combination of ciprofloxacin with ampicillin was bactericidal against five of seven E. faecium strains that exhibited a ciprofloxacin MIC < or = 4 mg/L, but was inactive against the three E. faecium that were highly resistant to ciprofloxacin. This combination was also bactericidal against the E. casseliflavus and all the E. faecalis strains. The combination of ciprofloxacin with trimethoprim-sulphamethoxazole was bactericidal against five of the seven E. faecium and seven of the nine E. faecalis strains with a ciprofloxacin MIC < or = 4 mg/L. No bactericidal activity of this combination was seen against the enterococci that were highly resistant to either ciprofloxacin or to trimethoprim-sulphamethoxazole. The combination of ciprofloxacin with glycopeptides was inactive against E. faecium and E. casseliflavus and against E. faecalis, it was either ineffective or antagonistic; in only one case it was bactericidal. Five strains of E. faecium were resistant to all antibiotic combinations tested. ### Response: ciprofloxacin, gentamicin

988f81203188bfe746d002e49e6c45d7

Randomized Trial of Lenalidomide Alone Versus Lenalidomide Plus Rituximab in Patients With Recurrent Follicular Lymphoma : CALGB 50401 ( Alliance ) .

Randomized Trial of Lenalidomide Alone Versus Lenalidomide Plus Rituximab in Patients With Recurrent Follicular Lymphoma : CALGB 50401 ( Alliance ) . lenalidomide and rituximab (LR) are active agents in follicular lymphoma (FL). Combination regimens have not been previously assessed in randomized studies. ### Patients And Methods The Cancer and Leukemia Group B (Alliance) 50401 trial is a randomized phase II trial studying rituximab (375 mg/m(2) weekly for 4 weeks), lenalidomide (15 mg per day on days 1 to 21, followed by 7 days of rest, in cycle 1 and then 20 mg per day on days 1 to 21, followed by 7 days of rest, in cycles 2 to 12), or LR. The rituximab-alone arm was discontinued as a result of poor accrual. Eligibility included recurrent FL and prior rituximab with time to progression of ≥ 6 months from last dose. aspirin or heparin was recommended for patients at high thrombosis risk. ### results Ninety-one patients (lenalidomide, n = 45; LR, n = 46) received treatment; median age was 63 years (range, 34 to 89 years), and 58% were intermediate or high risk according to the Follicular Lymphoma International Prognostic Index. In the lenalidomide and LR arms, grade 3 to 4 adverse events occurred in 58% and 53% of patients, with 9% and 11% of patients experiencing grade 4 toxicity, respectively; grade 3 to 4 adverse events included neutropenia (16% v 20%, respectively), fatigue (9% v 13%, respectively), and thrombosis (16% [n = 7] v 4% [n = 2], respectively; P = .157). Thirty-six percent of lenalidomide patients and 63% of LR patients completed 12 cycles. lenalidomide alone was associated with more treatment failures, with 22% of patients discontinuing treatment as a result of adverse events. Dose-intensity exceeded 80% in both arms. Overall response rate was 53% (20% complete response) and 76% (39% complete response) for lenalidomide alone and LR, respectively (P = .029). At the median follow-up of 2.5 years, median time to progression was 1.1 year for lenalidomide alone and 2 years for LR (P = .0023). ### conclusion LR is more active than lenalidomide alone in recurrent FL with similar toxicity, warranting further study in B-cell non-Hodgkin lymphoma as a platform for addition of novel agents.

https://pubmed.ncbi.nlm.nih.gov/26304886/

### 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 Trial of Lenalidomide Alone Versus Lenalidomide Plus Rituximab in Patients With Recurrent Follicular Lymphoma : CALGB 50401 ( Alliance ) . lenalidomide and rituximab (LR) are active agents in follicular lymphoma (FL). Combination regimens have not been previously assessed in randomized studies. ### Patients And Methods The Cancer and Leukemia Group B (Alliance) 50401 trial is a randomized phase II trial studying rituximab (375 mg/m(2) weekly for 4 weeks), lenalidomide (15 mg per day on days 1 to 21, followed by 7 days of rest, in cycle 1 and then 20 mg per day on days 1 to 21, followed by 7 days of rest, in cycles 2 to 12), or LR. The rituximab-alone arm was discontinued as a result of poor accrual. Eligibility included recurrent FL and prior rituximab with time to progression of ≥ 6 months from last dose. aspirin or heparin was recommended for patients at high thrombosis risk. ### results Ninety-one patients (lenalidomide, n = 45; LR, n = 46) received treatment; median age was 63 years (range, 34 to 89 years), and 58% were intermediate or high risk according to the Follicular Lymphoma International Prognostic Index. In the lenalidomide and LR arms, grade 3 to 4 adverse events occurred in 58% and 53% of patients, with 9% and 11% of patients experiencing grade 4 toxicity, respectively; grade 3 to 4 adverse events included neutropenia (16% v 20%, respectively), fatigue (9% v 13%, respectively), and thrombosis (16% [n = 7] v 4% [n = 2], respectively; P = .157). Thirty-six percent of lenalidomide patients and 63% of LR patients completed 12 cycles. lenalidomide alone was associated with more treatment failures, with 22% of patients discontinuing treatment as a result of adverse events. Dose-intensity exceeded 80% in both arms. Overall response rate was 53% (20% complete response) and 76% (39% complete response) for lenalidomide alone and LR, respectively (P = .029). At the median follow-up of 2.5 years, median time to progression was 1.1 year for lenalidomide alone and 2 years for LR (P = .0023). ### conclusion LR is more active than lenalidomide alone in recurrent FL with similar toxicity, warranting further study in B-cell non-Hodgkin lymphoma as a platform for addition of novel agents. ### Response: Lenalidomide, Lenalidomide, Rituximab

2f4875c70156aa249196fc0eaef130a8

Potential cost-effectiveness of rifampin vs. isoniazid for latent tuberculosis : implications for future clinical trials .

Potential cost-effectiveness of rifampin vs. isoniazid for latent tuberculosis : implications for future clinical trials . Standard treatment for latent tuberculosis infection (LTBI) is 9 months daily isoniazid (9INH). An alternative is 4 months daily rifampin (4RMP), associated with better completion and less toxicity; however, its efficacy remains uncertain. ### objectives To assess the cost-effectiveness of these regimens for treating LTBI in human immunodeficiency virus negative persons, using results from a recent clinical trial, plus different scenarios for 4RMP efficacy, and to estimate the costs of an adequately powered noninferiority trial and resulting savings from substitution with 4RMP. ### design A decision-analysis model tracked TB contacts and lower-risk tuberculin reactors receiving 9INH, 4RMP or no treatment. For different 4RMP efficacy scenarios, we estimated the cost-effectiveness, sample size and cost of non-inferiority trials, and potential cost savings substituting 4RMP for 9INH for 10 years in Canada. ### results With an assumed 4RMP efficacy of 60%, 9INH was more effective but slightly more expensive. Above a threshold efficacy of 69%, 4RMP was cheaper and more effective than 9INH. If the true efficacy of 4RMP is ≥75%, a trial powered to detect non-inferiority with a lower limit of 60% estimated efficacy (~20 000 subjects) may lead to cost savings within 10 years, even with the extreme assumption that Canada bears the entire cost. ### conclusion 4RMP may be a reasonable alternative to 9INH. Costs of a large-scale non-inferiority trial may be offset by subsequent savings.

https://pubmed.ncbi.nlm.nih.gov/22283892/

### 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: Potential cost-effectiveness of rifampin vs. isoniazid for latent tuberculosis : implications for future clinical trials . Standard treatment for latent tuberculosis infection (LTBI) is 9 months daily isoniazid (9INH). An alternative is 4 months daily rifampin (4RMP), associated with better completion and less toxicity; however, its efficacy remains uncertain. ### objectives To assess the cost-effectiveness of these regimens for treating LTBI in human immunodeficiency virus negative persons, using results from a recent clinical trial, plus different scenarios for 4RMP efficacy, and to estimate the costs of an adequately powered noninferiority trial and resulting savings from substitution with 4RMP. ### design A decision-analysis model tracked TB contacts and lower-risk tuberculin reactors receiving 9INH, 4RMP or no treatment. For different 4RMP efficacy scenarios, we estimated the cost-effectiveness, sample size and cost of non-inferiority trials, and potential cost savings substituting 4RMP for 9INH for 10 years in Canada. ### results With an assumed 4RMP efficacy of 60%, 9INH was more effective but slightly more expensive. Above a threshold efficacy of 69%, 4RMP was cheaper and more effective than 9INH. If the true efficacy of 4RMP is ≥75%, a trial powered to detect non-inferiority with a lower limit of 60% estimated efficacy (~20 000 subjects) may lead to cost savings within 10 years, even with the extreme assumption that Canada bears the entire cost. ### conclusion 4RMP may be a reasonable alternative to 9INH. Costs of a large-scale non-inferiority trial may be offset by subsequent savings. ### Response: rifampin, isoniazid

029f80670066e918ad09b45caa1e326d

Treatments included once daily erlotinib , which was given alone for the first 7 days of treatments , then in combination with once daily sirolimus .

A dose escalation trial for the combination of erlotinib and sirolimus for recurrent malignant gliomas. In order to achieve higher dosages than previously used in clinical trials, we conducted a phase I trial to determine the maximum tolerated dose (MTD) for the combination of erlotinib and sirolimus for the treatments of recurrent malignant gliomas. Patients with pathologically proven World Health Organization (WHO) grade III glioma and grade IV glioblastoma and radiographically proven tumor recurrence were eligible for this study. Treatments included once daily erlotinib , which was given alone for the first 7 days of treatments , then in combination with once daily sirolimus . sirolimus was given with a loading dose on day 8 followed by a maintenance dose starting on day 9. Dose-limiting toxicity (DLT) was determined over the first 28 days of treatments, and the MTD was determined in a 3 + 3 classic study design. 19 patients were enrolled, and 13 patients were eligible for MTD determination. The MTD was determined to be 150 mg daily for erlotinib and 5 mg daily (after a 15 mg loading dose) for sirolimus. The DLTs included rash and mucositis (despite maximal medical managements), hypophosphatemia, altered mental status, and neutropenia. The combination of erlotinib and sirolimus is difficult to tolerate at dosages higher than previously reported in phase II trials.

https://pubmed.ncbi.nlm.nih.gov/22918789/

### 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 dose escalation trial for the combination of erlotinib and sirolimus for recurrent malignant gliomas. In order to achieve higher dosages than previously used in clinical trials, we conducted a phase I trial to determine the maximum tolerated dose (MTD) for the combination of erlotinib and sirolimus for the treatments of recurrent malignant gliomas. Patients with pathologically proven World Health Organization (WHO) grade III glioma and grade IV glioblastoma and radiographically proven tumor recurrence were eligible for this study. Treatments included once daily erlotinib , which was given alone for the first 7 days of treatments , then in combination with once daily sirolimus . sirolimus was given with a loading dose on day 8 followed by a maintenance dose starting on day 9. Dose-limiting toxicity (DLT) was determined over the first 28 days of treatments, and the MTD was determined in a 3 + 3 classic study design. 19 patients were enrolled, and 13 patients were eligible for MTD determination. The MTD was determined to be 150 mg daily for erlotinib and 5 mg daily (after a 15 mg loading dose) for sirolimus. The DLTs included rash and mucositis (despite maximal medical managements), hypophosphatemia, altered mental status, and neutropenia. The combination of erlotinib and sirolimus is difficult to tolerate at dosages higher than previously reported in phase II trials. ### Response: erlotinib, sirolimus

0713ecdff351b72f27677723d0a8cc65

Cabazitaxel effectively killed PC-3R cells , and MDR1 knockdown improved the sensitivity of PC-3R cells to docetaxel but not to cabazitaxel .

Serum exosomal P-glycoprotein is a potential marker to diagnose docetaxel resistance and select a taxoid for patients with prostate cancer. docetaxel is used as the first-line chemotherapy for castration-resistant prostate cancer (CRPC), but docetaxel resistance occurs in part owing to induction of P-glycoprotein (P-gp) encoded by multidrug resistance protein 1 (MDR1) gene. A recently developed taxane-cabazitaxel-has poor affinity for P-gp and is thereby effective in docetaxel-resistant CRPC. It has been recently demonstrated that exosomes in the body fluids could serve as a diagnostic marker because they contain proteins and RNAs specific to the cells from which they are derived. In this study, we aimed to investigate if P-gp in blood exosomes could be a marker to diagnose docetaxel resistance and select a taxoid for patients with CRPC. ### Methods And Materials Exosomes were isolated by differential centrifugation from docetaxel-resistant prostate cancer (PC-3) cells (PC-3R) and their parental PC-3 cells and from the serum of patients. Silencing of P-gp was performed by small interfering RNA transfection. Protein expression was examined by Western blot analysis. Viability of cells treated with docetaxel or cabazitaxel was determined by water soluble tetrazolium salt (WST) assay. ### results The level of P-gp was higher in exosomes as well as cell lysates from PC-3R cells than in those from PC-3 cells. Cabazitaxel effectively killed PC-3R cells , and MDR1 knockdown improved the sensitivity of PC-3R cells to docetaxel but not to cabazitaxel . The P-gp level in blood exosomes was relatively higher in clinically docetaxel-resistant patients than in therapy-naïve patients. ### conclusions Our results suggest that detection of P-gp in blood exosomes, which is involved in resistance to docetaxel but not to cabazitaxel, could be useful to diagnose docetaxel resistance and select an appropriate taxoid for patients with CRPC-docetaxel or cabazitaxel.

https://pubmed.ncbi.nlm.nih.gov/26027763/

### 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: Serum exosomal P-glycoprotein is a potential marker to diagnose docetaxel resistance and select a taxoid for patients with prostate cancer. docetaxel is used as the first-line chemotherapy for castration-resistant prostate cancer (CRPC), but docetaxel resistance occurs in part owing to induction of P-glycoprotein (P-gp) encoded by multidrug resistance protein 1 (MDR1) gene. A recently developed taxane-cabazitaxel-has poor affinity for P-gp and is thereby effective in docetaxel-resistant CRPC. It has been recently demonstrated that exosomes in the body fluids could serve as a diagnostic marker because they contain proteins and RNAs specific to the cells from which they are derived. In this study, we aimed to investigate if P-gp in blood exosomes could be a marker to diagnose docetaxel resistance and select a taxoid for patients with CRPC. ### Methods And Materials Exosomes were isolated by differential centrifugation from docetaxel-resistant prostate cancer (PC-3) cells (PC-3R) and their parental PC-3 cells and from the serum of patients. Silencing of P-gp was performed by small interfering RNA transfection. Protein expression was examined by Western blot analysis. Viability of cells treated with docetaxel or cabazitaxel was determined by water soluble tetrazolium salt (WST) assay. ### results The level of P-gp was higher in exosomes as well as cell lysates from PC-3R cells than in those from PC-3 cells. Cabazitaxel effectively killed PC-3R cells , and MDR1 knockdown improved the sensitivity of PC-3R cells to docetaxel but not to cabazitaxel . The P-gp level in blood exosomes was relatively higher in clinically docetaxel-resistant patients than in therapy-naïve patients. ### conclusions Our results suggest that detection of P-gp in blood exosomes, which is involved in resistance to docetaxel but not to cabazitaxel, could be useful to diagnose docetaxel resistance and select an appropriate taxoid for patients with CRPC-docetaxel or cabazitaxel. ### Response: Cabazitaxel, docetaxel, cabazitaxel

bf761dcf8faf97dba0151338f99b7f8a

The results suggest that rational therapy for severe CHF includes addition of the aldosterone antagonist spironolactone to low doses of captopril ( or another ACE inhibitor ) and high doses of loop diuretics , provided renal function is adequate .

Captopril and spironolactone therapy for refractory congestive heart failure. Short- and long-term clinical effects of the angiotensin-converting enzyme (ACE) inhibitor captopril in severe congestive heart failure (CHF) were evaluated during a 3-year open study of 124 inpatients with New York Heart Association (NYHA) functional class III or IV CHF refractory to treatment with cardiac glycosides and high doses of loop diuretics. captopril was added to each patient's regimen, which comprised combinations of furosemide (124 patients), digitalis (117 patients), and spironolactone (90 patients). By the end of the first month of captopril administration, improvement in NYHA functional class was seen in 89 patients (72%). During the first year of captopril treatment, the number of hospital admissions and hospital days declined significantly (p < 0.001) and functional class improved significantly (p < 0.001). Although most patients tolerated captopril well, 44% experienced hypotension, which in 10% of patients necessitated termination of captopril therapy. Although mean serum potassium levels tended to increase, serious hyperkalemia did not occur. After 1 year, a subset of 30 patients who had not initially received spironolactone deteriorated clinically and manifested increasing urinary aldosterone levels. Hypotension precluded increasing the captopril dose, but introduction of spironolactone improved clinical status in this cohort. The results suggest that rational therapy for severe CHF includes addition of the aldosterone antagonist spironolactone to low doses of captopril ( or another ACE inhibitor ) and high doses of loop diuretics , provided renal function is adequate .

https://pubmed.ncbi.nlm.nih.gov/8422001/

### 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: Captopril and spironolactone therapy for refractory congestive heart failure. Short- and long-term clinical effects of the angiotensin-converting enzyme (ACE) inhibitor captopril in severe congestive heart failure (CHF) were evaluated during a 3-year open study of 124 inpatients with New York Heart Association (NYHA) functional class III or IV CHF refractory to treatment with cardiac glycosides and high doses of loop diuretics. captopril was added to each patient's regimen, which comprised combinations of furosemide (124 patients), digitalis (117 patients), and spironolactone (90 patients). By the end of the first month of captopril administration, improvement in NYHA functional class was seen in 89 patients (72%). During the first year of captopril treatment, the number of hospital admissions and hospital days declined significantly (p < 0.001) and functional class improved significantly (p < 0.001). Although most patients tolerated captopril well, 44% experienced hypotension, which in 10% of patients necessitated termination of captopril therapy. Although mean serum potassium levels tended to increase, serious hyperkalemia did not occur. After 1 year, a subset of 30 patients who had not initially received spironolactone deteriorated clinically and manifested increasing urinary aldosterone levels. Hypotension precluded increasing the captopril dose, but introduction of spironolactone improved clinical status in this cohort. The results suggest that rational therapy for severe CHF includes addition of the aldosterone antagonist spironolactone to low doses of captopril ( or another ACE inhibitor ) and high doses of loop diuretics , provided renal function is adequate . ### Response: spironolactone, captopril, loop diuretics

2639e095391228a032ec68c2c3f598ad

The MICs of erythromycin and clindamycin for most of the LAB were within the normal range of susceptibility .

Antibiotic resistance in lactic acid bacteria isolated from some pharmaceutical and dairy products. A total of 244 lactic acid bacteria (LAB) strains were isolated from 180 dairy and pharmaceutical products that were collected from different areas in Minia governorate, Egypt. LAB were identified phenotypically on basis of morphological, physiological and biochemical characteristics. Lactobacillus isolates were further confirmed using PCR-based assay. By combination of phenotypic with molecular identification Lactobacillus spp. were found to be the dominant genus (138, 76.7%) followed by Streptococcus spp. (65, 36.1%) and Lactococcus spp. (27, 15%). Some contaminant organisms such as (Staphylococcus spp., Escherichia coli, Salmonella spp., mould and yeast) were isolated from the collected dairy samples but pharmaceutical products were free of such contaminants. Susceptibility of LAB isolates to antibiotics representing all major classes was tested by agar dilution method. Generally, LAB were highly susceptible to Beta-lactams except penicillin. Lactobacilli were resistant to vancomycin, however lactococci and streptococci proved to be very susceptible. Most strains were susceptible to tetracycline and showed a wide range of streptomycin MICs. The MICs of erythromycin and clindamycin for most of the LAB were within the normal range of susceptibility . Sixteen Lactobacillus, 8 Lactococcus and 8 Streptococcus isolates including all tetracycline and/or erythromycin resistant strains were tested for the presence of tetracycline and/or erythromycin resistant genes [tet(M) and/or erm(B)]. PCR assays shows that some resistant strains harbor tet(M) and/or erm(B) resistance genes.

https://pubmed.ncbi.nlm.nih.gov/24948910/

### 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 resistance in lactic acid bacteria isolated from some pharmaceutical and dairy products. A total of 244 lactic acid bacteria (LAB) strains were isolated from 180 dairy and pharmaceutical products that were collected from different areas in Minia governorate, Egypt. LAB were identified phenotypically on basis of morphological, physiological and biochemical characteristics. Lactobacillus isolates were further confirmed using PCR-based assay. By combination of phenotypic with molecular identification Lactobacillus spp. were found to be the dominant genus (138, 76.7%) followed by Streptococcus spp. (65, 36.1%) and Lactococcus spp. (27, 15%). Some contaminant organisms such as (Staphylococcus spp., Escherichia coli, Salmonella spp., mould and yeast) were isolated from the collected dairy samples but pharmaceutical products were free of such contaminants. Susceptibility of LAB isolates to antibiotics representing all major classes was tested by agar dilution method. Generally, LAB were highly susceptible to Beta-lactams except penicillin. Lactobacilli were resistant to vancomycin, however lactococci and streptococci proved to be very susceptible. Most strains were susceptible to tetracycline and showed a wide range of streptomycin MICs. The MICs of erythromycin and clindamycin for most of the LAB were within the normal range of susceptibility . Sixteen Lactobacillus, 8 Lactococcus and 8 Streptococcus isolates including all tetracycline and/or erythromycin resistant strains were tested for the presence of tetracycline and/or erythromycin resistant genes [tet(M) and/or erm(B)]. PCR assays shows that some resistant strains harbor tet(M) and/or erm(B) resistance genes. ### Response: erythromycin, clindamycin

5ce6e216b05e1bb1b1ed43e0bc86e44d

Based on HRs for RFS/DFS , the risk of recurrence with nivolumab was similar to that of pembrolizumab and lower than that of ipilimumab 3 mg/kg , ipilimumab 10 mg/kg , or interferon .

Comparative efficacy and safety of adjuvant nivolumab versus other treatments in adults with resected melanoma: a systematic literature review and network meta-analysis. Immune checkpoint inhibitors and targeted therapies are approved for adjuvant treatment of patients with resected melanoma; however, they have not been compared in randomized controlled trials (RCTs). We compared the efficacy and safety of adjuvant nivolumab with other approved treatments using available evidence from RCTs in a Bayesian network meta-analysis (NMA). ### methods A systematic literature review was conducted through May 2019 to identify relevant RCTs evaluating approved adjuvant treatments. Outcomes of interest included recurrence-free survival (RFS)/disease-free survival (DFS), distant metastasis-free survival (DMFS), all-cause grade 3/4 adverse events (AEs), discontinuations, and discontinuations due to AEs. Time-to-event outcomes (RFS/DFS and DMFS) were analyzed both assuming that hazard ratios (HRs) are constant over time and that they vary. ### results Of 26 identified RCTs, 19 were included in the NMA following a feasibility assessment. Based on HRs for RFS/DFS , the risk of recurrence with nivolumab was similar to that of pembrolizumab and lower than that of ipilimumab 3 mg/kg , ipilimumab 10 mg/kg , or interferon . Risk of recurrence with nivolumab was similar to that of dabrafenib plus trametinib at 12 months, however, was lower beyond 12 months (HR [95% credible interval] at 24 months, 0.46 [0.27-0.78]; at 36 months, 0.28 [0.14-0.59]). Based on HRs for DMFS, the risk of developing distant metastases was lower with nivolumab than with ipilimumab 10 mg/kg or interferon and was similar to dabrafenib plus trametinib. ### conclusion Adjuvant therapy with nivolumab provides an effective treatment option with a promising risk-benefit profile.

https://pubmed.ncbi.nlm.nih.gov/33402121/

### 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 and safety of adjuvant nivolumab versus other treatments in adults with resected melanoma: a systematic literature review and network meta-analysis. Immune checkpoint inhibitors and targeted therapies are approved for adjuvant treatment of patients with resected melanoma; however, they have not been compared in randomized controlled trials (RCTs). We compared the efficacy and safety of adjuvant nivolumab with other approved treatments using available evidence from RCTs in a Bayesian network meta-analysis (NMA). ### methods A systematic literature review was conducted through May 2019 to identify relevant RCTs evaluating approved adjuvant treatments. Outcomes of interest included recurrence-free survival (RFS)/disease-free survival (DFS), distant metastasis-free survival (DMFS), all-cause grade 3/4 adverse events (AEs), discontinuations, and discontinuations due to AEs. Time-to-event outcomes (RFS/DFS and DMFS) were analyzed both assuming that hazard ratios (HRs) are constant over time and that they vary. ### results Of 26 identified RCTs, 19 were included in the NMA following a feasibility assessment. Based on HRs for RFS/DFS , the risk of recurrence with nivolumab was similar to that of pembrolizumab and lower than that of ipilimumab 3 mg/kg , ipilimumab 10 mg/kg , or interferon . Risk of recurrence with nivolumab was similar to that of dabrafenib plus trametinib at 12 months, however, was lower beyond 12 months (HR [95% credible interval] at 24 months, 0.46 [0.27-0.78]; at 36 months, 0.28 [0.14-0.59]). Based on HRs for DMFS, the risk of developing distant metastases was lower with nivolumab than with ipilimumab 10 mg/kg or interferon and was similar to dabrafenib plus trametinib. ### conclusion Adjuvant therapy with nivolumab provides an effective treatment option with a promising risk-benefit profile. ### Response: nivolumab, pembrolizumab, ipilimumab, ipilimumab

ce0aa908b93d64279ac44dcaf232b957

Combination therapy of infliximab and methotrexate is more effective in reducing clinical and biochemical disease activity than gold with methylprednisolone treatment in RA patients during 22 weeks of treatment , especially in the first 6 weeks .

[Analysis of efficacy and safety of multiple intravenous infusion of anti-tumor necrosis factor-alpha monoclonal antibody (Remicade) combined with methotrexate compared with sodium aurothiomalate and intramuscular depot methylprednisolone in rheumatoid arthritis]. The objective of the paper was compare the effects and tolerability of combined therapy of multiple intravenous infusions of anti-tumour necrosis factor-alfa (TNF-alfa) monoclonal antibody (Remicade) with methotrexate versus treatment with sodium aurothiomalate and intramuscular depot methylprednisolone in rheumatoid arthritis (RA). We investigate also the interval necessary to obtain the improvement in both treatment groups. 36 patients commencing intramuscular sodium aurothiomalate therapy with intramuscular depot methylprednisolone acetate at weeks 0, 4, 8 and 12 in addition to chrysotherapy were compared in retrospective analysis with 32 patients starting with multiple intravenous infusions of infliximab, anti-TNF-alfa monoclonal antibody (Remicade) and methotrexate at a stable dose. Patients were assessed by composite clinical score (DAS 28) and C-reactive protein during 22 weeks of therapy. At week 2 and 6 a significantly greater percentage of infliximab-treated than gold-treated RA patients achieved improvement in each clinical measurement of disease activity. At 22 week of treatment moderate and good response according to EULAR criteria was achieved in 91% of infliximab-treated patients and 58% gold treated patients (p < 0.001). Adverse events were more frequently observed in infliximab-treated patients, but only gold-treated patients discontinued treatment because adverse events (2 patients due to proteinuria, 2 patients due to mucocutaneous changes and one patient due to leucopenia). The higher percentage of adverse events in infliximab-treated patients was caused mainly by the occurrence of infusion reactions (23 reactions out of 160 infusions); most of them were mild (somnolentia and headache) and transient. Viral infections (including herpes simplex and zoster) were more common in patients treated with infliximab and methotrexate. Combination therapy of infliximab and methotrexate is more effective in reducing clinical and biochemical disease activity than gold with methylprednisolone treatment in RA patients during 22 weeks of treatment , especially in the first 6 weeks .

https://pubmed.ncbi.nlm.nih.gov/12685246/

### 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 efficacy and safety of multiple intravenous infusion of anti-tumor necrosis factor-alpha monoclonal antibody (Remicade) combined with methotrexate compared with sodium aurothiomalate and intramuscular depot methylprednisolone in rheumatoid arthritis]. The objective of the paper was compare the effects and tolerability of combined therapy of multiple intravenous infusions of anti-tumour necrosis factor-alfa (TNF-alfa) monoclonal antibody (Remicade) with methotrexate versus treatment with sodium aurothiomalate and intramuscular depot methylprednisolone in rheumatoid arthritis (RA). We investigate also the interval necessary to obtain the improvement in both treatment groups. 36 patients commencing intramuscular sodium aurothiomalate therapy with intramuscular depot methylprednisolone acetate at weeks 0, 4, 8 and 12 in addition to chrysotherapy were compared in retrospective analysis with 32 patients starting with multiple intravenous infusions of infliximab, anti-TNF-alfa monoclonal antibody (Remicade) and methotrexate at a stable dose. Patients were assessed by composite clinical score (DAS 28) and C-reactive protein during 22 weeks of therapy. At week 2 and 6 a significantly greater percentage of infliximab-treated than gold-treated RA patients achieved improvement in each clinical measurement of disease activity. At 22 week of treatment moderate and good response according to EULAR criteria was achieved in 91% of infliximab-treated patients and 58% gold treated patients (p < 0.001). Adverse events were more frequently observed in infliximab-treated patients, but only gold-treated patients discontinued treatment because adverse events (2 patients due to proteinuria, 2 patients due to mucocutaneous changes and one patient due to leucopenia). The higher percentage of adverse events in infliximab-treated patients was caused mainly by the occurrence of infusion reactions (23 reactions out of 160 infusions); most of them were mild (somnolentia and headache) and transient. Viral infections (including herpes simplex and zoster) were more common in patients treated with infliximab and methotrexate. Combination therapy of infliximab and methotrexate is more effective in reducing clinical and biochemical disease activity than gold with methylprednisolone treatment in RA patients during 22 weeks of treatment , especially in the first 6 weeks . ### Response: infliximab, methotrexate, methylprednisolone, gold

73b3eae39bac7bc40153d6a660377f2b

Serum homocysteine , cholesterol , retinol , alpha-tocopherol , glycosylated hemoglobin and inflammatory response during therapy with bevacizumab , oxaliplatin , 5-fluorouracil and leucovorin .

Serum homocysteine , cholesterol , retinol , alpha-tocopherol , glycosylated hemoglobin and inflammatory response during therapy with bevacizumab , oxaliplatin , 5-fluorouracil and leucovorin . Targeted agents present with a new spectrum of side-effects, including toxicities that negatively impact the risk of atherosclerosis. The aim of the present study was to evaluate the effect of the combination of targeted therapy and chemotherapy on serum homocysteine and other laboratory parameters of cardiovascular risk in patients with metastatic colorectal carcinoma. ### Patients And Methods Thirty-one patients with metastatic colorectal carcinoma treated with the combination of bevacizumab, oxaliplatin, 5-fluorouracil and leucovorin were studied before and during the therapy. ### results Serum homocysteine decreased significantly throughout the course of treatment. Total cholesterol and low-density lipoprotein cholesterol also decreased significantly during the first month of therapy. In contrast, serum retinol significantly increased during the second and third months of treatment. A significant increase in glycosylated hemoglobin was also observed. After an initial rise, serum C-reactive protein (CRP) and carcinoembryonic antigen (CEA) were significantly lower compared to baseline throughout the course of treatment. Serum ferritin increased throughout most of the course of treatment. A significant correlation was observed between CRP and high-density lipoprotein cholesterol, retinol, ferritin, and CEA. CEA correlated with hemoglobin, retinol, and ferritin. Retinol correlated significantly with hemoglobin. ### conclusion Tumor control, reflected in lower CEA, resulted in suppression of the acute phase response and generally in favorable effects on laboratory parameters indicative of risk factors of atherosclerosis, including lower homocysteine concentrations, and lower total and LDL cholesterol.

https://pubmed.ncbi.nlm.nih.gov/20032440/

### 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: Serum homocysteine , cholesterol , retinol , alpha-tocopherol , glycosylated hemoglobin and inflammatory response during therapy with bevacizumab , oxaliplatin , 5-fluorouracil and leucovorin . Targeted agents present with a new spectrum of side-effects, including toxicities that negatively impact the risk of atherosclerosis. The aim of the present study was to evaluate the effect of the combination of targeted therapy and chemotherapy on serum homocysteine and other laboratory parameters of cardiovascular risk in patients with metastatic colorectal carcinoma. ### Patients And Methods Thirty-one patients with metastatic colorectal carcinoma treated with the combination of bevacizumab, oxaliplatin, 5-fluorouracil and leucovorin were studied before and during the therapy. ### results Serum homocysteine decreased significantly throughout the course of treatment. Total cholesterol and low-density lipoprotein cholesterol also decreased significantly during the first month of therapy. In contrast, serum retinol significantly increased during the second and third months of treatment. A significant increase in glycosylated hemoglobin was also observed. After an initial rise, serum C-reactive protein (CRP) and carcinoembryonic antigen (CEA) were significantly lower compared to baseline throughout the course of treatment. Serum ferritin increased throughout most of the course of treatment. A significant correlation was observed between CRP and high-density lipoprotein cholesterol, retinol, ferritin, and CEA. CEA correlated with hemoglobin, retinol, and ferritin. Retinol correlated significantly with hemoglobin. ### conclusion Tumor control, reflected in lower CEA, resulted in suppression of the acute phase response and generally in favorable effects on laboratory parameters indicative of risk factors of atherosclerosis, including lower homocysteine concentrations, and lower total and LDL cholesterol. ### Response: bevacizumab, oxaliplatin, 5-fluorouracil, leucovorin

869722511c63922c25884fec67a7e0cb

Reversal of drug resistance by planetary ball milled ( PBM ) nanoparticle loaded with resveratrol and docetaxel in prostate cancer .

Reversal of drug resistance by planetary ball milled ( PBM ) nanoparticle loaded with resveratrol and docetaxel in prostate cancer . The folate receptor (FR) is a valued target that is highly expressed in various cancers, which will expedite the development of ligand-receptor binding based cancer therapeutics. In the present investigation, through tissue microarray analysis, we report higher levels of folate receptor expression in prostate cancer (PCa) tissue derived from patients, which were minimal in normal tissue. For folate-receptor based targeted therapy of PCa, we generated novel planetary ball milled (PBM) nanoparticles (NPs) encapsulated with resveratrol (RES), and in combination with docetaxel (DTX) and conjugated with folic acid (FA) on the surface. The cytotoxic effect of FA-conjugated DTX-nanoparticles was found effectual that reduced the concentration of free drug (DTX) to 28 times. Flow cytometry analysis showed a significant increase in the number of apoptotic cells by 30.92% and 65.9% in the FA-conjugated RES and in combination with DTX nanoparticle formulation respectively. However, only 8.9% apoptotic cells were found with control (empty NP). The expressions of NF-kB p65, COX-2, pro (BAX, BAK) and anti-apoptotic (BCL-2, BCL-XL) genes were significantly reduced after treatment with FA-RES + DTX-NP. In addition, the FA-conjugated DTX formulation exhibited additional cytotoxic effects with the down-regulation of survivin and an increased expression of Cleaved Caspase-3 in PCa cells. Further, we observed that treating DTX resistant PCa cells with FA-RES + DTX-NP exhibited a reversal of the ABC-transporter markers thereby limiting the multidrug resistance phenotype of the cancer cells. Our results strongly suggested that FA conjugated nanoparticle drugs acted as effective inhibitors of drug efflux that effectually enhances the intracellular concentration of the drug to exhibit their cytotoxic effect.

https://pubmed.ncbi.nlm.nih.gov/29678549/

### 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: Reversal of drug resistance by planetary ball milled ( PBM ) nanoparticle loaded with resveratrol and docetaxel in prostate cancer . The folate receptor (FR) is a valued target that is highly expressed in various cancers, which will expedite the development of ligand-receptor binding based cancer therapeutics. In the present investigation, through tissue microarray analysis, we report higher levels of folate receptor expression in prostate cancer (PCa) tissue derived from patients, which were minimal in normal tissue. For folate-receptor based targeted therapy of PCa, we generated novel planetary ball milled (PBM) nanoparticles (NPs) encapsulated with resveratrol (RES), and in combination with docetaxel (DTX) and conjugated with folic acid (FA) on the surface. The cytotoxic effect of FA-conjugated DTX-nanoparticles was found effectual that reduced the concentration of free drug (DTX) to 28 times. Flow cytometry analysis showed a significant increase in the number of apoptotic cells by 30.92% and 65.9% in the FA-conjugated RES and in combination with DTX nanoparticle formulation respectively. However, only 8.9% apoptotic cells were found with control (empty NP). The expressions of NF-kB p65, COX-2, pro (BAX, BAK) and anti-apoptotic (BCL-2, BCL-XL) genes were significantly reduced after treatment with FA-RES + DTX-NP. In addition, the FA-conjugated DTX formulation exhibited additional cytotoxic effects with the down-regulation of survivin and an increased expression of Cleaved Caspase-3 in PCa cells. Further, we observed that treating DTX resistant PCa cells with FA-RES + DTX-NP exhibited a reversal of the ABC-transporter markers thereby limiting the multidrug resistance phenotype of the cancer cells. Our results strongly suggested that FA conjugated nanoparticle drugs acted as effective inhibitors of drug efflux that effectually enhances the intracellular concentration of the drug to exhibit their cytotoxic effect. ### Response: resveratrol, docetaxel

3340a0163ab0c5a4a681d3b8d9a74668

Records of 63 patients diagnosis of IHCC who received Gemcitabine and Carboplatin ( G-C Regimen ) chemotherapy as a first line were retrospectively reviewed .

Gemcitabine with carboplatin for advanced intrahepatic cholangiocarcinoma: A study from North India Cancer Centre. gemcitabine plus cisplatin has been established as a standard chemotherapy regimen for advanced biliary tract cancers (BTCs) based on the phase III UK ABC-02 study, which included all types of biliary cancers. There is very limited data regarding the effectiveness of known chemotherapeutic regimens especially in IHCC. ### methods Records of 63 patients diagnosis of IHCC who received Gemcitabine and Carboplatin ( G-C Regimen ) chemotherapy as a first line were retrospectively reviewed . The primary aim of this study was to assess the response rate of gemcitabine carboplatin-based chemotherapy as a first line therapy in advanced intrahepatic cholangiocarcinoma (IHCC). The secondary objectives were to assess toxicity, progression free survival and overall survival. ### results There were 38 men and 25 women in our study with a median age of 56.75 years (range 31-78 years). Of the 38+25= 63 patients, 21 patients (33.8%) progressed, 5 patients (8.06%) had complete response, 25 patients (40.3%) had partial response, 12 patients (19.3%) had stable disease. Overall response rate was 48.36% and tumor control rate was 67.6%. Progression free survival was 5.3 months and overall survival of 10.3 months was seen. The most common grade 3-4 toxicities were anemia, neutropenia, and thrombocytopenia. Most common nonhematological toxicity was fatigue. ### conclusion gemcitabine in combination with carboplatin has activity against advanced IHCC. Our results are comparable with other gemcitabine carboplatin studies as well as gemcitabine cisplatin-based studies.

https://pubmed.ncbi.nlm.nih.gov/30693882/

### 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: Gemcitabine with carboplatin for advanced intrahepatic cholangiocarcinoma: A study from North India Cancer Centre. gemcitabine plus cisplatin has been established as a standard chemotherapy regimen for advanced biliary tract cancers (BTCs) based on the phase III UK ABC-02 study, which included all types of biliary cancers. There is very limited data regarding the effectiveness of known chemotherapeutic regimens especially in IHCC. ### methods Records of 63 patients diagnosis of IHCC who received Gemcitabine and Carboplatin ( G-C Regimen ) chemotherapy as a first line were retrospectively reviewed . The primary aim of this study was to assess the response rate of gemcitabine carboplatin-based chemotherapy as a first line therapy in advanced intrahepatic cholangiocarcinoma (IHCC). The secondary objectives were to assess toxicity, progression free survival and overall survival. ### results There were 38 men and 25 women in our study with a median age of 56.75 years (range 31-78 years). Of the 38+25= 63 patients, 21 patients (33.8%) progressed, 5 patients (8.06%) had complete response, 25 patients (40.3%) had partial response, 12 patients (19.3%) had stable disease. Overall response rate was 48.36% and tumor control rate was 67.6%. Progression free survival was 5.3 months and overall survival of 10.3 months was seen. The most common grade 3-4 toxicities were anemia, neutropenia, and thrombocytopenia. Most common nonhematological toxicity was fatigue. ### conclusion gemcitabine in combination with carboplatin has activity against advanced IHCC. Our results are comparable with other gemcitabine carboplatin studies as well as gemcitabine cisplatin-based studies. ### Response: Gemcitabine, Carboplatin

0bb682c2b7cf581f5630b073a89e2728

Drugs most commonly implicated in ADRs were amoxicillin + clavulanate ( 21.87 % ) followed by ceftriaxone ( 20.31 % ) .

Adverse Drug Reactions in Hospitalized Pediatric Patients: A Prospective Observational Study. To determine the incidence, pattern, causality, preventability, severity and predictors of adverse drug reactions (ADRs) in pediatric population. ### methods It was a prospective, observational study that included patients of either sex, of any age treated in the pediatric wards of a tertiary care hospital. Study patients were followed throughout their hospital stay. Whenever an ADR was detected, all the required data was collected and analyzed. Data was analyzed for incidence, causality (by using WHO Probability scale and Naranjo's algorithm), preventability (by using Modified Shumock and Thornton scale), severity (by using Modified Hartwig and Siegel scale) and predictors of ADRs. ### results Of the 1775 children admitted in the pediatrics ward, 1082 patients met study criteria and were enrolled into the study. A total of 64 ADRs were identified from 54 patients. The incidence of ADRs was 4.99 %. Male patients experienced majority (68.52 %) of ADRs. Drugs most commonly implicated in ADRs were amoxicillin + clavulanate ( 21.87 % ) followed by ceftriaxone ( 20.31 % ) . Most (51.56 %) of the ADRs reported belonged to the system organ class, gastrointestinal system disorders. Among the ADRs reported, 82.85 % of ADRs were mild. Majority (87.5 %) of the ADRs were of 'probable' causality category and 96.9 % were not preventable. There was a significant association between occurrence of ADRs and the use of ≥4 number of medications, age (infants) and gender (male). ### conclusions Among the pediatric population, infants, male gender and those receiving ≥4 number of medications are at risk of developing ADRs. Constant monitoring is required to address the safety issue in pediatric population especially in infants and patients receiving ≥4 drugs.

https://pubmed.ncbi.nlm.nih.gov/26916890/

### 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: Adverse Drug Reactions in Hospitalized Pediatric Patients: A Prospective Observational Study. To determine the incidence, pattern, causality, preventability, severity and predictors of adverse drug reactions (ADRs) in pediatric population. ### methods It was a prospective, observational study that included patients of either sex, of any age treated in the pediatric wards of a tertiary care hospital. Study patients were followed throughout their hospital stay. Whenever an ADR was detected, all the required data was collected and analyzed. Data was analyzed for incidence, causality (by using WHO Probability scale and Naranjo's algorithm), preventability (by using Modified Shumock and Thornton scale), severity (by using Modified Hartwig and Siegel scale) and predictors of ADRs. ### results Of the 1775 children admitted in the pediatrics ward, 1082 patients met study criteria and were enrolled into the study. A total of 64 ADRs were identified from 54 patients. The incidence of ADRs was 4.99 %. Male patients experienced majority (68.52 %) of ADRs. Drugs most commonly implicated in ADRs were amoxicillin + clavulanate ( 21.87 % ) followed by ceftriaxone ( 20.31 % ) . Most (51.56 %) of the ADRs reported belonged to the system organ class, gastrointestinal system disorders. Among the ADRs reported, 82.85 % of ADRs were mild. Majority (87.5 %) of the ADRs were of 'probable' causality category and 96.9 % were not preventable. There was a significant association between occurrence of ADRs and the use of ≥4 number of medications, age (infants) and gender (male). ### conclusions Among the pediatric population, infants, male gender and those receiving ≥4 number of medications are at risk of developing ADRs. Constant monitoring is required to address the safety issue in pediatric population especially in infants and patients receiving ≥4 drugs. ### Response: amoxicillin, clavulanate, ceftriaxone

c9b122c2f0b11e182b4ed52d9f390055

Dexamethasone and piroxicam provided in the diet were found to significantly inhibit lung tumors induced by 60 mg/kg vinyl carbamate at 24 weeks whereas myo-inositol also provided in the diet , did not significantly inhibit tumor formation .

Chemoprevention of vinyl carbamate-induced lung tumors in strain A mice. The ability of potential chemopreventive agents to prevent vinyl carbamate-induced lung tumors was determined in 2 different experiments. Female strain A mice administered intraperitoneally either a single injection of 60 mg/kg vinyl carbamate that induced 24.0 +/- 1.72 tumors/mouse at 24 weeks or 2 injections of 16 mg/kg vinyl carbamate each (32 mg/kg total dose) that induced 43.2 +/- 3.2 tumors/mouse at 20 weeks. Lung carcinomas were found as early as 16 weeks. Dexamethasone and piroxicam provided in the diet were found to significantly inhibit lung tumors induced by 60 mg/kg vinyl carbamate at 24 weeks whereas myo-inositol also provided in the diet , did not significantly inhibit tumor formation . In animals given 6 16-mg/kg doses of vinyl carbamate, tumor multiplicity was reduced roughly 25% by alpha-difluoromethylornithine and green tea and reduced 50% by dexamethasone and piroxicam. Combinations of these agents were also tested using a total dose of 32 mg/kg of vinyl carbamate. Although alpha-difluoromethylornithine and green tea did not result in a significant inhibition of lung tumor formation if used alone, the combination of alpha-difluoromethylornithine and green tea resulted in a significant reduction of tumor multiplicity. The combinations of alpha-difluoromethylornithine or green tea with either dexamethasone or piroxicam or the combination of dexamethasone and piroxicam did not decrease tumor multiplicity greater than achieved by dexamethasone and piroxicam alone. In summary, selected chemopreventive agents previously shown to inhibit lung tumors by other chemical carcinogens also inhibited vinyl carbamate-induced lung tumors.

https://pubmed.ncbi.nlm.nih.gov/11195469/

### 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: Chemoprevention of vinyl carbamate-induced lung tumors in strain A mice. The ability of potential chemopreventive agents to prevent vinyl carbamate-induced lung tumors was determined in 2 different experiments. Female strain A mice administered intraperitoneally either a single injection of 60 mg/kg vinyl carbamate that induced 24.0 +/- 1.72 tumors/mouse at 24 weeks or 2 injections of 16 mg/kg vinyl carbamate each (32 mg/kg total dose) that induced 43.2 +/- 3.2 tumors/mouse at 20 weeks. Lung carcinomas were found as early as 16 weeks. Dexamethasone and piroxicam provided in the diet were found to significantly inhibit lung tumors induced by 60 mg/kg vinyl carbamate at 24 weeks whereas myo-inositol also provided in the diet , did not significantly inhibit tumor formation . In animals given 6 16-mg/kg doses of vinyl carbamate, tumor multiplicity was reduced roughly 25% by alpha-difluoromethylornithine and green tea and reduced 50% by dexamethasone and piroxicam. Combinations of these agents were also tested using a total dose of 32 mg/kg of vinyl carbamate. Although alpha-difluoromethylornithine and green tea did not result in a significant inhibition of lung tumor formation if used alone, the combination of alpha-difluoromethylornithine and green tea resulted in a significant reduction of tumor multiplicity. The combinations of alpha-difluoromethylornithine or green tea with either dexamethasone or piroxicam or the combination of dexamethasone and piroxicam did not decrease tumor multiplicity greater than achieved by dexamethasone and piroxicam alone. In summary, selected chemopreventive agents previously shown to inhibit lung tumors by other chemical carcinogens also inhibited vinyl carbamate-induced lung tumors. ### Response: Dexamethasone, piroxicam

7d28ca2a855a5b496c60034074c7858a

We identified 938 patients with RCC who had initially been treated with sunitinib ( n = 554 ) or sorafenib ( n = 384 ) .

Initial patterns of care with oral targeted therapies for patients with renal cell carcinoma. To characterize the contemporary use of oral-targeted therapies (ie, sunitinib, sorafenib) among patients with renal cell carcinoma (RCC) and to assess the factors associated with short-term and sequential treatment. ### methods We used an administrative claims database of privately insured patients to evaluate oral-targeted therapy use among patients with RCC from 2006 to 2007. After identifying patients with RCC who had received sunitinib and/or sorafenib, we determined the prevalence of patients treated with short-term and/or sequential therapy. We performed bivariate and multivariate analyses to estimate the associations between the patient characteristics and receipt of short-term and/or sequential treatment regimens. ### results We identified 938 patients with RCC who had initially been treated with sunitinib ( n = 554 ) or sorafenib ( n = 384 ) . In this group, 36% and 23% of patients had received short-term or sequential therapy, respectively. Most patients (61%) who had received sequential therapy had undergone short-term treatment with ≥1 drugs, with second-line sorafenib more likely to be given as short-term therapy than sunitinib (63% vs 34%, P < .001). Short-term therapy was more common in female patients (odds ratio 1.53, 95% confidence interval 1.12-2.09) and patients in the Southern United States (odds ratio 1.71, 95% confidence interval 1.05-2.80). Sequential therapy was more common among patients receiving sorafenib first (odds ratio 2.30, 95% confidence interval 1.64-3.21). ### conclusions Short-term and sequential oral targeted therapy use was relatively prevalent among patients with RCC. For patients treated with sunitinib and sorafenib, the patterns of short-term use varied by the sequence of medications, suggesting differences in the effectiveness or tolerability of each regimen. These findings highlight the need for future studies to characterize the "real-world" clinical outcomes and economic effect associated with these treatment courses.

https://pubmed.ncbi.nlm.nih.gov/21256539/

### 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: Initial patterns of care with oral targeted therapies for patients with renal cell carcinoma. To characterize the contemporary use of oral-targeted therapies (ie, sunitinib, sorafenib) among patients with renal cell carcinoma (RCC) and to assess the factors associated with short-term and sequential treatment. ### methods We used an administrative claims database of privately insured patients to evaluate oral-targeted therapy use among patients with RCC from 2006 to 2007. After identifying patients with RCC who had received sunitinib and/or sorafenib, we determined the prevalence of patients treated with short-term and/or sequential therapy. We performed bivariate and multivariate analyses to estimate the associations between the patient characteristics and receipt of short-term and/or sequential treatment regimens. ### results We identified 938 patients with RCC who had initially been treated with sunitinib ( n = 554 ) or sorafenib ( n = 384 ) . In this group, 36% and 23% of patients had received short-term or sequential therapy, respectively. Most patients (61%) who had received sequential therapy had undergone short-term treatment with ≥1 drugs, with second-line sorafenib more likely to be given as short-term therapy than sunitinib (63% vs 34%, P < .001). Short-term therapy was more common in female patients (odds ratio 1.53, 95% confidence interval 1.12-2.09) and patients in the Southern United States (odds ratio 1.71, 95% confidence interval 1.05-2.80). Sequential therapy was more common among patients receiving sorafenib first (odds ratio 2.30, 95% confidence interval 1.64-3.21). ### conclusions Short-term and sequential oral targeted therapy use was relatively prevalent among patients with RCC. For patients treated with sunitinib and sorafenib, the patterns of short-term use varied by the sequence of medications, suggesting differences in the effectiveness or tolerability of each regimen. These findings highlight the need for future studies to characterize the "real-world" clinical outcomes and economic effect associated with these treatment courses. ### Response: sunitinib, sorafenib

9e5fb2640e823bd9f6060982fa8daf28

( 3 ) Observed facilitatory effects of caerulein on the hypothalamic defensive attack were very similar to those observed with dopamine ( DA ) agonists such as methamphetamine and apomorphine and opposite to those with DA antagonists such as haloperidol and chlorpromazine .

Facilitatory effects of caerulein on hypothalamic defensive attack in cats. Effects of intraventricularly microinjected caerulein (0.1, 1.0 and 10.0 micrograms) on the thresholds for hypothalamically elicited defensive attack and influences of haloperidol (0.5 mg/kg, i.p.) on the effects were studied in chronic cats. Directed attack and hissing were selected for threshold determination, and thresholds for these responses were measured under two situations: one with provocations by a human, and the other without such provocation. Results were as follows. (1) Caerulein lowered all thresholds in generally equal decrements and in a dose-related manner, accompanied by a general behavioral arousal. (2) Prior injection of haloperidol prevented the effects of caerulein, suggesting an antagonism-like interaction between haloperidol and caerulein. ( 3 ) Observed facilitatory effects of caerulein on the hypothalamic defensive attack were very similar to those observed with dopamine ( DA ) agonists such as methamphetamine and apomorphine and opposite to those with DA antagonists such as haloperidol and chlorpromazine . These findings suggest that caerulein exerts its facilitatory effects on the excitability of the ventromedial hypothalamic nucleus through its synergistic interaction with DA.

https://pubmed.ncbi.nlm.nih.gov/3179708/

### 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: Facilitatory effects of caerulein on hypothalamic defensive attack in cats. Effects of intraventricularly microinjected caerulein (0.1, 1.0 and 10.0 micrograms) on the thresholds for hypothalamically elicited defensive attack and influences of haloperidol (0.5 mg/kg, i.p.) on the effects were studied in chronic cats. Directed attack and hissing were selected for threshold determination, and thresholds for these responses were measured under two situations: one with provocations by a human, and the other without such provocation. Results were as follows. (1) Caerulein lowered all thresholds in generally equal decrements and in a dose-related manner, accompanied by a general behavioral arousal. (2) Prior injection of haloperidol prevented the effects of caerulein, suggesting an antagonism-like interaction between haloperidol and caerulein. ( 3 ) Observed facilitatory effects of caerulein on the hypothalamic defensive attack were very similar to those observed with dopamine ( DA ) agonists such as methamphetamine and apomorphine and opposite to those with DA antagonists such as haloperidol and chlorpromazine . These findings suggest that caerulein exerts its facilitatory effects on the excitability of the ventromedial hypothalamic nucleus through its synergistic interaction with DA. ### Response: methamphetamine, haloperidol, chlorpromazine

b6851a7dde2051096158e6c807455512

The NIBIT-MESO-1 study demonstrated the efficacy and safety of tremelimumab combined with durvalumab in patient with unresectable mesothelioma followed up for a median of 52 months [ IQR 49 - 53 ] .

Tremelimumab plus durvalumab retreatment and 4-year outcomes in patients with mesothelioma: a follow-up of the open label, non-randomised, phase 2 NIBIT-MESO-1 study. The NIBIT-MESO-1 study demonstrated the efficacy and safety of tremelimumab combined with durvalumab in patient with unresectable mesothelioma followed up for a median of 52 months [ IQR 49 - 53 ] . Here, we report 4-year survival and outcomes after retreatment, and the role of tumour mutational burden (TMB) in identifying patients who might have a better outcome in response to combined therapy. ### methods NIBIT-MESO-1 was an open-label, non-randomised, phase 2 trial of patients with unresectable pleural or peritoneal mesothelioma who received intravenous tremelimumab (1 mg/kg bodyweight) and durvalumab (20 mg/kg bodyweight) every 4 weeks for four doses, followed by maintenance intravenous durvalumab at the same dose and schedule for nine doses. In this follow-up study, patients with disease progression following initial clinical benefit-ie, a partial repsonse or stable disease-were eligible for retreatment and with the same doses and schedules for tremelimumab and durvalumab as used in the NIBIT-MESO-1 trial. The primary endpoint, immune-related objective response rate, was evaluated per immune-related modified Response Evaluation Criteria in Solid Tumors (RECIST) or immune-related RECIST 1.1 criteria for patients with pleural or peritoneal malignant mesothelioma, respectively. Key secondary endpoints were overall survival and safety, and TMB was also evaluated post hoc in patients who had tumour tissue available before treatment. The intention-to-treat population was used for analysis of all efficacy endpoints. This study is registered with ClinicalTrials.gov, number NCT02588131. ### findings 40 patients were enrolled in the NIBIT-MESO-1 study between Oct 30, 2015, and Oct 12, 2016. At data cut-off, April 30, 2020, five (13%) of 40 patients were alive, and 35 (88%) patients had died of progressive disease. At a median follow-up of 52 months (IQR 49-53), median overall survival was 16·5 months (95% CI 13·7-19·2). Survival was 20% (eight of 40 patients) at 36 months and 15% (six of 40 patients) and 48 months. 17 (43%) of 40 patients met the criteria for enrolment in the retreatment study and were retreated with at least one dose of tremelimumab and durvalumab. No immune-related objective responses were observed in the 17 retreated patients. Seven (41%) of 17 patients achieved immune-related stable disease. From the start of retreatment to a median follow-up of 24 months (22·0-25·0), median overall survival was 12·5 months (95% CI 0·0-25·8), and survival at 12 months was 52·9%, at 18 months was 35·3%, and at 24 months was 23·5%. There were no grade 3-4 immune-related adverse events in the retreatment cohort. In a post-hoc analysis of 28 patients for whom tumour tissue before treatment was available, patients with a TMB higher than the median value of 8·3 mutations per Mb had a higher median overall survival compared with patients with TMB below the median value, but this difference was non-significant. Moreover, when patients were additionally stratified for ICI retreatment (n=13), there was a significant difference in survival between those with a TMB higher than the median of 8·3 mutations per Mb and those with TMB lower than the median in the retreated cohort (41·3 months vs 17·4 months; p=0·02). ### interpretation tremelimumab combined with durvalumab was associated with long-term survival in patients with mesothelioma. Retreatment was safe and resulted in clinically meaningful outcomes, thus suggesting its potential application in the clinical practice of mesothalioma patients. ### funding NIBIT Foundation, Fondazione AIRC, AstraZeneca.

https://pubmed.ncbi.nlm.nih.gov/33844995/

### 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: Tremelimumab plus durvalumab retreatment and 4-year outcomes in patients with mesothelioma: a follow-up of the open label, non-randomised, phase 2 NIBIT-MESO-1 study. The NIBIT-MESO-1 study demonstrated the efficacy and safety of tremelimumab combined with durvalumab in patient with unresectable mesothelioma followed up for a median of 52 months [ IQR 49 - 53 ] . Here, we report 4-year survival and outcomes after retreatment, and the role of tumour mutational burden (TMB) in identifying patients who might have a better outcome in response to combined therapy. ### methods NIBIT-MESO-1 was an open-label, non-randomised, phase 2 trial of patients with unresectable pleural or peritoneal mesothelioma who received intravenous tremelimumab (1 mg/kg bodyweight) and durvalumab (20 mg/kg bodyweight) every 4 weeks for four doses, followed by maintenance intravenous durvalumab at the same dose and schedule for nine doses. In this follow-up study, patients with disease progression following initial clinical benefit-ie, a partial repsonse or stable disease-were eligible for retreatment and with the same doses and schedules for tremelimumab and durvalumab as used in the NIBIT-MESO-1 trial. The primary endpoint, immune-related objective response rate, was evaluated per immune-related modified Response Evaluation Criteria in Solid Tumors (RECIST) or immune-related RECIST 1.1 criteria for patients with pleural or peritoneal malignant mesothelioma, respectively. Key secondary endpoints were overall survival and safety, and TMB was also evaluated post hoc in patients who had tumour tissue available before treatment. The intention-to-treat population was used for analysis of all efficacy endpoints. This study is registered with ClinicalTrials.gov, number NCT02588131. ### findings 40 patients were enrolled in the NIBIT-MESO-1 study between Oct 30, 2015, and Oct 12, 2016. At data cut-off, April 30, 2020, five (13%) of 40 patients were alive, and 35 (88%) patients had died of progressive disease. At a median follow-up of 52 months (IQR 49-53), median overall survival was 16·5 months (95% CI 13·7-19·2). Survival was 20% (eight of 40 patients) at 36 months and 15% (six of 40 patients) and 48 months. 17 (43%) of 40 patients met the criteria for enrolment in the retreatment study and were retreated with at least one dose of tremelimumab and durvalumab. No immune-related objective responses were observed in the 17 retreated patients. Seven (41%) of 17 patients achieved immune-related stable disease. From the start of retreatment to a median follow-up of 24 months (22·0-25·0), median overall survival was 12·5 months (95% CI 0·0-25·8), and survival at 12 months was 52·9%, at 18 months was 35·3%, and at 24 months was 23·5%. There were no grade 3-4 immune-related adverse events in the retreatment cohort. In a post-hoc analysis of 28 patients for whom tumour tissue before treatment was available, patients with a TMB higher than the median value of 8·3 mutations per Mb had a higher median overall survival compared with patients with TMB below the median value, but this difference was non-significant. Moreover, when patients were additionally stratified for ICI retreatment (n=13), there was a significant difference in survival between those with a TMB higher than the median of 8·3 mutations per Mb and those with TMB lower than the median in the retreated cohort (41·3 months vs 17·4 months; p=0·02). ### interpretation tremelimumab combined with durvalumab was associated with long-term survival in patients with mesothelioma. Retreatment was safe and resulted in clinically meaningful outcomes, thus suggesting its potential application in the clinical practice of mesothalioma patients. ### funding NIBIT Foundation, Fondazione AIRC, AstraZeneca. ### Response: tremelimumab, durvalumab

6cfe3dd23724e0caa786ba26a68a658f

Sorafenib has been the standard of care for a decade , and promising results for regorafenib as a second-line and lenvatinib as a first-line treatment were reported only 1 or 2 years ago .

Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: Opportunities and Challenges. Hepatocellular carcinoma (HCC) is the most common malignancy worldwide, and is especially common in China. A total of 70%-80% of patients are diagnosed at an advanced stage and can receive only palliative care. Sorafenib has been the standard of care for a decade , and promising results for regorafenib as a second-line and lenvatinib as a first-line treatment were reported only 1 or 2 years ago . FOLFOX4 was recently recommended as a clinical practice guideline by the China Food and Drug Administration. All approved systemic therapies remain unsatisfactory, with limited objective response rates and poor overall survival. Immune checkpoint inhibitors (CPIs) offer great promise in the treatment of a rapidly expanding spectrum of solid tumors. Immune checkpoint molecules are involved in almost the whole process of viral-related hepatitis with cirrhosis and HCC and in the most important resistance mechanism of sorafenib. The approval of nivolumab by the U.S. Food and Drug Administration on September 23, 2017, for the treatment of patients with HCC, based only on a phase I/II clinical trial, is a strong hint that immunotherapy will introduce a new era of HCC therapy. CPI-based strategies will soon be a main approach in anticancer treatment for HCC, and we will observe the rapid advances in the therapeutic use of CPIs, even in an adjuvant setting, with great interest. How shall we face the opportunities and challenges? Can we dramatically improve the prognosis of patients with HCC? This review may provide some informed guidance. IMPLICATIONS FOR PRACTICE: Immune checkpoint molecules are involved in almost the whole process of viral-related hepatitis with cirrhosis and hepatocellular carcinoma (HCC) and in the most important resistance mechanism of sorafenib. As all approved systemic therapies in HCC remain unsatisfactory, checkpoint inhibitor (CPI)-based strategies will soon be a main approach in anticancer treatment for advanced stage of HCC, even in an adjuvant setting. In virus-related HCC, especially hepatitis B virus-related HCC, whether CPIs can control virus relapse should be further investigated. Combination strategies involving conventional therapies and immunotherapies are needed to increase clinical benefit and minimize adverse toxicities with regard to the underlying liver disease.

https://pubmed.ncbi.nlm.nih.gov/30819826/

### 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: Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: Opportunities and Challenges. Hepatocellular carcinoma (HCC) is the most common malignancy worldwide, and is especially common in China. A total of 70%-80% of patients are diagnosed at an advanced stage and can receive only palliative care. Sorafenib has been the standard of care for a decade , and promising results for regorafenib as a second-line and lenvatinib as a first-line treatment were reported only 1 or 2 years ago . FOLFOX4 was recently recommended as a clinical practice guideline by the China Food and Drug Administration. All approved systemic therapies remain unsatisfactory, with limited objective response rates and poor overall survival. Immune checkpoint inhibitors (CPIs) offer great promise in the treatment of a rapidly expanding spectrum of solid tumors. Immune checkpoint molecules are involved in almost the whole process of viral-related hepatitis with cirrhosis and HCC and in the most important resistance mechanism of sorafenib. The approval of nivolumab by the U.S. Food and Drug Administration on September 23, 2017, for the treatment of patients with HCC, based only on a phase I/II clinical trial, is a strong hint that immunotherapy will introduce a new era of HCC therapy. CPI-based strategies will soon be a main approach in anticancer treatment for HCC, and we will observe the rapid advances in the therapeutic use of CPIs, even in an adjuvant setting, with great interest. How shall we face the opportunities and challenges? Can we dramatically improve the prognosis of patients with HCC? This review may provide some informed guidance. IMPLICATIONS FOR PRACTICE: Immune checkpoint molecules are involved in almost the whole process of viral-related hepatitis with cirrhosis and hepatocellular carcinoma (HCC) and in the most important resistance mechanism of sorafenib. As all approved systemic therapies in HCC remain unsatisfactory, checkpoint inhibitor (CPI)-based strategies will soon be a main approach in anticancer treatment for advanced stage of HCC, even in an adjuvant setting. In virus-related HCC, especially hepatitis B virus-related HCC, whether CPIs can control virus relapse should be further investigated. Combination strategies involving conventional therapies and immunotherapies are needed to increase clinical benefit and minimize adverse toxicities with regard to the underlying liver disease. ### Response: Sorafenib, regorafenib, lenvatinib

0a7134a3a2612a4d409a7d631f5c6260

The addition of trastuzumab , pertuzumab , bevacizumab , or lapatinib to chemotherapy significantly ( P < .05 ) improved objective response rate ( ORR ) , time to failure ( TTF ) , and overall survival ( OS ) in patients with HER2-positive ( HER2(+ ) ) disease .

Effectiveness of targeted therapy in patients with previously untreated metastatic breast cancer: a systematic review and meta-analysis. Breast cancer is the most common cancer and the most frequent cause of death in women. Targeted therapies offer a possibility of effective and individualized therapy based on the molecular profile of the tumor. The aim of this systematic review was to evaluate the efficacy and safety of targeted agents added to chemotherapy or endocrine therapy in patients with previously untreated metastatic breast cancer (MBC) depending on their human epidermal growth factor receptor 2 (HER2) and hormone receptor (HR) status (positive or negative). The systematic literature search was performed in PubMed, EMBASE, and the Cochrane Library to identify randomized controlled trials (RCTs). Thirteen trials were included. The addition of trastuzumab , pertuzumab , bevacizumab , or lapatinib to chemotherapy significantly ( P < .05 ) improved objective response rate ( ORR ) , time to failure ( TTF ) , and overall survival ( OS ) in patients with HER2-positive ( HER2(+ ) ) disease . trastuzumab or lapatinib combined with endocrine therapy significantly (P < .05) improved ORR, time to progression (TTP), and progression-free survival (PFS) in patients with HER2(+) and HR(+) disease. In patients with HER2-negative (HER2(-)) cancer, bevacizumab or lapatinib added to chemotherapy significantly (P < .05), improved ORR but did not prolong PFS and OS (P > .05). In patients with HER2(-) and HR(-) disease, trastuzumab combined with chemotherapy did not significantly improve (P > .05) ORR or PFS. Targeted therapies also increased the overall risk of adverse events. So far, there is a lack of published results for everolimus and trastuzumab emtansine trials in patients with previously untreated MBC. The addition of targeted therapy to chemotherapy or endocrine therapy using HER2 and HR status significantly improved ORR, PFS, and OS in patients with previously untreated MBC.

https://pubmed.ncbi.nlm.nih.gov/25441421/

### 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: Effectiveness of targeted therapy in patients with previously untreated metastatic breast cancer: a systematic review and meta-analysis. Breast cancer is the most common cancer and the most frequent cause of death in women. Targeted therapies offer a possibility of effective and individualized therapy based on the molecular profile of the tumor. The aim of this systematic review was to evaluate the efficacy and safety of targeted agents added to chemotherapy or endocrine therapy in patients with previously untreated metastatic breast cancer (MBC) depending on their human epidermal growth factor receptor 2 (HER2) and hormone receptor (HR) status (positive or negative). The systematic literature search was performed in PubMed, EMBASE, and the Cochrane Library to identify randomized controlled trials (RCTs). Thirteen trials were included. The addition of trastuzumab , pertuzumab , bevacizumab , or lapatinib to chemotherapy significantly ( P < .05 ) improved objective response rate ( ORR ) , time to failure ( TTF ) , and overall survival ( OS ) in patients with HER2-positive ( HER2(+ ) ) disease . trastuzumab or lapatinib combined with endocrine therapy significantly (P < .05) improved ORR, time to progression (TTP), and progression-free survival (PFS) in patients with HER2(+) and HR(+) disease. In patients with HER2-negative (HER2(-)) cancer, bevacizumab or lapatinib added to chemotherapy significantly (P < .05), improved ORR but did not prolong PFS and OS (P > .05). In patients with HER2(-) and HR(-) disease, trastuzumab combined with chemotherapy did not significantly improve (P > .05) ORR or PFS. Targeted therapies also increased the overall risk of adverse events. So far, there is a lack of published results for everolimus and trastuzumab emtansine trials in patients with previously untreated MBC. The addition of targeted therapy to chemotherapy or endocrine therapy using HER2 and HR status significantly improved ORR, PFS, and OS in patients with previously untreated MBC. ### Response: trastuzumab, pertuzumab, bevacizumab, lapatinib, chemotherapy

ce729f6ebbcf5bb46bb08e16542fd835

The feasibility and efficacy of an intensified procarbazine-free consolidation regimen VECOPA ( vinblastine , etoposide , cyclophosphamide , vincristine , prednisone , doxorubicin ) were investigated .

Feasibility of VECOPA, a dose-intensive chemotherapy regimen for children and adolescents with intermediate and advanced stage Hodgkin lymphoma: results of the GPOH-HD-2002/VECOPA pilot trial. The GPOH-HD (Gesellschaft für Pädiatrische Onkologie und Hämatologie-Hodgkin Disease) strategy for children and adolescents with intermediate and advanced stage Hodgkin lymphoma is based on two induction cycles of OEPA (vincristine, etoposide, prednisone, doxorubicin) followed by COPP (cyclophosphamide, vincristine, procarbazine, prednisone) or COPDAC (cyclophosphamide, vincristine, prednisone, dacarbazine) consolidation. The feasibility and efficacy of an intensified procarbazine-free consolidation regimen VECOPA ( vinblastine , etoposide , cyclophosphamide , vincristine , prednisone , doxorubicin ) were investigated . Following two OEPA and one or two VECOPA cycles, involved field radiotherapy was applied. The main endpoint was feasibility. Secondary endpoints were toxicity, proportion of delayed cycles, granulocyte-colony stimulating factor use, and event-free and overall survival. The regimen was well tolerated with mostly hematotoxicity exceeding Common Toxicity Criteria grade 2. In most patients with advanced stage the second VECOPA cycle was delayed despite hematopoietic recovery and absence of serious adverse events. Event-free survival at 36 months was 0.86 (95% confidence interval 0.70-1). The VECOPA regimen is effective and tolerable. However, its time-intensification was not fully exploited within this trial.

https://pubmed.ncbi.nlm.nih.gov/25204374/

### 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: Feasibility of VECOPA, a dose-intensive chemotherapy regimen for children and adolescents with intermediate and advanced stage Hodgkin lymphoma: results of the GPOH-HD-2002/VECOPA pilot trial. The GPOH-HD (Gesellschaft für Pädiatrische Onkologie und Hämatologie-Hodgkin Disease) strategy for children and adolescents with intermediate and advanced stage Hodgkin lymphoma is based on two induction cycles of OEPA (vincristine, etoposide, prednisone, doxorubicin) followed by COPP (cyclophosphamide, vincristine, procarbazine, prednisone) or COPDAC (cyclophosphamide, vincristine, prednisone, dacarbazine) consolidation. The feasibility and efficacy of an intensified procarbazine-free consolidation regimen VECOPA ( vinblastine , etoposide , cyclophosphamide , vincristine , prednisone , doxorubicin ) were investigated . Following two OEPA and one or two VECOPA cycles, involved field radiotherapy was applied. The main endpoint was feasibility. Secondary endpoints were toxicity, proportion of delayed cycles, granulocyte-colony stimulating factor use, and event-free and overall survival. The regimen was well tolerated with mostly hematotoxicity exceeding Common Toxicity Criteria grade 2. In most patients with advanced stage the second VECOPA cycle was delayed despite hematopoietic recovery and absence of serious adverse events. Event-free survival at 36 months was 0.86 (95% confidence interval 0.70-1). The VECOPA regimen is effective and tolerable. However, its time-intensification was not fully exploited within this trial. ### Response: vinblastine, etoposide, cyclophosphamide, vincristine, prednisone, doxorubicin

447854f1de95488c44ec5e39824f21d7

The combination regimen of nivolumab plus ipilimumab demonstrates activity in metastatic uveal melanoma , with deep and sustained confirmed responses .

Nivolumab and Ipilimumab in Metastatic Uveal Melanoma: Results From a Single-Arm Phase II Study. Metastatic uveal melanoma has poor overall survival (OS) and no approved systemic therapy options. Studies of single-agent immunotherapy regimens have shown minimal benefit. There is the potential for improved responses with the use of combination immunotherapy. ### Patients And Methods We conducted a phase II study of nivolumab with ipilimumab in patients with metastatic uveal melanoma. Any number of prior treatments was permitted. Patients received nivolumab 1 mg/kg and ipilimumab 3 mg/kg for four cycles, followed by nivolumab maintenance therapy for up to 2 years. The primary outcome of the study was overall response rate (ORR) as determined by RECIST 1.1 criteria. Progression-free survival (PFS), OS, and adverse events were also assessed. ### results Thirty-five patients were enrolled, and 33 patients were evaluable for efficacy. The ORR was 18%, including one confirmed complete response and five confirmed partial responses. The median PFS was 5.5 months (95% CI, 3.4 to 9.5 months), and the median OS was 19.1 months (95% CI, 9.6 months to NR). Forty percent of patients experienced a grade 3-4 treatment-related adverse event. ### conclusion The combination regimen of nivolumab plus ipilimumab demonstrates activity in metastatic uveal melanoma , with deep and sustained confirmed responses .

https://pubmed.ncbi.nlm.nih.gov/33125309/

### 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: Nivolumab and Ipilimumab in Metastatic Uveal Melanoma: Results From a Single-Arm Phase II Study. Metastatic uveal melanoma has poor overall survival (OS) and no approved systemic therapy options. Studies of single-agent immunotherapy regimens have shown minimal benefit. There is the potential for improved responses with the use of combination immunotherapy. ### Patients And Methods We conducted a phase II study of nivolumab with ipilimumab in patients with metastatic uveal melanoma. Any number of prior treatments was permitted. Patients received nivolumab 1 mg/kg and ipilimumab 3 mg/kg for four cycles, followed by nivolumab maintenance therapy for up to 2 years. The primary outcome of the study was overall response rate (ORR) as determined by RECIST 1.1 criteria. Progression-free survival (PFS), OS, and adverse events were also assessed. ### results Thirty-five patients were enrolled, and 33 patients were evaluable for efficacy. The ORR was 18%, including one confirmed complete response and five confirmed partial responses. The median PFS was 5.5 months (95% CI, 3.4 to 9.5 months), and the median OS was 19.1 months (95% CI, 9.6 months to NR). Forty percent of patients experienced a grade 3-4 treatment-related adverse event. ### conclusion The combination regimen of nivolumab plus ipilimumab demonstrates activity in metastatic uveal melanoma , with deep and sustained confirmed responses . ### Response: nivolumab, ipilimumab

3727a540ed60fbcbe84867b9a216d7f7

The FDA reviewed data in electronic format from a randomized controlled clinical trial of 1106 adult patients with newly diagnosed Philadelphia chromosome-positive CML in chronic phase , comparing imatinib with the combination of IFN-alpha and cytarabine .

Approval summary: imatinib mesylate capsules for treatment of adult patients with newly diagnosed philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase. The purpose is to describe the Food and Drug Administration (FDA) review and approval of imatinib (Gleevec; Novartis Pharmaceuticals, East Hanover, NJ) for treatment of adult patients with newly diagnosed Philadelphia chromosome-positive chronic myelogenous leukemia (CML) in chronic phase. ### Experimental Design The FDA reviewed data in electronic format from a randomized controlled clinical trial of 1106 adult patients with newly diagnosed Philadelphia chromosome-positive CML in chronic phase , comparing imatinib with the combination of IFN-alpha and cytarabine . ### results imatinib showed clinically and statistically significantly better results for time-to-progression to accelerated phase or blast crisis, progression-free survival, complete hematological response rate, and cytogenetic response rate. With a median follow-up of 14 months, a maximum follow-up of 19.5 months, and an expected median survival of 5-6 years on the IFN-alpha/cytarabine control arm, few of the expected progressions to accelerated or blast phase or deaths have occurred. imatinib was also better tolerated. Edema, nausea, rigors, neutropenia, and headache were more frequent in women. Only 57% of the IFN-alpha target dose was administered, and only 68% of patients received any cytarabine. However, this does not appear to adequately explain the superiority of imatinib observed in this trial. Results of a population pharmacokinetic study in a subgroup of 371 patients and a separate rifampin-imatinib drug-drug interaction study in healthy volunteers are presented. ### conclusions On December 20, 2002, imatinib was granted accelerated approval under subpart H, rather than regular approval. Follow-up is short compared with the natural history of chronic phase CML or more mature results with established therapies such as IFN-alpha or transplantation. If imatinib should stop working after 1.5-2 years, the results could be importantly different from the present analysis. As a Phase IV postmarketing commitment, the applicant has agreed to provide follow-up reports on this imatinib study annually for the next 6 years.

https://pubmed.ncbi.nlm.nih.gov/12796358/

### 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: Approval summary: imatinib mesylate capsules for treatment of adult patients with newly diagnosed philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase. The purpose is to describe the Food and Drug Administration (FDA) review and approval of imatinib (Gleevec; Novartis Pharmaceuticals, East Hanover, NJ) for treatment of adult patients with newly diagnosed Philadelphia chromosome-positive chronic myelogenous leukemia (CML) in chronic phase. ### Experimental Design The FDA reviewed data in electronic format from a randomized controlled clinical trial of 1106 adult patients with newly diagnosed Philadelphia chromosome-positive CML in chronic phase , comparing imatinib with the combination of IFN-alpha and cytarabine . ### results imatinib showed clinically and statistically significantly better results for time-to-progression to accelerated phase or blast crisis, progression-free survival, complete hematological response rate, and cytogenetic response rate. With a median follow-up of 14 months, a maximum follow-up of 19.5 months, and an expected median survival of 5-6 years on the IFN-alpha/cytarabine control arm, few of the expected progressions to accelerated or blast phase or deaths have occurred. imatinib was also better tolerated. Edema, nausea, rigors, neutropenia, and headache were more frequent in women. Only 57% of the IFN-alpha target dose was administered, and only 68% of patients received any cytarabine. However, this does not appear to adequately explain the superiority of imatinib observed in this trial. Results of a population pharmacokinetic study in a subgroup of 371 patients and a separate rifampin-imatinib drug-drug interaction study in healthy volunteers are presented. ### conclusions On December 20, 2002, imatinib was granted accelerated approval under subpart H, rather than regular approval. Follow-up is short compared with the natural history of chronic phase CML or more mature results with established therapies such as IFN-alpha or transplantation. If imatinib should stop working after 1.5-2 years, the results could be importantly different from the present analysis. As a Phase IV postmarketing commitment, the applicant has agreed to provide follow-up reports on this imatinib study annually for the next 6 years. ### Response: imatinib, cytarabine, IFN-alpha

cd89968df90b1bb4fb356d8c717e3738

A total of 164 patients with recurrent ovarian cancer were selected and randomly divided into two groups : experimental group ( n=82 , BEV + paclitaxel + carboplatin ) and control group ( n=82 , paclitaxel + carboplatin ) .

Therapeutic effect of bevacizumab combined with paclitaxel and carboplatin on recurrent ovarian cancer. To observe the clinical efficacy and safety of bevacizumab (BEV) combined with paclitaxel on recurrent ovarian cancer. ### methods A total of 164 patients with recurrent ovarian cancer were selected and randomly divided into two groups : experimental group ( n=82 , BEV + paclitaxel + carboplatin ) and control group ( n=82 , paclitaxel + carboplatin ) . The clinical therapeutic effects including objective response rate (ORR), complete response (CR) rate, partial response (PR) rate, stable disease (SD), progressive disease (PD), progression free survival (PFS) and overall survival (OS) were evaluated, together with the adverse clinical reactions and improvement of quality of life (QoL). Immunohistochemistry was used to detect the expression of phosphate and tension homology deleted on chromosome ten (PTEN). ### results The PFS, OS and ORR of patients in the experimental group were significantly higher than those in the control group (p<0.05). In addition, the incidence rates of allergy, gastrointestinal reactions and leukopenia were significantly lower in the experimental group compared with those in the control group (p<0.05). There was no significant difference in QoL score between the two groups before treatment (p>0.05). However, after treatment, the QoL score in the experimental group was increased significantly compared with the control group (p<0.05). Moreover, the expression of PTEN in PR, SD and PD patients was lower, with significant difference between the two groups (p<0.05). ### conclusion The clinical therapeutic effect of BEV combined with paclitaxel in patients with recurrent ovarian cancer was improved, suggesting it might be beneficial for the treatment of ovarian cancer.

https://pubmed.ncbi.nlm.nih.gov/31424654/

### 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: Therapeutic effect of bevacizumab combined with paclitaxel and carboplatin on recurrent ovarian cancer. To observe the clinical efficacy and safety of bevacizumab (BEV) combined with paclitaxel on recurrent ovarian cancer. ### methods A total of 164 patients with recurrent ovarian cancer were selected and randomly divided into two groups : experimental group ( n=82 , BEV + paclitaxel + carboplatin ) and control group ( n=82 , paclitaxel + carboplatin ) . The clinical therapeutic effects including objective response rate (ORR), complete response (CR) rate, partial response (PR) rate, stable disease (SD), progressive disease (PD), progression free survival (PFS) and overall survival (OS) were evaluated, together with the adverse clinical reactions and improvement of quality of life (QoL). Immunohistochemistry was used to detect the expression of phosphate and tension homology deleted on chromosome ten (PTEN). ### results The PFS, OS and ORR of patients in the experimental group were significantly higher than those in the control group (p<0.05). In addition, the incidence rates of allergy, gastrointestinal reactions and leukopenia were significantly lower in the experimental group compared with those in the control group (p<0.05). There was no significant difference in QoL score between the two groups before treatment (p>0.05). However, after treatment, the QoL score in the experimental group was increased significantly compared with the control group (p<0.05). Moreover, the expression of PTEN in PR, SD and PD patients was lower, with significant difference between the two groups (p<0.05). ### conclusion The clinical therapeutic effect of BEV combined with paclitaxel in patients with recurrent ovarian cancer was improved, suggesting it might be beneficial for the treatment of ovarian cancer. ### Response: paclitaxel, carboplatin, paclitaxel, carboplatin, BEV

bd252f7e7872efdd84ff4314959d2793

Successful treatment of an adult with Kasabach-Merritt syndrome using thalidomide , vincristine , and prednisone .

Successful treatment of an adult with Kasabach-Merritt syndrome using thalidomide , vincristine , and prednisone . Kasabach-Merritt syndrome is a rare disease that mainly occurs in infants and adolescents. It usually manifests as disseminated intravascular coagulation and severe bleeding, and is associated with high mortality. However, its low incidence and clinical rarity in adults mean that there is currently no well-verified treatment regimen for this disease. We report on an effective novel therapeutic regimen in a patient with Kasabach-Merritt syndrome. ### methods A woman with Kasabach-Merritt syndrome presented with a recurrent subcutaneous mass and disseminated intravascular coagulation, and was treated with prednisone, vincristine and thalidomide. ### results This treatment regimen successfully resolved the patient's symptoms, with tumor regression. The patient remained disease-free after 6 years of follow-up. ### conclusions prednisone combined with vincristine and thalidomide may be an effective treatment for Kasabach-Merritt syndrome, but further studies are needed to verify the use of this regimen.

https://pubmed.ncbi.nlm.nih.gov/30806107/

### 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: Successful treatment of an adult with Kasabach-Merritt syndrome using thalidomide , vincristine , and prednisone . Kasabach-Merritt syndrome is a rare disease that mainly occurs in infants and adolescents. It usually manifests as disseminated intravascular coagulation and severe bleeding, and is associated with high mortality. However, its low incidence and clinical rarity in adults mean that there is currently no well-verified treatment regimen for this disease. We report on an effective novel therapeutic regimen in a patient with Kasabach-Merritt syndrome. ### methods A woman with Kasabach-Merritt syndrome presented with a recurrent subcutaneous mass and disseminated intravascular coagulation, and was treated with prednisone, vincristine and thalidomide. ### results This treatment regimen successfully resolved the patient's symptoms, with tumor regression. The patient remained disease-free after 6 years of follow-up. ### conclusions prednisone combined with vincristine and thalidomide may be an effective treatment for Kasabach-Merritt syndrome, but further studies are needed to verify the use of this regimen. ### Response: thalidomide, vincristine, prednisone

b8ca06ae2a24839388168c966f0eaed6

Superiority of sirolimus ( rapamycin ) over cyclosporine in augmenting allograft and xenograft survival in mice treated with antilymphocyte serum and donor-specific bone marrow .

Superiority of sirolimus ( rapamycin ) over cyclosporine in augmenting allograft and xenograft survival in mice treated with antilymphocyte serum and donor-specific bone marrow . sirolimus is a potent immunosuppressive agent with great therapeutic potential. The objective of our study was to evaluate the efficacy of sirolimus versus cyclosporine in augmenting the unresponsiveness induced by an antilymphocyte serum (ALS)/donor-specific bone marrow (BM)-based regimen across three levels of histoincompatibility: class I and II disparate (DBA/2 to B6AF1), complete mismatch (AKR to C57BL/6), and xenograft (ACI rat to B6AF1). ### methods Full-thickness skin grafts were taken from donors and placed on recipients in standard fashion. Seven groups of recipient mice (n=10-28) received various combinations of the following treatment protocols: sirolimus, 1.5 mg/kg (3.0 mg/kg for xenografts) every other day from day 0 to day 12; cyclosporine, 50 mg/kg every other day from day 10 through 22; ALS, 0.5 ml on days -1 and 2 for allografts and days -1, 2, and 4 for xenografts; and BM, 25 million donor-specific cells IV on day 7. ### results The administration of ALS or ALS/BM resulted in modest but significant prolongation of skin graft survival in all combinations tested. cyclosporine combined with ALS or ALS/BM significantly extended allograft survival compared with ALS or ALS/BM alone (P<0.05) but had no effect on xenograft survival. In contrast, the combination of sirolimus with ALS or ALS/BM resulted in a two- to threefold increase in allograft survival and over a fourfold increase in xenograft survival when compared with the comparable cyclosporine-based regimen. Additionally, lymphocytes isolated from class I and II incompatible mice with skin grafts surviving >100 days demonstrated markedly reduced interleukin 2 and interferon-gamma secretion in response to irradiated donor-specific lymphocytes in culture. ### conclusions In the regimens tested, sirolimus was superior to cyclosporine in augmenting donor BM-induced skin graft prolongation in ALS-treated mice across all levels of histoincompatibility.

https://pubmed.ncbi.nlm.nih.gov/9039923/

### 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: Superiority of sirolimus ( rapamycin ) over cyclosporine in augmenting allograft and xenograft survival in mice treated with antilymphocyte serum and donor-specific bone marrow . sirolimus is a potent immunosuppressive agent with great therapeutic potential. The objective of our study was to evaluate the efficacy of sirolimus versus cyclosporine in augmenting the unresponsiveness induced by an antilymphocyte serum (ALS)/donor-specific bone marrow (BM)-based regimen across three levels of histoincompatibility: class I and II disparate (DBA/2 to B6AF1), complete mismatch (AKR to C57BL/6), and xenograft (ACI rat to B6AF1). ### methods Full-thickness skin grafts were taken from donors and placed on recipients in standard fashion. Seven groups of recipient mice (n=10-28) received various combinations of the following treatment protocols: sirolimus, 1.5 mg/kg (3.0 mg/kg for xenografts) every other day from day 0 to day 12; cyclosporine, 50 mg/kg every other day from day 10 through 22; ALS, 0.5 ml on days -1 and 2 for allografts and days -1, 2, and 4 for xenografts; and BM, 25 million donor-specific cells IV on day 7. ### results The administration of ALS or ALS/BM resulted in modest but significant prolongation of skin graft survival in all combinations tested. cyclosporine combined with ALS or ALS/BM significantly extended allograft survival compared with ALS or ALS/BM alone (P<0.05) but had no effect on xenograft survival. In contrast, the combination of sirolimus with ALS or ALS/BM resulted in a two- to threefold increase in allograft survival and over a fourfold increase in xenograft survival when compared with the comparable cyclosporine-based regimen. Additionally, lymphocytes isolated from class I and II incompatible mice with skin grafts surviving >100 days demonstrated markedly reduced interleukin 2 and interferon-gamma secretion in response to irradiated donor-specific lymphocytes in culture. ### conclusions In the regimens tested, sirolimus was superior to cyclosporine in augmenting donor BM-induced skin graft prolongation in ALS-treated mice across all levels of histoincompatibility. ### Response: sirolimus, rapamycin, cyclosporine

ee9b23ccfb165468071d9c7bcef4f590

Profiling of drug-metabolizing enzymes/transporters in CD33 + acute myeloid leukemia patients treated with Gemtuzumab-Ozogamicin and Fludarabine , Cytarabine and Idarubicin .

Profiling of drug-metabolizing enzymes/transporters in CD33 + acute myeloid leukemia patients treated with Gemtuzumab-Ozogamicin and Fludarabine , Cytarabine and Idarubicin . Genetic heterogeneity in drug-metabolizing enzyme/transporter (DMET) genes affects specific drug-related cancer phenotypes. To investigate the relationships between genetic variation and response to treatment in acute myeloid leukemia (AML), we genotyped 1931 variants on DMET genes in 94 CD33-positive AML patients enrolled in a phase III multicenter clinical trial combining Gemtuzumab-ozogamicin (GO) with fludarabine-cytarabine-idarubicin (FLAI) regimen, with the DMET Plus platform. Two ADH1A variants showed statistically significant differences (odds ratio (OR)=5.68, P=0.0006; OR=5.35, P=0.0009) in allele frequencies between patients in complete/partial remission and patients without response, two substitutions on CYP2E1 (OR=0.13, P=0.001; OR=0.09, P=0.003) and one on SLCO1B1 (OR=4.68, P=0.002) were found to differently influence liver toxicity, and two nucleotide changes on SULTB1 and SLC22A12 genes correlated with response to GO (OR=0.24, P=0.0009; OR=2.75, P=0.0029). Genetic variants were thus found for the first time to be potentially associated with differential response and toxicity in AML patients treated with a combination of GO-FLAI regimen.

https://pubmed.ncbi.nlm.nih.gov/22584460/

### 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: Profiling of drug-metabolizing enzymes/transporters in CD33 + acute myeloid leukemia patients treated with Gemtuzumab-Ozogamicin and Fludarabine , Cytarabine and Idarubicin . Genetic heterogeneity in drug-metabolizing enzyme/transporter (DMET) genes affects specific drug-related cancer phenotypes. To investigate the relationships between genetic variation and response to treatment in acute myeloid leukemia (AML), we genotyped 1931 variants on DMET genes in 94 CD33-positive AML patients enrolled in a phase III multicenter clinical trial combining Gemtuzumab-ozogamicin (GO) with fludarabine-cytarabine-idarubicin (FLAI) regimen, with the DMET Plus platform. Two ADH1A variants showed statistically significant differences (odds ratio (OR)=5.68, P=0.0006; OR=5.35, P=0.0009) in allele frequencies between patients in complete/partial remission and patients without response, two substitutions on CYP2E1 (OR=0.13, P=0.001; OR=0.09, P=0.003) and one on SLCO1B1 (OR=4.68, P=0.002) were found to differently influence liver toxicity, and two nucleotide changes on SULTB1 and SLC22A12 genes correlated with response to GO (OR=0.24, P=0.0009; OR=2.75, P=0.0029). Genetic variants were thus found for the first time to be potentially associated with differential response and toxicity in AML patients treated with a combination of GO-FLAI regimen. ### Response: Fludarabine, Cytarabine, Idarubicin, Gemtuzumab-Ozogamicin

178e161c0e0960a219110932d3746c09

In addition , anti-PCSK9 drugs ( evolocumab and alirocumab ) provide an effective solution for patients with familial hypercholesterolemia ( FH ) and statin intolerance at very high cardiovascular risk .

Treatment Strategy for Dyslipidemia in Cardiovascular Disease Prevention: Focus on Old and New Drugs. Prevention and treatment of dyslipidemia should be considered as an integral part of individual cardiovascular prevention interventions, which should be addressed primarily to those at higher risk who benefit most. To date, statins remain the first-choice therapy, as they have been shown to reduce the risk of major vascular events by lowering low-density lipoprotein cholesterol (LDL-C). However, due to adherence to statin therapy or statin resistance, many patients do not reach LDL-C target levels. ezetimibe, fibrates, and nicotinic acid represent the second-choice drugs to be used in combination with statins if lipid targets cannot be reached. In addition , anti-PCSK9 drugs ( evolocumab and alirocumab ) provide an effective solution for patients with familial hypercholesterolemia ( FH ) and statin intolerance at very high cardiovascular risk . Recently, studies demonstrated the effects of two novel lipid-lowering agents (lomitapide and mipomersen) for the management of homozygous FH by decreasing LDL-C values and reducing cardiovascular events. However, the costs for these new therapies made the cost-effectiveness debate more complicated.

https://pubmed.ncbi.nlm.nih.gov/29361723/

### 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: Treatment Strategy for Dyslipidemia in Cardiovascular Disease Prevention: Focus on Old and New Drugs. Prevention and treatment of dyslipidemia should be considered as an integral part of individual cardiovascular prevention interventions, which should be addressed primarily to those at higher risk who benefit most. To date, statins remain the first-choice therapy, as they have been shown to reduce the risk of major vascular events by lowering low-density lipoprotein cholesterol (LDL-C). However, due to adherence to statin therapy or statin resistance, many patients do not reach LDL-C target levels. ezetimibe, fibrates, and nicotinic acid represent the second-choice drugs to be used in combination with statins if lipid targets cannot be reached. In addition , anti-PCSK9 drugs ( evolocumab and alirocumab ) provide an effective solution for patients with familial hypercholesterolemia ( FH ) and statin intolerance at very high cardiovascular risk . Recently, studies demonstrated the effects of two novel lipid-lowering agents (lomitapide and mipomersen) for the management of homozygous FH by decreasing LDL-C values and reducing cardiovascular events. However, the costs for these new therapies made the cost-effectiveness debate more complicated. ### Response: evolocumab, alirocumab

c13dbaaf1d499d927f9739805788022f

Likewise , emotional , functional well-being , and QoL aspects specifically related to lung cancer were better improved in the Gefitinib group than in the Pemetrexed group ( P<0.05 ) .

[A randomized clinical study of Gefitinib and pemetrexed as second line therapy for advanced non-squamous non-small cell lung cancer]. gefitinib and pemetrexed are drugs used as second-line therapy for advanced non-small cell lung cancer (NSCLC), although studies comparing the two drugs are limited. The aim of this study is to explore the effects, safety, and quality of life (QoL) of gefitinib and pemetrexed on patients with advanced non-squamous NSCLC. ### methods Forty-six advanced non-squamous NSCLC patients who failed to first-line therapy were randomly divided into two groups with 23 patients each, one using oral gefitinib (gefitinib group) and the other using intravenous injection pemetrexed (pemetrexed group). The effects, safety, and QoL were determined and analyzed. ### results For the pemetrexed group, objective response rate (ORR) was 13.0% (3/23), disease control rate (DCR) was 30.4% (7/23), and median progression-free survival (mPFS) was 3.1 months. In the gefitinib group, ORR was 17.3% (4/23), DCR was 39.1% (9/23), and mPFS was 4.4 months. Compared with the pemetrexed group, the ORR, DCR, and mPFS in the gefitinib group exhibited no statistical significance (P>0.05). Furthermore, the most common toxicities in the pemetrexed group were neutropenia (n=9, 39.13%) and fatigue (n=8, 34.78%), whereas those in the in gefitinib group were skin rash (n=8, 34.78%) and diarrhea (n=4, 17.39%). Compared with baseline, the QoL improved in both groups but to different degrees. Likewise , emotional , functional well-being , and QoL aspects specifically related to lung cancer were better improved in the Gefitinib group than in the Pemetrexed group ( P<0.05 ) . ### conclusions The effects of pemetrexed and gefitinib as second line therapy were similar, although with different AEs. Both drugs could improve the QoL, but gefitinib showed better overall results than pemetrexed.

https://pubmed.ncbi.nlm.nih.gov/23945243/

### 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 randomized clinical study of Gefitinib and pemetrexed as second line therapy for advanced non-squamous non-small cell lung cancer]. gefitinib and pemetrexed are drugs used as second-line therapy for advanced non-small cell lung cancer (NSCLC), although studies comparing the two drugs are limited. The aim of this study is to explore the effects, safety, and quality of life (QoL) of gefitinib and pemetrexed on patients with advanced non-squamous NSCLC. ### methods Forty-six advanced non-squamous NSCLC patients who failed to first-line therapy were randomly divided into two groups with 23 patients each, one using oral gefitinib (gefitinib group) and the other using intravenous injection pemetrexed (pemetrexed group). The effects, safety, and QoL were determined and analyzed. ### results For the pemetrexed group, objective response rate (ORR) was 13.0% (3/23), disease control rate (DCR) was 30.4% (7/23), and median progression-free survival (mPFS) was 3.1 months. In the gefitinib group, ORR was 17.3% (4/23), DCR was 39.1% (9/23), and mPFS was 4.4 months. Compared with the pemetrexed group, the ORR, DCR, and mPFS in the gefitinib group exhibited no statistical significance (P>0.05). Furthermore, the most common toxicities in the pemetrexed group were neutropenia (n=9, 39.13%) and fatigue (n=8, 34.78%), whereas those in the in gefitinib group were skin rash (n=8, 34.78%) and diarrhea (n=4, 17.39%). Compared with baseline, the QoL improved in both groups but to different degrees. Likewise , emotional , functional well-being , and QoL aspects specifically related to lung cancer were better improved in the Gefitinib group than in the Pemetrexed group ( P<0.05 ) . ### conclusions The effects of pemetrexed and gefitinib as second line therapy were similar, although with different AEs. Both drugs could improve the QoL, but gefitinib showed better overall results than pemetrexed. ### Response: Gefitinib, Pemetrexed

08fdd1d12a13087c9d06f4b30fd12542

To determine efficacy and safety of the association of IL-1 receptor antagonist anakinra plus methylprednisolone in severe COVID-19 pneumonia with hyperinflammation .

Anakinra combined with methylprednisolone in patients with severe COVID-19 pneumonia and hyperinflammation: an observational cohort study. Immunomodulants have been proposed to mitigate SARS-Cov-2-induced cytokine storm, which drives acute respiratory distress syndrome in COVID-19. ### objective To determine efficacy and safety of the association of IL-1 receptor antagonist anakinra plus methylprednisolone in severe COVID-19 pneumonia with hyperinflammation . ### methods Secondary analysis of prospective observational cohort studies at an Italian tertiary health-care facility. COVID-19 patients consecutively hospitalized (02/25/2020 to 03/30/2020), with hyperinflammation (ferritin ≥1000ng/mL and/or C-reactive protein >10mg/dL) and respiratory failure (oxygen therapy from 0.4 FiO2 Venturi mask to invasive mechanical ventilation) were evaluated to investigate the effect of high-dose anakinra plus methylprednisolone on survival. Patients were followed from study inclusion to day 28 or death. Crude and adjusted (sex, age, baseline PaO ### results 120 COVID-19 patients with hyperinflammation (median age 62 years, 80.0% males, median PaO ### conclusions Treatment with anakinra plus methylprednisolone may be a valid therapeutic option in COVID-19 patients with hyperinflammation and respiratory failure, also on mechanical ventilation. Randomized, controlled trials including use of either agent alone are needed to confirm these results.

https://pubmed.ncbi.nlm.nih.gov/33220354/

### 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: Anakinra combined with methylprednisolone in patients with severe COVID-19 pneumonia and hyperinflammation: an observational cohort study. Immunomodulants have been proposed to mitigate SARS-Cov-2-induced cytokine storm, which drives acute respiratory distress syndrome in COVID-19. ### objective To determine efficacy and safety of the association of IL-1 receptor antagonist anakinra plus methylprednisolone in severe COVID-19 pneumonia with hyperinflammation . ### methods Secondary analysis of prospective observational cohort studies at an Italian tertiary health-care facility. COVID-19 patients consecutively hospitalized (02/25/2020 to 03/30/2020), with hyperinflammation (ferritin ≥1000ng/mL and/or C-reactive protein >10mg/dL) and respiratory failure (oxygen therapy from 0.4 FiO2 Venturi mask to invasive mechanical ventilation) were evaluated to investigate the effect of high-dose anakinra plus methylprednisolone on survival. Patients were followed from study inclusion to day 28 or death. Crude and adjusted (sex, age, baseline PaO ### results 120 COVID-19 patients with hyperinflammation (median age 62 years, 80.0% males, median PaO ### conclusions Treatment with anakinra plus methylprednisolone may be a valid therapeutic option in COVID-19 patients with hyperinflammation and respiratory failure, also on mechanical ventilation. Randomized, controlled trials including use of either agent alone are needed to confirm these results. ### Response: anakinra, methylprednisolone

183c151df65c06b02c251456be7381a0

When rats were given Li for 3 days , followed by a single injection of imipramine , the concentrations of desipramine in the brain and serum were higher than those in the vehicle-treated rat , although the imipramine concentrations in both tissues did not differ in Li- and in vehicle-treated rats .

Effects of lithium on alterations of pharmacokinetics of imipramine and on the related changes of monoamines in rat brain. Rats were given chronically i.p. imipramine (20 mg/kg), LiCl (1 mg/kg) or both drugs to examine the effects of lithium (Li) on the alterations of imipramine pharmacokinetics in the whole brain and on the imipramine-related changes of norepinephrine (NE) and serotonin (5-HT) levels in the brain. When rats were given Li for 3 days , followed by a single injection of imipramine , the concentrations of desipramine in the brain and serum were higher than those in the vehicle-treated rat , although the imipramine concentrations in both tissues did not differ in Li- and in vehicle-treated rats . In rats receiving both drugs for 10 days, the steady state levels of imipramine and desipramine in the brain were the same as those in the vehicle-treated rats but the steady state level of desipramine was reached earlier with Li treatments presumably because of the enhanced demethylation of imipramine. Consequently, the desipramine-dependent alterations of NE and 3-methoxy-4-hydroxyphenylglycol levels in the brain appeared to be induced earlier and more markedly when Li was given simultaneously. As the 5-hydroxyindole acetic acid (5-HIAA) levels were elevated in the brains of Li-treated rats and reduced in brains of imipramine-treated rats as compared with the level in vehicle-treated rats, the 5-HIAA level in rats receiving both drugs was equivalent to that in vehicle-treated rats.

https://pubmed.ncbi.nlm.nih.gov/2625134/

### 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: Effects of lithium on alterations of pharmacokinetics of imipramine and on the related changes of monoamines in rat brain. Rats were given chronically i.p. imipramine (20 mg/kg), LiCl (1 mg/kg) or both drugs to examine the effects of lithium (Li) on the alterations of imipramine pharmacokinetics in the whole brain and on the imipramine-related changes of norepinephrine (NE) and serotonin (5-HT) levels in the brain. When rats were given Li for 3 days , followed by a single injection of imipramine , the concentrations of desipramine in the brain and serum were higher than those in the vehicle-treated rat , although the imipramine concentrations in both tissues did not differ in Li- and in vehicle-treated rats . In rats receiving both drugs for 10 days, the steady state levels of imipramine and desipramine in the brain were the same as those in the vehicle-treated rats but the steady state level of desipramine was reached earlier with Li treatments presumably because of the enhanced demethylation of imipramine. Consequently, the desipramine-dependent alterations of NE and 3-methoxy-4-hydroxyphenylglycol levels in the brain appeared to be induced earlier and more markedly when Li was given simultaneously. As the 5-hydroxyindole acetic acid (5-HIAA) levels were elevated in the brains of Li-treated rats and reduced in brains of imipramine-treated rats as compared with the level in vehicle-treated rats, the 5-HIAA level in rats receiving both drugs was equivalent to that in vehicle-treated rats. ### Response: Li, imipramine, desipramine, imipramine

92082bec5072473e89c67b616f8a0e15

Using population-based data from the province of Ontario , the benefit of first-line ipilimumab was estimated by comparing outcomes of patients treated with first-line dacarbazine over the period 2007 - 2009 with patients treated over the period 2010 - 2015 with first-line ipilimumab .

A population-based study of the treatment effect of first-line ipilimumab for metastatic or unresectable melanoma. ipilimumab is an anti-CTLA4 monoclonal antibody with demonstrated efficacy for metastatic melanoma in randomized controlled trials, including in the first-line setting. Population-based outcomes directly compared with historic chemotherapy treatment in metastatic or unresectable melanoma are lacking. Using population-based data from the province of Ontario , the benefit of first-line ipilimumab was estimated by comparing outcomes of patients treated with first-line dacarbazine over the period 2007 - 2009 with patients treated over the period 2010 - 2015 with first-line ipilimumab . Cutaneous and noncutaneous cases were included. The administrative data set utilized was high-dimensional; meaning, there was a large number of variables relative to the sample size. To adjust for important confounders among the many available variables, we utilized a double-selection method, a modified machine learning algorithm to extract the important variables that were related to both survival times and treatment usage. Time-dependent treatment modeling was utilized. Among the 2793 melanoma patients receiving palliative treatment (systemic therapy, surgery, or radiation) in Ontario (2007-2015), there were 289 patients treated with first-line ipilimumab (2010-2015) and 175 patients treated with first-line dacarbazine (2007-2009). For first-line ipilimumab, the adjusted hazard ratio compared with dacarbazine for overall survival (OS) was 0.63 (95% confidence interval: 0.47-0.84) with a 1-year survival of 46.5 versus 18.9% with dacarbazine. In subgroup analysis, ipilimumab was associated with improved OS across groups (age, sex, comorbidity, income quintile, previous interferon). First-line ipilimumab was found to have a significant OS benefit compared with historical controls in a population including those patients not routinely included in clinical trials. The treatment effect was similar to randomized controlled trials, suggesting a meaningful benefit when utilized in a population-based setting.

https://pubmed.ncbi.nlm.nih.gov/30789386/

### 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 population-based study of the treatment effect of first-line ipilimumab for metastatic or unresectable melanoma. ipilimumab is an anti-CTLA4 monoclonal antibody with demonstrated efficacy for metastatic melanoma in randomized controlled trials, including in the first-line setting. Population-based outcomes directly compared with historic chemotherapy treatment in metastatic or unresectable melanoma are lacking. Using population-based data from the province of Ontario , the benefit of first-line ipilimumab was estimated by comparing outcomes of patients treated with first-line dacarbazine over the period 2007 - 2009 with patients treated over the period 2010 - 2015 with first-line ipilimumab . Cutaneous and noncutaneous cases were included. The administrative data set utilized was high-dimensional; meaning, there was a large number of variables relative to the sample size. To adjust for important confounders among the many available variables, we utilized a double-selection method, a modified machine learning algorithm to extract the important variables that were related to both survival times and treatment usage. Time-dependent treatment modeling was utilized. Among the 2793 melanoma patients receiving palliative treatment (systemic therapy, surgery, or radiation) in Ontario (2007-2015), there were 289 patients treated with first-line ipilimumab (2010-2015) and 175 patients treated with first-line dacarbazine (2007-2009). For first-line ipilimumab, the adjusted hazard ratio compared with dacarbazine for overall survival (OS) was 0.63 (95% confidence interval: 0.47-0.84) with a 1-year survival of 46.5 versus 18.9% with dacarbazine. In subgroup analysis, ipilimumab was associated with improved OS across groups (age, sex, comorbidity, income quintile, previous interferon). First-line ipilimumab was found to have a significant OS benefit compared with historical controls in a population including those patients not routinely included in clinical trials. The treatment effect was similar to randomized controlled trials, suggesting a meaningful benefit when utilized in a population-based setting. ### Response: ipilimumab, dacarbazine, ipilimumab

383db1cc0a36e83b809ae71e8657387a

In the present study the combination of tamoxifen and bromocriptine was tried for the suppression of prolactin in prolactin secreting adenomas which were resistant to suppression with bromoergocriptine alone .

[Bromocriptine and tamoxifen--a new therapeutic approach in suppression-resistant prolactin-secreting adenomas]. In the present study the combination of tamoxifen and bromocriptine was tried for the suppression of prolactin in prolactin secreting adenomas which were resistant to suppression with bromoergocriptine alone . 10 women under treatment with 2.5-10 mg of parlodel (bromocriptine) for pituitary tumours of various sizes were additionally treated with tamoxifen 10-20 mg. (nolvadex) daily. Two patients had a previous incomplete resection for chromophobe adenomas. The other patients refused operation. Two women were also studied who did not tolerate a bromoergocriptine therapy because of side effects. In 6 of the 10 women with combination treatment a satisfactory suppression of the prolactin was observed. Four women were cleared of their amenorrhoea and galactorrhoea. One woman conceived. One woman lost her frigidity. Three women, among those the two with severe side effects from bromoergocriptine, tolerated the combined treatment well. Four women showed no success with the combined treatment. The effectiveness of the combined treatment was not correlated with the size of the tumour nor the clinical or biochemical baseline. The results lead to the conclusion that tamoxifen is capable of improving the suppression of prolactin or render the adenomas suppressible in a large number of cases.

https://pubmed.ncbi.nlm.nih.gov/6924910/

### 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: [Bromocriptine and tamoxifen--a new therapeutic approach in suppression-resistant prolactin-secreting adenomas]. In the present study the combination of tamoxifen and bromocriptine was tried for the suppression of prolactin in prolactin secreting adenomas which were resistant to suppression with bromoergocriptine alone . 10 women under treatment with 2.5-10 mg of parlodel (bromocriptine) for pituitary tumours of various sizes were additionally treated with tamoxifen 10-20 mg. (nolvadex) daily. Two patients had a previous incomplete resection for chromophobe adenomas. The other patients refused operation. Two women were also studied who did not tolerate a bromoergocriptine therapy because of side effects. In 6 of the 10 women with combination treatment a satisfactory suppression of the prolactin was observed. Four women were cleared of their amenorrhoea and galactorrhoea. One woman conceived. One woman lost her frigidity. Three women, among those the two with severe side effects from bromoergocriptine, tolerated the combined treatment well. Four women showed no success with the combined treatment. The effectiveness of the combined treatment was not correlated with the size of the tumour nor the clinical or biochemical baseline. The results lead to the conclusion that tamoxifen is capable of improving the suppression of prolactin or render the adenomas suppressible in a large number of cases. ### Response: tamoxifen, bromocriptine

84d5a3309ee9e753c55c12b8ae228c9c

The present case suggests that combination therapy with thalidomide and dexamethasone is still an alternative treatment regimen for resistant extramedullary plasmacytoma with a plasmablastic morphology .

Refractory plasmablastic type myeloma with multiple extramedullary plasmacytomas and massive myelomatous effusion: remarkable response with a combination of thalidomide and dexamethasone. A 74-year-old man with multiple myeloma was refractory to melphalan/prednisolone (MP), high-dose dexamethasone and VAD chemotherapy. He had the following poor prognostic factors: 1) multiple extramedullary plasmacytomas, 2) massive myelomatous effusion, 3) increasing immature myeloma cells with plasmablastic morphology, and 4) predominance of MPC1-CD49e-CD45+ phenotype immature myeloma cells. Combination therapy with thalidomide and dexamethasone resulted in a rapid response and a partial remission despite his multiple poor prognostic factors. The present case suggests that combination therapy with thalidomide and dexamethasone is still an alternative treatment regimen for resistant extramedullary plasmacytoma with a plasmablastic morphology .

https://pubmed.ncbi.nlm.nih.gov/19834276/

### 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: Refractory plasmablastic type myeloma with multiple extramedullary plasmacytomas and massive myelomatous effusion: remarkable response with a combination of thalidomide and dexamethasone. A 74-year-old man with multiple myeloma was refractory to melphalan/prednisolone (MP), high-dose dexamethasone and VAD chemotherapy. He had the following poor prognostic factors: 1) multiple extramedullary plasmacytomas, 2) massive myelomatous effusion, 3) increasing immature myeloma cells with plasmablastic morphology, and 4) predominance of MPC1-CD49e-CD45+ phenotype immature myeloma cells. Combination therapy with thalidomide and dexamethasone resulted in a rapid response and a partial remission despite his multiple poor prognostic factors. The present case suggests that combination therapy with thalidomide and dexamethasone is still an alternative treatment regimen for resistant extramedullary plasmacytoma with a plasmablastic morphology . ### Response: thalidomide, dexamethasone

975865298fd67bd4b6ff56a8d8929f5f

Among 788 eligible patients , the median ( SD ) age was 59 ( 22 - 74 ) years ; 263 patients were assigned to doxorubicin plus cisplatin treatment , 263 patients to docetaxel plus cisplatin treatment , and 262 patients to paclitaxel plus carboplatin treatment .

Effect of Taxane Plus Platinum Regimens vs Doxorubicin Plus Cisplatin as Adjuvant Chemotherapy for Endometrial Cancer at a High Risk of Progression: A Randomized Clinical Trial. The efficacy of taxane plus platinum regimens has been demonstrated for advanced or recurrent endometrial cancer; however, it has not been assessed in postoperative adjuvant chemotherapy for endometrial cancer. ### objective To evaluate the clinical benefit of taxane plus platinum compared with standard doxorubicin plus cisplatin as postoperative adjuvant chemotherapy in endometrial cancer. ### Design Setting And Participants In this multicenter, open-label, phase 3 randomized clinical trial, patients with endometrial cancer at high-risk stage I or II or stage III or IV that did not extend beyond the abdominal cavity and had 2 cm or greater residual tumor were included from 118 institutions in Japan from November 24, 2006, to January 7, 2011. Data was analyzed from March 15, 2017, to June 30, 2017. ### interventions Eligible patients were randomly assigned (1:1:1) to receive 6 cycles of doxorubicin, 60 mg/m2, plus cisplatin, 50 mg/m2, on day 1; docetaxel, 70 mg/m2, plus cisplatin, 60 mg/m2, on day 1; or paclitaxel, 180 mg/m2, plus carboplatin (area under the curve, 6.0 mg/mL × min) on day 1 every 3 weeks. ### Main Outcomes And Measures The primary end point was progression-free survival. Secondary end points were overall survival, occurrence of adverse events, tolerability, and status of lymph node dissection. ### results Among 788 eligible patients , the median ( SD ) age was 59 ( 22 - 74 ) years ; 263 patients were assigned to doxorubicin plus cisplatin treatment , 263 patients to docetaxel plus cisplatin treatment , and 262 patients to paclitaxel plus carboplatin treatment . The number of patients who did not complete 6 cycles was 53 (20.1%) for the doxorubicin plus cisplatin group, 45 (17.1%) for the docetaxel plus cisplatin group, and 63 (24.0%) for the paclitaxel plus carboplatin group. Tolerability of these regimens were not statistically different. After a median follow-up period of 7 years, there was no statistical difference of progression-free survival (doxorubicin plus cisplatin, 191; docetaxel plus cisplatin, 208; paclitaxel plus carboplatin, 187; P = .12) or overall survival (doxorubicin plus cisplatin, 217; docetaxel plus cisplatin, 223; paclitaxel plus carboplatin, 215; P = .67) among the 3 groups. The 5-year progression-free survival rate was 73.3% for the doxorubicin plus cisplatin group, 79.0% for the docetaxel plus cisplatin group, and 73.9% for the paclitaxel plus carboplatin group, while the 5-year overall survival rates were 82.7%, 88.1%, and 86.1%, respectively. ### Conclusions And Relevance There was no significant difference of survival among patients receiving doxorubicin plus cisplatin, docetaxel plus cisplatin, or paclitaxel plus carboplatin as postoperative adjuvant chemotherapy for endometrial cancer. Because each regimen showed adequate tolerability but different toxic effects, taxane plus platinum regimens may be a reasonable alternative to treatment with doxorubicin plus cisplatin. ### Trial Registration UMIN-CTR identifier: UMIN000000522.

https://pubmed.ncbi.nlm.nih.gov/30896757/

### 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 Taxane Plus Platinum Regimens vs Doxorubicin Plus Cisplatin as Adjuvant Chemotherapy for Endometrial Cancer at a High Risk of Progression: A Randomized Clinical Trial. The efficacy of taxane plus platinum regimens has been demonstrated for advanced or recurrent endometrial cancer; however, it has not been assessed in postoperative adjuvant chemotherapy for endometrial cancer. ### objective To evaluate the clinical benefit of taxane plus platinum compared with standard doxorubicin plus cisplatin as postoperative adjuvant chemotherapy in endometrial cancer. ### Design Setting And Participants In this multicenter, open-label, phase 3 randomized clinical trial, patients with endometrial cancer at high-risk stage I or II or stage III or IV that did not extend beyond the abdominal cavity and had 2 cm or greater residual tumor were included from 118 institutions in Japan from November 24, 2006, to January 7, 2011. Data was analyzed from March 15, 2017, to June 30, 2017. ### interventions Eligible patients were randomly assigned (1:1:1) to receive 6 cycles of doxorubicin, 60 mg/m2, plus cisplatin, 50 mg/m2, on day 1; docetaxel, 70 mg/m2, plus cisplatin, 60 mg/m2, on day 1; or paclitaxel, 180 mg/m2, plus carboplatin (area under the curve, 6.0 mg/mL × min) on day 1 every 3 weeks. ### Main Outcomes And Measures The primary end point was progression-free survival. Secondary end points were overall survival, occurrence of adverse events, tolerability, and status of lymph node dissection. ### results Among 788 eligible patients , the median ( SD ) age was 59 ( 22 - 74 ) years ; 263 patients were assigned to doxorubicin plus cisplatin treatment , 263 patients to docetaxel plus cisplatin treatment , and 262 patients to paclitaxel plus carboplatin treatment . The number of patients who did not complete 6 cycles was 53 (20.1%) for the doxorubicin plus cisplatin group, 45 (17.1%) for the docetaxel plus cisplatin group, and 63 (24.0%) for the paclitaxel plus carboplatin group. Tolerability of these regimens were not statistically different. After a median follow-up period of 7 years, there was no statistical difference of progression-free survival (doxorubicin plus cisplatin, 191; docetaxel plus cisplatin, 208; paclitaxel plus carboplatin, 187; P = .12) or overall survival (doxorubicin plus cisplatin, 217; docetaxel plus cisplatin, 223; paclitaxel plus carboplatin, 215; P = .67) among the 3 groups. The 5-year progression-free survival rate was 73.3% for the doxorubicin plus cisplatin group, 79.0% for the docetaxel plus cisplatin group, and 73.9% for the paclitaxel plus carboplatin group, while the 5-year overall survival rates were 82.7%, 88.1%, and 86.1%, respectively. ### Conclusions And Relevance There was no significant difference of survival among patients receiving doxorubicin plus cisplatin, docetaxel plus cisplatin, or paclitaxel plus carboplatin as postoperative adjuvant chemotherapy for endometrial cancer. Because each regimen showed adequate tolerability but different toxic effects, taxane plus platinum regimens may be a reasonable alternative to treatment with doxorubicin plus cisplatin. ### Trial Registration UMIN-CTR identifier: UMIN000000522. ### Response: doxorubicin, cisplatin, docetaxel, cisplatin, paclitaxel, carboplatin