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### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: In newly diagnosed patients with MCL ineligible for intensive therapy and ASCT , the standard-of-care has generally been R-CHOP ( rituximab , cyclophosphamide , doxorubicin , vincristine , and prednisone ) , followed by rituximab , maintenance . Paragraph: Mantle cell lymphoma: therapeutic options in transplant-ineligible patients. Management of patients with newly diagnosed mantle cell lymphoma (MCL) depends on the age and fitness of the patient. For younger patients, the commonly accepted standard of care is a high-dose cytarabine-based induction chemotherapy followed by autologous stem cell transplantation (ASCT). In newly diagnosed patients with MCL ineligible for intensive therapy and ASCT , the standard-of-care has generally been R-CHOP ( rituximab , cyclophosphamide , doxorubicin , vincristine , and prednisone ) , followed by rituximab , maintenance . In recent years, bendamustine-based therapy has been increasingly adopted for older MCL patients and more recently, vincristine has been replaced by bortezomib in the R-CHOP combination as VR-CAP for previously untreated patients. Novel targeted agents now offer more promise than traditional chemotherapy or immunochemotherapy for both previously treated and untreated disease, and should also improve outcomes for older MCL patients. Here, we review standard therapies currently in use and novel agents that may soon be available for MCL patients and particularly for those unsuitable for ASCT. ### Assistant: [{"class": "POS", "spans_text": ["rituximab", "cyclophosphamide", "doxorubicin", "vincristine", "prednisone", "rituximab"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: The results indicate that BU and IPSA behave additively with verapamil and carbamazepine , which may be due to a common action on the same subtype of calcium channels . Paragraph: Effects of the serotonin-1A agonists buspirone and ipsapirone on field potentials in the hippocampus slice: comparison with carbamzepine and verapamil. The serotonin-1A agonists buspirone (BU) and ipsapirone (IPSA) have been demonstrated to exert antidepressant and anxiolytic effects. Since some antidepressant drugs and the antiepileptic substance carbamazepine have calcium antagonistic properties, the interaction of BU and IPSA with carbamazepine and the organic calcium channel blocker verapamil was analyzed in the low Mg2+ induced model epilepsy which has been shown to be suppressed specifically by organic calcium antagonists. BU and IPSA reduced the frequency of occurrence of low magnesium induced field potentials in CA1 and CA3 areas of the hippocampus slice preparation (guinea pigs) in a dose dependent manner. The subthreshold concentrations which yielded no effect were 5 mumol/l for BU and IPSA, 10 mumol/l for carbamazepine and 2 mumol/l for verapamil. Combinations of these subthreshold concentrations elicited a reduction in the repetition rate of field potentials. The results indicate that BU and IPSA behave additively with verapamil and carbamazepine , which may be due to a common action on the same subtype of calcium channels . It may be assumed that besides their action on 5-HT1A receptors BU and IPSA may also have calcium antagonistic properties. ### Assistant: [{"class": "POS", "spans_text": ["BU", "IPSA", "verapamil", "carbamazepine"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: The combination of docetaxel and trastuzumab is well tolerated and has clinically meaningful antitumor activity . Paragraph: Safety and activity of docetaxel and trastuzumab in HER2 overexpressing metastatic breast cancer: a pilot phase II study. We conducted a pilot phase II trial of trastuzumab administered concurrently with docetaxel in women with HER2-overexpressing advanced breast cancer. Twenty-five women with HER2-positive (3+ by immunohistochemistry = 16, 2+ = 9) metastatic breast cancer received docetaxel (75 mg/m every 3 weeks for 6 cycles) and trastuzumab (4 mg/kg loading dose, 2 mg/kg weekly thereafter). Twenty-three patients (92%) had visceral metastatic involvement. Twenty-three patients had received prior chemotherapy as part of adjuvant (18), metastatic (2), and both (3) treatment. The number of cycles administered was 121 (median 6, range 1-6). Symptomatic cardiotoxicity (GIII) occurred in one patient. The most common grade GIII/IV toxicity was neutropenia (80% of the cycles), although febrile neutropenia did not occur. No other GIII/IV toxicities were observed. Response rate was 70% (1 complete response and 15 partial responses) in 23 evaluable patients. The combination of docetaxel and trastuzumab is well tolerated and has clinically meaningful antitumor activity . ### Assistant: [{"class": "POS", "spans_text": ["docetaxel", "trastuzumab"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Combined treatment using insulin-like growth factor-I with prednisolone or ursodeoxycholic acid additively increased bile flow volume . Paragraph: Choleretic actions of insulin-like growth factor-I, prednisolone, and ursodeoxycholic acid in rats. A recent study by our group demonstrated that a 1-week infusion of insulin-like growth factor-I increases bile flow volume and bile acid secretion in rats, suggesting it is important in in vivo choleresis. In the present study, the effect in rats of a single administration of insulin-like growth factor-I on bile flow volume was investigated and compared with the choleretic drugs prednisolone and ursodeoxycholic acid. A significant and long-lasting increase in bile flow volume was observed in rats treated with insulin-like growth factor-I or prednisolone. Ursodeoxycholic acid significantly, but transiently increased. Combined treatment using insulin-like growth factor-I with prednisolone or ursodeoxycholic acid additively increased bile flow volume . Overall, this study demonstrated that the stimulatory effect of insulin-like growth factor-I on bile flow volume is almost equally potent to that of prednisolone and ursodeoxycholic acid, indicating the possible therapeutic potential of insulin-like growth factor-I in cholestatic liver diseases. ### Assistant: [{"class": "POS", "spans_text": ["insulin-like growth factor-I", "prednisolone"]}, {"class": "POS", "spans_text": ["insulin-like growth factor-I", "ursodeoxycholic acid"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Pharmacodynamic modeling of combined chemotherapeutic effects predicts synergistic activity of gemcitabine and trabectedin in pancreatic cancer cells . Paragraph: Pharmacodynamic modeling of combined chemotherapeutic effects predicts synergistic activity of gemcitabine and trabectedin in pancreatic cancer cells . This study investigates the combined effects of gemcitabine and trabectedin (ecteinascidin 743) in two pancreatic cancer cell lines and proposes a pharmacodynamic (PD) model to quantify their pharmacological interactions. ### methods Effects of gemcitabine and trabectedin upon the pancreatic cancer cell lines MiaPaCa-2 and BxPC-3 were investigated using cell proliferation assays. Cells were exposed to a range of concentrations of the two drugs, alone and in combination. Viable cell numbers were obtained daily over 5 days. A model incorporating nonlinear cytotoxicity, transit compartments, and an interaction parameter ψ was used to quantify the effects of the individual drugs and combinations. ### results Simultaneous fitting of temporal cell growth profiles for all drug concentrations provided reasonable cytotoxicity parameter estimates (the cell killing rate constant K max and the sensitivity constant KC50) for each drug. The interaction parameter ψ was estimated as 0.806 for MiaPaCa-2 and 0.843 for BxPC-3 cells, suggesting that the two drugs exert modestly synergistic effects. ### conclusions The proposed PD model enables quantification of the temporal profiles of drug combinations over a range of concentrations with drug-specific parameters. Based upon these in vitro studies, trabectedin may have augmented benefit in combination with gemcitabine. The PD model may have general relevance for the study of other cytotoxic drug combinations. ### Assistant: [{"class": "POS", "spans_text": ["gemcitabine", "trabectedin"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Conversely , down-regulation of cyclin E1 gene expression or inhibition of cyclin E1 by the cyclin-dependent kinase ( CDK ) inhibitors dinaciclib ( DIN ) or flavopiridol sensitized HCC cells to regorafenib and sorafenib by inducing apoptosis . Paragraph: Inhibition of cyclin E1 sensitizes hepatocellular carcinoma cells to regorafenib by mcl-1 suppression. To clarify the effects of cylcin E1 expression on HCC tumor progression, we studied the expression of cyclin E1 and inhibitory efficacy of regorafenib and sorafenib in HCC cells, and investigated a potential therapy that combines regorafenib treatment with cyclin E1 inhibition. ### methods Western blotting for caspase-3 and Hoechst 33225 staining was used to measure the expression level of apoptosis-related proteins under drug treatment. ### results Our results showed that enhanced expression of cyclin E1 after transfection compromised apoptosis in HCC cells induced by regorafenib or sorafenib. Conversely , down-regulation of cyclin E1 gene expression or inhibition of cyclin E1 by the cyclin-dependent kinase ( CDK ) inhibitors dinaciclib ( DIN ) or flavopiridol sensitized HCC cells to regorafenib and sorafenib by inducing apoptosis . The expression of Mcl-1, which is modulated by STAT3, plays a key role in regulating the therapeutic effects of CDK inhibitors. Xenograft experiments conducted to test the efficacy of regorafenib combined with DIN showed dramatic tumor inhibitory effects due to induction of apoptosis. Our results suggested that the level of cyclin E1 expression in HCCs may be used as a pharmacodynamic biomarker to assess the antitumor effects of regorafenib or sorafenib. ### conclusions Combining regorafenib and CDK inhibitors may enhance the clinical efficiency of the treatment of HCCs. ### Assistant: [{"class": "POS", "spans_text": ["flavopiridol", "regorafenib"]}, {"class": "POS", "spans_text": ["dinaciclib", "regorafenib"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Cytarabine and etoposide intensification exceeded the acceptable toxic death rate of 10 % . Paragraph: Mitoxantrone and cytarabine induction, high-dose cytarabine, and etoposide intensification for pediatric patients with relapsed or refractory acute myeloid leukemia: Children's Cancer Group Study 2951. To evaluate the response rate, survival, and toxicity of mitoxantrone and cytarabine induction, high-dose cytarabine and etoposide intensification, and further consolidation/maintenance therapies, including bone marrow transplantation, in children with relapsed, refractory, or secondary acute myeloid leukemia (AML). To evaluate response to 2-chlorodeoxyadenosine (2-CDA) and etoposide (VP-16) in patients who did not respond to mitoxantrone and cytarabine. ### Patients And Methods Patients with relapsed/refractory AML (n = 101) and secondary AML (n = 13) were entered. ### results mitoxantrone and cytarabine induction achieved a remission rate of 76% for relapsed/refractory patients and 77% for patients with secondary AML, with a 3% induction mortality rate. Cytarabine and etoposide intensification exceeded the acceptable toxic death rate of 10 % . The response rate of 2-CDA/VP-16 was 8%. Two-year overall survival was estimated at 24% and was better than historical control data. Patients with secondary AML had similar outcomes to relapsed or refractory patients. Initial remission longer than 1 year was the most important prognostic factor for patients with primary AML (2-year survival rate, 75%), whereas for patients with primary AML, with less than 12 months of initial remission, survival was 13% and was similar to that of refractory patients (6%). ### conclusion mitoxantrone and cytarabine induction is effective with reasonable toxicity in patients with relapsed/refractory or secondary AML. The cytarabine and etoposide intensification regimen should be abandoned because of toxicity. Patients with relapsed AML with initial remissions longer than 1 year have a relatively good prognosis. ### Assistant: [{"class": "NEG", "spans_text": ["Cytarabine", "etoposide"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: After initiating warfarin plus lenvatinib , INR assays are necessary . Paragraph: Drug interactions between warfarin and lenvatinib in a patient with the CYP2C91/3 and VKORC1-1639G/A genotype. lenvatinib inhibits CYP2C8. (S)-warfarin is metabolized to (S)-7-hydroxywarfarin by CYP2C9 and (S)-4'-hydroxywarfarin by CYP2C8. Here, we report drug interactions between warfarin and lenvatinib in a patient with CYP2C91/3. ### Case Summary The patient was administered warfarin. His international normalized ratio (INR) was 1.92 before lenvatinib administration. On day 8 after beginning 12 mg/day lenvatinib, plasma trough concentrations of lenvatinib and (S)-warfarin were 33.3 ng/mL and 0.67 μg/mL, respectively. On day 10, his INR increased to 3.48. ### What Is New And Conclusion lenvatinib-dependent (S)-warfarin inhibition could involve CYP2C9 and CYP2C8. After initiating warfarin plus lenvatinib , INR assays are necessary . ### Assistant: [{"class": "COMB", "spans_text": ["warfarin", "lenvatinib"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Merimepodib ( MMPD ) is an orally administered , inosine monophosphate dehydrogenase inhibitor that has shown antiviral activity in nonresponders with chronic hepatitis C ( CHC ) when combined with pegylated interferon alfa 2a ( Peg-IFN-alfa-2a ) and ribavirin ( RBV ) . Paragraph: Merimepodib, pegylated interferon, and ribavirin in genotype 1 chronic hepatitis C pegylated interferon and ribavirin nonresponders. Merimepodib ( MMPD ) is an orally administered , inosine monophosphate dehydrogenase inhibitor that has shown antiviral activity in nonresponders with chronic hepatitis C ( CHC ) when combined with pegylated interferon alfa 2a ( Peg-IFN-alfa-2a ) and ribavirin ( RBV ) . We conducted a randomized, double-blind, multicenter, phase 2b study to evaluate the antiviral activity, safety, and tolerability of MMPD in combination with Peg-IFN-alfa-2a and RBV in patients with genotype 1 CHC who were nonresponders to prior therapy with Peg-IFN and RBV. Patients received 50 mg MMPD, 100 mg MMPD, or placebo every 12 hours, in addition to Peg-IFN-alfa-2a and RBV, for 24 weeks. Patients with a 2-log or more decrease from baseline or undetectable hepatitis C virus (HCV) RNA levels at week 24 were then eligible to continue Peg-IFN-alfa-2a and RBV for a further 24 weeks, followed by 24 weeks of follow-up. The primary efficacy endpoint was sustained virological response (SVR) rate at week 72 in all randomized patients who received at least one dose of study drug and had a history of nonresponse to standard therapy. A total of 354 patients were randomized to treatment (117 to placebo; 119 to 50 mg MMPD; 118 to 100 mg MMPD), and 286 completed the core study. The proportion of patients who achieved SVR was similar among the treatment groups: 6% (6/107) for 50 mg MMPD, 4% (5/112) for 100 mg MMPD, and 5% (5/104) for placebo (P = 0.8431). Adverse-event profiles for the MMPD combination groups were similar to that for Peg-IFN-alfa and RBV alone. Nausea, arthralgia, cough, dyspnea, neutropenia, and anemia were more common in patients taking MMPD. ### conclusion The addition of MMPD to Peg-IFN-alfa-2a and RBV combination therapy did not increase the proportion of nonresponder patients with genotype 1 CHC achieving an SVR. ### Assistant: [{"class": "POS", "spans_text": ["interferon alfa", "ribavirin", "Merimepodib"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: [ Effects of endostatin and doxycycline on microcirculation patterns in melanoma and their relevant molecular mechanisms ] . Paragraph: [ Effects of endostatin and doxycycline on microcirculation patterns in melanoma and their relevant molecular mechanisms ] . To investigate the effects of endostatin and doxycycline on microcirculation patterns in melanoma and their molecular mechanisms. ### methods To establish mouse B16 melanoma model by subcutaneous injection of B16 melanoma cell suspension. The mice were divided into 3 experimental groups and 1 control group. To treat the mice in the 3 experimental groups with endostatin, doxycycline, endostatin and doxycycline, respectively, and the control group without any treatment. The tumor volume was measured and recorded to make comparison of their growth rate. To assess the expression of MMP-2, MMP-9 and TIMP-2 by immunohistochemical staining. The three microcirculation patterns of endothelium-dependent vessels, mosaic vessels and vasculogenic mimicry were counted. The activity of MMP-2, MMP-9 between different groups was examined by gelatin zymography. ### results Tumor growth in the three experimental groups was statistically significantly slower than that in the control group. The expression of MMP-2, MMP-9 and TIMP-2 in each treated group was significantly different with that in the control group. The amount of three microcirculation patterns in three experimental groups was less than that of the control group, and the amount of MV and VM in each experimental group was significantly less than that in the control group. By gelatin zymography, the enzyme activity of MMP-9, actived-MMP-2 and MMP-2/proMMP-2 in ES, DOX and ES + DOX group was lower than that in the control group, but the enzyme activity of pro-MMP-2 among the four groups was not significantly different. ### conclusion The combined use of doxycycline and endostatin in melanoma can inhibit the expression of MMPs, influencing the formation of different microcirculation patterns in melanoma. ### Assistant: [{"class": "COMB", "spans_text": ["endostatin", "doxycycline"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Subsequent investigation of therapeutic responsiveness upon treatment with the current systemic gold standard EDP-M ( etoposide , doxorubicin , cisplatin and mitotane ) demonstrated maintenance of the clinically observed drug resistance for MUC-1 exclusively . Paragraph: Targeting heterogeneity of adrenocortical carcinoma: Evaluation and extension of preclinical tumor models to improve clinical translation. In recent years it has been recognized that clinical translation of novel therapeutic strategies for patients with adrenocortical carcinoma (ACC) often fails. These disappointing results indicate that the currently utilized tumor models only poorly reflect relevant pathophysiology and, thereby, do not predict clinical applicability of novel pharmacological approaches. However, also the development of new preclinical ACC models has remained a challenge with only one human cell line (NCI-H295R) and one recently established human pediatric xenograft model (SJ-ACC3) being available for this highly heterogeneous malignancy. Our current study furthermore reveals a poor reproducibility of therapeutic action between different clones of the most commonly used tumor model NCI-H295R. In an attempt to broaden the current preclinical armamentarium, we aimed at the development of patient-individual tumor models. During these studies, one xenograft (MUC-1) displayed marked engraftment and sustained tumor growth. MUC-1 tumor analysis revealed highly vascularized, proliferating and SF-1 positive xenografts. In a next step, we characterized all currently available human tumor models for ACC for Ki67, SF-1 and EGF-receptor status in comparison with MUC-1-xenografts. In addition, we established a primary culture, which is now viable over 31 passages with sustained nuclear SF-1 and cytoplasmic 3βHSD immuno-positivity. Subsequent investigation of therapeutic responsiveness upon treatment with the current systemic gold standard EDP-M ( etoposide , doxorubicin , cisplatin and mitotane ) demonstrated maintenance of the clinically observed drug resistance for MUC-1 exclusively . In summary, we provide evidence for a novel patient-derived tumor model with the potential to improve clinical prediction of novel therapeutic strategies for patients with ACC. ### Assistant: [{"class": "POS", "spans_text": ["etoposide", "doxorubicin", "cisplatin", "mitotane"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Oxaliplatin is active in NSCLC , offers advantage in terms of toxicity , and shows synergism with gemcitabine . Paragraph: Gemcitabine and oxaliplatin: a safe and active regimen in poor prognosis advanced non-small cell lung cancer patients. Most patients with non-small cell lung cancer (NSCLC) cannot tolerate a cisplatin-based chemotherapy because of old age, general conditions, and/or multiorgan metastatic sites. Oxaliplatin is active in NSCLC , offers advantage in terms of toxicity , and shows synergism with gemcitabine . The aims of this phase II study were to evaluate the response rate and toxicity of the gemcitabine-oxaliplatin combination in patients with advanced NSCLC and poor prognosis. ### methods Patients were given a gemcitabine infusion (1000 mg/m(2) over 30 min on days 1 and 8) followed by oxaliplatin (65 mg/m(2) over 120 min on days 1 and 8) every 21 days for six cycles. ### results Thirty-two patients with poor-prognosis advanced NSCLC received 136 cycles. There were 25 males and seven females, and the median age was 65 years (range 29-76). Fifty-six percent of patients had adenocarcinoma, and 31% had squamous cell carcinoma. Sixty-six percent of patients had stage IV disease, and 34% had stage IIIB disease. Eastern cooperative oncology group (ECOG) performance status was 2-3 in 50%, 1 in 44%, and 0 in 6% of patients. Eight patients (25%) had been previously treated with cisplatin or carboplatin. All patients were symptomatic. Of the 32 patients who received study drug, five (16%) achieved partial response, six (19%) had minor response, three (9%) had stable disease, and 15 (47%) progressed. The median overall survival was 27 weeks. Thirty-one patients were evaluable for toxicity: seven patients (23%) had grade 3-4 thrombocytopenia with no bleeding; four patients (13%) had grade 3-4 neutropenia with no febrile neutropenia, and three patients (10%) had grade 3 anemia. Two patients (6%) had grade 3, and six patients (19%) had grade 1-2 neurotoxicity. ### conclusion The combination of gemcitabine and oxaliplatin seems to be well tolerated and active in patients with poor prognosis advanced NSCLC and deserves further evaluation in phase II clinical trials. ### Assistant: [{"class": "POS", "spans_text": ["Oxaliplatin", "gemcitabine"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Doxorubicin and lapatinib combination nanomedicine for treating resistant breast cancer . Paragraph: Doxorubicin and lapatinib combination nanomedicine for treating resistant breast cancer . Our objective was to design a polymeric micelle-based doxorubicin and lapatinib combination therapy for treating multidrug resistant (MDR) breast cancers. Poly(ethylene glycol)-block-poly(2-methyl-2-benzoxycarbonylpropylene carbonate) (PEG-PBC) polymers were synthesized for preparing doxorubicin and lapatinib loaded micelles using a film dispersion method. Micelles were characterized by determining critical micelle concentration (CMC), particle size distribution, and drug loading. The anticancer effects were determined in vitro with MTT assays as well as with lactate dehydrogenase (LDH) release studies. In addition, the cellular uptake of drug-loaded micelles was determined with fluorescence microscopy and flow cytometry. Finally, in vivo anticancer activity and tolerance of developed formulations were evaluated in resistant breast tumor bearing mice. PEG5K-PBC7K polymer synthesized in this study had a low CMC value (1.5 mg/L) indicating an excellent dynamic stability. PEG-PBC micelles could efficiently load both doxorubicin and lapatinib drugs with a loading density of 21% and 8.4%, respectively. The mean particle size of these micelles was 100 nm and was not affected by drug loading. The use of lapatinib as an adjuvant sensitized drug resistant MCF-7/ADR cells to doxorubicin treatment. Cellular uptake studies showed enhanced doxorubicin accumulation in MCF-7/ADR cells in the presence of lapatinib. The doxorubicin and lapatinib combination therapy showed a significant decrease in tumor growth compared to doxorubicin monotherapy. In conclusion, we have developed PEG-PBC micelle formulations for the delivery of doxorubicin and lapatinib. The combination therapy of doxorubicin plus lapatinib has a great potential for treating MDR breast cancer. ### Assistant: [{"class": "POS", "spans_text": ["Doxorubicin", "lapatinib"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: The HIV protease inhibitor ritonavir , a strong CYP3A4 inhibitor , decreased first-pass metabolism of orally administered docetaxel . Paragraph: Ritonavir inhibits intratumoral docetaxel metabolism and enhances docetaxel antitumor activity in an immunocompetent mouse breast cancer model. docetaxel (Taxotere(®)) is currently used intravenously as an anticancer agent and is primarily metabolized by Cytochrome P450 3A (CYP3A). The HIV protease inhibitor ritonavir , a strong CYP3A4 inhibitor , decreased first-pass metabolism of orally administered docetaxel . Anticancer effects of ritonavir itself have also been described. We here aimed to test whether ritonavir co-administration could decrease intratumoral metabolism of intravenously administered docetaxel and thus increase the antitumor activity of docetaxel in an orthotopic, immunocompetent mouse model for breast cancer. Spontaneously arising K14cre;Brca1(F/F) ;p53(F/F) mouse mammary tumors were orthotopically implanted in syngeneic mice lacking Cyp3a (Cyp3a(-/-)) to limit ritonavir effects on systemic docetaxel clearance. Over 3 weeks, docetaxel (20 mg/kg) was administered intravenously once weekly, with or without ritonavir (12.5 mg/kg) administered orally for 5 days per week. Untreated mice were used as control for tumor growth. ritonavir treatment alone did not significantly affect the median time of survival (14 vs. 10 days). Median time of survival in docetaxel-treated mice was 54 days. ritonavir co-treatment significantly increased this to 66 days, and substantially reduced relative average tumor size, without altering tumor histology. Concentrations of the major docetaxel metabolite M2 in tumor tissue were reduced by ritonavir co-administration, whereas tumor RNA expression of Cyp3a was unaltered. In this breast cancer model, we observed no direct antitumor effect of ritonavir alone, but we found enhanced efficacy of docetaxel treatment when combined with ritonavir. Our data, therefore, suggest that decreased docetaxel metabolism inside the tumor as a result of Cyp3a inhibition contributes to increased antitumor activity. ### Assistant: [{"class": "POS", "spans_text": ["ritonavir", "docetaxel"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Ramucirumab plus osimertinib demonstrated encouraging safety and antitumor activity in T790M-positive EGFR-mutant NSCLC . Paragraph: Phase 1 Study of the Efficacy and Safety of Ramucirumab in Combination with Osimertinib in Advanced T790M-Positive EGFR-Mutant Non-Small Cell Lung Cancer. We report the final analysis of JVDL (NCT02789345), which examined the combination of the EGFR TKI osimertinib plus the VEGFR2-directed antibody ramucirumab in patients with T790M-positive EGFR-mutant NSCLC. ### Experimental Design This open-label, single-arm phase 1 study enrolled patients with EGFR T790M-positive NSCLC, who had progressed following EGFR TKI but were third-generation EGFR TKI-naïve. A dose-limiting toxicity (DLT) period with as-needed dose de-escalation was followed by an expansion cohort. Patients received daily oral osimertinib and intravenous ramucirumab every 2 weeks until progression or discontinuation. ### results Twenty-five patients were enrolled. No DLTs were observed. Median follow-up time was 25.0 months. Common Grade 3 or higher treatment-related adverse events (TRAEs) were hypertension (8%) and platelet count decreased (16%); Grade 5 TRAE (subdural hemorrhage) occurred in one patient. Patients with (N=10) and without CNS metastasis (N=15) had similar safety outcomes. Five patients remain on treatment. Objective response rate (ORR) was 76%. Median duration of response was 13.4 months (90% CI: 9.6-21.2). Median progression-free survival (PFS) was 11.0 months (90% CI: 5.5-19.3). Efficacy was observed in patients with and without CNS metastasis (ORR 60% and 87%; median PFS 10.9 and 14.7 months, respectively). Exploratory biomarker analyses in circulating tumor DNA suggested that on-treatment loss of EGFR Exon 19 deletion or L858R mutations, detectable at baseline, correlated with longer PFS, but on-treatment loss of T790M did not. Emergent genetic alterations post progression included C797S, MET amplification, and EGFR amplification. ### conclusions Ramucirumab plus osimertinib demonstrated encouraging safety and antitumor activity in T790M-positive EGFR-mutant NSCLC . ### Assistant: [{"class": "POS", "spans_text": ["Ramucirumab", "osimertinib"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: The patient was complicated with hemophagocytic lymphohistiocytosis ( HLH ) and invasive aspergillosis ( IPA ) after re-induction treatment with FLAG-IDA following etoposide , cytarabine , and mitoxantrone . Paragraph: [Refractory acute myeloid leukemia developed malignancy-associated hemophagocytic lymphohistiocytosis during treatment of invasive fungal infection]. We here report a 2-year-old female with relapsed acute myeloid leukemia (AML) with MLL gene rearrangement in the bone marrow and central nervous system. The 3'-RACE (Rapid Amplification of cDNA Ends) method identified the MLLT10 gene as a fusion partner of the MLL gene. The patient was complicated with hemophagocytic lymphohistiocytosis ( HLH ) and invasive aspergillosis ( IPA ) after re-induction treatment with FLAG-IDA following etoposide , cytarabine , and mitoxantrone . Although treatment with systemic anti-fungal drugs was effective for IPA, HLH did not improve. We considered tumor-associated HLH to be initiated from leukemic stem cells (LSCs) in the bone marrow niche because reverse transcription-polymerase chain reaction (RT-PCR) analysis of a bone marrow biopsy sample was positive for MLL-MLLT10. gemtuzumab ozogamicin and sorafenib had no major effect on acquiring complete remission, and the patient died of progressive AML with an exacerbation of HLH and aspergillosis. LSCs are known to be resistant to conventional chemotherapy due to their quiescence in the cell cycle. Novel therapeutic concepts are important to eradicate LSCs in order to cure AML patients. ### Assistant: [{"class": "COMB", "spans_text": ["etoposide", "cytarabine", "mitoxantrone"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Pretreatment of the rats with methamphetamine ( MAP ) for 8 days prior to chronic haloperidol significantly enhanced the DOPAC and HVA increase produced by the challenge with haloperidol in both brain areas . Paragraph: Enhancement of haloperidol-induced increase in rat striatal or mesolimbic 3,4-dihydroxyphenylacetic acid and homovanillic acid by pretreatment with chronic methamphetamine. After a drug-free period of 1 week following 2 weeks of haloperidol treatment, the increased response of striatal 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) to a challenge dose of haloperidol was significantly reduced. Tolerance to this effect was not, however, seen in the mesolimbic system. Pretreatment of the rats with methamphetamine ( MAP ) for 8 days prior to chronic haloperidol significantly enhanced the DOPAC and HVA increase produced by the challenge with haloperidol in both brain areas . The reduced response of striatal DOPAC or HVA after chronic haloperidol was prevented by pretreatment with MAP. The data suggest that the long-term dopamine receptor stimulation induced by MAP may antagonize the tolerance produced by chronic haloperidol treatment. ### Assistant: [{"class": "POS", "spans_text": ["methamphetamine", "haloperidol"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: The quantity and composition of bacterial communities were altered by treatment with the five-antibiotic cocktail and by treatment with vancomycin and ampicillin . Paragraph: Related Enteric Viruses Have Different Requirements for Host Microbiota in Mice. Accumulating evidence suggests that intestinal bacteria promote enteric virus infection in mice. For example, previous work demonstrated that antibiotic treatment of mice prior to oral infection with poliovirus reduced viral replication and pathogenesis. Here, we examined the effect of antibiotic treatment on infection with coxsackievirus B3 (CVB3), a picornavirus closely related to poliovirus. We treated mice with a mixture of five antibiotics to deplete host microbiota and examined CVB3 replication and pathogenesis following oral inoculation. We found that, as seen with poliovirus, CVB3 shedding and pathogenesis were reduced in antibiotic-treated mice. While treatment with just two antibiotics, vancomycin and ampicillin, was sufficient to reduce CVB3 replication and pathogenesis, this treatment had no effect on poliovirus. The quantity and composition of bacterial communities were altered by treatment with the five-antibiotic cocktail and by treatment with vancomycin and ampicillin . To determine whether more-subtle changes in bacterial populations impact viral replication, we examined viral infection in mice treated with milder antibiotic regimens. Mice treated with one-tenth the standard concentration of the normal antibiotic cocktail supported replication of poliovirus but not CVB3. Importantly, a single dose of one antibiotic, streptomycin, was sufficient to reduce CVB3 shedding and pathogenesis while having no effect on poliovirus shedding and pathogenesis. Overall, replication and pathogenesis of CVB3 are more sensitive to antibiotic treatment than poliovirus, indicating that closely related viruses may differ with respect to their reliance on microbiota. ### Assistant: [{"class": "COMB", "spans_text": ["vancomycin", "ampicillin"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Successful treatment of an elderly Langerhans cell sarcoma patient by EPOCH ( etoposide , prednisone , vincristine , cyclophosphamide , and doxorubicin ) chemotherapy . Paragraph: Successful treatment of an elderly Langerhans cell sarcoma patient by EPOCH ( etoposide , prednisone , vincristine , cyclophosphamide , and doxorubicin ) chemotherapy . ### Assistant: [{"class": "POS", "spans_text": ["etoposide", "prednisone", "vincristine", "cyclophosphamide", "doxorubicin"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Tremelimumab plus gemcitabine demonstrated a safety and tolerability profile , warranting further study in patients with metastatic pancreatic cancer . Paragraph: A phase I dose escalation trial of tremelimumab (CP-675,206) in combination with gemcitabine in chemotherapy-naive patients with metastatic pancreatic cancer. tremelimumab (CP-675,206) is a fully human monoclonal antibody binding to cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) on T cells that stimulates the immune system by blocking the CTLA4-negative regulatory signal. Combination with standard chemotherapy may strengthen antitumor therapy. This is a phase Ib, multisite, open-label, nonrandomized dose escalation trial evaluating the safety, tolerability, and maximum tolerated dose (MTD) of tremelimumab combined with gemcitabine in patients with metastatic pancreatic cancer. ### Patients And Methods gemcitabine (1000 mg/m(2) on days 1, 8, and 15 of each 28-day cycles) was administrated with escalating doses of i.v. tremelimumab (6, 10, or 15 mg/kg) on day 1 of each 84-day cycle for a maximum of 4 cycles. The first 18 patients had an initial 4-week gemcitabine-only lead-in period. Dose-limiting toxicities (DLTs) related to tremelimumab were evaluated during the first 6 weeks after the first dose of tremelimumab. ### results From June 2008 to August 2011, 34 patients were enrolled and received at least one dose of tremelimumab. No DLTs related to tremelimumab were observed at any dose, even when the maximum dose established for tremelimumab (15 mg/kg) was used. Most frequent grade 3/4 toxicities were asthenia (11.8%) and nausea (8.8%). Only one patient had a serious drug-related event (diarrhea with dehydration). The median overall survival was 7.4 months (95% confidence interval 5.8-9.4 months). At the end of treatment, two patients achieved partial response. Both patients received tremelimumab 15-mg/kg group (n = 2/19, 10.5%). ### conclusion Tremelimumab plus gemcitabine demonstrated a safety and tolerability profile , warranting further study in patients with metastatic pancreatic cancer . ### Clinicaltrialsgov Id NCT00556023. ### Assistant: [{"class": "POS", "spans_text": ["Tremelimumab", "gemcitabine"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Longer progression-free survival ( PFS ) and overall survival ( OS ) were observed with T-DM1 compared with capecitabine plus lapatinib in all biomarker subgroups . Paragraph: Relationship between Tumor Biomarkers and Efficacy in EMILIA, a Phase III Study of Trastuzumab Emtansine in HER2-Positive Metastatic Breast Cancer. HER2-positive breast cancer is heterogeneous. Some tumors express mutations, like activating PIK3CA mutations or reduced PTEN expression, that negatively correlate with response to HER2-targeted therapies. In this exploratory analysis, we investigated whether the efficacy of trastuzumab emtansine (T-DM1), an antibody-drug conjugate comprised of the cytotoxic agent DM1 linked to the HER2-targeted antibody trastuzumab, was correlated with the expression of specific biomarkers in the phase III EMILIA study. ### Experimental Design Tumors were evaluated for HER2 (n = 866), EGFR (n = 832), and HER3 (n = 860) mRNA expression by quantitative reverse transcriptase PCR; for PTEN protein expression (n = 271) by IHC; and for PIK3CA mutations (n = 259) using a mutation detection kit. Survival outcomes were analyzed by biomarker subgroups. T-DM1 was also tested on cell lines and in breast cancer xenograft models containing PIK3CA mutations. ### results Longer progression-free survival ( PFS ) and overall survival ( OS ) were observed with T-DM1 compared with capecitabine plus lapatinib in all biomarker subgroups . PIK3CA mutations were associated with shorter median PFS (mutant vs. wild type: 4.3 vs. 6.4 months) and OS (17.3 vs. 27.8 months) in capecitabine plus lapatinib-treated patients, but not in T-DM1-treated patients (PFS, 10.9 vs. 9.8 months; OS, not reached in mutant or wild type). T-DM1 showed potent activity in cell lines and xenograft models with PIK3CA mutations. ### conclusions Although other standard HER2-directed therapies are less effective in tumors with PI3KCA mutations, T-DM1 appears to be effective in both PI3KCA-mutated and wild-type tumors. Clin Cancer Res; 22(15); 3755-63. ©2016 AACR. ### Assistant: [{"class": "COMB", "spans_text": ["capecitabine", "lapatinib"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Pharmacokinetics , Safety , and Antitumor Effect of Apalutamide with Abiraterone Acetate plus Prednisone in Metastatic Castration-Resistant Prostate Cancer : Phase Ib Study . Paragraph: Pharmacokinetics , Safety , and Antitumor Effect of Apalutamide with Abiraterone Acetate plus Prednisone in Metastatic Castration-Resistant Prostate Cancer : Phase Ib Study . apalutamide is a next-generation androgen receptor (AR) inhibitor approved for patients with nonmetastatic castration-resistant prostate cancer (CRPC) and metastatic castration-sensitive prostate cancer. We evaluated the pharmacokinetics, safety, and antitumor activity of apalutamide combined with abiraterone acetate plus prednisone (AA-P) in patients with metastatic CRPC (mCRPC). ### Patients And Methods Multicenter, open-label, phase Ib drug-drug interaction study conducted in 57 patients with mCRPC treated with 1,000 mg abiraterone acetate plus 10 mg prednisone daily beginning on cycle 1 day 1 (C1D1) and 240 mg apalutamide daily starting on C1D8 in 28-day cycles. Serial blood samples for pharmacokinetic analysis were collected on C1D7 and C2D8. ### results Systemic exposure to abiraterone, prednisone, and prednisolone decreased 14%, 61%, and 42%, respectively, when apalutamide was coadministered with AA-P. No increase in mineralocorticoid excess-related adverse events was observed. Patients without prior exposure to AR signaling inhibitors had longer median treatment duration and greater mean decrease in prostate-specific antigen (PSA) from baseline compared with those who had received prior therapy. Confirmed PSA reductions of ≥50% from baseline at any time were observed in 80% (12/15) of AR signaling inhibitor-naïve patients and 14% (6/42) of AR signaling inhibitor-treated patients. ### conclusions Treatment with apalutamide plus AA-P was well tolerated and showed evidence of antitumor activity in patients with mCRPC, including those with disease progression on AR signaling inhibitors. No clinically significant pharmacokinetic interaction was observed between abiraterone and apalutamide; however, apalutamide decreased exposure to prednisone. These data support development of 1,000 mg abiraterone acetate plus 10 mg prednisone daily with 240 mg apalutamide daily in patients with mCRPC. ### Assistant: [{"class": "POS", "spans_text": ["Apalutamide", "Abiraterone", "Prednisone"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Combined treatment with nintedanib ( 200 mg/bid ) plus letrozole ( 2.5 mg/day ) effectively suppressed FGFR1 and aromatase activity , and these respective doses can be used as starting doses in any subsequent trials . Paragraph: Nintedanib plus letrozole in early breast cancer: a phase 0/I pharmacodynamic, pharmacokinetic, and safety clinical trial of combined FGFR1 and aromatase inhibition. The combined use of a FGFR1 blocker and aromatase inhibitors is appealing for treating breast cancer patients with FGFR1 amplification. However, no pharmacodynamic studies have addressed the effects of this combined target modulation. We conducted a phase 0/I clinical trial in an adjuvant setting, with the goal of obtaining pharmacodynamic proof of the effects of combined aromatase and FGFR1 inhibition and to establish the RP2D for nintedanib combined with letrozole. ### Patients And Methods Women with early-stage luminal breast cancer were eligible for enrollment in the study. Dose level 1 was nintedanib (150 mg/bid) plus letrozole (2.5 mg/day) administered for a single 28-day cycle (DLT assessment period), followed by a classic 3 + 3 schedule. FGF23 and 17-B-estradiol levels were determined on days 0 and 15; pharmacokinetic parameters were assessed on days 1 and 28. Patients were allowed to continue treatment for 6 cycles. The primary study endpoint was a demonstration of FGFR1 modulation (defined as a 25% increase in the plasma FGF23 level). ### results A total of 19 patients were enrolled in the study (10 in the expansion cohort following dose escalation). At the RP2D (nintedanib 200 mg/bid plus letrozole 2.5 mg/day), we observed a 55% mean increase in the plasma FGF23 level, and 81.2% of the patients had no detectable level of 17-B-estradiol in their plasma (87.5% of the patients treated with letrozole alone). nintedanib and letrozole displayed a pharmacokinetic interaction that led to three- and twofold increases in their respective plasma concentrations. Most G3 toxic events (5 out of 6: 2 diarrhea and 3 hypertransaminasemia) occurred subsequent to the DLT assessment period. ### conclusion Combined treatment with nintedanib ( 200 mg/bid ) plus letrozole ( 2.5 mg/day ) effectively suppressed FGFR1 and aromatase activity , and these respective doses can be used as starting doses in any subsequent trials . However, drug-drug interactions may produce tolerability issues when these drugs are co-administered for an extended time period (e.g., 6 months). Patients enrolled in future trials with these drugs should be carefully monitored for their FGF23 levels and signs of toxicity, and those findings should guide individualized treatment decisions. ### Trial Registration This trial was registered at www.clinicaltrials.gov under reg. # NCT02619162, on December 2, 2015. ### Assistant: [{"class": "POS", "spans_text": ["nintedanib", "letrozole"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: A significant response to a combination of trastuzumab and vinorelbine in HER2-negative metastatic breast cancer with HER2 V777L mutation . Paragraph: A significant response to a combination of trastuzumab and vinorelbine in HER2-negative metastatic breast cancer with HER2 V777L mutation . Metastatic breast cancer (MBC) is the most life-threatening disease in women worldwide. HER2-mutated breast carcinoma has been reported to benefit from HER2-targeted tyrosine kinase inhibitors recently. Here, we presented a heavy pretreated and harbored HER2 V777L mutation de novo stage IV Luminal B (HER2 unamplified) breast cancer patient who achieved an unexpected good response to trastuzumab combined with vinorelbine therapy. Although HER2-unamplified MBC patients do not regularly benefit from anti-HER2 target therapy, HER2 V777L mutation detected by next-generation sequencing from ctDNA may present as a predictive biomarker for anti-HER2-based strategy therapy in HER2-negative MBC patients. ### Assistant: [{"class": "POS", "spans_text": ["trastuzumab", "vinorelbine"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Patients ( n = 28 ) with metastatic solid tumors were randomized to receive pretreatment with Dex or GM-CSF or no pretreatment prior to courses 1 or 2 of carboplatin and ifosfamide . Paragraph: Hematopoietic protection by dexamethasone or granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients treated with carboplatin and ifosfamide. Based on preclinical studies, the authors undertook a pilot study to determine the hematologic and biologic effects of pretreatment with dexamethasone (Dex) or granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients receiving carboplatin and ifosfamide. Patients ( n = 28 ) with metastatic solid tumors were randomized to receive pretreatment with Dex or GM-CSF or no pretreatment prior to courses 1 or 2 of carboplatin and ifosfamide . No alteration in dose of chemotherapy was allowed between course 1 and 2. Alterations of hematologic and nonhematologic toxicity and selected biologic parameters were compared between courses 1 and 2. Patients without any pretreatment demonstrated worsening hematologic toxicity in course 2 compared to course 1. In contrast, Dex pretreatment reduced hematopoietic toxicity and improved the absolute granulocyte count (AGC) and platelet count recovery times. For example, course 1 versus course 2 (with Dex pretreatment): AGC nadir (mm3) 153 versus 549 (p = 0.07), days AGC <500/mm3 7.8 versus 4.0 (p = 0.10), days to AGC recovery >1,500/mm3, 26 versus 22 (p = 0.034). Overall comparison between all five cohorts by analyses of variance demonstrated that intervention with Dex improved multiple hematopoietic toxicities, including AGC nadir (p = 0.015), and recovery times to AGC >1,500/mm3 (p = 0.07) and platelet count to >100,000/mm3 (p = 0.05). GM-CSF pretreatment did not worsen hematopoietic parameters after course 2 compared to course 1. Expected biologic effects of Dex and GM-CSF treatment were observed. Patients demonstrated an overall response rate of 32%, 1 complete response, and 8 partial responses. In patients with cancer, pretreatment with Dex or GM-CSF may significantly decrease the hematopoietic toxicity of chemotherapeutic agents. ### Assistant: [{"class": "POS", "spans_text": ["carboplatin", "ifosfamide", "Dex"]}, {"class": "POS", "spans_text": ["carboplatin", "ifosfamide", "GM-CSF"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: After a thyroidectomy , she was treated with intravenous methylprednisolone pulse therapy and oral prednisolone followed by tacrolimus therapy . Paragraph: The association between dermatomyositis and papillary thyroid cancer: a case report. We report the case of a 66-year-old woman who developed progressive proximal muscle weakness and papillary thyroid cancer. After a thyroidectomy , she was treated with intravenous methylprednisolone pulse therapy and oral prednisolone followed by tacrolimus therapy . However, her clinical symptoms and laboratory data did not improve sufficiently. Therefore, we administered intravenous immunoglobulin. As a result, she regained substantial muscle strength along with complete normalization of serum muscle enzymes and showed no evidence of recurrence of papillary thyroid cancer or exacerbation of dermatomyositis (DM). Although there is controversy as to whether papillary thyroid cancer is involved in DM, the results of this study support a connection between these two conditions. ### Assistant: [{"class": "NEG", "spans_text": ["methylprednisolone", "prednisolone", "tacrolimus"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: The vinca alkaloid , vinorelbine , and the multi-targeted antifol , pemetrexed , were additive with imexon in both cell lines . Paragraph: Imexon-based combination chemotherapy in A375 human melanoma and RPMI 8226 human myeloma cell lines. This study evaluated the cytotoxic effects of imexon (NSC-714597) in tumor cells when combined with a broad panel of chemotherapeutic drugs. ### methods The sulforhodamine B (SRB) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cytotoxicity assays were used to analyze the degree of growth inhibition for the combination studies in the A375 human malignant melanoma and RPMI 8226 human multiple myeloma cell lines, respectively. Cells were continuously exposed to both drugs at a constant molar ratio for 4-5 days. Combination effects were analyzed using the Median Effect method. Statistical significance was inferred if the 95% confidence interval for the combination interaction (C.I.) values for a particular two-drug combination did not include 1.0 (additivity). Synergy was inferred for C.I. values<1.0 and antagonism for CI values>1.0. ### results Imexon was synergistic when combined with DNA-binding agents (cisplatin, dacarbazine, melphalan) and pyrimidine-based antimetabolites (cytarabine, fluorouracil, gemcitabine) in both cell lines. Antagonistic combinations with imexon included methotrexate and the topoisomerase I (TOPO I) and II (TOPO II) inhibitors irinotecan, doxorubicin, mitoxantrone and etoposide. docetaxel was synergistic with imexon in both cell lines whereas paclitaxel and fludarabine showed a mixed result. dexamethasone and the proteasome inhibitor bortezomib showed synergy in myeloma cells and additivity in the melanoma cells. The vinca alkaloid , vinorelbine , and the multi-targeted antifol , pemetrexed , were additive with imexon in both cell lines . ### discussion The consistent synergy seen for imexon and alkylating agents may relate to the sulfhydryl-lowering effect of imexon, which would render cells more sensitive to electrophilic species from the alkylators. The marked synergy noted with pyrimidine-based antimetabolites was unexpected and may relate to the induction of cell cycle arrest in S-phase. The strong antagonism noted for imexon with topoisomerase I and II inhibitors may be due to the effect of imexon at increasing oxidant levels which are known to antagonize the cytotoxic effects of topoisomerase poisons. In contrast, the synergy seen with bortezomib in myeloma cells may be related to an increase in reactive oxygen species (ROS) from both drugs. These results suggest that combinations of imexon with alkylating agents and pyrimidine-based antimetabolites are rational to pursue in therapeutic studies in vivo. ### Assistant: [{"class": "POS", "spans_text": ["vinorelbine", "pemetrexed", "imexon"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Supine blood pressures ( group means ) were 171/97 ( placebo ) , 147/85 ( enalapril ) , 154/84 ( atenolol ) and 144/78 ( enalapril plus atenolol ) ( S.E.M. + /- 2/+/- 1-ANOVA ) , and standing blood pressures were 170/105 ( placebo ) , 146/92 ( enalapril ) , 154/92 ( atenolol ) and 147/86 ( enalapril plus atenolol ) ( S.E.M. + /- 3/+/- 1 ) . Paragraph: Enalapril and atenolol in essential hypertension: attenuation of hypotensive effects in combination. In 16 patients with essential hypertension the effects of enalapril 20 mg once daily were compared with those of atenolol 50 mg once daily, with the two drugs in combination and with placebo using a double-blind cross-over design with allocation of treatment order by randomised Latin squares. For each patient there were four treatment phases, each of four weeks duration, which together comprised a 2 x 2 factorial experiment. All blood pressure parameters were reduced in the three active treatment phases compared to placebo (p less than 0.001). Supine blood pressures ( group means ) were 171/97 ( placebo ) , 147/85 ( enalapril ) , 154/84 ( atenolol ) and 144/78 ( enalapril plus atenolol ) ( S.E.M. + /- 2/+/- 1-ANOVA ) , and standing blood pressures were 170/105 ( placebo ) , 146/92 ( enalapril ) , 154/92 ( atenolol ) and 147/86 ( enalapril plus atenolol ) ( S.E.M. + /- 3/+/- 1 ) . In the combination phase there was an additional hypotensive response but the potential fully additive effects of the two agents were attenuated by 30-50%. The mechanism of the attenuated hypotensive effect of the combined agents has not been determined. Plasma atrial natriuretic peptide (ANP) concentration was doubled in the presence of atenolol (P less than 0.01) suggesting that ANP may contribute to the hypotensive effect of the beta-blocker. ### Assistant: [{"class": "POS", "spans_text": ["enalapril", "atenolol"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: To evaluate the toxicity and activity of infusional fluorouracil ( FU ) , folinic acid ( FA ) , and oxaliplatin , administered every 2 weeks in patients with metastatic gastric cancer . Paragraph: Phase II trial of biweekly infusional fluorouracil, folinic acid, and oxaliplatin in patients with advanced gastric cancer. To evaluate the toxicity and activity of infusional fluorouracil ( FU ) , folinic acid ( FA ) , and oxaliplatin , administered every 2 weeks in patients with metastatic gastric cancer . ### Patients And Methods Forty-one previously untreated patients with measurable adenocarcinoma of the stomach were eligible for the study. Patients received FU 2.6 g/m(2) (24-hour continuous infusion), FA 500 mg/m(2) (2-hour intravenous infusion), and oxaliplatin 85 mg/m(2) (2-hour intravenous infusion) every 2 weeks for 6 weeks. Treatment was continued until progression of disease was observed. ### results All patients were assessable for toxicity and 37 of 41 patients were assessable for response. Patient characteristics were: sex (male, 28; female,13), median age 60 years (range, 20 to 77 years), and median Eastern Cooperative Oncology Group performance status of 1. Response was evaluated every 6 weeks. Of 37 assessable patients, one complete and 15 partial remissions were observed (overall response rate, 43%). Stable disease was observed in 12 patients (32%) and progressive disease in nine patients (24%). The median overall survival was 9.6 months. WHO grade 3 or 4 hematologic toxicities included neutropenia in two patients (4.9%) and thrombocytopenia in one patient (2.4%). Other WHO grade 3 or 4 toxicities included diarrhea in three patients (7.3%) and vomiting in two patients (4.9%). There were no cases of grade 3 peripheral neuropathy and no treatment-related deaths. ### conclusion Biweekly fluorouracil, folinic acid, and oxaliplatin is active and well-tolerated in patients with advanced gastric cancer. Response rates, time to progression, and overall survival were comparable to those achieved with other combination chemotherapy regimens, including FOLFOX6, with significantly less toxicity. ### Assistant: [{"class": "POS", "spans_text": ["fluorouracil", "folinic acid", "oxaliplatin"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Bevacizumab in combination with interferon alfa is now approved for treatment-naïve advanced renal cell carcinoma ( RCC ) in both the US and Europe . Paragraph: The bevacizumab experience in advanced renal cell carcinoma. Bevacizumab in combination with interferon alfa is now approved for treatment-naïve advanced renal cell carcinoma ( RCC ) in both the US and Europe . Its objective response rates of 30% and progression-free survival rates of 9-10 months are comparable to the other approved first-line multityrosine kinase inhibitors, sunitinib and pazopanib. Its advantages include a different toxicity profile and assurance of administration compliance given its intravenous formulation. Enthusiasm for its use is blunted by the increased costs, the potential infusion-related reactions, the associated interferon-related toxicities, and the inconvenience of its nonoral formulation. Further study is warranted to assess its efficacy both as a single agent and in combination with the targeted agents and other immunotherapies. With multiple agents now available for the treatment of advanced RCC, identification of patient and tumor-specific biomarkers to inform our choice of first-line therapy and the proper sequence of subsequent therapies is imperative. ### Assistant: [{"class": "POS", "spans_text": ["Bevacizumab", "interferon alfa"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: YM155 in combination with rituximab was tolerable with encouraging antitumor activity and durable responses in relapsed aggressive B-cell NHL patients . Paragraph: A multicenter phase II study of sepantronium bromide (YM155) plus rituximab in patients with relapsed aggressive B-cell Non-Hodgkin lymphoma. This phase II study evaluated ym155, a novel small-molecule survivin suppressant, in combination with rituximab in patients with relapsed aggressive B-cell non-Hodgkin lymphoma (NHL) who failed or were not candidates for autologous stem cell transplant (ASCT). During 14-day cycles, 41 patients received ym155 (5mg/m(2)/d) by continuous intravenous (IV) infusion for 168 hours (day 1-7), and rituximab (375mg/m(2)) IV on days 1 and 8 during cycles 1-4 and repeated for 4 cycles every 10 cycles. Forty patients (97.6%) had prior rituximab and 15 patients (36.6%) prior ASCT. Most frequent grade 3-4 adverse events were neutropenia (19.5%) and thrombocytopenia (12.2%). In the per-protocol set (n = 34), objective response rate was 50% and median progression-free survival 17.9 months. Median overall survival was not reached at study termination (median follow-up, 23 months). YM155 in combination with rituximab was tolerable with encouraging antitumor activity and durable responses in relapsed aggressive B-cell NHL patients . ### Assistant: [{"class": "POS", "spans_text": ["YM155", "rituximab"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Similarly , a significant benefit in progression-free survival for carboplatin plus gemcitabine versus carboplatin monotherapy was seen in the Gynecologic Cancer InterGroup trial . Paragraph: Management of platinum-sensitive recurrent ovarian cancer. The majority of patients with ovarian cancer will relapse despite state-of-the-art first-line surgery and chemotherapy. There are two subgroups of patients with recurrent ovarian cancer: those with platinum-resistant disease and those with platinum-sensitive disease. Re-treatment with single-agent platinum has long been considered standard therapy for patients with platinum-sensitive disease, and, based on its favorable therapeutic profile, carboplatin has become the treatment agent of choice. High response rates are seen with platinum agents used in combination with paclitaxel or gemcitabine. The International Collaborative Group for Ovarian Neoplasia (ICON) and the Arbeitsgemeinschaft für Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) recently conducted a trial (ICON4/AGO-OVAR-2.2) comparing platinum monotherapy with platinum plus paclitaxel combined. Results showed that overall survival and progression-free survival are improved by combination therapy. Similarly , a significant benefit in progression-free survival for carboplatin plus gemcitabine versus carboplatin monotherapy was seen in the Gynecologic Cancer InterGroup trial . The toxicity profiles and schedules of carboplatin plus paclitaxel and carboplatin plus gemcitabine are different, with the taxane combination having greater neurotoxicity and alopecia, less hematologic toxicity, and requiring longer drug infusions (although fewer days of treatment per cycle) than the gemcitabine combination. Based on the results of these two trials, combination chemotherapy should be considered the standard treatment of recurrent platinum-sensitive ovarian cancer. The choice of treatment needs to take into account the increase in side effects when using combination chemotherapy compared with carboplatin monotherapy, and the different toxicities of the two combination regimens. ### Assistant: [{"class": "POS", "spans_text": ["carboplatin", "gemcitabine"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: We report a case series of 10 patients that were treated with betamethasone valerate foam ( 0.12 % ) in the morning and topical tazarotene cream ( 0.1 % ) in the evening for a total of 12 weeks or until plaques cleared . Paragraph: Tazarotene cream (0.1%) in combination with betamethasone valerate foam (0.12%) for plaque-type psoriasis. A combination of multiple agents is often required to achieve treatment success for plaque-type psoriasis. We report a case series of 10 patients that were treated with betamethasone valerate foam ( 0.12 % ) in the morning and topical tazarotene cream ( 0.1 % ) in the evening for a total of 12 weeks or until plaques cleared . Erythema, scale, and thickness along with an aggregate severity score were determined at weeks 4, 8, and 12. One patient was lost to follow-up. Eight of the other 9 patients experienced improvement in their disease by week 12. Two patients were clear of their psoriasis at week 4 and 4 were clear at week 8. No adverse events, including irritation were reported; the use of the corticosteroid foam may protect against potential local irritation reported with tazarotene. The combination of tazarotene cream and betamethasone valerate foam is an effective combination approach to treating localized plaque-type psoriasis. ### Assistant: [{"class": "POS", "spans_text": ["betamethasone", "tazarotene"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Valsartan and sulfasalazine also reduced markers of oxidative stress after DSS administration . Paragraph: The beneficial effect of combination therapy with sulfasalazine and valsartan in the treatment of ulcerative colitis. Inflammatory bowel disease (IBD) is defined by the chronic inflammation of the digestive tract. Ulcerative colitis is one of the most prevalent chronic IBDs. The increase in the mucosal expression of angiotensin II (AT-II) in colitis suggests a possible role of AT-II in colitis-associated inflammation. Here, we examined the potential therapeutic effects of combination therapy regarding valsartan (Val), as an AT-II receptor blocker, with sulfasalazine (SSZ) in a murine colitis model. DSS induced colitis was initiated by the administration of dextran sodium sulfate (DSS) in male C57BL/6 mice for 1 week. Val (160 mg/kg/day, gavage) was given on the third day and continued for seven days. SSZ (100 mg/kg/day) was used as reference drug and also used in combination in one group (Val; 160 mg/kg/day and/or SSZ; 100 mg/kg/day). Colonic mucosal inflammation was evaluated clinically, biochemically, and histologically. The disease activity index in DSS-treated mice, including weight loss, stool consistency, and rectal bleeding, were significantly lower in the group of mice receiving the combination of valsartan and sulfasalazine compared to the DSS-treated group. valsartan and sulfasalazine treatment was associated with a lower reduction in colon length, diminished colon weight, and high sensitivity C-reactive protein level in mice with DSS-induced colitis. Valsartan and sulfasalazine also reduced markers of oxidative stress after DSS administration . Our findings demonstrate the anti-inflammatory and anti-fibrotic activities of a combination therapy with sulfasalazine and valsartan in experimentally induced colitis, indicating its value as a potential therapeutic option for the treatment of colitis. ### Assistant: [{"class": "POS", "spans_text": ["Valsartan", "sulfasalazine"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Metronomic 5-fluorouracil , oxaliplatin and irinotecan in colorectal cancer . Paragraph: Metronomic 5-fluorouracil , oxaliplatin and irinotecan in colorectal cancer . Metronomic chemotherapy (the frequent, long term, low dose administration of chemotherapeutic drugs) is a promising therapy because it enhances the anti-endothelial activity of conventional chemotherapeutics, but with lower or no toxic effects compared to maximum tolerated dose administration. The aims of the present study were to compare, in vitro and in vivo, the antiangiogenic and antitumor activities of metronomic irinotecan (CPT-11), oxaliplatin (L-OHP) and 5-fluorouracil (5-FU) in colorectal cancer and to investigate the metronomic combination of these drugs. In vitro cell proliferation, combination studies and vascular endothelial growth factor (VEGF) secretion analyses were performed on endothelial (HMVEC-d) and colorectal cancer (HT-29) cells exposed for 144 h to metronomic concentrations of SN-38, the active metabolite of CPT-11, L-OHP and 5-FU. HT-29 human colorectal cancer xenograft model was used and tumour growth, microvessel density and VEGF quantification were performed in tumours after the administration of metronomic CPT-11, L-OHP, 5-FU and their simultaneous combination. Low concentrations of SN-38, but not 5-FU and L-OHP, preferentially inhibited endothelial cell proliferation. Simultaneous and continuous exposure of HT-29 and HMVEC-d cells to low concentrations SN-38+L-OHP+5-FU for 144 h showed a strong antagonism and an unfavorable dose-reduction index. Moreover, the ternary combination resulted in a significant increase of VEGF secretion in HT-29 cancer cells. In a xenograft model metronomic CPT-11, but not 5-FU and L-OHP, significantly inhibits HT-29 tumor growth and microvessel density in the absence of toxicity. On the contrary, metronomic 5-FU+L-OHP+CPT-11 therapy did not affect the microvascular count. The metronomic concept might not universally apply to every cytotoxic drug in colorectal cancer and metronomic combination regimens should be used with caution. ### Assistant: [{"class": "COMB", "spans_text": ["5-fluorouracil", "oxaliplatin", "irinotecan"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Combination of mefloquine and praziquantel gave better curative effects than praziquantel or mefloquine given alone . Paragraph: Therapeutic effect of mefloquine on Schistosoma mansoni in experimental infection in mice. Schistosomiasis is one of the most prevalent parasitic infections worldwide. praziquantel is the drug of choice for treatment of schistosomiasis for its high efficacy. The present work was carried out on 160 mice to evaluate the therapeutic effect of mefloquine on experimental schistosomiasis mansoni. Mice were classified into 3 groups; group I (20 infected non-treated mice), group II included 60 infected mice which were further divided into group IIm (20 mice treated with 400 mg/kg mefloquine), group IIp (20 mice treated with 1,000 mg/kg/2 days praziquantel) and group IIpm (20 mice treated with 200 mg/kg mefloquine and 500 mg/kg praziquantel), group III included 80 non-infected mice subdivided into group IIIn (20 non-treated mice), group IIIm (20 mice treated with 400 mg/kg mefloquine), group IIIp (20 mice treated with 1,000 mg/kg/2 days praziquantel), group IIIpm (20 mice treated with 200 mg mefloquine and 500 mg praziquantel). mefloquine significantly reduced worm burden, tissue egg load, number of liver granulomas and increased the percent of dead ova within granulomas. Combination of mefloquine and praziquantel gave better curative effects than praziquantel or mefloquine given alone . ### Assistant: [{"class": "POS", "spans_text": ["mefloquine", "praziquantel"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: The aim of this study was to evaluate whether trastuzumab modifies the pharmacokinetics of epirubicin and its metabolites . Paragraph: Influence of trastuzumab on epirubicin pharmacokinetics in metastatic breast cancer patients. Anthracycline cardiotoxicity is increased by the contemporaneous administration of trastuzumab. The mechanism by which it occurs is as yet unknown. The aim of this study was to evaluate whether trastuzumab modifies the pharmacokinetics of epirubicin and its metabolites . ### Patients And Methods Women with HER2-positive metastatic breast cancer were treated with epirubicin 75 mg/m(2) i.v. bolus followed by docetaxel 75 mg/m(2) in a 1-h infusion, every 3 weeks for six cycles, and trastuzumab (once at 4 mg/m(2), then 2 mg/m(2) weekly thereafter) in a 30-min infusion. epirubicin pharmacokinetic data of seven patients were evaluated at the first cycle of therapy (baseline, with trastuzumab administered 24 h after epirubicin), and at the sixth cycle (i.e. 15 weeks after baseline, with trastuzumab administered immediately before epirubicin). ### results No pharmacokinetic change in the parent compound epirubicin was detected. The area under the plasma concentration-time curve (AUC(0-24 h)) was 1230 +/- 318 [mean +/- standard deviation (SD)] at the first cycle and 1287 +/- 385 h. micro g/l at the sixth. The mean (+/-SD) maximum plasma concentration (C(max)) and the terminal elimination half-life at the first cycle (1303 +/- 490 micro g/l and 12.5 +/- 3.1 h, respectively) were similar to those obtained at the sixth cycle (1229 +/- 580 micro g/l and 11.5 +/- 2.9 h, respectively). Pharmacokinetic data of epirubicin metabolites evaluated at the first and sixth cycle of chemotherapy were superimposable without any statistical difference. ### conclusion Enhanced anthracycline cardiotoxicity related to trastuzumab administration was not linked to pharmacokinetic interferences with epirubicin and its metabolites. ### Assistant: [{"class": "COMB", "spans_text": ["trastuzumab", "epirubicin"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Cardiac safety analysis of doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in the North Central Cancer Treatment Group N9831 adjuvant breast cancer trial . Paragraph: Cardiac safety analysis of doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in the North Central Cancer Treatment Group N9831 adjuvant breast cancer trial . To assess cardiac safety and potential cardiac risk factors associated with trastuzumab in the NCCTG N9831 Intergroup adjuvant breast cancer trial. ### Patients And Methods Patients with HER2-positive operable breast cancer were randomly assigned to doxorubicin plus cyclophosphamide (AC) followed by either weekly paclitaxel (arm A); paclitaxel then trastuzumab (arm B); or paclitaxel plus trastuzumab then trastuzumab alone (arm C). Left ventricular ejection fraction (LVEF) was evaluated at registration and 3, 6, 9, and 18 to 21 months. ### results Of 2,992 patients completing AC, 5.0% had LVEF decreases disallowing trastuzumab (decrease below normal: 2.4%, decrease > 15%: 2.6%). There were 1,944 patients with satisfactory or no LVEF evaluation who proceeded to post-AC therapy. Cardiac events (congestive heart failure [CHF] or cardiac death [CD]): arm A, n = 3 (2 CHF, 1 CD); arm B, n = 19 (18 CHF, 1 CD); arm C, n = 19 (all CHF); 3-year cumulative incidence: 0.3%, 2.8%, and 3.3%, respectively. Cardiac function improved in most CHF cases following trastuzumab discontinuation and cardiac medication. Factors associated with increased risk of a cardiac event in arms B and C: older age (P < .003), prior/current antihypertensive agents (P = .005), and lower registration LVEF (P = .033). Incidence of asymptomatic LVEF decreases requiring holding trastuzumab was 8% to 10%; LVEF recovered and trastuzumab was restarted in approximately 50%. ### conclusion The cumulative incidence of post-AC cardiac events at 3 years was higher in the trastuzumab-containing arms versus the control arm, but by less than 4%. Older age, lower registration LVEF, and antihypertensive medications are associated with increased risk of cardiac dysfunction in patients receiving trastuzumab following AC. ### Assistant: [{"class": "POS", "spans_text": ["doxorubicin", "cyclophosphamide", "paclitaxel"]}, {"class": "NEG", "spans_text": ["doxorubicin", "cyclophosphamide", "paclitaxel", "trastuzumab"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Bupropion differentially alters the aversive , locomotor and rewarding properties of nicotine in CD-1 mice . Paragraph: Bupropion differentially alters the aversive , locomotor and rewarding properties of nicotine in CD-1 mice . The present experiments determined the effects of bupropion on the motivational (aversive and rewarding) and locomotor properties of nicotine in CD-1 mice. Preliminary experiments determined effective nicotine doses (0.1-2.0 mg/kg) to produce a conditioned taste aversion (CTA) or conditioned place preference (CPP; Experiments 1a and 2a, respectively). Mice were administered vehicle or bupropion (1-20 mg/kg) followed by vehicle or nicotine after drinking saccharin during CTA training (Experiment 1b). Mice were administered vehicle or bupropion (1-20 mg/kg) 15 (Experiment 2b) or 30 (Experiment 2c) minutes (min) prior to vehicle or nicotine during CPP training. The two highest nicotine doses produced CTAs and a moderate nicotine dose (0.4 mg/kg) produced a CPP. bupropion dose-dependently blocked nicotine CTA. For the 15-min pretreatment interval, bupropion dose-dependently increased locomotor activity and produced CPPs when administered alone; whereas for the 30-min pretreatment interval, only the highest bupropion dose increased locomotor activity and produced a CPP. However, bupropion failed to alter nicotine CPP and the co-administration of bupropion and nicotine did not increase locomotor activity more so than when bupropion was administered alone regardless as to the pretreatment interval. Thus, bupropion selectively altered the aversive properties of nicotine in CD-1 mice. ### Assistant: [{"class": "POS", "spans_text": ["Bupropion", "nicotine"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: The first trial was a multicenter randomized phase III study of chemotherapy ( doxorubicin/cyclophosphamide or paclitaxel ) + /- trastuzumab , and the second was a multicenter phase II trial of vinorelbine + trastuzumab . Paragraph: Isolated central nervous system metastases in patients with HER2-overexpressing advanced breast cancer treated with first-line trastuzumab-based therapy. The aim of this study was to characterize the prevalence and predictors of central nervous system (CNS) metastasis among women with HER2-overexpressing metastatic breast cancer receiving trastuzumab-based therapy. ### methods The frequency and time course of isolated CNS progression were characterized among women with HER2-positive metastatic breast cancer, receiving chemotherapy with or without trastuzumab as first-line treatment for metastatic disease in two clinical trials. The first trial was a multicenter randomized phase III study of chemotherapy ( doxorubicin/cyclophosphamide or paclitaxel ) + /- trastuzumab , and the second was a multicenter phase II trial of vinorelbine + trastuzumab . All patients had measurable disease and were free of symptomatic CNS disease at initiation of study treatment. ### results Nearly 10% of patients receiving trastuzumab in combination with chemotherapy developed isolated CNS metastases as first site of tumor progression. Progression in the CNS tended to be a later event than progression at other sites among women receiving trastuzumab-based therapy. trastuzumab-based treatment did not substantially delay onset of CNS metastases as initial site of progression. Following diagnosis with primary breast cancer, tumors with HER2 gene amplification tend to be associated with greater risk of isolated CNS progression compared with those lacking gene amplification. ### conclusions Patients with HER2-overexpressing metastatic breast cancer are at risk for isolated CNS progression, reflecting improved peripheral tumor control and patient survival through use of trastuzumab-based therapy, and a relative lack of CNS activity with trastuzumab. Clinicians should be aware of this association. Better treatments for CNS recurrences are needed. ### Assistant: [{"class": "COMB", "spans_text": ["doxorubicin/cyclophosphamide", "trastuzumab"]}, {"class": "COMB", "spans_text": ["paclitaxel", "trastuzumab"]}, {"class": "COMB", "spans_text": ["vinorelbine", "trastuzumab"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Peginterferon alfa-2a ( 40KD ) plus ribavirin has given an overall sustained virological response of 18 % in F3/F4 previous nonresponder US patients . Paragraph: Peginterferon alfa-2a (40KD) (PEGASYS) plus ribavirin (COPEGUS) in retreatment of chronic hepatitis C patients, nonresponders and relapsers to previous conventional interferon plus ribavirin therapy. Peginterferon alfa plus ribavirin is currently the treatment of choice for chronic hepatitis C. Peginterferon alfa-2a ( 40KD ) plus ribavirin has given an overall sustained virological response of 18 % in F3/F4 previous nonresponder US patients . We evaluated the effectiveness of peginterferon alfa-2a (40KD) plus ribavirin in Brazilian patients who were relapsers or nonresponders to previous interferon-based therapy. One-hundred-thirty-four patients with biopsy-proven chronic hepatitis C, HCV RNA positive, elevated ALT and who were either relapsers (n=37) or nonresponders (n=97) to at least 24 weeks of conventional interferon/ribavirin therapy were retreated with peginterferon alfa-2a (40KD) 180mg/qw and ribavirin 800 mg bid for 48 weeks. Efficacy was assessed as virological response (defined as undetectable HCV RNA) at the end of treatment (EoT) and at the end of follow-up (SVR - Sustained Virological Response). Safety assessments consisted of clinical and laboratory evaluations. In the patient sample, 72% were genotype 1 and 34% were cirrhotic. In an intention-to-treat analysis, relapser patients showed 78% EoT response and 51% SVR. Nonresponders showed 57% EoT response and 26% SVR. Positive predictive factors of SVR were non-1 genotype and relapser state. Six percent of the patients interrupted treatment because of adverse events and 45% had dose reduction (mainly associated with leucopenia and anemia). Brazilian patient relapsers and nonresponders to conventional interferon and ribavirin treatment can achieve a sustained virological response when retreated with peginterferon alfa-2a (40KD) and ribavirin. The safety profile is similar to that of naive patients. ### Assistant: [{"class": "POS", "spans_text": ["Peginterferon alfa-2a", "ribavirin"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: We conducted a phase I and pharmacokinetic study with the erlotinib and celecoxib combination in patients with advanced premalignant lesions . Paragraph: Chemoprevention of head and neck cancer with celecoxib and erlotinib: results of a phase ib and pharmacokinetic study. Epidermal growth factor receptor (EGFR) and COX-2 inhibitors synergistically inhibit head and neck squamous cell carcinoma tumorigenesis in preclinical studies. We conducted a phase I and pharmacokinetic study with the erlotinib and celecoxib combination in patients with advanced premalignant lesions . Thirty-six subjects with oral leukoplakia, mild, moderate, or severe dysplasia, or carcinoma in situ were screened for study participation; 12 consented and received therapy for a median of 5.38 months. erlotinib was escalated following a standard 3+3 design at 50, 75, and 100 mg orally daily and celecoxib was fixed at 400 mg twice daily for 6 months. Biopsy of lesions and cytobrush of normal mucosa were performed at baseline, 3, 6, and 12 months. erlotinib pharmacokinetics were analyzed in 10 subjects. The maximum tolerated dose of erlotinib with celecoxib 400 mg BID was 50 mg per day with skin rash being the main observed toxicity. Overall histologic response rate was 63% (complete response, 43%; partial response, 14%; stable disease, 29%; and disease progression, 14%). With median follow-up of 36 months, mean time to progression to higher-grade dysplasia or carcinoma was 25.4 months. Downregulation of EGFR and p-ERK in follow-up biopsies correlated with response to treatment. Larger average erlotinib V/F (approximately 308 L) and CL/F (8.3 L/h) compared with previous studies may be related to relatively large average bodyweights. Average erlotinib t1/2 was 25.6 hours. Encouraging responses to the celecoxib and erlotinib combination correlated with EGFR pathway inhibition. Although erlotinib-related rash was the main limitation to dose escalation, the intervention was well tolerated. ### Assistant: [{"class": "POS", "spans_text": ["erlotinib", "celecoxib"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: [ Efficacy of combination therapy of lamivudine and adefovir dipivoxyl for patients with hepatitis B-induced decompensated liver cirrhosis ] . Paragraph: [ Efficacy of combination therapy of lamivudine and adefovir dipivoxyl for patients with hepatitis B-induced decompensated liver cirrhosis ] . To evaluate the efficacy of combination therapy of lamivudine (LAM) and adefovir dipivoxyl (ADV) for patients with hepatitis B-induced decompensated cirrhosis. ### methods A total of 81 patients were randomly divided into a combination group and an ADV group over 48 week treatment course. The combination group were treated with LAM (100 mg/d) plus ADV (10 mg/d), and the ADV group with ADV (10 mg/d ) for 48 weeks. All patients received hepatic function support and symptomatic treatment. The levels of HBV DNA, liver function, Child-Pugh scores and HBV DNA indicators were observed before and after the treatment. ### results At week 4, the mean reduction of HBV DNA was 1.83 lgIU/mL, 17.9% of the patients achieved undetectable HBV DNA and 28.2% showed normal ALT in the combination group. The counterpart in the ADV group was 0.96 lgIU/mL, 5.3% and 10.5%. At week 4, 12, 24 and 48, the differences in the mean reduction of HBV DNA, undetectable HBV DNA and ALT normalization were statistically significant between the 2 groups. The difference in HBeAg negative conversion rates and HBeAg seroconversion at week 24 and 48 was not significant. ### conclusion The combination therapy results in HBV suppression and improved liver function and Child-Pugh score. The combination treatment has an advantage over ADV due to low drug resistance rate and good tolerance. ### Assistant: [{"class": "POS", "spans_text": ["lamivudine", "adefovir"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: The effervescent aspirin preparation is at least as effective as the combination of aspirin plus metoclopramide , but has fewer side effects . Paragraph: Aspirin in the treatment of acute migraine attacks. Acetylsalicylic acid (aspirin or ASA) has been used for many years as an analgesic, antipyretic and anti-inflammatory drug. In recent years, evidence for its effectiveness in migraine headache has been demonstrated in several clinical trials. The effervescent highly buffered preparation of aspirin was shown to be effective, safe and well tolerated compared with placebo or other treatment options. The effervescent aspirin preparation is at least as effective as the combination of aspirin plus metoclopramide , but has fewer side effects . This review summarizes and analyzes clinical data of aspirin in the treatment of acute migraine attacks with respect to the different galenic formulations. ### Assistant: [{"class": "COMB", "spans_text": ["aspirin", "metoclopramide"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: This is an investigator-initiated , multicenter randomized controlled trial ( RCT ) designed to compare the combination treatment of adalimumab and methotrexate with adalimumab monotherapy in patients with psoriasis . Paragraph: Optimizing adalimumab treatment in psoriasis with concomitant methotrexate (OPTIMAP): study protocol for a pragmatic, single-blinded, investigator-initiated randomized controlled trial. The introduction of anti-tumor necrosis factor medications has revolutionized the treatment of psoriasis with achievement of treatment goals (Psoriasis Area and Severity Index score 75, remission) that are not usually met with conventional systemics. Nevertheless, some patients continue to experience persistent disease activity or treatment failure over time. Strategies to optimize treatment outcomes include the use of concomitant methotrexate, which has demonstrated beneficial effects on pharmacokinetics and treatment efficacy in psoriasis and other inflammatory diseases. ### methods This is an investigator-initiated , multicenter randomized controlled trial ( RCT ) designed to compare the combination treatment of adalimumab and methotrexate with adalimumab monotherapy in patients with psoriasis . The primary outcome is adalimumab drug survival at week 49. Other outcomes include improvement in disease severity and quality of life, tolerability, and safety. Moreover, anti-adalimumab antibodies and adalimumab serum concentrations will be measured and correlations between genotypes and clinical outcomes will be assessed. Patient recruitment started in March 2014. Up to now, 36 patients have been randomized. Many more patients have been (pre)screened. A total of 93 patients is desired to meet an adequate sample size. In our experience, the main limitation for recruitment is prior adalimumab therapy and intolerability or toxicity for methotrexate in the past. ### discussion OPTIMAP is the first RCT to examine combination therapy with adalimumab and methotrexate in a psoriasis population. With data derived from this study we expect to provide valuable clinical data on long-term treatment outcomes. These data will be supported by assessment of the impact of concomitant methotrexate on adalimumab pharmacokinetics. Furthermore, the influence of several single nucleotide polymorphisms on adalimumab response will be analyzed in order to support the development of a more personalized approach for this targeted therapy. ### Trial Registration NTR4499 . Registered on 7 April 2014. ### Assistant: [{"class": "COMB", "spans_text": ["adalimumab", "methotrexate"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: These results provide compelling preclinical rationale indicating lapatinib to be a potentially efficacious chemotherapeutic combination partner for irinotecan in the treatment of gastrointestinal carcinomas . Paragraph: The dual EGFR/HER-2 tyrosine kinase inhibitor lapatinib sensitizes colon and gastric cancer cells to the irinotecan active metabolite SN-38. Members of the human epidermal receptor (HER) family are frequently associated with aggressive disease and poor prognosis in multiple malignancies. lapatinib is a dual tyrosine kinase inhibitor targeting the epidermal growth factor receptor (EGFR) and HER-2. This study evaluated the therapeutic potential of lapatinib, alone and in combination with SN-38, the active metabolite of irinotecan (CPT-11), in colon and gastric cancer cell lines. Concentration-dependent antiproliferative effects of both lapatinib and SN-38 were observed in all colon and gastric cancer cell lines tested but varied significantly between individual cell lines (lapatinib range 0.08-11.7 muM; SN-38 range 3.6-256 nM). lapatinib potently inhibited the growth of a HER-2 overexpressing gastric cancer cell line and demonstrated moderate activity in gastric and colon cancer cells with detectable HER-2 expression. The combination of lapatinib and SN-38 interacted synergistically to inhibit cell proliferation in all colon and gastric cancer cell lines tested. Cotreatment with lapatinib and SN-38 also resulted in enhanced cell cycle arrest and the induction of apoptosis with subsequent cellular pharmacokinetic analysis demonstrating that lapatinib promoted the increased intracellular accumulation and retention of SN-38 when compared to SN-38 treatment alone. Finally, the combination of lapatinib and CPT-11 demonstrated synergistic antitumor efficacy in the LoVo colon cancer mouse xenograft model with no apparent increase in toxicity compared to CPT-11 monotherapy. These results provide compelling preclinical rationale indicating lapatinib to be a potentially efficacious chemotherapeutic combination partner for irinotecan in the treatment of gastrointestinal carcinomas . ### Assistant: [{"class": "POS", "spans_text": ["lapatinib", "irinotecan"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Women with previously untreated bulky ( primary tumor > /= 4 cm ) stage IB or IIA non-small-cell carcinoma of the uterine cervix were randomly assigned to receive either cisplatin 50 mg/m(2 ) and vincristine 1 mg/m(2 ) for 1 day and bleomycin 25 mg/m(2 ) for 3 days for three cycles followed by radical hysterectomy ( NAC arm ) or receive primary pelvic radiotherapy only ( R/T arm ) . Paragraph: Randomized trial of neoadjuvant cisplatin, vincristine, bleomycin, and radical hysterectomy versus radiation therapy for bulky stage IB and IIA cervical cancer. To compare the efficacy of neoadjuvant chemotherapy (NAC) followed by radical hysterectomy with that of radiotherapy (R/T) for bulky early-stage cervical cancer. ### Patients And Methods Women with previously untreated bulky ( primary tumor > /= 4 cm ) stage IB or IIA non-small-cell carcinoma of the uterine cervix were randomly assigned to receive either cisplatin 50 mg/m(2 ) and vincristine 1 mg/m(2 ) for 1 day and bleomycin 25 mg/m(2 ) for 3 days for three cycles followed by radical hysterectomy ( NAC arm ) or receive primary pelvic radiotherapy only ( R/T arm ) . The ratio of patient allocation was 6:4 for the NAC and R/T arms. Women with enlarged para-aortic lymph nodes on image study were ineligible unless results of cytologic or histologic studies were negative. ### results Of the 124 eligible patients, 68 in the NAC arm and 52 in the R/T arm could be evaluated. The median duration of follow-up was 39 months. Thirty-one percent of patients in the NAC arm and 27% in the R/T arm had relapse or persistent diseases after treatment, and 21% in each group died of disease. Estimated cumulative survival rates at 2 years were 81% for the NAC arm and 84% for the R/T arm; the 5-year rates were 70% and 61%, respectively. There were no significant differences in disease-free survival and overall survival. ### conclusion NAC followed by radical hysterectomy and primary R/T showed similar efficacy for bulky stage IB or IIA cervical cancer. Further study to identify patient subgroups better suited for either treatment modality and to evaluate the concurrent use of cisplatin and radiation without routine hysterectomy is necessary. ### Assistant: [{"class": "COMB", "spans_text": ["cisplatin", "vincristine", "bleomycin"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: The purpose of this study was to evaluate the efficacy of long-term use of bupropion sustained release ( SR ) , the nicotine patch , and the combination of these 2 treatments in patients who initially failed treatment . Paragraph: Late-term smoking cessation despite initial failure: an evaluation of bupropion sustained release, nicotine patch, combination therapy, and placebo. The purpose of this study was to evaluate the efficacy of long-term use of bupropion sustained release ( SR ) , the nicotine patch , and the combination of these 2 treatments in patients who initially failed treatment . ### methods This was a post hoc analysis of a multicenter, double-blind, randomized, placebo-controlled clinical trial in 893 smokers. Patients were randomly assigned to 9 weeks of treatment with placebo (n = 160), bupropion SR (n = 244), nicotine patch (n = 244), or a combination of nicotine patch and bupropion SR (n = 245). The study was originally designed with a follow-up period of 52 weeks. In this analysis, short-term success was defined as smoking cessation after 14 or 21 days of therapy and long-term success was defined as smoking cessation after >21 days of therapy. Patients who did not achieve short-term success were evaluated for long-term success at week 9 (end of treatment), 6 months, and 1 year after the start of the study. ### results The mean age of the smokers was 44 years. The majority (93%) of patients were white, and 52% were female. The study subjects smoked an average of 27 cigarettes per day. Among the 467 patients who initially failed treatment in the first 3 weeks, treatment with bupropion SR alone and in combination with the nicotine patch produced significant increases in successful smoking cessation rates from weeks 4 to 9 (19% bupropion SR or combination, 7% nicotine patch, 7% placebo), at month 6 (11% bupropion SR, 13% combination, 2% nicotine patch, 3% placebo), and at month 12 (10% bupropion SR, 7% combination, 2% nicotine patch, 1% placebo) (P < 0.05 for bupropion SR and combination vs nicotine patch or placebo). ### conclusion Among patients who initially failed treatment, continued therapy with bupropion SR, either alone or in combination with the nicotine patch, resulted in significantly higher short- and long-term smoking cessation rates than treatment with the nicotine patch alone or placebo. ### Assistant: [{"class": "POS", "spans_text": ["bupropion", "nicotine"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Systemic chemotherapy with vincristine , actinomycin D , plus cyclophosphamide ( VAC therapy ) , and etoposide plus cisplatin ( EP therapy ) were made according to Intergroup Rhabdomyosarcoma Study (IRS)-IV Regimen 45 . Paragraph: [Intrascrotal rhabdomyosarcoma in adult: a case report]. The patient was a 34-year-old man presenting with the right intra-scrotal painless mass. With a diagnosis of right intrascrotal tumor, the patient underwent right high orchiectomy. The pathological diagnosis of pleomorphic rhabdomyosarcoma arisen from the right spermatic cord was made. Computed tomography revealed a single metastasis in the para-vena cava lymph node. Systemic chemotherapy with vincristine , actinomycin D , plus cyclophosphamide ( VAC therapy ) , and etoposide plus cisplatin ( EP therapy ) were made according to Intergroup Rhabdomyosarcoma Study (IRS)-IV Regimen 45 . But the chemotherapy was ineffective and a retoroperitoneal lymphadenectomy (RPLND) was therefore performed. After 3 months following RPLND, the tumor relapsed in a pelvic lymph node involved in right ureter and ileocaecal valve. Resection of the tumor with ileocaecum was performed and then intraoperative radiotherapy (15 Gy) against the tumor bed was performed to ensure the curative effects. After his recovery, he received a total of 6 courses of systemic chemotherapy consisting of vincristin, ifosphamide, etoposide (IRS-IV Regimen 47). The patient was rigorously followed up for 42 months after the final chemotherapy, with no tumor recurrence. ### Assistant: [{"class": "NEG", "spans_text": ["vincristine", "actinomycin D", "cyclophosphamide", "etoposide", "cisplatin"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: He was asymptomatic half a year after the rituximab with cyclophosphamide , vincristine , doxorubicin , methotrexate/ifosfamide , etoposide , and high-dose cytarabine protocol therapy ; the lymphoma is in remission . Paragraph: Non-Hodgkin Lymphoma in a Kidney Transplant Patient: A Case Report. Post-transplant lymphoproliferative disorders are a possible complication of kidney transplant due to chronic immunosuppressive therapy, and they can elevate the mortality rate. Furthermore, the type of clinical appearance has a wide range. We describe a case of a 38-year-old male recipient who developed post-transplant lymphoproliferative disorders and received successful treatment. The recipient had received a kidney with 1 HLA-B and 1 HLA-DR match, and the deceased donor allotransplant was performed successfully on December 9, 2012. The cause of kidney failure was membranoproliferative-glomerulonephritis proved by biopsy results. The induction therapy was antithymocyte globulin; the basic immunosuppressive therapy consisted of tacrolimus, steroid, and mycophenolate mofetil. After 2 months the patient had elevated serum creatinine level, and biopsy results revealed cellular rejection (Banff grade I). We applied steroid bolus therapy. After that the graft worked properly for 5 years, and the patient had no symptoms or complaints; then he had right lower abdomen pain. After urgent procedures (laboratory diagnostics, abdominal ultrasonography, computed tomography), we operated on the patient in a short time, and after a few weeks the fluorescence in situ hybridization confirmed the translocation of region C-myc; the diagnosis was diffuse large B-cell lymphoma. With the assistance of hematologists, the patient received adequate therapy. He was asymptomatic half a year after the rituximab with cyclophosphamide , vincristine , doxorubicin , methotrexate/ifosfamide , etoposide , and high-dose cytarabine protocol therapy ; the lymphoma is in remission . Our case is worth presenting because immunosuppressive drugs can modify the clinical picture, complicating the diagnosis and delaying treatment. ### Assistant: [{"class": "POS", "spans_text": ["rituximab", "cyclophosphamide", "vincristine", "doxorubicin", "methotrexate/ifosfamide", "etoposide", "cytarabine"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: To evaluate empiric nifuratel , amoxicillin , and bismuth triple therapy for H. pylori gastritis in childhood . Paragraph: Nifuratel-containing initial anti-Helicobacter pylori triple therapy in children. Proton pump inhibitor-containing triple therapy with amoxicillin and metronidazole is recommended as initial treatment of Helicobacter pylori in childhood. However, eradication rate with this "classic" regimen is relatively low in Russia. ### aim To evaluate empiric nifuratel , amoxicillin , and bismuth triple therapy for H. pylori gastritis in childhood . ### Materials And Methods Pediatric outpatients with H. pylori-associated chronic gastritis who underwent endoscopy for dyspeptic symptoms received the combination of bismuth subcitrate (8 mg/kg/day, q.d.s.), nifuratel (30 mg/kg/day, q.d.s.), and amoxicillin (50 mg/kg/day, q.d.s.) for 10 days. H. pylori status was determined before and after the treatment (in 4-6 weeks) by modified Giemsa staining. ### results Seventy-three children (48 boys, 25 girls, age range 9-14) were entered. H. pylori was eradicated in 63 patients (86%; 95% confidence interval: 76.6-93.2; intention-to-treat and per protocol). There were no serious adverse reactions and were no withdrawals due to any side-effects. All of side-effects were self-limiting (dark stools, urine discoloration, blackening of the tongue, and others). ### conclusions The combination of nifuratel, bismuth subcitrate, and amoxicillin was an effective and tolerable regimen for H. pylori eradication. ### Assistant: [{"class": "POS", "spans_text": ["nifuratel", "amoxicillin", "bismuth"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: The patient was treated in July 1998 with anthracycline , etoposide , and behenoyl cytarabine chemotherapy for AML ( French-American-British classification , M2 ; World Health Organization classification , AML with maturation ) and achieved complete remission . Paragraph: Therapy-related myelodysplastic syndrome with monosomy 5 after successful treatment of acute myeloid leukemia (M2). We describe a patient who developed myelodysplastic syndrome over 2 years after achieving complete remission of acute myeloid leukemia (AML). The patient was treated in July 1998 with anthracycline , etoposide , and behenoyl cytarabine chemotherapy for AML ( French-American-British classification , M2 ; World Health Organization classification , AML with maturation ) and achieved complete remission . At presentation, no chromosomal abnormalities were detected. In December 2000, the patient's peripheral blood revealed pancytopenia, and his bone marrow was hypocellular with trilineage myelodysplasia and no blasts. Chromosomal analysis revealed complex karyotypic abnormalities, including monosomy 5. The patient was diagnosed with high-grade myelodysplastic syndrome (MDS)/refractory anemia with excess blasts (RAEB) subtype. The pancytopenia progressed rapidly, and he died 2 months after the diagnosis of MDS. Therapy-related MDS and AML (t-MDS/t-AML) developing after treatment for acute leukemia is unusual; the primary leukemia associated with most cases of t-MDS/t-AML is acute promyelocytic leukemia (APL). This unusual case suggests that AML excluding APL should be considered a primary hematologic malignancy for t-MDS/t-AML. ### Assistant: [{"class": "POS", "spans_text": ["anthracycline", "etoposide", "behenoyl cytarabine"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: The risk increased when ASA was combined with clopidogrel , compared with aspirin alone ( OR , 1.86 ; 95 % CI , 1.49 - 2.31 ) , anticoagulants vs low doses of ASA alone ( OR , 1.93 ; 95 % CI , 1.42 - 2.61 ) , or in studies that included patients with a history of GI bleeding or of longer duration . Paragraph: Low doses of acetylsalicylic acid increase risk of gastrointestinal bleeding in a meta-analysis. We performed a meta-analysis of data from randomized trials to estimate the risk of all-cause mortality and bleeding (and especially gastrointestinal [GI] bleeding) in patients treated with low doses of acetylsalicylic acid (ASA) (75-325 mg/d), alone or in combination with other medications. ### methods We searched 10 electronic databases (until October 2010) and collected data on adverse events in randomized controlled studies that evaluated low doses of ASA, alone (35 trials) or in combination with anticoagulants (18 trials), clopidogrel (5 trials), or proton pump inhibitors (PPIs; 3 trials). We analyzed data using random-effects meta-analysis and meta-regression, applying Peto's odds ratio (OR) for adverse events. ### results Low doses of ASA alone decreased the risk for all-cause mortality (relative risk, 0.93, 95% confidence interval [CI], 0.87-0.99), largely because of effects in secondary prevention populations. The risk of major GI bleeding increased with low doses of ASA alone (OR, 1.55; 95% CI, 1.27-1.90), compared with inert control reagents. The risk increased when ASA was combined with clopidogrel , compared with aspirin alone ( OR , 1.86 ; 95 % CI , 1.49 - 2.31 ) , anticoagulants vs low doses of ASA alone ( OR , 1.93 ; 95 % CI , 1.42 - 2.61 ) , or in studies that included patients with a history of GI bleeding or of longer duration . Importantly, PPI use reduced the risk for major GI bleeding in patients given low doses of ASA (OR, 0.34; 95% CI, 0.21-0.57). ### conclusions In a meta-analysis, low doses of ASA increased the risk for GI bleeding; risk increased with accompanying use of clopidogrel and anticoagulant therapies, but decreased in patients who took PPIs. ### Assistant: [{"class": "NEG", "spans_text": ["clopidogrel", "ASA"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Raloxifene , an anti-osteoporotic drug , is recently approved for prevention of breast cancer in postmenopausal women and thus the drug may be employed to combat the bony adverse effects of letrozole , another anticancer drug . Paragraph: Combined Raloxifene and Letrozole for Breast Cancer Patients. Raloxifene , an anti-osteoporotic drug , is recently approved for prevention of breast cancer in postmenopausal women and thus the drug may be employed to combat the bony adverse effects of letrozole , another anticancer drug . However, the cytotoxic effect of their combination on human breast cancer (MCF-7) and human embryonic kidney (HEK) cell lines is not known. MCF-7 and HEK cell lines were treated with different graded doses of letrozole, raloxifene and their combination, then incubated for 24-48 h. MTT assay was performed to check the cytotoxicity of the drugs. The study indicates that the combination of letrozole and raloxifene possess additive effect in terms of cytotoxicity of cancer cell lines (MCF-7) and negligible effects in normal cell lines (HEK). Our study indicates that the addition of raloxifene doesn't interfere with anticancer efficacy of letrozole rather the combination acted additively for the treatment of breast cancer. ### Assistant: [{"class": "POS", "spans_text": ["Raloxifene", "letrozole"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: In a previous trial , we found that adding the antiandrogen flutamide to leuprolide acetate ( a synthetic gonadotropin-releasing hormone that results in medical ablation of testicular function ) significantly improved survival as compared with that achieved with placebo plus leuprolide acetate . Paragraph: Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. Combined androgen blockade for the treatment of metastatic prostate cancer consists of an antiandrogen drug plus castration. In a previous trial , we found that adding the antiandrogen flutamide to leuprolide acetate ( a synthetic gonadotropin-releasing hormone that results in medical ablation of testicular function ) significantly improved survival as compared with that achieved with placebo plus leuprolide acetate . In the current trial, we compared flutamide plus bilateral orchiectomy with placebo plus orchiectomy. ### methods We randomly assigned patients who had never received antiandrogen therapy and who had distant metastases from adenocarcinoma of the prostate to treatment with bilateral orchiectomy and either flutamide or placebo. Patients were stratified according to the extent of disease and according to performance status. ### results Of the 1387 patients who were enrolled in the trial, 700 were randomly assigned to the flutamide group and 687 to the placebo group. Overall, the incidence of toxic effects was minimal; the only notable differences between the groups were the greater rates of diarrhea and anemia with flutamide. There was no significant difference between the two groups in overall survival (P=0.14). The estimated risk of death (hazard ratio) for flutamide as compared with placebo was 0.91 (90 percent confidence interval, 0.81 to 1.01). flutamide was not associated with enhanced benefit in patients with minimal disease. ### conclusions The addition of flutamide to bilateral orchiectomy does not result in a clinically meaningful improvement in survival among patients with metastatic prostate cancer. ### Assistant: [{"class": "POS", "spans_text": ["flutamide", "leuprolide acetate"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Contraceptives containing desogestrel or levonorgestrel have different effects on serum lipoproteins and post-heparin plasma lipase activities . Paragraph: Contraceptives containing desogestrel or levonorgestrel have different effects on serum lipoproteins and post-heparin plasma lipase activities . We examined the effects of mono and polyphasic oral contraceptives containing desogestrel or levonorgestrel on serum lipoproteins, sex hormone binding globulin and post-heparin plasma lipase activities. ### design The women took either desogestrel or levonorgestrel during the first menstrual cycle on days 15-28. They then received monophasic ethinyloestradiol plus either desogestrel or levonorgestrel for three cycles. After this, the women took sequential pills containing ethinyloestradiol plus either desogestrel or levonorgestrel for the three following cycles. Fasting blood samples were drawn pretreatment and at the end of each treatment. ### patients The study group consisted of 30 apparently healthy women, aged 18-35. They were randomly divided into desogestrel and levonorgestrel groups, each consisting of 15 women. ### measurements Cholesterol, triglyceride and phospholipids were determined in whole serum and in all lipoprotein fractions (following isolation of lipoproteins by ultracentrifugation). Plasma apolipoprotein A-I concentration, post-heparin plasma lipase activities and serum sex hormone binding globulin were also measured. ### results desogestrel (150 micrograms/day) did not change serum total triglyceride concentration, whereas levonorgestrel (150 micrograms/day) decreased it. Except for monophasic ethinyloestradiol plus levonorgestrel, the oestrogen-containing combinations increased serum triglyceride level. Low density lipoprotein (LDL) cholesterol remained stable with all treatments, but the cholesterol/triglyceride ratio of LDL decreased during all combinations with ethinyloestradiol. levonorgestrel reduced total high density lipoprotein (HDL) cholesterol and both progestins reduced HDL2 cholesterol concentration. Addition of ethinyloestradiol reversed this change in the desogestrel but not in the levonorgestrel group. The polyphasic ethinyloestradiol plus levonorgestrel combination did not change total HDL cholesterol. Hepatic lipase was activated with either progestin when administered alone but its activity was suppressed below the baseline level when ethinyloestradiol was added. Conversely, both progestins suppressed sex hormone binding globulin levels, but addition of ethinyloestradiol caused marked increases above baseline. These increases were greater in women taking desogestrel than in those taking levonorgestrel. No treatment affected lipoprotein lipase activity significantly. ### conclusions Monophasic or polyphasic combinations of ethinyloestradiol and desogestrel do not have deleterious effects on serum lipoproteins. If levonorgestrel is used as the progestin component, polyphasic ethinyloestradiol plus levonorgestrel appears more favourable than monophasic ethinyloestradiol plus levonorgestrel. ### Assistant: [{"class": "COMB", "spans_text": ["desogestrel", "levonorgestrel"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Concentrations of guaifenesin , diphenhydramine , and chlorpheniramine detected in the heart blood were 27.4 , 8.8 , and 0.2 mg/L , respectively . Paragraph: Acute intoxication with guaifenesin, diphenhydramine, and chlorpheniramine. Mixed drug reactions are frequently encountered in emergency department overdose cases and also in fatal intoxications. Assessment of the relative contribution of each drug in producing adverse effects is often compounded by lack of case history and the paucity of cases reported in the literature. This report describes a fatal intoxication with three common over-the-counter medications: guaifenesin, diphenhydramine, and chlorpheniramine. A 48-year-old woman was found dead in the attic bedroom of her residence. Specimens obtained at autopsy for toxicologic analysis included heart blood, urine, bile, gastric contents, vitreous humor, and cerebrospinal fluid. The over-the-counter drugs were identified and quantitated by acid/neutral or basic liquid-liquid extraction followed by gas chromatographic analysis with nitrogen phosphorus detection. Concentrations of guaifenesin , diphenhydramine , and chlorpheniramine detected in the heart blood were 27.4 , 8.8 , and 0.2 mg/L , respectively . The cause of death was determined to be acute intoxication by the combined effects of guaifenesin, diphenhydramine, and chlorpheniramine, and the manner of death was determined to be suicide. To our knowledge, the blood guaifenesin concentration in this case is the highest reported concentration to date associated with an acute intoxication. ### Assistant: [{"class": "NEG", "spans_text": ["guaifenesin", "diphenhydramine", "chlorpheniramine"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: The standard chemotherapy for localized ESFT now comprises vincristine , actinomycin D , cyclophosphamide and doxorubicin ( VACD ) in Europe or vincristine , doxorubicin , cyclophosphamide , ifosfamide and etoposide ( VDC-IE ) in North America . Paragraph: [Ewing sarcoma]. Ewing sarcoma is the second most frequent primary bone cancer affecting children or young adults. Advances in molecular biology have revealed common chromosomal translocations such as EWS-FLI 1 among Ewing sarcoma and related diseases such as primitive neuroectodermal tumor (PNET), so these are considered as Ewing sarcoma family tumor (ESFT). Although fewer than 10% of patients with ESFT survived before establishment of modern multiagent chemotherapy, the multimodal therapeutic regimens including combination chemotherapy, radiotherapy, and surgery can cure 60% of patients with localized disease, due to the collaborative research in European-American or the international trials. The standard chemotherapy for localized ESFT now comprises vincristine , actinomycin D , cyclophosphamide and doxorubicin ( VACD ) in Europe or vincristine , doxorubicin , cyclophosphamide , ifosfamide and etoposide ( VDC-IE ) in North America . Meanwhile, those with metastatic disease have a much worse outcome with an approximately 10-30% 5-year event-free survival rate. New American-European collaborative trials such as EURO-E.W.I.N.G.99 are in progress for further improvement of the cure rate in localized and metastatic ESFT. In Japan, Japan Ewing Sarcoma Study Group (JESS) phase II clinical trial for localized ESFT, and some clinical trials including new drugs are ongoing and waiting for results. ### Assistant: [{"class": "COMB", "spans_text": ["vincristine", "actinomycin D", "cyclophosphamide", "doxorubicin"]}, {"class": "COMB", "spans_text": ["vincristine", "doxorubicin", "cyclophosphamide", "ifosfamide", "etoposide"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Ceftriaxone plus gentamicin or ceftriaxone alone for streptococcal endocarditis in Japanese patients as alternative first-line therapies . Paragraph: Ceftriaxone plus gentamicin or ceftriaxone alone for streptococcal endocarditis in Japanese patients as alternative first-line therapies . This study included 31 patients who had definite or possible infectious endocarditis as defined by the modified Duke's criteria Of these patients, 27 were treated with ceftriaxone plus gentamycin combination therapy and four with ceftriaxone monotherapy. Of these 31 cases, 29 had infections with Streptococcus species, and showed good responses to penicillin G and cefotaxime. Excluding one patient who died because of the underlying disease, all patients achieved clinical cure after treatment with either of the two regimens, showing no recurrence during a follow-up period of 6 months after completion of drug treatment. Although valve replacement was performed in 10 patients during the follow-up period, there were no recurrences in any of these patients 6 months postoperatively. ceftriaxone allows a simple regimen of once-daily administration. Although indications are limited, ceftriaxone therapy is feasible on an outpatient basis, offering favorable medical economics. Consistent with previous reports, the therapeutic effect of ceftriaxone was equivalent to that of penicillin G in this study, showing this agent to be an alternative first-line drug for infectious endocarditis. ### Assistant: [{"class": "NEG", "spans_text": ["Ceftriaxone", "gentamicin"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Combined therapy : what does acamprosate and naltrexone combination tell us ? Paragraph: Combined therapy : what does acamprosate and naltrexone combination tell us ? Relapse prevention treatment with both acamprosate and naltrexone has been shown to be efficacious in the treatment of alcoholism. Whereas both compounds act pharmacologically differently, there is up to now only limited evidence as to whether combined treatment is efficacious and pharmacologically safe. It remains to be answered whether data justify the combination of both drugs in clinical practice. ### methods Review of the three pre-clinical and four clinical studies that have been published to date on either combined tolerability or efficacy. ### results Data available up to now show no occurrence of severe adverse events during combined treatment. Diarrhoea and nausea were shown to be the most significant side-effects. Whereas pre-clinical studies regarding efficacy of combined treatment are not yet conclusive, clinical data show the superiority of combined treatment compared with both placebo and acamprosate monotherapy. The synergistic effect of combined treatment remained after 12 weeks of drug-free follow-up. ### conclusions The combination of acamprosate with naltrexone in a clinical sample seems to be efficacious and safe. Numerous alcohol dependent patients could benefit, particularly those that responded insufficiently on monotherapeutic treatment with either acamprosate or naltrexone. ### Assistant: [{"class": "POS", "spans_text": ["acamprosate", "naltrexone"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Reflecting the role of STAT3 in inducing localized immune suppression , using both atovaquone and pyrimethamine resulted in the modulation of immunoregulatory genes predicted to enhance an immune response , including upregulation of ICOSLG ( Inducible T-Cell Costimulator Ligand or B7H2 ) . Paragraph: Inhibitors of the Transcription Factor STAT3 Decrease Growth and Induce Immune Response Genes in Models of Malignant Pleural Mesothelioma (MPM). Malignant pleural mesothelioma (MPM) is an aggressive cancer defined by loss-of-function mutations with few therapeutic options. We examined the contribution of the transcription factor Signal transducer and activator of transcription 3 (STAT3) to cell growth and gene expression in preclinical models of MPM. STAT3 is activated in a variety of tumors and is thought to be required for the maintenance of cancer stem cells. Targeting STAT3 using specific small hairpin RNAs (shRNAs) or with the pharmacologic inhibitors atovaquone or pyrimethamine efficiently reduced cell growth in established cell lines and primary-derived lines while showing minimal effects in nontransformed LP9 mesothelial cells. Moreover, atovaquone significantly reduced viability and tumor growth in microfluidic cultures of primary MPM as well as in an in vivo xenotransplant model. Biological changes were linked to modulation of gene expression associated with STAT3 signaling, including cell cycle progression and altered p53 response. Reflecting the role of STAT3 in inducing localized immune suppression , using both atovaquone and pyrimethamine resulted in the modulation of immunoregulatory genes predicted to enhance an immune response , including upregulation of ICOSLG ( Inducible T-Cell Costimulator Ligand or B7H2 ) . Thus, our data strongly support a role for STAT3 inhibitors as anti-MPM therapeutics. ### Assistant: [{"class": "POS", "spans_text": ["atovaquone", "pyrimethamine"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: TVR can be used in combination with tenofovir , emtricitabine and raltegravir for patients with hemophilia . Paragraph: A case of successful hepatitis C virus eradication by 24 weeks of telaprevir-based triple therapy for a hemophilia patient with hepatitis C virus/human immunodeficiency virus co-infection who previously failed pegylated interferon-α and ribavirin therapy. In Japan, the human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfection of some patients with hemophilia was caused by the transfusion of imported blood products, such as unheated coagulation factor. With the development of antiretroviral therapy (ART) for HIV, chronic HCV infection has become a major cause of liver disease and mortality for hemophiliac patients coinfected with HCV/HIV. Data is limited regarding the efficacy and safety of antiviral therapy with the HCV protease inhibitor telaprevir (TVR) in combination with pegylated interferon-α (PegIFN-α) and ribavirin (RBV) for hemophilia patients coinfected with HCV/HIV. We report a case of a Japanese patient with hemophilia and HCV/HIV coinfection who had partial response to prior to PegIFN-α and RBV therapy. This is the first published report of 24-week TVR-based triple therapy for a hemophilia patient coinfected with HCV/HIV. The patient had HCV genotype 1a infection with a high viral load. His single-nucleotide polymorphism of the interleukin 28B (rs8099917) gene was the TT major allele. He presented with undetectable HIV RNA and a high CD4(+) T cell counts by taking ART including tenofovir, emtricitabine and raltegravir. He was again treated for HCV with TVR plus PegIFN-α2b and RBV for the first 12 weeks, followed by the continuation of PegIFN-α2b and RBV for 12 additional weeks while continuing ART. He had rapid virological response and achieved sustained virological response with the 24-week treatment. No serious adverse events such as skin rash, severe anemia or exacerbated bleeding tendency were observed, only a mild headache. No dose adjustment was necessary when tenofovir and raltegravir were used in combined with TVR, and no HIV breakthrough was observed. TVR-based triple therapy with ART could can an effective treatment for hemophilia patients coinfected with HCV (genotype 1)/HIV regardless of prior response. TVR can be used in combination with tenofovir , emtricitabine and raltegravir for patients with hemophilia . Furthermore, patients with undetectable HCV RNA at week 4 could be successfully treated with a 24-week regimen. ### Assistant: [{"class": "POS", "spans_text": ["tenofovir", "emtricitabine", "raltegravir", "TVR"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Topical therapy with azithromycin and oral therapy with doxycycline relieved signs and symptoms and restored the lipid properties of the meibomian gland secretion toward normal . Paragraph: Topical azithromycin and oral doxycycline therapy of meibomian gland dysfunction: a comparative clinical and spectroscopic pilot study. Meibomian gland dysfunction (MGD) is a common clinical problem that is often associated with evaporative dry eye disease. Alterations of the lipids of the meibomian glands have been identified in several studies of MGD. This prospective, observational, open-label clinical trial documents the improvement in both clinical signs and symptoms of disease as well as spectroscopic characteristics of the meibomian gland lipids after therapy with topical azithromycin ophthalmic solution and oral doxycycline treatment. ### methods Subjects with symptomatic MGD were recruited. Signs of MGD were evaluated with a slit lamp. Symptoms of MGD were measured by the response of subjects to a questionnaire. Meibum lipid-lipid interaction strength, conformation, and phase transition parameters, and meibum protein content were measured using Fourier transform infrared spectroscopy and principal component analysis. Terpenoids, short-chain CH3 moieties, lipid oxidation, wax, cholesterylesters and glycerides were measured with a proton nuclear magnetic resonance (H-NMR) spectrometer. ### results Topical therapy with azithromycin and oral therapy with doxycycline relieved signs and symptoms and restored the lipid properties of the meibomian gland secretion toward normal . Compared with 4 weeks of azithromycin treatment reported in our previous study, oral doxycycline treatment was slightly less effective in improving foreign body sensation and the signs of plugging and secretion. In subjects with clinical evidence of MGD, changes in ordering of the lipids and phase transition temperature were brought closer to normal with azithromycin treatment than doxycycline treatment. Treatment with doxycycline but not azithromycin restored the Fourier transform infrared spectroscopy-principal component analysis scores and relative area of the H-NMR resonance at 1.26 ppm. Both doxycycline and azithromycin treatment restored the levels of the relative areas of the H-NMR resonance at 5.2 and 7.9 ppm to normal levels. The levels of meibum protein and meibum lipid oxidation were not influenced by azithromycin or doxycycline treatment. ### conclusions The mechanism of action of doxycycline may be different from that of azithromycin in therapy of MGD. It is notable that when carotenoids in meibum are low, as in MGD, the tear film is unstable and patients have the signs and symptoms of dry eyes. When carotenoids are restored with azithromycin and doxycycline treatment, tear film stability is restored and patients no longer have the signs and symptoms of dry eyes. ### Assistant: [{"class": "POS", "spans_text": ["azithromycin", "doxycycline"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Drug combinations , especially rapamycin + doxycycline may have promising anti-tumour effect in gliomas . Paragraph: Targeting cellular metabolism using rapamycin and/or doxycycline enhances anti-tumour effects in human glioma cells. Glioma is the most common highly aggressive, primary adult brain tumour. Clinical data show that therapeutic approaches cannot reach the expectations in patients, thus gliomas are mainly incurable diseases. Tumour cells can adapt rapidly to alterations during therapeutic treatments related to their metabolic rewiring and profound heterogeneity in tissue environment. Renewed interests aim to develop effective treatments targeting angiogenesis, kinase activity and/or cellular metabolism. mTOR (mammalian target of rapamycin), whose hyper-activation is characteristic for many tumours, promotes metabolic alterations, macromolecule biosynthesis, cellular growth and survival. Unfortunately, mTOR inhibitors with their lower toxicity have not resulted in appreciable survival benefit. Analysing mTOR inhibitor sensitivity, other metabolism targeting treatments and their combinations could help to find potential agents and biomarkers for therapeutic development in glioma patients. ### methods In vitro proliferation assays, protein expression and metabolite concentration analyses were used to study the effects of mTOR inhibitors, other metabolic treatments and their combinations in glioma cell lines. Furthermore, mTOR activity and cellular metabolism related protein expression patterns were also investigated by immunohistochemistry in human biopsies. temozolomide and/or rapamycin treatments altered the expressions of enzymes related to lipid synthesis, glycolysis and mitochondrial functions as consequences of metabolic adaptation; therefore, other anti-metabolic drugs (chloroquine, etomoxir, doxycycline) were combined in vitro. ### results Our results suggest that co-targeting metabolic pathways had tumour cell dependent additive/synergistic effects related to mTOR and metabolic protein expression patterns cell line dependently. Drug combinations , especially rapamycin + doxycycline may have promising anti-tumour effect in gliomas . Additionally, our immunohistochemistry results suggest that metabolic and mTOR activity alterations are not related to the recent glioma classification, and these protein expression profiles show individual differences in patients' materials. ### conclusions Based on these, combinations of different new/old drugs targeting cellular metabolism could be promising to inhibit high adaptation capacity of tumour cells depending on their metabolic shifts. Relating to this, such a development of current therapy needs to find special biomarkers to characterise metabolic heterogeneity of gliomas. ### Assistant: [{"class": "POS", "spans_text": ["rapamycin", "doxycycline"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Treatment with PUVA ( psoralen-ultraviolet-A ) combined with 40 - -80 mg prednisolone and then with chemotherapy [ COPP regimen ( cyclophosphamide , vincristine , procarbacine , prednisone ) , high-dosage methotrexate followed by citrovorum factor rescue ] was not successful . Paragraph: Cutaneous immunoblastic T-cell lymphoma. The case of a 69-year-old male patient with an unusual type of malignant lymphoma is presented. Clinically, it was at first characterized by follicular papules and erythematous patches, later, by the development of cutaneous tumors and enlarged lymph nodes, and by a severe, finally excruciating pruritus. Treatment with PUVA ( psoralen-ultraviolet-A ) combined with 40 - -80 mg prednisolone and then with chemotherapy [ COPP regimen ( cyclophosphamide , vincristine , procarbacine , prednisone ) , high-dosage methotrexate followed by citrovorum factor rescue ] was not successful . The patient died of pneumonia 2.5 years after the onset of the first clinical symptoms. An immunoblastic infiltrate was observed histologically and electromicroscopically in the initial lesions of the skin. Therefore, the diagnosis of a cutaneous immunoblastic T-cell lymphoma was tentatively made at the beginning, which was later confirmed in numerous biopsies and laboratory investigations. Immunocytologically and enzymecytochemically, the infiltrating cells were shown to be immature T cells; in the lymph nodes, numerous immunoblasts and large Sézary cells was observed in the peripheral blood, though there were no very large Sézary cells or blast cells. In the autopsy, a systemic involvement with an atypical lymphoid infiltration was found in numerous internal organs. The special nature of this case justifies its classification as high-grade malignant lymphoma and its differentiation from normal cases of mycosis fungoides. In contrast, mycosis fungoides generally fulfils criteria typical of low-grade malignant lymphomas. ### Assistant: [{"class": "NEG", "spans_text": ["prednisolone", "cyclophosphamide", "vincristine", "prednisone", "methotrexate", "psoralen-ultraviolet-A", "procarbacine", "citrovorum"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: We evaluated a sequential treatment with Vinorelbine followed by Gemcitabine to determine its effect on survival and the toxicity in this patient population . Paragraph: Sequential therapy with Vinorelbine followed by Gemcitabine in patients with metastatic non small cell lung cancer (NSCLC), performance status (PS) 2, or elderly with comorbidities--a multicenter phase II trial. High risk patients with metastatic non small cell lung cancer (NSCLC) including patients with performance status (PS) 2 or elderly with comorbidities do poorly on combination chemotherapy regimens. We evaluated a sequential treatment with Vinorelbine followed by Gemcitabine to determine its effect on survival and the toxicity in this patient population . ### methods Forty-two evaluable patients, median age 75, 21 patients with PS 2 and 21 patients with PS 0 or 1, 37 patients with stage IV and five patients with stage III B NSCLC entered the trial. They received vinorelbine 30 mg/m2, i.v., on days 1+8 every 3 weeks followed by gemcitabine 1000 mg/m2, i.v., on days 1+8 every 3 weeks, each for two cycles for stable disease or one cycle after best response. Then stable patients continued until progressive disease on vinorelbine or gemcitabine according to the patient's preference. ### results A total of 126 cycles of vinorelbine were administered to 42 patients, median of three cycles per patient and 74 cycles of gemcitabine, median of 1.0 cycle per patient. Sixteen patients (38%) achieved PR, 11 patients on vinorelbine, 5 patients on gemcitabine; 12 patients (26%) had stable disease, 7 patients on vinorelbine, 5 patients on gemcitabine. Of 24 patients with progressive disease on vinorelbine, 3 patients (12.5%) responded to gemcitabine. Median time-to-first progression was 3.5 months, median survival was 8 months, 1-year survival was 12 patients (28.5%). No grade 3 or 4 toxicities were reported. ### conclusion This sequential treatment offers excellent palliative treatment with minimal toxicity for high-risk patients with metastatic NSCLC. ### Assistant: [{"class": "POS", "spans_text": ["Vinorelbine", "Gemcitabine"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Apoptosis in Hep2 cells treated with etoposide and colchicine . Paragraph: Apoptosis in Hep2 cells treated with etoposide and colchicine . When malignant cells undergo apoptosis, they exhibit many distinct patterns of behavior, with blebbing being one of the most spectacular and mysterious features. Despite huge advancements in our understanding of cell death, the mechanisms of apoptosis associated blebbing have not been elucidated. In order to verify the putative involvement of actin and tubulin in this process, Hep2 cells were treated with a combination of etoposide (10 microg/ml) and colchicine (0.2 microg/ml) for 24 h. Blebbing was analyzed using immunofluorescence staining of actin and tubulin, and the course of apoptosis was followed by time-lapse videomicroscopy, immunofluorescence detection of caspase-3 and cytokeratin fragment 18. The results indicate that microfilaments (actin) and not microtubules (tubulin) are involved in blebbing of Hep2 cells. Furthermore, despite the different mechanisms by which both chemicals act, their combined effects are not additive, but rather eliminate each other. ### Assistant: [{"class": "NEG", "spans_text": ["etoposide", "colchicine"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: The objective of this phase II study was to evaluate the efficacy and toxicity of carboplatin and weekly paclitaxel combination chemotherapy in previously untreated , advanced non-small cell lung cancer ( NSCLC ) . Paragraph: Phase II study of carboplatin and weekly paclitaxel combination chemotherapy in advanced non-small cell lung cancer: a Kansai Clinical Oncology Group study. The objective of this phase II study was to evaluate the efficacy and toxicity of carboplatin and weekly paclitaxel combination chemotherapy in previously untreated , advanced non-small cell lung cancer ( NSCLC ) . Patients received paclitaxel at a dose of 70 mg/m(2) on days 1, 8, 15, and carboplatin with the target dose of area under the curve (AUC) of 6 on day 1 every 28 days. Forty-six patients were enrolled. A median of four cycles (range, 1-13) were administered. Complete response was observed in one patient (2.2%) and partial response in 23 patients (50%), yielding an overall intent-to-treat response rate of 52.2% (95% confidence interval, 37.8-66.6%). The median survival time was 395 days and 1-year survival rate was 51.4%. Toxicities were mild. Twelve patients (26%) had grade 3 and three patients (7%) had grade 4 neutropenia. Grade 3 thrombocytopenia was seen in four patients (8%). Massive hematoemesis due to duodenal ulcer was observed in one patient, but no other patients experienced grade 3 or more non-hematological toxicities. There was no treatment-related death. carboplatin and weekly paclitaxel combination chemotherapy is an efficacious and feasible regimen in patients with advanced NSCLC, and this treatment will be a reasonable alternative to the conventional triweekly regimen of paclitaxel and carboplatin. ### Assistant: [{"class": "POS", "spans_text": ["carboplatin", "paclitaxel"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Therapy consisted of seven cycles of VCAP ( vincristine , cyclophosphamide , doxorubicin and prednisone ) , AMP ( doxorubicin , ranimustine and prednisone ) and VECP ( vindesine , etoposide , carboplatin and prednisone ) . Paragraph: A new G-CSF-supported combination chemotherapy, LSG15, for adult T-cell leukaemia-lymphoma: Japan Clinical Oncology Group Study 9303. This phase II trial was performed to evaluate the efficacy of a new granulocyte colony-stimulating factor (G-CSF)-supported multi-agent chemotherapy protocol, LSG15, for aggressive adult T-cell leukaemia-lymphoma (ATL). Ninety-six previously untreated patients with aggressive ATL were enrolled and grouped as: acute type (58), lymphoma type (28) and unfavourable chronic type (10). Therapy consisted of seven cycles of VCAP ( vincristine , cyclophosphamide , doxorubicin and prednisone ) , AMP ( doxorubicin , ranimustine and prednisone ) and VECP ( vindesine , etoposide , carboplatin and prednisone ) . G-CSF was administered during the intervals between chemotherapy until neutrophil reconstitution was achieved. Eighty-one per cent of the 93 eligible patients responded [95% confidence interval (CI), 71.1-88.1%], with 33 patients obtaining complete response (35.5%) and 42 obtaining partial response (45.2%). The median survival time (MST) after registration was 13 months and the median follow-up duration of the 20 surviving patients was 4.2 years (range 2.8-5.6). Overall survival at 2 years was estimated to be 31.3% (95% CI, 22.0-40.5%). Grade 4 haematological toxicity of neutropenia and thrombocytopenia were observed in 65.3% and 52.6% of the patients respectively, but grade 4 non-haematological toxicity was observed in only one patient. LSG15 is feasible with mild non-haematological toxicity and improved the clinical outcome of ATL patients. MST and overall survival at 2 years were superior to those obtained by our previous trials. ### Assistant: [{"class": "POS", "spans_text": ["vincristine", "cyclophosphamide", "doxorubicin", "prednisone", "doxorubicin", "ranimustine", "prednisone", "etoposide", "carboplatin", "prednisone", "vindesine"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: In HER2-amplified cells , the combination of trastuzumab and lapatinib was evaluated using the median effects principal . Paragraph: Lapatinib, a dual EGFR and HER2 kinase inhibitor, selectively inhibits HER2-amplified human gastric cancer cells and is synergistic with trastuzumab in vitro and in vivo. HER2 amplification occurs in 18% to 27% of gastric and gastroesophageal junction cancers. lapatinib, a potent ATP-competitive inhibitor simultaneously inhibits both EGFR and HER2. To explore the role of HER family biology in upper gastrointestinal cancers, we evaluated the effect of lapatinib, erlotinib, and trastuzumab in a panel of molecularly characterized human upper gastrointestinal cancer cell lines and xenografts. ### Experimental Design EGFR and HER2 protein expression were determined in a panel of 14 human upper gastrointestinal cancer cell lines and HER2 status was assessed by fluorescent in situ hybridization. Dose-response curves were generated to determine sensitivity to lapatinib, erlotinib, and trastuzumab. In HER2-amplified cells , the combination of trastuzumab and lapatinib was evaluated using the median effects principal . The efficacy of lapatinib, trastuzumab, or the combination was examined in HER2-amplified xenograft models. ### results lapatinib had concentration-dependent antiproliferative activity across the panel with the greatest effects in HER2-amplified cells. There was no association between EGFR protein expression and sensitivity to any of the HER-targeted agents. Cell cycle analysis revealed that lapatinib induced G(1) arrest in sensitive lines and phosphorylated AKT and phosphorylated ERK were decreased in response to lapatinib as well. The combination of lapatinib and trastuzumab was highly synergistic in inhibiting cell growth with a combination index of <1. The combination also induced greater decreases in AKT and ERK activation, G(0)-G(1) cell cycle arrest, and increased rates of apoptosis. In vivo studies showed that the combination of lapatinib and trastuzumab had greater antitumor efficacy than either drug alone. ### conclusion Together, these data suggest that lapatinib has activity in HER2-amplified upper gastrointestinal cancer and supports the ongoing clinical investigation of lapatinib in patients with HER2-amplified disease. ### Assistant: [{"class": "POS", "spans_text": ["trastuzumab", "lapatinib"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Sorafenib monotherapy and combinations with taxanes , bevacizumab and ixabepilone showed inadequate efficacy , while efficacy results from combinations with gemcitabine and/or capecitabine and possibly tamoxifen were more promising . Paragraph: Sorafenib in breast cancer treatment: A systematic review and overview of clinical trials. To evaluate the current role of sorafenib, an oral multikinase inhibitor in the treatment of breast cancer. ### methods An extensive search of the literature until March 2016 was carried out in Medline and clinicaltrials.gov, by using the search terms "sorafenib" and "breast cancer". Papers found were checked for further relevant publications. Overall, 21 relevant studies were found, 18 in advanced breast cancer (16 in stage IV and two in stages III-IV) and three in early breast cancer. ### results Among studies in advanced breast cancer, there were two trials with sorafenib as monotherapy, four trials of sorafenib in combination with taxanes, two in combination with capecitabine, one with gemcitabine and/or capecitabine, one with vinorelbine, one with bevacizumab, one with pemetrexed and one with ixabepilone, three trials of sorafenib in combination with endocrine therapy and two trials in women with brain metastases undergoing whole brain radiotherapy. In addition, there was one trial of sorafenib added to standard chemotherapy in the adjuvant setting, and two trials in the neoadjuvant setting. In general, sorafenib was well tolerated in breast cancer patients, though its dosage had to be adjusted in some trials, and discontinuation rates were high, particularly for the combination of sorafenib with anastrozole. Sorafenib monotherapy and combinations with taxanes , bevacizumab and ixabepilone showed inadequate efficacy , while efficacy results from combinations with gemcitabine and/or capecitabine and possibly tamoxifen were more promising . ### conclusion At present, sorafenib should not be used for the treatment of breast cancer outside of clinical trials and more clinical data are needed in order to support its standard use in breast cancer therapy. ### Assistant: [{"class": "POS", "spans_text": ["Sorafenib", "gemcitabine"]}, {"class": "POS", "spans_text": ["Sorafenib", "capecitabine"]}, {"class": "POS", "spans_text": ["Sorafenib", "tamoxifen"]}, {"class": "COMB", "spans_text": ["Sorafenib", "bevacizumab"]}, {"class": "COMB", "spans_text": ["Sorafenib", "ixabepilone"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: This article reviews the pertinent studies regarding paclitaxel combined with cisplatin or carboplatin , discusses the remaining controversies surrounding how best to combine these agents , and provides opinions regarding the discordant outcomes noted in studies of the paclitaxel-platinum doublet . Paragraph: Current status of taxane and platinum-based chemotherapy in ovarian cancer. Before 1993, the standard of care for the chemotherapeutic management of advanced ovarian cancer was cisplatin or carboplatin combined with a classic alkylating agent (typically cyclophosphamide). Studies in the 1990s have changed this standard to one of the platinum-containing agents combined with a taxane, paclitaxel, or docetaxel. This article reviews the pertinent studies regarding paclitaxel combined with cisplatin or carboplatin , discusses the remaining controversies surrounding how best to combine these agents , and provides opinions regarding the discordant outcomes noted in studies of the paclitaxel-platinum doublet . A separate article discusses the docetaxel-platinum doublet and how that might be considered an appropriate option for first-line therapy in patients with advanced, newly diagnosed ovarian cancer. ### Assistant: [{"class": "COMB", "spans_text": ["paclitaxel", "cisplatin"]}, {"class": "COMB", "spans_text": ["paclitaxel", "carboplatin"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Hyperthermia could increase the sensitivity of SKOV3 to cis-platinum , carboplatin and oxaliplatin ( P < 0.05 ) . Paragraph: [Effects of hyperthermia combined platinum-based drugs on ovarian cancer cell lines SKOV3]. To investigate the effects and mechanisms of hyperthermia combined with various platinum-based drugs cis-platinum (DDP), carboplatin (CBP), oxaliplatin (OXA) on the proliferation and apoptosis of ovarian cancer cell lines SKOV3. ### methods SKOV3 cells were treated with different concentrations of anticancer drugs DDP (final concentration respectively 0, 1.25, 2.5, 5.0, 10.0, 20.0 microg/mL), CBP and OXA (both final concentration respectively 0, 2.5, 5.0, 10.0, 20.0, 40 microg/mL) at a temperature of 42 degrees C for hyperthermia or 37 degrees C for normal temperature. Methyl thiazolyl tetrazolium (MTT) method was used to test growth ratios of ovarian cancer cell lines SKOV3. Real-time PCR was adopted to detect the expression level of excision repair cross-complementing group 1 (ERCC1) and Survivin mRNA in SKOV3 cells. ### results DDP, CBP and OXA inhibited the growth of SKOV3 in a dose-dependent manner (P < 0.05). Hyperthermia could increase the sensitivity of SKOV3 to cis-platinum , carboplatin and oxaliplatin ( P < 0.05 ) . The half inhibitory concentration (IC50) values of DDP, CBP and OXA were (7.271 +/- 0.096) microg/mL, (37.609 +/- 0.779) microg/mL and (28.328 +/- 0.698) microg/mL respectively. When combined with hyperthermia, the IC50 values of DDP, CBP, and OXA were (2.075 +/- 0.244) microg/mL, (19.591 +/- 0.453) microg/mL, (19.089 +/- 0.424) microg/mL (P < 0.05). The increased sensitivity index was 2.075 +/- 0.244 for cis-platinum, 1.92 +/- 0.044 for carboplatin, 1.484 +/- 0.039 for oxaliplatin. After the treatment of hyperthermia, the expression of ERCC1 and Survivin mRNA showed downward trend. ERCC1 decreased more significantly in the group of hyperthermia combined with carboplatin, and Survivin decreased more significantly in the group of hyperthermia combined with oxaliplatin (P < 0.05). ### conclusion Hyperthermia can enhance the sensitivity of ovarian cancer SKOV3 cells to platinum-based drugs, which may be related to the down regulation of ERCC1 and Survivin expression. ### Assistant: [{"class": "POS", "spans_text": ["cis-platinum", "Hyperthermia"]}, {"class": "POS", "spans_text": ["carboplatin", "Hyperthermia"]}, {"class": "POS", "spans_text": ["oxaliplatin", "Hyperthermia"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: A prospective phase 2 trial of short-course ( SC ) radiation therapy ( RT ) with 25 Gy over 5 fractions , followed by 4 cycles of 5-fluorouracil , oxaliplatin , and leucovorin ( mFOLFOX6 ) before surgery was recently completed at our institution . Paragraph: Quality of Life Outcomes From a Phase 2 Trial of Short-Course Radiation Therapy Followed by FOLFOX Chemotherapy as Preoperative Treatment for Rectal Cancer. A prospective phase 2 trial of short-course ( SC ) radiation therapy ( RT ) with 25 Gy over 5 fractions , followed by 4 cycles of 5-fluorouracil , oxaliplatin , and leucovorin ( mFOLFOX6 ) before surgery was recently completed at our institution . We present here the patient-reported quality of life (QOL) outcomes from this trial. ### Methods And Materials Eighty patients with cT3/T4, any N, any M rectal adenocarcinoma planned for resection were enrolled between 2009 and 2012. The QOL data were obtained prospectively using the Functional Assessment of Cancer Therapy-Colon (FACT-C) questionnaire before RT, before surgery, and 1 year after surgery. The previously validated minimally importance difference (MID) method was used to measure clinically significant QOL changes in FACT-C scores for each patient across time points. We examined the role of ostomy on QOL. We also compared QOL with disease outcomes and physician-reported toxicity. ### results The FACT-C questionnaire was completed by 97% of patients before RT, 85% immediately before surgery, and 62% 1 year after surgery. There was no statistically significant change in mean FACT-C scores from before treatment to after treatment. The majority of patients had either no change or an increase in QOL 1 year after treatment using the MID method. There were significant changes in QOL between patients with ostomy versus no ostomy 1 year after treatment for functional well-being (FWB) (14.81 vs 20.52, P=.018) and the colorectal cancer subscale (CCS) using the MID method (P=.004). Patients without ostomy reported stable changes in bowel control 1 year after surgery. There was no statistically significant correlation between QOL and disease recurrence, pathologic complete response, pathologic T stage downstaging, or acute/late toxicity. ### conclusions SC-RT and sequential mFOLFOX6 as preoperative therapy for rectal cancer results in stable patient-reported QOL outcomes 1 year after treatment. These findings in conjunction with previously reported oncologic outcomes support further evaluation of this regimen in a phase 3 setting. ### Assistant: [{"class": "POS", "spans_text": ["5-fluorouracil", "oxaliplatin", "leucovorin"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: [ A case of advanced gastric cancer successfully treated with trastuzumab , capecitabine , and Cisplatin therapy followed by curative resection ] . Paragraph: [ A case of advanced gastric cancer successfully treated with trastuzumab , capecitabine , and Cisplatin therapy followed by curative resection ] . We report a case of human epidermal growth factor receptor 2(HER2)-positive advanced gastric cancer successfully treated with combination therapy of trastuzumab, capecitabine, and cisplatin, followed by a curative resection. A 23-year-old woman was diagnosed with advanced type 3 gastric cancer, and the clinical findings were T3N0M0, StageIIA. A laparoscopic exploration revealed that it was a CY1 unresectable StageIV cancer. Initially, docetaxel, cisplatin, and S-1 therapy was chosen. However, the patient's HER2 status proved to be positive (IHC 3+), and so trastuzumab, capecitabine and cisplatin therapy was administered. After four cycles, the tumor significantly decreased in size, suggesting a partial response(PR). A further laparoscopic exam showed no apparent dissemination or metastatic cancer cells. We performed a curative resection consisting of a laparoscopic distal gastrectomy and D2 lymphadenectomy. The patient's postoperative course has been uneventful. She has been alive for 4 months and is receiving adjuvant chemotherapy comprising trastuzumab and S-1. ### Assistant: [{"class": "POS", "spans_text": ["trastuzumab", "capecitabine", "Cisplatin"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Sulpiride plus hydroxyzine decrease tinnitus perception . Paragraph: Sulpiride plus hydroxyzine decrease tinnitus perception . The aim of the study is to confirm the effectiveness of sulpiride and hydroxyzine in tinnitus patients. The administration of sulpiride, a D2 antagonist of dopamine receptors, together with hydroxyzine, a subcortical sedative, covers the areas of tinnitus perception. ### methods A prospective, randomized, single blinded, placebo-control study was done in general otorhinolaryngology consultations for 2002-2004 in Seville and Zaragoza (Spain). One hundred and fifty patients consulted for subjective tinnitus. They were included randomly in three groups of 50. A group took sulpiride (50 mg/8 h) alone, other the same dose of sulpiride plus hydroxyzine (25 mg/12 h), and the third placebo (lactose), for 1 month. One hundred and twenty-two patients completed the study. Clinical history, tonal audiometry, tympanometry, and tinnitometry were done in the beginning and end of the study. Subjective Grading of Tinnitus Perception and visual analogical scale (0-10) were done for result evaluation. ### results Based on the Subjective Grading of Tinnitus Perception, tinnitus perception diminished by 56% in patients treated with sulpiride and by 81% in patients treated with sulpiride plus hydroxyzine. Based on the visual analogical scale, tinnitus perception diminished from 7.8 to 6.3 in the patients treated with sulpiride, and from 7.8 to 5.1 in those treated with sulpiride plus hydroxyzine. ### conclusions sulpiride plus hydroxyzine decreases tinnitus perception. Tinnitus auditolimbic dopaminergic pathway opens wide therapeutical implications. ### Assistant: [{"class": "POS", "spans_text": ["Sulpiride", "hydroxyzine"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: We gave 2 , 3 , 5 and 5 mg/day/body of recombinant tissue plasminogen activator ( tPA ) followed by heparin and prostaglandin E1 ( PGE1 ) effectively and without significant side effect on days 9 , 10 , 13 and 14 , respectively . Paragraph: Successful treatment of an infant with veno-occlusive disease developed after allogeneic bone marrow transplantation by tissue plasminogen activator, heparin and prostaglandin E1. A 15-month-old boy with severe aplastic anemia developed veno-occlusive disease (VOD) after allogeneic bone marrow transplantation (BMT), in which the preparative regimen included 50 mg/kg/day cyclophosphamide and anti-lymphocyte globulin for 4 consecutive days. The diagnosis was made based on clinical symptoms and data including, hepatomegaly, right upper quadrant abdominal pain, jaundice, ascites, coagulopathy and thrombocytopenia which was refractory to transfusions of platelet concentrate. We gave 2 , 3 , 5 and 5 mg/day/body of recombinant tissue plasminogen activator ( tPA ) followed by heparin and prostaglandin E1 ( PGE1 ) effectively and without significant side effect on days 9 , 10 , 13 and 14 , respectively . Clinical and biochemical improvement was steady and dramatic. We suggest that tPA following continuous heparin and PGE1 infusion may be useful in the treatment of VOD even in infantile cases. ### Assistant: [{"class": "POS", "spans_text": ["tissue plasminogen activator", "heparin", "prostaglandin E1"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Roxithromycin and clarithromycin , 14-membered ring macrolides , potentiate the antitumor activity of cytotoxic agents against mouse B16 melanoma cells . Paragraph: Roxithromycin and clarithromycin , 14-membered ring macrolides , potentiate the antitumor activity of cytotoxic agents against mouse B16 melanoma cells . We previously reported antiangiogenic activity of roxithromycin and clarithromycin, 14-membered ring macrolide antibiotics. In the present study, we examined the antitumor effects of roxithromycin and clarithromycin, alone and in combination with several cytotoxic drugs, on mouse B16BL6 melanoma cells in vivo and in vitro. Both roxithromycin and clarithromycin potentiated the inhibition of tumor growth induced by cyclophosphamide, cis-diamminedichloroplatinum(II), Adriamycin and vindesine in vivo. However, neither roxithromycin nor clarithromycin, altered the cytotoxicity of 4-hydroperoxycyclophosphamide, cis-diamminedichloroplatinum(II), Adriamycin or vindesine in an in vitro cell proliferation assay. These results suggest that the antiangiogenic activity of roxithromycin and clarithromycin may provide beneficial effects in combination with cytotoxic therapies against solid tumors. ### Assistant: [{"class": "POS", "spans_text": ["Roxithromycin", "clarithromycin"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: The EVA regimen ( etoposide , vinblastine , doxorubicin ) is an attempt to substitute a known active agent , etoposide , for bleomycin and dacarbazine . Paragraph: Primary systemic treatment of advanced Hodgkin's disease with EVA (etoposide, vinblastine, doxorubicin): 10-year follow-up. The most commonly used regimen for the treatment of advanced Hodgkin's disease (HD) is ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine). Two of these components, bleomycin and dacarbazine, have defined toxicities such as pulmonary fibrosis and nausea/vomiting, and also uncertain single-drug activity. The EVA regimen ( etoposide , vinblastine , doxorubicin ) is an attempt to substitute a known active agent , etoposide , for bleomycin and dacarbazine . ### Patients And Methods A series of 51 patients with advanced HD without prior systemic therapy were treated. The series included 12 stage II patients with bulky (>10 cm) mediastinal tumors, 10 of whom received complementary radiation therapy. The remaining patients received EVA only. Response, duration of response, survival, toxicity and the efficacy of salvage therapy were evaluated in all patients. The median follow-up time was 111 months and permitted an assessment of the long-term effects of treatment and natural history of a cohort of treated patients. ### results EVA achieved a complete response (or clinical complete response) in 48/51 patients (94%). Of these 48 responders, 16 relapsed in a median of 11 months (range 3-48 months). In follow-up, 32/51 patients had no evidence of relapsed HD, although three died from other causes (two from vascular events and one from large cell lymphoma), resulting in progression-free survival for the entire group of 57% at 111 months. Eight of the 16 were alive and free from disease at follow-up at 111 months. In the entire series, only seven patients (14%) died of HD. 37 patients (73%) continued free from disease. There was no pulmonary toxicity. ### conclusions The EVA regimen appears to have an overall survival (OS) outcome comparable to ABVD, but without the lung toxicity. The high salvage rate of second-line therapy, in most instances at conventional dosage, suggests an absence of cross-resistance to alkylating agents in patients treated with EVA. ### Assistant: [{"class": "POS", "spans_text": ["etoposide", "vinblastine", "doxorubicin"]}, {"class": "COMB", "spans_text": ["vinblastine", "doxorubicin", "bleomycin", "dacarbazine"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Carvedilol and imatinib mesylate alone reduced cell number , BrDU-LI , cAMP levels and spheroid volume . Paragraph: Carvedilol in glioma treatment alone and with imatinib in vitro. The purpose of the study was to investigate whether carvedilol has an antiproliferative effect alone and whether carvedilol provides an additive, synergistic or antagonistic effect on imatinib mesylate-induced cytotoxicity in both C6 glioma monolayer and spheroid culture. The C6 rat glioma chemoresistant experimental brain tumour cell line, that is notoriously difficult to treat with combination chemotherapy, was used both in monolayer and spheroid cultures. We treated C6 glioma cells with carvedilol alone and a combination of carvedilol and imatinib mesylate at a concentration of 10 microM. Following treatment, we evaluated cell proliferation index, bromodeoxyuridine labelling index (BrDU-LI), cell cycle distributions, apoptotic cell percentages, cAMP levels and three dimensional cell morphology at monolayer cultures. In addition BrDU-LI, volume and morphology of spheroids were also assessed. Carvedilol and imatinib mesylate alone reduced cell number , BrDU-LI , cAMP levels and spheroid volume . carvedilol and imatinib mesylate arrested cells at G0/G1 phase in a time-dependent manner and time-independent manner, respectively. carvedilol increased apoptosis rate only at the 24th h, but imatinib mesylate did for all time intervals. Interestingly carvedilol, drug with well-known protective effect on mitochondria, induced severe mitochondria damage, and imatinib mesylate induced autophagy confirmed only by transmission electron microscopy. These results suggest that carvedilol showed antitumour activity against rat C6 glioma cells and a combination of carvedilol with imatinib mesylate resulted in enhanced in vitro antitumour activity. ### Assistant: [{"class": "POS", "spans_text": ["Carvedilol", "imatinib"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: The recommended phase II dose ( RP2D ) was cytarabine 10 mg bid days 1 - 10 and sorafenib 600 mg/day days 2 - 28 . Paragraph: A phase I/II study of sorafenib in combination with low dose cytarabine in elderly patients with acute myeloid leukemia or high-risk myelodysplastic syndrome from the National Cancer Institute of Canada Clinical Trials Group: trial IND.186. sorafenib is active in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The National Cancer Institute of Canada (NCIC) Clinical Trials Group initiated a phase I/II study of the combination of sorafenib with cytarabine in older patients with AML or high-risk MDS who were unsuitable for intensive chemotherapy. FLT3 mutational status was determined in all patients. Twenty-one patients were enrolled (four MDS, 17 AML) with a median age of 77 years. The recommended phase II dose ( RP2D ) was cytarabine 10 mg bid days 1 - 10 and sorafenib 600 mg/day days 2 - 28 . Dose-limiting toxicities were fatigue, sepsis and skin rash. Of 15 evaluable patients treated at the RP2D, two patients responded. The overall response rate for eligible patients was 10%. FLT3 mutations were found in only three patients. We conclude that this combination of sorafenib and cytarabine has limited activity in this unselected cohort of elderly patients with AML/MDS in which FLT3 mutations seemed underrepresented. ### Assistant: [{"class": "POS", "spans_text": ["cytarabine", "sorafenib"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: We performed a single-arm phase II trial of panitumumab in patients with KRAS wild-type metastatic colorectal cancer that had progressed on prior cetuximab . Paragraph: Panitumumab in patients with KRAS wild-type colorectal cancer after progression on cetuximab. cetuximab and panitumumab are monoclonal antibodies that target the epidermal growth factor receptor (EGFR) and are approved for the treatment of patients with KRAS wild-type meta-static colorectal cancer. There are no data that describe the activity of panitumumab in patients with progressive disease on cetuximab. We performed a single-arm phase II trial of panitumumab in patients with KRAS wild-type metastatic colorectal cancer that had progressed on prior cetuximab . ### Patients And Methods We used a two-stage study design to treat patients with panitumumab at 6 mg/kg every 14 days (cycle length = 28 days). Treatment was continued until disease progression, death, inability to tolerate panitumumab, or study withdrawal. The primary endpoint was response rate; secondary endpoints included progression-free survival and overall survival. Twenty patients were treated in the first stage, with plans to treat an additional twelve patients if there was at least one objective response. We collected blood samples at baseline and prior to cycles 2 and 3 to evaluate for the presence of anti-cetuximab and anti-panitumumab antibodies. ### results We treated twenty patients for a median of two cycles (range 1-4). No patients responded, and 45% had a best response of stable disease (no progression for at least two cycles). Median progression-free survival was 1.7 months and median overall survival was 5.2 months. panitumumab was well tolerated. Thirteen patients (65%) had grade 1-2 dry skin or rash, and three patients had treatment-related grade 3 toxicities (one each with hyperglycemia, hyperbilirubinemia, and hypokalemia). No patients had detectable anti-cetuximab antibodies at any time point; one patient developed anti-panitumumab antibodies. ### conclusions panitumumab has minimal benefit in patients with KRAS wild-type metastatic colorectal cancer that has progressed on prior cetuximab. Discussion Both cetuximab and panitumumab competitively inhibit ligand binding to EGFR, thereby promoting receptor internalization and blocking receptor-mediated signaling. Although the two agents have never been compared directly in a randomized clinical trial, they produce similar response rates when used alone as well as in combination with cytotoxic agents. cetuximab is a chimeric antibody with approximately 30% murine protein, while panitumumab is a fully human monoclonal antibody. Correspondingly, rates of severe hypersensitivity reactions are somewhat increased with cetuximab (3%) compared to panitumumab (1%). However, the potential efficacy of panitumumab in patients who have developed disease progression on cetuximab has been an open question. Metges et al. (PANERB trial) prospectively treated 32 KRAS wild-type metastatic colorectal cancer patients with cetuximab and irinotecan followed by panitumumab monotherapy after progression. Remarkably, the authors reported an objective response rate of 22% to panitumumab, including a disease control rate (objective response plus stable disease) of 73% in 11 patients who had previously responded to cetuximab and irinotecan. In contrast, we found no responders and a stable disease rate of 45% with a median duration of only 1.7 months in our trial of 20 patients. Moreover, no patients had detectable anti-cetuximab antibodies at baseline. It is not clear to what extent the PANERB trial included patients without objective disease progression on cetuximab or for whom cetuximab-containing regimens may have been ceased due to toxicity in the absence of disease progression. In both circumstances, retreatment with panitumumab may be expected to demonstrate some degree of clinical activity. In our study, disease progression after at least 4 weeks of cetuximab documented radiographically or by increased carcinoembryonic antigen (CEA) levels was required for inclusion in order to ensure that the study population demonstrated unequivocal evidence of progression on cetuximab. While it remains possible that a small subset of patients may benefit from panitumumab after progression on cetuximab, our results suggest that this approach should not be adopted until predictive biomarkers for panitumumab response in this setting have been discovered and validated. Until then, patients who develop progression on cetuximab should be enrolled in trials of novel agents. ### Assistant: [{"class": "NEG", "spans_text": ["panitumumab", "cetuximab"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Two Phase 1 studies assessed effects of ABT-450 ( 150 mg coadministered with ritonavir 100 mg once daily ) , ombitasvir ( 25 mg once daily ) , and dasabuvir ( 400 mg twice daily ) on the pharmacokinetics , safety , and tolerability of a single dose of cyclosporine ( 30 mg ) or tacrolimus ( 2 mg ) in healthy volunteers ( N = 12 per study ) . Paragraph: Pharmacokinetics and dose recommendations for cyclosporine and tacrolimus when coadministered with ABT-450, ombitasvir, and dasabuvir. ABT-450, ombitasvir, and dasabuvir are direct-acting antiviral agents (DAAs) that have been developed for combination treatment of chronic hepatitis C virus (HCV) infection. Because these DAAs have metabolic and transporter profiles that overlap with cyclosporine and tacrolimus disposition, there is potential for drug interactions. Two Phase 1 studies assessed effects of ABT-450 ( 150 mg coadministered with ritonavir 100 mg once daily ) , ombitasvir ( 25 mg once daily ) , and dasabuvir ( 400 mg twice daily ) on the pharmacokinetics , safety , and tolerability of a single dose of cyclosporine ( 30 mg ) or tacrolimus ( 2 mg ) in healthy volunteers ( N = 12 per study ) . In the presence of steady-state concentrations of all 3 DAAs, dose-normalized cyclosporine concentration at 24 hours (C₂₄), and area under the concentration-time curve from time 0 to infinity (AUC(∞)) were 15.8-fold and 5.8-fold, respectively, and dose-normalized tacrolimus C₂₄ and AUC(∞) were 17-fold and 57-fold, respectively, of either agent alone. cyclosporine and tacrolimus half-lives increased from 7 to 25 h and 32 to 232 h, respectively. There were no major safety or tolerability issues in these studies. The results suggest that cyclosporine and tacrolimus doses and dosing frequency should be reduced in HCV-infected posttransplant patients being treated with this 3-DAA regimen. ### Assistant: [{"class": "POS", "spans_text": ["ABT-450", "ritonavir", "ombitasvir", "dasabuvir", "cyclosporine"]}, {"class": "POS", "spans_text": ["ABT-450", "ritonavir", "ombitasvir", "dasabuvir", "tacrolimus"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Antiplatelet therapy with dipyridamole , 100 mg q.i.d . , starting 2 days before surgery , followed by aspirin , 325 mg t.i.d . plus dipyridamole , 75 mg t.i.d . , 7 hours after surgery was assessed in the prevention of saphenous vein bypass graft occlusion . Paragraph: Effect of dipyridamole and aspirin on vein graft patency after coronary bypass operations. Antiplatelet therapy with dipyridamole , 100 mg q.i.d . , starting 2 days before surgery , followed by aspirin , 325 mg t.i.d . plus dipyridamole , 75 mg t.i.d . , 7 hours after surgery was assessed in the prevention of saphenous vein bypass graft occlusion . Early (less than or equal to 1 month) and late (1 year) occlusions were reduced both on a per patient and a per distal anastomosis basis. Bleeding complications were not increased. Graft occlusion in high-risk situations (low-flow grafts and endarterectomy) was reduced, but not eliminated, by this antiplatelet regimen. The authors recommend this combination of dipyridamole before surgery, adding aspirin after surgery, to prevent coronary artery bypass graft occlusion. ### Assistant: [{"class": "POS", "spans_text": ["dipyridamole", "aspirin", "dipyridamole"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Toxicity patterns following stepwise combinations of cyclophosphamide , methotrexate and fluorouracil . Paragraph: Toxicity patterns following stepwise combinations of cyclophosphamide , methotrexate and fluorouracil . The contribution of the agents used in the CMF regimen, i.e., cyclophosphamide (CY), methotrexate (MTX) and fluorouracil (FUra), to the development of toxicity was determined in tumor-bearing WAG/Rij rats. Data from untreated (U) rats were compared with data from rats treated with single-agent therapy (C-, M- and F-treatment groups), with data from double-agent therapy (CM-, MF- and CF-treatment groups) and with data from the triple combination: the CMF-treatment group. Doses of agents of interest were the same in all treatment groups. The sequence of administration was (1) CY; (2) MTX and (3) FUra which is similar to clinical treatment with CMF. Systemic levels of CY, MTX and FUra were comparable to those found in patients treated according to the CMF regimen. Toxicity was evaluated by body-weight changes, water and food consumption, white blood cell (WBC) and platelet cell (Pts) counts. With the exception of WBC and Pts nadirs, estimated toxicity parameters reflected toxicity over the whole treatment period of 14 days. The toxicity was generally mild and well tolerated, with one fatality in the M-treatment group. CY was the main contributor to toxicity; it caused both myelotoxicity and gastro-intestinal toxicity. The contribution of FUra was judged to be negligible. MTX + FUra did not increase host toxicity in a synergistic or even an additional fashion. The absence of addition or synergism of toxic side-effects can be explained both by site-specific interactions at the pharmacodynamic level and by interactions at the pharmacokinetic level. ### Assistant: [{"class": "POS", "spans_text": ["cyclophosphamide", "methotrexate", "fluorouracil"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: All patients were treated with the combination of lapatinib ( 1250 mg/day , continuously ) and capecitabine ( 2000 mg/m(2 ) on days 1 through 14 of a 21-day cycle ) . Paragraph: Lapatinib plus capecitabine for HER2-positive advanced breast cancer: a multicentre study of Anatolian Society of Medical Oncology (ASMO). lapatinib is the first dual tyrosine kinase inhibitor of human epidermal growth factor receptor type 2 (HER2/neu) and epidermal growth factor receptor (EGFR). The present study evaluated the efficacy and tolerability of the combination of lapatinib and capecitabine in patients with metastatic breast cancer (MBC) who progressed after therapy with trastuzumab, a taxane and/or anthracycline. A total of 203 patients with a median age of 48 years (range: 25-82 years) were evaluated retrospectively in 11 centres between September 2007 and May 2011. All the patients had HER2-positive MBC progressing after trastuzumab and chemotherapy including an anthracycline and/or taxane. All patients were treated with the combination of lapatinib ( 1250 mg/day , continuously ) and capecitabine ( 2000 mg/m(2 ) on days 1 through 14 of a 21-day cycle ) . Data on demographics, clinical outcome, and toxicity were collected for descriptive analyses. The median follow-up was 10·7 months (range: 1-40 months). An overall response rate (ORR) of 33·4% was achieved including 7 complete responses (CR, 3·4%), 61 partial responses (PR, 30·0%), and 44 stable disease (37·9%). Clinical benefit rate of 71·3% was achieved. Median progression-free survival (PFS) was 7 months (95% CI: 6-10 months), with a median overall survival (OS) of 15 months (95% CI: 12-18 months). The most common side effects were hand-foot syndrome (46·8%), nausea (42·3%), fatigue (42·2%), anorexia (38·5%), diarrhea (31·5%), and rash (29·6%). Grade 3-4 toxicities were identified as hand foot syndrome (7·9%), diarrhea (6·9%), fatigue (5·9%), and rash (5·4%). There were no symptomatic cardiac events. lapatinib and capecitabine combination therapy is effective and well tolerated in patients with MBC who had progressive disease after trastuzumab, taxane, and/or anthracycline therapy, as evidenced by this retrospective evaluation. Toxicity was mild to moderate with low grade 3-4 toxicity. ### Assistant: [{"class": "POS", "spans_text": ["lapatinib", "capecitabine"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Effect of curcumin , a natural phytochemical in restoring doxorubicin sensitivity by targeting Aurora A was assessed furthermore . Paragraph: Curcumin Rescues Doxorubicin Responsiveness via Regulating Aurora a Signaling Network in Breast Cancer Cells. Insensitivity towards anthracycline drugs like doxorubicin poses a significant challenge in the treatment of breast cancer. Among several factors, Aurora A (a mitotic serine threonine kinase) plays crucial roles in acquiring non-responsiveness towards doxorubicin. However, the mechanisms underlying need to be elucidated. The present study was therefore designed to evaluate the underlying mechanisms of Aurora A mediated doxorubicin insensitivity in MCF-7Dox/R, an isolated resistant-subline of MCF-7 (breast adenocarcinoma cell line). Effect of curcumin , a natural phytochemical in restoring doxorubicin sensitivity by targeting Aurora A was assessed furthermore . ### methods A doxorubicin resistant subline (MCF-7Dox/R) was isolated from the parental MCF-7 cells by treating the cell with gradual step-wise increasing concentration of the drug. Expressions of Aurora A and its target proteins (Akt, IκBα and NFκB) were assessed in both parental and MCF-7Dox/R cells. Both the cell lines were pretreated with curcumin prior to doxorubicin treatment. Cellular proliferation rate was measured using BrdU (5-bromo-2'-deoxyuridine) assay kit. Intracellular doxorubicin accumulation was estimated spectrofluorimetrically. Cellular uptake of curcumin (spectrophotometric and spectrofluorimetric method) and its nuclear localization was confirmed by confocal microscopic study. Protein expressions were determined by western blot analysis. Localization of Aurora A was ascertained by immunofluorescence assay. To explore the possible outcome of impact of curcumin on Aurora A, cell-cycle distribution and apoptosis were performed subsequently. ### results Higher expressions of Aurora A in MCF-7Dox/R cells led to phosphorylation of Akt as well as IκBα. Phosphorylated IκBα preceded release of NFκB. Phospho-Akt, NFκB consequentially decreased doxorubicin accumulation by enhancing the expressions of ABCG2 and Pgp1 respectively. curcumin by regulating Aurora A and its target molecules sensitized resistant subline towards doxorubicin mediated G2/M-arrest and apoptosis. ### conclusion Molecular targeting of Aurora A by curcumin restores chemosensitivity by increasing the efficacy of doxorubicin in breast cancer.. ### Assistant: [{"class": "POS", "spans_text": ["curcumin", "doxorubicin"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Our goals were to : establish the maximum-tolerated dose of olaparib tablets combined with metronomic carboplatin and paclitaxel in patients with relapsed high-grade serous ovarian cancer ; evaluate dose-limiting toxicities ; and evaluate efficacy at the maximum tolerated dose . Paragraph: Phase Ib with expansion study of olaparib plus weekly (Metronomic) carboplatin and paclitaxel in relapsed ovarian cancer patients. Our goals were to : establish the maximum-tolerated dose of olaparib tablets combined with metronomic carboplatin and paclitaxel in patients with relapsed high-grade serous ovarian cancer ; evaluate dose-limiting toxicities ; and evaluate efficacy at the maximum tolerated dose . ### methods In this open-label, single-arm, investigator-initiated trial (ClinicalTrials.gov NCT01650376), patients with high-grade serous ovarian cancer who failed primary platinum and taxane therapy received oral olaparib tablets twice daily days 1-3 each week combined with fixed-dose metronomic carboplatin AUC2 and paclitaxel 60 mg/m ### results The maximum tolerated dose of olaparib tablets was 150 mg twice daily with metronomic carboplatin and paclitaxel. 54 women were enrolled, 14 in phase Ib and 40 in the expansion phase. The median number of prior therapeutic regimens was 3. Response included 13 complete remission (24%) and 16 partial remission (30%) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) for an overall response rate of 54% (95% CI 40% to 67%). Of 47 patients who underwent ### conclusions olaparib 150 mg tablet twice daily can be safely administered in combination with metronomic carboplatin and paclitaxel in pre-treated relapsed ovarian cancer with 24% complete remission. ### Trial Registration Number NCT01650376. ### Assistant: [{"class": "POS", "spans_text": ["olaparib", "carboplatin", "paclitaxel"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: All patients in this study were treated with decitabine of 15 mg/m2 for 5 days and G-CSF for priming , in combination with cytarabine of 10-mg/m2 q12h for 7 days and aclarubicin of 10 mg/day for 4 days ( D-CAG ) . Paragraph: Efficacy and safety of decitabine in combination with G-CSF, low-dose cytarabine and aclarubicin in newly diagnosed elderly patients with acute myeloid leukemia. This prospective phase II, open label, study was designed to assess the efficacy and safety of D-CAG induction treatment for elderly patients with newly diagnosed AML. ### Experimental Design All patients in this study were treated with decitabine of 15 mg/m2 for 5 days and G-CSF for priming , in combination with cytarabine of 10-mg/m2 q12h for 7 days and aclarubicin of 10 mg/day for 4 days ( D-CAG ) . ### results Among 85 evaluable patients, overall response rate (ORR) and complete remission (CR) were 82.4% and 64.7%, respectively, after 1 cycle of therapy. The ORR in patients aged <70 years was 83.0% and 81.6% in patients aged ≥70 years. There was a significantly longer median overall survival (OS) in patients with response (16 months) than in those without response (7 months, p< 0.0001). The OS for patients aged ≥70 years and 60-69 years was 10 months and 12 months, respectively (p=0.4994). The two-year OS probability was 19.2% and the twenty-month survival rate was 33.8%. Induction mortality of D-CAG treated elderly patients with AML is 4.4%. ### conclusion D-CAG regimen was well tolerated and showed a promising clinic efficacy in elderly patients with AML (≥70 years). ### Assistant: [{"class": "POS", "spans_text": ["decitabine", "cytarabine", "aclarubicin"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Pertuzumab is the most recent agent approved by the US Food and Drug Administration in combination with trastuzumab and docetaxel for the treatment of patients with HER2(+ ) metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease . Paragraph: Pertuzumab in breast cancer: a systematic review. pertuzumab is a monoclonal antibody that represents the first among a new class of agents known as human epidermal growth factor receptor (HER) dimerization inhibitors. This is the first systematic review according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to synthesize all available data of pertuzumab in breast cancer. The search strategy retrieved 11 studies that evaluated pertuzumab. One study was conducted in the neoadjuvant setting (417 patients), whereas all the others dealt with patients with recurrent, metastatic, or refractory disease (1023 patients). Six studies were conducted in HER2(+) breast cancer population (1354 patients), whereas 5 studies (86 patients) were conducted in HER2(-) (or unknown HER2 status) disease. Pertuzumab is the most recent agent approved by the US Food and Drug Administration in combination with trastuzumab and docetaxel for the treatment of patients with HER2(+ ) metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease . This approval has been based on data from a phase III Clinical Evaluation of pertuzumab and trastuzumab (CLEOPATRA) study. The antitumor activity with the significant reduction in the risk of progression or death, as reflected upon the increase of 6.1 months in median progression-free survival, indicates that pertuzumab may provide an avenue for achieving additional benefit for patients with HER2(+). Moreover, pertuzumab seems to have a putative role in the management of patients with HER2 who are resistant to trastuzumab. The promising role of pertuzumab in the neoadjuvant and adjuvant settings remains to be further investigated and established in the future. ### Assistant: [{"class": "POS", "spans_text": ["Pertuzumab", "trastuzumab", "docetaxel"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Safety and efficacy of sorafenib followed by regorafenib or lenvatinib in patients with hepatocellular carcinoma . Paragraph: Safety and efficacy of sorafenib followed by regorafenib or lenvatinib in patients with hepatocellular carcinoma . Sequential administration of sorafenib followed by regorafenib or lenvatinib is effective against advanced hepatocellular carcinoma (HCC). In this study, we compared the safety profiles and anti-tumor effects of sequential sorafenib and regorafenib or lenvatinib therapy in patients with HCC. ### methods We investigated adverse events, treatment responses and dose intensities in patients with HCC who were consecutively treated with sorafenib followed by regorafenib or lenvatinib at the individual level. ### results Each group included 20 patients. The safety profiles of regorafenib and sorafenib were similar. The severity of hypophosphatemia, palmar-plantar erythrodysesthesia syndrome, and decreased neutrophil counts associated with regorafenib or sorafenib was similar in 12 patients. Conversely, the incidences and grades of adverse events differed between sorafenib and lenvatinib treatment. The anti-tumor effects of regorafenib and lenvatinib compared with sorafenib were significantly different for each patient. The response to treatment and progression-free survival were comparable for regorafenib and lenvatinib. The median relative dose intensities during the first 56 days of regorafenib and lenvatinib treatment were 83.6 and 80.0%, respectively. ### conclusions Similar adverse events were experienced by patients during consecutive treatment with sorafenib and regorafenib, which was not observed during treatment with sorafenib and lenvatinib. The obtained safety profile of sorafenib provided meaningful insights for selecting sequential therapy for patients with advanced HCC. ### Assistant: [{"class": "COMB", "spans_text": ["sorafenib", "regorafenib"]}, {"class": "COMB", "spans_text": ["sorafenib", "lenvatinib"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: The combination of boceprevir or telaprevir with peginterferon-alfa and ribavirin for the treatment of patients infected with HCV genotype 1 has led to significantly increased rates of sustained virological response ( SVR ) in phase III trials . Paragraph: Safety and efficacy of protease inhibitor based combination therapy in a single-center "real-life" cohort of 110 patients with chronic hepatitis C genotype 1 infection. The combination of boceprevir or telaprevir with peginterferon-alfa and ribavirin for the treatment of patients infected with HCV genotype 1 has led to significantly increased rates of sustained virological response ( SVR ) in phase III trials . There is only limited data regarding the safety and efficacy in a "real-life" cohort. ### methods We analyzed a cohort of 110 unselected HCV patients who started triple therapy from September 2011 to February 2013 by chart review with focus on the individual course of treatment, complications and outcome. We excluded 8 patients from analysis because of HIV-coinfection (N = 6) or status post liver transplant (N = 2). Importantly, 41 patients displayed F3 or F4 fibrosis, 10 patients had a history of treatment with protease/polymerase inhibitors and 15 patients were prior partial- or null-responder. ### results SVR12 was achieved in 62 of the 102 patients (60.8%). A high rate of serious adverse events (N = 30) was observed in 22 patients including 2 fatalities in cirrhotic diabetes patients. Age >50 years, liver cirrhosis, bilirubin >1.1 mg/dl (P < 0.01, each), platelets <100,000/μl (P = 0.01), ASAT >100 U/l (P = 0.03) and albumin ≤35 g/l (P = 0.04) at baseline were associated with occurence of a SAE. ### conclusions The frequency of SVR in a "real-life" treatment setting is slightly lower as compared to the results of the phase III trials for telaprevir or boceprevir. Importantly, we observed a high frequency of SAE in triple therapy, especially in patients with liver cirrhosis. ### Assistant: [{"class": "POS", "spans_text": ["boceprevir", "peginterferon-alfa", "ribavirin"]}, {"class": "POS", "spans_text": ["telaprevir", "peginterferon-alfa", "ribavirin"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: In contrast , the combination of plumbagin with AR antagonists , such as bicalutamide and enzalutamide , showed no improvement over AR antagonists alone . Paragraph: Plumbagin improves the efficacy of androgen deprivation therapy in prostate cancer: A pre-clinical study. Plumbagin is a candidate drug for the treatment of prostate cancer. Previous observations indicated that it may improve the efficacy of androgen deprivation therapy (ADT). This study evaluates the effectiveness of treatment with combinations of plumbagin and alternative strategies for ADT in mouse models of prostate cancer to support its clinical use. ### methods Plumbagin was administered per oral in a new sesame oil formulation. Standard toxicology studies were performed in rats. For tumor growth studies, mouse prostate cancer cell spheroids were placed on top of grafted prostate tissue in a dorsal chamber and allowed to form tumors. Mice were separated in various treatment groups and tumor size was measured over time by intra-vital microscopy. Survival studies were done in mice after injection of prostate cancer cells in the prostate of male animals. Androgen receptor (AR) levels were analyzed by Western blot from prostate cancer cells treated with plumbagin. ### results Plumbagin caused a decrease in AR levels in vitro. In mice, plumbagin at 1 mg/kg in sesame oil displayed low toxicity and caused a 50% tumor regression when combined with castration. The combination of plumbagin with various forms of chemical ADT including treatment with a GnRH receptor agonist, a GnRH receptor antagonist, or CYP17A1 inhibitors, outperformed ADT alone, increasing mouse survival compared to the standard regimen of castration alone. In contrast , the combination of plumbagin with AR antagonists , such as bicalutamide and enzalutamide , showed no improvement over AR antagonists alone . Thus, plumbagin is effective in combination with drugs that prevent the synthesis of testosterone or its conversion to dihydrotestosterone, but not with drugs that bind to AR. ### conclusion Plumbagin significantly improves the effect of ADT drugs currently used in the clinic, with few side effects in mice. ### Assistant: [{"class": "COMB", "spans_text": ["bicalutamide", "plumbagin"]}, {"class": "COMB", "spans_text": ["enzalutamide", "plumbagin"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: The B-cell lymphoma 2 ( BCL-2 ) inhibitor venetoclax has an emerging role in acute myeloid leukemia ( AML ) , with promising response rates in combination with hypomethylating agents or low-dose cytarabine in older patients . Paragraph: Chemotherapy and Venetoclax in Elderly Acute Myeloid Leukemia Trial (CAVEAT): A Phase Ib Dose-Escalation Study of Venetoclax Combined With Modified Intensive Chemotherapy. The B-cell lymphoma 2 ( BCL-2 ) inhibitor venetoclax has an emerging role in acute myeloid leukemia ( AML ) , with promising response rates in combination with hypomethylating agents or low-dose cytarabine in older patients . The tolerability and efficacy of venetoclax in combination with intensive chemotherapy in AML is unknown. ### Patients And Methods Patients with AML who were ≥ 65 years (≥ 60 years if monosomal karyotype) and fit for intensive chemotherapy were allocated to venetoclax dose-escalation cohorts (range, 50-600 mg). venetoclax was administered orally for 14 days each cycle. During induction, a 7-day prephase/dose ramp-up (days -6 to 0) was followed by an additional 7 days of venetoclax combined with infusional cytarabine 100 mg/m ### results Fifty-one patients with a median age of 72 years (range, 63-80 years) were included. The maximum tolerated dose was not reached with venetoclax 600 mg/day. The main grade ≥ 3 nonhematologic toxicities during induction were febrile neutropenia (55%) and sepsis (35%). In contrast to induction, platelet recovery was notably delayed during consolidation cycles. The overall response rate (complete remission [CR]/CR with incomplete count recovery) was 72%; it was 97% in de novo AML and was 43% in secondary AML. During the venetoclax prephase, marrow blast reductions (≥ 50%) were noted in ### conclusion venetoclax combined with 5 + 2 induction chemotherapy was safe and tolerable in fit older patients with AML. Although the optimal postremission therapy remains to be determined, the high remission rate in de novo AML warrants additional investigation (ANZ Clinical Trial Registry No. ACTRN12616000445471). ### Assistant: [{"class": "POS", "spans_text": ["venetoclax", "cytarabine"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Combination chemotherapy with vincristine , bleomycin , and methotrexate for advanced head and neck cancers . Paragraph: Combination chemotherapy with vincristine , bleomycin , and methotrexate for advanced head and neck cancers . Thirty-three patients with a histologically confirmed diagnosis of advanced squamous cell carcinoma of the head and neck were treated with a combination of vincristine, methotrexate, and bleomycin. The regimen was as follows: Day 1, vincristine (2 mg iv) and methotrexate (200 mg/m2 iv over 24 hours); Day 2, bleomycin (15 mg/day by iv infusion for 48 hours). Folinic acid rescue began 36 hours after the start of methotrexate. The regimen was repeated at intervals of 3 weeks. Toxicity was minimal but the overall response rate was only 24% (three complete responses and five partial responses) and the median duration of remission was only 16 weeks overall. The combination of vincristine, methotrexate, and bleomycin in this dosage schedule has a response rate lower than that reported with single-agent treatment of advanced head and neck cancers. ### Assistant: [{"class": "NEG", "spans_text": ["vincristine", "bleomycin", "methotrexate"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Combination therapy with labetalol ( 400 mg/day ) and prazosin ( 6 mg/day ) was unsatisfactory , and the addition of long-acting nifedipine ( 40 mg/day ) produced a marked decrease in blood pressure . Paragraph: Effectiveness of long-acting nifedipine in pheochromocytoma. In the present study, we report a case of pheochromocytoma whose high blood pressure was well controlled by single-agent therapy with long-acting nifedipine, in spite of the failure of the combination of labetalol and prazosin in lowering blood pressure satisfactorily. A 48 year old female was first noted to have hypertension (160/100 mmHg) at 45 years of age. Hypertension was not controlled by conventional antihypertensive drugs. She was admitted to Fukui Prefectural Hospital in September, 1985. Her blood pressure on admission was 210/110 mmHg. Extraction of the left adrenal gland containing a pheochromocytoma (30 x 37 x 10 mm) was performed in November, 1985. Her hypertension and abnormally high plasma noradrenaline (NA) concentration (1,760 pg/ml, normal value 40-350 pg/ml) were sustained even after operation. Combination therapy with labetalol ( 400 mg/day ) and prazosin ( 6 mg/day ) was unsatisfactory , and the addition of long-acting nifedipine ( 40 mg/day ) produced a marked decrease in blood pressure . Furthermore, single therapy with long-acting nifedipine was effective. No reduction of urinary NA excretion was observed in our patient during long-acting nifedipine therapy, suggesting that the decrease in blood pressure was not caused by suppression of NA release from pheochromocytoma tissue. ### Assistant: [{"class": "NEG", "spans_text": ["labetalol", "prazosin"]}, {"class": "POS", "spans_text": ["labetalol", "prazosin", "nifedipine"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: It was identified as C. lunata ( Wakker ) Boedijn var . aeria ( Batista , Lima and Vasconcelos ) Ellis ( IMI 253204 ) and its growth was better at 28 degrees C than at 37 degrees C. In vitro , the fungus was most sensitive to amphotericin B followed by miconazole nitrate , clotrimazole and triphenyltin isoselenocyanate 4-picoline which had the same activity . Paragraph: Clinical and experimental keratitis due to Curvularia lunata (Wakker) Boedijn var. aeria (Batista, Lima and Vasconcelos) Ellis. A case of mycotic keratitis due to Curvularia lunata var. aeria is reported for the first time from India. Direct microscopic examination of the corneal scrapings in KOH (50 g1(-1)), stained with lactophenol cotton blue, revealed brown septate hyphae and the cultures were found positive for fungus. It was identified as C. lunata ( Wakker ) Boedijn var . aeria ( Batista , Lima and Vasconcelos ) Ellis ( IMI 253204 ) and its growth was better at 28 degrees C than at 37 degrees C. In vitro , the fungus was most sensitive to amphotericin B followed by miconazole nitrate , clotrimazole and triphenyltin isoselenocyanate 4-picoline which had the same activity . Lactones were least active and tolciclate and arnebins and inactive. The fungus produced experimental keratomycosis in the rabbit cornea and the infection severity as well as histopathological changes were more pronounced in rabbits that received penicillin, streptomycin and cortisone. ### Assistant: [{"class": "POS", "spans_text": ["amphotericin", "miconazole", "clotrimazole", "triphenyltin isoselenocyanate 4-picoline"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: Conclusions Everolimus plus mFOLFOX-6 + bevacizumab is tolerable and demonstrated preliminary efficacy for first-line mCRC . Paragraph: Phase I/II study of everolimus combined with mFOLFOX-6 and bevacizumab for first-line treatment of metastatic colorectal cancer. Background This phase I/II trial evaluated toxicity and antitumor activity of everolimus plus mFOLFOX6 + bevacizumab for first-line treatment of metastatic colorectal cancer (mCRC). Methods A phase I, modified 3 + 3 Fibonacci schema determined the maximum tolerated dose (MTD) of everolimus, followed by phase II dose expansion. The phase II primary objective was progression-free survival at 6 months (PFS-6 m). Results The everolimus MTD was 10 mg daily with mFOLFOX6 + bevacizumab based on safety from phase I (n = 22). Twenty-five patients were treated in the phase II at 10 mg everolimus daily. Frequent grade 3-4 adverse events were neutropenia (64%), leukopenia (28%) and hypokalemia (26%). Grade 2 stomatitis was observed in 62% of patients. Two dose-limiting toxicities were observed with one attributed to everolimus 10 mg daily (grade 3 diarrhea, hypokalemia, and anorexia) and grade 3 coronary vasospasm attributed to fluorouracil. The objective response rate was 53% and was higher (86%) in those with PTEN deficiency. PFS-6 m was 96% (95% CI 89-99.9%) at the MTD (n = 35). The everolimus recommended phase II dose of this regimen is 7.5 mg daily due to frequent stomatitis and dose reductions. Conclusions Everolimus plus mFOLFOX-6 + bevacizumab is tolerable and demonstrated preliminary efficacy for first-line mCRC . Further studies are warranted in PTEN deficiency. ### Assistant: [{"class": "POS", "spans_text": ["Everolimus", "bevacizumab", "mFOLFOX-6"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: We conducted a prospective phase II study to determine the response rate , toxicity , and survival rate of concurrent weekly paclitaxel , carboplatin , and hyperfractionated radiation therapy ( paclitaxel/carboplatin/HFX RT ) followed by 2 cycles of paclitaxel and carboplatin for locally advanced unresectable non-small cell lung cancer ( NSCLC ) . Paragraph: A phase II study of paclitaxel, carboplatin, and hyperfractionated radiation therapy for locally advanced inoperable non-small-cell lung cancer (a Vanderbilt Cancer Center Affiliate Network Study). We conducted a prospective phase II study to determine the response rate , toxicity , and survival rate of concurrent weekly paclitaxel , carboplatin , and hyperfractionated radiation therapy ( paclitaxel/carboplatin/HFX RT ) followed by 2 cycles of paclitaxel and carboplatin for locally advanced unresectable non-small cell lung cancer ( NSCLC ) . The weekly paclitaxel and carboplatin regimen was designed to optimize the radiosensitizing properties of paclitaxel during the concurrent phase of treatment. ### Methods And Materials Forty-three patients with unresectable stage IIIA and IIIB NSCLC from the Vanderbilt Cancer Center and Affiliate Network (VCCAN) institutions were entered onto the study from June 1996 until May 1997. Weekly intravenous (IV) paclitaxel (50 mg/m(2)/l-hour) and weekly carboplatin (AUC 2) plus concurrent hyperfractionated chest RT (1.2 Gy/BID/69.6 Gy) were delivered for 6 weeks followed by 2 cycles of paclitaxel (200 mg/m(2)) and carboplatin (AUC 6). ### results Forty-two patients were evaluable for response and toxicities. Three patients achieved a complete response (7.2%) and 30 patients achieved a partial response (71.4%), for an overall response rate of 78.6% [95% C.I. (66.2%-91.0%)]. The 1- and 2-year overall and progression-free survival rates of all 43 patients were 61.6% and 35% respectively, with a median survival time of 14.3 months. The median follow-up time was 14 months. Esophagitis was the principal toxicity. Grade 3 or 4 esophagitis occurred in 11 patients (26%). There was an incidence of 7% grade 3 and 9.5% grade 4 pulmonary toxicities. ### conclusions Weekly paclitaxel, carboplatin, plus concurrent hyperfractionated RT is a well-tolerated outpatient regimen. The response rate from this regimen is encouraging and appears to be at least equivalent to the more toxic chemoradiation trials. These findings warrant further clinical evaluation of weekly paclitaxel/carboplatin/HFX RT in a phase III study. ### Assistant: [{"class": "POS", "spans_text": ["paclitaxel", "carboplatin"]}]
### Human:Examine the following content to understand the effects of drug combinations. Then, output a set of relationships, each comprising a set of participating drugs and a corresponding relation label. 'POS' indicates that the combination of drugs has a positive effect, 'COMB' denotes that the drugs are used together but their effect is uncertain, and 'NEG' signifies that the drug combination results in a negative effect. Sentence: A phase Ib study of pertuzumab , a recombinant humanised antibody to HER2 , and docetaxel in patients with advanced solid tumours . Paragraph: A phase Ib study of pertuzumab , a recombinant humanised antibody to HER2 , and docetaxel in patients with advanced solid tumours . pertuzumab represents the first in a new class of targeted therapeutics known as HER dimerisation inhibitors. We conducted a phase Ib study to determine the maximum-tolerated dose, the dose limiting toxicities (DLT), and pharmacokinetic (PK) interaction of docetaxel when administered in combination with pertuzumab. Initially, two dose levels of docetaxel (60 and 75 mg m(-2)) were explored in combination with a fixed dose of 1050 mg of pertuzumab; then two dose levels of docetaxel (75 and 100 mg m(-2)) were explored in combination following a fixed dose of 420 mg of pertuzumab with a loading dose of 840 mg. Both drugs were administered intravenously every 3 weeks. The latter dose of pertuzumab was allowed after an amendment to the original protocol when phase II data suggesting no difference in toxicity or activity between the 2 doses became available. Two patients out of two treated at docetaxel 75 mg m(-2) in combination with pertuzumab 1050 mg suffered DLT (grade 3 diarrhoea and grade 4 febrile neutropaenia). Two out of five patients treated at docetaxel 100 mg m(-2) in combination with pertuzumab 420 mg with a loading dose of 840 mg suffered DLT (grade 3 fatigue and grade 4 febrile neutropaenia). Stable disease was observed at four cycles in more than half of the patients treated and a confirmed radiological partial response with a >50% decline in PSA in a patient with hormone refractory prostate cancer were observed. There were no pharmacokinetic drug-drug interactions. The recommended phase II dose of this combination was docetaxel 75 mg m(-2) and 420 mg pertuzumab following a loading dose of 840 mg. ### Assistant: [{"class": "POS", "spans_text": ["pertuzumab", "docetaxel"]}]