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zx2045284

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llama2_medicine

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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: He was initially treated with combination chemotherapy regimen of vincristine , actinomycin-D and cyclophosphamide ( VAC therapy ) . Paragraph: [Rhabdomyosarcoma of the bladder: a case report]. A 15-year-old man with the chief complaint of general fatigue was referred to our hospital on November 11, 1993. Bilateral percutaneous nephrostomy was performed for postrenal anuria. X-ray examinations revealed a huge intrapelvic tumor, and it was histopathologically diagnosed as rhabdomyosarcoma by transrectal needle biopsy. He was initially treated with combination chemotherapy regimen of vincristine , actinomycin-D and cyclophosphamide ( VAC therapy ) . Pelvic exenteration was performed on December 15, 1993. Histopathological findings were alveolar rhabdomyosarcoma with degenerative change and partial necrosis. After the operation, he was given two course of VAC therapy. In May, 1994, brain metastasis occurred, so 4 courses of VAC therapy were administered. For a very short period, neurological symptoms improved, but he died of pneumonia on November 15, 1994. ### Assistant: [{"class": "COMB", "spans_text": ["vincristine", "cyclophosphamide", "actinomycin-D"]}]

### 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: However , when a lung mass was noted two months later , he started to receive combination chemotherapy consisting of cyclophosphamide , adriamycin , vincristine , and prednisolone every three months . Paragraph: [Lymphomatoid granulomatosis (LYG) occurring in a patient with follicular lymphoma during remission]. A 49 years-old man presented with dry cough, low grade fever, and abnormal shadow on a chest X-ray. He had suffered from follicular lymphoma of the liver 5 years previously. He received irradiation therapy in combination with chemotherapy for approximately three years and had been in complete remission. Physical and radiological examination revealed pleural effusion and softly dense masses in the right lung. The laboratory data were within normal limits. He was diagnosed as having lymphomatoid granulomatosis (LYG) by open lung biopsy. The lung lesion was mainly infiltrated with T cells. The patient received prednisolone and the lung lesions disappeared. However , when a lung mass was noted two months later , he started to receive combination chemotherapy consisting of cyclophosphamide , adriamycin , vincristine , and prednisolone every three months . He has not shown relapse of LYG so far. To investigate the association between the preceding follicular lymphoma and subsequent LYG at this time, DNA analysis using the PCR technique was carried out. The LYG lesion did not show a rearranged band for the JH probe, while the paraffin-embedded specimen of the preceding follicular lymphoma had shown rearranged band for the JH band. Southern blot analysis of the LYG lesion, showed no rearrangement for TCR beta, gamma or JH probe. These findings indicate that the LYG was different from the preceding follicular lymphoma in terms of origin. LYG is considered to be induced in the immunosuppressive state due to lymphoma. ### Assistant: [{"class": "COMB", "spans_text": ["cyclophosphamide", "vincristine", "prednisolone", "adriamycin"]}]

### 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 used MCF-7 and MDA-MB231 breast cancer cells incubated with Curcumin and Quercetin for 24h , in the absence and presence of Somatostatin , at their EC50 concentrations , to evaluate membrane fatty acid-based functional lipidomics together with the follow-up of EGFR and MAPK signaling pathways . Paragraph: Effects of Somatostatin, Curcumin and Quercetin on the fatty acid profile of breast cancer cell membranes. We used MCF-7 and MDA-MB231 breast cancer cells incubated with Curcumin and Quercetin for 24h , in the absence and presence of Somatostatin , at their EC50 concentrations , to evaluate membrane fatty acid-based functional lipidomics together with the follow-up of EGFR and MAPK signaling pathways . The two cell lines gave different membrane free fatty acid reorganization: in MCF-7 cells, the following changes observed: increase of omega-6 linoleic acid in the cells incubated with Somatostatin+Quercetin and Quercetin and decrease of omega-3 acids in the cells incubated with Somatostatin+Curcumin compared to Somatostatin, and significant increases of monounsaturated fatty acid (MUFA), mono-trans arachidonic acid levels and docosapentaenoic acid for the cells incubated with Somatostatin+Quercetin compared to the control cells. In MDA-MB231 cells, incubations with Curcumin, Quercetin and Somatostatin+Quercetin induced the most significant membrane remodeling with the increase of stearic acid, diminution of omega-6 linoleic, arachidonic acids and omega-3 (docosapentaenoic and docosahexaenoic acids). Distinct signaling pathway changes were found for these cell lines. In MCF-7 cells, separate or combined incubations with Somatostatin and Quercetin, significantly decreased EGFR and incubation with Curcumin decreased MAPK signaling. In MDA-MB231 cells, incubation with Curcumin decreased AKT1 and p-AKT1(Thr308) levels. Incubation with Curcumin and Quercetin decreased the EGFR levels. ### Assistant: [{"class": "COMB", "spans_text": ["Curcumin", "Somatostatin", "Quercetin"]}]

### 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: Following corneal scrapings and culture , topical 0.5 % moxifloxacin and 0.5 % tobramycin were administered hourly . Paragraph: A case of Stenotrophomonas maltophilia keratitis effectively treated with moxifloxacin. A 70-year-old man with a long history of diabetes mellitus presented to our hospital (Department of Ophthalmology, Sahm Yook Medical Center, Seoul, Korea) complaining of severe ocular pain and visual disturbance in his left eye that had started three days prior to admission. A round 3.7 × 5.0 mm dense central stromal infiltrate with an overlying epithelial defect was noted on slit-lamp examination. Following corneal scrapings and culture , topical 0.5 % moxifloxacin and 0.5 % tobramycin were administered hourly . A few days later, Stenotrophomonas maltophilia was isolated in a bacterial culture from a corneal specimen. According to the results of susceptibility tests, topical 0.5% moxifloxacin was given every hour and 0.5% tobramycin was stopped. The patient's clinical features improved steadily with treatment. The corneal epithelium healed rapidly, and the infiltrate resolved within four weeks of the initiation of treatment. The patient's best corrected visual acuity improved from hand motion to 20 / 25. ### Assistant: [{"class": "COMB", "spans_text": ["moxifloxacin", "tobramycin"]}]

### 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 treatment with cetuximab and nystatin selectively increased cetuximab uptake by tumor tissues , translating into potentiated antitumor efficacy of cetuximab in vivo ( A431 and A549 tumors ) . Paragraph: Enhancement of tumor uptake and therapeutic efficacy of EGFR-targeted antibody cetuximab and antibody-drug conjugates by cholesterol sequestration. Cetuximab, a monoclonal antibody (mAb) targeting the epidermal growth factor receptor (EGFR), has been intensively investigated as a promising cancer treatment strategy. The specific mechanism of cetuximab endocytosis and its influence on cetuximab uptake, biodistribution and efficacy still remain elusive. Recently, statins have been reported to synergize with EGFR-targeting agents. Our prior work established that nystatin, a cholesterol-sequestering antifungal drug, facilitates endocytosis via the clathrin-dependent pathway. This study aimed to investigate whether nystatin regulates the uptake and efficacy of cetuximab and cetuximab-based antibody-drug conjugates (cetuximab-ADCs). In vitro and in vivo efficacies of nystatin on the uptake and activity of cetuximab/cetuximab-ADCs were studied in multiple human carcinoma cell lines and xenograft models, respectively. We identified that cholesterol sequestration by nystatin enhanced cetuximab internalization in EGFR-positive carcinoma cells by regulating EGFR trafficking/turnover and facilitating a switch from lipid rafts to clathrin-mediated endocytosis. Combination treatment with cetuximab and nystatin selectively increased cetuximab uptake by tumor tissues , translating into potentiated antitumor efficacy of cetuximab in vivo ( A431 and A549 tumors ) . Nystatin-enhanced internalization of cetuximab further improved the uptake and potency of cetuximab-doxorubicin and cetuximab-methotrexate conjugates in EGFR-positive cetuximab-resistant tumors. Combination therapy with nystatin plus either cetuximab or cetuximab-ADC further prolonged animal survival and significantly suppressed tumor growth, as compared with single-agent cetuximab or cetuximab-ADC. In summary, our results identify a novel mechanism whereby cholesterol sequestration enhances the uptake of EGFR-targeting mAb and ADCs, therefore providing preclinical proof-of-concept that combination with nystatin can potentiate the delivery and efficacy of these EGFR-targeted agents. ### Assistant: [{"class": "POS", "spans_text": ["cetuximab", "nystatin"]}]

### 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 effects of combination therapy with chenodeoxycholic acid ( CDCA ) and simvastatin on serum cholestanol , low-density lipoprotein ( LDL ) cholesterol , and lathosterol levels were investigated in seven adult patients with cerebrotendinous xanthomatosis ( CTX ) who were on long-term treatment with CDCA . Paragraph: Effect of simvastatin in addition to chenodeoxycholic acid in patients with cerebrotendinous xanthomatosis. The effects of combination therapy with chenodeoxycholic acid ( CDCA ) and simvastatin on serum cholestanol , low-density lipoprotein ( LDL ) cholesterol , and lathosterol levels were investigated in seven adult patients with cerebrotendinous xanthomatosis ( CTX ) who were on long-term treatment with CDCA . The patients were treated with a combination of CDCA 750 mg daily and an increasing dose of simvastatin from 10 mg to 40 mg daily for a period of 6 months. We found a significant effect of this combination therapy compared with CDCA alone in terms of decreasing the serum cholestanol and LDL cholesterol levels, particularly with a daily dose of 40 mg simvastatin. The mean cholestanol level decreased from 9.27 micromol/L (baseline) to 6.69 micromol/L (40 mg simvastatin), while the mean LDL cholesterol level decreased from 5.08 mmol/L (baseline) to 3.04 mmol/L (40 mg simvastatin). No side effects were reported, and there were no effects on the clinical condition, cerebral magnetic resonance imaging (MRI), visual evoked potentials, and electroencephalographic features. We conclude that a combination of 750 mg CDCA and 40 mg simvastatin daily is effective to further reduce serum cholestanol, LDL cholesterol, and lathosterol in adult CTX patients treated with long-term CDCA. Whether this combination treatment will be effective for the long-term prevention of neurological deterioration and atherosclerosis remains to be established. ### Assistant: [{"class": "POS", "spans_text": ["chenodeoxycholic", "simvastatin"]}]

### 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: Paclitaxel ( Taxol ; Bristol-Myers Squibb Company , Princeton , NJ ) has been demonstrated to be highly effective in treating patients with advanced breast cancer , including those with anthracycline-resistant breast cancer , a fact that has led to efforts to combine paclitaxel and anthracyclines . Paragraph: Paclitaxel and doxorubicin in metastatic breast cancer. For the past decades the anthracyclines have been regarded as among the most active drugs for the treatment of metastatic breast cancer. However, the 5-year survival rate in patients with stage IV breast cancer continues to be below 20%, and new active drugs and drug combinations clearly must be explored. Paclitaxel ( Taxol ; Bristol-Myers Squibb Company , Princeton , NJ ) has been demonstrated to be highly effective in treating patients with advanced breast cancer , including those with anthracycline-resistant breast cancer , a fact that has led to efforts to combine paclitaxel and anthracyclines . Several studies aiming to define the optimal dose and schedule of combination paclitaxel/doxorubicin have now been completed or are ongoing. Phase I/II studies have yielded encouraging preliminary response rates but quite variable toxicity profiles depending on the schedule used. These clinical trials involving combination paclitaxel/doxorubicin are reviewed, with special emphasis on the short-infusion trials. ### Assistant: [{"class": "COMB", "spans_text": ["paclitaxel", "anthracyclines"]}]

### 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: Additivity , synergy , or competition was observed with MIS and rapamycin , AzadC , doxorubicin , cisplatin , and paclitaxel , suggesting that MIS in combination with selective targeted therapies might achieve greater activity against ovarian cancer than the use of each individual agent alone . Paragraph: Mullerian Inhibiting Substance enhances subclinical doses of chemotherapeutic agents to inhibit human and mouse ovarian cancer. Mullerian Inhibiting Substance (MIS), a biological modifier that causes regression of Mullerian ducts in male embryos, is effective as a single agent in vitro and in vivo against human and mouse ovarian cancer cell lines expressing MIS type II receptor; however, little is known about how recombinant human MIS (rhMIS), now being scaled for preclinical trials, could be used in combination with cytotoxic or targeted chemotherapeutic agents. Mouse serous and endometrioid ovarian carcinoma cell lines were tested in vitro against rhMIS alone and with doxorubicin, paclitaxel, or cisplatin as agents in clinical use. Because MIS releases FK506 binding protein (FKBP12), which activates the mammalian target of rapamycin (mTOR) downstream of Akt, rhMIS and rapamycin combinations were tested. MIS increases p16 protein levels, and 5'-Aza-2'-deoxycytidine (AzadC) induces p16 mRNA; therefore, they were used in combination in vitro and in vivo with a human ovarian cancer cell line. A paclitaxel-resistant human ovarian cancer cell line and its parental line both respond to rhMIS in vitro. Additivity , synergy , or competition was observed with MIS and rapamycin , AzadC , doxorubicin , cisplatin , and paclitaxel , suggesting that MIS in combination with selective targeted therapies might achieve greater activity against ovarian cancer than the use of each individual agent alone . These assays and statistical analyses could be useful in selecting rhMIS and chemotherapeutic agent combinations that enhance clinical efficacy and reduce toxicity. ### Assistant: [{"class": "POS", "spans_text": ["rapamycin", "MIS"]}, {"class": "POS", "spans_text": ["MIS", "AzadC"]}, {"class": "POS", "spans_text": ["doxorubicin", "MIS"]}]

### 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: Several first-line phase III trials , as well as ongoing trials for which only preliminary results have been published , have fueled debates on the optimal dose and schedule ; these have focused not only on weekly vs q3-weeks paclitaxel , but also on other modifications and the advisability of adding bevacizumab . Paragraph: Carboplatin/Paclitaxel Induction in Ovarian Cancer: The Finer Points. The carboplatin/paclitaxel doublet remains the chemotherapy backbone for the initial treatment of ovarian cancer. This two-drug regimen, with carboplatin dosed using the Calvert formula, yielded convincing noninferior outcomes when compared with the prior, more toxic, regimen of cisplatin/paclitaxel. Carboplatin's dose-limiting toxicity is thrombocytopenia; however, when this drug is properly dosed and combined with paclitaxel, the doublet's cycle 1 dose in chemotherapy-naive women is generally safe. Carboplatin (unlike cisplatin) contributes minimally to the cumulative sensory neuropathy of paclitaxel, thus ensuring noticeable reversibility of neuropathy symptoms following completion of 6 cycles and only occasionally requiring cessation or substitution of the taxane. Paclitaxel is responsible for the hair loss associated with the carboplatin/paclitaxel doublet; preventive measures must be considered for patients who would otherwise refuse treatment. Several first-line phase III trials , as well as ongoing trials for which only preliminary results have been published , have fueled debates on the optimal dose and schedule ; these have focused not only on weekly vs q3-weeks paclitaxel , but also on other modifications and the advisability of adding bevacizumab . Our view is that results of this doublet in the first-line treatment of ovarian cancer are driven primarily by carboplatin, given that ovarian cancer is a platinum-sensitive disease. Consequently, the roles of the accompanying paclitaxel dose and schedule and the addition of bevacizumab are currently unsettled, and questions regarding these issues should be decided based on patient tolerance and comorbidities until additional data are available. ### Assistant: [{"class": "COMB", "spans_text": ["paclitaxel", "bevacizumab"]}]

### 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 primary goal was achieve the correct estimation of the target plasma area against the topotecan concentration-time curve ( AUC ) in a 5 day course of cladribine followed by monitored topotecan in pediatric patients with recurrent/refractory AML . Paragraph: Topotecan exposure estimation in pediatric acute myeloid leukemia supported by LC-MS-based drug monitoring and pharmacokinetic analysis. Individualization of the topotecan dosing can reduce inter-patient variability, toxicity, and at the same time increases chemotherapy efficacy. Topotecan dosing based on simultaneous drug monitoring and pharmacokinetic analysis can yield more accurate and precise estimation of the topotecan systemic exposure than that attainable with the fixed dosing approach. Therefore, a combined approach could provide a tool assisting the clinicians in individualization of the topotecan dosing. The aim of the study was to estimate the topotecan exposure in pediatric patients with acute myeloid leukemia (AML) based on the plasma concentration-time data and using the pharmacokinetic analysis. The primary goal was achieve the correct estimation of the target plasma area against the topotecan concentration-time curve ( AUC ) in a 5 day course of cladribine followed by monitored topotecan in pediatric patients with recurrent/refractory AML . A sensitive and selective reversed-phase liquid chromatographic-mass spectrometry (LC-MS) assay was developed to quantify total topotecan in the human plasma samples. This method, with its lower quantification limit of 1 ng/ml, was validated over a linear range of 1-150 ng/ml. Under the proposed approach, the topotecan dosing was selected so as to achieve the final AUC value of 140±20 ng/ml h. The presented analytical and pharmacokinetic data demonstrate that the proposed approach can be a practical, useful, efficient, and accurate tool for individualizing the topotecan dosing in children with AML. ### Assistant: [{"class": "COMB", "spans_text": ["cladribine", "topotecan"]}]

### 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 patients with NPSLE , the use of high-dose corticosteroids is recommended in combination with immunosuppressants , such as mycophenolate mofetil and intravenous cyclophosphamide pulse therapy . Paragraph: [Neuropsychiatric Systemic Lupus Erythematosus]. Central nervous system damage, a major organ manifestation of systemic lupus erythematosus (SLE), causes significant morbidity and mortality. Designating this condition as neuropsychiatric SLE (NPSLE), the American College of Rheumatology defines it as involving the central and peripheral nervous systems and being characterized by various manifestations including stroke, seizures, and psychosis. NPSLE treatment mainly seeks to reduce damage accrual. In patients with NPSLE , the use of high-dose corticosteroids is recommended in combination with immunosuppressants , such as mycophenolate mofetil and intravenous cyclophosphamide pulse therapy . This can be accomplished by controlling the activity of the disease, minimizing the use of corticosteroids, and optimizing the management of comorbidities, including cardiovascular risk factors. An international task force analysis of a treat-to-target strategy for SLE (T2T/SLE) recommended targeting remission, preventing damage, and improving quality of life. Thus, more effective and less toxic treatments, such as those using biologics or kinase inhibitors, are still being developed for the treatment of SLE/NPSLE. ### Assistant: [{"class": "POS", "spans_text": ["mycophenolate", "corticosteroids"]}, {"class": "POS", "spans_text": ["cyclophosphamide", "corticosteroids"]}, {"class": "POS", "spans_text": ["corticosteroids", "mofetil"]}]

### 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: Thirty-three women diagnosed with metastatic breast cancer participated in a phase 1 clinical trial of a new combination of cyclophosphamide ( CTX ) and mitoxantrone ( MXT ) , with dose escalation of paclitaxel . Paragraph: Longitudinal effects of high-dose chemotherapy and autologous stem cell transplantation on quality of life in the treatment of metastatic breast cancer. This study determined the effects of high-dose chemotherapy (HDCT) with autologous blood stem cell transplantation (ASCT) on quality of life (QL) in women with metastatic breast cancer prior to, and during treatment, and up to 1-year post-ASCT. Thirty-three women diagnosed with metastatic breast cancer participated in a phase 1 clinical trial of a new combination of cyclophosphamide ( CTX ) and mitoxantrone ( MXT ) , with dose escalation of paclitaxel . Longitudinal QL data were collected using the functional living index-cancer (FLIC) and symptom scales at seven time periods: pre-induction chemotherapy (CT), post-induction CT, post-high dose CT (HDCT), and at 3, 6, 9 and 12 months post-ASCT. FLIC scores indicated that the worst problems for patients were feelings of hardship on themselves and their families, followed by psychological functioning and physical functioning problems. The time around diagnosis of the metastatic disease and following HDCT were the worst times for all levels of quality of life, but anxiety and depression symptoms continued to increase in severity across the entire follow-up period. The symptoms that were most problematic were worry about the future, loss of sexual interest, anxiety about the treatment, general worrying, and joint pain. These data highlight the problems that women with metastatic breast cancer encounter at different stages of the disease and treatment process, and can be used to tailor psychosocial interventions appropriate for treating the relevant issues at different points in time. ### Assistant: [{"class": "COMB", "spans_text": ["cyclophosphamide", "mitoxantrone", "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: These studies suggest a slight advantage to the combined approaches that contain flutamide and bicalutamide , but the lack of dramatic differences in outcome makes monotherapy reasonable , especially in patients with more indolent disease . Paragraph: The selection of hormonal therapy in prostate cancer: who, when, and for how long? Androgen deprivation is the foundation for the systemic therapy of advanced prostate cancer. Multiple trials have tested combined androgen blockade versus androgen deprivation alone in patients with advanced disease. These studies suggest a slight advantage to the combined approaches that contain flutamide and bicalutamide , but the lack of dramatic differences in outcome makes monotherapy reasonable , especially in patients with more indolent disease . Intermittent androgen deprivation is an alternative that may allow patients to reduce the total time on androgen suppression as well as possibly delay the onset of androgen independence. A number of secondary hormonal therapies, including deferred and secondary antiandrogens, ketoconazole, and estrogens have shown modest response proportions. Patients with less advanced disease such as a rising prostate-specific antigen have varied outcomes, and no standard approach exists. In this group, noncastrating forms of hormonal therapy are being evaluated. Patients undergoing definitive local therapy who have high-risk features may benefit from early, as opposed to deferred, androgen deprivation. This review examines the evidence for the current state of the art in hormonal therapy in patients with prostate cancer and focuses, in particular, on treatment composition and timing as well as the rationale for the use of hormonal therapy in early stage disease. ### Assistant: [{"class": "POS", "spans_text": ["flutamide", "bicalutamide"]}]

### 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 examined the feasibility and safety of using paclitaxel and trastuzumab as maintenance therapy after high-dose chemotherapy ( HDC ) with autologous hematopoietic stem cell transplantation ( AHST ) for patients with HER2-positive metastatic breast cancer . Paragraph: Paclitaxel and Trastuzumab as Maintenance Therapy in Patients with HER2-Positive Metastatic Breast Cancer Who Underwent High-Dose Chemotherapy and Autologous Hematopoietic Stem Cell Transplantation. We examined the feasibility and safety of using paclitaxel and trastuzumab as maintenance therapy after high-dose chemotherapy ( HDC ) with autologous hematopoietic stem cell transplantation ( AHST ) for patients with HER2-positive metastatic breast cancer . Ten patients (9 women and 1 man) were enrolled in the study. The median age was 46.5 years (range, 27-65 years). The median follow-up time was 1003 days (range, 216-2526 days). All patients had metastatic disease, but 2 had only bone metastasis. One patient had complete response, 6 had partial response and 3 had stable disease to the standard-dose chemotherapy prior to transplantation. The conditioning regimen consisted of cyclophosphamide, carmustine, and thiotepa. After AHST, patients received weekly paclitaxel for 12 doses and trastuzumab every 3 weeks for 1 year as maintenance therapy. All patients experienced successful engraftment. The only grade 4 toxic effects observed were leukopenia and thrombocytopenia. The most common grade 3 toxic effect was neutropenic fever. No treatment-related deaths were observed. The median progression-free survival time was 441 days, and the median overall survival time was 955 days. Two patients died in accidents while their disease remained in remission. Five patients died with disease progression. At the time of this report, 3 patients are alive with stable disease, 1 of whom has remained free of disease progression for 2526 days since transplantation. Our findings indicate that paclitaxel plus trastuzumab as maintenance therapy after HDC with AHST for patients with HER2-positive metastatic breast cancer not only is feasible and safe but also results in survival outcomes similar to historical results. ### Assistant: [{"class": "POS", "spans_text": ["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: Dual antiplatelet therapy with aspirin and clopidogrel ( the preferred thienopyridine because of its superior hematologic safety ) is recommended for at least 4 weeks to prevent subacute stent thrombosis with bare-metal stents and 3 to 6 months to prevent late-stent thrombosis with drug-eluting stents . Paragraph: Long-term care after percutaneous coronary intervention: focus on the role of antiplatelet therapy. Arterial wall injury caused by percutaneous coronary intervention (PCI) triggers transient platelet activation and mural thrombosis; these effects are superimposed on the preexisting platelet hyperreactivity associated with underlying atherothrombosis. Platelet activation has been implicated in the major complications of PCI: acute and subacute thrombosis and restenosis. Antithrombotic and anticoagulant therapy minimizes thrombotic complications after PCI. Aspirin plus a thienopyridine (ticlopidine or clopidogrel) is more effective than aspirin plus heparin and extended warfarin therapy in preventing periprocedural ischemic events and subsequent stent thrombosis and results in less major and minor bleeding. Dual antiplatelet therapy with aspirin and clopidogrel ( the preferred thienopyridine because of its superior hematologic safety ) is recommended for at least 4 weeks to prevent subacute stent thrombosis with bare-metal stents and 3 to 6 months to prevent late-stent thrombosis with drug-eluting stents . Coronary atherothrombosis is a diffuse vascular disease, and reduction of the risk of future ischemic events requires strategies that extend beyond the focal treatment of stenotic lesions. Optimal long-term care after PCI requires aggressive systemic pharmacotherapy (antiplatelet agents, statins, beta-blockers, and angiotensin-converting enzyme Inhibitors) in conjunction with therapeutic lifestyle changes (smoking cessation, weight reduction, dietary measures, and exercise). In this context, dual antiplatelet therapy (aspirin plus clopidogrel) is recommended for at least 12 months after PCI for prophylaxis of future atherothrombotic events. ### Assistant: [{"class": "POS", "spans_text": ["aspirin", "clopidogrel"]}]

### 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: Furthermore , in non-metastatic castration-resistant prostate cancer ( M0 CRPC ) , two second-generation anti-androgens , apalutamide and enzalutamide , when used in combination with ADT , have demonstrated a significant benefit in metastasis-free survival . Paragraph: Recent trends in the management of advanced prostate cancer. Advanced prostate cancer includes a wide spectrum of disease ranging from hormone naïve or hormone sensitive to castration resistant, both containing populations of men who have demonstrable metastatic and non-metastatic states. The mainstay of treatment for metastatic hormone-sensitive prostate cancer is androgen deprivation therapy (ADT). However, recent level 1 evidence demonstrates that the addition of chemotherapy or abiraterone acetate to ADT results in significant survival advantage as compared with ADT alone. Furthermore , in non-metastatic castration-resistant prostate cancer ( M0 CRPC ) , two second-generation anti-androgens , apalutamide and enzalutamide , when used in combination with ADT , have demonstrated a significant benefit in metastasis-free survival . Here, we review the most recent studies leading to these significant changes in the treatment of advanced prostate cancer. ### Assistant: [{"class": "POS", "spans_text": ["apalutamide", "ADT"]}, {"class": "POS", "spans_text": ["enzalutamide", "ADT"]}]

### 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: Phase Ib Study of the Oral Proteasome Inhibitor Ixazomib ( MLN9708 ) and Fulvestrant in Advanced ER+ Breast Cancer Progressing on Fulvestrant . Paragraph: Phase Ib Study of the Oral Proteasome Inhibitor Ixazomib ( MLN9708 ) and Fulvestrant in Advanced ER+ Breast Cancer Progressing on Fulvestrant . fulvestrant is a selective estrogen receptor (ER)-downregulating anti-estrogen that blocks ER transcriptional activity and is approved for ER+ breast cancer. fulvestrant also induces accumulation of insoluble ER and activates an unfolded protein response; proteasome inhibitors have been shown to enhance these effects in preclinical models. ### background fulvestrant is a selective estrogen receptor (ER)-downregulating anti-estrogen that blocks ER transcriptional activity and is approved for ER+ breast cancer. fulvestrant also induces accumulation of insoluble ER and activates an unfolded protein response; proteasome inhibitors have been shown to enhance these effects in preclinical models. ### methods This is a single-center phase Ib study with a 3+3 design of fulvestrant and the proteasome inhibitor ixazomib (MLN9708) in patients with advanced ER+ breast cancer that was progressing on fulvestrant. A dose-escalation design allowed establishment of the ixazomib maximum tolerated dose (MTD). Secondary objectives included progression-free survival, pharmacokinetics, and tumor molecular analyses. ### results Among nine evaluable subjects, treatment was well-tolerated without dose-limiting toxicities The MTD of ixazomib was 4 mg in combination with fulvestrant. Plasma concentrations of the active form of ixazomib (MLN2238) in the 4-mg dose cohort had a median (range) Cmax of 155 (122-171) ng/mL; Tmax of 1 (1-1.5) h; terminal elimination half-life of 66.6 (57.3-102.6) hr after initial dose; AUC of 5,025 (4,160-5,345) ng*h/mL. One partial response was observed, and median progression-free survival was 51 days (range 47-137). ### conclusion This drug combination has a favorable safety profile and anti-tumor activity in patients with fulvestrant-resistant advanced ER+ breast cancer that justifies future testing. ### Assistant: [{"class": "POS", "spans_text": ["Ixazomib", "Fulvestrant"]}]

### 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: Pharmacokinetic studies showed that chronic lymphocytic leukemia involving more than 80 % of the bone marrow at study start was associated with lower trough concentrations of alemtuzumab and rituximab , and that higher trough serum concentrations of alemtuzumab were associated with complete bone marrow clearance . Paragraph: A phase I study of escalated dose subcutaneous alemtuzumab given weekly with rituximab in relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma. This study assessed the safety and preliminary efficacy of escalated dose subcutaneous alemtuzumab in combination with rituximab in chronic lymphocytic leukemia. Twenty-eight patients with relapsed refractory chronic lymphocytic leukemia were treated on four dosing cohorts of weekly rituximab at 375 mg/m(2) and alemtuzumab doses that started at 30 mg three times per week and escalated to weekly dosing over four weeks, culminating with 90 mg weekly. One dose limiting toxicity of a rituximab infusion reaction was seen in cohort 2, but the regimen was otherwise well tolerated without evidence of differential toxicity by cohort. The overall response rate by National Cancer Institute-Working Group criteria was 61%, and the rate of complete bone marrow response was 43%, most of whom were negative for minimal residual disease. The addition of CT scan evaluation per International Workshop on Chronic Lymphocytic Leukemia 2008 criteria reduced the overall response rate to 14%. Median overall survival was 35 months, with 12 patients able to proceed to stem cell transplantation. Pharmacokinetic studies showed that chronic lymphocytic leukemia involving more than 80 % of the bone marrow at study start was associated with lower trough concentrations of alemtuzumab and rituximab , and that higher trough serum concentrations of alemtuzumab were associated with complete bone marrow clearance . We conclude that escalated subcutaneous doses of alemtuzumab given weekly are well tolerated and result in excellent bone marrow clearance of chronic lymphocytic leukemia, helping patients to proceed to stem cell transplantation. This study is registered at ClinicalTrials.gov (Identifier:00330252). ### Assistant: [{"class": "POS", "spans_text": ["alemtuzumab", "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: Compared with risedronate alone , at 6 months , risedronate plus atorvastatin produced significantly greater increases in the bone mineral density of the lumbar spine ( 1.58 % versus 0.75 % , p < 0.05 ) . Paragraph: Statins have additive effects to vertebral bone mineral density in combination with risedronate in hypercholesterolemic postmenopausal women. Recent data suggest that statins used in the treatment of hypercholesterolaemia decrease fracture risk. In this study, we aimed to investigate prospectively whether statins have an additive effect to bisphosphonates (risedronate) according to the primary hypothesis that the addition of atorvastatin to risedronate would produce an increase, from baseline, in lumbar vertebrae and total hip BMD that was greater than that observed with risedronate alone. ### methods A total of 120 hypercholesterolaemic postmenopausal women with osteoporosis or osteopenia were randomized to receive risedronate (5 mg/day) or risedronate (5 mg/day) plus atorvastatin (20 mg/day). Changes in bone mineral density in the lumbar spine and hip, and serum lipid and glucose metabolism changes were assessed. ### results Compared with risedronate alone , at 6 months , risedronate plus atorvastatin produced significantly greater increases in the bone mineral density of the lumbar spine ( 1.58 % versus 0.75 % , p < 0.05 ) . We found no difference after therapy in BMD of the total hip (1.2% versus 1.1%). risedronate plus atorvastatin therapy had favorable effects on the serum lipid profile: LDL and total cholesterol. Serum fasting glucose and HbA1c levels were not affected during the treatments. ### conclusion Statins have modest additive effects to bisphosphonates in improving lumbar spine bone mineral density in hypercholesterolaemic postmenopausal women with established osteoporosis-osteopenia. A long-term study with adequate sample size is necessary to assess the effects of statins -- in combination or alone -- on the bones and prevention of fractures. ### Assistant: [{"class": "POS", "spans_text": ["risedronate", "atorvastatin"]}]

### 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 registered with the German ACC Registry with refractory ACC progressing after cytotoxic therapies were offered treatment with bevacizumab ( 5 mg/kg body weight i.v . every 21 days ) and oral capecitabine ( 950 mg/m(2 ) twice daily for 14 days followed by 7 days of rest ) in 2006 - 2008 . Paragraph: Bevacizumab plus capecitabine as a salvage therapy in advanced adrenocortical carcinoma. No standard therapy for advanced adrenocortical carcinoma (ACC) is established by any randomized trial but a consensus conference 2003 recommended mitotane as monotherapy or combined with etoposide, doxorubicin and cisplatin or with streptozotocin as first-line systemic therapy. However, there is no evidence for any therapy beneficial in patients failing these therapies. Therefore, we evaluated the effects of the anti-VEGF antibody bevacizumab plus capecitabine as salvage therapy in ACC. ### methods Patients registered with the German ACC Registry with refractory ACC progressing after cytotoxic therapies were offered treatment with bevacizumab ( 5 mg/kg body weight i.v . every 21 days ) and oral capecitabine ( 950 mg/m(2 ) twice daily for 14 days followed by 7 days of rest ) in 2006 - 2008 . Evaluation of tumour response was performed by imaging according to response evaluation criteria in solid tumours every 12 weeks. ### results Ten patients were treated with bevacizumab plus capecitabine. None of them experienced any objective response or stable disease. Two patients had to stop therapy after few weeks due to hand-foot syndrome, and three patients died on progressive disease within 12 weeks. Other adverse events were mild (grade I-II). Median survival after treatment initiation was 124 days. ### conclusions bevacizumab plus capecitabine has no activity in patients with very advanced ACC. Hence, this regimen cannot be recommended as a salvage therapy. ### Assistant: [{"class": "NEG", "spans_text": ["bevacizumab", "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: Patients who had pathologically been proven to have measurable lesions were treated with paclitaxel ( 200 mg/m(2 ) for 3 h ) and carboplatin [ area under the concentration-time curve ( AUC = 6 ) ] on day 1 and in 21 day cycles . Paragraph: Phase II study of paclitaxel and carboplatin in advanced gastric cancer previously treated with 5-fluorouracil and platinum. The combination of paclitaxel and carboplatin has been used to treat patients with many types of tumor, including gastric cancer. We evaluated the efficacy and safety of this combination in advanced gastric cancer patients previously treated with 5-fluorouracil and platinum. ### methods Patients who had pathologically been proven to have measurable lesions were treated with paclitaxel ( 200 mg/m(2 ) for 3 h ) and carboplatin [ area under the concentration-time curve ( AUC = 6 ) ] on day 1 and in 21 day cycles . ### results A partial response was achieved in 10 of 45 patients [22%, 95% confidence interval (CI), 10-34]. Of the 32 patients previously treated with cisplatin, four (13%) achieved partial response, whereas, of the 13 patients previously treated with heptaplatin, six (46%) achieved partial response. In all patients, the median time to progression was 14 weeks (95% CI, 10-18), and the median overall survival was 32 weeks (95% CI, 26-38). The most common grade 3/4 adverse events were neutropenia (40% of patients) and neuropathy (2.2%). Two patients developed neutropenic fever. However, there were no treatment-related deaths. ### conclusions Combination chemotherapy with paclitaxel and carboplatin is feasible in patients with advanced gastric cancer who were previously treated with 5-fluorouracil and platinum. ### 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: Eligible patients received ramucirumab ( 10mg/kg ) + dacarbazine ( 1000 mg/m(2 ) ) ( Arm A ) or ramucirumab only ( 10mg/kg ) ( Arm B ) every 3 weeks . Paragraph: A phase 2 randomised study of ramucirumab (IMC-1121B) with or without dacarbazine in patients with metastatic melanoma. To evaluate the efficacy and safety of ramucirumab (IMC-1121B; LY3009806), a fully human monoclonal antibody targeting the vascular endothelial growth factor receptor-2, alone and in combination with dacarbazine in chemotherapy-naïve patients with metastatic melanoma (MM). ### methods Eligible patients received ramucirumab ( 10mg/kg ) + dacarbazine ( 1000 mg/m(2 ) ) ( Arm A ) or ramucirumab only ( 10mg/kg ) ( Arm B ) every 3 weeks . The primary end-point was progression-free survival (PFS); secondary end-points included overall survival (OS), overall response and safety. ### findings Of 106 randomised patients, 102 received study treatment (Arm A, N=52; Arm B, N=50). Baseline characteristics were similar in both arms. Median PFS was 2.6 months (Arm A) and 1.7 months (Arm B); median 6-month PFS rates were 30.7% and 17.9% and 12-month PFS rates were 23.7% and 15.6%, respectively. In Arm A, 9 (17.3%) patients had partial response (PR) and 19 (36.5%), stable disease (SD); PR and SD in Arm B were 2 (4.0%) and 21 (42.0%), respectively. Median OS was 8.7 months in Arm A and 11.1 months in Arm B. Patients in both arms tolerated the treatment with limited Grade 3/4 toxicities. ### interpretation ramucirumab alone or in combination with dacarbazine was associated with an acceptable safety profile in patients with MM. Although the study was not powered for comparison between treatment arms, PFS appeared greater with combination therapy. Sustained disease control was observed on both study arm. ### Assistant: [{"class": "POS", "spans_text": ["ramucirumab", "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: The aim of this study was to investigate the mutagenic and antigenotoxic effects of different doses of the flavonoid , apigenin , alone and in combination with the antitumor drugs , cyclophosphamide and doxorubicin , in vitro and in vivo . Paragraph: The effect of apigenin on cyclophosphamide and doxorubicin genotoxicity in vitro and in vivo. The aim of this study was to investigate the mutagenic and antigenotoxic effects of different doses of the flavonoid , apigenin , alone and in combination with the antitumor drugs , cyclophosphamide and doxorubicin , in vitro and in vivo . Using bacterial reverse mutation inhibition in vitro, with and without metabolic activation, the effect of apigenin (10-400 μg/plate) was studied on genotoxicity induced by cyclophosphamide (800 μg/plate) and by doxorubicin (0.2 μg/plate). Subsequent to a dose-finding study in vivo, CD1 mice were treated with either cyclophosphamide (40 mg/kg, i.p.) or doxorubicin (5 mg/kg, i.p.) with or without co-administration of apigenin (1-100 mg/kg, p.o.). Micronuclei were determined microscopically in blood smears and glutathione peroxidase (GPX), superoxide dismutase (SOD) and total antioxidative status (TAS) in whole blood, erythrocytes and plasma, respectively. Apigenin decreased doxorubicin-induced, but not cyclophosphamide-induced mutagenicity in vitro. In vivo, apigenin caused a statistically significant decrease in micronucleus frequency in response to cyclophosphamide, possibly due to active flavonoid metabolite formation or inhibition of cyclophosphamide metabolic activation. In animals treated with apigenin and doxorubicin, a significant decrease in micronucleus frequency was not observed, probably due to interindividual variability. No changes in GPX, SOD or TAS were observed in response to either cytotoxic agents or the flavonoid, possibly due to limited metabolic transformation of the drugs at the doses used. The results of the present study provide further evidence for the chemo-preventative properties of apigenin. ### Assistant: [{"class": "POS", "spans_text": ["apigenin", "doxorubicin"]}, {"class": "POS", "spans_text": ["apigenin", "cyclophosphamide"]}]

### 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: More effective regimens are urgently needed for squamous cell carcinoma of esophagus ( SCCE ) , therefore , we conducted a phase I/II trial of a combination of docetaxel , platinum , and fluorouracil ( TPF ) for treating metastatic SCCE . Paragraph: Phase I/II study of docetaxel/cisplatin/fluorouracil combination chemotherapy against metastatic esophageal squamous cell carcinoma. More effective regimens are urgently needed for squamous cell carcinoma of esophagus ( SCCE ) , therefore , we conducted a phase I/II trial of a combination of docetaxel , platinum , and fluorouracil ( TPF ) for treating metastatic SCCE . ### methods This phase I/II trial (n = 12/39) was conducted in our institute from April 2005 to June 2008. Progression-free survival (PFS) and overall survival were analyzed by the Kaplan-Meier method. ### results The recommended dose of docetaxel was determined to be 50 mg/m in phase I. In phase II with a mean follow-up period of 13.3 months, the objective response rate was 66.6%, a median survival period of 13 months and PFS of 7 months was achieved, and the 1-year survival and PFS rates were 52.9% and 19.6%, respectively. Grade 3/4 toxicities of leukopenia, neutropenia, and anorexia were observed in 53.8%, 43.6%, and 25.6%, respectively. ### conclusions A TPF regimen against metastatic SCCE was well tolerated and achieved a favorable objective response rate and survival benefit compared with other recently reported regimens. Randomized phase III trials of the TPF regimen are warranted and urgently required. ### Assistant: [{"class": "POS", "spans_text": ["docetaxel", "platinum"]}]

### 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: Gemcitabine with cyclosporine or with tacrolimus exerts a synergistic effect and induces tolerance in the rat . Paragraph: Gemcitabine with cyclosporine or with tacrolimus exerts a synergistic effect and induces tolerance in the rat . This study investigated the effect of the antineoplastic agent gemcitabine (dFdC) in combination with cyclosporine (CsA) or with FK506 on acute heart allograft rejection in a rat model. ### methods Transplantations were performed in the fully allogeneic Lewis-to-Brown Norway strain combination. dFdC, CsA, and FK506 single-drug therapy and combinations of dFdC with CsA and FK506 were administered at various dosages starting on day 1 to prevent and on day 4 to treat acute rejection until day 20. Animals who did not reject their graft were intraperitoneally injected with 108 splenic donor-type lymphocytes. In addition, Lewis and third-party skin grafts were transplanted to these animals. ### results Mean graft survival times under CsA, FK506, and dFdC monotherapy were 18.3/63.7 days (1 mg/5 mg per kg), 41.7 days, and 24.7/38.7 days (100 microg/150 microg per kg), respectively. CsA and FK506 in combination with dFdC prolonged graft survival to more than 100 days (CsA) and more than 95.2 days (FK506). Graft survival after treatment of an ongoing rejection was 21.5/38.3 days for CsA (1 mg/5 mg per kg) and 17.7/59.2 days for dFdC (100 microg/150 microg per kg). The combination of CsA+dFdC prompted indefinite survival of five of six hearts. Lymphocyte inoculation did not induce graft rejection. Notably, none of the Lewis, but all third-party, skin grafts were rejected immediately. Histomorphologic analysis of grafted hearts, however, demonstrated typical features of chronic rejection. ### conclusions The combination of CsA and FK506 with low-dose dFdC exerts a synergistic effect in the prevention and treatment of acute allograft rejection in this model. Although chronic rejection could not be prevented, strain-specific tolerance was achieved. Therefore, combining standard immunosuppressants with dFdC is a novel, promising strategy for prevention and treatment of acute allograft rejection. ### Assistant: [{"class": "POS", "spans_text": ["Gemcitabine", "cyclosporine"]}, {"class": "POS", "spans_text": ["Gemcitabine", "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: We determined the effects of diclofenac sodium , octreotide , and their combination on extrapancreatic organ injuries in caerulein-induced acute pancreatitis in mice . Paragraph: Diclofenac Sodium Treatment Ameliorates Extrapancreatic Organ Injuries in a Murine Model of Acute Pancreatitis Induced by Caerulein. We determined the effects of diclofenac sodium , octreotide , and their combination on extrapancreatic organ injuries in caerulein-induced acute pancreatitis in mice . ### methods A total of 58 BALB-C male mice (25 g) were divided into seven groups and used to create a caerulein-induced acute pancreatitis model. diclofenac sodium, octreotide, and their combination were given for treatment of caerulin-induced acute pancreatitis in mice. At the end of the experiment, the lung, liver, kidney, and stomach were removed for histopathologic assessment. ### results Histopathologic investigation revealed a statistically significant difference between the groups in mean congestion, edema, tubular injury, perirenal fat tissue inflammation, and tubular stasis scores in kidney tissue ( ### conclusion diclofenac sodium alone ameliorates lung edema due to caerulin-induced acute pancreatitis. ### Assistant: [{"class": "COMB", "spans_text": ["diclofenac", "octreotide"]}]

### 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: Caspofungin and amphotericin B association has been shown to be synergistic in vitro and effective in murine models . Paragraph: [Successful treatment of a persistent rhino-cerebral mucormycosis in a pediatric patient with a debut of acute lymphoblastic leukemia]. The fungi of the order Mucorales cause mucormycosis, which usually presents as an invasive fungal disease with rapid angioinvasion in immunocompromised patients. Rhinocerebral is the most common presentation. The lipid formulations of amphotericin B are used as primary treatment in invasive mucormycosis; the combined use of posaconazole could allow a reduction in the dose of amphotericin B improving tolerance and adherence to treatment. Caspofungin and amphotericin B association has been shown to be synergistic in vitro and effective in murine models . We present the case of a preschool patient that during the debut of acute lymphoblastic leukemia developed a rhinocerebral mucormycosis successfully responding to antifungal treatment with the combination of liposomal amphotericin and caspofungin. ### Assistant: [{"class": "POS", "spans_text": ["Caspofungin", "amphotericin"]}]

### 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: Canine leishmaniosis is most frequently treated with the drugs meglumine antimoniate , allopurinol , amphotericin B , or a combination of meglumine antimoniate and allopurinol . Paragraph: Chemotherapy of canine leishmaniosis. Visceral leishmaniosis is a widespread and potentially fatal disease of dogs and humans common in the Mediterranean region, the Middle East, and South America. Canine leishmaniosis is most frequently treated with the drugs meglumine antimoniate , allopurinol , amphotericin B , or a combination of meglumine antimoniate and allopurinol . Therapy with the currently used drugs often achieves temporary clinical improvement and changes in immunologic parameters with restoration of the ability to mount parasite-specific cell mediated responses and decrease in anti-leishmanial antibody titers. However, treatment usually does not prevent relapse of disease or eliminate parasite carriage. Due to the current lack of an ultimate and effective therapy for canine leishmaniosis, new drugs, delivery systems and treatment strategies are necessary to achieve a consistent parasitological cure in infected dogs. ### Assistant: [{"class": "POS", "spans_text": ["meglumine", "allopurinol"]}, {"class": "POS", "spans_text": ["allopurinol", "amphotericin", "antimoniate"]}]

### 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: Haloperidol , carbamazepine and levomepromazine were then discontinued . Paragraph: Pituitary microadenoma treated with antipsychotic drug aripiprazole. Male patient 24 years old with a pituitary microadenoma and mental and behavioural disorders due to multiple drug use and use of other psychoactive substances (cocaine, cannabis and alcohol) were treated with haloperidol (dopamine receptor blocker) 10 mg daily. In the last control, the patient presented mammary hypertrophy; laboratory testing and brain magnetic resonance imaging (MRI) was performed, reporting the presence of a pituitary microadenoma syndrome with hormonal alteration (Prolactin levels 28.4 ng/ml). Haloperidol , carbamazepine and levomepromazine were then discontinued . He was started on aripiprazole 15 mg po daily for 4 days; the dosage was then increased to 30 mg po daily, with valproic Acid 500 mg po tid. After 3 weeks on aripiprazole, the mammary hypertrophy that had increased in the patient had resolved. After 10 weeks follow up of prolactin revealed a normal level, at 4.33 ng/ml. Insomnia, aggressiveness, irritability, visual, tactile and auditory hallucinations remained absent after treatment with aripiprazole which is not a first line drug in multiple drug use patient with psychosis. We also consider the correlation of drug use in patient with psychosis, haloperidol treatment, pituitary microadenoma syndrome, hyperprolactinemia, and dopamine D2- receptor partial agonist aripiprazole treatment. This article also summarizes some relevant patents. ### Assistant: [{"class": "COMB", "spans_text": ["Haloperidol", "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: Recent clinical work has questioned the safety of a combined therapy of oral quinidine and intravenous verapamil , because some patients were reported to react with severe hypotension probably due to drug interactions with vascular alpha-adrenergic receptors . Paragraph: Additive competitive interaction of verapamil and quinidine at alpha-adrenergic receptors of isolated cardiac guinea pig myocytes and human platelets. Recent clinical work has questioned the safety of a combined therapy of oral quinidine and intravenous verapamil , because some patients were reported to react with severe hypotension probably due to drug interactions with vascular alpha-adrenergic receptors . In order to obtain further quantitative information on the underlying mechanism, we used the radioligands (3H)-prazosin and (3H)-yohimbine to perform binding studies on intact cells, with predominantly alpha-1 (isolated myocytes) or alpha-2 subtypes (human platelets) of adrenergic receptors. Our studies confirm that both verapamil and quinidine possess a distinct alpha-adrenergic receptor blocking activity and do not discriminate between the alpha-1 and alpha-2 subtype (Ki-values were between 0.24-0.28 mumol/l for alpha-1 receptors and 0.49-0.50 mumol/l for alpha-2 receptors). Their interaction was competitive and in the presence of both drugs inhibition of radioligand binding was additive. The alpha-adrenergic blockade by verapamil was stereospecific as D-verapamil increased the dissociation constant of the radioligand to a much lesser degree than L-verapamil (Ki = 1.67 +/- 0.29 mumol/l for D-verapamil). The calcium channel blocker nitrendipine, a 1,4-dihydropyridine derivative, did not show any competition up to concentrations of 10 mumol/l. Our results thus give evidence that verapamil and quinidine have already at therapeutic blood levels significant alpha-adrenergic blocking activities which may be of clinical interest. In addition our results show that adult cardiac myocytes are very well suited for pharmacological adrenergic interaction studies. ### Assistant: [{"class": "NEG", "spans_text": ["quinidine", "verapamil"]}]

### 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 increase the dose-intensity of two drugs in metastatic breast cancer , we tested the feasibility , in phase I studies , of two schedules of epirubicin ( E ) and cyclophosphamide ( C ) - sequential ( E-- > C ) and alternating ( E/C ) - with respect to the standard combination ( EC ) . Paragraph: The impact of schedule on acute toxicity and dose-intensity of high-dose chemotherapy with epirubicin and cyclophosphamide plus colony stimulating factors in advanced breast cancer. To increase the dose-intensity of two drugs in metastatic breast cancer , we tested the feasibility , in phase I studies , of two schedules of epirubicin ( E ) and cyclophosphamide ( C ) - sequential ( E-- > C ) and alternating ( E/C ) - with respect to the standard combination ( EC ) . Drugs were given at three planned-dose levels, plus either G-CSF or GM-CSF. Patients with metastatic (30), inoperable stage IIIb (2) or inflammatory (7) breast cancer were treated. The doses of EC, given every 21 days (4 cycles), were 75/1500, 82.5/2250, 90/3000 mg/m2. In the E/C schedule, epirubicin was given at cycles 1, 3 and 5, and cyclophosphamide at cycles 2, 4 and 6. In the E--> C schedule, three cycles of epirubicin then three cycles of cyclophosphamide were administered. In both experimental schedules, drugs were given every 14 days for 6 cycles at doses of 100, 110, 120 mg/m2 (E) and 2000, 3000, 4000 mg/m2 (C). The average relative dose-intensity was 1.2-fold and 2-fold greater with E/C and E--> C, respectively, than with EC. The third level dose was feasible with all schedules. Grade 4 leucopenia occurred in 77% of patients. Thrombocytopenia was absent in 6 cases and grade 4 in 12 (30.8%). Eighty-one percent of patients on experimental schedules required red blood cell support versus 44.4% of patients on EC. At the third level, platelet transfusions were more frequent among patients treated with EC (27. 8%). Non-haematological toxicity was mild: about 20% of patients experienced grade 3 vomiting, irrespective of schedule. Only 2 patients had grade 3 mucositis; no patient developed heart failure. Fever (61% of patients) and bone pain (55.5% of patients) were relevant in the GM-CSF treated groups and 12 patients shifted to G-CSF. The overall response rate was 84.6%: 5/39 (12.8%) complete response and 28/39 (71.8%) partial response. At 30/9/98, median survival was 29.5 months, with no difference between patients with metastatic and stage IIIb/inflammatory breast cancer. Median follow-up of surviving patients was 62 months (range 17-83). The 5-year estimated survival was 19% (95% confidence intervals = 7-31%). Rapidly alternating or sequential cycles of epirubicin and cyclophosphamide with CSF support is a feasible strategy that allows a higher increase of dose-intensity of the single drugs. Hospitalization and anemia were more frequent with the experimental schedules, and thrombocytopenia with the standard schedule. Overall, this intensified therapy was very active. ### Assistant: [{"class": "POS", "spans_text": ["epirubicin", "cyclophosphamide"]}]

### 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: On February 3 , 2015 , the FDA granted accelerated approval to palbociclib ( IBRANCE , Pfizer Inc. ) , an inhibitor of cyclin-dependent kinases 4 and 6 ( CDK4 and CDK6 ) , for use in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive , HER2-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease . Paragraph: FDA Approval: Palbociclib for the Treatment of Postmenopausal Patients with Estrogen Receptor-Positive, HER2-Negative Metastatic Breast Cancer. On February 3 , 2015 , the FDA granted accelerated approval to palbociclib ( IBRANCE , Pfizer Inc. ) , an inhibitor of cyclin-dependent kinases 4 and 6 ( CDK4 and CDK6 ) , for use in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive , HER2-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease . The approval is based on a randomized, multicenter, open-label phase I/II trial (PALOMA-1) in 165 patients randomized to palbociclib (125 mg orally daily for 21 consecutive days, followed by 7 days off treatment) plus letrozole (2.5 mg orally daily) or letrozole alone. The phase II portion of the trial was divided into two cohorts: cohort 1 enrolled 66 biomarker-unselected patients and cohort 2 enrolled 99 biomarker-positive patients. The major efficacy outcome measure was investigator-assessed progression-free survival (PFS). A large magnitude of improvement in PFS was observed in patients receiving palbociclib plus letrozole compared with patients receiving letrozole alone (HR, 0.488; 95% confidence interval, 0.319-0.748). Multiple sensitivity analyses were supportive of clinical benefit. The most common adverse reaction in patients receiving palbociclib plus letrozole was neutropenia. This article summarizes the FDA thought process and data supporting accelerated approval based on PALOMA-1 that may be contingent upon verification and description of clinical benefit in the ongoing and fully accrued confirmatory trial PALOMA-2. ### Assistant: [{"class": "POS", "spans_text": ["palbociclib", "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 combination treatment : estramustine phosphate , cyproterone acetate or estrogens plus bromocriptine . Paragraph: [Current aspects of hormonal therapy in prostate cancer]. The following endocrine treatment modalities have been used in advanced prostatic carcinoma: 1. orchiectomy plus estrogens; 2. primary orchiectomy with delayed estrogen employment; 3. initial estrogen therapy with delayed orchiectomy; 4. initial cyproterone acetate or medroxyprogesterone acetate; 5. a combination treatment : estramustine phosphate , cyproterone acetate or estrogens plus bromocriptine . The application of phase-III studies permits the subsequent conclusions: Simultaneous orchiectomy is to no advantage (exception: urinary stasis). cyproterone acetate does neither yield better nor worse results regarding survival than estrogen alone, but has fewer side effects. Estrogens and cyproterone acetate produce a rise of serum prolactin justifying the use of bromocriptine (or lisuride). estramustine phosphate should be reserved for relapsing prostatic cancer. ### Assistant: [{"class": "POS", "spans_text": ["estramustine", "cyproterone"]}, {"class": "POS", "spans_text": ["bromocriptine", "estrogens"]}]

### 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: Hormone induced elevations in temperature and possibly other unidentified factors during thyroid crisis may facilitate the triggering of MH following halothane and succinylcholine challenge . Paragraph: Differential diagnosis of thyroid crisis and malignant hyperthermia in an anesthetized porcine model. The intra-operative differential diagnosis between thyroid crisis and malignant hyperthermia can be difficult. Also stress alone can trigger MH. The purposes of this study were: 1) to investigate the metabolic and hemodynamic differences between thyroid crisis and MH, 2) determine how thyroid crisis affects the development of MH, and 3) determine if the stress of thyroid crisis can trigger MH in susceptible individuals. We studied MH susceptible and normal swine. Two groups of animals (MH susceptible and normal) were induced into thyroid crisis (critical core hyperthermia, sustained tachycardia and increase in oxygen consumption) by pretreatment with intraperitoneal triiodothyronine (T3) followed by large hourly intravenous injections of T3. Two similar groups were given intravenous T3 but no pretreatment. These animals did not develop thyroid crisis and served as controls. Thyroid crisis did not result in metabolic changes or rigidity characteristic of an acute episode of MH. When the animals were subsequently challenged with MH triggering agents (halothane plus succinylcholine) dramatic manifestations of fulminant MH episodes (acute serious elevation in exhaled carbon dioxide, arterial CO2, rigidity and acidemia) were noted only in the MH susceptible animals. Although thyroid crisis did not trigger MH in the susceptible animals it did decrease the time to trigger MH (14.1 +/- 7.2 minutes versus 47.2 +/- 17.7 minutes, p < 0.01) in susceptible animals. Hormone induced elevations in temperature and possibly other unidentified factors during thyroid crisis may facilitate the triggering of MH following halothane and succinylcholine challenge . ### Assistant: [{"class": "COMB", "spans_text": ["halothane", "succinylcholine"]}]

### 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: Mitomycin C plus vinblastine is an effective and well-tolerated regimen for anthracycline resistant cancer . Paragraph: Mitomycin C and vinblastine in anthracycline-resistant metastatic breast cancer: a phase II study. The purpose of this phase II study was to evaluate the clinical efficacy of mitomycin C and vinblastine in patients with anthracycline-resistant metastatic breast cancer. This single-center, non-randomized trial enrolled 39 patients. Eligible patients must have received at least three chemotherapy regimens with epirubicin or CAF and had treatment failure while on chemotherapy or within 6 months of completing therapy. Treatment consisted of mitomycin C at a starting dose of 8 mg/m2 on day 1 and vinblastine (8 mg/m2, days 1 and 28). The regimen was repeated every 6 weeks with a 20% dose escalation of both drugs after the first cycle in the absence of grade III hematologic or other toxicity. On an intent-to-treat basis, 38 patients were eligible for assessment; 9 (23.7%, 95% confidence interval 1.92-2.45%) achieved a partial response and 13 (34.2%) had stable disease. The median time to disease progression was 6.21+/-4.26 months (range, 1-15; 95% confidence interval, 4.81-7.61), and the median survival was 10.76+/-7.6 (range, 1-29; 95% confidence interval 8.0-13.1%). Responsive patients had a significantly better survival than those with stable and progressive disease. Treatment was well tolerated. Anemia and neutropenia (grade I-III) developed in 28.9% and 26.3% of the patients, respectively. One patient with grade III granulocytopenia developed fever and infection that required hospitalization. Moderate neurotoxicity, myalgia, constipation, diarrhea and alopecia were observed. No toxic death occurred. Mitomycin C plus vinblastine is an effective and well-tolerated regimen for anthracycline resistant cancer . ### Assistant: [{"class": "POS", "spans_text": ["Mitomycin", "vinblastine"]}]

### 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: An angiotensin 2 type 1 receptor blocker , olmesartan , and a calcium channel blocker , azelnidipine , possess not only an antihypertensive effect but also an antioxidative effect and other beneficial effects . Paragraph: Synergistic neuroprotective effects of combined treatment with olmesartan plus azelnidipine in stroke-prone spontaneously hypertensive rats. An angiotensin 2 type 1 receptor blocker , olmesartan , and a calcium channel blocker , azelnidipine , possess not only an antihypertensive effect but also an antioxidative effect and other beneficial effects . In the present study, we examined the efficacy of olmesartan and azelnidipine monotherapy (2 mg/kg or 10 mg/kg each) and their combination therapy (1 mg/kg each) on stroke-prone spontaneously hypertensive rats (SHR-SP) in relation to oxidative stress, inflammation, and the neurovascular unit. In comparison with the vehicle group, body weight, regional cerebral blood flow, and motor function were preserved, whereas systolic blood pressure and diastolic blood pressure decreased in the five drug-treatment groups. Spontaneous infarct volume decreased with the low-dose combination of olmesartan plus azelnidipine and with the high-dose olmesartan, with a further decrease in the high-dose azelnidipine group. In addition, these drugs dose-dependently reduced oxidative stresses, proinflammatory molecules, and well-preserved components of the neurovascular unit. The low-dose combination of olmesartan plus azelnidipine showed a better effect than the low-dose olmesartan or azelnidipine monotherapy. The present study shows that the low-dose combination of olmesartan plus azelnidipine demonstrates a greater synergistic benefit than monotherapy with a low-dose of olmesartan or azelnidipine in SHR-SP for preventing spontaneous infarct volume, reducing oxidative stresses and proinflammatory molecules, and imparting neurovascular protection. In addition, a high-dose of olmesartan showed a greater benefit without the lowering of blood pressure, probably because of the antioxidative and anti-inflammatory effects. A high dose of azelnidipine showed the best benefit, probably because of the two effects mentioned above related to the lowering of blood pressure. ### Assistant: [{"class": "POS", "spans_text": ["olmesartan", "azelnidipine"]}]

### 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: Forty patients with metastatic breast cancer who had received no previous cytotoxic therapy were treated with a combination chemotherapy program CMF ( P ) , which included methotrexate , 60 mg/m2 , and 5-fluorouracil , 700 mg/m2 intravenously on the first and eighth days , in addition to cyclophosphamide , 100 mg/m2 , and prednisone , 40 mg/m2 , by mouth daily from the first to the fourteenth day of a 28-day cycle . Paragraph: Combination chemotherapy for advanced breast cancer: response and effect on survival. Forty patients with metastatic breast cancer who had received no previous cytotoxic therapy were treated with a combination chemotherapy program CMF ( P ) , which included methotrexate , 60 mg/m2 , and 5-fluorouracil , 700 mg/m2 intravenously on the first and eighth days , in addition to cyclophosphamide , 100 mg/m2 , and prednisone , 40 mg/m2 , by mouth daily from the first to the fourteenth day of a 28-day cycle . Only 2 of 25 patients responded to hormonal therapy or endocrine ablation. Twenty-seven of the 40 patients (68%) had a complete response (8 patients) or partial response (19 patients). Lung, soft tissue, and nodal metastases were the most responsive sites. The median survival of 18 months for the responding group. The nonresponders had a median survival of 4 months. The toxicity was primarily hematologic and was especially severe in patients with functional liver impairment due to metastatic disease. ### Assistant: [{"class": "POS", "spans_text": ["methotrexate", "cyclophosphamide", "prednisone", "5-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: At present , it seems to us that progress has not been made since Grignani reported a phase II cohort trial of sorafenib and sorafenib combined with everolimus for advanced osteosarcoma , which , in a sense , have become a milestone as a second-line therapy for osteosarcoma . Paragraph: Anti-angiogenesis target therapy for advanced osteosarcoma (Review). Osteosarcomas (OS), especially those with metastatic or unresectable disease, have limited treatment options. The greatest advancement in treatments occurred in the 1980s when multi-agent chemotherapy, including doxorubicin, cisplatin, high-dose methotrexate, and, in some regimens, ifosfamide, was demonstrated to improve overall survival compared with surgery alone. However, standard chemotherapeutic options have been limited by poor response rates in patients with relapsed or advanced cases. It has been reported that VEGFR expression correlates with the outcome of patients with osteosarcoma and circulating VEGF level has been associated with the development of lung metastasis. At present , it seems to us that progress has not been made since Grignani reported a phase II cohort trial of sorafenib and sorafenib combined with everolimus for advanced osteosarcoma , which , in a sense , have become a milestone as a second-line therapy for osteosarcoma . Although the recognization of muramyltripepetide phosphatidyl-ethanolamine has made some progress based on its combination with standard chemotherapy, its effect on refractory cases is controversial. Personalized comprehensive molecular profiling of high-risk osteosarcoma up to now has not changed the therapeutic prospect of advanced osteosarcoma significantly. Thus, how far have we moved forward and what therapeutic strategy should we prefer for anti-angiogenesis therapy? This review provides an overview of the most updated anti-angiogenesis therapy in OS and discusses some clinical options in order to maintain or even improve progression-free survival. ### Assistant: [{"class": "COMB", "spans_text": ["sorafenib", "everolimus"]}]

### 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: Thirteen patients with interstitial cystitis diagnosed by the NIH criteria were treated with intravesical electromotive administration of lidocaine and dexamethasone followed by cystodistention . Paragraph: Electromotive drug administration and hydrodistention for the treatment of interstitial cystitis. Thirteen patients with interstitial cystitis diagnosed by the NIH criteria were treated with intravesical electromotive administration of lidocaine and dexamethasone followed by cystodistention . After a mean follow-up of 10 (range 3-22) months, 8/13 (62%) of the patients reported complete resolution of bladder symptoms lasting an average 4.5 (range 0.75-17) months. Partial or short-term improvement of bladder symptoms was observed in three patients, while two patients reported aggravation of pain for several days after therapy. A significant increase in bladder capacity, to an average 166% of the pretreatment capacity, was observed in all patients. Whenever symptoms recurred after initially effective therapy, retreatments were performed with equal efficacy in 11 patients. This promising new therapeutic approach, performed on an outpatient basis, may become first-line treatment for patients with interstitial cystitis. ### Assistant: [{"class": "POS", "spans_text": ["lidocaine", "dexamethasone", "cystodistention"]}]

### 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 therapy included omega-3 fish oil , extended-release niacin , colesevelam hydrochloride , and a fixed combination of 10-mg ezetimibe and 40-mg simvastatin . Paragraph: Lipoprotein-associated phospholipase A2 mass is significantly reduced in dyslipidemic patients treated with lifestyle modification and combination lipid-modifying drug therapy. Lipoprotein-associated phospholipase A2 (Lp-PLA(2)) mass is a novel inflammatory biomarker. In human blood, Lp-PLA(2) is predominately associated with low-density lipoprotein (LDL). This study examines the ability of lifestyle modification (diet and exercise) and combination lipid therapy to reduce Lp-PLA(2) levels while also determining the relationship between changes in LDL cholesterol and Lp-PLA(2). Thirty dyslipidemic patients who received lifestyle intervention and combination lipid therapy for an average of 6 months were included in these analyses (mean age, 60.9 years); 40% had stable angiographically established coronary artery disease, 40% had the metabolic syndrome, and 70% were men. Drug therapy included omega-3 fish oil , extended-release niacin , colesevelam hydrochloride , and a fixed combination of 10-mg ezetimibe and 40-mg simvastatin . The study revealed a 33% reduction in mean Lp-PLA(2) values (baseline 224.9+/-47.5 vs posttreatment 149.5+/-35.5 ng/mL; P<.001). Significant changes in mean LDL cholesterol from baseline (127.9+/-49.3 vs posttreatment 65.2+/-32.1 mg/dL; P<.001) were also observed. However, regression analysis revealed only a weak positive relationship between changes in LDL cholesterol and Lp-PLA(2) mass (R(2)=0.29; P<.01). Thus, Lp-PLA(2) mass is significantly reduced with lifestyle and combination lipid therapy. Changes in Lp-PLA(2) were only partially explained by the changes observed for LDL cholesterol. ### Assistant: [{"class": "POS", "spans_text": ["omega-3", "niacin", "colesevelam hydrochloride", "ezetimibe", "simvastatin"]}]

### 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: Twenty-one Japanese colorectal cancer patients received intravenous FOLFIRI ( bolus irinotecan , folinic acid , and fluorouracil followed by 46-hour fluorouracil infusion ) followed by bevacizumab ( 5 mg/kg ) in Cycle 1 . Paragraph: Pharmacokinetics, safety, and efficacy of FOLFIRI plus bevacizumab in Japanese colorectal cancer patients with UGT1A1 gene polymorphisms. Previous reports of the influence of UGT1A1 gene polymorphisms on the pharmacokinetics of irinotecan metabolism have not assessed Asian patients treated with FOLFIRI plus bevacizumab for advanced and recurrent colorectal cancer. Twenty-one Japanese colorectal cancer patients received intravenous FOLFIRI ( bolus irinotecan , folinic acid , and fluorouracil followed by 46-hour fluorouracil infusion ) followed by bevacizumab ( 5 mg/kg ) in Cycle 1 . In Cycle 2, patients received bevacizumab followed by FOLFIRI. The regimen was in 2-week cycles. The area under-the-curves ratio (AUC0-last) (Cycle 2/Cycle 1) was determined from plasma concentrations of irinotecan and metabolites (SN-38, SN-38G). Safety, efficacy, and drug-drug interactions were analyzed. Median observation period was 7.8 months; median number of cycles 15. Drug-drug interactions were evaluated in eight patients without irinotecan dose reduction. Mean AUC0-last ratios (with/without bevacizumab) of irinotecan, SN-38, and SN-38G were 0.959, 0.927, and 0.931 respectively. Response rate was 65%; median progression-free survival 16.4 months. Response occurred in four patients with, and nine without, UGT1A1 polymorphism. No significant differences occurred between efficacy, safety, or polymorphism status. This cohort showed no differences in safety or efficacy compared to previous reports. bevacizumab did not affect the pharmacokinetics of irinotecan and its metabolites, irrespective of UGT1A1 polymorphism status. ### Assistant: [{"class": "COMB", "spans_text": ["irinotecan", "folinic acid", "fluorouracil", "fluorouracil", "bevacizumab"]}]

### 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 received vinorelbine starting at 20 mg/m(2 ) ( to 25 mg/m(2 ) ) and carboplatin area under the curve ( AUC ) 2.5 in divided-doses , both given on Days 1 and 8 every 21-day cycle for up to 6 cycles or until disease progression . Paragraph: Phase I/II trial of vinorelbine and divided-dose carboplatin in advanced non-small cell lung cancer. vinorelbine administered in a doublet with cisplatin has become a standard treatment in patients with advanced non-small cell lung cancer (NSCLC). However, carboplatin appears to provide comparable efficacy with a better nonhematologic safety profile than cisplatin. Herein we report the results of a phase I/II trial of weekly vinorelbine and divided-dose carboplatin in patients with stage IIIB/IV NSCLC, Eastern Cooperative Oncology Group performance status < or = 2, and adequate bone marrow. Patients received vinorelbine starting at 20 mg/m(2 ) ( to 25 mg/m(2 ) ) and carboplatin area under the curve ( AUC ) 2.5 in divided-doses , both given on Days 1 and 8 every 21-day cycle for up to 6 cycles or until disease progression . Dose-limiting toxicity was defined for Cycles 1 and 2. Tumor response and toxicity were assessed using standard criteria. Twenty-one patients with a mean age of 67 years (range, 43-79) and stage IIIB/IV (8/13) disease were enrolled. All but 1 patient were chemotherapy-nai;ve; the majority (n = 20) had good performance status (< or = 1). Seventy-nine courses (median, 4) were administered. The vinorelbine/carboplatin doublet was well tolerated, with 7 courses interrupted or delayed because of toxicity. Toxicities were generally mild and evenly divided between hematologic (i.e., neutropenia) and nonhematologic (i.e., fatigue). No growth factor support was required for hematologic toxicity. There was only one case of grade 2 alopecia, and no cases of > or = grade 2 neurotoxicity. There were 5 (24%) partial responses, and 9 (43%) patients had stable disease. Weekly vinorelbine 25 mg/m(2) and divided-dose carboplatin AUC 2.5 is a well tolerated regimen with activity in advanced NSCLC patients. Further evaluation of this regimen in combination with novel targeted biologic therapy is warranted. ### Assistant: [{"class": "POS", "spans_text": ["vinorelbine", "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: Dexamethasone exhibited the highest effect on paclitaxel anti-tumor activity , in a dose-dependent fashion . Paragraph: Efficacy of paclitaxel/dexamethasone intra-tumoral delivery in treating orthotopic mouse breast cancer. The effect of topical co-administration of promoter drugs with paclitaxel to increase anti-tumor effects of paclitaxel was investigated. Mice with orthotopic 4T1-Luc breast cancer received single intra-tumoral injection of a polymeric formulation with paclitaxel and a specific promoter drug. Several promoter drugs were evaluated, including: dexamethasone, losartan, nicotinamide, Azone, and oleic acid. Dexamethasone exhibited the highest effect on paclitaxel anti-tumor activity , in a dose-dependent fashion . However, this effect was accompanied by systemic effects of dexamethasone, and inability to prevent tumor metastasis to the lungs. Topical co-administration of promoter drugs with anti-cancer agents can enhance their anti-tumor effects. Further investigations are needed to identify the most efficient combinations of promoter and anti-cancer drugs, and their suitability for the clinical management of the breast cancer disease. ### Assistant: [{"class": "COMB", "spans_text": ["Dexamethasone", "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: We therefore explored the in vitro combination of amphotericin B with itraconazole against 14 clinical Aspergillus fumigatus isolates ( 9 itraconazole susceptible and 5 itraconazole resistant ) with a colorimetric broth microdilution checkerboard technique using two drug interaction models able to explore complicated patterns of interactions : the response surface analysis of Bliss independence and the isobolographic analysis of Loewe additivity zero interaction theories . Paragraph: The concentration-dependent nature of in vitro amphotericin B-itraconazole interaction against Aspergillus fumigatus: isobolographic and response surface analysis of complex pharmacodynamic interactions. The interaction between polyenes and azoles is not well understood. We therefore explored the in vitro combination of amphotericin B with itraconazole against 14 clinical Aspergillus fumigatus isolates ( 9 itraconazole susceptible and 5 itraconazole resistant ) with a colorimetric broth microdilution checkerboard technique using two drug interaction models able to explore complicated patterns of interactions : the response surface analysis of Bliss independence and the isobolographic analysis of Loewe additivity zero interaction theories . Synergy was found at combinations with low concentrations of amphotericin B (<0.125 mg/L), whereas antagonism was found at combinations with higher concentrations of amphotericin B. For itraconazole-resistant isolates, synergistic interactions were observed at high concentrations of itraconazole (>0.5 mg/L). Synergy was more frequently observed for the itraconazole-resistant isolates than for the itraconazole-susceptible isolates. ### Assistant: [{"class": "POS", "spans_text": ["amphotericin", "itraconazole"]}]

### 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 study evaluated the safety and efficacy of inotuzumab ozogamicin ( INO ) , a targeted humanized anti-CD22 antibody conjugated to calicheamicin , plus rituximab ( R-INO ) every 3 weeks , up to six cycles , followed by high dose therapy and autologous stem cell transplant ( HDT-aSCT ) in patients with high-risk relapsed/refractory diffuse large B-cell lymphoma ( DLBCL ) . Paragraph: A phase 2 study of inotuzumab ozogamicin and rituximab, followed by autologous stem cell transplant in patients with relapsed/refractory diffuse large B-cell lymphoma. This study evaluated the safety and efficacy of inotuzumab ozogamicin ( INO ) , a targeted humanized anti-CD22 antibody conjugated to calicheamicin , plus rituximab ( R-INO ) every 3 weeks , up to six cycles , followed by high dose therapy and autologous stem cell transplant ( HDT-aSCT ) in patients with high-risk relapsed/refractory diffuse large B-cell lymphoma ( DLBCL ) . The primary endpoint was overall response (OR) rate after three cycles of R-INO. Sixty-three patients were enrolled. Common grade 3/4 adverse events during R-INO treatment were thrombocytopenia, lymphopenia and neutropenia. OR rate after three cycles of R-INO was 28.6% (95% confidence interval: 17.9-41.4). Eighteen patients underwent HDT-aSCT; 2-year progression-free survival (PFS) for these patients was 61.1%. Serious infections and hepatic toxicity following aSCT occurred in 33% and 22%, respectively. One- and 2-year PFS rates for all enrolled patients were 28.9% and 25.3%, respectively (median, 3.0 months). R-INO had lower than expected activity as a salvage regimen for transplant eligible patients with DLBCL. ### Assistant: [{"class": "COMB", "spans_text": ["inotuzumab", "rituximab", "HDT-aSCT"]}]

### 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 are the first 2 reports of successful treatment of this condition by use of a combination of methylprednisolone and mycophenolate mofetil , and , in 1 of the cases , additional medication with intravenous immunoglobulin . Paragraph: Severe Ocular Myositis After Ipilimumab Treatment for Melanoma: A Report of 2 Cases. ipilimumab binds and blocks cytotoxic T-lymphocyte-associated antigen-4, causing enhanced T-cell reaction, antitumor response, and significant improvement of the overall survival of patients with metastatic melanoma. Patients treated with ipilimumab can develop immune-related adverse effects, primarily dermatitis, colitis, hepatitis, and hypophysitis. Although, in phase I-III studies, 64.2% of all patients suffered from immune-related adverse effects, ocular adverse effects occurred in 1.3% only. In the cases reported below, 2 patients with metastatic melanoma developed severe ocular myositis after treatment with ipilimumab. These are the first 2 reports of successful treatment of this condition by use of a combination of methylprednisolone and mycophenolate mofetil , and , in 1 of the cases , additional medication with intravenous immunoglobulin . ### Assistant: [{"class": "POS", "spans_text": ["methylprednisolone", "mycophenolate"]}, {"class": "POS", "spans_text": ["methylprednisolone", "mycophenolate", "immunoglobulin"]}]

### 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 conclusion , concurrent introduction of ATGAM and tacrolimus is a promising therapeutic combination for GVHD refractory to steroids and cyclosporine . Paragraph: Combination therapy with tacrolimus and anti-thymocyte globulin for the treatment of steroid-resistant acute graft-versus-host disease developing during cyclosporine prophylaxis. We report our experience with the combination of anti-thymocyte globulin (ATGAM) and tacrolimus in the treatment of 20 patients with steroid refractory and dependent acute graft-versus-host disease (GVHD) transplanted between August 1996 and February 2000. All patients received cyclosporine-based GVHD prophylaxis. Thirteen patients developed a maximum of grade IV, five grade III and two grade II acute GVHD, with 15 patients being refractory to steroids and five dependent on steroids. Patients were treated with ATGAM (15 mg/kg for 5 d) and tacrolimus (0.025--0.1 mg/kg/d) in addition to continuation of their high-dose steroids and cessation of their cyclosporine. Within 28 d of treatment, we observed eight complete responses (CR), six partial responses (PR) and six with no response. Overall response (CR + PR) was predicted by GVHD severity. Infectious complications occurred in 80% of patients. The median survival was 86.5 d (range, 21--1081 d) with 35% of patients remaining alive. Survival following combination therapy was significantly more likely in men (P < 0.001), skin-only GVHD (P = 0.027), less severe GVHD (P = 0.048), and in responders to tacrolimus and ATGAM (P < 0.001). In conclusion , concurrent introduction of ATGAM and tacrolimus is a promising therapeutic combination for GVHD refractory to steroids and cyclosporine . ### Assistant: [{"class": "POS", "spans_text": ["ATGAM", "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: Comparison of geometric least-squares mean PK parameters between arms showed no impact of pertuzumab on the PK of trastuzumab or docetaxel . Paragraph: Absence of pharmacokinetic drug-drug interaction of pertuzumab with trastuzumab and docetaxel. pertuzumab is a novel antihuman epidermal growth factor receptor 2 (HER2) humanized monoclonal antibody. Combined with trastuzumab plus docetaxel, pertuzumab improved progression-free and overall survival versus trastuzumab plus docetaxel in the phase III CLEOPATRA trial (NCT00567190) in first-line HER2-positive metastatic breast cancer. Thirty-seven patients participated in a pharmacokinetic (PK)/corrected QT interval substudy of CLEOPATRA, which evaluated potential PK drug-drug interaction (DDI). PK parameters were calculated using noncompartmental methods, and DDI analyses were carried out. In the presence of trastuzumab and docetaxel, the mean pertuzumab Cmin and Cmax in cycle 3 were 63.6 and 183 µg/ml, respectively. The pertuzumab concentrations observed were consistent with simulations from a validated population PK model, indicating that trastuzumab and docetaxel did not alter pertuzumab PK. Comparison of geometric least-squares mean PK parameters between arms showed no impact of pertuzumab on the PK of trastuzumab or docetaxel . In conclusion, no PK DDI was observed when pertuzumab, trastuzumab, and docetaxel were combined for the treatment of HER2-positive metastatic breast cancer. ### Assistant: [{"class": "COMB", "spans_text": ["pertuzumab", "trastuzumab"]}, {"class": "COMB", "spans_text": ["pertuzumab", "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: We proved experimentally the use of ECEEM for multiplex determination of kinetic parameters describing weak ( 3 mM > K(d ) > 80 μM ) and fast ( 0.25 s ≥ τ ≥ 0.9 ms ) noncovalent interactions between four small molecule drugs ( ibuprofen , S-flurbiprofen , salicylic acid and phenylbutazone ) and α- and β-cyclodextrins . Paragraph: Revealing equilibrium and rate constants of weak and fast noncovalent interactions. Rate and equilibrium constants of weak noncovalent molecular interactions are extremely difficult to measure. Here, we introduced a homogeneous approach called equilibrium capillary electrophoresis of equilibrium mixtures (ECEEM) to determine k(on), k(off), and K(d) of weak (K(d) > 1 μM) and fast kinetics (relaxation time, τ < 0.1 s) in quasi-equilibrium for multiple unlabeled ligands simultaneously in one microreactor. Conceptually, an equilibrium mixture (EM) of a ligand (L), target (T), and a complex (C) is prepared. The mixture is introduced into the beginning of a capillary reactor with aspect ratio >1000 filled with T. Afterward, differential mobility of L, T, and C along the reactor is induced by an electric field. The combination of differential mobility of reactants and their interactions leads to a change of the EM peak shape. This change is a function of rate constants, so the rate and equilibrium constants can be directly determined from the analysis of the EM peak shape (width and symmetry) and propagation pattern along the reactor. We proved experimentally the use of ECEEM for multiplex determination of kinetic parameters describing weak ( 3 mM > K(d ) > 80 μM ) and fast ( 0.25 s ≥ τ ≥ 0.9 ms ) noncovalent interactions between four small molecule drugs ( ibuprofen , S-flurbiprofen , salicylic acid and phenylbutazone ) and α- and β-cyclodextrins . The affinity of the drugs was significantly higher for β-cyclodextrin than α-cyclodextrin and mostly determined by the rate constant of complex formation. ### Assistant: [{"class": "COMB", "spans_text": ["ibuprofen", "\u03b2-cyclodextrins"]}, {"class": "COMB", "spans_text": ["S-flurbiprofen", "\u03b2-cyclodextrins"]}, {"class": "COMB", "spans_text": ["phenylbutazone", "\u03b2-cyclodextrins"]}]

### 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 the stem cell mobilization regimen of high-dose ifosfamide plus etoposide in 32 patients with epithelial ovarian cancer , who had a positive second-look laparatomy or recurrent disease . Paragraph: High-dose ifosfamide and etoposide with filgrastim for stem cell mobilization in patients with advanced ovarian cancer. High-dose chemotherapy combined with autologous peripheral blood stem cell transplantation has shown promise as treatment for recurrent or persistent epithelial ovarian cancer. We evaluated the stem cell mobilization regimen of high-dose ifosfamide plus etoposide in 32 patients with epithelial ovarian cancer , who had a positive second-look laparatomy or recurrent disease . ifosfamide was given at 10 g/m2 by continuous i.v. from days 1 to 3. etoposide was given at 150 mg/m2 every 12 h for six doses on days 1-3. filgrastim was given at 10 microg/kg/d s.c. from day 5 until the completion of peripheral blood stem cell harvest. Fourteen of 32 patients had measurable or evaluable disease before mobilization therapy and were assessed for response. In nine (64%) of the 14 patients, treatment response was demonstrated, and these patients received a second cycle of mobilization therapy. The target CD34+ cell dose (>8 x 106 cells/kg) was achieved with a median of one apheresis (range 1-5). A median of 25.1 (range 8.0-122.5) x 106 CD34+ cells/kg body weight was collected. Non-hematologic toxicity was limited to grade 2 renal dysfunction in one patient and grade 2 hepatic dysfunction in three patients. In this patient group, high-dose ifosfamide plus etoposide with filgrastim support was well tolerated, lead to successful stem cell harvest and had antitumor activity. ### Assistant: [{"class": "COMB", "spans_text": ["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: Combinations of alkylating agents and fludarabine or cladribine are also synergistic in producing significantly enhanced activity against refractory lymphoid malignancies , but at the cost of increased haematological toxicity . Paragraph: Clinical pharmacokinetics of nucleoside analogues: focus on haematological malignancies. This review establishes the pharmacokinetic characteristics of the major nucleoside analogues with cytotoxic activity. cytarabine, pentostatin, fludarabine, cladribine and gemcitabine are all prodrugs whose plasma pharmacokinetics do not fully reflect their therapeutic activity; after cellular uptake, these compounds undergo phosphorylation by deoxycytidine kinase before their incorporation into DNA results in cell death. cytarabine is principally active in the S phase of the cell cycle and is most toxic to replicating cells, whereas pentostatin, fludarabine and cladribine are incorporated into DNA during the process in which strand breaks are repaired and are therefore cytotoxic to slowly replicating cells (although the action of pentostatin results from its inhibition of adenosine deaminase). gemcitabine is unusual in being highly metabolised in solid tumour cells. The cytotoxic activity of pentostatin, fludarabine and cladribine against the clonal cells of lymphoproliferative disorders is accompanied by damage to normal lymphoid cells, which results in significant and long-lasting immunosuppression. Useful interactions between nucleoside analogues have been defined. Cells that are primed by exposure to fludarabine or cladribine exhibit enhanced accumulation of cytarabine triphosphate (the cytotoxic nucleotide of cytarabine) and an improved therapeutic effect against acute myeloid leukaemia and chronic lymphocytic leukaemia can be achieved by clinical schedules that exploit this effect. Combinations of alkylating agents and fludarabine or cladribine are also synergistic in producing significantly enhanced activity against refractory lymphoid malignancies , but at the cost of increased haematological toxicity . Developments in the clinical administration of gemcitabine are concentrating on efforts to extend the duration of exposure to the drug as a means of counteracting its rapid catabolism in the circulation. Future developments with this group of agents will further explore the use of fludarabine-based combination therapies to produce a transient period of myelosuppression and immunosuppression that is sufficient to permit the engraftment of allogeneic haemopoietic stem cells and also exploit the immunological benefits of graft-versus-tumour reactions. In addition, the clinical spectrum of activity of gemcitabine is also being extended by combining the drug with other active chemotherapeutic agents, such as cisplatin, and by early studies of its role as a radiosensitiser. ### Assistant: [{"class": "COMB", "spans_text": ["alkylating agents", "fludarabine"]}, {"class": "COMB", "spans_text": ["alkylating agents", "cladribine"]}]

### 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 pharmacodynamic effects of single doses of trazodone ( 100 mg ) , amitriptyline ( 50 mg ) or placebo either alone or with ethanol ( 0.5 ml/kg ) were investigated in 6 healthy volunteers in a double-blind crossover study . Paragraph: Evaluation of possible interactions between ethanol and trazodone or amitriptyline. The pharmacodynamic effects of single doses of trazodone ( 100 mg ) , amitriptyline ( 50 mg ) or placebo either alone or with ethanol ( 0.5 ml/kg ) were investigated in 6 healthy volunteers in a double-blind crossover study . Plasma concentrations of the drugs and ethanol were also measured. Pharmacodynamic tests were critical flicker fusion frequency threshold (CFF), choice reaction time (CRT), manual dexterity, a digit span test and visual analogue scales. Blood ethanol concentrations were not influenced by the co-administration of either antidepressant. tmax for trazodone was prolonged by ethanol but the other pharmacokinetic parameters for trazodone and amitriptyline were not influenced by ethanol. trazodone and amitriptyline caused the expected profound depressant effects on CFF, CRT, manual dexterity and on the rating scales for drowsiness, 'clearheadedness', aggression and disinhibition. Ethanol alone impaired manual dexterity, increased drowsiness, reduced 'clearheadedness' and also tended to reduce feelings of aggression. In combination with either trazodone or amitriptyline, ethanol caused little additional effect except in the case of manual dexterity, which was further impaired. This result may reflect the profound effects of the antidepressants alone and does not suggest that it is safe for patients receiving antidepressant medication to take ethanolic drinks. ### Assistant: [{"class": "COMB", "spans_text": ["trazodone", "ethanol"]}, {"class": "COMB", "spans_text": ["amitriptyline", "ethanol"]}, {"class": "COMB", "spans_text": ["ethanol", "placebo"]}]

### 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 70-year-old Asian man was diagnosed with PVT two months after initiating 5-fluorouracil/leucovorin , irinotecan , and bevacizumab therapy for rectal cancer with liver metastases . Paragraph: Portal Vein Thrombosis in Metastatic Colorectal Cancer During FOLFIRI-bevacizumab Chemotherapy Successfully Treated with Apixaban. Portal vein thrombosis (PVT) while using an angiogenesis inhibitor is relatively rare. A 70-year-old Asian man was diagnosed with PVT two months after initiating 5-fluorouracil/leucovorin , irinotecan , and bevacizumab therapy for rectal cancer with liver metastases . Because the metastases were small and shrinking, we suspected that the thrombosis might have been caused by bevacizumab-containing chemotherapy. We stopped bevacizumab and started apixaban, a direct oral anticoagulant (DOAC). Eight months later, the complete dissolution of the thrombus and recanalization of the portal vein were attained. Our case suggests that PVT can occur during bevacizumab-containing chemotherapy, and DOAC therapy might be beneficial for treating PVT in patients with cancer. ### Assistant: [{"class": "COMB", "spans_text": ["5-fluorouracil/leucovorin", "irinotecan", "bevacizumab"]}]

### 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: Results of cell viability assays revealed that treatment with a combination of imatinib and chemotherapy agents irinotecan or 5‑Fu synergistically inhibited cell growth , compared with treatment with any of these drugs alone . Paragraph: Imatinib‑induced apoptosis of gastric cancer cells is mediated by endoplasmic reticulum stress. imatinib is a powerful tyrosine kinase inhibitor that specifically targets BCR‑ABL, c‑KIT, and PDGFR kinases, and is used in the treatment of chronic myelogenous leukemia, gastrointestinal stromal tumors, and other types of cancers. However, the possible anticancer effects of imatinib in gastric cancer have not yet been explored. The present study evaluated the in vitro effects of imatinib on gastric cancer cells and determined the molecular mechanism underlying these effects. We determined that imatinib induced mitochondria‑mediated apoptosis of gastric cancer cells by involving endoplasmic reticulum (ER) stress‑associated activation of c‑Jun NH2‑terminal kinase (JNK). We also found that imatinib suppressed cell proliferation in a time‑ and dose‑dependent manner. Cell cycle analysis revealed that imatinib‑treated AGS cells were arrested in the G2/M phase of the cell cycle. Moreover, imatinib‑treated cells exhibited increased levels of phosphorylated JNK, and of the transcription factor C/EBP homologous protein, an ER stress‑associated apoptotic molecule. Results of cell viability assays revealed that treatment with a combination of imatinib and chemotherapy agents irinotecan or 5‑Fu synergistically inhibited cell growth , compared with treatment with any of these drugs alone . These data indicated that imatinib exerted cytotoxic effects on gastric cancer cells by inducing apoptosis mediated by reactive oxygen species generation and ER stress‑associated JNK activation. Furthermore, we revealed that imatinib induced the apoptosis of gastric cancer cells by inhibiting platelet‑derived growth factor receptor signaling. Collectively, our results strongly support the use of imatinib in the treatment of treating gastric cancer. ### Assistant: [{"class": "POS", "spans_text": ["imatinib", "irinotecan"]}, {"class": "POS", "spans_text": ["imatinib", "5\u2011Fu"]}]

### 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 a fluoropyrimidine ( 5-fluorouracil or capecitabine ) with either oxaliplatin or irinotecan has been widely accepted as standard cytotoxic chemotherapy for either the first- or second-line treatment of mCRC . Paragraph: Options for Second-Line Treatment in Metastatic Colorectal Cancer. Colorectal cancer (CRC) remains a major public health problem in the United States and worldwide. The majority of patients who have CRC eventually present with metastatic disease. The overall therapeutic goals for most patients with metastatic CRC (mCRC) are to control the disease, prolong life span, and maximize quality of life. Therefore, the ratio of efficacy to toxicity is one of the most important factors in choosing among treatment options and sequencing regimens. In addition, the choice of first-line systemic therapy will affect the options for second-line treatment. Several newer cytotoxic agents for the treatment of mCRC have been approved during the past 2 decades by the US Food and Drug Administration (FDA), including irinotecan, oxaliplatin, and capecitabine. The combination of a fluoropyrimidine ( 5-fluorouracil or capecitabine ) with either oxaliplatin or irinotecan has been widely accepted as standard cytotoxic chemotherapy for either the first- or second-line treatment of mCRC . The FDA has approved several pathway-targeting agents for the treatment of mCRC; these include agents that target the vascular endothelial growth factor receptor pathway (bevacizumab, ziv-aflibercept, and ramucirumab) and those that target the epidermal growth factor receptor pathway (cetuximab and panitumumab). Here, we review the current clinical options for the second-line treatment of mCRC and the rationales for their use. ### Assistant: [{"class": "COMB", "spans_text": ["fluoropyrimidine", "oxaliplatin"]}, {"class": "COMB", "spans_text": ["fluoropyrimidine", "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: Utilizing this data , we suggest that nivolumab plus ipilimumab and cabozantinib may be favored for first-line treatment of specific populations of older patients . Paragraph: Treatment Decisions for Metastatic Clear Cell Renal Cell Carcinoma in Older Patients: The Role of TKIs and Immune Checkpoint Inhibitors. Given the underrepresentation of older patients in registration trials for metastatic renal cell carcinoma (mRCC), data to support the use of any particular systemic therapy over others, based on age, is limited. This is further complicated by clinical trials not commonly reporting adverse events by age. Thus, recommendations on treatment of older patients with mRCC are generally extrapolated from data on younger patients enrolled in these trials, which may not be ideal as many older patients are frail, have age-related organ dysfunction, or have multiple medical co-morbidities. In the last decade, the treatment landscape for mRCC has drastically changed with the approval of more than ten targeted therapies, as well as immune checkpoint inhibitors. Thus, treatment selection and sequencing of treatments can be especially challenging for clinicians. We begin this review by analyzing the available efficacy and toxicity data of these treatments in younger and older patients. We also discuss a network meta-analysis that compares the efficacy of these agents in older patients with mRCC. Utilizing this data , we suggest that nivolumab plus ipilimumab and cabozantinib may be favored for first-line treatment of specific populations of older patients . For salvage treatment, we suggest that cabozantinib may be the preferred agent for older patients. ### Assistant: [{"class": "POS", "spans_text": ["nivolumab", "ipilimumab", "cabozantinib"]}]

### 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 all E. coli positive blood cultures collected during a 4-y period in a haematological department using piperacillin plus netilmicin for empiric treatment of febrile episodes . Paragraph: Piperacillin-resistant Escherichia coli bacteraemia: relation to empiric therapy and clinical outcome. Escherichia coli is a leading cause of bacteraemia. The aim of this study was to evaluate all E. coli positive blood cultures collected during a 4-y period in a haematological department using piperacillin plus netilmicin for empiric treatment of febrile episodes . We measured the incidence of piperacillin-resistant E. coli bacteraemia among haematological and non-haematological patients, described the importance of previous antibiotic treatment for resistance development in E. coli and evaluated the impact of piperacillin resistance on the clinical outcome of E. coli bacteraemia. 114 episodes of E. coli bacteraemia in 104 patients were recorded and 98 episodes in 88 patients (42 males and 46 females) with a median age of 64 y (range 19-85 y) were evaluated. In 81.6% of the episodes the patients had a haematological disorder, dominated by acute leukaemia (41.3%), chronic leukaemia (16.3%) and lymphoma (10%). The proportion of piperacillin-resistant E. coli was higher among haematological patients than non-haematological patients (25% vs 0%, p=0.02) and resistance was associated with piperacillin therapy during the previous month (p=0.05). No difference in clinical outcome was found between haematological patients infected with piperacillin-susceptible or -resistant E. coli (intensive care 12% vs 15%; mortality 22% vs 25%). ### Assistant: [{"class": "COMB", "spans_text": ["piperacillin", "netilmicin"]}]

### 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: Thirty-five percent ( 6 of 17 ) of the patients receiving docetaxel alone and 53 % ( 19 of 36 ) of those receiving docetaxel and thalidomide have had a PSA decrease of at least 50 % . Paragraph: A randomized phase II trial of docetaxel (taxotere) plus thalidomide in androgen-independent prostate cancer. New therapeutic alternatives are needed to improve outcomes in patients with androgen-independent prostate cancer (AIPC). For several years, researchers at the National Cancer Institute have been interested in elucidating the importance of angiogenesis in the pathogenesis of prostate cancer and in identifying inhibitors of this process. thalidomide has been shown to inhibit the ability of tumors to recruit new blood vessels. In a recent phase II trial of thalidomide in AIPC, 28% of patients achieved a prostate-specific antigen (PSA) decrease of >40%. The taxane docetaxel also produces PSA and measurable disease responses when used as monotherapy or as a component of combination chemotherapy for AIPC. Thus, based on the single-agent activity of thalidomide and docetaxel, we initiated a randomized phase II study of weekly docetaxel with or without thalidomide, 200 mg at bedtime, in patients with chemotherapy-naive metastatic AIPC. docetaxel, 30 mg/m(2) intravenously, was administered every 7 days for 3 weeks, followed by a 1-week rest period. Both regimens have been well tolerated among the first 59 treated patients, with a near absence of grade (3/4) myelosuppression. Fatigue, hyperglycemia, and pulmonary toxicity were seen in both groups. Thrombotic events have been seen in the combination arm. Thirty-five percent ( 6 of 17 ) of the patients receiving docetaxel alone and 53 % ( 19 of 36 ) of those receiving docetaxel and thalidomide have had a PSA decrease of at least 50 % . Combining a cytotoxic agent with an angiogenesis inhibitor is a promising area of investigation for prostate cancer management. ### Assistant: [{"class": "POS", "spans_text": ["docetaxel", "thalidomide"]}]

### 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: Reduction of ASS1 expression by siRNA significantly sensitized mesothelioma spheroids to the pro-apoptotic effects of bortezomib and of cisplatin plus pemetrexed . Paragraph: Analysis of Gene Expression in 3D Spheroids Highlights a Survival Role for ASS1 in Mesothelioma. To investigate the underlying causes of chemoresistance in malignant pleural mesothelioma, we have studied mesothelioma cell lines as 3D spheroids, which acquire increased chemoresistance compared to 2D monolayers. We asked whether the gene expression of 3D spheroids would reveal mechanisms of resistance. To address this, we measured gene expression of three mesothelioma cell lines, M28, REN and VAMT, grown as 2D monolayers and 3D spheroids. A total of 209 genes were differentially expressed in common by the three cell lines in 3D (138 upregulated and 71 downregulated), although a clear resistance pathway was not apparent. We then compared the list of 3D genes with two publicly available datasets of gene expression of 56 pleural mesotheliomas compared to normal tissues. Interestingly, only three genes were increased in both 3D spheroids and human tumors: argininosuccinate synthase 1 (ASS1), annexin A4 (ANXA4) and major vault protein (MVP); of these, ASS1 was the only consistently upregulated of the three genes by qRT-PCR. To measure ASS1 protein expression, we stained 2 sets of tissue microarrays (TMA): one with 88 pleural mesothelioma samples and the other with additional 88 pleural mesotheliomas paired with matched normal tissues. Of the 176 tumors represented on the two TMAs, ASS1 was expressed in 87 (50%; staining greater than 1 up to 3+). For the paired samples, ASS1 expression in mesothelioma was significantly greater than in the normal tissues. Reduction of ASS1 expression by siRNA significantly sensitized mesothelioma spheroids to the pro-apoptotic effects of bortezomib and of cisplatin plus pemetrexed . Although mesothelioma is considered by many to be an ASS1-deficient tumor, our results show that ASS1 is elevated at the mRNA and protein levels in mesothelioma 3D spheroids and in human pleural mesotheliomas. We also have uncovered a survival role for ASS1, which may be amenable to targeting to undermine mesothelioma multicellular resistance. ### Assistant: [{"class": "POS", "spans_text": ["pemetrexed", "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: In conclusion , the combination of thalidomide and cyclosporine in subtherapeutic doses may be useful for the treatment of skin allografts . Paragraph: Effects of thalidomide, cyclosporine, and diclofenac on skin allograft survival in rabbits. The present study evaluated the effects of thalidomide, cyclosporine, and diclofenac on skin allograft survival in 42 rabbits divided into the following groups (n = 6): group 1, autograft control; group 2, allograft control; group 3, allografts under thalidomide (100 mg/kg/d); group 4, allografts under sodium diclofenac (2 mg/kg/d); group 5, allografts under cyclosporine (10 mg/kg/d); group 6, allografts under cyclosporine (5 mg/kg/d); group 7, allografts under cyclosporine (5 mg/kg/d) plus thalidomide (100 mg/kg/d). The drugs were given via the orogastric tube the day before transplantation and daily during the postoperative period. Total circular skin grafts from the ear were exchanged between California and White New Zealand rabbits. cyclosporine (10 mg/kg/d) increased allograft survival, an effect that was comparable to cyclosporine (5 mg/kg/d) plus thalidomide (100 mg/kg/d). thalidomide and diclofenac given alone had minimally significant effects on the mean survival of skin allografts. The number of eosinophils around the necrotic skin was higher in the diclofenac group. The group receiving cyclosporine combined with thalidomide displayed the lowest number of eosinophils surrounding the allograft. In conclusion , the combination of thalidomide and cyclosporine in subtherapeutic doses may be useful for the treatment of skin allografts . ### Assistant: [{"class": "POS", "spans_text": ["thalidomide", "cyclosporine"]}]

### 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: Rats were subchronically primed with nicotine , clozapine or saline . Paragraph: Nicotine and clozapine cross-prime the locus coeruleus noradrenergic system to induce long-lasting potentiation in the rat hippocampus. A priming-challenge schedule of nicotine treatment causes long-lasting potentiation (LLP), a form of synaptic plasticity closely associated with the norepinephrine (NE) neurotransmitter system, at the medial perforant path (MPP)-dentate gyrus (DG) synapse in the rat hippocampus. Previous reports revealed that nicotine activates the locus coeruleus (LC) noradrenergic (NAergic) system and this mechanism may underlie its beta-adrenoceptor sensitive LLP effects. clozapine, an atypical antipsychotic, is also known to activate the LC. Interactions between nicotine and clozapine are of interest because of the prevalence of smoking in patients with schizophrenia and increasing interest in the use of nicotinic receptor ligands as cognitive enhancers. Rats were subchronically primed with nicotine , clozapine or saline . Twenty-one to twenty-eight days later, the effects of the nicotine, clozapine or saline challenge on the evoked field excitatory postsynaptic potentials (fEPSP) at the MPP-DG monosynaptic pathway were recorded as a measure of LLP. We confirmed the hypothesis that a challenge dose of either nicotine or clozapine induces LLP exclusively in nicotine- and clozapine-primed rats, and not in saline-primed rats, thus indicating a cross-priming effect. Moreover, unilateral suppression of LC using lidocaine abolished the LLP induced by nicotine in clozapine-primed rats. Furthermore, systemic treatment with clonidine (an α2 adrenoceptor agonist that reduces NAergic activity via autoreceptors) prior to the challenge doses blocked the nicotine/clozapine-induced LLP in nicotine- and clozapine-primed rats. These findings may add to understanding of the cognitive enhancing effects of nicotine. ### Assistant: [{"class": "COMB", "spans_text": ["nicotine", "clozapine", "saline"]}]

### 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: New agents , such as taxane , irinotecan and oxaliplatin , combined with old agents , such as cisplatin and 5-FU , are currently under evaluation to further improve treatment outcomes . Paragraph: Chemotherapy for advanced gastric cancer: slow but further progress. Gastric cancer remains a significant problem in terms of global health, and is the most common cancer in Korea. Surgery is the only potentially curative treatment for localized gastric cancer, but most cases present at an advanced stage. Randomized trials have demonstrated that chemotherapy for advanced gastric cancer improves the quality of life and extends survival, by 4 approximately 6 months, compared with best supportive care alone. Single agents with a proven activity in a first-line setting include 5-fluorouracil (5-FU), doxorubicin, mitomycin C, cisplatin, taxanes (docetaxel and paclitaxel) and oral fluoropyrimidines (capecitabine and TS-1). Based on the results from several large scale randomized trials, FP (5-FU/cisplatin) and ECF (epirubicin/cisplatin/5-FU) combinations are the most widely used regimen against advanced gastric cancer. Phase II studies of the FP and ECF combination reported a 40~51% response rate in previously untreated patients, and this regimen also produced a significantly higher response rate than the FAM (5-FU/doxorubicin/mitomycin) and FAMTX (5-FU/doxorubicin/methotrexate) regimens, respectively. However, significant treatment related-toxicities and discomfort were reported from ECF, which prevents this combination from becoming the standard treatment regimen. While no one combination chemotherapy regimen is accepted as the standard for advanced gastric cancer, FP is currently considered a suitable reference regimen worldwide. New agents , such as taxane , irinotecan and oxaliplatin , combined with old agents , such as cisplatin and 5-FU , are currently under evaluation to further improve treatment outcomes . Also, oral 5-FU prodrugs are replacing the cumbersome 5-FU long-term infusion due to its convenience and superior toxicity profile. However, the low complete response rate and short response duration are still the main obstacles in the chemotherapy for gastric cancer. Only large scale comparative clinical trials will give clues to improve the results of gastric cancer treatments. ### Assistant: [{"class": "COMB", "spans_text": ["taxane", "cisplatin", "5-FU"]}, {"class": "COMB", "spans_text": ["irinotecan", "cisplatin", "5-FU"]}, {"class": "COMB", "spans_text": ["oxaliplatin", "cisplatin", "5-FU"]}]

### 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: One group was given enalapril ( EN ) 50 mg/l dissolved in the drinking water ; the second received lovastatin ( L ) 15 mg/kg given daily by gavage ; the third received both agents ; the fourth was left untreated , and the final group received no puromycin and served as the control group . Paragraph: The combination of lovastatin and enalapril in a model of progressive renal disease. puromycin-induced nephrotic syndrome is an animal model of progressive renal disease. Both angiotensin converting enzyme inhibitors and lipid-lowering agents have been used to preserve renal structure and function in this model, although neither completely prevents progression. We tested the hypothesis that the combination of the two agents would be more protective than either alone. Rats were divided into five groups; all were uninephrectomized. Four groups were given puromycin at a dose of 10 mg/100 g body weight (BW) with additional doses of 4 mg/100 g BW given intraperitoneally at 4, 5, and 6 weeks thereafter. One group was given enalapril ( EN ) 50 mg/l dissolved in the drinking water ; the second received lovastatin ( L ) 15 mg/kg given daily by gavage ; the third received both agents ; the fourth was left untreated , and the final group received no puromycin and served as the control group . Eight weeks after the initial dose of puromycin, glomerular filtration rate (GFR), as inulin clearance, and protein excretion were determined and blood was collected for cholesterol and triglycerides. Blood pressure was not different between any of the groups. At the end of the study period, serum cholesterol [mean +/- SD, 252 +/- 185 mg/dl (L), 135 +/- 101 mg/dl (L + EN)] and triglycerides (239 +/- 200, 148 +/- 158 mg/dl) were significantly lower (P < 0.001) in the lovastatin-treated groups than in the untreated puromycin group (535 +/- 255 mg/dl and 579 +/- 561 mg/dl, cholesterol and triglyceride, respectively).(ABSTRACT TRUNCATED AT 250 WORDS) ### Assistant: [{"class": "COMB", "spans_text": ["enalapril", "lovastatin"]}]

### 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: Using the Killing-curve method , we tested the in vitro bactericidal activity of fosfomycin alone or in combination with vancomycin or teicoplanin at a concentration of 8 microg/mL , that is easily achievable in serum at standard dosing regimens , against seven methicillin-resistant Staphylococcus aureus strains , isolated from patients with well documented device-associated infections unresponsive to or relapsing after glycopeptide therapy . Paragraph: In vitro activity of fosfomycin in combination with vancomycin or teicoplanin against Staphylococcus aureus isolated from device-associated infections unresponsive to glycopeptide therapy. fosfomycin is a molecule that inhibits the early stage of peptidoglycan synthesis and shows a broad-spectrum bactericidal activity against Gram-positive and Gram-negative bacteria. Using the Killing-curve method , we tested the in vitro bactericidal activity of fosfomycin alone or in combination with vancomycin or teicoplanin at a concentration of 8 microg/mL , that is easily achievable in serum at standard dosing regimens , against seven methicillin-resistant Staphylococcus aureus strains , isolated from patients with well documented device-associated infections unresponsive to or relapsing after glycopeptide therapy . MICs of vancomycin ranged from 1 to 4 microg/mL, MICs of teicoplanin from 2 to 8 microg/mL; MICs of fosfomycin were 8 microg/mL for two strains and >128 microg/mL for the remaining strains. The seven strains proved tolerant when tested for vancomycin and teicoplanin used alone at 2x MIC concentration. fosfomycin was bactericidal (reduction of 2 log of the inoculum) only against the two susceptible strains. In all cases both vancomycin and teicoplanin in combination with fosfomycin developed bactericidal synergism already at a concentration of 1x MIC. If these results are confirmed by in vivo experiments, the combination of fosfomycin with glycopeptides might be useful for treating device-associated infections, and in preventing the phenomenon of increasing MICs for glycopeptides. ### Assistant: [{"class": "COMB", "spans_text": ["fosfomycin", "vancomycin"]}, {"class": "COMB", "spans_text": ["fosfomycin", "teicoplanin"]}]

### 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 mitomycin , tamoxifen , and UFT proved to be an effective postoperative chemoendocrine therapy for stage II , ER-positive breast cancer . Paragraph: UFT and mitomycin plus tamoxifen for stage II, ER-positive breast cancer. Hokkaido ACETBC Study Group. A trial was designed to examine the combination of UFT and mitomycin (Mutamycin) plus tamoxifen (Nolvadex) as postoperative adjuvant therapy in the treatment of patients with stage II, estrogen receptor (ER)-positive primary breast cancer. mitomycin was administered intravenously at 13 mg/m2 on the day of surgery. Patients judged to be ER-positive were randomly allocated to either group A, which received oral tamoxifen 20 mg/day 14 days after surgery for 2 years, or group B, receiving oral UFT 400 mg/day plus tamoxifen 20 mg/day. A total of 219 patients were enrolled in group A, of which 213 (97.3%) were determined to be eligible; 225 patients enrolled in group B and 223 (99.1%) were eligible. The 5-year survival rates were 93.0% for group A and 95.4% for group B, with no significant difference between groups. The 5-year relapse-free survival rates were 83.1% for group A and 90.7% for group B, a significant advantage (P = .020) for the UFT plus tamoxifen group. Combination therapy with mitomycin , tamoxifen , and UFT proved to be an effective postoperative chemoendocrine therapy for stage II , ER-positive breast cancer . ### Assistant: [{"class": "POS", "spans_text": ["mitomycin", "tamoxifen", "UFT"]}]

### 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 remaining 76 patients did not receive anti-thymocyte globulin but were given cyclosporine A and methotrexate or mycophenolate mofetil ( group 3 ) . Paragraph: The impact of graft-versus-host disease prophylaxis in reduced-intensity conditioning allogeneic stem cell transplant in acute myeloid leukemia: a study from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. The impact of the intensity of graft-versus-host-disease immunoprophylaxis on transplantation outcomes in patients undergoing transplantation following reduced-intensity conditioning is unclear. This study addresses this issue in 228 adult patients above 50 years of age with acute myeloid leukemia in first complete remission given peripheral blood stem cells from HLA-identical siblings after fludarabine and 2 days of intravenous busulfan reduced-intensity conditioning. A total of 152 patients received anti-thymocyte globulin, either in combination with cyclosporine A in 86 patients (group 1), or with cyclosporine A and mycophenolate mofetil or short course methotrexate in 66 patients (group 2). The remaining 76 patients did not receive anti-thymocyte globulin but were given cyclosporine A and methotrexate or mycophenolate mofetil ( group 3 ) . Incidences of grade II-IV acute graft-versus-host-disease were comparable in the three groups (16.5%, 29.5% and 19.5% in groups 1, 2 and 3, respectively, P=0.15). In multivariate analysis, the absence of anti-thymocyte globulin was the only factor associated with a higher risk of chronic graft-versus-host-disease (P=0.005), while the use of triple immunosuppression (group 3) was associated with an increased risk of relapse (P=0.003). In comparison to anti-thymocyte globulin and cyclosporine A alone, the other two strategies of graft-versus-host-disease prophylaxis were associated with reduced leukemia-free survival and overall survival (P=0.001 for each parameter), independently of the dose of anti-thymocyte globulin. These data suggest that fine tuning of the intensity of this prophylaxis can affect the outcome of transplantation and that anti-thymocyte globulin and cyclosporine A alone should be the preferred combination with the fludarabine-busulfan reduced-intensity conditioning regimen and sibling donors. ### Assistant: [{"class": "COMB", "spans_text": ["cyclosporine", "methotrexate"]}, {"class": "COMB", "spans_text": ["cyclosporine", "mycophenolate"]}]

### 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: Propranolol significantly decreased the maximum plasma concentration ( Cmax ) and area under the plasma concentration-time curve ( AUC ) of lacidipine ( by 38 % and 42 % , respectively ) whereas lacidipine significantly increased the Cmax and AUC of propranolol ( by 35 % and 26 % , respectively ) ; neither the time to maximum plasma concentration ( tmax ) nor the terminal half-life ( t 1/2 ) were affected . Paragraph: The pharmacokinetic and pharmacodynamic interaction between lacidipine and propranolol in healthy volunteers. The pharmacokinetic and pharmacodynamic profiles of lacidipine, a 1,4-dihydropyridine calcium antagonist, and the beta-adrenoceptor blocker propranolol were determined alone and in combination in 24 healthy male volunteers. One group (I) of 12 subjects received a single oral dose of 4 mg lacidipine on two separate occasions, which was taken together with a single oral dose of either 160 mg propranolol or placebo; a second group (II) of 12 subjects received propranolol on two occasions, taken with either lacidipine or placebo. Propranolol significantly decreased the maximum plasma concentration ( Cmax ) and area under the plasma concentration-time curve ( AUC ) of lacidipine ( by 38 % and 42 % , respectively ) whereas lacidipine significantly increased the Cmax and AUC of propranolol ( by 35 % and 26 % , respectively ) ; neither the time to maximum plasma concentration ( tmax ) nor the terminal half-life ( t 1/2 ) were affected . With regard to the pharmacodynamics, in Group I, there was a greater reduction in supine systolic blood pressure (6 mm Hg) and diastolic blood pressure (4 mm Hg) compared to the reduction produced by lacidipine alone, and pulse rate was approximately 5 beats/min less. In Group II, a significantly greater reduction (6 mm Hg) in supine systolic blood pressure compared to the reduction produced by propranolol alone occurred, but there was no marked difference in supine diastolic blood pressure and pulse rate. In conclusion, a modest pharmacokinetic and pharmacodynamic interaction is evident and should be evaluated further in patients with hypertension. ### Assistant: [{"class": "COMB", "spans_text": ["Propranolol", "lacidipine"]}]

### 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 received chemotherapy comprising vincristine , actinomycin D , doxorubicin , cisplatin , and cyclophosphamide . Paragraph: Autologous peripheral blood stem cell transplantation in a patient with relapsed pleuropulmonary blastoma. Pleuropulmonary blastoma (PPB) is a rare and aggressive primary intrathoracic neoplasma of children. The prognosis is extremely poor with frequent metastasis to the brain and bone. We present a 4-year-old girl with a tumor mass in the right hemithorax initially diagnosed as pneumoniae. Tumor resection was performed and the histologic report indicated the diagnosis of PPB. The patient received chemotherapy comprising vincristine , actinomycin D , doxorubicin , cisplatin , and cyclophosphamide . Irradiation was performed with total 45 Gy at the right lower pulmonary lobe. She relapsed 29 months later at the pleura between the right middle and lower pulmonary lobe. Tumor resection and total 45 Gy of irradiation were performed again. High-dose chemotherapy comprising cisplatin, adriamycin, and cyclophosphamide was performed followed by autologous peripheral blood stem cell transplantation (PBSCT). The patient achieved complete hematologic recovery. Thirty-one months after PBSCT, no signs of relapse have been observed. Although it might be that the patient could have been cured with second surgery alone or by the surgery and subsequent chemotherapy, high-dose chemotherapy and PBSCT should be considered for the treatment of relapsed PPB. ### Assistant: [{"class": "COMB", "spans_text": ["vincristine", "doxorubicin", "cyclophosphamide", "actinomycin", "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: Because gemcitabine has been considered a standard treatment for advanced pancreatic cancer for the past decade , several randomized trials have tested the combination of gemcitabine plus a second agent , including platinum based agents , topoisomerase inhibitors , taxanes , bevacizumab and cetuximab , as biologically " targeted " agents . Paragraph: First-line treatment for advanced pancreatic cancer. Highlights from the "2011 ASCO Gastrointestinal Cancers Symposium". San Francisco, CA, USA. January 20-22, 2011. Pancreatic adenocarcinoma remains a treatment-refractory cancer. Although pancreatic adenocarcinoma is only the 10th most common cause of new cancer in the United States, it is the fourth most common cause of cancer-related death. Most cases are not suitable for resection and a majority is metastatic at presentation. gemcitabine, with or without erlotinib, has been the standard chemotherapy in this setting but the benefit is only modest. Because gemcitabine has been considered a standard treatment for advanced pancreatic cancer for the past decade , several randomized trials have tested the combination of gemcitabine plus a second agent , including platinum based agents , topoisomerase inhibitors , taxanes , bevacizumab and cetuximab , as biologically " targeted " agents . At large this approach has not been successful and novel strategies are clearly needed. In this article, the authors summarizes the data from the 2011 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, including: Abstract #175 (review of survival data in a large cohort); Abstract #286 (rapid change in prescriber patterns after the suggestion of benefit of a new regimen, FOLFIRINOX); Abstracts #238, #277, #304, and #315 (phase II trials looking at combinations that utilized EGFR blockade); Abstracts #221, #266, and #284 (phase I/II trials including VEGF blockade, anticoagulation, and traditional Chinese medicines). ### Assistant: [{"class": "COMB", "spans_text": ["gemcitabine", "bevacizumab"]}, {"class": "COMB", "spans_text": ["gemcitabine", "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: No synergism was found against Pneumococci and Meningococci but also no antagonism of the lower MIC and MBC values seen with ampicillin and penicillin G. The combination of chloramphenicol with either penicillin or ampicillin constitutes a clinically successful therapeutic regimen which is now also proven by in vitro investigations . Paragraph: [Bactericidal action of chloramphenicol and synergism with beta-lactam antibiotics]. Excellent clinical results were observed with the combination therapy of chloramphenicol with beta-lactam-antibiotics in the treatment of purulent meningitis. This came as a surprise as bacteriostatic antibiotics like chloramphenicol are commonly thought to antagonize the bactericidal action of penicillin or ampicillin. We reevaluated the mode of action of chloramphenicol against the three most common meningeal pathogens after the newborn period. chloramphenicol was found to be bactericidal against H. influenzae, Streptococcus pneumoniae and Neisseria meningitidis at clinically achievable levels in the CSF. In addition chloramphenicol showed synergistic action with ampicillin against H. influenzae which can possess clinical relevance particularly with the high inoculum of 10(7) organisms/ml which is frequently seen in bacterial meningitis. No synergism was found against Pneumococci and Meningococci but also no antagonism of the lower MIC and MBC values seen with ampicillin and penicillin G. The combination of chloramphenicol with either penicillin or ampicillin constitutes a clinically successful therapeutic regimen which is now also proven by in vitro investigations . ### Assistant: [{"class": "COMB", "spans_text": ["ampicillin", "penicillin"]}, {"class": "POS", "spans_text": ["chloramphenicol", "penicillin"]}, {"class": "POS", "spans_text": ["chloramphenicol", "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: Bendamustine is effective both with rituximab and as a monotherapy in rituximab-refractory patients . Paragraph: Bendamustine in chronic lymphocytic leukemia and refractory lymphoma. bendamustine is a water-soluble, bifunctional chemotherapeutic agent with characteristics of both an alkylator and a purine analog. bendamustine combined with rituximab in vitro shows synergistic effects against various leukemia and lymphoma cell lines. Clinical trials supporting these results show that bendamustine plus rituximab is highly effective in relapsed and refractory patients with indolent lymphoma. The results have been found in rituximab-naive, rituximab-pretreated, and rituximab-refractory patients with excellent response rates and toxicity profiles. Bendamustine is effective both with rituximab and as a monotherapy in rituximab-refractory patients . Interim results from a phase III, randomized trial comparing bendamustine and rituximab to a standard CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and rituximab regimen suggest that combination bendamustine and rituximab may provide a viable alternative for treatment of many indolent lymphomas. ### Assistant: [{"class": "POS", "spans_text": ["Bendamustine", "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 effects of multiple combination chemotherapy with vincristine , cyclophosphamide ( Endoxan ) , methotrexate , 5-fluorouracil , adriamycin and prednisolone ( VEMFAH ) for advanced breast cancer . Paragraph: The effects of multiple combination chemotherapy with vincristine , cyclophosphamide ( Endoxan ) , methotrexate , 5-fluorouracil , adriamycin and prednisolone ( VEMFAH ) for advanced breast cancer . Thirty-eight patients with advanced breast cancer were treated with the 'VEMFAH' multiple-drug combination chemotherapy, consisting of vincristine (V), cyclophosphamide (Endoxan; E), methotrexate (M), 5-fluorouracil (F), adriamycin (A), and prednisolone (H). Disease response was evaluated by the UICC criteria. Among the 35 evaluable cases, 4 complete responses (CR), 23 partial responses (PR), 2 cases of no change (NC), and 6 of progressive disease (PD) were observed. The response rate (CR + PR) was 77.1%. The median duration of response was 52 weeks (8-192 weeks) or 12 months. In 32 patients who received more than two courses of therapy the 50% survival time of responders was 27.0 months, which was significantly longer than the 10.3 months of nonresponders (P less than 0.05). Except for 2 patients who developed myocardial damage, the therapy was never terminated because of side effects. Cumulative cardiotoxicity was not apparent in this study. This multiple-drug combination chemotherapy with 'VEMFAH' is concluded to be an effective treatment for advanced and disseminated breast cancer. ### Assistant: [{"class": "POS", "spans_text": ["vincristine", "cyclophosphamide", "methotrexate", "5-fluorouracil", "adriamycin", "prednisolone"]}]

### 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: Association of rash with outcomes in a randomized phase II trial evaluating cetuximab in combination with mitoxantrone plus prednisone after docetaxel for metastatic castration-resistant prostate cancer . Paragraph: Association of rash with outcomes in a randomized phase II trial evaluating cetuximab in combination with mitoxantrone plus prednisone after docetaxel for metastatic castration-resistant prostate cancer . cetuximab (C), a chimeric monoclonal antibody that binds epidermal growth factor receptor (EGFR), is active against androgen-independent prostate cancer cell lines and might enhance the activity of chemotherapy. The efficacy of combining cetuximab with mitoxantrone (M) plus prednisone (MP) was evaluated in progressive metastatic castrate-resistant prostate cancer (CRPC) after receiving docetaxel. ### Materials And Methods Patients with progression after receiving docetaxel were eligible and randomized 2:1 to CMP or MP. Therapy was mitoxantrone 12 mg/m(2) intravenously (I.V.) on day 1, oral prednisone 10 mg daily in both arms, and cetuximab 250 mg/m(2) I.V. (400 mg/m(2) day 1, cycle 1) on days 1, 8, and 15 in the CMP arm. Cycles were repeated every 21 days. Radiologic assessments of disease and PSA (prostate-specific antigen) occurred every 4 cycles. The primary endpoint was time to progression (TTP). ### results A total of 115 patients were enrolled, 75 in the CMP and 40 in the MP arm: the median TTP was 4.9 and 6.6 months, respectively; the measurable disease response rate was 2% and 4%, the PSA response rate 7.7% and 17.6%, and median survival 11.9 and 15.7 months, respectively. Key grade 3-4 toxicities were neutropenia 44% and 25.6%, anemia 6.7% and 7.7%, thrombocytopenia 6.7% and 2.6%, and fatigue 8% in both arms. In an unplanned exploratory analysis, median TTP with (n = 24) and without rash (n = 51) in the CMP arm was 10.3 months vs. 2.8 months (P = .004). On multivariable analysis,rash was significantly associated with TTP (hazard ratio [HR] = 0.43; P = .01). ### conclusions The treatment with CMP is not recommended in unselected men with docetaxel-treated CRPC, although rash might help develop tailored therapy. ### Assistant: [{"class": "NEG", "spans_text": ["cetuximab", "mitoxantrone", "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: CDM mice show decreased Homer1a and Homer1b/c mRNA expression in cortex and blood samples , while chronic treatment with imipramine and fluoxetine or acute ketamine application increases their level only in the cortex . Paragraph: Antidepressant treatment is associated with epigenetic alterations of Homer1 promoter in a mouse model of chronic depression. Understanding the neurobiology of depression and the mechanism of action of therapeutic measures is currently a research priority. We have shown that the expression of the synaptic protein Homer1a correlates with depression-like behavior and its induction is a common mechanism of action of different antidepressant treatments. However, the mechanism of Homer1a regulation is still unknown. ### methods We combined the chronic despair mouse model (CDM) of chronic depression with different antidepressant treatments. Depression-like behavior was characterized by forced swim and tail suspension tests, and via automatic measurement of sucrose preference in IntelliCage. The Homer1 mRNA expression and promoter DNA methylation were analyzed in cortex and peripheral blood by qRT-PCR and pyrosequencing. ### results CDM mice show decreased Homer1a and Homer1b/c mRNA expression in cortex and blood samples , while chronic treatment with imipramine and fluoxetine or acute ketamine application increases their level only in the cortex . The quantitative analyses of the methylation of 7 CpG sites, located on the Homer1 promoter region containing several CRE binding sites, show a significant increase in DNA methylation in the cortex of CDM mice. In contrast, antidepressant treatments reduce the methylation level. ### limitations Homer1 expression and promotor methylation were not analyzed in different blood cell types. Other CpG sites of Homer1 promoter should be investigated in future studies. Our experimental approach does not distinguish between methylation and hydroxymethylation. ### conclusions We demonstrate that stress-induced depression-like behavior and antidepressant treatments are associated with epigenetic alterations of Homer1 promoter, providing new insights into the mechanism of antidepressant treatment. ### Assistant: [{"class": "COMB", "spans_text": ["imipramine", "fluoxetine"]}]

### 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 retrospective analysis was conducted on the clinical data of 122 advanced NSCLC patients with pleural effusion , and among them , 61 received thoracic hyperthermic perfusion with recombinant human endostatin ( ES ) plus nedaplatin ( Endostatin group ) , while the other 61 underwent thoracic hyperthermic perfusion with cisplatin alone ( Cisplatin group ) . Paragraph: Effect of thoracic hyperthermic perfusion with recombinant human endostatin plus nedaplatin in treating pleural effusion in patients with advanced non-small cell lung cancer. To explore the efficacy and safety of thoracic hyperthermia perfusion with recombinant human endostatin plus nedaplatin in the treatment of pleural effusion in patients with advanced non-small cell lung cancer (NSCLC). ### methods A retrospective analysis was conducted on the clinical data of 122 advanced NSCLC patients with pleural effusion , and among them , 61 received thoracic hyperthermic perfusion with recombinant human endostatin ( ES ) plus nedaplatin ( Endostatin group ) , while the other 61 underwent thoracic hyperthermic perfusion with cisplatin alone ( Cisplatin group ) . The short-term efficacy, changes in the pleural effusion and serum immunological indicators before and after treatment, quality of life, and incidence of adverse reactions were compared between the two groups of patients. Finally, the progression of pleural effusion in patients were followed up and recorded. ### results After treatment, the overall response rate of patients in endostatin group was considerably higher than that in Cisplatin group (p=0.030). At 2 weeks after treatment, the level of alanine transferase (ALT) rose notably, while that of carcinoembryonic antigen (CEA) declined dramatically in both groups of patients, and the patients in endostatin group had markedly lower levels of ALT and CEA than those in Cisplatin group (p=0.007, p=0.003). After treatment, the Karnofsky Performance status (KPS) score of patients was prominently raised in the two groups, and endostatin group exhibited considerably higher KPS scores than Cisplatin group (p=0.045). The incidence rates of nausea and vomiting as well as diarrhea in endostatin group were prominently lower than those in Cisplatin group (p=0.039, p=0.048). According to the follow-up results, the median time to the progression of pleural effusion in endostatin group was markedly longer than that in Cisplatin group (p=0.008). ### conclusions Compared with the thoracic hyperthermic perfusion with cisplatin alone, the thoracic hyperthermic perfusion with recombinant human endostatin plus nedaplatin showed dramatically potential efficacy, decrease of the incidence rate of adverse reactions in the digestive system, improvement of quality of life of patients, and prolongation of progression of pleural effusion. ### Assistant: [{"class": "POS", "spans_text": ["endostatin", "nedaplatin"]}]

### 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 addition , stimulation of erythropoiesis with recombinant human erythropoietin , supplemental iron therapy , and improving haemostasis by aprotinin may further reduce homologous blood requirements . Paragraph: [Reduction in the use of donated blood in surgical medicine]. After rapid changes in transfusion practice over the past few years, blood conservation techniques have become standard in modern perioperative management. As a result, the amount of homologous blood products transfused has been markedly reduced in some types of surgical procedures. Provided that skillful surgical technique is applied and the use of blood products is restricted, autologous transfusion techniques (predonation of autologous blood, preoperative plasmapheresis, acute normovolaemic haemodilution, and intra- and postoperative blood salvage) can be performed with an acceptable risk for patients. In addition , stimulation of erythropoiesis with recombinant human erythropoietin , supplemental iron therapy , and improving haemostasis by aprotinin may further reduce homologous blood requirements . All patients undergoing elective surgery have to be informed about the side effects of transfusion of homologous blood products and the possibility of blood-saving methods. An individual blood conservation plan, based on the patient's status and surgery, the equipment available, and personal experience should be worked out by the responsible anaesthesiologist, whereby a combination of different methods may be most effective. If storage is necessary, autologous blood products should be preparated like homologous products. The feasibility of predonation and retransfusion of autologous blood in patients with infectious diseases like hepatitis or acquired immune deficiency syndrome and the amount of labaratomy testing are still under discussion. Although blood conservation programs are time-consuming and more expensive, they reduce the various risks of using homologous blood products. ### Assistant: [{"class": "POS", "spans_text": ["erythropoietin", "iron", "aprotinin"]}]

### 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 the presence of heparin and cortisone and of cortisone alone there was a 4.5- and 2.3-fold reduction , respectively , in the growth of the 9L glioma . Paragraph: Growth inhibition of the 9L glioma using polymers to release heparin and cortisone acetate. Malignant gliomas are difficult to treat systemically because of exclusion of many chemotherapeutic agents by the blood brain barrier. Furthermore, as opposed to other neoplasms, malignant gliomas recur locally, at the site of original presentation. These tumors are remarkably vascular and hence may be more dependent on angiogenesis for continued growth than other tumors. The inhibition of tumor angiogenesis can control tumor growth by preventing the exponential vascular growth phase. We report the inhibition of the growth of the 9L glioma by the localized, controlled release of known angiogenesis inhibitors administered in a biodegradable polyanhydride polymer matrix. In the presence of heparin and cortisone and of cortisone alone there was a 4.5- and 2.3-fold reduction , respectively , in the growth of the 9L glioma . We compared these results to the inhibition of tumor neovascularization in the rabbit cornea by the localized delivery of the same agents. In the rabbit cornea model, the local release of heparin and cortisone and of cortisone alone resulted in a 2.5- and 2.0-fold reduction, respectively, in the angiogenesis response evoked by the VX2 carcinoma. This study introduces two new potential therapeutic modalities for the treatment of malignant gliomas: the use of the combination of heparin and cortisone as antineoplastic agents and the use of polymeric carriers for the local delivery of such agents in the central nervous system. ### Assistant: [{"class": "POS", "spans_text": ["heparin", "cortisone"]}]

### 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 the aim of this study to evaluate maintenance therapy with bevacizumab + capecitabine following induction with bevacizumab + capecitabine + oxaliplatin ( XELOX ) versus bevacizumab + XELOX until progression as first-line therapy in metastatic colorectal cancer ( mCRC ) . Paragraph: Bevacizumab + capecitabine as maintenance therapy after initial bevacizumab + XELOX treatment in previously untreated patients with metastatic colorectal cancer: phase III 'Stop and Go' study results--a Turkish Oncology Group Trial. It was the aim of this study to evaluate maintenance therapy with bevacizumab + capecitabine following induction with bevacizumab + capecitabine + oxaliplatin ( XELOX ) versus bevacizumab + XELOX until progression as first-line therapy in metastatic colorectal cancer ( mCRC ) . ### methods Patients received either bevacizumab (7.5 mg/kg) + XELOX (capecitabine 1,000 mg/m(2) twice daily on days 1-14 + oxaliplatin 130 mg/m(2) on day 1 every 3 weeks) until disease progression (arm A) or the same doses of bevacizumab + XELOX for 6 cycles followed by bevacizumab + capecitabine until disease progression (arm B). The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), objective response rate (ORR) and safety. ### results One hundred and twenty-three patients were randomized. Treatment compliance was similar in both groups. Median PFS was significantly longer for arm B than for arm A (11.0 vs. 8.3 months; p = 0.002). There was no significant difference between the two arms for ORR (66.7 vs. 59.0%; p = 0.861) or median OS (23.8 vs. 20.2 months; p = 0.100). Tolerability was acceptable in both treatment arms; the most frequent grade 3/4 treatment-related adverse events (arm B vs. arm A) were fatigue (6.6 vs. 16.1%), diarrhoea (3.3 vs. 11.3%), anorexia (3.3 vs. 11.3%), and neuropathy (1.6 vs. 8.1%). ### conclusions Maintenance therapy with bevacizumab + capecitabine can be considered an appropriate option following induction bevacizumab + XELOX in patients with mCRC instead of continuation of bevacizumab + XELOX. ### Assistant: [{"class": "POS", "spans_text": ["bevacizumab", "capecitabine"]}, {"class": "COMB", "spans_text": ["bevacizumab", "capecitabine", "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: Etoposide ( 25 mg , twice daily ) and prednisone ( 5 mg , twice daily ) were administered orally . Paragraph: Oral etoposide and oral prednisone for the treatment of castration resistant prostate cancer. Treatment options for patients with castration-resistant prostate cancer (CRPC) are limited. The purpose of our study was to investigate the safety and efficacy in terms of prostate-specific antigen (PSA) response of a low-dose oral combination of etoposide and prednisone in patients with CRPC. Thirty-nine patients with prostate cancer (median age, 77.9 years) with progressive disease after standard hormonal therapy were enrolled. Etoposide ( 25 mg , twice daily ) and prednisone ( 5 mg , twice daily ) were administered orally . Each cycle comprised 21 consecutive days of treatment followed by a 7-day drug holiday. All patients previously treated with an antiandrogen were required to undergo antiandrogen withdrawal prior to entry into the study. A total of 226 cycles were administered with a median of 6.7 cycles per patient (range, 1-18 cycles). Sixteen of 39 patients (41%) with elevated PSA levels at baseline achieved at least a 50% reduction in PSA levels. Median progression-free survival for all patients was 5.9 months (range, 1-17 months). No Grade 4 toxicities were observed. The predominant toxicities were mucositis, nausea, fatigue, and anemia in twelve, nine, eight, and seven patients, respectively. Hematologic toxicity was infrequent, with no episodes of febrile neutropenia. The combination of low-dose etoposide and prednisone is an efficacious and reasonably well-tolerated oral regimen in the treatment of elderly patients with CRPC. This regimen can be easily administered in an outpatient setting and does not require frequent patient visits. ### Assistant: [{"class": "POS", "spans_text": ["Etoposide", "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: Rosuvastatin + ezetimibe , simvastatin + ezetimibe , and atorvastatin + ezetimibe were the most cost-effective combination therapies for reducing LDL-C levels . Paragraph: The cost effectiveness of statin therapies in Spain in 2010, after the introduction of generics and reference prices. HMG-CoA reductase inhibitors (statins) are the first-line drugs for use in the reduction of low-density lipoprotein cholesterol (LDL-C) levels and prevention of coronary heart disease (CHD) in patients with hypercholesterolemia. Generic statins could change the cost effectiveness of statin therapies in Spain, and more population groups could be included in the recommendations for reduction of cholesterol levels based on cost effectiveness. ### objectives The objectives of this study were: (i) to assess the cost effectiveness of available statins for the reduction of LDL-C levels in Spain in 2010, after the introduction of generics and reference prices; (ii) to assess the cost effectiveness of combination therapy using a statin plus cholestyramine or ezetimibe; and (iii) to estimate the mean cost per patient to achieve National Cholesterol Education Program (Adult Treatment Panel-III) therapeutic objectives. ### methods The following treatments were evaluated: rosuvastatin 5-20 mg/day; atorvastatin, simvastatin, and pravastatin 10-40 mg/day; lovastatin and fluvastatin 20-80 mg/day; and combination therapy with a statin plus either cholestyramine 12-24 g/day or ezetimibe 10 mg/day. The cost effectiveness was evaluated in terms of cost per percentage point reduction in LDL-C, comparing the annual treatment costs with the effectiveness in reducing LDL-C. Treatment costs included those for medications (2010 wholesale prices), control measures, and treatment of adverse drug effects. The effectiveness of statins was estimated by developing a meta-analysis of clinical trials published between 1993 and 2005 that met several inclusion criteria. Average and incremental cost-effectiveness ratios were calculated to assess the efficiency of individual statin and combination therapies in reducing LDL-C levels. ### results The effectiveness in terms of percentage reduction in LDL-C ranged from 19% for pravastatin 10 mg/day to 55% for atorvastatin 80 mg/day. Annual treatment costs ranged from Euro 189.7 for simvastatin 10 mg/day to Euro 759.3 for atorvastatin 80 mg/day. The cost-effectiveness ratios, in terms of cost per percentage point reduction in LDL-C, were: Euro 6 for simvastatin, Euro 10-12 for rosuvastatin, Euro 10 for lovastatin, Euro 13-16 for atorvastatin, Euro 13-14 for fluvastatin, and Euro 14-20 for pravastatin. Rosuvastatin + ezetimibe , simvastatin + ezetimibe , and atorvastatin + ezetimibe were the most cost-effective combination therapies for reducing LDL-C levels . rosuvastatin was the most cost-effective statin for achieving the LDL-C therapeutic goal in patients at high risk for CHD, with a mean cost per patient of Euro 516. simvastatin was the most cost-effective statin to achieve the LDL-C goal in patients with moderate or low CHD risk, with a cost per patient of Euro 217 and Euro 190, respectively. ### conclusion rosuvastatin should be the first-choice agent in patients with high CHD risk, while simvastatin should be the first choice in patients with moderate or low risk. The addition of ezetimibe to rosuvastatin, simvastatin, or atorvastatin should be the preferred combination therapies when greater LDL-C reductions are required. The cost effectiveness of all statin therapies has increased in Spain after the introduction of generic statins and reference prices. ### Assistant: [{"class": "POS", "spans_text": ["Rosuvastatin", "ezetimibe"]}, {"class": "POS", "spans_text": ["simvastatin", "ezetimibe"]}, {"class": "POS", "spans_text": ["atorvastatin", "ezetimibe"]}]

### 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 40-week open-label extension of the 12-week double-blind Triple Therapy With Olmesartan Medoxomil , Amlodipine , and Hydrochlorothiazide in Hypertensive Patients Study ( TRINITY ) evaluated the efficacy and safety of triple-combination treatments with olmesartan medoxomil , amlodipine besylate , and hydrochlorothiazide ( OM/AML/HCTZ ) in 2112 participants with moderate to severe hypertension . Paragraph: Long-term efficacy and safety of triple-combination therapy with olmesartan medoxomil and amlodipine besylate and hydrochlorothiazide for hypertension. J Clin Hypertens (Greenwich). 2012;14:149-157. ©2012 Wiley Periodicals, Inc. Most patients with hypertension require combination therapy in order to achieve blood pressure (BP) goals. This 40-week open-label extension of the 12-week double-blind Triple Therapy With Olmesartan Medoxomil , Amlodipine , and Hydrochlorothiazide in Hypertensive Patients Study ( TRINITY ) evaluated the efficacy and safety of triple-combination treatments with olmesartan medoxomil , amlodipine besylate , and hydrochlorothiazide ( OM/AML/HCTZ ) in 2112 participants with moderate to severe hypertension . Following 2 weeks of initial treatment with OM 40/AML 5/HCTZ 12.5 mg, participants not achieving BP goal were titrated to OM 40/AML 5/HCTZ 25 mg or OM 40/AML 10/HCTZ 12.5 mg on a randomized basis. At week 16, participants who did not achieve BP goal were further titrated to OM 40/AML 10/HCTZ 25 mg. At the end of the study, 44.5% to 79.8% of participants reached BP goal and the mean BP decreased from 168.6/100.7 mm Hg (baseline BP at randomization) to 125.0 to 136.8 mm Hg/77.8 to 82.5 mm Hg, depending on treatment. Long-term treatment with OM/AML/HCTZ was well tolerated and effective with no new safety concerns. ### Assistant: [{"class": "POS", "spans_text": ["Olmesartan", "Amlodipine", "Hydrochlorothiazide"]}]