Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042963 (vomiting)
 31,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of this report is to summarize information on pemetrexed (LY231514; MTA; Alimta; Eli Lilly and Company; Indianapolis, IN), a drug recently approved by the U.S. Food and Drug Administration (FDA). The review of the efficacy and safety of pemetrexed is summarized below. Pemetrexed is a pyrrolopyrimidine antifolate. It inhibits thymidylate synthase, glycinamide ribonucleotide formyltransferase, and dihydrofolate reductase. In a single, randomized, single-blind, multicenter phase III trial, the efficacy and safety of pemetrexed combined with cisplatin (Platinol; Bristol-Myers Squibb; Princeton, NJ) were compared with those of single-agent cisplatin in 448 patients with malignant pleural mesothelioma. Two hundred twenty-six patients were randomized to receive pemetrexed and cisplatin, while 222 patients were randomized to receive cisplatin alone. The primary study end point was survival. Median survival times were 12.1 months for the pemetrexed plus cisplatin treated arm and 9.3 months for the cisplatin alone arm. Pemetrexed causes myelosuppression. The most common adverse events were neutropenia, fatigue, leukopenia, nausea, dyspnea, and vomiting. On February 4, 2004, pemetrexed was approved by the FDA in combination with cisplatin for the treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery. The recommended dose of pemetrexed is 500 mg/m(2) administered as an i.v. infusion over 10 minutes on day 1 of each 21-day cycle together with cisplatin at a dose of 75 mg/m(2) infused over 2 hours beginning 30 minutes after the pemetrexed infusion. Patients must receive oral folic acid and vitamin B(12) injections prior to the start of therapy and continue these during therapy to reduce severe toxicities. Patients should also receive corticosteroids with chemotherapy to reduce the risk of skin rashes. Approval was based on superior survival as a clinical benefit.
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PMID:FDA drug approval summaries: pemetrexed (Alimta). 1547 32

In the present article, we have summarized the phase I/II clinical trials on combination therapy of S-1 and docetaxel. With result of the phase I study, patients were treated with intravenous infusion of 40 mg/m2 docetaxel on day 1 and oral S-1 80 mg/m2/day on days 1 to 14 every 3 weeks. Forty eight patients received a total of 272 treatment cycles. No complete responses (CRs) and 27 partial responses (PRs) were observed for an overall response rate (CR+PR) of 56.2% (95% CI, 38-66%). Eighteen patients (37.5%) had stable disease (SD), and 3 patients (6.2%) had progressive disease (PD) as best response. The tumor control rate (CR+PR+SD) was 93.8% (95% CI, 83-98%). The median overall survival was 14.3 months (95% CI: 10.7-20.3 months) and the median time to tumor progression was 7.3 months (95% CI: 4.2-10.7 months). The most common grade 3-4 hematologic toxicities were neutropenia 58.3%, leukopenia 41.7%, febrile neutropenia 8.3%, and anemia 8.3%. The most common grade 3 nonhematologic toxicities were anorexia 14.6%, stomatitis 8.3%, nausea 6.3%, diarrhea 4.2%, constipation 4.2%, and vomiting 2.1%. No grade 4 nonhematologic toxicities were reported, and all treatment-related toxicities were resolved. The mechanisms underlying these synergistic effects of S-1 and docetaxel were examined by expression and activity analyses of 5-FU metabolic enzymes. The expressions of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) were decreased and that of orotate phosphorybosyl transferase (OPRT) was increased in mRNA, protein level and activity assay after the treatment with docetaxel and 5-FU in the TMK-1 gastric cancer cell. These findings strongly indicate that the combination chemotherapy of docetaxel and S-1 is effective against gastric carcinomas and therefore is a good candidate as a standard chemotherapeutic strategy in treating these tumors.
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PMID:[Combination chemotherapy of S-1 and docetaxel on advanced and recurrent gastric cancer]. 1689 78

5-Fluorouracil (5-FU) is an antimetabolite that acts during the S phase of the cell cycle. The active metabolite, 5-fluorodeoxyuridine monophosphate inhibits thymidylate synthase (TS), thus preventing DNA synthesis, which leads to imbalanced cell growth and ultimately cell death. 5-FU and its oral prodrug capecitabine are used in the treatment of a number of solid tumors, including colorectal, breast, gastric, pancreatic, prostate, and bladder cancers. Common side effects include leukopenia, diarrhea, stomatitis, nausea, vomiting, and alopecia. Hand-foot syndrome (HFS) is a relatively common side effect of cytotoxic chemotherapy. It is more frequently associated with 5-FU, capecitabine, and cytarabine. This article reports on the case of a 55-year-old black man with metastatic colorectal carcinoma that was refractory to recommended treatment measures who developed grade 3 HFS after treatment with modified FOLFOX6 (leucovorin [LV]/5-FU/oxaliplatin) and bFOL (bolus 5-FU/LV/oxaliplatin) regimens. Treatment was discontinued despite excellent response to chemotherapy. The patient had progression of disease on IROX (irinotecan/oxaliplatin) and irinotecan/cetuximab regimens. He was started on gemcitabine/capecitabine and developed HFS again, which was controlled with aggressive skin care and vitamin B6 treatment. Full sequencing of the dihydropyrimidine dehydrogenase (DPYD) gene and analysis of the human TS gene (TYMS) promoter region was performed. Pharmacogenetic testing revealed 2R/2R genotype of TYMS gene, which is associated with up to a 2.5-fold risk of toxicity to 5-FU therapy. Hand-foot syndrome has proven to be a dose-limiting toxicity of 5-FU, especially of capecitabine, leading to significant morbidity. Hand-foot syndrome seems to be dose dependent, and both peak drug concentration and total cumulative dose determine its occurrence. Genetic variations such as polymorphic abnormality of TYMS are potential causative factors for a significant portion of serious adverse reactions to 5-FU-based therapy.
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PMID:Toxicity and efficacy of 5-fluorouracil and capecitabine in a patient with TYMS gene polymorphism: A challenge or a dilemma? 1982 15

Introduction: High dose methotrexate (HD-Mtx) is highly effective and significantly improves overall acute lymphoblastic leukemia (ALL) patients survival. The pharmacodynamics of Mtx depends on the polymorphism of genes encoding proteins engaged in the folate metabolism pathway. The aim of the current study is to determine the relationship between variants of folate metabolism-related genes and the frequency of acute toxicities of HD-Mtx. Material and Methods: A group of 133 patients aged 1.5-18.1 years (median: 6.3) was treated in accordance with the ALL-IC-2002 and ALL-IC-2009 protocols. The following polymorphisms were determined: 80 G>A SLC19A1 (solute carrier family 19 member 1; rs1051266) with direct DNA sequencing, as well as 677 C>T MTHFR (methylenetetrahydrofolate reductase; rs1801133) and the tandem repeats of the TS (thymidylate synthase) with PCR technique. HD-Mtx organ toxicities were evaluated based on the laboratory tests results and the National Cancer Institute criteria. Results: In patients with genotypes AA for SLC19A1 and CC or CT for MTHFR Mtx steady state concentrations (Css) and AUCinf were distinctly higher. In patients with genotype 3R/3R for TS initial elimination rate constant was significantly higher (P = 0.003). Patients receiving Mtx at the dose of 5 g/m2 had lower clearance (4.35 vs. 8.92 L/h/m2) as compared to the ones receiving 2 g/m2 that indicates non-linear Mtx elimination at the higher dose. Liver impairment was the most frequently observed toxicity. The homozygous genotype was associated with a significantly higher incidence of hepatic toxicity for both the SLC19A1 (P = 0.037) and TS (P = 0.002). Logistic regression analysis indicated an increased risk of vomiting for the 2R/3R genotype of the TS gene (OR 3.20, 95% CI 1.33-7.68, P = 0.009) and for vomiting and hepatic toxicity for the 3R/3R genotype (vomiting: OR 3.39, 95% CI 1.12-10.23, P = 0.031; liver toxicity: OR 2.28, 95% CI 1.05-4.95, P = 0.038). None of the acute toxicities differed between the analyzed dosing groups. Conclusions: Determination of polymorphisms of SLC19A1, MTHFR, and TS genes might allow for a better prior selection of patients with higher risk of elevated Mtx levels. Our study is the first one to report the increased risk of hepatotoxicity and vomiting in patients with TS polymorphisms.
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PMID:Polymorphisms of SLC19A1 80 G>A, MTHFR 677 C>T, and Tandem TS Repeats Influence Pharmacokinetics, Acute Liver Toxicity, and Vomiting in Children With Acute Lymphoblastic Leukemia Treated With High Doses of Methotrexate. 3261 64


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