Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027497 (nausea)
 23,468 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Merbarone, a nonsedating derivative of thiobarbituric acid, has demonstrated excellent activity against certain murine tumors, including L1210 and P388 leukemias, B16 melanoma, and M5076 sarcoma. Preclinical studies suggested that the antitumor effects of this drug were schedule dependent, since repeated dosing increased killing of tumor cells when compared to intermittent injections. We have completed a Phase I clinical and pharmacological study of merbarone in which the drug was administered both as a 2-h infusion and as a continuous i.v. infusion over 24 h. In view of the increased toxicity observed in animals following bolus injections and the possibility of schedule-dependent anticancer activity, a schedule of drug administration daily for 5 days was selected. Fifty patients with advanced cancer were treated at dose levels that ranged from 100 to 1500 mg/m2/day. When the drug was administered by peripheral vein, phlebitis was observed at the infusion site at daily doses greater than or equal to 150 mg/m2. Therefore, all patients who received drug doses greater than or equal to 200 mg/m2 were treated by continuous i.v. infusion using central venous catheters. Renal insufficiency, initially observed at a dose of 1000 mg/m2/day, was the dose-limiting toxic reaction at 1500 mg/m2/day. Three of five patients treated at the highest dose level were unable to complete the infusion due to this effect. Marked hypouricemia was observed in all patients. Other toxic effects were mild and included nausea, fatigue, leukopenia, thrombocytopenia, and anorexia. Alopecia was noted in several patients who received doses greater than or equal to 1000 mg/m2/day. No major antitumor effects were observed. Dose-dependent, steady-state plasma concentrations of merbarone were reached within 24-48 h after beginning the continuous i.v. infusion. Elimination of drug from plasma followed a two-compartment model, with a t1/2 alpha of 4.2 h and a t1/2 beta of 15.3 h. Renal excretion of merbarone and its major metabolites accounted for less than 30% of the administered dose. We conclude that merbarone is relatively well tolerated with few constitutional symptoms. The current formulation of the drug causes phlebitis when administered by peripheral vein, and renal insufficiency is commonly observed at daily doses which exceed 1250 mg/m2. The recommended dose for extended Phase II evaluation is 1000 mg/m2/day daily for 5 days administered by central venous catheter.
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PMID:Phase I clinical and pharmacological study of merbarone. 229 63

The Southwest Oncology Group (SWOG) studied the response rate and toxicity of merbarone (1,000 mg/m2 IV continuous infusion days 1-5, q 21 days) in patients with advanced metastatic renal cell carcinoma. Among 36 eligible patients, there was one partial response for a response rate of 3% (95% C.I. 0.1-15%). There were no mixed responses. There were no treatment related deaths or adverse drug reactions. Significant anemia, diarrhea, and hypercalcemia were observed. Mild to moderate degrees of malaise/fatigue/lethargy, dizziness/vertigo, hyperglycemia, creatinine increase, nausea, vomiting, weight loss, pedal edema, dyspnea, and granulocytopenia were noted. Merbarone does not have significant activity as a single agent in advanced renal cell carcinoma.
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PMID:Phase II evaluation of merbarone in renal cell carcinoma. 786 Feb 33

Merbarone, NSC 336628, is an investigational anticancer drug with activity against experimental animal tumors including melanoma. This paper presents results of a Phase II clinical study of merbarone in patients with biopsy proven stage IV malignant melanoma without prior chemotherapy and with no evidence of CNS involvement. Thirty-five patients with median age 58 (range 27-81), with performance status 0-2 were treated with merbarone 1000 mg/m2/day for five days by intravenous continuous infusion repeated every 3 weeks. All patients (21 males and 14 females) were evaluable for toxicity. Two patients were not evaluable for response having been removed from protocol treatment due to toxicity and received other treatment during the first course of chemotherapy. Among the evaluable patients there was one complete response in a supraclavicular lymph node lasting four months and one partial liver response lasting three months. The remaining thirty-one patients were non-responders. Of these one had a stable disease lasting 21 months. The overall objective response rate was 6% (2/35) with a 95% confidence interval of 1%-19%. Twenty-six of the 35 patients have died. The estimated median survival of the entire group was 9 months with a 95% confidence interval six to eleven months. Renal toxicity was dose-limiting and manifested as increasing serum creatinine (54% of patients), proteinuria (51%) and hematuria (9%). One patient experienced grade 4 creatinine increase, proteinuria and acute renal failure. Other toxicities included nausea (71%), vomiting (51%0, malaise (23%), weakness (20%), alopecia (17%), diarrhea (17), anorexia (14%) transaminase (SGOT, SGPT) increase (14%), constipation (14%), alkaline phosphatase or 5'nucleotidase increase (9%), and fever (9%). Hematologic toxicity (granulocytopenia, leukopenia, and anemia) was generally mild and infrequent (29%, only one patient had grade 4 granulocytopenia). Overall 9 patients (26%) had at least one grade 3 toxicity. We conclude that merbarone at this dose and schedule has detectable but minimal activity in the treatment of metastatic malignant melanoma and given the significant renal toxicity this schedule does not merit further evaluation in this disease.
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PMID:Evaluation of merbarone (NSC 336628) in disseminated malignant melanoma. A Southwest Oncology Group study. 861 77