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)

Tiazofurin (2-B-D-Ribofuranosylthiazole-4-Carboxamide: NSC 286193) is a nucleoside antimetabolite that acts as a potent inhibitor of IMP dehydrogenase resulting in a guanine nucleotide deprivation. Recent in vivo biochemical observations in rats bearing hepatoma suggested a correlation between depletion of guanine nucleotides and antitumor effect. The present phase I trial utilized a weekly x 3 bolus infusion schedule, repeated every 5 weeks. Biochemical measurements of GTP and dGTP were performed in patients at each dose level. Twelve patients received 16 courses of the drug in doses ranging from 1100 to 2050 mg/m2 weekly x 3. The dose limiting toxicities were pericarditis and clinical symptoms suggestive of a more generalized serositis (chest and abdominal pain). Other toxicities included reversible elevations in CPK (MM band only) and SGOT, nausea, vomiting, and arthralgias. Neurotoxic effects were generally mild, including headaches, anxiety, and malaise. Only 1 of 6 patients evaluated for tiazofurin's biochemical activity showed a sustained depletion of guanine nucleotide pools. No antitumor activity was observed. The maximally tolerated dose of tiazofurin on this intermittent weekly x 3 schedule was 1650 mg/m2. Toxicity and the overall lack of biochemical and biologic effect at clinically achievable doses may preclude further clinical evaluation of this drug on a weekly schedule. The toxicities observed in our study were similar to those reported for phase I investigations using a considerably higher dose intensity with daily x 5 schedules.
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PMID:Phase I trial and biochemical evaluation of tiazofurin administered on a weekly schedule. 234 2

Brequinar sodium is a quinoline carboxylic acid derivative that has shown antitumor activity in a number of in vivo murine and human tumor xenograft models. Its mechanism of action is blockade of de novo pyrimidine biosynthesis by inhibition of dihydroorotic acid dehydrogenase. In vitro and in vivo studies demonstrate the superiority of prolonged drug exposure in achieving tumor growth inhibition. This phase I study evaluated the administration of brequinar sodium by short, daily i.v. infusion for 5 days repeated every 4 weeks. Fifty-four subjects were enrolled in the study and received drug in doses ranging from 36-300 mg/m2. The dose-limiting toxicities were mucositis and diffuse skin rash. Other toxicities included myelosuppression, nausea, vomiting, malaise, and burning at the infusion site. The maximum tolerated dose on the "daily times 5" schedule was 300 mg/m2. The recommended phase II dose is 250 mg/m2. Pharmacokinetic analysis of the day 1 drug clearance curves in 51 subjects showed slight nonlinearity in the relationship between dose and area under the clearance curve (AUC). The dose versus AUC relationship was well described using a Michaelis-Menten model of brequinar elimination kinetics with Vmax = 45 (micrograms/ml)/h and Km = 123 micrograms. Analysis of the day 5 drug clearance curves revealed a diminution in Vmax to 30 (micrograms/ml)/h. As a consequence of the reduction in Vmax brequinar plasma concentrations on day 5 were higher than predicted from day 1 drug kinetics. Pharmacodynamic analysis of the day 1 kinetic parameters and the toxicities occurring during the first cycle of drug therapy revealed significant correlations between mucositis and dose, AUC, and peak brequinar concentration; between leukopenia and AUC and peak drug concentration; and between thrombocytopenia and beta elimination rate.
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PMID:Phase I and pharmacokinetic study of brequinar sodium (NSC 368390). 236 34

A phase I trial of 2-beta-D-ribofuranosylthiazole-4-carboxamide (NCS 286193, tiazofurin) was conducted using a 5-day i.v. bolus schedule, every 21 days. Thirty one patients with advanced cancer were entered on the trial. A total of 106 cycles were administered with doses ranging from 550 to 2750 mg/m2. Concomitant administration of Allopurinol was necessary to prevent hyperuricemia. Tiazofurin was difficult to evaluate and many side effects were variable and sporadic. The dose limiting toxicities were nonhematologic consisting particularly of myalgias, headaches and general malaise. Other toxicities included nausea, vomiting, stomatitis, lethargy, sleeping difficulty, sinus bradycardia, skin rash, desquamation of the palms and soles, photophobias and burning of the eyes. Hematologic toxicity was mild and not dose related though it led to a neutropenic septic death in one patient at 2750 mg/m2. Anemia was documented in 60% of cycles. Biochemical abnormalities consisted of mild hyperglycemia, hyperuricemia and elevated skeletal creatinine phosphokinase levels which did not correlate with the incidence or degree of myalgias. Though some patients were able to tolerate higher doses, the recommended dose for phase 2 study is 1650 mg/m2. Further studies will be required to achieve a better understanding of this interesting drug.
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PMID:Phase I study of tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide, NSC 286193). 238 15

Preclinical data suggest synergy of interleukin-2 (IL-2) combined with alpha-interferon (IFN). In addition, toxicities of IL-2 may be decreased by intermittent continuous infusion. The purpose of this trial was to determine the maximum tolerated dose (MTD) of recombinant IL-2 combined with alpha-IFN in patients with renal cancer, colon cancer, melanoma, and malignant B-cell disease. IL-2 was given by continuous i.v. infusion at an initial dose of 5 X 10(5) units (U)/m2/d for 4 days plus IFN at 6 X 10(6) U/m2/d intramuscularly days 1 and 4 weekly for 4 weeks. Patients who achieved a response or stable disease received an additional 4 weeks of therapy. IL-2 doses were increased to 1, 2, 3, 5, and 7 X 10(6) U/m2/d with three to eight patients at each dose level, at each of the two participating institutions. The dose of IFN was 6 X 10(6) U/m2 days 1 and 4 for all but five patients whose IFN dose was doubled to 12 X 10(6) U/m2/d. Forty-three patients were entered on this study with 34 completing at least 4 weeks of therapy. Six patients were taken off study because of Grades III or IV pulmonary, neurologic, or cardiac toxicity; one for progressive disease; one for CNS metastases, and one for personal reasons. All of the toxicities were reversible. Chills and fever were universal, especially on days 1 and 4. Mild and moderate nausea, vomiting, diarrhea, anorexia, malaise, and cutaneous erythema were present in most patients. Fluid retention and occasional pleural effusions were observed at the higher IL-2 doses but were not dose-limiting. Significant hypotension associated with oliguria was seen, and these patients were treated with vasopressors and colloids. None of the patients required ICU admission. Thirty-four patients were evaluable for response. There were 4/18 (22%) renal cell patients who experienced a partial response. No responses were seen in patients with melanoma, lymphoma, or colorectal cancer. The combined debilitating symptoms of fatigue, diarrhea, hypotension, fluid retention, and anorexia defined the MTD as 5 X 10(6) U/m2/d of IL-2 and 6 X 10(6) U/m2 of alpha-IFN.
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PMID:A phase I study of recombinant human interleukin-2 and alpha-interferon-2a in patients with renal cell cancer, colorectal cancer, and malignant melanoma. 238 96

Thirty-one patients were entered into a pilot study combining oral quinidine with epirubicin 100 mg m-2 as first line chemotherapy in advanced breast cancer. Three patients were treated with quinidine 1 g b.d., and developed symptoms of toxicity. Of eight subsequent patients treated with quinidine 500 mg b.d., two experienced tiredness and nausea and one severe oral toxicity with epirubicin. The remaining 20 patients received quinidine 250 mg b.d.; one developed cinchonism and one malaise, the remainder showing no excess toxicity compared with epirubicin alone. The median nadir WBC was similar with or without quinidine (2.3 vs 1.6 x 10(9) l-1) as was median nadir platelet count (175 vs 157 x 10(9) l-1). There was no evidence of significant cardiac toxicity. The median plasma quinidine level achieved was 5.6 mumol l-1 (range 2.1-22.1), which is within the range of concentrations which is effective in vitro at reversing experimental anthracycline resistance. A randomised controlled study is proposed to assess the impact of this potential modulation on the efficacy of epirubicin in advanced breast cancer.
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PMID:A pilot study of quinidine and epirubicin in the treatment of advanced breast cancer. 239 Apr 73

Acute fatty liver of pregnancy is considered an uncommon disorder that may complicate the third trimester of pregnancy, with high fetal and maternal mortality rates. However, in recent years it has become clear that the course of the disorder can be less fulminant than previously believed. The diagnosis is also made more frequently. The case histories of three patients are described followed by a review of the clinical and diagnostic features. It is concluded that with all women showing symptoms of malaise, nausea, vomiting and upper abdominal pain in the third trimester of pregnancy liver enzymes should be measured. If evidence of liver dysfunction is found, acute fatty liver of pregnancy should be considered in the differential diagnosis. Only early recognition and prompt treatment will improve both fetal and maternal survival.
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PMID:[Acute fatty degeneration of the liver in pregnancy]. 239 79

Travelers' diarrhea is only mild or moderate in the majority of cases. Consequently, severe fluid and electrolyte losses are encountered only rarely. Secretory, osmotic, and inflammatory processes in the intestine result in increased losses of fluid and electrolytes due to diarrhea. Disorders of intestinal motor activity, coupled with fluid secretion, may also have a role in causing an increase in the frequency of bowel movements. Several systemic symptoms, such as malaise, fatigue, anorexia, nausea, and fever, are commonly associated with diarrhea and contribute to significant morbidity, which is often sufficient to compromise effective participation in a vacation or business trip. Several putative mechanisms for the systemic symptoms associated with travelers' diarrhea are discussed in light of recent understanding of the enteric nervous system, intestinal neuropeptides and hormones, and other inflammatory mediators released from the bowel wall during enteric infections.
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PMID:Pathophysiology of diarrheal disorders. 240 54

A phase II study of peplomycin, an analogue of bleomycin, was carried out in 42 patients with advanced or recurrent breast cancer by a cooperative group consisting of 15 institutes throughout Japan, and the following results were obtained. Among the 42 patients, 38 were evaluable, in whom the overall response rate was 7.9% (3/38). For the various histologic types, the response rate was 33.3% (2/6) for papillotubular carcinoma and 9.1% (1/11) for medullary tubular carcinoma. The response rate was 33.3% (2/6) in patients without prior treatment and 3.1% (1/32) in those with prior treatment. Side effects of nausea, anorexia, malaise, alopecia and pyrexia occurred frequently, and a decrease in WBC and an increase in GOT were observed temporally. Pulmonary toxicity was observed in 7 patients.
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PMID:[Phase II study of peplomycin in breast cancer. A cooperative study. Clinical Study Group of Peplomycin for Breast Cancer in Japan]. 244 Mar 87

Combined chemotherapy with cisplatin was performed in patients with advanced esophageal cancer. Two types of administration schedule were used: method I (three-drug combination of cisplatin, bleomycin and methotrexate) and method II (combination of cisplatin, peplomycin and methotrexate). Of 16 cases, 6 (37.5%) showed partial remission. With regard to the method of administration, the response rate for method I was 33%, and that for method II was 43%. Nausea (84%), vomiting (56%), loss of appetite (94%), malaise (75%) and alopecia (25%) were observed as side effects. Nausea and vomiting were ameliorated by use of metoclopramide. In bloodchemistry, anemia (87%), leukopenia (56%), thrombopenia (31%) and increase of BUN (63%) were observed. However, these changes were ameliorated by hydration or blood transfusion. Combined chemotherapy with CDDP should be a more useful future treatment for esophageal cancer.
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PMID:[Combined chemotherapy with cisplatin in esophageal cancer]. 244 65

Twenty-eight evaluable patients with metastatic cancer refractory to standard therapy received escalating doses of muramyl tripeptide phosphatidylethanolamine (MTP-PE) (.05 to 12 mg/m2) in phosphatidylserine (PC):phosphatidylcholine (PS) liposomes (lipid:MTP-PE) ratio 250:1). Liposomal MTP-PE (L-MTP-PE) was infused over 1 hour twice weekly; doses were escalated within individual patients every 3 weeks as tolerated for a total treatment duration of 9 weeks. Routine clinical laboratory parameters, acute phase reactants and various immunologic tests were monitored at various time points during treatment. Toxicity was moderate (less than or equal to grade II) in 24 patients with chief side effects being chills (80% of patients), fever (70%), malaise (60%), and nausea (55%). In four patients L-MTP-PE treatment was deescalated due to severe malaise and recurrent fever higher than 38.8 degrees C. The maximum-tolerated dose (MTD) was 6 mg/m2. Significant (P less than .05) increases in WBC count, absolute granulocyte count, ceruloplasmin, beta 2-microglobulin, c-reactive protein, monocyte tumoricidal activity, and serum IL-1 beta were found. Significant decreases in serum cholesterol were also observed. Clearance of intravenously (iv)-infused technetium-99 (99mTc)-labeled liposomes containing MTP-PE in four patients was biphasic; gamma camera scans revealed uptake of radiolabel in liver, spleen, lung, nasopharynx, thyroid gland, and tumor (two patients). No objective tumor regression was seen. In view of its definite immunobiologic activity and lack of major toxicity, additional phase II and adjuvant trials of L-MTP-PE are warranted.
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PMID:Phase I trial of liposomal muramyl tripeptide phosphatidylethanolamine in cancer patients. 247 21


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