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 effect of deoxynivalenol (DON, vomitoxin) on brain amine levels was investigated in swine. DON, a trichothecene mycotoxin, causes suppression of feed intake (anorexia) in susceptible species. Following acute administration of DON to pigs (0.25 mg/kg, IV), concentrations of endogenous catecholamines norepinephrine (NE), dopamine (DA), 3,4-dihydroxyphenyl-acetic acid (DOPAC), and homovanillic acid (HVA), and the indoleamines, 5-hydroxytryptamine (5HT, serotonin) and 5-hydroxyindoleacetic acid (5HIAA) were determined in five brain regions, periodically during the 24 h post-dosing. Analysis was carried out by high performance liquid chromatography, using electrochemical detection. Effects of DON in the swine brain were transmitter, time and region-specific. It was observed that levels of the major transmitters (NE, DA and 5HT) were statistically different from controls in the hypothalamus (Hypo), frontal cortex (FCX) and cerebellum (Cb) up to 8 h post-dosing. Overall, DON administration elevated NE and depressed DA concentrations in these regions, and levels of 5HT which increased initially in Hypo (1 h), had dropped significantly below controls in both Hypo and FCX at 8 h. These alterations, however, were not indicative of known neurochemical changes associated with chemical-induced anorexia. Instead, this data suggested that the neurochemical effects of acute DON exposure might be due to peripheral toxicological events (i.e., vomiting), which overwhelmed its more subtle feed refusal activity.
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PMID:Effect of deoxynivalenol on neurotransmitters in discrete regions of swine brain. 137 99

Ninety-eight patients with previously-treated advanced soft tissue sarcoma, bone sarcoma, or mesothelioma were randomly assigned to one of two intravenous single-agent treatment regimens, either 6-diazo-5-oxo-l-norleucine (DON; brief infusions of 50 mg/m2/day for 5 consecutive days every 4 weeks) or aclacinomycin-A (ACM-A, as 30-min infusions of 100 mg/m2 or 85 mg/m2, administered every 3 weeks). Of 43 patients who were evaluable for response, survival and toxicity, there were two responses (5%) produced by ACM-A; one in a male with mesothelioma, and one in a female with malignant fibrous histiocytoma. None of the 36 evaluable patients treated with DON developed an objective tumor response. Median survival was 4.8 months in the DON treatment arm, and 6.8 months in the ACM-A treatment arm. No patients on the DON arm experienced lethal or life-threatening toxicities, and severe toxicities resulting from this treatment included nausea and emesis (10%), stomatitis (2%), gastrointestinal toxicity (2%), and anemia (2%). Moderate toxicities included vomiting (24%), hematologic toxicity (24%), neurologic toxicity (7%), diarrhea (7%), mucositis (5%), fever (5%), palpitations (2%), hepatotoxicity (2%), bleeding (2%) and edema (2%). Fifteen percent experienced at least one severe reaction, and 63% experienced at least one moderate or greater toxicity. ACM-A was associated with four cases of life-threatening myelosuppression (7%); severe toxicities included myelosuppression (11%), neurologic toxicity (4%), diarrhea (2%), respiratory toxicity (2%), pain and muscle spasms (2%), edema (2%), and ulceration following extravasation (2%).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Phase II trial of 6-diazo-5-oxo-L-norleucine versus aclacinomycin-A in advanced sarcomas and mesotheliomas. 218 26

DON (6-diazo-5-oxo-L-norleucine), a glutamine antagonist, has been subjected to limited clinical trials since 1957. Use of the drug in adults has been curtailed due to sparse reports of effectiveness as well as its dose-limiting toxicities, i.e., severe nausea, vomiting and mucositis. In earlier studies, children given DON orally in combination with 6-mercaptopurine had significant prolongation of remission of acute leukemias during maintenance therapy. As DON is acid-labile and relatively unstable in solution, oral administration does not appear to be ideal for DON. In the trial described in this report, i.v. DON therapy was studied, using i.v. chlorpromazine to control vomiting, in 20 children, 17 of whom were evaluable following treatment at DON dose levels ranging from 150 mg/m2 to 520 mg/m2. Nausea and vomiting, the dose-limiting toxicity for adults, was controlled with chlorpromazine. Mucositis, which has also been observed in adults, did not occur in the children given DON i.v. A maximum tolerated dose was not defined; however, the projected maximum tolerated dose appears to be in excess of 450 mg/m2. DON was measured in plasma using a rapid-sampling HPLC procedure. The total body clearance, plasma t1/2, and area under the plasma concentration curve (AUC) were calculated using a noncompartmental method. The drug is rapidly cleared from plasma (t 1/2 = 3 h), and its volume of distribution is approximately twice that of total body water in children. These pharmacokinetic data, differ from that of adults reported by others. Specifically, the plasma t 1/2 for children is longer: total body clearance (Cl), and volume of distribution at steady state (Vss) are greater. In addition, no dose dependency of t 1/2, Cl or Vss was observed in this study, and the DON pharmacokinetics were linear and predictable. Five of nine children with acute leukemia showed improvement, though insufficient for classification as partial response, and five of eight children with solid tumors also showed improvement. Further trials using DON in combination with thiopurines or other agents appear indicated.
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PMID:Pharmacokinetic and phase I study of intravenous DON (6-diazo-5-oxo-L-norleucine) in children. 334 70

Study was made of the pharmacokinetics and toxicopathy of deoxynivalenol (DON, vomitoxin) given IV to swine. In the 24 hours after swine were given DON, clinical signs of vomiting, diarrhea, muscular weakness, tremors, and twilight coma were similar to those observed with other 12,13-epoxytrichothecenes. Hypoglycemia and pancreatic islet cell lesions were observed which indicated that DON-induced changes in intermediary metabolism may be an insidious aspect of DON intoxication. Histopathologic examination of all organ systems revealed pancreatic acinar and islet cell necrosis and mild lympholysis of the mesenteric lymph nodes. The renal excretion of DON was altered by IV infusion of saline solution. Pharmacokinetic findings may indicate that DON was both secreted and reabsorbed by the renal tubules. The half-life of DON ranged from 2.08 to 3.65 hours. Residues of DON were not found in skeletal muscle of swine at 24 hours after dosing.
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PMID:Preliminary study of the pharmacokinetics and toxicopathy of deoxynivalenol (vomitoxin) in swine. 397 Apr 24

The toxicity of the glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON) administered as a 24 hour infusion has been evaluated. Studies of the clinical pharmacology of the drug have also been performed in 3 patients. The limiting toxicity of the drug was acute nausea, vomiting and diarrhea that was dose dependent in its severity and duration. The maximum tolerated dose was 600 mg/m2 over 24 hours. The other major toxicity was thrombocytopenia that was maximal 7-10 days after the completion of the infusion. The drug does not exhibit renal, hepatic or central nervous system toxicity. DON achieves steady state levels during these infusions and is eliminated by first order kinetics when the infusion is completed (t1/2 alpha = 1.81 h). The principal route of excretion is renal. A starting dose of 400 mg/m2 would be acceptable for Phase II studies of this drug administered on this schedule.
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PMID:Phase I study and clinical pharmacology of 6-diazo-5-oxo-L-norleucine (DON). 408 44

Nutritional and toxicologic feeding trials with 3 species of farm animals demonstrated that decreased feed consumption and reduced weight gains in pigs are the main effects of ingestion of a diet with low vomitoxin (deoxynivalenol; DON) content, eg, 2 mg of DON/kg of feed, ie, 2 ppm. The feeding trials indicated that swine can ingest up to 2 mg of DON/kg of feed without serious adverse effects. Poultry can tolerate at least 5 mg of DON/kg feed. In fact, at concentrations up to 5 mg of DON/kg feed, some beneficial effects on poultry were observed. In dairy cattle, feed consumption decreased slightly when a wheat-oats diet containing 6 mg of DON/kg was fed at the rate of 1% of body weight/day, with hay offered ad libitum. In surveys of Canadian grains carried out during the past 3 years, the DON content (maximum of 8.5 mg/kg) in eastern Canadian wheats probably was not high enough to account for reports of feed refusal, vomiting, and reproductive problems in livestock operations. This conclusion is based partly on the fact that even at the highest concentrations of DON found in wheat, formulated diets comprise, at maximum, about 70% to 80% wheat. Consequently, the actual DON content of diets fed to farm animals would be much lower.
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PMID:Feeding trials with vomitoxin (deoxynivalenol)-contaminated wheat: effects on swine, poultry, and dairy cattle. 648 Apr 67

6-Diazo-5-oxo-L-norleucine (DON), an L-glutamine antagonist, was administered to 25 evaluable patients with refractory advanced solid tumors in a phase I trial. A total of 58 evaluable courses of five daily iv injections every 3-4 weeks were given, at doses ranging from 7.5 to 90 mg/m2/day. The major dose-limiting toxicity was a syndrome of nausea, vomiting, malaise, and anorexia, which became severe at doses greater than 52.5 mg/m2/day. Diarrhea and stomatitis were less frequent. Hematologic toxicity included mild leukopenia with nadir on Day 6-8 and mild thrombocytopenia with nadir on Day 7-12. Transient decreases in serum calcium to 8.5--8.9 mg/dl were seen in seven of 12 patients receiving greater than or equal to 67.5 mg/m2/day. Dose reduction was required for all patients who received a course of DON at greater than 67.5 mg/m2/day, and a maximum tolerated total dose of 250 mg/m2 (50 mg/m2/day x 5) is suggested for this schedule. Mixed responses were seen in one patient with bladder carcinoma and in one with pulmonary adenocarcinoma.
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PMID:Phase I trial of 6-diazo-5-oxo-L-norleucine (DON) administered by 5-day courses. 708 23

Twenty-three patients with advanced colorectal carcinoma, previously treated with chemotherapy, were entered in a phase II trial of DON (6-Diazo-5-Oxo-L-Norleucine), an antagonist of L-glutamine. One of 14 adequately treated patients had a partial response of 6 weeks duration. The dose-limiting toxicity was nausea and vomiting; 48% of patients originally entered on the study withdrew because of vomiting. Myelosuppression was minimal, with only mild thrombocytopenia noted. The dose and schedule used in this study were beyond the maximally tolerated dose for many patients; future phase II studies of DON will be difficult to complete unless schedules and doses are found which result in less nausea and vomiting.
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PMID:Phase II evaluation of DON (6-diazo-5-oxo-L-norleucine) in patients with advanced colorectal carcinoma. 718 Aug 33

Trichothecene mycotoxins are a group of structurally similar fungal metabolites that are capable of producing a wide range of toxic effects. Deoxynivalenol (DON, vomitoxin), a trichothecene, is prevalent worldwide in crops used for food and feed production, including in Canada and the United States. Although DON is one of the least acutely toxic trichothecenes, it should be treated as an important food safety issue because it is a very common contaminant of grain. This review focuses on the ability of DON to induce toxicologic and immunotoxic effects in a variety of cell systems and animal species. At the cellular level, the main toxic effect is inhibition of protein synthesis via binding to the ribosome. In animals, moderate to low ingestion of toxin can cause a number of as yet poorly defined effects associated with reduced performance and immune function. The main overt effect at low dietary concentrations appears to be a reduction in food consumption (anorexia), while higher doses induce vomiting (emesis). DON is known to alter brain neurochemicals. The serotoninergic system appears to play a role in mediation of the feeding behavior and emetic response. Animals fed low to moderate doses are able to recover from initial weight losses, while higher doses induce more long-term changes in feeding behavior. At low dosages of DON, hematological, clinical, and immunological changes are also transitory and decrease as compensatory/adaptation mechanisms are established. Swine are more sensitive to DON than mice, poultry, and ruminants, in part because of differences in metabolism of DON, with males being more sensitive than females. The capacity of DON to alter normal immune function has been of particular interest. There is extensive evidence that DON can be immunosuppressive or immunostimulatory, depending upon the dose and duration of exposure. While immunosuppression can be explained by the inhibition of translation, immunostimulation can be related to interference with normal regulatory mechanisms. In vivo, DON suppresses normal immune response to pathogens and simultaneously induces autoimmune-like effects which are similar to human immunoglobulin A (IgA) nephropathy. Other effects include superinduction of cytokine production by T helper cells (in vitro) and activation of macrophages and T cells to produce a proinflammatory cytokine wave that is analogous to that found in lipopolysaccharide-induced shock (in vivo). To what extent the elevation of cytokines contributes to metabolic effects such as decreased feed intake remains to be established. Although these effects have been largely characterized in the mouse, several investigations with DON suggest that immunotoxic effects are also likely in domestic animals. Further toxicology studies and an assessment of the potential of DON to be an etiologic agent in human disease are warranted.
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PMID:Toxicology of deoxynivalenol (vomitoxin). 863 56

Studies were conducted to determine the dietary amounts of deoxynivalenol (DON; vomitoxin) in dog and cat food that are required to produce overt signs of toxicity (e.g., vomiting or reduced food intake). Wheat naturally contaminated with 37 mg of DON/kg was used to manufacture pet foods containing 0, 1, 2, 4, 6, 8, and 10 mg of DON/kg. Deoxynivalenol concentration in pet food following manufacture was unchanged, indicating that the toxin was stable during conventional extrusion processing. Dogs previously fed DON-contaminated food were able to preferentially select uncontaminated food. Dogs not previously exposed to DON-contaminated food consumed equal quantities of contaminated and uncontaminated food. There was no effect of 6 mg of DON/kg on dog food digestibility. Food intake of dogs was significantly reduced by DON concentrations greater than 4.5 +/- 1.7 mg/kg, and DON greater than 7.7 +/- 1.1 mg/kg reduced cat food intake. Vomiting by dogs and cats was commonly observed at the 8 and 10 mg DON levels.
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PMID:Overt signs of toxicity to dogs and cats of dietary deoxynivalenol. 1022 66


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