Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Studies were undertaken to define the subchronic toxicologic profile of ameltolide, an aminobenzamide anticonvulsant, in young adult rhesus monkeys. Daily doses of ameltolide, dissolved in 10% aqueous acacia, were administered orally via nasogastric intubation at dosages of 5, 10, 20, 45, and 100 mg/kg. Deaths occurred in two monkeys, one each at 45 and 100 mg/kg, which were directly attributable to the effects of the compound. The exact cause of death in these monkeys was not readily apparent. A third monkey (100 mg/kg) was killed moribund on Day 82 of the study due to conditions not directly related to treatment. Clinical signs in monkeys treated with 100 mg/kg included convulsions, diarrhea, weakness, inappetance, vomition, and ataxia. Plasma concentrations of the N-acetyl metabolite of ameltolide were greater than parent drug concentrations by one to two orders of magnitude. Mean area under the plasma-time curve (AUC) values for ameltolide were larger than expected at doses of 20 mg/kg or greater, while AUC values for the metabolite were less than expected at 45 and 100 mg/kg. These findings suggest a saturation of metabolism and/or excretion at the two higher doses. Similar nonlinearity was seen with mean peak concentrations for both parent and metabolite. No specific target organ toxicity was found on histological evaluation of tissue sections. Methemoglobin concentration was increased in monkeys given 45 or 100 mg ameltolide/kg. This change was not considered to be toxicologically important as there were no corroborative clinical, gross, or histopathological findings. Ameltolide administered by nasogastric intubation at doses up to 20 mg/kg/day for 3 months did not cause any toxicologically important alterations in rhesus monkeys.
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PMID:Subchronic toxicity, metabolism, and pharmacokinetics of the aminobenzamide anticonvulsant ameltolide (LY201116) in rhesus monkeys. 151 75

LY201116 [4-amino-N-(2,6-dimethylphenyl)benzamide], an effective anticonvulsant in several animal models, is rapidly metabolized by N-acetylation in rats, mice and monkeys. In an attempt to preclude metabolic N-acetylation sterically, we investigated LY201409, an analogue possessing two methyl groups ortho to the 4-amino substituent. This structural modification successfully altered the metabolic pathway, and LY201409 displayed potent anticonvulsant activity. LY201409 antagonized maximal electroshock (MES)-induced seizures with ED50 values of 16.2 and 4.2 mg/kg after oral administration to mice and rats, respectively. The compound did not effectively antagonize seizures induced by a variety of chemical convulsants in rats, but did block pentylenetetrazol-induced seizures in mice. Thus, among the classic anticonvulsants, the profile of phenytoin most closely resembles that of LY201409. Studies conducted with the rotorod and horizontal screen assays in mice and behavioral studies in rats suggested that doses of LY201409 that produced CNS side-effects such as sedation or ataxia were well separated from the anti-MES doses. LY201409 was a potent, dose-dependent potentiator of hexobarbital-induced sleeping time in mice. Oral administration of 6.0 mg/kg led to a 372% increase in sleep time relative to control values. Although LY201409 is a potent and effective anticonvulsant, it is also one of the most potent potentiators of hexobarbital-induced sleep time yet described.
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PMID:Pharmacology of LY201409, a potent benzamide anticonvulsant. 319 92