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)

Brotizolam (2-bromo-4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f]-1,2,4-triazolo [4,3-a]-1,4-diazepine, We 941, Lendormin) is a thienotriazolo-diazepine with profound sedative and hypnogenic properties. The side effects of the drug on general behavior, motocoordination, feeding pattern, body temperature, uropoietic and gastrointestinal functions, cardiovascular system, and respiration, as well as interactions with some biogenic amines are reported and discussed. The findings correlate with those known for other diazepines. Accordingly, effects on motocoordination were prominent, but were limited to an ataxia, whereas even extremely high doses scarcely eliminated the postural reflexes. Sleeping animals could invariably be woken and were capable of locomotion; thus, no comatose condition developed. The cardiovascular functions were not appreciably altered by brotizolam in anesthetized cats, while in conscious dogs minor fluctuations of blood pressure and heart rate occurred. Respiration was clearly inhibited when brotizolam was given intravenously. The cardiovascular effects of acetylcholine, norepinephrine, epinephrine, isoprenaline, and histamine were only slightly modulated. The orexigenic and hypothermic effects equalled those of other diazepines. The functions of kidney, stomach, and intestines were not affected. The entirety of the observations procured in ten different species suggest that brotizolam is well tolerated when given orally.
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PMID:General pharmacology of brotizolam in animals. 371 76

Brotizolam (2-bromo-4-(2-chlorophenyl)-9-methyl-6H-thieno [3,2-f]-1,2,4-triazolo[4,3-a]-1,4-diazepine, We 941, Lendormin), a new hypnotic, was submitted to a comprehensive range of safety assessment tests. Acute (single dose) toxicity was very low, while in subacute and chronic studies in rodents, signs of toxicity were first seen at doses of 400 mg/kg or more. Histopathological changes were only seen in the 1 1/2-year study. Ataxia, salivation, and diarrhea were observed in a 4-week intravenous study in dogs, and ataxia, increased feed intake, muscular spasms, increased liver weight, and lipid depletion of the adrenal cortex in two oral studies in monkeys. Reproductive studies in the rat and the rabbit revealed no disturbances in fertility, nor were any embryotoxic or teratogenic effects detected in doses of up to 30 mg/kg. Only at 400 mg/kg was litter mortality increased. Local tolerance tests in rabbits indicated good compatibility of brotizolam when administered intramuscularly, intra-arterially, or intravenously. No signs of any genotoxic action could be detected. A carcinogenicity study in mice showed no evidence of any oncogenic effect, while in rats, although the incidence of certain tumors appeared somewhat higher in the high-dose group, this could be explained by the range of biological variation within the strain, a possible modulating effect on the immune system due to the stress of a very high dose, and a functional effect on the thyroid. These studies thus demonstrate that brotizolam has a remarkably wide therapeutic range.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Safety assessment of brotizolam. 371 82

The photopalpebral reflex (PPR) is a useful method to assess level of arousal. Healthy males were given either brotizolam (0.0625, 0.125, 0.25 or 0.5 mg) or placebo within a double-blind, crossover design. Changes in PPR and subjective assessments were observed for 5 h after medication. Prolongation of the latencies of PPR were dose dependent, and the amplitude tended to be reduced. These effects appeared within 30 min, and lasted about 4 h. The dose-response curve of the maximum prolongation of the latencies was linear. Sleepiness and slight ataxia were observed after drug ingestion. Sleepiness was correlated with the prolongation of the PPR latencies. Brotizolam could be a potent hypnotic, with rapid onset and moderate duration of action, and it has no severe side-effects.
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PMID:Effect of brotizolam on the averaged photopalpebral reflex in man. 666 78

Acute studies. Following oral or intraperitoneal administration, toxicity was very low (LD50 in rodents greater than 10,000 and greater than 900 mg/kg, respectively). Subacute and chronic studies in rodents. Signs of toxicity were seen only at doses of 400 mg/kg or more. Histopathological changes were found only in the 78-week study. Subacute studies in dogs (intravenous) and primates (oral). In dogs, doses of 0.1 and 0.3 mg/kg produced ataxia, salivation, and diarrhoea. In monkeys doses of 7 mg/kg or higher produced ataxia, increased appetite, hyperreflexive muscular spasms, increase in liver weight, and lipid depletion of the adrenal cortex. Reproductive studies in the rat and rabbit. Repeated doses of up to 30 mg/kg were not associated with any disturbance in fertility; nor were any embryotoxic or teratogenic effects observed. When dams wer treated with 400 mg/kg, litter mortality was markedly increased. Mutagenicity studies. The four different tests performed gave no indication of any mutagenic effect. Local tolerance tests in the rabbit. Brotizolam was well tolerated when administered intramuscularly, intra-arterially, or intravenously. Carcinogenicity studies in rodents. The mouse study showed no evidence of a tumourigenic effect. The rat study is still being evaluated. The toxicological studies demonstrate that brotizolam has an unusually wide therapeutic range. Findings of toxicological significance, most of which were reversible, were first recorded at doses of 7-10 mg/kg, i.e. at more than 100-times the intended human therapeutic dose.
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PMID:The toxicology of brotizolam. 668 62