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)

Abecarnil (ZK 112119; isopropyl-6-benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylate), a novel beta-carboline with high affinity for central benzodiazepine (BZ) receptors, has been shown recently to be a potent anxiolytic and anticonvulsant in animal models whereas lacking ataxia-producing effects, a profile typical for a partial agonist at BZ receptors. In the present study abecarnil was tested in dogs after acute and chronic administration. Pharmacokinetic studies showed that abecarnil was eliminated rapidly after i.v. or p.o. administration, but elimination was delayed substantially after s.c. injection. After i.v. injection, the drug penetrated rapidly into the cerebrospinal fluid, but maximum concentrations reached in cerebrospinal fluid were only 6 to 8% of those in plasma. Anticonvulsant potency of abecarnil in dogs was studied by means of seizures induced by i.v. infusion of pentylenetetrazol. After i.v. administration of single doses, abecarnil was about half as potent as diazepam, dose-dependently increasing the pentylenetetrazol threshold by doses of 0.1-1 mg/kg. In contrast to diazepam, most dogs injected with abecarnil at anticonvulsant doses showed no ataxia. During chronic s.c. administration of abecarnil for 6 weeks, the anticonvulsant efficacy of the drug increased markedly during the first week(s) of treatment, possibly indicating drug accumulation in the brain. During the subsequent weeks of treatment, there was a slight reduction in anticonvulsant potency. No withdrawal symptoms were observed after cessation of the 6-week administration period. Furthermore, injection of the BZ antagonist Ro 15-1788 (flumazenil), 1 mg/kg i.v., after 5 weeks of treatment did not precipitate withdrawal symptoms except slight tremor in two of seven dogs studied.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pharmacokinetics, anticonvulsant efficacy and adverse effects of the beta-carboline abecarnil, a novel ligand for benzodiazepine receptors, after acute and chronic administration in dogs. 197 30

Development of novel antiepileptic drugs (AEDs) requires determining the margin between the desired anticonvulsant effect and undesired adverse effects (AE) (therapeutic index). For this purpose, drug-induced "minimal neurological deficits" (e.g., motor dysfunctions) are commonly quantified by simple tests, such as the rotarod test, in normal, i.e., nonepileptic animals. However, increasing evidence shows that chronic brain dysfunction associated with epilepsy may increase susceptibility to the AE of certain AEDs, e.g., N-methyl-D-aspartate (NMDA) receptor antagonists. The increased AE potential of such investigational drugs can be predicted by using kindled rats instead of normal rodents in preclinical drug evaluation studies. In the present experiments, we wished to determine whether kindled rats also exhibit an altered susceptibility to neurological adverse effects of standard AEDs, i.e., carbamazepine (CBZ), phenobarbital (PB), valproate (VPA), and diazepam (DZP). Abecarnil, a novel benzodiazepine (BZD) receptor agonist, was included in the study for comparison. All drugs were administered in diverse doses in kindled and nonkindled rats, and all behavioral alterations were scored in the cage and open field. Furthermore, the rotarod test was used to detect and quantify motor impairment induced by drug treatments. Kindled rats were more susceptible than nonkindled rats to motor impairment (ataxia and/or rotarod failures) induced by high doses of AEDs, although differences were noted between the drugs tested. VPA was the only drug that induced stereotyped behavior; it was much more potent in this respect in kindled than nonkindled rats. Abecarnil did not differ substantially in its AE in either subgroup of animals. Our data indicate that epileptogenesis induced by kindling renders the brain more susceptible to certain AE of AEDs.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Kindling increases the sensitivity of rats to adverse effects of certain antiepileptic drugs. 763 95

The experiments in this study compared the pharmacological properties of several BZ-omega receptor ligands, including the imidazobenzodiazepine imidazenil, the beta-carboline abecarnil, the pyridazinone Y-23684, the pyrido [1,2-a]benzimidazole RWJ 46771 and the 1,6-naphthyridin-2(1H)-one derivative SX-3228, with the prototypical BZs diazepam, clobazam and bretazenil. In in vitro experiments diazepam, bretazenil, imidazenil and Y-23684 displaced [3H]flumazenil binding non-selectively in membranes from rat cerebellum and spinal cord, two brain areas enriched in the BZ-omega 1 and BZ-omega 2 receptor subtypes, respectively. In contrast, abecarnil, RWJ 46771 and SX-3228 were more potent in displacing [3H]flumazenil binding to membranes from rat cerebellum than from spinal cord or hippocampus, indicating selectivity for the BZ-omega 1 receptor subtype. The in vivo experiments showed that all compounds increased the latency to clonic seizures produced by isoniazid. However, the maximal increase in latency induced by diazepam, clobazam, abecarnil, RWJ 46771 and SX-3228 was greater than that of bretazenil, imidazenil and Y-23684, thereby indicating that these latter compounds have low intrinsic efficacy. In the punished drinking, the punished lever pressing and the elevated plus-maze tests in rats, three models of anxiety, diazepam, clobazam and imidazenil elicited clear anxiolytic-like effects but at doses which were close to those producing hypolocomotion, ataxia and myorelaxation as measured in activity cages, the rotarod and the loaded grid tests, respectively. In contrast, bretazenil and Y-23684 induced anxiolytic-like activity at much lower doses than those which impaired motor performances. The magnitude of the positive effects of Y-23684 was similar to that of the reference BZs, suggesting that it may become a valuable alternative to currently used agents for the treatment of anxiety disorders. Abecarnil, RWJ 46771 and SX-3228 produced weaker or non-specific anxiolytic-like effects as they decreased anxiety-related behaviours at doses similar or close to those impairing motor performance. However, unlike the other compounds they induced myorelaxation at doses which were 3-10 times higher than those needed to produce decrease in exploratory activity. It is suggested that the behavioural profiles of abecarnil, RWJ 46771 and SX-3228 may be attributed to their selectivity for the BZ-omega 1 receptor subtype which may account for their sedative activity, thereby masking other effects including anxiolytic-like activity. This suggests that BZ receptor modulation of anxiety may involve BZ receptor subtypes other than BZ-omega 1.
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PMID:Comparison of the pharmacological properties of classical and novel BZ-omega receptor ligands. 1078 Feb 55