Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of the benzodiazepine (BZ) receptor antagonists flumazenil (Ro 15-1788) and the beta-carboline ZK 93426 were compared in dogs before and after chronic treatment with diazepam or the novel BZ receptor ligand abecarnil (ZK 112119). Abecarnil, a beta-carboline, is thought to act as partial (low efficacy) and/or subtype selective agonist at central BZ receptors. Diazepam and abecarnil were administered at doses which, based on previous experiments on anticonvulsant activity, resulted in about equieffective drug concentrations during treatment. In dogs treated with diazepam, 6 mg/kg/day p.o., for 2 weeks, severe abstinence symptoms, including seizures, were precipitated in all animals by i.v. infusion of the BZ receptor antagonists, differences being found in the type of symptoms caused by flumazenil and ZK 93426. In dogs treated with abecarnil, 4 mg/kg/d s.c., for 6 weeks, only relatively mild abstinence symptoms were precipitated by infusion of flumazenil or ZK 93426, although pharmacologically active plasma concentrations of abecarnil had been maintained throughout the period of treatment. This suggests that BZ receptor ligands which act as partial and/or selective agonists might be more favourable than traditional agonists, such as diazepam, regarding the induction of physical dependence.
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PMID:Withdrawal precipitation by benzodiazepine receptor antagonists in dogs chronically treated with diazepam or the novel anxiolytic and anticonvulsant beta-carboline abecarnil. 135 84

Abecarnil, a beta-carboline acting at benzodiazepine receptors, has been shown to have anxiolytic and anticonvulsant properties in a number of models. It has reduced muscle relaxant and incoordinating effects in comparison to diazepam. Given the wide clinical application of diazepam to prevent alcohol withdrawal seizures, a genetic animal model was employed to compare abecarnil with diazepam for its anti-withdrawal effects. Withdrawal Seizure Prone (WSP) mice, genetically selected to develop severe handling-induced convulsions after withdrawal from chronic ethanol treatment, were exposed to ethanol vapor for 24 h. WSP mice given doses of abecarnil or diazepam at the peak of withdrawal had significantly reduced handling-induced convulsion scores. While abecarnil was slightly more potent than diazepam, its effects were shorter-lasting. Similar results were seen in an experiment where withdrawal handling-induced convulsions were assessed after a single high-dose ethanol injection. Abecarnil and diazepam also reduced the smaller handling-induced convulsion scores seen in naive WSP mice. Single doses of abecarnil or diazepam did not lead to a rebound elevation of handling-induced convulsion scores suggestive of a withdrawal reaction.
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PMID:Antagonism of ethanol withdrawal convulsions in Withdrawal Seizure Prone mice by diazepam and abecarnil. 136 Sep 3

Abecarnil (ZK 112119; isopropyl-6-benzyloxy-4-methoxymethyl-beta-carboxylate) is a metabolically stable beta-carboline derivative with potent anxiolytic and few sedative and ataxic effects in rodents. The anticonvulsant and muscle relaxant actions of abecarnil have been evaluated in mice, rats, gerbils and baboons. Abecarnil raised the threshold for tonic electroconvulsions in mice after corneal but not after auricular application, had no effect on maximal electroshock-induced tonic convulsions triggered by either method, protected mice against the tonic hindlimb extension in PTZ-, picrotoxin- and 3-mercaptopropionate-induced seizures and blocked clonus after PTZ, DMCM (methyl-4-ethyl-6,7-dimethoxy-9H-pyrido-(3,4-b)-indol-3-carboxylate) and 3-mercaptopropionate. Abecarnil had no effect on convulsions induced by bicuculline and strychnine. Furthermore, abecarnil blocked kindled seizures after chronic administration of PTZ and FG 7142 (beta-carboline-3-carboxylic acid methylamide) and protected mice and rats against limbic convulsions induced by pilocarpine. Severity and afterdischarge duration of amygdala-kindled seizures were reduced in rats treated with abecarnil. Abecarnil also antagonized selectively convulsions induced by i.c.v. administration of kainate, but not those triggered by N-methyl-D-aspartate or quisqualate. In genetic models of reflex epilepsy, abecarnil was effective against sound-induced convulsions in DBA/2 mice, against air blast-induced generalized seizures in gerbils and against myoclonus in baboons Papio papio. The anticonvulsant effect of abecornil in a PTZ seizure model in mice was potentiated by ethosuximide, whereas no significant potentiation was found with diazepam, clonazepam, diphenylhydantoin, carbamazepine and phenobarbital. Electromyographic monitoring in a etorphine model of muscle rigidity in rats showed no or little muscle relaxant effect of abecarnil.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Anticonvulsant action of the beta-carboline abecarnil: studies in rodents and baboon, Papio papio. 197 Mar 62

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

Abecarnil, a novel beta-carboline anxiolytic, has been shown to possess potent anxiolytic and anticonvulsant activities with weak or no sedative and ataxic effects in relevant animal models. In the present study, anxiolytic, anticonvulsant and amnesic effects of abecarnil after single and repeated treatments in rats were compared with those of diazepam. Both abecarnil (0.52-10 mg/kg, p.o.) and diazepam (20 and 50 mg/kg, p.o.) exhibited significant anticonflict effects in the water-lick test. Neither abecarnil (5 mg/kg, p.o.) nor diazepam (50 mg/kg, p.o.) produced any tolerance to anticonflict effects after 14 days of repeated treatment. Both abecarnil (5-50 mg/kg, p.o.) and diazepam (20 and 50 mg/kg, p.o.) exhibited significant anticonvulsant effects against pentylenetetrazol-induced seizure. The anticonvulsant effects of abecarnil (5 mg/kg, p.o.) were not attenuated during 14 days of repeated treatment, but diazepam (20 and 50 mg/kg, p.o.) produced tolerance to anticonvulsant effects after 5 days of repeated treatment. In the three-panel runway task, abecarnil at 5 mg/kg, p.o. impaired only working memory, but diazepam at 20 mg/kg, p.o. impaired working memory and at 50 mg/kg, p.o. markedly impaired reference and working memories. The amnesic effects of abecarnil disappeared rapidly within 2 to 3 days of repeated treatment, whereas that of diazepam decreased rapidly but persisted during 14 days of repeated treatment. Thus, chronic abecarnil was found to exhibit persistent anxiolytic and anticonvulsant effects without any amnesic effects, in contrast to chronic diazepam.
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PMID:Chronic pharmacological activities of the novel anxiolytic beta-carboline abecarnil in rats. 791 Feb 8

Abecarnil (isopropyl-6-benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylate) is a metabolically stable anxiolytic and anticonvulsant beta-carboline derivative with few sedative and muscle relaxant effects in rodents. Abecamil binds with high affinity to benzodiazepine receptors. Because long-term treatment with benzodiazepines leads to development of dependence, we evaluated in mice whether abecarnil also possesses a potential for producing dependence, using electroencephalographic and electromyographic monitoring, and behavioral assessment of anxiety to detect withdrawal responses after chronic treatment. Diazepam was used as a reference. Mice withdrawn from chronic treatment with diazepam (15 mg/kg/day for 12 days) showed a time-related evolution of anxiety, muscle rigidity and seizures between days 4 and 21 after discontinuation of the treatment. A period between withdrawal days 1 and 3 was symptom free. Mice withdrawn from chronic administration of abecarnil (6 mg/kg/day for 12 days) showed no anxiety and no changes in seizure susceptibility and muscle tone. The doses of diazepam and abecarnil used for chronic treatment were equivalent in terms of kinetics and binding to benzodiazepine receptors. These data indicate that long-term treatment with abecarnil does not induce benzodiazepine-like dependence in mice. Thus, it may be predicted that chronic treatment with abecarnil in humans may offer an important alternative to benzodiazepines in the treatment of anxiety.
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PMID:Long-term treatment with abecarnil does not induce diazepam-like dependence in mice. 809 51

The role of gamma-aminobutyric acid (GABA) modulation of septohippocampal cholinergic neurons in kindling was investigated. Hippocampal acetylcholine release was evaluated with the microdialysis technique in freely moving rats either after acute administration of isoniazid (an inhibitor of GABA synthesis) or pentylenetetrazole (PTZ) (a blocker of the GABAA receptor-associated Cl- channel) or after chronic administration of PTZ. Short-term treatment with PTZ (5-50 mg/kg, i.p.) or isoniazid (150-250 mg/kg, s.c.) increased hippocampal acetylcholine release in a dose-dependent manner. In contrast, the basal concentration of acetylcholine in the dialysate from the hippocampus of rats chronically treated with PTZ (kindled animals) was significantly reduced relative to that of vehicle-treated rats (2.39 +/- 0.21 vs. 4.2 +/- 0.31 pmol per 20-min sample; p < 0.01). Moreover, the release of acetylcholine was markedly more sensitive to the effect of a challenge injection of PTZ (10 or 20 mg/kg, i.p.) in kindled rats than in naive rats or rats chronically treated with vehicle. Abecarnil, a selective benzodiazepine receptor agonist with marked anticonvulsant activity, was administered together with chronic PTZ to evaluate whether persistent activation of GABAA receptors and suppression of seizures during kindling might affect the sensitivity of septohippocampal cholinergic neurons to a challenge dose of PTZ. Abecarnil (1 mg/kg, i.p.) administered 40 min before each PTZ injection neither antagonized the decrease in basal acetylcholine release (2.26 +/- 0.19 pmol per 20-min sample) nor prevented the development of kindling. In contrast, abecarnil prevented the chronic PTZ-induced increase in the sensitivity of acetylcholine release to a challenge dose of PTZ. These results provide novel in vivo data concerning the role of hippocampal acetylcholine function in the development of kindling and potentially in the learning and memory deficits associated with this phenomenon.
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PMID:Effect of pentylenetetrazole-induced kindling on acetylcholine release in the hippocampus of freely moving rats. 897 40

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

Benzodiazepines (BZDs) are highly effective to suppress various types of seizures; however, their clinical use is limited due to adverse effects and tolerance and dependence liability. Drugs that act only as partial agonists at the BZD recognition site (initially termed "BZD receptor") of the GABAA receptor chloride ionophore complex or exhibit a GABAA receptor subtype-selectivity are thought to have advantages vs. full agonists such as diazepam and most other clinically used BZDs in that such compounds have less adverse effects and reduced or absent tolerance and dependence liability. One of such compounds, abecarnil, has been clinically evaluated as a novel anxiolytic drug, but, despite its potent preclinical anti-seizure activity, it has not yet been evaluated in patients with epilepsy. In the present proof-of-concept study, we performed a within-subject placebo-controlled, single oral dose study of abecarnil in patients with photosensitive epilepsy. Flumazenil, which is generally considered a BZD receptor antagonist, but has slight partial agonistic properties, was used for comparison. In total, 12 patients were enrolled in this study. Abecarnil, 5 or 10mg, completely abolished the photo-paroxysmal EEG response, while flumazenil, 30, 60 or 100mg, was less effective. The anti-epileptic effect of abecarnil was significantly different from both placebo and flumazenil. Sedative adverse effects were observed after abecarnil but not flumazenil. The study substantiates previous pre-clinical experiments that abecarnil exerts pronounced anti-seizure activity. Epilepsy is often associated with anxiety, so that the anxiolytic activity of abecarnil would be an added advantage when using this compound in epilepsy patients.
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PMID:Single dose efficacy evaluation of two partial benzodiazepine receptor agonists in photosensitive epilepsy patients: A placebo-controlled pilot study. 2692 54