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

The partial agonist at benzodiazepine receptors, Ro 19-8022, has been characterized as a putative anxiolytic drug with an improved side effect profile. This orally active compound is a representative of a quinolizinone structure class and shows potent anticonflict activity in mice and rats. It protects rodents from convulsions induced by pentylenetetrazol, N-methyl-D-aspartic acid and maximal electroshock, as well as against audiogenic seizures, with an efficacy comparable to that of the full agonist alprazolam. No appreciable sedative or motor-impairing effects could be detected up to a very high dose (100 mg/kg) in the horizontal wire test or the rotarod performance test in mice and rats and in spontaneous behavior in monkeys. Consistent with its characterization as a partial agonist, Ro 19-8022 antagonized the motor impairment induced by the full agonists diazepam or meclonazepam measured in horizontal wire and rotarod tests in rodents, and reduced flunitrazepam-induced effects in squirrel monkeys, with an efficacy comparable to that of the benzodiazepine receptor antagonist flumazenil. After subchronic administration of Ro 19-8022 to mice, antagonist-precipitated withdrawal syndrome was dramatically weaker than after alprazolam treatment, which is indicative of a lower physical dependence liability of Ro 19-8022. Pharmacodynamic effects recorded in convulsion and reversal of motor impairment tests after i.v. administration suggest a long duration of action of this compound. Taken together, such preclinical data suggest that benzodiazepine receptor partial agonists with a neurological and behavioral profile such as that of Ro 19-8022 may offer an innovative therapeutic approach to the treatment of anxiety disorders.
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PMID:Ro 19-8022, a nonbenzodiazepine partial agonist at benzodiazepine receptors: neuropharmacological profile of a potential anxiolytic. 135 50

Male Wistar rats were subjected to repeated weekly episodes of 2 days severe alcohol intoxication (intragastric intubation) and 5 days of withdrawal. In half of the animals the withdrawal reaction was attenuated during the first nine weekly episodes by intragastric intubations with phenobarbital. During episodes 10-14 both phenobarbital treated and phenobarbital untreated animals were allowed to develop a withdrawal reaction; all animals were video-recorded during withdrawal and the records were rated blindly for the occurrence of convulsive seizures. The results were analyzed by step-wise logistic analysis of regression including phenobarbital treatment, alcohol dose and intoxication score as explanatory variables for the occurrence of convulsive seizures. The animals that had been in withdrawal during all episodes developed significantly more convulsive seizures compared with animals that had their first nine withdrawal episodes attenuated by phenobarbital. The development of withdrawal seizures depended on repeated episodes of withdrawal, whereas repeated alcohol intoxication per se did not explain the development of seizures. There were no differences between the groups in the severity of the non-convulsive signs of alcohol withdrawal. Thus the development of seizures and the non-convulsive signs of alcohol withdrawal may result from two pathogenetically different mechanisms: 1) seizures from a cumulative kindling-like effect over long time periods and 2) physical signs of alcohol withdrawal may reflect the degree of physical dependence during the most recent drinking bout.
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PMID:Convulsive behaviour during alcohol dependence: discrimination between the role of intoxication and withdrawal. 158 67

We have developed a model of benzodiazepine-type physical dependence in which mice were injected subcutaneously with the test compound on a fixed schedule (0800 and 1600 for 3 days, the PM dose = AM dose x 2). If tolerated, then a starting dose of 150 mg/kg/day was generally used initially and the dose was lowered to 15 and 1.5 mg/kg/day in subsequent assays if the higher doses were active in the test. Twenty-four hours after the last dose, the mice received an intravenous injection of flumazenil (2.5 mg/kg), and 5 min later they were tested for electroshock seizure thresholds by an up-down titration method. Flumazenil-precipitated withdrawal was manifested by a lowering of the mA seizure threshold. We have found that compounds with benzodiazepine agonist properties significantly lower these thresholds in a dose-related fashion. For example, the following compounds (lowest effective mg/kg/day dose) were active in this regard, chlordiazepoxide (150), diazepam (15), flurazepam (15), alprazolam (15), triazolam (15), midazolam (15), zopiclone (150), Ro 16-6028 (150), and Ro 17-1812 (150). In contrast, zolpidem (150), tracazolate (15), and CL 218872 (15) did not cause physical dependence by this criterion. This rapid and simple screening test may be readily used to predict the physical-dependence-inducing properties of compounds that act at the benzodiazepine receptor.
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PMID:A rapid screening method for the assessment of benzodiazepine receptor-related physical dependence in mice. Evaluation of benzodiazepine-related agonists and partial agonists. 168 Nov 36

Halazepam administered chronically to dogs in oral doses of 180 and 450 mg/kg/day produced physical dependence which was revealed by a flumazenil precipitated abstinence syndrome and measured by the Nordiazepam Precipitated Abstinence Scale score (NPAS) (McNicholas et al., 1988; Sloan et al., 1990). This abstinence as measured by the NPAS score was more severe in diazepam- and halazepam-dependent than in nordiazepam-dependent dogs whereas the incidence of precipitated clonic seizures was greater in the diazepam- and nordiazepam-dependent than in the halazepam-dependent dogs. Pharmacokinetic studies showed that in the dog the major conversion of halazepam, like diazepam, was to nordiazepam and an oxazepam conjugate. Appreciable quantities of oxazepam, 3-OH halazepam and its conjugated metabolite were also identified in plasma. The NPAS score obtained in the halazepam-dependent dogs, however, was greater than the NPAS score obtained in nordiazepam-dependent dogs who had nordiazepam plasma levels over three times higher than those obtained in the halazepam-dependent dogs. Further, the precipitated abstinence observed in the halazepam-, diazepam- and nordiazepam-dependent dogs differed in qualitative as well as in quantitative aspects including marked differences in the time course of abstinence signs. These data argue that the different dependencies produced by halazepam, diazepam and nordiazepam are not due solely to either the parent compound or to a single metabolite but most likely to their combined effects.
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PMID:Chronic administration of and dependence on halazepam, diazepam, and nordiazepam in the dog. 168 20

Concern about physical dependence seems to be the major limiting factor in the long-term treatment with benzodiazepines (BZD). The severity of the withdrawal syndrome is determined by multiple factors, e.g. dose, duration of use, frequency of dose interval, mode of discontinuation, the pharmacologic characteristics of the BZD, personality and previous or concurrent use of cross-dependent drugs and/or alcohol. There is evidence that BZD with a short elimination half-life cause a more severe withdrawal syndrome than those with a long elimination half-life. Besides pharmacokinetic properties, pharmacodynamic factors such as potency may also covary with the liability of a BZD to induce physical dependence. There is an increasing body of literature indicating that quickly eliminated, high potency BZD such as alprazolam and lorazepam may be more likely to cause severe withdrawal reactions than slowly eliminated compounds such as diazepam or less potent derivatives such as oxazepam. Alprazolam seems to play an exceptional role, insofar as relatively soon after its introduction to the market a number of case reports of withdrawal psychoses, seizures and intense rebound anxiety were published. Data reviewed from the literature correspond well with the results of interviews conducted with 31 clinicians across the United States with experience in detoxifying patients dependent on BZD, 84% of these physicians mentioning alprazolam as especially problematic with respect to the intensity and/or duration of the withdrawal syndrome.
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PMID:Physical dependence on benzodiazepines: differences within the class. 168 52

The functional state of GABAA receptors during physical dependence on ethanol was evaluated in two ways. First, the ability of ethanol dependence to change the convulsant potency of GABAA antagonists microinjected into the inferior colliculus was examined. A second approach evaluated the effects of ethanol dependence on the ability of muscimol or pentobarbital to stimulate chloride uptake in rat brain vesicles. In the studies examining changes in convulsant potency, bilateral microinfusions of GABAA antagonists, bicuculline methiodide and picrotoxinin, as well as the excitatory amino acid agonist, kainic acid (used as a positive control) induced similar dose-related increases in the frequency of wild-running seizures. Ethanol dependence did not significantly change susceptibility to wild-running seizure induction by an of the convulsants, although susceptibility to the more severe, clonic seizures was significantly increased for each convulsant. This suggested that the receptor-blocking effects of GABAA antagonists responsible for inducing wild-running seizures were not selectively increased by ethanol dependence, but that spread of seizure activity responsible for clonic seizures following the initiation of wild running was generally increased. Finally, in studies examining changes in GABAA receptor-mediated chloride uptake, both muscimol and pentobarbital were found to induce concentration-dependent increases in chloride uptake in rat brain vesicles. However, responses to these drugs were not reduced by ethanol dependence suggesting that a generalized adaptive decrease in GABAA receptor function was unlikely. Together these results do not provide support for the hypothesis that the GABAA receptor-chloride channel complex is down-regulated during the development of physical dependence on ethanol.
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PMID:Effect of ethanol dependence on GABAA antagonist-induced seizures and agonist-stimulated chloride uptake. 178 22

Dogs dosed chronically (4-7 weeks) with oral flunitrazepam (7.6 mg/kg/day) or diazepam (24-36 mg/kg/day) administered in 4 equally divided doses had dose-related flumazenil precipitated benzodiazepine abstinence scale scores (BPAS) of comparable intensities despite the fact that plasma levels of flunitrazepam and its metabolites were much lower than nordiazepam levels in the diazepam-dependent dog. Both groups of dependent dogs had clonic and tonic-clonic seizures after oral and IV flumazenil. Precipitated abstinence signs persisted longer in the diazepam than in the flunitrazepam-dependent dogs. Differences in the pharmacokinetics of the drugs of dependence, their metabolites, and their interactions at receptor sites offer a partial explanation for the high level of dependence seen in the flunitrazepam dog. The finding that the estimated plasma free concentration of flunitrazepam and its metabolites is equal to or greater than that of diazepam and its metabolites together with the fact that flunitrazepam has a higher affinity for the benzodiazepine receptor than either diazepam, nordiazepam or oxazepam can explain why the intensity of the precipitated abstinence syndrome is comparable in flunitrazepam- and diazepam-dependent dogs. Although the flumazenil-induced precipitated abstinence syndromes observed in flunitrazepam- and diazepam-dependent dogs differed qualitatively they did not differ quantitatively. It is therefore concluded from these data that the doses of flunitrazepam and diazepam, chosen for producing comparable degrees of weight loss during dose escalation, did not differ in the degree of physical dependence that they produced in the dog.
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PMID:A comparison of the physical dependence inducing properties of flunitrazepam and diazepam. 194 80

A model for the development of pentobarbital tolerance and dependence was characterized and correlated with changes in radioligand binding to the GABAA-benzodiazepine receptor chloride channel complex. While one day of pentobarbital exposure decreased the duration of loss of righting reflex, tolerance to the hypothermic effects of thiopental and barbital took 7 days to develop, indicating that pharmacokinetic and pharmacodynamic tolerance are separable. Increased sensitivity to pentylenetetrazol-induced seizures was first observed after 3 days of pentobarbital exposure, suggesting brain areas involved in seizure control develop tolerance to, and dependence on pentobarbital faster than those involved in temperature regulation. Acute exposure to pentobarbital in vivo did not affect cortical binding of [3H]muscimol in vitro, while tolerance caused a decrease in binding due to an increase in the low-affinity site KD. Pentobarbital tolerance also caused a decrease in the cortical binding of the benzodiazepine, [3H]flunitrazepam. These observations suggest that the acute effects of barbiturates on the GABAA receptor complex are reversible, while tolerance causes receptor modifications which may be related to the development of physical dependence.
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PMID:Pentobarbital tolerance and withdrawal: correlation with effects on the GABAA receptor. 196 22

Alprazolam (48 mg/kg/day) administered orally to dogs 4 times a day in equally divided doses produced physical dependence. This dependence was revealed by a precipitated abstinence syndrome which occurred after either oral administration of flumazenil (6, 18 and 36 mg/kg) or intravenous administration of a liposomal suspension of flumazenil. Flumazenil alone (18, 36 and 72 mg/kg) produced no significant signs of precipitated abstinence in naive dogs. This precipitated abstinence syndrome in alprazolam-dependent dogs was characterized by both clonic and tonic-clonic seizures. Other signs of precipitated abstinence which comprise the NPAS score were less intense in the alprazolam-dependent than in diazepam-dependent dogs. Alprazolam is extensively metabolized in the dog and does not accumulate whereas its predominant metabolite, alpha hydroxyalprazolam, does accumulate. The data suggest that alpha hydroxyalprazolam plays a role in the dependence-producing properties of alprazolam in the dog as revealed by the precipitated abstinence syndrome.
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PMID:Dependence-producing properties of alprazolam in the dog. 211 Oct 29


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