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 relative contribution of different recognition sites within the GABAA receptor supramolecular complex (GRSC) to the pharmacological effects of anxiolytic and hypnotic drugs is unknown. The development of the omega 1 (ex BZ1) specific hypnotic zolpidem allows a more direct approach to the problem. In contrast to many benzodiazepine hypnotic/anxiolytics (e.g., flunitrazepam, diazepam), zolpidem shows a specificity for GABAergic function, e.g., selectively reversing isoniazide-induced seizures. Furthermore, zolpidem produces a highly specific hypnotic action as compared to myorelaxant or amnesic effects (ratio of ED50's greater than 4.0 for zolpidem; less than 1 for flunitrazepam). Zolpidem exerts its action within the GRSC as it enhances 35S-TBPS binding, as do mixed omega 1/omega 2 compounds or GABA agonists. Both the in vivo and in vitro actions of zolpidem are reversed by flumazenil and the enhanced 35S-TBPS binding is also bicuculline-sensitive. Thus, omega 1 recognition site stimulation (e.g., by zolpidem) is sufficient to produce potent pharmacological effects and modulation of the GABAA receptor-gated chloride ionophore.
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PMID:Specificity within the GABAA receptor supramolecular complex: a consideration of the new omega 1-receptor selective imidazopyridine hypnotic zolpidem. 284 10

One week oral flurazepam (FZP) administration in rats results in anticonvulsant tolerance in vivo, tolerance measured in vitro in hippocampal CA1 pyramidal cells, and regulation of hippocampal gamma-aminobutyric acid(A)-receptor subunit protein expression. A single injection (4 or 20 mg/kg i.p) of the benzodiazepine antagonist flumazenil (FLM) was given 1 day after FZP treatment, and tolerance and subunit protein expression were evaluated 1 day later. In vivo tolerance was measured by a reduced ability of the alpha(1)-subunit-selective agonist zolpidem to suppress pentylenetetrazole-induced seizures. This tolerance was reversed by 20 but not 4 mg/kg FLM. In in vitro hippocampal slices, there was tolerance to the effect of zolpidem to prolong the decay of pyramidal cell miniature inhibitory postsynaptic currents, which was reversed by FLM (4 mg/kg) pretreatment. A reduction in miniature inhibitory postsynaptic current amplitude ( approximately 50%) was also restored by FLM injection. [(3)H]Zolpidem binding measured 0, 2, and 7 days after FZP treatment was significantly decreased in the hippocampus and cortex at 0 days but not thereafter. Changes in alpha(1)- and beta(3)-subunit protein expression were examined via quantitative immunohistochemical techniques. alpha(1)-Subunit protein levels were down-regulated in the CA1 stratum oriens and beta subunit levels were up-regulated in the stratum oriens and stratum radiatum of the CA3 region. Chronic FZP effects on alpha(1)- and beta(3)-subunit protein levels were also reversed by prior FLM injection. FLM's effect on both functional and structural correlates of benzodiazepine tolerance suggests that each of these measures plays an interdependent role in mediating benzodiazepine tolerance.
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PMID:Antagonist-induced reversal of functional and structural measures of hippocampal benzodiazepine tolerance. 1056 8

(1) Loss of efficacy can occur after a few weeks of treatment with zolpidem and zopiclone. This is not a reason to increase the dose. (2) Zolpidem and zopiclone carry a risk of dependence and of potentially severe disorders (e.g. seizures) during withdrawal. (3) The risk-benefit ratio of benzodiazepines and related drugs (zopiclone and zolpidem) remains more favourable than that of other drugs used in insomnia. However, first-line treatment of sleep disorders should not necessarily be drug-based.
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PMID:Hypnotic dependence: zolpidem and zopiclone too. 1150 51

Zolpidem is a sedative and hypnotic drug belonging to imidazopyridine family. Zolpidem facilitates GABAA function more selectively than benzodiazepines, and produces a selective hypnotic effect. In comparison with benzodiazepines this mechanism could be reduce liability to induce dependence. Recently, some cases of zolpidem abuse and dependence have been published. The Authors report 2 cases of addiction to high dose of zolpidem and compare them with others described in the literature. Both patients had been reknown drug addicts before their first prescription of zolpidem and a borderline personality disorder was diagnosed. The patients rapidly developed over consumption and dependence of the molecule, when taking doses as high as 240 and 400 mg daily. To get zolpidem, one patient falsifies prescriptions. They don't suffer from the sedative effects while searching for anxiolytic and stimulating effects. They were also dysarthric, confused, high energy for mental and physical activity. The cases of zolpidem abuse and dependence in the literature describe these symptoms and others such as losing sense of orientation in time and space, amnesia and visual hallucinations. The most typical withdrawal symptom is high levels of anxiety. Moreover, one patient presents an epileptic seizure whereas the other display a severe psychiatric complication such a psychosis. In the literature, withdrawal was accompanied by confusion, suicidal ideas, nausea, vomiting, sweat, tremors, tachycardia and insomnia rebound. The epileptic seizures are described but acute psychosis complication is rare. Pharmacological hypotheses are described. The effects of zolpidem on GABAA receptor gene expression are consistent with the reduced tolerance liability of this drug as well as with other ability to induce both physical dependence and withdrawal syndrome. Through the review of the literature, the Authors noted that 50% of the cases of dependence on zolpidem are drug addicts, therefore concluding that drug addicts are more likely to become dependent on zolpidem.
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PMID:[Dependence on zolpidem: a report of two cases]. 1510 18

Zolpidem is a non-benzodiazepine hypnotic drug, acts selectively through omega 1 receptors of GABAA. It is thought to be safer than benzodiazepines but we report a case of zolpidem drug abuse, dependence and withdrawal seizure.
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PMID:Zolpidem at supratherapeutic doses can cause drug abuse, dependence and withdrawal seizure. 1584 35

Domestic Mongolian gerbils, a model of inherited epilepsy, begin having spontaneous seizures at approximately 1.5 mo of age, making it possible to evaluate them during epileptic and pre-epileptic stages. Previous studies have shown that GABA binding is reduced in the substantia nigra pars reticulata (SNr) of both epileptic and pre-epileptic gerbils compared with controls, suggesting that reduced expression of GABAA receptors in SNr might be epileptogenic in this model. To test this hypothesis, we measured the expression of the GABAA receptor alpha1 subunit, the dominant alpha subunit expressed in the SNr, and evaluated GABAA receptor-mediated postsynaptic currents in SNr neurons. GABA(A) alpha1 subunit mRNA levels in substantia nigra-rich tissue from pre-epileptic animals were similar to controls, and immunocytochemistry for the alpha1 subunit showed similar strong expression in the SNr in both groups. Western analysis confirmed that expression of the alpha1 subunit protein was similar in substantia nigra-rich tissue from pre-epileptic and control gerbils. The frequency and amplitude of spontaneous inhibitory postsynaptic currents (IPSCs) and the frequency of miniature (m)IPSCs in SNr neurons of pre-epileptic gerbil were similar to those of controls. The amplitude of mIPSCs in the pre-epileptics was significantly larger than controls. Zolpidem, an alpha1 subunit-specific modulator of the GABAA receptor, was equally efficacious in prolonging the decay time of mIPSCs in both groups. Hence, contrary to the predictions of the hypothesis, mRNA and protein expression levels of the major GABAA receptor alpha subunit were normal, and neurons of the SNr in pre-epileptic gerbils displayed normal or enhanced IPSC frequencies and amplitudes. Therefore reduced expression of GABAA receptors in SNr is not likely to be an epileptogenic mechanism in this model.
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PMID:GABAA receptor-mediated IPSCs and alpha1 subunit expression are not reduced in the substantia nigra pars reticulata of gerbils with inherited epilepsy. 1640 26

Zolpidem is chemically unrelated to classical benzodiazepines but has demonstrated relatively high affinity binding to the alpha(1) GABA(A) receptor. To assess pharmacodynamic and neurochemical effects of zolpidem, open-field behavior, pentylenetetrazole-induced seizure threshold and benzodiazepine receptor binding in vitro were evaluated in the same animal following a single dose of zolpidem. Zolpidem (2, 5 and 10 mg/kg), lorazepam (2 mg/kg) or vehicle was administered intraperitoneally in male CD-1 mice. Behavioral activity, assessed by three open-field parameters, was decreased following the two highest doses of zolpidem (5 and 10 mg/kg), and reached significance at the 10 mg/kg dose. Locomotor activity was also decreased significantly by lorazepam as expected. Pentylenetetrazole-induced seizure threshold was increased with the administration of 2 and 10 mg/kg zolpidem as well as with lorazepam. Apparent affinity (K(D)) of [3H]flunitrazepam, a non-selective ligand, for the benzodiazepine receptor in cortical membrane preparations was not significantly changed, while receptor number (Bmax) was decreased at all doses of zolpidem, reaching significance at the 10 mg/kg dose. These results confirm that the behavioral effects of zolpidem are similar to those of classical benzodiazepines. In addition, zolpidem had no significant effect on the affinity of the benzodiazepine receptor for [3H]flunitrazepam, but did decrease the density of receptor binding sites.
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PMID:Acute zolpidem administration produces pharmacodynamic and receptor occupancy changes at similar doses. 1643 7

Zolpidem is a short acting hypnotic drug belonging to imidazopyridine family. It produces its hypnotic effects via the GABA-A benzodiazepine receptor complex, and binds preferentially to those receptors containing the alpha-1 subunit. In comparison with benzodiazepines this mechanism is thought to reduce liability to induce dependence. Several case reports of zolpidem abuse and dependence have been published along with a small number of cases demonstrating seizures after sudden zolpidem withdrawal. We describe a case of a 29-year-old Caucasian woman who developed a generalized seizure following sudden zolpidem withdrawal subsequent to drug dependence to 160mg of zolpidem. The clinical effects of zolpidem seem to be comparable to those of benzodiazepines and abuse, dependence and withdrawal seizures belong to the spectrum of its adverse drug reactions.
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PMID:Seizure following sudden zolpidem withdrawal. 1695 May 52

To evaluate the possible age-related differences in the behavioral effects of zolpidem, a widely used hypnotic, we compared the effects of zolpidem on the locomotor activity and on the seizure threshold for pentylenetetrazole (PTZ) and picrotoxin (given by i.v. infusion) between adult (3 months) and aged (13 months) mice. Zolpidem (10 mg/kg) produced similar enhancements of the seizure threshold in adult and aged mice. The drug was more potent against PTZ- than against picrotoxin-induced seizures. Diazepam (1 mg/kg), which was taken for comparison, had a weaker effect on picrotoxin-induced tonic seizures in aged than in adult mice. Sedative effect of zolpidem (10 mg/kg), as assessed by its effect on the locomotor activity, was very strong in both groups of mice. The results suggest that sedative and antiseizure effects of zolpidem are not changed in aged mice.
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PMID:Sedative and anticonvulsant effects of zolpidem in adult and aged mice. 1821 89

Zolpidem and diazepam are widely used drugs acting via benzodiazepine binding sites on GABA(A) receptors. While diazepam is non-selective, zolpidem has a high affinity for alpha1-, and no affinity for alpha5-containing receptors. Several studies suggested that behavioral effects of zolpidem might be more similar to classical benzodiazepines than previously thought. To compare the sedative and anticonvulsant properties of these drugs and to evaluate the importance of GABA(A) receptor subunits for development of tolerance during chronic treatment, we tested the effects of acute and repeated administration of zolpidem and diazepam on ambulatory locomotor activity (a measure of sedation) and on the threshold for myoclonic, clonic and tonic seizures in response to i.v. infusion of pentylenetetrazole (PTZ). Both drugs given acutely in doses 0.3, 1 and 3 mg/kg reduced locomotion, and in doses 1 and 3 mg/kg elevated the threshold for PTZ-induced seizures. The effects of zolpidem and diazepam on the tonic seizure threshold were greater than on myoclonus and clonic seizure threshold. Diazepam and zolpidem (3 mg/kg), given 18 or 42 h after repeated drug treatment (10 days, 5 mg/kg, twice daily), decreased the PTZ seizure threshold and increased the locomotor activity as compared to control mice, indicating development of tolerance to their anticonvulsant and sedative effects. After repeated treatment the PTZ seizure threshold was not different between the two drugs, while differences in sedation became larger than after the acute treatment. The results suggest that alpha5-containing GABA(A) receptors are not crucial for the development of sedative and anticonvulsant tolerance.
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PMID:Effects of acute and repeated zolpidem treatment on pentylenetetrazole-induced seizure threshold and on locomotor activity: comparison with diazepam. 1934 34


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