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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clozapine, an atypical neuroleptic, functionally antagonizes the gamma-aminobutyric acid-induced chloride uptake via the main central inhibitory receptor, gamma-aminobutyric acid type A (GABAA) receptor, in brain vesicles. GABAA antagonism by micromolar concentrations of clozapine is more efficient in rat cerebrocortical and hippocampal membranes than in cerebellar membranes, as evidenced by clozapine reversal GABA-inhibition of [35S]t-butylbicyclophosphorothionate ([35S]TBPS) binding. A typical neuroleptic, haloperidol, failed to antagonize GABA in any of these brain regions, while the specific GABAA antagonist 2'-(3'-carboxy-2',3'-propyl)-3-amino-6-p -methoxyphenylpyrazinium bromide (SR 95531) was efficient in all three brain regions. Clozapine action on [35S]TBPS binding was unaffected by the benzodiazepine receptor antagonist flumazenil. Clozapine inhibited the binding of [3H]muscimol and [3H]SR 95531 to the GABA recognition site, but this effect only partially correlated with the regional differences in and the potency of clozapine antagonism of GABA-inhibition of [35S]TBPS binding, suggesting that also other than GABA sites may mediate clozapine actions. Autoradiography of [35S]TBPS binding revealed GABA antagonism by clozapine in most brain regions. Main exceptions were cerebellar granule cell and molecular layers, olfactory bulb external plexiform and glomerular layers and primary olfactory cortex, where clozapine antagonized GABA inhibition less than average, and lateral hypothalamic and preoptic areas where its antagonism was greater than average. Recombinant alpha 6 beta 2 gamma 2 receptors, the predominant alpha 6 subunit-containing receptor subtype in cerebellar granule cells, failed to show GABA antagonism by clozapine up to 100 microM. In contrast, recombinant alpha 1 beta 2 gamma 2 receptors, forming the predominant receptor subtype in the brain, were clozapine sensitive. Recombinant alpha 6 beta 2 gamma 2 and alpha 6 beta 3 gamma 2 receptors resulted in clozapine-insensitive receptors, whereas alpha 6 beta 1 gamma 2 receptors were clozapine sensitive. The efficacy of clozapine to antagonize GABA in alpha 1 beta x gamma 2 receptors decreased in the order of alpha 1 beta 1 gamma 2 > alpha 1 beta 2 gamma 2> alpha 1 beta 3 gamma 2. The results indicate that clozapine antagonizes the function of most GABAA receptor subtypes, and that the interaction is determined by the interaction of the alpha and beta subunit variants. GABA antagonism is a unique property of clozapine, not shared by haloperidol, which might be involved in the pharmacological mechanism for the increased seizure susceptibility associated with clozapine treatment.
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PMID:Subtype specificity of gamma-aminobutyric acid type A receptor antagonism by clozapine. 853 64

Bromide toxicosis was diagnosed in an 8-year-old Labrador Retriever that had been treated for epilepsy with potassium bromide, at a dosage of 29 mg/kg of body weight/d. Clinical signs included hind limb weakness, ataxia, and disorientation. Renal insufficiency, diagnosed by determination of endogenous creatinine clearance, was believed to be responsible for the development of bromide toxicosis in this dog. Diuresis with physiologic saline solution and discontinuation of bromide and phenobarbital treatment resulted in rapid resolution of abnormal neurologic signs; however, serum bromide concentrations decreased dramatically during diuresis and seizures recurred. Although saline diuresis has been recommended for the treatment of bromide intoxication in human beings, more conservative measures, such as discontinuation of bromide and short-term fluid administration, may be more appropriate for epileptic dogs.
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PMID:Bromide toxicosis secondary to renal insufficiency in an epileptic dog. 856 78

Bromide treatment was successful in controlling seizures in an 11-year-old Dachshund with epilepsy and presumptive phenobarbital-associated hepatopathy. Because bromide does not induce liver enzyme activity and does not seem to be hepatotoxic, it can be used to control seizures in dogs with concurrent epilepsy and hepatic disease. In this dog, institution of a special calculolytic diet with high chloride content was associated with a decrease in serum bromide concentrations and the recurrence of seizures. High chloride intake increases the elimination of bromide in dogs, leading to higher dosage requirements for bromide in dogs fed high-chloride diets.
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PMID:High dietary chloride content associated with loss of therapeutic serum bromide concentrations in an epileptic dog. 856 79

Synthesis and physicochemical properties of new derivatives of alpha-substituted gamma-phthalimidobutyric acid are described. N-substituted amides of alpha-(4-phenylpiperazine)-gamma- phthalimidobutyric acid were prepared by condensation of the acid with the corresponding derivatives of benzylamine in the presence of BOP reagent. 2-(4-Phenylpiperazine)- or 2-(4-benzylpiperidine)-4-phthalimidobutyric acid were esterified with alkyl bromide in the presence of DBU or tetrabutylammonium bromide as catalyst. The obtained compounds were evaluated for anticonvulsant activity. 2-(4-Phenylpiperazine)-4-phthalimidobutyric acid and three N-substituted amides of this acid displaced protection against MES and scMet-induced seizures.
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PMID:Search for new anticonvulsant compounds. Part 1: Synthesis, physicochemical and anticonvulsant properties of new derivatives of alpha-amino-gamma-phthalimidobutyric acid. 857 Jun 69

Our earlier observations showed that L-lysine enhanced the activity of diazepam against seizures induced by pentylenetetrazol (PTZ), and increased the affinity of benzodiazepine receptor binding in a manner additive to that caused by gamma-aminobutyric acid (GABA). The present paper provides additional evidence to show that L-lysine has central nervous system depressant-like characteristics. L-lysine enhanced [3H]flunitrazepam (FTZ) binding in brain membranes was dose-dependent and stimulated by chloride, bromide and iodide, but not fluoride. Enhancement of [3H]FTZ binding by L-lysine at a fixed concentration was increased by GABA but inhibited by pentobarbital between 10(-7) to 10(-3)M. While GABA enhancement of [3H]FTZ binding was inhibited by the GABA mimetics imidazole acetic acid and tetrahydroisoxazol pyridinol, the enhancement by pentobarbital and L-lysine of [3H]FTZ binding was dose-dependently increased by these two GABA mimetics. The above results suggest that L-lysine and pentobarbital acted at the same site of the GABA/benzodiazepine receptor complex which was different from the GABA binding site. The benzodiazepine receptor antagonist imidazodiazepine Ro15-1788 blocked the antiseizure activity of diazepam against PTZ. Similar to pentobarbital, the anti-PTZ effect of L-lysine was not blocked by Ro15-1788. Picrotoxinin and the GABA, receptor antagonist bicuculline partially inhibited L-lysine's enhancement of [3H]FTZ binding with the IC50s of 2 microM and 0.1 microM, respectively. The convulsant benzodiazepine Ro5-3663 dose-dependently inhibited the enhancement of [3H]FTZ binding by L-lysine. This article shows the basic amino acid L-lysine to have a central nervous system depressant characteristics with an anti-PTZ seizure activity and an enhancement of [3H]FTZ binding similar to that of barbiturates but different from GABA.
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PMID:L-lysine is a barbiturate-like anticonvulsant and modulator of the benzodiazepine receptor. 858 51

Epileptic seizures are the most common neurologic problem of the dog. The ability of a clinician to start proper management does not require elaborate equipment or specialized skills. What is needed is a thorough assessment of the history and examination findings. Dogs with a history of seizures at less than 1 or greater than 7 years of age, a history of behavioral changes, an initial interictal interval of less than 4 weeks, or an initial partial seizure should be suspected of having an identifiable underlying cause for the seizures. As such, an appropriate diagnostic evaluation should be done. Once a cause has been determined, PB is the AED of choice for dogs without underlying liver disease. Factors that enhance successful PB therapy are early initiation of therapy and proper monitoring of trough serum concentrations. Dogs that develop functional tolerance to PB should be given oral potassium bromide as the second AED. Diazepam per rectum can be used as an at-home therapy to stop cluster seizure activity. Overall, improved seizure control can be achieved by establishing a well-thought out therapeutic monitoring schedule. This approach will lead to improved quality of life for the patient, resulting in greater client satisfaction and less clinician frustration.
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PMID:Seizures in dogs. 881 50

The use of AEDs in the management of epilepsy requires an ongoing risk-benefit analysis that attempts to maximize seizure control while minimizing adverse cognitive side-effects. Although the effects of other factors on cognition are generally greater than AED effects in patients with epilepsy, the cognitive effects of AEDs are of special concern because they are iatrogenically induced. Baseline evaluation of mental functioning is essential and should be repeated whenever a change in cognitive performance is suspected. The cognitive effects of the major AEDs, including phenytoin, carbamazepine and valproate, appear modest when dosages are kept within standard therapeutic ranges and polypharmacy is avoided. Violation of these guidelines increases the risk of alterations in arousal, attention, memory and psychomotor functioning. In turn, dysfunction in these areas can contribute to deficits in higher cognitive processes. Evidence suggests that these primary and secondary deficits are relatively greater for benzodiazepines, bromide and phenobarbital. Initial studies involving the newer AEDs suggest that the cognitive profile of these drugs is favourable, but further research is required to determine their relative effects to each other and to the older AEDs. For some patients, optimal seizure management may require the use of polypharmacy or AED dosages that exceed the standard therapeutic range. In such cases, the physician should remain sensitive to the increased risk of cognitive side-effects. The impact of such effects will be greatest for those whose daily functioning requires sustained attention or psychomotor speed. Although the cognitive risks of AEDs appear rather modest for most adults, questions remain regarding the impact of AEDs on patients at extremes of age. Initial studies with children and older adults suggest that the effects of the major AEDs are comparable across the developmental lifespan. However, during the formative years of a child's intellectual development, close scrutiny should be paid to the possibility that subtle attentional or arousal deficits could contribute to cumulative deficits in learning or memory. Preliminary studies involving both animals and humans suggest that the impact of AEDs might be greatest during in utero exposure; however, additional research is required to fully delineate the long-term effects of AED exposure in this earliest period of neurodevelopment.
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PMID:Epilepsy, anticonvulsant drugs and cognition. 906 86

In the therapy of absence epilepsies, a combination of ethosuximide (ESM) and valproic acid (VPA) is sometimes necessary for a successful seizure control. Previous studies of the interaction between ESM and VPA revealed contradictory results. We investigated the influence of ESM on VPA serum concentrations in children with epilepsy. In case of ineffectiveness of the drug, ESM was withdrawn (n = 9). Four children treated with VPA got ESM additionally because their seizure control was insufficient with VPA alone. Two children had bromide, and one clobazam as comedicament. Both of these antiepileptic drugs (AEDs) do not have any known interactions with ESM or VPA. Serum levels of VPA were higher in monotherapy than in combination with ESM (120.0 +/- 20.1 micrograms/ml; range, 88.9-153.4 micrograms/ml; vs. 87.0 +/- 13.1 micrograms/ml; range, 67.4-108.0 micrograms/ml). The difference was statistically significant (P < 0.01). After stopping ESM the serum concentrations of VPA rose about 36.7%; when combined with ESM they fell about 28.3%. Neither the age of the patients nor the serum concentrations of ESM influenced significantly the changes of VPA serum levels in either group. The mechanism of ESM to influence the serum levels of VPA remains unknown. ESM has no known enzyme inducing properties. The interaction of ESM and VPA ought to be considered in a combination therapy of these drugs.
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PMID:Influence of ethosuximide on valproic acid serum concentrations. 909 96

Bromide, the first effective therapy for epilepsy, is not commonly prescribed today but has been advocated by some pediatric neurologists for the treatment of intractable seizures in children. We report a 17-year-old female patient with intractable epilepsy who insidiously developed bromism while on treatment with triple bromide elixir. We review the clinical presentation, diagnosis, pathophysiology, and management of bromism.
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PMID:Bromism: intoxication from a rare anticonvulsant therapy. 929 16

The anticonvulsant topiramate is effective in laboratory animals against maximal electroshock seizures, amygdala kindling, and spike-wave discharges and has demonstrated efficacy in humans for the treatment of complex partial seizures. However, its mechanism of action has yet to be clearly elucidated. When the chloride-sensitive fluorescent probe N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide (MQAE) was used as a tool for estimating the effect of anticonvulsant drugs on GABA receptor function, topiramate was observed to enhance GABA-stimulated chloride (Cl-) flux. At a therapeutic concentration, topiramate (10 microM) enhanced GABA-stimulated (10 microM) Cl- influx into cerebellar granule neurons but did not significantly increase Cl- influx alone. Phenytoin (10 microM) and acetazolamide (300 microM) did not enhance GABA-stimulated Cl- influx. In patch-clamp electrophysiological studies, topiramate also enhanced GABA-evoked whole cell Cl- currents in mouse cerebral cortical neurons in culture. In vivo anticonvulsant studies confirmed that topiramate, like phenytoin, is primarily effective against tonic extension seizures induced by maximal electroshock and is ineffective against clonic seizures induced by the subcutaneously administered chemoconvulsants pentylenetetrazol (PTZ), bicuculline (Bic), and picrotoxin (Pic). In contrast to phenytoin, topiramate, at a dose equivalent to the MES median effective dose (ED50), was found to elevate seizure threshold as estimated by the intravenous PTZ seizure threshold test. Taken together these results support the conclusion that enhancement of GABA-mediated Cl- flux may represent one mechanism that contributes to the anticonvulsant activity of topiramate.
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PMID:Topiramate enhances GABA-mediated chloride flux and GABA-evoked chloride currents in murine brain neurons and increases seizure threshold. 933 82


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