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)

Thirty-two metabolites and analogues of the antiepileptic drug valproic acid (2-propylpentanoic acid; VPA) were tested for anticonvulsant and toxic effects in mice, in an attempt to find out if any of these compounds were superior to valproic acid. Valproic acid and ethosuximide, another clinically established antiepileptic drug, were included in these studies for comparison. After intraperitoneal administration, the anticonvulsant potency of the various drugs was determined in three seizure tests: the threshold for maximal electroconvulsions, the maximal electroshock seizure test and seizures induced by subcutaneous injection of pentylenetetrazol. For the most potent compounds, median minimal neurotoxic doses (TD50S) and LD50S (after i.p. and i.v. injection) were determined. Valpramide, the primary amide of valproic acid, proved to be the most potent compound in the three seizure tests, used, being 2-5 times as potent as valproic acid, but valpramide was also considerably more sedative and toxic than valproic acid or ethosuximide. Of the metabolites of valproic acid tested, the unsaturated compounds 4-en-valproic acid (4-en-VPA) and the trans-isomer of 2-en-valproic acid (2-en-VPA) were most potent and, depending on the seizure test used, reached 60-100% of the efficacy of the parent drug. Both metabolites had LD50 values which were similar or greater than those of valproic acid but they were more sedative than the parent compound.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pharmacological evaluation of various metabolites and analogues of valproic acid. Anticonvulsant and toxic potencies in mice. 392 83

We studied the pharmacokinetics of valproic acid (VPA) in 11 children before and after discontinuance of enzyme-inducing antiepileptic drugs (AEDs). Valproic acid elimination half-life increased from 7.1 to 11.8 hours. Total and intrinsic VPA clearance decreased by approximately 40%. Valproic acid serum protein binding varied among patients from 7 to 23.8%, but was not altered by AEDs. Seizure control was maintained and mental status improved once all other AEDs were withdrawn. After discontinuation of enzyme-inducing AEDs, serum VPA concentrations can be maintained with a lower VPA dosage given less frequently.
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PMID:Valproic acid pharmacokinetics in children. II. Discontinuation of concomitant antiepileptic drug therapy. 393 98

Valproic acid represents a new class of anticonvulsants that are widely employed in the management of many types of seizure disorders. Compared with other anticonvulsants, it has been considered relatively free of adverse effects. Recently, acute hepatic failure has been ascribed to valproic acid. Now experience is accumulating that implicates this agent in causing pancreatitis. Contributing to this evidence, the patient described herein had well-documented, recurrent pancreatitis while he was taking valproic acid. Nonspecific vomiting and abdominal pain frequently occur with valproic acid; however, pancreatitis must be considered whenever these symptoms are severe or protracted.
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PMID:Recurrent pancreatitis induced by valproic acid. A case report and review of the literature. 616 6

VEPs to checkerboard pattern-reversal were recorded from 18 epileptic patients who had EEG photoparoxysmal responses to stroboscopic light. Patients were grouped according to whether seizures were precipitated by environmental light stimuli, or television viewing. Longitudinal studies were conducted on 8 patients treated with valproic acid. We concluded the following: (1) Latency of the major positive peak (P2) of the pattern-reversal VEP was shorter among photosensitive patients than among normal controls. This was especially true of television-sensitive patients. (2) Valproic acid, when effective in controlling seizures, lengthened the P2 latency and decreased VEP amplitude. Studies of drug effects on VEPs may help to elucidate neurochemical mechanisms of the visual cortex. (3) Because of overlap of values with normals, VEP measurements are not at present very sensitive in the diagnosis of photosensitivity. However, longitudinal studies in individuals parallel clinical changes and may be useful as objective measures of improvement.
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PMID:Pattern-reversal visual evoked potentials in photosensitive epilepsy. 620 Mar 6

A pharmacological trial has been performed for the prophylaxis of febrile convulsions in childhood. The administration of two antiepileptic drugs, Sodium Valproate and Clonazepam, reduces significantly seizures occurrence compared with unmedicated controls. Furthermore, Sodium Valproate has been found to be more effective than Clonazepam. Both anticonvulsants are thought to act by a Gabaergic modulation in CNS.
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PMID:[DPA and clonazepam activity in febrile convulsions: preliminary results]. 625 70

Phenibut, sodium hydroxybutyrate and baclofen are selectively effective against seizures induced in mice by the endogenous metabolites of tryptophan, L-kynurenine and quinolinic acid. The seizures were not affected by the drugs in doses under study. Depakine and aminooxyacetic acid as well as diazepam and phenobarbital appeared the most effective against pentylenetetrazole seizures. GABA and muscimol administered intracerebroventricularly merely prolonged the latency of seizures. Dissimilarities in the GABA-ergic mechanisms of the anticonvulsant effects of the drugs under consideration are discussed.
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PMID:[Convulsions induced by kynurenine and quinolinic acid as a sensitive test for assessing the anticonvulsant activity of GABA-ergic preparations]. 629 32

DMCM (methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate) is a very potent convulsant with high affinity for specific benzodiazepine binding sites. A number of compounds were compared for their ability to prevent seizures induced by DMCM and pentylenetetrazol. DMCM seizures were antagonized by benzodiazepine (BZ) receptor antagonists, such as Ro 15-1788, CGS 8216 and several beta-carboline-3-carboxylates, which all fail to inhibit pentylenetetrazol seizures. The benzodiazepines diazepam, clonazepam and lorazepam as well as valproate, ethosuximid, phenobarbital, primidone, diphenylhydantoin and carbamazepine antagonized both DMCM and pentylenetetrazol. Muscimol and gamma-vinyl-GABA did not inhibit DMCM seizures whereas THIP showed a weak and selective effect against DMCM. Valproate showed a relatively potent (60 mg/kg i.p.) and competitive antagonism of short duration. Baclofen antagonized DMCM at 3 mg/kg. Valproate and baclofen were at least 5 times more potent against DMCM-induced than against pentylenetetrazol-induced seizures. DMCM most probably induces the seizures by selective impairment of the functions mediated by the GABA/BZ receptor-chloride channel complex (inverse agonism) and therefore differs from GABA receptor blockers.
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PMID:DMCM: a potent convulsive benzodiazepine receptor ligand. 631 96

Seven GABAmimetic drugs, namely cetyl gamma-aminobutyric acid (cetyl GABA), 4,5,6,7-tetrahydroisoxazolo [5,4-c]pyridine-3-ol, progabide, aminooxyacetic acid, alpha-acetylenic GABA, (-)-nipecotic acid ethyl ester and (+/-)-cis-4-hydroxynipecotic acid methyl ester, were tested for their potency to block "major" (generalized clonic-tonic) seizures in gerbils, induced by blowing at the animals with compressed air. Valproic acid was included as a reference standard. All drugs proved able to protect gerbils from induced seizures. Most effective were 4,5,6,7-tetrahydroisoxazolo [5,4-c] pyridine-3-ol (ED50, 1.3 mg/kg i.p.), aminooxyacetic acid (0.9), cetyl GABA (4.5) and gamma-acetylenic GABA (2.1). A comparison with anticonvulsant ED50 values of common antiepileptics in the gerbil showed that these four GABAmimetics were clearly more potent than phenobarbital, phenytoin, carbamazepine, ethosuximide and valproic acid and were only surpassed in potency by diazepam. Furthermore, most GABAmimetics proved strikingly more active in the gerbil compared with the classical electroshock and pentylenetetrazol seizure models in mice. After administration of gamma-acetylenic GABA, GABA increases in the brain of only about 40% were found sufficient to reach almost complete seizure protection in gerbils. The present data are compatible with the possibility that the GABA system is critically involved in the seizure-prone state in the gerbil.
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PMID:High anticonvulsant potency of gamma-aminobutyric acid (GABA)mimetic drugs in gerbils with genetically determined epilepsy. 641 1

A 7-year-old boy developed a severe unilateral grand mal seizure at the age of 5 years (phenobarbitone therapy); 1.5 years later valproate (2-propylpentanoic acid, VPA) was added to the therapy. After a seizure-free period of 3 months the patient died from hepatic failure resembling Reye syndrome. Several plasma and urine samples from the final stage before and during peritoneal dialysis were analyzed by GC/MS. The predominant feature was the abnormally increased formation of both 3 mono- and 4 double unsaturated metabolites of VPA amounting in plasma to 58%-71% of the sum of VPA plus all analyzed metabolites (controls maximal 15%) and in urine to 34%-61% (controls maximal 10%). The beta-oxidation pathway of VPA was shown to be suppressed (lack of 3-keto-VPA), whereas metabolites from the omega-oxidation pathway could still be measured (urinary 5-OH-VPA plus 2-propylglutaric acid ca. 1.6%, controls more than 10%). 4-en-VPA (2-propyl-4-pentenoic acid) (5%-21% in plasma) and 4,4'-dien-VPA (2(2-propenyl)-4-pentenoic acid) (4%-7%) have been found as abnormal unsaturated metabolites not detectable in controls. Additional typical findings were the high excretion of adipic acid, suberic acid, and 4-octen-1,8-dicarboxylic acid demonstrating the enhanced capacity of omega-oxidation in fatty acid oxidation.
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PMID:Abnormal metabolism of valproic acid in fatal hepatic failure. 641 45

Twelve patients with benign juvenile myoclonic epilepsy (BJME) representing 4% of our population of epileptics (n = 275) are presented. Only two patients (17%) had myoclonic jerks as the only seizure type. Seven (58%) had generalized tonic-clonic seizures (GTCS) and myoclonus. Three patients (25%) had absence seizures (AS), GTCS, and myoclonic jerks. Electroencephalographic evidence of photosensitivity was found in four (33%). Auditory precipitation of seizures was found in one patient. As is the case with other primary generalized epilepsies, the onset of BJME seems to be age specific. In our series the mean age of onset in years was 4.3 for AS, 14.75 for myoclonic jerks, and 16.4 for GTCS. It took an average of 8.5 years from the onset of BJME (range, 2-20 years) and 6.5 years from the onset of GTCS (range, 2 months-6 years) until the condition was properly recognized. Five patients experienced at least one episode of myoclonic status epilepticus. Generalized, paroxysmal, symmetric polyspike and slow wave discharges are the typical EEG finding. These complexes, however, showed considerable interpatient variability. Sleep deprivation proved to be the most valuable activating procedure. Valproic acid monotherapy effectively controlled myoclonic jerks as well as associated GTCS in most patients.
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PMID:Some clinical and EEG aspects of benign juvenile myoclonic epilepsy. 642 Jan 45


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