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

Amygdala-kindled rats were treated with valproic acid (VPA; administered as its sodium salt) 3 times daily at 200 mg/kg i.p. for 6 weeks, and anticonvulsant and adverse effects during this period were studied. Groups of nonkindled rats were treated in parallel for determination of VPA and its major active metabolites in various brain regions after different durations of treatment. After the first injection of VPA, 200 mg/kg, seizure severity, seizure duration and duration of electrical afterdischarges recorded from the stimulated amygdala were reduced significantly, but only one of nine animals was protected completely from kindled seizures. At day 3 of chronic treatment, the anticonvulsant activity of VPA had increased markedly so that seven of nine animals were totally protected from seizures. However, this potent anticonvulsant effect was only transitory so that after 1 week of treatment the anticonvulsant effect of the medication was similar to that obtained after the first dosing. The effect of VPA remained at this level for the subsequent weeks, but there was a second, more permanent increase in the number of protected animals after 4 to 6 weeks. Plasma and brain levels of VPA and its metabolites remained relatively constant throughout the chronic treatment although there was a moderate accumulation of some metabolites, e.g., trans isomer of 2-propyl-2-pentenoic acid, in specific brain nuclei. The most prominent adverse effects of VPA were ataxia, muscle relaxation, wet-dog shake behavior and an increase in body temperature. Except for body temperature, tolerance developed to these adverse effects, but escape from wet-dog shake behavior occurred much more rapidly than reduction of other adverse effects. Pathohistological examination of liver sections from animals treated with VPA for 6 weeks showed no indication of any hepatotoxic effects. After drug withdrawal, kindled seizure parameters returned toward control values without evidence of significant carry-over effects. Five days after termination of treatment, only minute amounts of VPA and trans isomer of 2-propyl-2-pentenoic acid were determined in some brain regions, indicating that there was no persistence of active drug or metabolite concentrations in the brain.
 ...
PMID:Valproic acid in amygdala-kindled rats: alterations in anticonvulsant efficacy, adverse effects and drug and metabolite levels in various brain regions during chronic treatment. 250 34

The anticonvulsant potency of 2-propyl-2-pentenoic acid (2-en-VPA; trans isomer), a major metabolite of the antiepileptic valproic acid (VPA), was evaluated in different animal models of epilepsy and compared with the respective data for VPA. Four models were used: the maximal electroshock seizure (MES) test in mice, the pentylenetetrazol seizure test in mice, gerbils with 'major' (generalized tonic-clonic) seizures in response to specific sensory stimulation, and rats with chronically recurring, spontaneous 'petit mal' seizures. The overall anticonvulsant profile of 2-en-VPA in these models compared favourably with that of VPA. Both drugs were considerably more potent to block seizures in epileptic rats and gerbils than in the traditional MES and pentylenetetrazol mouse models. As regards toxicity, no side-effects were observed with effective doses of 2-en-VPA in rats and gerbils, whereas in the doses necessary to block MES and pentylenetetrazol seizures in mice (200-300 mg/kg i.p.) 2-en-VPA was more sedative than VPA. LD50 values determined for both drugs were comparable. A major difference between 2-en-VPA and VPA was found with respect to embryotoxicity. Single doses of VPA administered to pregnant mice gave rise to significant teratogenic effects (exencephaly, embryolethality , growth retardation), whereas 2-en-VPA was not embryotoxic, even at extremely high doses (600 mg/kg). The data suggest that 2-en-VPA may be a valuable alternative antiepileptic drug.
 ...
PMID:Comparative evaluation of anticonvulsant and toxic potencies of valproic acid and 2-en-valproic acid in different animal models of epilepsy. 642 23

The slow onset and carry-over effect of valproic acid (VPA) therapy observed in some clinical as well as experimental animal studies have been examined by parallel pharmacokinetic and pharmacological investigations in a mouse model. VPA was rapidly transferred into brain and was cleared from that tissue with rates which exceeded plasma clearance rates. Of several VPA metabolites present in plasma, only one could be found in the brain: 2-propyl-2-pentenoic acid. This metabolite was cleared from plasma and from brain slower than the parent drug. gamma-Aminobutyric acid (GABA) concentrations were increased within 15 min after VPA injection and remained significantly elevated for at least 8 h. A similar time course was found in regard to the increase of the electroconvulsive threshold (maximal seizures) induced by VPA administration. The activity of glutamic acid decarboxylase rose parallel to the elevation of brain GABA levels, whereas the activity of GABA aminotransferase was not affected. Whereas the rapid onset of the effect on electroconvulsive threshold and on GABA metabolism can be explained by the rapid entrance of VPA into brain, the carry-over effects observed correlated with the kinetics of the metabolite 2-propyl-2-pentenoic acid better than with those of VPA due to the persistence of this metabolite in brain.
 ...
PMID:Valproic acid: brain and plasma levels of the drug and its metabolites, anticonvulsant effects and gamma-aminobutyric acid (GABA) metabolism in the mouse. 680 Dec 54

Mice were continuously treated with valproic acid (VPA) via the drinking water for period from 1 to 12 days. The daily drug intake varied between 500 and 580 mg/kg. However, due to the rapid elimination of VPA in this species average plasma concentrations of only 3-4 micrograms/ml VPA were present at 8:30 a.m., the time chosen for determinations. In the brain, VPA levels were about 10% of those in plasma. In regard to VPA metabolism the products of beta-oxidation 2-en-VPA 2-propyl-2-pentenoic acid) and 3-keto-VPA (2-propyl-3-oxopentanoic acid) proved to be the main metabolites in plasma although other (minor) metabolites of VPA were also present. The only metabolite of VPA detected in the brain was 2-en-VPA. VPA medication caused a significant increase in the threshold for electroconvulsions which was associated with a slight increment of brain GABA levels. The activity of glutamic acid decarboxylase was significantly elevated whereas GABA aminotransferase was not affected. After withdrawal of VPA, a delayed effect on seizure threshold was observed which extended to time periods where VPA could no longer be detected in the brain, but 2-en-VPA was still present.
 ...
PMID:Valproic acid: metabolite concentrations in plasma and brain, anticonvulsant activity, and effects on GABA metabolism during subacute treatment in mice. 681 Jul 78