No abstract

In the electroshock test--taking hind-limb tonic extension as the end point--apomorphine (10 mg/kg) exerted no effect on the anticonvulsant action of phenobarbital (PB; 20 mg/kg) or diphenylhydantoin (DPH; 8 mg/kg); amantadine (25 and 100 mg/kg) decreased that of DPH, while L-DOPA (500 mg/kg) and d,l-amphetamine (10 mg/kg) potentiated the action of both anticonvulsants. Fluphenazine (4 mg/kg) had no influence on the effects of the two anticonvulsants, but haloperidol lessened that of DPH. All GABA-ergic stimulants used, i.e., gamma-hydroxybutyric acid (GHBA/250 mg/kg), baclofen (2.5 and 10 mg/kg) and aminooxoacetic acid (AOAA; 15 and 20 mg/kg) potentiated the action of PB; the action of DHP was unaffected by these drugs except for AOAA (20 mg/kg). The combined treatment with dopaminergic and GABA-ergic stimulants, being ineffective in terms of anticonvulsant activity, resulted in a marked potentiation of the action of the anticonvulsants tested in this study. The most distinct potentiation was noted in the case of PB, baclofen (1 mg/kg), and amantadine (25 mg/kg).

Endogenous histamine has been reported to be involved in regulation of seizure susceptibility. Enhancement of histamine neurotransmission engendered by L-histidine treatment produces anticonvulsant effects in experimental animals. The present study investigated the influence of L-histidine on the protective effects of carbamazepine and phenytoin against maximal electroshock-induced seizures in mice.L-Histidine, administered at the doses that did not influence the threshold for electroconvulsions (250-500 mg/kg), enhanced by nearly 30% the protective effects of carbamazepine against maximal electroshock-induced seizures. D-Histidine (1000 mg/kg), an inactive isomer of histidine, was without any effect in this regard. L-Histidine (500 mg/kg) also augmented the protective effects of phenytoin. Importantly, the enhancement of the anticonvulsant effects of these antiepileptic drugs produced by L-histidine co-administration was not associated with augmentation of their unwanted effects on memory and motor performance. A pharmacokinetic interaction was also excluded since the free plasma levels of these antiepileptics remained unchanged in the presence of L-histidine. It may be suggested that L-histidine could serve as a beneficial adjuvant for selected antiepileptic drugs.

Aminophylline (theophylline2.ethylenediamine) in the dose of 12.5 mg/kg (i.p.) was ineffective upon all antiepileptic drugs studied and at the higher dose of 25 mg/kg, impaired the anticonvulsant action of phenobarbital and valproate against maximal electroshock in mice. The protection offered by diphenylhydantoin was diminished by aminophylline at 50 mg/kg (0.238 mmol of anhydrous theophylline/kg). In contrast, 8-(p-sulfophenyl)theophylline (a theophylline derivative unable to cross the blood-brain barrier) in the dose of 80 mg/kg (0.238 mmol/kg) did not influence the protective activity of diphenylhydantoin, phenobarbital, and valproate. It might be concluded that the aminophylline-induced impairment of the anticonvulsant action of common antiepileptic drugs results from the central effects of this methylxanthine.

Excitatory amino acids participate in the generation of seizure activity. Consequently, the effects of GYKI 52466 [1-(4-aminophenyl)-4-methoxy-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride], an antagonist of glutamate-mediated events, on the protective activity of conventional antiepileptic drugs against pentetrazol were studied. GYKI 52466 (up to 10 mg/kg, i.p.) did not affect the clonic phase of pentetrazol (injected s.c. at its CD97 of 90 mg/kg) convulsions. Only the antipentetrazol activity of valproate (100 mg/kg) was enhanced by GYKI 52466 (10 mg/kg)--the percentage of mice protected was significantly increased from 20 to 90%. The anticonvulsive activity of clonazepam (at 0.01), ethosuximide (at 50), and phenobarbital (at 2.5 mg/kg) was not modified by GYKI 52466 (up to 10 mg/kg). The combination of valproate (100 mg/kg) with GYKI 52466 (10 mg/kg) did not affect the performance of mice evaluated in the chimney test. However, this combination resulted in significant memory deficits, measured in the passive avoidance task. In no case did GYKI 52466 (10 mg/kg) affect either total or free plasma levels of antiepileptic drugs (as measured by immunofluorescence), so a pharmacokinetic interaction is not probable. Finally, the interaction of the non-NMDA receptor antagonist with antiepileptic drugs does not seem promising in the pentetrazol test, recognized as a model of human myoclonic epilepsy.