Effect of p-isopropoxyphenylsuccinimide monohydrate on the anticonvulsant action of carbamazepine, phenobarbital, phenytoin and valproate in the mouse maximal electroshock-induced seizure model.
This study was designed to determine the effects of p-isopropoxyphenylsuccinimide monohydrate (IPPS) on the protective action of four classical antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) in the mouse maximal electroshock seizure model. Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (sine-wave, 25 mA, 500 V, 50 Hz, 0.2 s stimulus duration) delivered via auricular electrodes. Acute adverse-effect profiles with respect to motor performance, long-term memory and skeletal muscular strength were measured along with total brain antiepileptic drug concentrations. Results indicate that IPPS administered intraperitoneally (ip) at doses of 75 and 150 mg/kg significantly elevated the threshold for electroconvulsions in mice. IPPS at lower doses of 18.75 and 37.5 mg/kg had no impact on the threshold for electroconvulsions in mice. Moreover, 37.5 mg/kg IPPS significantly enhanced the anticonvulsant activity of phenytoin and valproate, but not that of carbamazepine or phenobarbital, in the maximal electroshock seizure test in mice. IPPS (18.75 mg/kg) had no impact on the antiseizure action of phenytoin and valproate against maximal electroshock-induced seizures in mice. Pharmacokinetic experiments revealed that IPPS did not alter total brain concentrations of phenytoin or valproate in mice. In conclusion, the enhanced anticonvulsant action of phenytoin and valproate by IPPS in the mouse maximal electroshock-induced seizure model and lack of pharmacokinetic interactions make the combinations of IPPS with phenytoin and valproate of pivotal importance for further experimental and clinical studies. The combinations of IPPS with carbamazepine and phenobarbital are neutral from a preclinical viewpoint.
Łuszczki
Jarogniew J
JJ
Department of Pathophysiology, Medical University of Lublin, Jaczewskiego 8, PL 20-090 Lublin, Poland. jluszczki@yahoo.com
Kocharov
Sergey L
SL
Czuczwar
Stanisław J
SJ
D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D002220:Carbamazepine / Q000493:pharmacokinetics / Q000494:pharmacology; D004347:Drug Interactions; D004597:Electroshock; D016231:Fluorescence Polarization Immunoassay; D018737:Hand Strength; D008297:Male; D008568:Memory / Q000187:drug effects; D051379:Mice; D053580:Muscle Strength / Q000187:drug effects; D010634:Phenobarbital / Q000493:pharmacokinetics / Q000494:pharmacology; D010672:Phenytoin / Q000493:pharmacokinetics / Q000494:pharmacology; D011597:Psychomotor Performance / Q000187:drug effects; D012640:Seizures / Q000517:prevention & control*; D013388:Succinimides / Q000493:pharmacokinetics* / Q000494:pharmacology*; D014635:Valproic Acid / Q000493:pharmacokinetics / Q000494:pharmacology
C550531:4-isopropoxyphenylsuccinimide; D000927:Anticonvulsants; D013388:Succinimides; D002220:Carbamazepine; D014635:Valproic Acid; D010672:Phenytoin; D010634:Phenobarbital