A potential anti-asthmatic drug, CR 2039, enhances the anticonvulsive activity of some antiepileptic drugs against pentetrazol in mice.
CR 2039 (4-(1H-tetrazol-5-yl)-N-[4-(1H-tetrazol-5-yl]phenylbenzam ide), in doses of 10, 20, and 100 mg/kg i.p., did not modify the seizure pattern observed after subcutaneous pentetrazol, administered at its CD97 of 90 mg/kg for the clonic phase. However, when combined with antiepileptic drugs, this phenylbenzamide derivative (20 mg/kg) converted the subprotective doses of ethosuximide (100 mg/kg) or valproate (100 mg/kg) against the clonic phase into anticonvulsive ones. The protection observed was comparable to that noted after doubling the doses of these antiepileptics. Also, a combination of valproate (100 mg/kg) with CR 2039 (10 mg/kg) resulted in a clear-cut protection against clonic seizures induced by pentetrazol. The protective efficacy of clonazepam was not affected by the phenylbenzamide derivative up to 40 mg/kg. The potentiation of the anticonvulsive activity of ethosuximide or valproate was not accompanied by increased adverse effects, evaluated in the chimney test (motor coordination) and passive avoidance task (long-term memory). Finally, CR 2039 (20 mg/kg) did not alter the plasma levels of the antiepileptic drugs studied, which speaks against a pharmacokinetic mechanism in the observed results. In conclusion, CR 2039 seems devoid of a hazardous influence of the anti-asthmatic drug, aminophylline, on the anticonvulsive effects of conventional antiepileptics.
Department of Pharmacology, Lublin Medical University School, Poland. czuczwar@galen.imw.lublin.pl
S J
SJ
Czuczwar
M
M
Gasior
M
M
Kozicka
T
T
Pietrasiewicz
W A
WA
Turski
Z
Z
Kleinrok
D000818:Animals; D000927:Anticonvulsants / Q000819:agonists / Q000494:pharmacology* / Q000627:therapeutic use; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use; D001993:Bronchodilator Agents / Q000494:pharmacology*; D002998:Clonazepam / Q000819:agonists / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use; D003292:Convulsants / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004357:Drug Synergism; D005013:Ethosuximide / Q000819:agonists / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D010433:Pentylenetetrazole / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D012640:Seizures / Q000517:prevention & control; D013777:Tetrazoles / Q000494:pharmacology* / Q000627:therapeutic use
D000927:Anticonvulsants; D001549:Benzamides; D001993:Bronchodilator Agents; D003292:Convulsants; D004338:Drug Combinations; D013777:Tetrazoles; C078154:4-(1H-tetrazol-5-yl)-N-(4-(1H-tetrazol-5-yl)phenyl)benzamide; D002998:Clonazepam; D005013:Ethosuximide; D010433:Pentylenetetrazole