A potential anti-asthmatic drug, CR 2039, enhances the anticonvulsive activity of some antiepileptic drugs against pentetrazol in mice

• Published in: European neuropsychopharmacology 1998-08, Vol.8 (3), p.233-238
• Main Authors: Czuczwar, S.J, Gasior, M, Kozicka, M, Pietrasiewicz, T, Turski, W.A, Kleinrok, Z
• Format: Article
• Language: English
• Subjects: Animals; Anticonvulsants - agonists; Anticonvulsants - pharmacology; Anticonvulsants - therapeutic use; Benzamides - pharmacology; Benzamides - therapeutic use; Bronchodilator Agents - pharmacology; Clonazepam; Clonazepam - agonists; Clonazepam - blood; Clonazepam - pharmacology; Clonazepam - therapeutic use; Convulsants - antagonists & inhibitors; Convulsants - pharmacology; CR 2039; Dose-Response Relationship, Drug; Drug Combinations; Drug Synergism; Ethosuximide; Ethosuximide - agonists; Ethosuximide - blood; Ethosuximide - pharmacology; Ethosuximide - therapeutic use; Male; Mice; Pentylenetetrazole - antagonists & inhibitors; Pentylenetetrazole - pharmacology; Seizures; Seizures - prevention & control; Tetrazoles - pharmacology; Tetrazoles - therapeutic use; Valproate
• ISSN: 0924-977X; 1873-7862
• DOI: 10.1016/S0924-977X(97)00077-1

CR 2039 (4-(1H-tetrazol-5-yl)- N-[4-(1H-tetrazol-5-yl]phenylbenzamide), in doses of 10, 20, and 100 mg/kg i.p., did not modify the seizure pattern observed after subcutaneous pentetrazol, administered at its CD 97 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.