Molsidomine enhances the protective activity of valproate against pentylenetetrazole-induced seizures in mice.
Molsidomine (25 mg kg(-1)), a donor of nitric oxide, commonly used in the treatment of coronary artery disease, enhanced the protective activity of valproate against the clonic phase of pentylenetetrazole-induced seizures in mice, significantly reducing the ED(50) of valproate from 123.5 to 78 mg kg(-1). Molsidomine was found to be ineffective with respect to the protective action of clonazepam, ethosuximide and phenobarbital. Alone, molsidomine in a dose of 25 mg kg(-1) was ineffective in this model of seizures. Since N(G)-nitro-L-arginine, an inhibitor of nitric oxide synthase, failed to reverse the effect of molsidomine on valproate, an involvement of nitric oxide in the mechanism of the anticonvulsive efficacy of valproate does not seem to be probable. Molsidomine (25 mg kg(-1)) significantly elevated the free plasma level of valproate from 33.8 to 46.2 microg ml(-1). Therefore, we conclude that the interaction of molsidomine with valproate is at the pharmacokinetic level. The combination of valproate with molsidomine appears beneficial because is free from adverse effects, in terms of motor impairment and long-term memory deficit. Our results suggest that the dosage of valproate in patients with coronary artery disease treated with molsidomine should be decreased. It would allow us to reduce adverse effects of valproate.
Tutka
P
P
Department of Pharmacology and Toxicology, Medical University of Lublin, Poland. tutkap@itsa.ucsf.edu
Łuszczki
J
J
Kleinrok
Z
Z
Arent
K
K
Wielosz
M
M
D000818:Animals; D000927:Anticonvulsants / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003292:Convulsants; D004357:Drug Synergism; D008297:Male; D051379:Mice; D008981:Molsidomine / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010433:Pentylenetetrazole; D012640:Seizures / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy*; D014635:Valproic Acid / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014665:Vasodilator Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*
D000927:Anticonvulsants; D003292:Convulsants; D014665:Vasodilator Agents; D014635:Valproic Acid; D008981:Molsidomine; D010433:Pentylenetetrazole