Influence of etoricoxib on anticonvulsant activity of phenytoin and diazepam in experimental seizure models in mice.

Objectives: Our aim was to investigate the effect of etoricoxib on the anticonvulsant activity of phenytoin and diazepam against seizure models in mice. In addition the acute adverse effect of etoricoxib was assessed with a chimney test.
Methods: The maximal seizure pattern was induced in mice by giving an alternating current of 50 mA for 0.2 s, while chemical seizures were induced by intraperitoneal injection of pentylenetetrazole at its CD97 dose (97% convulsive dose for the clonic phase). Test drug was administered 45 min before the electrical or chemical induction of seizures in combination with conventional antiepileptics. The ability of the test drug to reduce or abolish the extensor phase of maximal electroshock and clonic-type seizures in the chemical induction method was selected as anti-seizure criteria.
Key Findings: Concurrent treatment with etoricoxib at an oral dose of 10 mg/kg reduced the anticonvulsant potency of phenytoin. The protective effects of diazepam against pentylenetetrazole-induced convulsions was significantly increased and the mortality rate was reduced by concurrent treatment with etoricoxib (10 mg/kg p.o.) when compared with diazepam groups. No neurotoxic effect was observed with etoricoxib (10 mg/kg p.o.) and it had no impact on motor coordination in the chimney test in mice. Etoricoxib applied at its highest dose (10 mg/kg) significantly enhanced the free plasma levels of diazepam whereas the free plasma levels of phenytoin were significantly reduced.
Conclusions: The obtained results suggest that the preferential cyclooxygenase-2 inhibitor etoricoxib significantly reduced the anticonvulsant action of phenytoin and significantly increased the beneficial action of diazepam against maximal electroshock and pentylenetetrazole-induced convulsions in a mouse model.