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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 
 
 

Interaction of the neurosteroid alphaxalone with conventional antiepileptic drugs in different types of experimental seizures.

A number of neurosteroids exert antiseizure and/or neuroprotective properties. The aim of this study was to evaluate the effect of the neurosteroid alphaxalone on the protective action of conventional antiepileptics in four seizure tests. Alphaxalone (up to 5 mg/kg) did not exert a significant action against amygdala-kindled seizures in rats, or against pentetrazole- or aminophylline-induced convulsions in mice. The neuroactive steroid at the dose of 2.5 mg/kg significantly raised the threshold for electroconvulsions in mice. At 2.5 mg/kg, alphaxalone diminished the protective activity of valproate against maximal electroshock and at 2.5-5 mg/kg against pentetrazole-induced seizures in mice. However, alphaxalone (2.5 mg/kg) did not affect the protective activity of carbamazepine, diphenylhydantoin, phenobarbital or clonazepam against maximal electroshock and at 5 mg/kg did not affect that of phenobarbital, clonazepam and ethosuximide against pentetrazole-induced convulsions. Insignificant results were also obtained in the case of co-administration of alphaxalone with phenobarbital, valproate, clonazepam and carbamazepine against aminophylline-evoked seizures in mice. Also, in the kindling model of epilepsy, combinations of the neuroactive steroid (2.5 mg/kg) with valproate, carbamazepine, phenobarbital, diphenylhydantoin or clonazepam at their subprotective doses did not result in pro- or anticonvulsant activity. Valproate (284 mg/kg; the dose used in combination with alphaxalone) produced significant memory deficits in mice. Alphaxalone (2.5 mg/kg), valproate (at its ED(50) value of 226 mg/kg) and the combination of valproate (284 mg/kg) with alphaxalone (2.5 mg/kg) did not affect long-term memory, evaluated in the passive avoidance task with mice. Alphaxalone administered alone or in combination with valproate caused no motor impairment in experimental animals. Finally, alphaxalone (2.5 and 5 mg/kg) significantly increased the free plasma levels of valproate, strongly indicating that the neuroactive steroid-induced reduction of the protective activity of valproate is not related to pharmacokinetic phenomena. Summing up, alphaxalone does not seem to be a promising candidate for adjunctive treatment of epilepsy.[1]

References

  1. Interaction of the neurosteroid alphaxalone with conventional antiepileptic drugs in different types of experimental seizures. Borowicz, K.K., Zadrozniak, M., Swiader, M., Kowalska, A., Kleinrok, Z., Czuczwar, S.J. Eur. J. Pharmacol. (2002) [Pubmed]
 
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