ISOBOLS OF DOSE-EFFECT RELATIONS IN THE COMBINATION OF NIKETHAMIDE (CORAMINE) AND PHENOBARBITAL

¹ Department of Pharmacology, Univ. of Utah School of Medicine, Salt Lake City, Utah

Ten separate endpoints of effect of the combination of nikethamide and phenobarbital were studied in mice; the combined doses required for equieffectiveness were determined and the course of the isobols of the endpoint effects was established. Seven of the endpoints were, as in previous studies: threshold seizure (Th), generalized clonic seizure (Cl), tonic extensor seizure (TE), ejaculation (Ej), prehypnotic excitatory (Ex), hypnotic (H), and lethal effect (L). In addition, isobols were determined for rapid (< 30 minutes Lr), early (< 120 minutes Le), and late death (> 120 minutes Ll), and for tonic extensor seizure in 10 per cent of animals (TE10). The combined-dose field extended to 47 lethal doses of the nikethamide component and 1.2 lethal doses of the phenobarbital component. In the preliminary determination of the endpoint doses of the components, the TE and the Ej effect of nikethamide were found to have diphasic dose-effect curves and, hence, to be limited to a rather small dosage range of the convulsant.

Tonic convulsant effects (TE and TE10) were counteracted even by very small doses of phenobarbital. Its counteraction to Cl was less but also very potent. Ej was still less effectively counteracted and was even restituted in a large range of phenobarbital doses which, alone, were non-ejaculatory. The Ex effect of phenobarbital was insignificantly, the H effect greatly synergized by nikethamide. The Th effect of Metrazol was counteracted in some, but facilitated in other areas of the combination.

The lethal effect of nikethamide was vigorously counteracted by phenobarbital, up to 3.8 lethal doses of nikethamide; the lethal effect of phenobarbital was somewhat antagonized by small doses of nikethamide. Rapid (Lr) or early death (Le) prevailed at all nikethamide dose levels when the phenobarbital dose was low; late death (Li) prevailed at all higher phenobarbital dose levels.

The characteristics of all these variations in effects are referred to the inter-play between the various actions of the combination. The major differences between the nikethamide-phenobarbital and the previously studied Metrazol-phenobarbital combination can be referred to the very significant central-depressant components of the action of nikethamide.