THE EFFECT OF -DIETHYLAMINOETHYLDIPHENYLPROPYLACETATE (SKF NO. 525A) ON THE ANTICONVULSANT PROPERTIES OF ANTIEPILEPTIC DRUGS

¹ Departments of Pharmacology, University of Utah College of Pharmacy and College of Medicine, Salt Lake City, Utah

Seven antiepileptic drugs (5,5-diphenylhydantoin sodium [diphenylhydantoin sodium, Dilantin sodium]; 3-methyl-5-phenyl-5-ethythydantoin [Mesantoin]; 5-phenyl-5-ethylhydantoin [Nirvanol]; 5-ethyl-5-phenylbarbiturate sodium [phenobarbital sodium]; 5-ethyl-1-methyl-5-phenylbarbiturate [mephobarbital, Mebaral]; 3,5,5-trimethyloxazolidine-2,4-dione [trimethadione, Tridione]; phenylacetylurea [phenacemide, Phenurone]) were assayed quantitatively for anticonvulsant potency and neurotoxicity in control mice and in mice pre-treated with -diethylaminoethyldiphenylpropylacetate (SKF No. 525A). The results were analyzed statistically for the effect of SKF No. 525A on potency, neurotoxicity, duration of anticonvulsant action and margin of safety. The data obtained justify the following conclusions.

(1) Except for phenacemide, SKF No. 525A increased the potency and the duration of anticonvulsant action of all compounds tested ; the increase in potency varied from 30 per cent for trimethadione (3rd hour) to 313 per cent for Mesantoin (12th hour). The increase in duration of action varied from 60 per cent for diphenylhydantoin to 300 per cent for Mesantoin. There was no significant effect of SKF No. 525A on the potency or the duration of anticonvulsant action of phenacemide.

(2) Except for trimethadione, SKF No. 525A significantly increased the toxicity of all compounds included in this study; the increase varied from 14 per cent for phenacemide (6th hour) to 104 per cent for Mesantoin (6th hour). The toxicity of trimethadione was not altered by SKF No. 525A.

(3) SKF No. 525A increased the protective index (P.I.) ratios of Nirvanol and trimethadione at all times at which the drugs were tested; the average increase was 68 per cent for Nirvanol and 43 per cent for trimethadione. The P.I. ratios for phenobarbital and for Mesantoin were increased at the 12- and 24-hour tests after drug administration; the average increase was 72 per cent for phenobarbital (12th and 24th hour data) and 180 per cent for Mesantoin (12th hour data). The P.I. ratio for diphenylhydantoin was increased only at the 12-hour test (31 per cent) and that for mephobarbital only at the 24-hour test (52 per cent).

(4) Evidence is presented which indicates that prevention of demethylation of nitrogen and inhibition of aliphatic sidechain oxidation are not the only mechanisms by which SKF No. 525A potentiates antiepileptic drugs.

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