ANTICONVULSANT PROPERTIES OF 5-PHENYL-5-ETHYL-HEXAHYDROPYRIMIDINE-4,6-DIONE (MYSOLINE), A NEW ANTIEPILEPTIC

¹ Departments of Pharmacology and Psychiatry, University of Utah College of Medicine and College of Pharmacy, Salt Lake City
² Department of Pharmacology, Medical College, Amritsar, Punjab, India

The anticonvulsant properties of 5-phenyl-5-ethyl-hexahydropyrimidine-4,6-dione (Mysoline) have been compared with those of phenobarbital by a variety of electroshock and chemoshock seizure tests in mice, rats, cats and rabbits. In addition, the role of the kidney in determining the potency of the drug has been studied in rats. Finally, Mysoline has been tested in psychiatric patients for its ability to modify therapeutic electroshock seizures. On the basis of the results obtained, the following conclusions are reached:

(1) Mysoline is markedly less neurotoxic than phenobarbital in mice and rats. In both species, however, Mysoline is much less potent than phenobarbital by the variety of assay procedures employed, except that Mysoline is more potent than phenobarbital by the maximal electroshock seizure test. The higher margin of safety of Mysoline in rats and mice is a direct result of its lower neurotoxicity. The limited value of margin of safety data obtained after acute doses of anti-convulsant drugs in laboratory animals is discussed. Mysoline is able to protect cats and rabbits against maximal seizures induced by supramaximal electroshock and intravenous pentylenetetrazol. The drug is many times more toxic in cats and rabbits than in rats and mice.

(2) Nephrectomy in rats increases the anticonvulsant "potency" of Mysoline two-fold. Rats and mice exhibit crystalluria after Mysoline administration. The crystals in rat urine have been identified (by others) as phenylethylmalondiamide. The possible role of this compound in determining the anticonvulsant potency of Mysoline is discussed.

(3) Mysoline, in doses not much larger than those conventionally used in epilepsy, was able to alter the pattern of therapeutic electroshock seizure in only three of nine psychiatric patients, and caused side reactions in seven.

(4) The change in chemical structure from phenobarbital to Mysoline (replacement of the oxygen in the urea moiety by two atoms of hydrogen) does not alter the spectrum of anticonvulsant activity of the parent compound, but results in a less potent anticonvulsant agent, as measured by several of a battery of laboratory tests.

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