ANTICONVULSANT PROPERTIES OF 5,5-DIPHENYL-TETRAHYDRO GLYOXALINE-4-ONE (SKF NO. 2599)

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

Quantitative anticonvulsant assays of 5,5-diphenyl-tetrahydroglyoxaline-4-one (SKF No. 2599) in comparison with diphenylhydantoin (Dilantin) were performed by a variety of electroshock and chemoshock seizure threshold and pattern tests in mice and rats. In addition, SKF No. 2599 was tested in cats and rabbits, and in psychiatric patients undergoing electroshock therapy. On the basis of the results obtained the following conclusions have been reached.

(1) SKF No. 2599 is less neurotoxic than diphenylhydantoin in mice. Direct toxicity comparison in rats is not possible because of the limited absorption of diphenylhydantoin after its oral administration in this species. In mice, SKF No. 2599 is less potent than diphenylhydantoin in its ability to modify seizure pattern, but it is generally more potent in its ability to elevate seizure threshold. In rats, both SKF No. 2599 and diphenylhydantoin are essentially equipotent in their ability to modify the maximal electroshock seizure pattern and to raise the threshold for minimal electroshock seizures in hyponatremic animals, but SKF No. 2599 also effectively elevates the threshold for minimal electroshock seizures in normal rats. The generally higher margin of safety of SKF No. 2599 is a direct result of its lower neurotoxicity. SKF No. 2599 also exhibits marked ability to prevent maximal electroshock and maximal Metrazol convulsions in cats and rabbits.

(2) SKF No. 2599 is able to modify or to abolish the maximal seizures induced by therapeutic electroshock in psychiatric patients. Effective doses occasionally produce mild and transient untoward responses (nausea, drowsiness).

(3) Substitution of 2 atoms of hydrogen for the oxygen on the carbon in position 2 of diphenylhydantoin to yield SKF No. 2599 decreases anticonvulsant potency and toxicity but increases margin of safety. The oxygen on the carbon of the urea moiety of diphenylhydantoin is not essential for anticonvulsant activity.