EFFECTS OF CHRONIC ADMINISTRATION OF ANTICONVULSANT DRUGS, ALONE AND ON COMBINATION WITH DESOXYCORTICOSTERONE, ON ELECTROSHOCK SEIZURE THRESHOLD AND TISSUE ELECTROLYTES

¹ Department of Pharmacology, University of Utah College of Medicine, Salt Lake City, Utah

Diphenylhydantoin given chronically to rats elevated the electroshock seizure threshold (EST) by 15 per cent. This result contrasts sharply with the ineffectiveness of single doses of the drug. Chronic administration of diphenylhydantoin in combination with DCA caused an increase in the EST (31 per cent) greater than the sum of the increases produced by the two drugs given separately.

Chronic treatment with phenobarbital elevated the EST by 28 per cent. The combination of phenobarbital and DCA increased the EST by 45 per cent, an elevation which is greater than the sum of the increases produced by the two drugs given separately.

In the dose used, trimethadione given chronically did not elevate the EST during the nineteen-day period of observation. Trimethadione in combination with DCA increased the EST to a much greater extent than did DCA alone, for the first five days; the EST then declined steadily until at the end of nineteen days it was lower than that of animals which received DCA alone. The initial action of trimethadione to enhance the effect of DCA on the EST is considered as one of true potentiation.

The effects of chronic treatment with diphenythydantoin, phenobarbital and trimethadione, alone and in combination with DCA, on electrolyte metabolism in cerebral cortex, plasma, skeletal muscle and heart muscle are presented. No significant influence on brain electrolytes was noted. DCA produced au increase in Na and decrease in K concentration in skeletal muscle and heart muscle; skeletal muscle showed the more marked change after DCA. Diphenylhydantoin accentuated the effect of DCA on skeletal muscle Na and K concentration. Phenobarbital and trimethadione alone had no significant influence on skeletal muscle and heart muscle electrolyte concentration.

Diphenyihydantoin caused pituitary-adrenocortical stimulation, as shown by its ability to increase adrenal weight when given alone and in combination with DCA. Phenobarbital and trimethadione had no such effect on adrenal weight.

Phenobarbital in combination with DCA produced a greater increase in body weight than did DCA alone. Diphenylhydantoin in combination with DCA resulted in less gain in body weight than did DCA or diphenylhydantoin alone. A possible explanation of these results is presented.

The importance of chronic administration in assessing the value of candidate agents for potential usefulness as antiepileptic drugs is emphasized and discussed.

The experiments reported herein provide an experimental basis for the use of DCA as a supplement to anticonvulsants in the treatment of epilepsy.

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