Louis S. Goodman

The anticonvulsant properties of tridione: Laboratory and clinical investigations

T RIDIONE, 3,5,5-trimethyloxazolidine2, 4-dione, has recently been made available to physicians as a specific symptomatic therapy for petit ma1 epilepsy, and has been accepted by the Council on Pharmacy and Chemistry of the American Medical Association for inclusion in New and Nonofficial Remedies. The drug was synthesized by Spielman31 and initially studied and reported as an analgesic agent. 26,28 Its pharmacological and anticonvulsant properties were described by Richards and Everett8r26,27,28 and by LIS.~~~~~,-

THE EFFECT OF EXPERIMENTALLY-INDUCED STRESS ON PENTYLENETETRAZOL SEIZURE THRESHOLD IN MICE.

SummaryThe effect of 20 min of intermittent foot shock on spontaneous activity and overt behavior was studied in mice. In addition, the effect of a pain-induced conditioned emotional response, and of total body immobilization and postural disequilibrium on the pentylenetetrazol seizure threshold was determined. Foot shock decreased spontaneous motor activity, and induced responses characterized by immobility, crouching, and increased defecation. The pain-induced conditioned emotional response, total body immobilization, and postural disequilibrium all lowered seizure threshold. Data are presented which indicate that there is a direct relation between the reduction in seizure threshold and the intensity of the disturbed emotional state. In addition, it is suggested that the observed increase in brain excitability caused by apprehension and anxiety may result from the effect of endogenouslyreleased catecholamines on the central nervous system. Reference is made to the relation between these findings and the effect of emotional disturbances on seizure frequency in human epileptics.

Antagonism of Adrenocortical Extract and Cortisone to Desoxycorticos-terone Brain Excitability in Adrenalectomized Rats.

SummaryThe electroshock seizure thresholds (EST) of intact and adrenalectomized rats implanted with desoxycorticosterone acetate (DCA) and given water or a 0.9% sodium chloride solution to drink have been measured. The rate of elevation of EST was as follows, in increasing order: intact controls on water; intact DCA-implanted animals on water; adrenalectomized DCA-implanted rats on water; adrenalectomized DCA-implanted rats on 0.9% sodium chloride solution. These rates correspond to those predicted on the basis of the known effects of the secretion of the adrenal cortex and the concentration of extracellular sodium on brain excitability. Cortisone and adrenocortical extract (ACE) lowered the elevated EST of adrenalectomized DCA-implanted rats which were given a solution of sodium chloride to drink by 8.5% in 6 days. Following withdrawal of cortisone or ACE the EST returned to pretreatment levels in 11 days. Cortisone lowered the elevated EST of adrenalectomized DCA-implanted rats given water to drink by 1...Summary The electroshock seizure thresholds (EST) of intact and adrenalectomized rats implanted with desoxycorticosterone acetate (DCA) and given water or a 0.9% sodium chloride solution to drink have been measured. The rate of elevation of EST was as follows, in increasing order: intact controls on water; intact DCA-implanted animals on water; adrenalectomized DCA-implanted rats on water; adrenalectomized DCA-implanted rats on 0.9% sodium chloride solution. These rates correspond to those predicted on the basis of the known effects of the secretion of the adrenal cortex and the concentration of extracellular sodium on brain excitability. Cortisone and adrenocortical extract (ACE) lowered the elevated EST of adrenalectomized DCA-implanted rats which were given a solution of sodium chloride to drink by 8.5% in 6 days. Following withdrawal of cortisone or ACE the EST returned to pretreatment levels in 11 days. Cortisone lowered the elevated EST of adrenalectomized DCA-implanted rats given water to drink by 10% in 3 days; following withdrawal of cortisone the EST returned to the pretreatment level in 2 days. It has been suggested that the results obtained provide evidence for the concept that cortisone and DCA compete for strategic loci in target cells.

Anticonvulsant Properties of Benadryl, Pyribenzamine

Summary Benadryl, Pyribenzamine and Dilantin were tested in rats for toxicity and for ability to modify maximal electroshock seizure pattern and to prevent Metrazol convulsions. The data indicate that all three drugs modify maximal electroshock seizure pattern but do not prevent Metrazol convulsions. The significance of the data is discussed.

Anticonvulsant Properties of 5,5-Phenyl Thienyl Hydantoin in Comparison with Dilantin and Mesantion.∗†‡

Summary A new anticonvulsant, 5,5-phenyl thienyl hydantoin, proposed for the treatment of epilepsy, has been compared with Dilantin and Mesantoin and Mesantoin by 4 different assay methods in rats and examined for its ability to modify the electroshock seizure pattern in man. The thienyl congener more closely resembles Dilantin than Mesantoin in its spectrum of antiepileptic actions.

Anticonvulsant properties of l-glutamine and l-asparagine in mice and rats.

Summary Two amides, l-glutamine and l-asparagine, were tested for anti-convulsant activity in mice after acute administration by a battery of 6 anticonvulsant assay procedures and after chronic administration by 3 tests. In addition, both agents were tested in mice for ability to prevent methionine sulfoximine-induced seizures and in rats for ability to elevate the minimal electroshock seizure threshold lowered by food restriction. The results indicate that both these agents are virtually devoid of anticonvulsant activity as measured by a number of diverse laboratory screening procedures.

Postictal Recovery in Normal and Diphenylhydantoin (Dilantin)-Treated Mice.∗:

Summary In order to study postictal recovery, groups of normal and Dilantin-treated mice were given a supramaximal electroshock and the durations of the hindleg components of the “first” seizure recorded. At various time intervals after the “first” seizure, a “second” supramaximal electroshock was given and the durations of the hindleg components of the “second” seizure recorded. This procedure was repeated, with longer time intervals between seizures, until the observed durations of the “second” seizure components were not significantly different from their “first” seizure values. In addition, the time (RT50) required for 50% of animals to recover ability to exhibit a second tonicclonic seizure after a first was determined. The data obtained may be summarized as follows: The order in which the durations of the various components and the total duration of the “second” seizure returned to their “first” seizure values were the same in both groups: total seizure duration, terminal clonus, tonic extension, and tonic flexion. The total duration of a maximal seizure is relatively independent of marked changes in duration of the individual seizure components. Dilantin prolonged the recovery time of terminal clonus, tonic extension, and tonic flexion by approximately 300%, 150%, and 170%, respectively. In addition, Dilantin prolonged RT50 by 325%. Evidence is presented which suggests that Dilantin acts to prolong the latent period before recovery of the tonic-extensor component starts, and that the recovery process per se, once initiated, is relatively unaffected by the drug.

Effect of Liver Damage and Nephrectomy on Convulsant Potency of Pentylenetetrazol (Metrazol)

Summary The convulsant potency of intravenously administered Metrazol for maximal and minimal seizures was determined in control, liver-damaged, and nephrectomized mice. In addition, the convulsant potency of subcutaneously administered Metrazol for minimal seizures was determined in control, liver-damaged, nephrectomized, and sham-operated mice and rats. The results obtained were analyzed to determine the relative importance of the liver and the kidney in the fate and excretion of the drug. Neither liver damage nor nephrectomy had any significant effect on the potency of intravenously administered Metrazol for maximal or minimal seizures. Liver damage significantly increased the potency of subcutaneously administered Metrazol for minimal seizures; on the other hand, bilateral nephrectomy and sham operation had no significant effect on the potency of this drug. The data indicate that, in both mice and rats, the liver is the principal organ for the conversion of Metrazol into products devoid of convulsant activity, and that, within the time required for the complete absorption of subcutaneously injected Metrazol, the kidney plays no important role in the metabolic alteration or excretion of this compound.

Effects of Liver Injury and Nephrectomy on the Anticonvulsant Activity of Phenacemide.

Summary Phenurone was tested at various time intervals after administration in normal, liver-injured and nephrectomized rats for its ability to prevent the tonic extensor component of maximal electroshock seizures. The results were analyzed for the effect of liver injury and nephrectomy on the potency and the duration of anticonvulsant action of this compound. Liver injury significantly increased the potency and the duration of anticonvulsant action; on the other hand, bilateral nephrectomy had no significant effect on the anticonvulsant properties of this agent. The results suggest that, in the rat, the liver is the principal organ for the degradation of Phenurone into products devoid of anticonvulsant action, and that the kidney plays no important role in the metabolic alteration or excretion of this compound.