Anticonvulsant Activity and Toxicity of Phensuximide, Methsuximide and Ethosuximide

Abstract

SUMMARY The anticonvulsant properties and toxicity of phensuximide (Milontin), methsuximide (Celontin) and ethosuximide (Zarontin) have been investigated in laboratory animals. The three compounds were very effective in suppressing the initial clonic seizures induced by Metrazol in rats and mice. Whereas methsuximide and phensuximide were capable of protecting mice from tonic extensor seizures to supramaximal electroshock at non‐neurotoxic and slightly ataxic doses respectively, ethosuximide could do so only at anesthetic dose levels. The anticonvulsant spectrum of methsuximide was shown to be similar to that of phenacemide; ethosuximide, on the other hand, resembles trimethadione very closely in anticonvulsant action. A discussion was given to correlate the anticonvulsant properties of these drugs as examined in mice and their therapeutic indications for the management of petit mal, grand mal and psychomotor epilepsy. There were no abnormalities shown on hematological and biochemical analyses of the blood and on gross and microscopic examinations of various organs and tissues of rats which ingested 0.75 g/kg of the three drugs daily in the diet for 6 months, and of dogs and monkeys which received these drugs at 50 and 100 mg/kg orally, 5 days a week, for 6 months to one year. RÉSUMÉ Les propriétés anticonvulsives et la toxicité de la phensuximide (Milonttn), methsuximide (Célontin) et éthosuximide (Zarontin) ont étéétudiées sur des animaux de laboratoire. Les trois composés se sont montrés très efficaces en ce qu'ils suppriment la crise clonique initiate provoquée chez les rats et les souris par le cardiazol. Tandis que la methsuximide et la phensuximide en doses non‐neurotoxiques respectivement provoquant une légère ataxie, sont capables de protéger des souris contre des crises toniques des extenseurs causées par l'électrochoc supramaximal, l'éthosuximide ne peut agir de même qu'en des doses de niveaux anesthésiques. Le spectre anticonvulsif de la methsuximide s'est révelé semblable à celui de la phénacémide; par ailleurs, l'éthosuximide ressemble fortement en son action anticonvulsive à la triméthadione. Les auteurs discutent sur le fait d'établir une corrélation entre les propriétés anticonvulsives de ces médicaments en ce qui concerne leur action chez les souris et leurs indications thérapeutiques dans le traitement du petit mal, du grand mal et de l'epilepsie psychomotrice. On n'a pas observé d'anomalies dans les analyses hématologiques et biochimiques du sang et dans les examens microscopiques ou macroscopiques d'organes et tissus variés de rats ayant ingéré quotidiennement dans leur régime 0.75 g/kg de ces substances pendant 6 mois, et ceux de chiens et de singes les ayant reçues oralement à doses de 50 et 100 mg/kg 5 jours par semaine pendant une période de six mois à un an.

Mobile Telephones and Cancer—a Review of Epidemiological Evidence

“…Early chronic administration studies with phensuximide and methsuximide failed to demonstrate evidence for nephrotoxicity in mice, rats, dogs, or rhesus monkeys (Chen et al, 1963). In addition, when administered at several times their therapeutic dose, the three antiepileptic succinimides did not induce acute nephrotoxicity in Sprague-Dawley or Fischer 344 rats (Rankin et al, 1986a(Rankin et al, , 1990b.…”

“…The non-C-arylsuccinimide derivative, ethosuximide, is commonly used and does not appear to induce significant nephrotoxicity in humans (McNamara, 2001) or laboratory animals (Chen et al, 1963;Rankin et al, 1990b). However, a few reports of altered renal function in patients taking ethosuximide have been published.…”

The physiological disposition of 14C‐methsuximide in the rat

“…It was decided to administer "C-methsuximide at a dosage known to be effective against both leptazol-and electrically-induced convulsions. A dose of 100 mg/kg was therefore chosen (Chen et al*, 1963;Miller & Long, 1951). Radioactivity measurement Radioactivity was measured by liquid scintillation counting with a Tracerlab Coru/Matic 100 Dual Channel Scintillation Spectrometer.…”

“…Although its pharmacological and clinical efficacy has been extensively studied (Zimmerman, 1953(Zimmerman, , 1956Gibbs & Stamp, 1958;Dow, Macfarlane & Stevens, 1958;Carter & Maley, 1957;Chen, Weston & Bratton, 1963), there is no information available on the fate of the drug in animals and man apart from a recent preliminary study (Nicholls & Orton, 1971). …”

Antiepileptic Drug Development: I. History and a Program for Progress

“…A comparison of ethosuximide with its previously marketed analogs revealed it to be nearly as potent an inhibitor of subcutaneous pentylenetetrazol seizures as methsuximide, but far less potent against maximal electroshock (Chen et al, 1963).…”