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Primidone, phenobarbitai and PEMA

II. Seizure protection, neurotoxicity, and therapeutic index of varying combinations in mice

Division of Clinical Neuropharmacology, the Department of Neurology and Neurological Surgery (Neurology), The Edward Mallinckrodt Department of Pediatrics (Drs. Bourgeois and Dodson), and the Department of Pharmacology (Dr. Ferrendelli), Washington University School of Medicine, St. Louis, Missouri, and the Division of Pediatric Neurology (Drs. Bourgeois and Dodsonl. St. Louis Children's Hospital, St. Louis, MO.

Neurotoxicity and protection against maximal electroshock (MES) and pentylenetrazol (Metrazol) seizures were determined in mice for various combinations of primidone (PRM), phenobarbital (PB), and phenyl-ethylmalonamide (PEMA). The results suggest that PRM and PB together are superior to either one alone in terms of spectrum of activity and relative toxicity. The protection against Metrazol and the toxicity of PB are both potentiated by PEMA at low concentrations. PEMA also potentiates the toxicity of combined PRM plus PB, without altering their protection against MES, thus lowering their therapeutic index. We conclude that PRM and PB together have an advantage over PB alone, especially when their brain concentration ratio is at or above 1 and PEMA concentrations are low. These conditions are usually not present at steady state in patients treated with PRM.

Address correspondence and reprint requests to Dr. Dodson, St. Louis Children's Hospital, 500 S. Kingshighway, PO Box 14871, St. Louis, MO 63178.

Supported in part by NIH Grants Nos. RR-00954 and NS-14834. Dr. Bourgeois is the recipient of a Merritt-Putnam Clinical Research Fellowship of the Epilepsy Foundation of America (now at Schweizerische Epilepsie-Klinik, Zurich, Switzerland).

Accepted for publication June 24, 1982

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