Valproate: a simple chemical with so much to offer

Abstract

The debate exists amongst clinical pharmacologists as to unlimited supplies of which drug would be most useful when stranded on a deserted island. The tricyclic antidepressants have always rated highly because of their variety of useful therapeutic effects, but valproate also deserves to be high on the list. Of course, it will protect against seizures, if they arise, but it could also be useful for analgesia, preventing migraine and stabilizing the mood particularly if one becomes mentally unbalanced on the island. It might even help to prevent the development of cancer. It would not be an overstatement to suggest that valproate is truly a remarkable drug – a multitude of therapeutic effects from such a simple chemical structure (2-propylpentanoic acid; Fig. 1) – with a remarkable story; it was discovered by chance and is now well-established in the management of a number of neurological conditions and psychiatric disorders. An American chemist (Burton) first synthesized valproate as an organic solvent in 1882 (1). It is a clear, colourless to pale yellow liquid at room and body temperature, and only slightly soluble in water, but highly soluble in organic solvents. The current generic name (valproic acid) was derived from the more descriptive name 2-propylvaleric acid (2). Valproate had been used infrequently as a solvent until its therapeutic properties were serendipitously discovered in 1962 by French researchers, when it was being used as a solvent for other compounds (khelline derivatives) that were being tested for potential anticonvulsant activity (2–4). Eynard and colleagues had encountered difficulty in dissolving some of the derivatives in water or common organic solvents. Valproate was then used to solubilize these compounds and anticonvulsant activity was subsequently observed for the entire test compounds at all doses. Laboratory studies demonstrated anti-seizure activity with valproate (5) and the first clinical trial in epilepsy using the sodium salt of valproic acid was reported in 1964 (6, 7). It was released in France in 1967 (as ‘Depakine’), in Great Britain in 1973 and was approved by the US Food and Drug Administration (FDA) in 1978. It was the only new anticonvulsant drug marketed for many years, beforehand and afterwards. Valproate is currently marketed in over 100 countries and is well established as a first-line and widely used antiepileptic agent, with a very broad spectrum of activity against both generalized and partial seizures in adults and children (4, 8, 9). It is effective against absences and myoclonic, and generalized tonic-clonic seizures. In addition, the drug is useful in the treatment of partial seizures, with or without secondary generalization (2–4, 8, 9). Intravenous valproate has also been shown to be effective against status epilepticus (10). Results from numerous clinical trials suggest that valproate probably has the widest spectrum of anticonvulsant activity of all current antiepileptic drugs in adults and children with epilepsy (4, 8, 9). Received 9 May 2005, Accepted 19 May 2005 Correspondence: Gregory Peterson, Unit for Medication Outcomes Research and Education, School of Pharmacy, University of Tasmania, Locked Bag 26, Hobart TAS 7001, Australia. Tel.: 61 3 62262197; fax: 61 3 62267627; e-mail: g.peterson@utas.edu.au OH H3C H3C