Putnam, Merritt, and the Discovery of Dilantin®

Abstract

In the first part of this essay, the "common wisdom" about Putnam and Merritt's contributions to the treatment of epilepsy was summarized (Rowland, 1982). Based on the history that has been presented here, how true are these "wisdoms"? Putnam and Merritt did devise "a simple and reliable method to test drugs of anticonvulsant effect" and they did show "that anticonvulsant effects in cats accurately predicted effects in humans," but others before them had done these same things. Dilantin, contrary to common wisdom, was not the first anticonvulsant drug to be tested in animals before it was given to human subjects; at least a year before, Cobb and his co-workers had done the same thing using vital dyes. However, Dilantin did represent the first time an anticonvulsant tested in animals was subsequently studied in a large series of patients. Nor were Putnam and Merritt the first to show that "anticonvulsant and sedative effects of drugs could be separated." Potassium borotartrate, ketogenic diet, ketone bodies, and vital dyes were anticonvulsive without necessarily being sedative. However, Putnam and Merritt were probably the first to make so explicit a statement to this effect. It may well have been this particular statement--and the fact that it was so well heard by other researchers--that represented their greatest achievement. In Kuhn's theory of scientific revolutions, the great step forward may not be so much the accumulation of evidence that the existing paradigm is not a feasible one, but rather the use of this evidence to form a new model or paradigm which is then accepted by normal science in such a fashion that the results prove to be productive. This, it would seem, is what Putnam and Merritt did. From it came their own major discovery, Dilantin, which, in Rowland's words, remains "a mainstay of treatment" for epilepsy up to the present time, and which "opened the way to the development of other anticonvulsant drugs."

Frontmatter

“…As Friedlander points out in his excellent review (from which this account is heavily drawn [12]), the discovery of phenytoin -as innovative as indeed it was -should be considered within the context of the times. There had of course been an enormous growth in organic chemistry in the previous 30 years.…”

“…It was in general use as a hypnotic in the 1920s and 1930s and although there was little doubt that it was clinically effective in epilepsy, it was not widely used because of toxicity. By the early 1930s, it had also been recognized that Nirvanol was a racemic mixture and that the drug toxicity could be reduced by removing the laevo derivative without altering beneficial effects [12,13], but the drug was not tested in any large clinical trial. Mesantoin was the second antiepileptic drug (AED) (after phenytoin) to be introduced into wide practice, and became very popular.…”

“…The discovery of phenytoin itself has an interesting history, which was well rehearsed in the subsequent 50 years. In its retelling, facts may have been jumbled and Friedlander's paper on the subject is a model of historical detective work [12].…”

“…Cohen et al [36] for instance summed up contemporary opinion in 1940 in a paper submitted to the American Psychopathological Association [12] in which they concluded that the history of drug treatment in epilepsy could be divided into three epochs, the first of bromide, the second of phenobarbital and 'the third era is very recent in origin and is characterized by the introduction in 1938 of Dilantin Sodium'.…”

Phenytoin

“…Almost two-thirds of a century after its introduction into therapeutics, the drug remains extensively used worldwide, and has served as the paradigm for the development of many of the antiepileptic drugs (AEDs) which have subsequently been marketed. Several accounts of the discovery of phenytoin are available [1,2].…”