Phenytoin: 80 years young, from epilepsy to breast cancer, a remarkable molecule with multiple modes of action.

In 1908 phenytoin (5,5-diphenylhydantoin) was first synthesized as a barbiturate derivative in Germany by professor Heinrich Biltz (1865-1943) and subsequently resynthesized by an American chemist of the pharmaceutical company Parke-Davis in 1923 in Detroit. Screening phenytoin did not reveal comparable sedative side effects as barbiturates and, thus, Parke-Davis discarded this compound as a useful drug. In 1936, phenytoin's anticonvulsive properties were identified via a new animal model for convulsive disorders, developed by Putnam and Merritt, who also evaluated its clinical value in a number of patients in the period 1937-1940. For many diseases, mechanism of action of phenytoin remains obscure. The voltage-gated sodium channel was and is generally regarded as the main target to explain phenytoin's activity as an anticonvulsant and an anti-arrhythmic drug. This target, however, does not explain many of the other clinical properties of phenytoin. We will explore a number of original articles on phenytoin published in its 80 years history and give extra attention to the various hypothesis and experiments done to elucidate its mechanisms of action. Phenytoin has been explored in over 100 different disorders; the last two promising indications tested in the clinic are breast cancer and optic neuritis. Most probably, there are multiple targets active for these various disorders, and the insight into which targets are relevant is still very incomplete. It is remarkable that many pharmacological studies tested one dose only, mostly 50 or 100 µM, doses which most probably are higher than the non-plasma bound phenytoin plasma levels obtained during treatment.

How did phenobarbital's chemical structure affect the development of subsequent antiepileptic drugs (AEDs)?

Phenobarbital has been in clinical use as an antiepileptic drug (AED) since 1912. The initial clinical success of phenobarbital and other barbiturates affected the design of subsequent AEDs (e.g., phenytoin, primidone, ethosuximide), developed between 1938 and 1962, the chemical structures of which resemble that of phenobarbital. However, the empirical discovery of carbamazepine (1962) and the serendipitous discovery of valproic acid (1967) led to subsequent AEDs having chemical structures that are diverse and completely different from that of phenobarbital. Sixteen AEDs were introduced between 1990 and 2012. Most of these AEDs were developed empirically, using mechanism-unbiased anticonvulsant animal models. The empirical nature of the discovery of these AEDs, coupled with their multiple mechanisms of action, explains their diverse chemical structures. The antiepileptic market is therefore crowded. Future design of new AEDs must have a potential for treating nonepileptic central nervous system (CNS) disorders (e.g., bipolar disorder, neuropathic pain, migraine prophylaxis, or restless legs syndrome). The barbiturates were once used as sedative-hypnotic drugs, but have been largely replaced in this role by the much safer benzodiazepines. In contrast, phenobarbital is still used worldwide in epilepsy. Nevertheless, the development of nonsedating phenobarbital derivatives will answer a clinical unmet need and might make this old AED more attractive.

Drug treatment of epilepsy in the century of the ILAE: the first 50 years, 1909-1958.

This paper provides a review of the drug treatment of epilepsy from 1909, the year of the foundation of the International League Against Epilepsy (ILAE), to 1958. It was during this period that modern approaches to the medicinal therapy of epilepsy were formulated and many new drugs were introduced. Of these, both phenytoin and phenobarbital continue to be widely used today. This was the period when scientific screening was also introduced into drug discovery. The leading figures in the ILAE played an important role in guiding the evolution of the treatment of epilepsy during this period.

Clinical experience with new antiepileptic drugs: antiepileptic drugs in Europe.

The use of antiepileptic drugs (AEDs), singly and in combination, has been marked by variation among European countries and by a slow progress toward a standard of care that is still far from uniform. Phenobarbital, phenytoin, trimethadione, and primidone, given in various combinations, were the predominant agents used in the first half of this century. Prescribing habits differed among the Latin countries, the United Kingdom, and Scandinavia, based on local trends, divergent teaching philosophies of medical schools, and the medical specialty of the prescribing physician. The advent of carbamazepine and valproate, in the early 1960s, changed European prescribing habits. Despite early fears regarding bone marrow toxicity, carbamazepine was found to be superior for treatment of complex partial seizures. Valproate, when the proper therapeutic dosage was belatedly realized, was seen as a superior treatment for generalized and partial epilepsies. Both agents are now considered first-line treatments for these seizure types. The role of the benzodiazepines as adjunctive anticonvulsant therapy remains controversial because of concerns about neurotoxicity and patient tolerance. The number of AEDs marketed in Europe has grown dramatically in the past decade, with agents such as felbamate, gabapentin, lamotrigine, and tiagabine having been approved as either adjunctive or sole therapy. However, not all new agents are available in each European country, and some variation in prescribing persists.

Putnam, Merritt, and the discovery of Dilantin.

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."

Discovery of phenytoin.

Numerous letters and reports located in the Parke, Davis and Smithsonian files add to the story of Merritt's and Putnam's discovery of the anticonvulsant (AC) properties of phenytoin. The major events preceding this work were the fortuitous discovery of phenobarbital as an AC agent, structure/hypnotic activity studies with barbiturates and hydantoins in the early 1920s by A. W. Dox in the Parke, Davis laboratories, and the development of AC assay techniques in animals, by a number of laboratories. Phenytoin was the first item on the list of compounds sent to Putnam by Dox and W. G. Bywater in April 1936. It was found to have AC properties in animals late in 1936, but no public reports were issued until the following year. Clinical efficacy was established in 1937, but no public reports were issued until 1938. Dilantin sodium capsules were prepared by Parke, Davis & Co. and were ready for marketing the same year.

Landmark article Sept 17, 1938: Sodium diphenyl hydantoinate in the treatment of convulsive disorders. By H. Houston Merritt and Tracy J. Putnam.

In a previous study it has been shown that sodium diphenyl hydantoinate is effective in preventing electrically induced convulsive seizures in cats. The drug is relatively nontoxic and well tolerated by the usual laboratory animals. A clinical trial of sodium diphenyl hydantoinate was made in 200 patients with frequent convulsive seizures which had not been relieved by the previous modes of therapy. In 142 such patients who have received the treatment for periods varying from two to eleven months, grand mal attacks were relieved in 58 per cent and greatly decreased in frequency in an additional 27 per cent; petit mal attacks were relieved in 35 per cent and greatly decreased in frequency in an additional 49 per cent, and psychic equivalent attacks were relieved in 67 per cent and greatly decreased in frequency in 33 per cent. There were no fatalities. A toxic dermatitis occurred in ten patients (5 per cent), nonthrombocytopenic purpura in one patient and minor (in many instances, transient) toxic reactions, tremors, ataxia, dizziness and the like in approximately 15 per cent.