New Antiepileptic Drugs

TREATMENT OF CHILDREN WITH SEIZURES New antiepileptic drugs ROGER J. PORTER, MD EW medications are the best hope for tens of that could be used to test anticonvulsant activity, the thousands of patients in the United discovery of the antiepileptic effect of bromide and States—and many more worldwide—for phenobarbital was serendipitous. Later, with the devel- control of their epileptic seizures. Only a opment of seizure models, the search for new AEDs was Nfew patients whose disease is currently refractory to based on scientific screening programs. available medications can be considered for surgical The year 1937 marked the beginning of the experi- intervention; other nonmedical therapies such as bio- mental evaluation of promising anticonvulsant chemi- feedback appear to have a similarly limited role. This cals prior to clinical use. Employing a seizure model paper examines a few of the issues related to the based on a new electroshock technique for producing development of new antiepileptic drugs (AEDs) and convulsions in animals,5 Merritt and Putnam6-7 considers some of the data on the most important of screened a group of compounds supplied to them by these new compounds. Current therapy has been re- Parke-Davis and discovered the anticonvulsant proper- viewed in detail elsewhere.1-2 ties of phenytoin, then called diphenylhydantoin. Be- cause phenytoin was well tolerated by laboratory animals, it was subjected to clinical trials in 1938 and EARLY ANTIEPILEPTIC DRUGS marketed that same year. The absence of a sedative effect and the dramatic control of seizures observed In the nineteenth century, bromides were widely when phenytoin was added to barbiturate therapy were used as antiepileptic agents. In the United States, the the key factors in its rapid marketing. In addition, its modern history of AEDs begins in 1912 with the entry into the market was not delayed by regulatory introduction of phénobarbital, a synthetic sedative- requirements, since at that time the introduction of hypnotic drug which was shown to reduce seizure new drugs was controlled by the Federal Food and frequency (Table I).3 Drugs Act of 1906, which mandated that drugs be As it proved to be more effective and less toxic than accurately labeled but required proof of neither safety 8 potassium bromide, phénobarbital soon became the nor efficacy. drug of choice. Since the barbituric acid molecule is The reliability and quantitative capacity of Merritt's easily modified, many analogues of phénobarbital were method demonstrated the feasibility of testing new synthesized, of which approximately 50 were marketed chemicals for anticonvulsant activity.4 Administration in the first 35 years of this century. One of these to humans, a more costly, time-consuming, and risky analogues, mephobarbital, demonstrated good antiepi- procedure, was reserved for the most effective experi- leptic activity and was marketed in the United States in mental compounds that emerged from animal testing 1935.4 programs. In addition, the process through which In the absence of experimental models of seizures phenytoin came onto the market demonstrated that academic investigators could work successfully with the pharmaceutical industry, encouraging a relationship From the National Institute of Neurological and Communicative Disorders and Stroke, National Institutes of Health, Bethesda, that flourished for the next 20 years. Maryland. In 1944, Richards and Everett9 reported that trimeth- S-260 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 56 SUPPL. PART 2 Downloaded from www.ccjm.org on September 28, 2021. For personal use only. All other uses require permission. NEW ANTIEPILEPTIC DRUGS • PORTER TABLE 1 tors, began in 1968 to con- ANTIEPILEPTIC DRUGS MARKETED IN THE UNITED STATES duct controlled clinical Year International U.S. Trade trials of seven drugs, many Introduced Nonproprietary Name Name Company of which were already marketed abroad.4 Between 1912 phenobarbital Luminal Winthrop 1935 mephobarbital Mebaral Winthrop 1974 and 1978, three of 1938 phenytoin Dilantin Parke-Davis these drugs—carbamaze- 1946 trimethadione Tridione Abbott pine, clonazepam, and val- 1947 mephenytoin Mesantoin Sandoz 1949 paramethadione Paradione Abbott proic acid—were approved 1950 phethenylate* Thiantoin Lilly as primary antiepileptic 1951 phenacemide Phenurone Abbott agents; clorazepate dipotas- 1952 metharbital Gemonil Abbott 1952 benzchlorpropamidet Hibicon Lederle sium was marketed in 1981 1953 phensuximide Milontin Parke-Davis as an adjunctive drug. 1954 primidone Mysoline Ayerst These efforts by the Epilepsy 1957 methsuximide Celontin Parke-Davis 1957 ethotoin Peganone Abbott Branch became known as 1960 aminoglutethimidet Elipten Ciba the Antiepileptic Drug De- 1960 ethosuximide Zarontin Parke-Davis velopment (ADD) Pro- 1968 diazepam Valium Roche gram. Since its inception 1974 carbamazepine Tegretol Geigy 1975 clonazepam Clonopin Roche this program has encouraged 1978 valproic acid Depakene Abbott the search for new AEDs by 1981 clorazepate dipotassium§ Tranxene Abbott conducting and/or funding screening programs for new • Withdrawn in 1952. compounds, toxicity testing t Withdrawn in 1955. t Withdrawn in 1966. for advanced and promising § Approved by the FDA as an adjunct. preclinical compounds, and clinical trials. As a result, waning interest in the adione, a potent analgesic compound that was to United States in new medical therapies for epilepsy has been replaced by a productive coalition of government, become the first antiabsence drug, prevented threshold 12 seizures induced by pentylenetetrazol (PTZ) in rodents. industry, and academia. They also showed that these seizures were prevented by phenobarbital, but not by phenytoin.9 Goodman et 10 al confirmed these results and demonstrated that PRECLINICAL DRUG DEVELOPMENT phenytoin and phenobarbital modified the pattern of maximal electroshock (MES) seizures while trimeth- All drugs currently in use have some effect in either adione did not. These findings indicated the varying MES or PTZ models, even though many were not anticonvulsant actions of these drugs and the quali- discovered by experimental means. Furthermore, drugs tative difference between threshold and maximal tend to be profiled clinically as a function of their seizures.4 effectiveness in these two models. Phenytoin, which is Interestingly, all AEDs developed from 1912 to 1960 effective in partial and generalized tonic-clonic sei- were based on a simple heterocyclic ring structure zures, is effective against MES but not against PTZ (Figure 1). (when used as a threshold test). Ethosuximide, which is During this period, genuinely novel structures were effective against absence seizures in humans, has more ignored in the development of AEDs; instead, atten- effectiveness against PTZ. These two tests—considered tion centered on the hydantoins, barbiturates, oxazo- by some to represent together the final common path- lidinediones, succinimides, and acetylureas.4 By the way for many epileptic seizures—have been further late 1960s, for a variety of reasons, very few innovative refined and used to screen more than 12,000 com- AEDs were under development.11-12 In an effort to pounds in the ADD program of the Epilepsy Branch.4 reverse this trend, the Epilepsy Branch of the National The screening is performed in a progressively more Institute of Neurological and Communicative Disor- sophisticated manner, with the elimination of less ders and Stroke, in collaboration with other investiga- promising compounds at each step.13 VOLUME 56 SUPPL. PART 2 CLEVELAND CLINIC JOURNAL OF MEDICINE S-261 Downloaded from www.ccjm.org on September 28, 2021. For personal use only. All other uses require permission. NEW ANTIEI'ILEI'TIC DRUGS • PORTER was the search for drugs that act—by various mecha- B nisms—to enhance neuronal inhibition. The second and more recent phase of rational approach to AED development has been the effort to find drugs that HCCV C H CCH diminish neuronal excitation. These approaches have 5 6X / 2 5 6" "5 J been considered in some detail by Meldrum.14 \ H5C6-C / \ 0=C, NH NH \ / / CLINICAL DRUG DEVELOPMENT HN- HN- A potential drug must successfully undergo a variety of clinical studies before being approved for use by the general public. These studies may include early toler- ance and pharmacologic trials in normal volunteers as well as pilot studies of potential efficacy, but the controlled trial to evaluate efficacy is usually the most difficult and the most important. In any clinical trial, CH, ÇH2CH3 P the peculiarities of the disorder being treated must be examined. Clinical trials in epilepsy, therefore, have to H3C-C H3C-C \ \ be designed to deal with the characteristics of that complex disorder. Of primary importance is the real- /N-CH3 ization that many different syndromes are included in \\ r H2C- the epilepsies, so that, to be meaningful, data must be collected from a differentiated group of epileptic per- sons. Patients are usually categorized according to clinical seizure type. Fortunately, this categorization is FIGURE 1. Heterocyclic ring structure: phénobarbital based upon very empirical information and correlates (A); phenytoin (B); trimethadione (C); ethosuximide (D). well with the various therapeutic measures. Clinical seizure types are usually classified according to the 1981 15 One of the major arguments against the use of International Classification of Epileptic Seizures, and MES and PTZ is that the mechanisms by which drugs the resulting data serve as

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