INTRODUCTION
Today we have many agents with us to treat epilepsy. However, the story of how these agents were discovered is very interesting and fascinating. Many agents were not originally intended to be used as antiepileptics and their antiepileptic properties were accidentally discovered.
BROMIDE: FIRST AED EVER USED
The story begins in the 18th century and the credit of being the first antiepileptic drug (AED) used for treating epilepsy goes to bromide (Table 1 and Fig. 1).
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On May 11, 1857, Sir Charles Lacock, who was Queen Victoria's personal physician, first mentioned the use of bromide for treating epilepsy at a meeting of the Royal Medical and Chirurgical Society held in London.1 He had successfully treated a female suffering from so-called “hysterical epilepsy” using bromide. In that era, epilepsy was attributed to uterine irritation, sexual excitement and menstruation (hence the term hysterical epilepsy; hysteros = uterus). Probably the patient Lacock had treated and other subjects with so-called “hysterical epilepsy” might have had catamenial epilepsy. Why Lacock thought of using bromide in epilepsy? Because he had read a German report, which stated that bromide caused reversible sexual impotence prompting him to use it in the female suffering from epilepsy to calm down her sexual excitement/uterine irritation.1 However, Lacock did not publish his experience about the efficacy of bromides until Dr Charles Bland Radcliffe credited him with the discovery of bromides in 1860 based on his personal experience of the use of bromides in effectively controlling epilepsy. Gradually, bromide became a popular agent for treating epilepsy and remained so for many years. However, its use was associated with bromism, which manifested with dermatological conditions such as severe rash and psychological symptoms such as irritability, emotional instability, schizophrenia-like psychosis, memory disturbance and dementia. This led to a gradual decline in the popularity of bromide.2 The subsequent emergence of phenobarbitone as a safe and effective AED led to the almost complete demise of this drug.3
ACCIDENTAL DISCOVERY OF PHENOBARBITONE
The antiepileptic properties of phenobarbitone were accidentally discovered by Alfred Hauptmann, a German psychiatrist in the year 1912. Before its antiepileptic properties were discovered, phenobarbitone (then branded as Luminal) was used as a hypnotic/sedative drug, which was marketed by F. Bayer and Company. Hauptmann in his residency days used to stay near a ward full of epilepsy patients. He was particularly troubled by patients having seizures at night because of which they kept falling out of bed. To have a sound sleep at night, he once gave phenobarbitone to his patients with an intention to sedate them. Not only did he sleep well that night but to his surprise patients who were given phenobarbitone did not have seizures next day leading him to publish his findings and thus highlighting antiepileptic properties of this drug.3 To commemorate his landmark contribution in the field of epilepsy, the Alfred-Hauptmann Award is given for epilepsy research. Phenobarbitone after its discovery continued to remain a popular and effective AED even till date. However, sedative properties of phenobarbitone prompted a need for the search of a less sedative but equally effective AED, which led to the discovery of phenytoin in the year 1938.
THE ERA OF CONVENTIONAL AEDS
Tracy Putnam, the director of neurology unit in Boston city hospital wanted to try out nonsedative phenyl compounds provided to him by Parke, Davis and Company. Phenytoin was the only safe compound amongst them. It was found that phenytoin was very effective in preventing electrically induced convulsions in cats. So, Putnam gave it to one of his assistant Houston Merritt for clinical use. He found out that it effectively controlled seizures in a patient who had suffered seizures for many years thus bringing it in routine practice as an effective AED without any sedative effects.4 Next anticonvulsant to be discovered was carbamazepine by a chemist Walter Schindler at JR Geigy Ltd (now Novartis), Switzerland, in 1953. He developed this tricyclic compound along with imipramine when he was trying to find alternatives for chlorpromazine.4 However, it was not first marketed as an AED but as a medication for trigeminal neuralgia in the year 1962. One year later, its anticonvulsive properties were confirmed by randomized trials and it was marketed in Europe for epilepsy in 1965. However, its use started in the USA almost a decade later in 1974 because of the fear of aplastic anemia. However, once its safety was confirmed, it became the most prescribed AED in the 1980s in Europe and still remains first choice drug for focal onset epilepsy worldwide. 4Next in the line was valproate. Valproate was synthesized not as an AED but rather as an organic solvent in 1881 by a chemist Beverly Burton, in the USA; and its anticonvulsant properties were unknown then. Pierre Eymard, who worked at Firma Berthier Laboratories in Grenoble, accidentally discovered anticonvulsant properties of valproate almost 80 years later.5 Because valproic acid was a liquid, it was used as a lipophilic vehicle to dissolve water-insoluble compounds during preclinical drug testing. Eymard had synthesized a number of khellin derivatives in the laboratory as part of his thesis. In order to evaluate the pharmacological activities of the khellin derivatives as tranquilizing agents in the rat, Carraz (one of the colleagues of Eymard) proposed to test the most active derivatives in the pentylenetetrazole (PTZ) seizure test. Apparently, all agents were found to have anticonvulsant properties. Meunier (another colleague of Eymard) dissolved a coumarin derivative in valproate to find an anticonvulsant effect in the PTZ test in rabbits. By doing this, the researchers found that it was the vehicle, valproate, which exerted an anticonvulsant effect rather than the primary drug tested.6 This unexpected finding was first presented at a meeting of the French Society of Therapeutics and Pharmacodynamics on December 19, 1962, and published by Meunier, Carraz and Eymard in the French journal Thérapie in 1963.7 It was marketed in France in 1967 and other European countries in 1970 as an AED. However, its marketing was delayed in the USA until 1978 owing to regulatory monitoring by FDA about the use of new drugs (following the thalidomide disaster). A drug named trimethadione, which was an oxazolidinedione compound, was originally identified as a specific treatment for absence epilepsy by Lennox in 1945.8 However, owing to its toxic and teratogenic effects, a research was initiated by Parke and Davis which led to the development of ethosuximide. Zimmerman and Burgemeister in 1958 were the first to report its effect in 109 cases of petit mal epilepsy after which it was marketed in 1958 for absence epilepsy.7
The major landmark in the history of epilepsy was the discovery of benzodiazepines. Credit for the same goes to Leo Sternbach, a polish Jewish chemist. While working for Hoffmann-La Roche in Nutley, New Jersey, he discovered Valium (diazepam) in 1963.9 This popular sedative became the most prescribed drug in the United States after its approval in 1963. Known as “mother's little helper”, or simply as V, nearly 2.3 billion Valium pills were sold in 1978.10 This earned tremendous profits for Roche making it a pharmaceutical giant. However, its antiepileptic properties were not harnessed until 1965 when Gastaut used diazepam for successfully treating a patient of status epilepticus after which it became a drug of choice for status epilepticus.115
THE ERA OF NEWER AEDS
After this came the era of newer AEDs. National Institute of Neurological Disorders and Stroke (NINDS) in the United States established the Anticonvulsant Drug Development Program in the year 1975. More than 28,000 chemicals were screened since then for anticonvulsant efficacy. Zonisamide was discovered by Uno et al. in 1972 in Japan during exploratory research on psychiatric drugs, where it was subsequently identified as having anticonvulsant activity during screening.12 Topiramate was discovered in 1979 by Bruce E Maryanoff and Joseph F Gardocki during their research work at McNeil Pharmaceuticals. Discovered accidently in the search for a sugar sulfamate in an antidiabetic project, topiramate was first introduced into clinical practice in 1995 and received United States Food and Drug Administration approval in 1996.13
Recently in 2012, topiramate got FDA approval for weight loss along with phentermine. Levetiracetam, which is ethyl analog of piracetam, was synthesized in 1974 by UCB Pharma as a second generation nootropic drug. However, levetiracetam did not show any significant nootropic activity. Rather it showed protection against seizure activity in the genetically sound-sensitive mouse model, suggesting potential antiepileptic properties in humans.14 However, levetiracetam was the drug which challenged conventional wisdom in AED discovery owing to its unique and unconventional mechanism of action. This prompted a change in the screening models employed both by the NIH and the pharmaceutical industry. All traditional AEDs were tested against two conventional screening models, viz., maximal electroshock seizure test and the pentylenetetrazol test. However, levetiracetam did not show any anticonvulsant properties in these two models. Rather, it effectively controlled seizures in rodents who had chronic epilepsies.14
Lamotrigine was originally synthesized by scientists at Wellcome Laboratories. In the mid-1960s, folate was considered a proconvulsant agent and the suggestion that many AEDs were folic acid antagonists, a drug discovery program was initiated keeping in reference pyrimethamine, a folic acid antagonist, previously developed for the treatment of malaria. Among the series of compounds developed, lamotrigine had the most anticonvulsant activity in animal models, although it was a weak inhibitor of dihydrofolate reductase.15 After extensive clinical trials, it was approved for use in epilepsy in 1990 in Ireland. In 1994, the FDA approved lamotrigine for adjunctive use in epilepsy in the US. Lacosamide was discovered by Dr Harold Kohn, Dr Shridhar Andurkar and colleagues at the University of Houston in 1996. They hypothesized that modified amino acids may be therapeutically useful in the treatment 6of epilepsy. A few hundred such molecules were synthesized over several years and these were tested in rats. N-benzyl-2-acetamido-3-methoxypropionamide was found to be highly efficacious, which was later renamed lacosamide after being licensed by Schwarz Pharma.16
Traditionally antiepileptic medication targeted sodium channels, calcium channels, and inhibitory GABA pathways. Excitatory neurotransmitters like glutamate were considered new targets for development for new AEDs. This led to the formulation of AMPA (glutamate receptor) antagonist perampanel, which is the latest AED approved for the treatment of epilepsy in the year 2016. The development of earlier AMPA receptor antagonists was hindered by poor blood–brain barrier permeability, structure-related toxicity, and short half-lives. Perampanel was discovered as a result of high-throughput screening campaigns, which addressed these shortcomings.17
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- Friedlander W. The rise and fall of bromide therapy in epilepsy. Arch Neurol. 2000;57(12):1782.
- Hauptmann A. Luminal bei Epilepsie. Munch Med Wochenshr. 1912;59:1907–9.
- Brodie M. Antiepileptic drug therapy the story so far. Seizure. 2010;19(10):650–5.
- Löscher W. The discovery of valproate. Valproate. 1999. pp. 1–3.
- Shorvon S. Drug treatment of epilepsy in the century of the ILAE: The second 50 years, 1959-2009. Epilepsia. 2009;50:93–130.
- Meunier H, Carraz G, Neunier Y, et al. Pharmacodynamic properties of N-dipropylacetic acid. Therapie. 1963;18:435–8.
- Rosenblum J. Trimethadione (Tridione) Nephrosis. Arch Pediatr Adolesc Med. 1959;97(6):790.
- Wick J. The History of Benzodiazepines. Consult Pharma. 2013;28(9):538–48.
- Calcaterra N, Barrow J. Classics in Chemical Neuroscience: Diazepam (Valium). ACS Chem Neurosci. 2014;5(4):253–60.
- Gastaut H, Naquet R, Poiré R, et al. Treatment of Status Epilepticus with Diazepam (Valium). Epilepsia. 1965;6(2):167–82.
- Uno H, Kurokawa M, Masuda Y, et al. Studies on 3-substituted 1, 2-benzisoxazole derivatives. 6. Syntheses of 3-(sulfamoylmethyl)-1,2-benzisoxazole derivatives and their anticonvulsant activities. J Med Chem. 1979;22(2):180–3.
- Shank R, Gardocki J, Streeter A, et al. An overview of the preclinical aspects of topiramate: pharmacology, pharmacokinetics, and mechanism of action. Epilepsia. 2000;41(s1):3–9.
- Klitgaard H, Verdru P. Levetiracetam: the first SV2A ligand for the treatment of epilepsy. Expert Opin Drug Discov. 2007;2(11):1537–45.
- Weisler R, Calabrese J, Bowden C, et al. Discovery and development of lamotrigine for bipolar disorder: A story of serendipity, clinical observations, risk taking, and persistence. J Affect Disord. 2008;108(1-2):1–9.
- Rogawski M, Tofighy A, White H, et al. Current understanding of the mechanism of action of the antiepileptic drug lacosamide. Epilepsy Res. 2015;110:189–205.
- Hanada T. The discovery and development of perampanel for the treatment of epilepsy. Expert Opin Drug Discov. 2014;9(4):449–58.