Luck, the wrong theory, and try it again: A history of the development of phenytoin, lamotrigine, and carbamazepine as anticonvulsants
Edward J. FINE1 and Sarah G. FINNEGAN2
Background: An ideal anti-convulsant should stop seizures, be dosed once or twice daily, have no incapacitating side effects, not interact with other drugs, not cause alteration of endogenous or exogenous hormones, cause no harm to a fetus or be excreted in mothers’ milk. Methodical searches for an ideal anticonvulsant began with phenytoin.
Hypothesis Examining the history of development of phenytoin, lamotrigine, and carbamazepine may provide conclusions about the methods of selection of putative anti-convulsants.
Results: H. Houston Merritt (1902-1979) and Tracy J. Putnam (1894-1975) collaborating at the Boston City Hospital (BCH) Epilepsy Unit recognized that phenobarbital, the leading anti-convulsant in 1930’s, caused side effects of ataxia and sedation. Writing to all drug manufacturers in the USA for potential anti-convulsant drugs, they received samples only from Parke-Davis. They developed a unique method to measure the maximum electrical stimulus (MES) needed to convulse cats. Diphenylhydantoin (phenytoin) raised the seizure threshold from 15 mA to 45 mA. Cats given enough phenobarbital to stop seizures were ataxic or somnolent in comparison with alert cats treated with phenytoin. They discovered phenytoin’s efficacy for generalized, partial simple motor and complex partial human seizures.
Lamotrigine was tested as an anti-convulsant, despite an incorrect theory that an effective anti-convulsant must reduce serum folate. In an open label study, Edward Reynolds demonstrated that about 50% of epileptics who were treated with phenytoin and megaloblastic anemia had increased seizures when treated with folic acid to correct anemia. Lamotrigine, a triazine, reduced serum folic acid. Despite a later double blind crossover study showed that folic acid did not increase seizures, Wellcome Laboratories used the MES test to determine that lamotrigine (LTG) was an anti-convulsant for rodents. Human studies showed LTG had efficacy for partial and generalized seizures and less cognitive impairment than with comparable doses of phenytoin.
Geigy Pharmaceutical developed carbamazepine (CBZ) as an anti-depressant to compete with a rival drug, but CBZ failed. However several patients, co-morbid for seizures, reported fewer seizures during the CBZ trial. CBZ raised the MES threshold in dogs and cats. Lorgé confirmed CBZ controlled generalized and partial seizures. Later studies demonstrated that CBZ produced less cognitive impairment than phenytoin. Both drugs are implicated in causing neural tubule closure defects in fetuses, because they may lower a mother’s serum folate.
Conclusion: These examples demonstrate that luck; illogical reasoning and acting clinical observation have provided some of the current anti-convulsants. Molecular structural analysis of putative anti-convulsants may provide drugs that are closer to the ideal in the future.
Pavia, Italy, 2006