The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. IV. Protective indices

Abstract

Calculation of protective or therapeutic indices is widely used in primary and secondary screening for drugs with selective anticonvulsant activity. The protective index is the median minimal 'neurotoxic' dose, TD50, divided by median effective dose, ED50. TD50s are usually determined by tests, such as the rotarod test or the chimney test, for quantification of 'minimal neurological deficit', such as motor impairment, while median effective doses are commonly determined in the maximal electroshock seizure (MES) test or the s.c. pentylenetetrazol (PTZ) seizure test in mice or rats. For antiepileptic drug development, it has been proposed previously that only compounds with an estimated protective index of at least 5 should proceed to further evaluation. However, various technical, biological and pharmacological factors can influence anticonvulsant or 'neurotoxic' potencies and thereby protective indices. In order to reevaluate the value of protective indexes in the prediction of drugs with selective anticonvulsant action, protective indices were determined for various clinically used antiepileptic drugs in standardized seizure tests, i.e. MES and s.c. PTZ tests in mice and rats, as well as in seizure threshold tests. For most drugs, similar TD50s were determined in the rotarod and chimney test. When protective indices were calculated for the different seizure models, only few drugs reached an index of 5 (some not even reaching an index of 2) in the traditional MES or s.c. PTZ tests in mice and rats. In contrast, using anticonvulsant doses determined by seizure threshold tests, the 5 primary drugs against generalized tonic-clonic seizures, i.e., carbamazepine, phenytoin, phenobarbital, primidone and valproate, had indices of more than 5 in the MES threshold model, while drugs with efficacy against absence and myoclonic seizures, i.e., valproate, ethosuximide and the benzodiazepines, had protective indices of at least 5 in the i.v. PTZ seizure threshold model. The data substantiate that valuable information can be obtained by estimation of protective indices. However, in order to minimize the possibility that an interesting new anticonvulsant compound is overlooked during primary or secondary screening, a protective index of 2 should be considered sufficient in case of traditional MES or s.c. PTZ models with fixed seizure stimulus. Alternatively, seizure threshold models could be used for calculation of protective indices in order to avoid underestimation of anticonvulsant selectivity of test compounds.