Neuroprotectants in Late Clinical Development – A Status Report

There are many neuroprotectants currently under evaluation for the treatment of acute ischaemic stroke, but encouraging clinical trials have been rare. Neuroprotective drugs interfere with various stages of the ischaemic cascade leading to irreversible tissue damage, and are not thought to affect bleeding. While trials of sodium/calcium channel modifiers have been problematic, there are hopes that the phenytoin derivative fos-phenytoin will yield interesting findings in phase II trials. Studies of several N-methyl-D-aspartate antagonists, such as selfotel and dextrorphan, have been suspended because of unacceptable side-effect profiles, while those with other agents, notably cerestat, are continuing. Gamma-aminobutyric acid agonists can induce hyperpolarisation, and thereby counteract the depolarisation seen in the ischaemic cascade. A safety analysis of such an agonist, the anti-epilepsy drug clomethiazole, has shown it is well tolerated and the results of a large phase III trial are anticipated. Lubeluzole, an inhibitor of glutamate-induced nitric oxide-related neurotoxicity, is another agent which has just completed phase III trials. Early studies have been promising and have shown that it is a well tolerated neuroprotectant.