Neuroprotective therapies for acute stroke
This thesis presents a series of clinical studies on neuroprotective drugs in both volunteers and stroke patients, and assesses the current methodology of clinical trials in stroke. Previous therapeutic trials in stoke have often been inadequate due to small numbers of patients and lack of robust outcome criteria. Overview analyses have not appreciated differences amongst impairment scales developed for clinical trials. Stroke scales are relevant to outcome and may provide surrogate end-points in exploratory trials. In three volunteer studies with the non-competitive NMDA antagonist aptiganel hydrochloride (CNS 1102), the side effect profile resembled that of other NMDA ion channel blocking drugs. The pharmacokinetics and effects upon cerebral blood flow of this drug are favourable for further trials. Magnesium sulphate is the endogenous blocker of the NMDA ion channel, and does not cause the central nervous symptoms of NMDA antagonists. In studies in both volunteers and stroke patients, no adverse haemodynamic or antiplatelet effects were observed. Another neuroprotective drug, the use-dependent sodium channel blocker 619C89, has significant side effects in stroke patients, both as a series of discrete infusions or by continuous infusion over 72 hours. However, until clinical benefit is shown with a neuroprotective drug, it will remain necessary to seek confirmation that potentially therapeutic agents active pharmacologically achieve concentrations in the brain, and side effects are inevitable.