Trends in Neurosciences
Perspectives on diseaseClinical trials with neuroprotective drugs in acute ischaemic stroke: are we doing the right thing?
Section snippets
Na+-channel blockers
The anticonvulsant phenytoin blocks voltage-dependent Na+ channels and reduces infarct size in both permanent and reperfusion models of focal brain ischaemia in rodents24, 25. Fosphenytoin is a prodrug of phenytoin that has been evaluated in a Phase III trial. Enrolment was halted after 462 patients had been included because no differences in primary or secondary endpoints were found in an interim analysis2.
Ca2+-channel blockers
One obvious treatment strategy for stroke involves the regulation of Ca2+ entry into the cell using inhibitors of voltage-sensitive Ca2+ channels. Nimodipine is an inhibitor of L-type Ca2+ channels, whereas flunarizine mainly acts as a T-type Ca2+-channel blocker26. Both these compounds can reduce infarct size when administered shortly after permanent and transient focal cerebral ischaemia26. However, their potency is less than that of glutamate-receptor antagonists. Nimodipine has been studied
Glutamate inhibition or GABA stimulation
Inhibitors of glutamate receptors, particularly those that block NMDA receptors, can reduce infarction volume and neurological deficits in permanent and reperfusion models of focal cerebral ischaemia28. The use of several NMDA-receptor antagonists was discontinued in Phase I and Phase II studies because of unacceptable adverse effects. The major problems with these compounds are psychomimetic effects (agitation, hallucinations, paranoia and delirium), sedation, catatonia and concerns about
NO-pathway inhibitors and free-radical scavengers
The neuroprotective effects of lubeluzole can be explained, at least partially, by a downregulation of the NO synthase (NOS) pathway, which reduces NO-related neurotoxicity33. In a small Phase II trial, a dose of 7.5 mg lubeluzole given within 6 h of the first symptoms, followed by 10 mg per day for five days, was associated with reduced mortality. A double-dose regimen, which yielded a plasma concentration equivalent to the levels associated with neuroprotection in rats, was associated with
Drugs that mainly act at the cell membrane
In preclinical studies, the ganglioside, GM1, conferred protection against ischaemic and excitotoxic insults38. However, two major Phase III trials produced negative results19, 20. Because of concerns regarding a possible association with the development of Guillain–Barré syndrome30, GM1-ganglioside product licences have been suspended.
After a number of small inconclusive clinical trials with citicholine (cytidine-5-diphosphocholine or CDP-choline), a multicentre dose-finding study in the USA
Anti-inflammatory agents
Within hours, endothelial adhesion molecule 1 (ICAM1) levels are increased in the zone of focal cerebral ischaemia, which allows an influx of white cells into the ischaemic brain area. Cytokines released from the invaded white cells contribute to brain-tissue damage. ICAM1 antibodies reduced infarct volume in rats, only when the model included reperfusion, but not with permanent middle-cerebral-artery occlusion41. Enlimomab, a murine monoclonal antibody against ICAM1, has been studied in a
Animal models
Because all the Phase III stroke trials with neuroprotective drugs have failed to live up to their promise, one could argue that the animal models that have been used to test these substances have no predictive value. Focal ischaemia models can be broadly categorized into two types: permanent and reversible42. In patients, both types of focal brain ischaemia can occur43, 44. Both forms of insult can produce a potentially salvageable penumbra. In the transient-occlusion model, reperfusion injury
Future prospects
In view of the fact that it is not possible to translate from the animal model to the clinical situation, it appears that the overall disappointing results of clinical trials that have accumulated over the past decade are probably due to protocol and dosage problems. More attention should be paid to properly conducted Phase II trials in order to obtain sufficient information regarding therapeutic time window, dosage, duration of therapy and safety. In small sample sizes of patients, this
Combination therapy
All neuroprotective agents studied so far target a specific pathway of the ischaemic cascade. It is evident that the administration of either an NMDA-receptor antagonist or a voltage-dependent Ca2+-channel blocker will not be able to control excessive neuronal Ca2+ accumulation completely. Although these compounds can reduce infarct size in animal models, we should not expect that any single drug that interferes with a specific event in the ischaemic cascade will have a large clinical impact.
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