Abstract
Background
Experimental studies have shown that ischaemic insults cause excess release of excitatory amino acid (EAA) neurotransmitters, particularly glutamate. Glutamate re-uptake is impaired under ischaemic conditions. In preclinical models of stroke, antagonists of excitatory amino acids or of glutamate release protect against ischaemic injury, even when administered after the ischaemic insult. Lubeluzole is a benzothiazole derivative that has shown neuroprotective properties in different experimental models inhibiting glutamate release, nitric oxide (NO) synthesis and blocking voltage-gated Na+ and Ca2+ ion channels.
Objectives
The objective of this review is to assess the effectiveness and safety of lubeluzole given in the acute phase of acute ischaemic stroke.
Search methods
We searched the Cochrane Stroke Group trials register, the Cochrane Controlled Trials Register (CENTRAL/CCTR), MEDLINE, EMBASE, Pascal BioMed (1996 to 2001) and Current Contents CCSearch (1996 to 2001). We contacted Janssen Research Foundation to identify further studies.
Selection criteria
All randomised unconfounded trials comparing intravenous lubeluzole with placebo or open control in patients with a clinical syndrome definitely considered as an acute stroke in whom CT scanning showed an infarct or was normal.
Data collection and analysis
Two reviewers independently selected trials for inclusion, assessed trial quality and extracted the data.
Main results
Five trials involving a total of 3510 patients were included. The quality of the trials did not vary considerably. Sensitivity/subgroups analysis was not completely performed because of lack of data. Lubeluzole given at the doses of 5, 10 and 20 mg/day for five days was tested against a placebo-control group. There was no evidence that lubeluzole given at any dose either reduced the odds of death from all causes (odds ratio (OR) 0.93, 95% confidence interval (CI) 0.79 to 1.09) or reduced the odds of being dead or dependent at the end of follow up (OR 1.04, 95% CI 0.91 to 1.19). On the other hand, given at any dose, lubeluzole was associated with a significant excess of heart-conduction disorders (Q-T prolonged > 450 msec) at the end of follow up (OR 1.43, 95% CI 1.09 to 1.87).
Authors’ conclusions
Lubeluzole, given in the acute phase of ischaemic stroke, is not associated with a significant reduction of death or dependency at the end of scheduled follow-up period but seems to be associated with a significant increase of heart-conduction disorders (Q-T prolonged > 450 msec).
Plain language summary
Lubeluzole for acute ischaemic stroke
Lubeluzole is not effective in patients with acute ischaemic stroke. After a stroke, where a part of the brain suffers from reduced blood supply, an excess of chemicals known as excitatory amino acid neurotransmitters is produced. This excess can cause some brain cells to be damaged or to die (permanent cell damage is called cerebral infarction). Drugs which block the effects of these amino acids can protect against the cerebral infarct. The review focuses on the effects of lubeluzole, an inhibitor of excitatory amino acids. The review of trials did not find any benefit of lubeluzole in humans either to prevent death after acute ischaemic stroke or to reduce disability from it. Moreover, lubeluzole may cause heart-conduction disorders.
