C Gandolfo1, P Sandercock, M Conti. 1. Neuroscience and Neurorehabilitation, School of Medicine - University of Genoa, Via De Toni 5, Genoa, Liguria, Italy, 16132. gandcaci@csita.unige.it
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 STRATEGY: The Cochrane Stroke Group trials register was searched. Additional searches of Cochrane Controlled Trials Register (CENTRAL/CCTR), Medline, Embase, Pascal BioMed (1996-2001) and Current Contents CCSearch reg 7 Editions (1996-2001) were made to supplement the Stroke Group general strategy. 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 3,510 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 5 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 (OR=0.93, 95% CI 0.79-1.09) or reduced the odds of being dead or dependent at the end of follow-up (OR=1.04, 95% CI 0.91-1.19). 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 1.09-1.87). REVIEWER'S 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).
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 STRATEGY: The Cochrane Stroke Group trials register was searched. Additional searches of Cochrane Controlled Trials Register (CENTRAL/CCTR), Medline, Embase, Pascal BioMed (1996-2001) and Current Contents CCSearch reg 7 Editions (1996-2001) were made to supplement the Stroke Group general strategy. 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 3,510 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 5 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 (OR=0.93, 95% CI 0.79-1.09) or reduced the odds of being dead or dependent at the end of follow-up (OR=1.04, 95% CI 0.91-1.19). 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 1.09-1.87). REVIEWER'S 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).