Lubeluzole in Acute Ischemic Stroke

Hc, Diener; Hacke, Werner; Mg, Hennerici; Rådberg, Johan; Hantson, L.; Keyser, Jacques De

doi:10.1161/01.str.27.1.76

Cited by 129 publications

(29 citation statements)

References 6 publications

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“…15 Lubeluzole inhibits glutamine rise and glutamine-stimulated rises in cyclic guanosine monophosphate-and nitric oxide-related neurotoxicity. 16 As suggested in the introduction and supported by the results of this study, the circumstances of CPB appear to offer a practical test bed for putative neuroprotective agents. The pathophysiology of massive focal infarction in an embolic stroke and the more diffuse microembolic damage combined with disordered blood flow during CABS are clearly different, so it could not be assumed that efficacy in one context was transferable to the other without a trial in stroke patients.…”

Section: Discussionsupporting

confidence: 63%

Neuroprotection of the Brain During Cardiopulmonary Bypass

Arrowsmith

Harrison

Newman

et al. 1998

Stroke

136

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Background and Purpose-Neuropsychological impairment may follow coronary artery bypass surgery as a result of peroperative cerebral microembolism. The hypothesis that remacemide, an NMDA receptor antagonist, would provide protection against such ischemic damage has been tested in a randomized trial. Methods-One hundred seventy-one patients undergoing coronary artery bypass surgery by a single cardiothoracic surgical team were randomized to receive remacemide (up to 150 mg every 6 hours) or placebo from 4 days before to 5 days after their bypass procedure. Peroperative monitoring included an estimate of the number of microembolic events detected by transcranial Doppler ultrasonography of the middle cerebral artery. A battery of 9 neuropsychological tests was administered before and 8 weeks after surgery. Results-The proportion of patients showing a decline in performance of 1 SD or more in 2 or more tests was reduced in the treated group (9% versus 12%), but this was not statistically significant. On the other hand, overall postoperative change (reflecting learning ability in addition to reduced deficits) was more favorable in the remacemide group, which demonstrated significantly greater improvement in a global z score (Pϭ0.028) and changes in 3 individual tests (PϽ0.05). The 2 patient groups were well matched, including for the burden of microembolic events. Conclusions-This is the first study to show statistically significant drug-based neuroprotection during cardiac surgery. In addition to offering improvement in cerebral outcome for such at-risk patients, it supports the hypothesis that drugs acting on the excitotoxic mechanism of ischemic cerebral damage can be effective in humans. (Stroke. 1998;29:2357-2362.)

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Section: Discussionsupporting

confidence: 63%

Neuroprotection of the Brain During Cardiopulmonary Bypass

Arrowsmith

Harrison

Newman

et al. 1998

Stroke

136

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“…5,6 Results of a double-blind, placebo-controlled phase II trial involving 193 patients with acute ischemic stroke showed that lubeluzole, administered intravenously within 6 hours of stroke onset with a 1-hour 7.5-mg loading dose followed by 10-mg/d infusion for 5 days, was safe and resulted in a statistically significant reduction in mortality. 7 In the same study, treatment with a higher lubeluzole dosage regimen of 15-mg loading dose followed by 20-mg/d infusion for 5 days was associated with a higher mortality rate that was attributable, at least in part, to an imbalance at randomization resulting in more patients with severe ischemic stroke being included in the high-dose group. On the basis of the results of this early phase II trial, a dosage regimen of 7.5-mg loading dose administered over 1 hour followed by a continuous infusion of 10 mg/d for 5 days was selected for use in subsequent phase III studies.…”

mentioning

confidence: 96%

Lubeluzole in Acute Ischemic Stroke Treatment

Diener

Cortens

Ford

et al. 2000

Stroke

Self Cite

116

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on behalf of the LUB-INT-13 InvestigatorsBackground and Purpose-This trial was a double-blind, placebo-controlled, phase III trial with an 8-hour inclusion window to assess the efficacy and safety of an intravenous loading dose of 7.5 mg followed by a daily intravenous dose of 10 mg lubeluzole for 5 days in acute ischemic stroke patients. Methods-A total of 1786 patients were randomized: 901 to lubeluzole and 885 to placebo. Overall, 212 patients (23.5%) from the lubeluzole group and 213 (24.1%) from the placebo group discontinued the trial prematurely. In the lubeluzole group 201 patients (22.3%) discontinued because of adverse events compared with 193 patients (21.8%) in the placebo group. Results-The primary population for the efficacy analysis comprised the core stroke patients (exclusion of older patients aged Ͼ75 years with severe stroke) in the 0-to 6-hour inclusion time window. The primary efficacy parameter was a 3-category functional status (Barthel Index 70 to 100/0 to 70/vegetative, dead) at week 12. In the lubeluzole group 207 patients (47.8%) were classified as mildly dependent/independent at week 12, 131 (30.3%) were moderately/severely dependent, and 95 (21.9%) were vegetative/dead. In the placebo group these numbers were 221 (54.4%), 112 (27.6%), and 73 (18.0%), respectively. Logistic regression analysis showed no statistically significant difference between the treatment groups (Pϭ0.162). Additionally, for none of the secondary efficacy parameters (mortality at week 12, modified Rankin score, total Barthel score) was a statistically significant difference between the lubeluzole and placebo groups obtained. There were no statistically significant differences between the 2 treatments for all treated patients, patients included within the 6-to 8-hour window, and patients with severe strokes aged Ͼ75 years. Overall, of all treated patients, 401 (22.5%) died: 203 (22.5%) in the lubeluzole group and 198 (22.4%) with placebo. Of all subjects treated, 853 (95%) on lubeluzole and 826 (93%) on placebo reported an adverse event during their treatment period or within the next 2 days after discontinuation of treatment. The most frequently observed adverse events were fever (25.9% lubeluzole; 23.4% placebo), constipation (20.2%; 19.7%), and headache (17.6%; 21.2%). Imbalances were found for atrial fibrillation (1.8% lubeluzole; 1.1% placebo) and QT prolongation (0.9%; 0.2%). Conclusions-This study failed to show an efficacy of lubeluzole in the treatment of acute stroke. On the other hand, lubeluzole treatment by the current dosage schedule was not associated with a significant safety problem. (Stroke.

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“…Lubeluzole shows beneficial efficacy in clinical cases. 30) These results suggest that NHE inhibitors have beneficial efficacy that is as good as other neuroprotective compounds.…”

Section: Discussionmentioning

confidence: 92%

Relationship between the Neuroprotective Effect of Na<SUP>+</SUP>/H<SUP>+</SUP> Exchanger Inhibitor SM-20220 and the Timing of Its Administration in a Transient Middle Cerebral Artery Occlusion Model of Rats

Horikawa¹,

Kuribayashi²,

Matsui³

et al. 2001

Biological & Pharmaceutical Bulletin

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The aim of this study was to determine the relationship between the neuroprotective effect of SM-20220 (N-(aminoiminomethyl)-1-methyl-1H-indole-2-carboxamide methanesulfonate) and the timing of its administration in an experimental stroke model. Two hours of occlusion followed by 22 h of perfusion of the left middle cerebral artery (MCA) was performed by inserting a nylon thread into the MCA to occlude it, and pulling the thread to initiate reperfusion. Intravenous infusion of SM-20220 for 1 h reduced the infarct volume at doses of 0.2-0.8 mg/kg in a dose-dependent manner without causing changes in the systemic arterial blood pressure or blood gases, when SM-20220 administration was started 1 h after the onset of occlusion. Administration of SM-20220 at a dose of 0.4 mg/kg also reduced the edema formation induced by ischemia. In contrast, SM-20220 failed to reduce the infarction, even at 1.6 mg/kg, when administration was started 2 h after the onset of occlusion. Thus, the therapeutic time window of SM-20220 for this transient MCA occlusion model is 1 h. Daily administration of SM-20220 (0.4 mg/kg) for the 7 d following 1.5 h of middle cerebral artery occlusion reduced the infarct volume with statistical significance ( pϽ0.05), showing that SM-20220 did not merely delay but prevented ischemic damage. Key words Naϩ /H ϩ exchanger; brain ischemia; infarction; SM-20220; edema; therapeutic time window centage of the area of the left hemisphere for each coronal section. The infarct volume was calculated by integration of the infarct areas and the areas of the left hemisphere that were determined for the five coronal sections. Measurement of Arterial Blood Pressure, Gases, and pH In some animals, a femoral artery was cannulated to directly and continuously measure the systemic arterial blood pressure with a pressure transducer (P10EZ, Nihon Kohden, Osaka, Japan) attached to a blood-pressure amplifier (AP-641G, Nihon Kohden) and to sample blood for the analysis of blood gases and pH using I-STAT (Fuso Chemicals, Osaka, Japan). Measurement of Cerebral Water ContentTo measure the brain water content, rats were decapitated 4 h after the onset of reperfusion and the left hemisphere of the occluded MCA territory was cut into 4-mm-thick slices (1 mm anterior-3 mm posterior to the bregma).10) The water content was determined by the dry-weight method. 13)Experimental Protocol The experimental protocol is shown in Fig. 1. SM-20220 was dissolved in 8% polyethylene glycol 400 (w/v) to 0.4 mg/ml and diluted with the same solution to 0.04, 0.08, 0.16, and 0.32 mg/ml. The diluted SM-20220 or just the solution as vehicle was given as an intravenous infusion (5 ml/kg/h) for 1 h using an infusion pump (model 100, KD Scientific, U.S.A.).For the first experiment, the administration of SM-20220 or vehicle was started 1 h after the onset of occlusion, and physiological variables were measured before surgery, before drug administration, and 30 min after the onset of reperfusion; the infarct size was measured 22 h after the onset.For the sec...

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Lubeluzole in Acute Ischemic Stroke

Abstract: In patients with acute ischemic stroke, the dosage regimen of 7.5 mg over 1 hour followed by 10 mg/d of intravenous lubeluzole is safe and statistically significantly reduced mortality. Further clinical trials in a larger number of patients are ongoing to confirm efficacy.

Cited by 129 publications

References 6 publications

Neuroprotection of the Brain During Cardiopulmonary Bypass

Neuroprotection of the Brain During Cardiopulmonary Bypass

Lubeluzole in Acute Ischemic Stroke Treatment

Relationship between the Neuroprotective Effect of Na<SUP>+</SUP>/H<SUP>+</SUP> Exchanger Inhibitor SM-20220 and the Timing of Its Administration in a Transient Middle Cerebral Artery Occlusion Model of Rats

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