Lubeluzole in Acute Ischemic Stroke Treatment

Diener, Hans Christoph; Cortens, M.; Ford, Gary A.; Grotta, James; Hacke, Werner; Kaste, Markku; Koudstaal, Peter J.; Wessel, Thomas

doi:10.1161/01.str.31.11.2543

Cited by 116 publications

(27 citation statements)

References 24 publications

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“…13 Of 1786 patients in the European lubeluzole study, 48 (2.7%) died of cardiovascular-related causes; 10 of these deaths were due to MI (0.5%). 14 In the US lubeluzole study, among 721 patients monitored for up to 90 days, there were 39 cardiacrelated deaths (5.4%), but only 4 of these deaths were due to MI (0.5%). 15 In the Tinzaparin in Acute Ischemic Stroke (TAIST) study, 16 49 fatal cardiac events (including sudden death) were reported among 1486 patients (3%), but deaths from MI were not reported separately.…”

Section: Cardiac Comorbidity In Cerebrovascular Patientsmentioning

confidence: 99%

Coronary Risk Evaluation in Patients With Transient Ischemic Attack and Ischemic Stroke

Adams¹,

Chimowitz²,

Alpert³

et al. 2003

Circulation

226

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Stroke and myocardial infarction (MI) share common risk factors and pathological mechanisms, and coronary artery disease (CHD) is an important cause of death in patients with cerebrovascular disease. This Scientific Statement addresses issues in management of the relatively healthy patient with brain ischemia (a transient ischemic attack [TIA] or an ischemic stroke) who does not have recognized CHD but often has risk factors in addition to having had a TIA or stroke that indicate an increased likelihood of disability or death from cardiac disease in the future. This Statement should not be confused with the official American College of Cardiology (ACC)/American Heart Association (AHA) practice guidelines. The reader is referred to the ACC/AHA guidelines for management of recognized and symptomatic CHD 1 and the American College of Chest Physicians (ACCP) 2 and American Stroke Association (ASA) 3-5 guidelines for evaluation of cardiac causes of TIA and stroke, which are important related but separate issues.

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Section: Cardiac Comorbidity In Cerebrovascular Patientsmentioning

confidence: 99%

Coronary Risk Evaluation in Patients With Transient Ischemic Attack and Ischemic Stroke

Adams¹,

Chimowitz²,

Alpert³

et al. 2003

Circulation

226

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“…Phase III trials have provided different results. Whereas Grotta (12) described a neuroprotective effect of lubeluzole in patients suffering from acute ischemic stroke, this finding could not be confirmed in other trials (13,14).The present knowledge on the safety profile and efficiency of lubeluzole seems to be promising enough to warrant further studies in immature animals. Recently, we were able to show that lubeluzole does not affect fetal circulatory centralization during acute asphyxia.…”

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confidence: 64%

mentioning

confidence: 78%

Lubeluzole Pretreatment Does Not Provide Neuroprotection Against Transient Global Cerebral Ischemia in Fetal Sheep Near Term

et al. 2002

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The aim of the present study was to test the neuroprotective effect of the novel benzothiazol compound lubeluzole on neuronal cell damage in fetal sheep arising from global cerebral ischemia. Thirteen fetal sheep were prepared at a mean gestational age of 127 Ϯ 1 d (term is at 147 d). Six fetuses were treated with lubeluzole (0.33 mg/kg estimated body weight) before induction of global cerebral ischemia (Ϫ90, Ϫ60, and Ϫ30 min), while the remainder (n ϭ 7) received solvent. Cerebral ischemia was induced by occluding both carotid arteries for 30 min. Cerebral blood flow was measured by injecting radiolabeled microspheres before (Ϫ90 min), during (ϩ3 min and ϩ27 min), and after (ϩ40 min, ϩ3 h, and ϩ72 h) cerebral ischemia. Neuronal cell damage was assessed in the cerebrum and deeper brain structures by light microscopy. Values are given as means Ϯ SD. In control fetuses, blood flow to the cerebrum was reduced from 100 Ϯ 25 mL·100 g Ϫ1 min Ϫ1 to less than 20 mL·100 g Ϫ1 min Ϫ1 during ischemia. Shortly after ischemia, hyperperfusion occurred (217 Ϯ 66 mL·100 g Ϫ1 min Ϫ1 ) followed by a tendency toward hypoperfusion (72 Ϯ 17 mL·100 g Ϫ1 min Ϫ1 ) later on (ϩ3 h). Significant differences in blood flow to the various brain structures between the control and study groups could not be observed. Neuronal cell damage was concentrated in the parasagittal regions of the cerebrum. Hypoxic-ischemic cerebral damage is an important contributor to perinatal mortality and morbidity including long-term neurologic sequelae in term and preterm fetuses (1). Although over the last decade many therapeutic strategies have been developed in various animal models to reduce neuronal cell damage caused by ischemic insults, their clinical application has often been rejected due to major drug-related side-effects (2). Especially after application of calcium antagonists and inhibitors of NOS, alterations of fetal cardiovascular control have been observed (3, 4). However, the recently developed benzothiazole compound lubeluzole seems to justify further research in this field. The neuroprotective efficiency of this drug has been shown in a variety of in vitro as well as in vivo experiments (5-10). In clinical safety studies, severe drugrelated side-effects could be excluded (11). Phase III trials have provided different results. Whereas Grotta (12) described a neuroprotective effect of lubeluzole in patients suffering from acute ischemic stroke, this finding could not be confirmed in other trials (13,14).The present knowledge on the safety profile and efficiency of lubeluzole seems to be promising enough to warrant further studies in immature animals. Recently, we were able to show that lubeluzole does not affect fetal circulatory centralization during acute asphyxia. This mechanism is of major importance, because it protects the fetal brain from neuronal injury by increasing blood flow to the central organs, i.e. brain, heart, adrenals, when oxygen is in short supply (15). The present study was performed to clarify whether lubeluzole protects the ...

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“…26 Two subsequent trials evaluated the use of lubeluzole but showed no difference in primary outcome of mortality at 3 months. 31,56 The most recent trial in 1786 patients failed to show a difference in primary outcome of trichotomized Barthel Index at 3 months or in secondary outcomes. 31 A meta-analysis of 5 trials and 3510 patients also failed to show a difference in mortality or dependence.…”

Section: Nitric Oxidementioning

confidence: 99%

Neuroprotective strategies and the underlying molecular basis of cerebrovascular stroke

Karsy¹,

Brock²,

Guan³

et al. 2017

FOC

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Stroke is a leading cause of disability in the US. Although there has been significant progress in the area of medical and surgical thrombolytic technologies, neuroprotective agents to prevent secondary cerebral injury and to minimize disability remain limited. Only limited success has been reported in preclinical and clinical trials evaluating a variety of compounds. In this review, the authors discuss the most up-to-date information regarding the underlying molecular biology of stroke as well as strategies that aim to mitigate this complex signaling cascade. Results of historical research trials involving N-methyl-d-aspartate and α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor antagonists, clomethiazole, antioxidants, citicoline, nitric oxide, and immune regulators have laid the groundwork for current progress. In addition, more recent studies involving therapeutic hypothermia, magnesium, albumin, glyburide, uric acid, and a variety of other treatments have provided more options. The use of neuroprotective agents in combination or with existing thrombolytic treatments may be one of many exciting areas of further development. Although past trials of neuroprotective agents in ischemic stroke have been limited, significant insights into mechanisms of stroke, animal models, and trial design have incrementally improved approaches for future therapies.

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Lubeluzole in Acute Ischemic Stroke Treatment

Cited by 116 publications

References 24 publications

Coronary Risk Evaluation in Patients With Transient Ischemic Attack and Ischemic Stroke

Coronary Risk Evaluation in Patients With Transient Ischemic Attack and Ischemic Stroke

Lubeluzole Pretreatment Does Not Provide Neuroprotection Against Transient Global Cerebral Ischemia in Fetal Sheep Near Term

Neuroprotective strategies and the underlying molecular basis of cerebrovascular stroke

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