Narrow temporal therapeutic window for NMDA antagonist protection against focal cerebral ischaemia

Steinberg, Gary K.; Panahian, Nariman; Pérez-Pinzón, Miguel A.; Sun, Guo Hua; Modi, Marlene; Sepinwall, Jerry

doi:10.1006/nbdi.1995.0011

Cited by 26 publications

(17 citation statements)

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“…Alternative explanations of the worse outcome in DCLHb patients are the role of chance in this small study; the imbalance, although not statistically significant, of stroke severity at randomization; or bias due to the single-blinded nature of the study. Furthermore, in analogy with other stroke treatments, 17,18 it may be beneficial to administer DCLHb immediately after the onset of ischemia but harmful to give it during a later phase. In most animal experiments, a highly favorable response was found after a single, high-dose exchange transfusion of DCLHb, either before or within 1 hour after initiation of ischemia.…”

Section: Discussionmentioning

confidence: 99%

Controlled Safety Study of a Hemoglobin-Based Oxygen Carrier, DCLHb, in Acute Ischemic Stroke

Saxena

Wijnhoud

Carton

et al. 1999

Stroke

212

132

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Background and Purpose-Diaspirin cross-linked hemoglobin (DCLHb) is a purified, cell-free human hemoglobin solution. In animal stroke models its use led to a significant reduction in the extent of brain injury. The primary objective of this study was to evaluate the safety of DCLHb in patients with acute ischemic stroke. Methods-DCLHb or saline was administered to 85 patients with acute ischemic stroke in the anterior circulation, within 18 hours of onset of symptoms, in a multicenter, randomized, single-blind, dose-finding, controlled safety trial, consisting of 3 parts: 12 doses of 25, 50, and 100 mg/kg DCLHb over 72 hours. Results-DCLHb caused a rapid rise in mean arterial blood pressure. The pressor effect was not accompanied by complications or excessive need for antihypertensive treatment. Two patients in the 100 mg/kg group had adverse events that were possibly drug related: one suffered fatal brain and pulmonary edema, the other transient renal and pancreatic insufficiency. Multivariate logistic regression analysis showed that a severe stroke at baseline and treatment with DCLHb (OR, 4.0; CI, 1.4 to 12.0) were independent predictors of a worse outcome (Rankin Scale score of 3 to 6) at 3 months. Conclusions-Outcome scale scores were worse in the DCLHb group, and more serious adverse events and deaths occurred in DCLHb-treated patients than in control patients. We recommend that additional safety studies be performed, preferably with a second generation, genetically engineered hemoglobin. (Stroke. 1999;30:993-996.)

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Section: Discussionmentioning

confidence: 99%

Controlled Safety Study of a Hemoglobin-Based Oxygen Carrier, DCLHb, in Acute Ischemic Stroke

Saxena

Wijnhoud

Carton

et al. 1999

Stroke

212

132

View full text Add to dashboard Cite

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“…Excitotoxicity is a particularly important cell death mechanism in stroke involving ischemia-reperfusion (43,57,141). However, the beneficial effects of NMDA receptor blockade in stroke require intervention at relatively short time points after onset of ischemia or reperfusion, typically within 3 h (167,174). Clinical studies corroborate this result; interventions targeting excitotoxic injury have had no demonstrable efficacy when initiated many hours after ischemia onset, but more rapid initiation has shown salutary effects (74).…”

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confidence: 99%

NADPH Oxidase-2: Linking Glucose, Acidosis, and Excitotoxicity in Stroke

Brennan-Minnella

Won

Swanson

2015

Antioxidants & Redox Signaling

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Significance: Neuronal superoxide production contributes to cell death in both glutamate excitotoxicity and brain ischemia (stroke). NADPH oxidase-2 (NOX2) is the major source of neuronal superoxide production in these settings, and regulation of NOX2 activity can thereby influence outcome in stroke. Recent Advances: Reduced NOX2 activity can rescue cells from oxidative stress and cell death that otherwise occur in excitotoxicity and ischemia. NOX2 activity is regulated by several factors previously shown to affect outcome in stroke, including glucose availability, intracellular pH, protein kinase f/d, casein kinase 2, phosphoinositide-3-kinase, Rac1/2, and phospholipase A2. The newly identified functions of these factors as regulators of NOX2 activity suggest alternative mechanisms for their effects on ischemic brain injury. Critical Issues: Key aspects of these regulatory influences remain unresolved, including the mechanisms by which rac1 and phospholipase activities are coupled to N-methyl-D-aspartate (NMDA) receptors, and whether superoxide production by NOX2 triggers subsequent superoxide production by mitochondria. Future Directions: It will be important to establish whether interventions targeting the signaling pathways linking NMDA receptors to NOX2 in brain ischemia can provide a greater neuroprotective efficacy or a longer time window to treatment than provided by NMDA receptor blockade alone. It will likewise be important to determine whether dissociating superoxide production from the other signaling events initiated by NMDA receptors can mitigate the deleterious effects of NMDA receptor blockade. Antioxid. Redox Signal. 22,[161][162][163][164][165][166][167][168][169][170][171][172][173][174]

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“…One study performed in the early 1990s reported a trend toward worse outcomes with dextrorphan than with placebo when administered to rabbits as little as 4 hours after stroke onset. 42 Although the therapeutic window for neuroprotective agents remains uncertain in humans, most experts have put it far short of 31 hours, the mean interval to the initiation of treatment in this study. 43,44 If this estimate of the therapeutic window is even close to correct, there could be little if any expectation that these patients would benefit medically from receiving dextrorphan.…”

Section: The Timing Of Neuroprotective Drugsmentioning

confidence: 95%

Ethical Challenges in Stroke Research

Slyter

1998

Stroke

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Background-Ethical issues are a critical consideration in the design and conduct of clinical research. Summary of Review-A number of completed trials of proposed stroke treatments raise classical ethical issues in challenging ways. The combination of acutely ill and vulnerable patients, the use of potentially toxic drugs, and very short time frames for decision making and drug administration demand an especially careful evaluation of risk and benefit, the process of consent, and the permissible treatment of control patients. Conclusions-The study of acute stroke treatments may require more complex safeguards than other neuroclinical trials.

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Narrow temporal therapeutic window for NMDA antagonist protection against focal cerebral ischaemia

Cited by 26 publications

References 0 publications

Controlled Safety Study of a Hemoglobin-Based Oxygen Carrier, DCLHb, in Acute Ischemic Stroke

Controlled Safety Study of a Hemoglobin-Based Oxygen Carrier, DCLHb, in Acute Ischemic Stroke

NADPH Oxidase-2: Linking Glucose, Acidosis, and Excitotoxicity in Stroke

Ethical Challenges in Stroke Research

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