Rationale for Early Intervention in Acute Stroke

Rationale for Early Intervention in Acute Stroke Gregory W. Albers,

MD

Ischemic stroke occurs after an abrupt reduction in cerebral blood flow, usually related to thrombosis of an intracranial or extracranial artery. The presenting symptoms and signs of stroke vary greatly, depending on the region of the brain involved. Most individuals are unaware of the warning signs or symptoms of stroke and do not seek medical care immediately after stroke onset. Recently, thrombolytic therapy with intravenous tissue plasminogen activator (t-PA) has been shown to be effective for treatment of selected stroke patients if administered <3 hours after stroke onset. This therapy is now approved for stroke treatment, but relatively few stroke patients currently receive t-PA. Neuroprotective agents that improve the intrinsic ability of brain parenchyma to withstand ischemia are currently undergoing intensive

clinical evaluation. Their development has been facilitated by significant scientific advances in the understanding of the pathophysiology of acute ischemic neuronal injury. Strategies aimed at interfering with these fundamental processes of ischemic neuronal injury have shown encouraging results in several preliminary clinical trials. However, these agents probably must also be administered within a few hours of stroke onset to be beneficial. Eventually, combined neuroprotective and thrombolytic therapy will likely be used for acute stroke treatment. This strategy’s success will depend on increased public and professional education efforts dealing with stroke recognition, evaluation, and treatment. Q1997 by Excerpta Medica, Inc. Am J Cardiol 1997;80(4C):4D–10D

he approval of tissue plasminogen activator (t-PA) T for treatment of acute ischemic stroke has ushered in an era of optimism regarding emergency stroke

of neuroprotective agents, is reviewed, and 2 promising members of this class, aptiganel and ACEA-1021, are discussed. Finally, lubeluzole—a neuroprotective agent that appears to act by inhibiting the glutamateactivated nitric oxide synthase pathway, and is in the final stages of evaluation in clinical trials—is described.

treatment. Although many stroke patients benefit greatly from thrombolytic therapy, this treatment also has many limitations. Because thrombolytics cannot be given to patients with hemorrhagic stroke, candidates for lytic therapy must first have a computed tomography (CT) scan. Ideally, to minimize neuronal damage, pharmacotherapy for stroke should begin almost immediately after symptoms are recognized. In theory, the emerging class of neuroprotective agents allows for a prompt response. Within the next few years, neuroprotectants may be administered by emergency medical system personnel to prolong the life of ischemic neurons. Then, after thrombolytic therapy, a neuroprotective agent probably will be administered for several days to prevent or limit the complex series of harmful biochemical events that occur after a stroke. At present, this combination of neuroprotective and thrombolytic therapy seems to offer the best hope for optimal patient outcomes after acute ischemic stroke. This article emphasizes the need for prompt recognition and response to the signs and symptoms of stroke. It summarizes recent advances in the understanding of the therapeutic window for stroke treatment and distinguishes between thrombolytics and neuroprotectants, the 2 major pharmacologic strategies that have emerged to treat acute ischemic stroke. The mechanism of action of N-methyl-D-aspartate (NMDA) receptor antagonists, an important category From the Department of Neurology and the Stanford Stroke Center, Stanford University Medical Center, Stanford, California. Address for reprints: Gregory W. Albers, MD, Stanford Stroke Center, Department of Neurology, Stanford University Medical Center, 701 Welch Road, Building B, Suite 325, Palo Alto, California 94304-1705.

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©1997 by Excerpta Medica, Inc. All rights reserved.

HEART–BRAIN INTERACTION Stroke is an area that invites collaboration between cardiologists and neurologists. Stroke occurs when blood flow to the brain is abruptly disrupted. Up to a third of cases may occur due to an embolism from the heart,1 and most occur because of intracranial or extracranial atherosclerosis, the same pathophysiology that causes myocardial infarction. Atherosclerotic plaque can lead to stroke by causing an occlusive thrombus or an artery-to-artery embolism of either thrombotic material or platelet aggregates.

DELAYED PRESENTATION IN STROKE PATIENTS Although there is now much public awareness of the symptoms of myocardial infarction (with most people realizing that they should immediately go to the emergency room if they experience these symptoms), a recent survey sponsored by the National Stroke Association (NSA) has shown that there is not a comparable level of public awareness about stroke.2 An important reason for this deficiency is that stroke can cause a wide variety of signs and symptoms, depending on which part of the brain is involved. Common symptoms are weakness or numbness of one side of the body.1 If the dominant hemisphere is involved, the patient may have language problems such as expressive or receptive aphasia. Visual disturbances are also common. Unilateral blindness can occur if the carotid distribution is involved, and bilat0002-9149/97/$17.00 PII S002-9149(97)00579-1

eral loss of vision may occur if the occipital lobe or visual projections are involved. Patients with vertebral/basilar symptoms can experience vertigo, gait imbalance, double vision, or bilateral numbness and weakness. Headache, often described as the worst of the patient’s life, is the hallmark of subarachnoid or intracranial hemorrhage; mild headaches often accompany ischemic stroke. Despite the difficulties inherent in attempting to familiarize the public with such a wide range of symptoms, communicating this message is more important now than ever. In June 1996, the US Food and Drug Administration (FDA) approved t-PA for the treatment of selected patients with ischemic stroke when administered #3 hours after stroke onset.3 Furthermore, a number of neuroprotective drugs are now under investigation, and it seems likely that several will be available for general use within the next few years. These agents must also be given within hours of symptom onset. Therefore, educational efforts such as those currently being spearheaded by the NSA, the American Heart Association, and the American Academy of Neurology must be pursued aggressively.

THE THERAPEUTIC WINDOW IN STROKE A key issue in stroke research has been to establish the time interval between the onset of stroke symptoms and the occurrence of irreversible neuronal injury. Previously it was thought that this time interval might be as short as 5 minutes, which would severely limit the therapeutic options. Fortunately, recent research has disproved that bleak hypothesis and has established that onset of irreversible damage depends not only on the duration, but also on the severity, of ischemia. In cardiac arrest, during which there is no blood flow to the brain, there appears to be only a few minutes between the cessation of blood flow and the onset of irreversible changes in at least the most susceptible regions of the brain. The situation is very different during a stroke. There may be very low blood flow in the center of the area of ischemia, but in the regions surrounding the core of the infarct, known as the ischemic penumbra, collateral circulation can provide sufficient blood flow to delay the onset of irreversible changes for many hours.4 Figure 1 summarizes the results of studies in experimental animals subjected to different degrees of cerebral blood flow deprivation.5 These investigations were performed to determine how long it takes for infarction to occur at different degrees of ischemia. In humans, normal blood flow is about 50 mL/100 g of tissue/min. When blood flow is dropped to about 25 mL, affected neurons will become electrically silent. Although neurons cannot function normally when they are not electrically active, they can remain alive in this state for many hours. Then, when the blood flow returns to normal, the brain’s normal functions resume. Even when blood flow is more severely restricted, affected neurons can remain alive for several hours. A schematic diagram of a person with an occlusion

FIGURE 1. Thresholds of ischemia for the induction of functional, metabolic, and histologic lesions. ATP 5 adenosine triphosphate; CMRG 5 cerebral metabolic rate of glucose; Pcr 5 phosphocreatine. (Reprinted with permission from Ann Neurol.5)

of the left middle cerebral artery shows that the brain of the typical stroke patient has multiple zones with differing levels of perfusion (Figure 2). A core of tissue, at the center of the infarct, may depend entirely on the middle cerebral artery for blood flow and therefore may develop an infarction very rapidly. However, depending on the patient’s collateral circulation, there may be large areas within the ischemic penumbra with blood flows of 15–25 mL/100 g of tissue/min. These areas can remain viable for many hours and retain the potential for considerable recovery of function. If this region can be salvaged, substantial recovery may be possible in an individual who presents with what appears to be a devastating stroke.

ACUTE PHARMACOLOGIC TREATMENT OF STROKE Two pharmacologic approaches are now being investigated to treat acute ischemic stroke. These are thrombolytic agents, which can recanalize occluded blood vessels and restore blood flow, and neuroprotective agents, which are designed to make the brain more resistant to ischemia and to extend the time during which neurons within the ischemic penumbra remain viable.

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FIGURE 2. Zones with differing levels of perfusion in a patient with a middle cerebral artery occlusion. The blood-deprived tissue at the core of the stroke will die rapidly. Depending on the individual patient’s collateral circulation, the various areas within the ischemic penumbra may remain viable for many hours and retain the potential for considerable function. (Reprinted with permission from Sci Am.13)

Benefits and limitations of thrombolytic therapy:

Since the mid-1960s, thrombolytic therapy for stroke has been studied in individual patients, open-label studies, and, more recently, in 5 large, randomized, placebo-controlled trials using either t-PA or streptokinase.6 –10 Although efficacy was not demonstrated in 4 of these 5 large studies,7–10 the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Study6 showed that t-PA can be an effective treatment for acute ischemic stroke when administered #3 hours after stroke onset to carefully selected patients. This study served as the basis for the FDA’s recent approval of t-PA for stroke. Another major North American trial, the Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke study (ATLANTIS), is currently investigating the risks and benefits of t-PA administration 3–5 hours after symptom onset. Today, the biggest obstacle to thrombolytic therapy for ischemic stroke is that comparatively few patients are eligible for it. They must present at the hospital early enough to have a CT scan and other diagnostic tests completed in time to receive t-PA within 3 hours of symptom onset. The time of symptom onset must be known; therefore, patients are usually ineligible to receive t-PA if their stroke occurred 6D

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at night (i.e., while sleeping). Marked hypertension and a number of other conditions are also contraindications to t-PA therapy.11 In addition, many hospital emergency departments are not adequately prepared to evaluate and treat stroke patients on an emergent basis. For all these reasons, only a small percentage of patients with acute ischemic stroke actually receive t-PA. Unfortunately, even the majority of patients who present rapidly to a well-prepared facility, meet all eligibility criteria, and receive t-PA within the prescribed time fail to respond dramatically to thrombolytic therapy. Based on the results of the NINDS rt-PA Stroke Study, it is estimated that for every 100 patients treated with t-PA, an additional 12–14 patients who would have been disabled from their stroke will have an excellent recovery.6 Furthermore, intracerebral hemorrhage is a potential complication of t-PA therapy for stroke. In the NINDS trial, 6.4% of patients treated with t-PA experienced symptomatic intracerebral hemorrhage within 36 hours of stroke onset, and about half these patients died. Thus, although intravenous t-PA therapy represents an important breakthrough in the treatment of acute ischemic stroke, there is great opportunity for improvement. Additional clinical trials of thrombo-

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FIGURE 3. Mechanisms of neuronal death during focal brain ischemia. Ca21 5 intracellular free calcium ion; G 5 glutamate; Na1 5 oxidized sodium ion; NMDA 5 N-methyl-D-aspartate.

lytic therapy are now in progress. At the same time, studies involving several different types of neuroprotective agents are ongoing. Eventually, the best outcomes may be obtained with combination therapy that includes both a thrombolytic and a neuroprotectant.

INTRODUCTION TO NEUROPROTECTION Neuroprotective (cytoprotective) agents allow the brain to withstand ischemia and extend the time during which the neurons within the ischemic penumbra remain viable.12 These agents could be initially administered by paramedics as soon as they reach an apparent stroke patient. After transport to the hospital and CT confirmation that the patient has not had a hemorrhagic stroke, thrombolytic therapy could be initiated and neuroprotective therapy continued. Although the concept of neuroprotection has been considered for many years, the development of effective neuroprotective agents has greatly accelerated because of recent advances in the understanding of cellular mechanisms that mediate ischemic neuronal injury. Glutamate and neuronal damage: A schematic of a typical excitatory neuronal synapse is shown in Figure 3. Note that during normal neuronal function, when a neuron is “excited” to fire, it can, depending on its function, release either excitatory or inhibitory neurotransmitters. The most common excitatory neurotransmitter in the brain is glutamate.13,14 During normal neuronal transmission, glutamate is released briefly into the synapse of glutamatergic neurons, where it excites postsynaptic receptors. Subsequently, rapid reuptake of glutamate into axon terminals and nearby glial cells occurs. Although glutamate functions as an essential neurotransmitter in glutamatergic neurons during normal neurologic function, it is also a key mediator of brain injury during an ischemic stroke. Shortly after disruption of blood flow to the brain, neuronal depolarization causes a massive release of glutamate and related excitatory amino acids into the synapse. Because of the lack of glucose and oxygen, no energy is available for glutamate reuptake into the axon terminals and glial cells.

Thus, there is a toxic accumulation of glutamate and other excitatory neurotransmitters in the synapse. These substances cause excessive stimulation of glutamate receptors. The glutamate receptor that appears to play a particularly important role in the pathophysiology of stroke is the NMDA receptor subtype. This receptor is linked to an ion channel that is highly permeable to sodium and calcium. In response to excessive glutamate stimulation, sodium can rush through the channel into the neuron, pulling water with it, which leads to neuronal swelling. Simultaneously, an even more dangerous influx of calcium occurs. High concentrations of calcium in any cell can activate a cascade of cellular reactions, including activation of phospholipases, lipid peroxidation, and free radical formation, that lead to membrane destruction. Proteolytic enzymes that can destroy cellular proteins are also activated. Neuroprotection and the NMDA receptor: Soon after stroke onset, glutamate activates NMDA receptors, prompting excessive opening of the NMDA ion channel (Figure 4). Therefore, many of the early strategies for neuroprotection involved development of agents that would block the NMDA ion channel. These agents were intended to prevent sodium and calcium from damaging the neuron even in the presence of excess extracellular glutamate. Many of these agents, which are referred to as NMDA receptor antagonists, have been shown to be highly effective in the treatment of experimental ischemic neuronal injury.15 Studies in multiple experimental stroke models have shown that NMDA receptor antagonists can significantly reduce the volume of stroke injury (usually by about 50%) when they are administered before or shortly after stroke induction.

NEUROPROTECTIVE AGENTS Given their success in animal models of stroke, a number of NMDA receptor antagonists have also been assessed in clinical trials.12 A full review of these agents is beyond the scope of this article, but 2 potentially beneficial members of this class, which work by different mechanisms, are reviewed below.

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FIGURE 4. The N-methyl-D-aspartate (NMDA) receptor. Soon after stroke onset, glutamate binds to the NMDA receptor in the extracellular space, causing the ion channel to open and allow sodium and calcium to flow from the extracellular space into the neuron.

Aptiganel: One of the most promising NMDA receptor antagonists currently under investigation is aptiganel HCl (CNS 1102, Cerestat; Cambridge NeuroScience and Boehringer Ingelheim). This noncompetitive NMDA antagonist is effective in animal models of focal ischemia.15 It does not induce brain vacuolization, an effect noted with dizocilpine (MK801), one of the first noncompetitive NMDA antagonists to be studied. Aptiganel has also shown potential efficacy in preliminary clinical trials.16,17 Safety data from early clinical trials of this agent were also reassuring. NMDA receptor antagonists, like other neuroprotectants, are not associated with the increased risk of bleeding complications seen with thrombolytics. Unfortunately, many of these compounds, which block the NMDA receptor in a manner similar to phencyclidine (PCP; “angel dust”), can cause a number of transient but severe neurologic adverse events, especially when given at high doses. These include paranoia, hallucinations, agitation, confusion, somnolence, and decreased consciousness.15 Although neurologic adverse events occur with aptiganel, they tend to be less frequent than those reported with some of the previously tested NMDA antagonists. Headache, nausea and vomiting, hypertension, and paresthesias have also been reported.12 Rapid-onset, dose-related, symptomatic hypotension, which contributed to the discontinuation of the clinical development of dextrorphan,18 an early noncompetitive antagonist, has not been observed with aptiganel. On the basis of the encouraging results of the phase II study of aptiganel, a pivotal phase III trial was begun in July 1996.19 The study plans to enroll 900 patients in the United States, Canada, Australia, and 8D

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South Africa. It will compare the effects of treatment with 2 doses of aptiganel and placebo, given within 6 hours of stroke onset. If the results are favorable, aptiganel could be one of the first neuroprotective agents to be approved for the treatment of acute ischemic stroke. ACEA-1021: In light of the problematic side-effect profile of most NMDA receptor antagonists, many researchers have focused their attention on compounds that can prevent the consequences of excitatory amino acid–induced injury without causing neurotoxicity. Agents that block the glycine site on the NMDA receptor complex appear to be particularly

FIGURE 5. One-month survival curve in patients receiving lubeluzole 10 mg/day, lubeluzole 20 mg/day, or placebo in a randomized, double-blind, placebo-controlled phase II study. (Reprinted with permission from Stroke.31)

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TABLE I Phase II Clinical Trial of Lubeluzole: Adverse Events Lubeluzole Type of Adverse Event

Placebo (n 5 61)

Adverse Event

Frequently reported Fever Hypertension Headache Constipation Vomiting Depression Insomnia Bronchopneumonia Urinary tract infection Superficial phlebitis at infusion site Serious cardiac events Ventricular fibrillation Ventricular tachycardia Bradycardia Cardiac Arrest Suspected myocardial infarction Symptomatic heart failure

7 8 2 8 3 5 8 11 10 1

(11) (13) (3) (13) (5) (8) (13) (18) (16) (2)

1 (2) 1 (2) 2 (3) 1 (2) — 1 (2)

10 mg/day (n 5 66) 9 8 10 14 3 9 8 10 6 9

(14) (12) (15) (21) (5) (14) (12) (15) (9) (14)

1 (2) — — 1 (2) — 1 (2)

20 mg/day (n 5 66) 7 6 3 8 9 2 3 15 10 7

(11) (9) (5) (12) (14) (3) (5) (23) (15) (11)

4 (6) — 5 (8) 1 (2) 1 (2) 2 (3)

Adverse events reported in .10% of patients, and all serious cardiac adverse events, given in absolute numbers and percentages (in parentheses). Reproduced, with permission, from Stroke.31

promising. ACEA-1021 (Ciba/CoCensys) acts competitively at the glycine site by preventing glycine from binding to its specific regulatory site on the NMDA receptor (Figure 5).20 –22 When glycine is not bound to this site, glutamate cannot activate the receptor. In animal models of focal ischemia, ACEA1021 provides neuroprotection similar to that offered by noncompetitive NMDA receptor antagonists.23 Preclinical studies have also suggested that it does not produce phencyclidine-like side effects or brain vacuolization.22,24 ACEA-1021 has been evaluated in 2 recently completed phase I, placebo-controlled clinical trials.25 In these studies, ACEA-1021 was administered by short intravenous infusion to 30 healthy volunteers and 42 stroke patients. Severe neurologic or neurotoxic adverse effects were not reported. If follow-up trials establish that ACEA is effective as well as safe, this agent may be preferable to other NMDA antagonists. Its failure to induce significant adverse effects would facilitate its use in a prehospital setting and thus expedite the administration of neuroprotective therapy. Lubeluzole: In addition to developing compounds that act safely and effectively at the beginning of the ischemic cascade, researchers are also seeking opportunities to intervene later in the ischemic process. These “downstream” approaches may be inherently safer than NMDA receptor antagonism. A particularly promising strategy is inhibition of the nitric oxide synthase pathway, which can be activated by excessive extracellular glutamate concentrations.26 Research has shown that intracellular intracellular nitric oxide is a mediator of neuronal death during brain ischemia. Therefore, agents that can inhibit intracel-

lular nitric oxide formation, or its effects within the neuron, may be effective neuroprotectants. The most clinically advanced inhibitor of the glutamate-activated nitric oxide synthase pathway is lubeluzole (Prosynap; Janssen Pharmaceutica).27 This benzothiazole has been shown to protect neurologic function and improve the viability of the ischemic penumbra after experimental thrombotic stroke in rats.28 –30 Potential for beneficial effects in humans treated with lubeluzole was demonstrated in a doubleblind, placebo-controlled, phase II trial of 232 patients diagnosed with acute ischemic stroke in the carotid artery territory.31 In this study, patients were treated within 6 hours of stroke onset and received placebo or lubeluzole at either a loading dose of 7.5 mg over 1 hour followed by a continuous infusion of 10 mg/day for 5 days or a loading dose of 15 mg over 1 hour followed by a continuous infusion of 20 mg/day for 5 days. Patients’ neurologic status was evaluated using the National Institutes of Health Stroke Scale and the European Stroke Scale; their functional status was assessed using the Barthel Index. There was a marked intergroup difference in 28day mortality rates among the 3 treatment groups: 10% in the lubeluzole 10-mg/day group, 19% in the placebo group, and 31% in the lubeluzole 20-mg/day group (Figure 5). Survival in the lubeluzole 10-mg/ day group was significantly better than survival in placebo-treated patients (p 5 0.019). Treatment with 10 mg/day of lubeluzole was also associated with better functional outcomes at 28 days than either placebo or 20 mg/day of lubeluzole: 39% of patients in the low-dose lubeluzole group had a Barthel Index score $70, indicating a good outcome. Comparable scores were attained by only 34% of patients in the

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placebo group and 29% of those in the high-dose lubeluzole group (p 5 nonsignificant). One likely explanation for the higher mortality in the lubeluzole 20-mg/day group than in the other groups is that, by chance, patients who were randomized to the high-dose group had significantly poorer baseline neurologic scores. It was also noted that 5 patients in the high-dose lubeluzole group died of ventricular fibrillation or cardiac arrest, compared with no patients in the low-dose lubeluzole group and 2 patients in the placebo group. Adverse events reported in .10% of patients and all serious cardiac adverse events reported in this study are listed in Table I. Overall, adverse experiences were similar in the 3 groups. In phase I safety studies of lubeluzole, some healthy volunteers and stroke patients with plasma concentrations .100 ng/mL experienced prolongation of the QTc interval.31 In the phase II study, there were more adverse cardiac events reported in patients in the 20-mg/day group than in the 10-mg/day group. However, the higher incidence of cardiac adverse events in the 20-mg/day group cannot be solely attributed to the higher dose of lubeluzole because more patients in the high-dose group also had severe strokes, and severe strokes may predispose patients to adverse cardiac events. To characterize the cardiac effects of lubeluzole more fully, a separate cardiac safety study was conducted in 46 patients with acute ischemic stroke.32 In this study, patients received either a 1-hour infusion of 3.75 mg of lubeluzole followed by a 5-day continuous infusion of 5 mg/day, or a 1-hour infusion of 7.5 mg of lubeluzole followed by a 5-day continuous infusion of 10 mg/day. Patients received continuous cardiac monitoring during the treatment period and for 2 days thereafter. Neither dose of lubeluzole was found to have a clinically relevant effect on QTc or other electrocardiographic parameters. More recently, the safety and efficacy of lubeluzole 10 mg/day have been assessed in 2 large Phase III clinical trials, one in Europe and the other in the United States. These 2 trials have been completed, but the results have not been published. If they are favorable, lubeluzole could be the first neuroprotective drug to be approved for the treatment of acute ischemic stroke. In conclusion, our hope for the near future is that through educational efforts the general public will become familiar with stroke signs and symptoms. Emergency medical systems can then be activated promptly. Paramedics can arrive and administer a neuroprotective drug, ideally within the first half hour after stroke onset. Patients can then be rushed to the hospital, where they can be evaluated to determine whether they are appropriate candidates for thrombolytic therapy. Ideally, most stroke patients who receive immediate medical attention and combination therapy with both a neuroprotectant and a thrombolytic will recover completely or substantially. 1. Mohr JP, Sacco RL. Classification of ischemic strokes. In: Wolf PA, Cobb JL, D’Agostino RB. Epidemiology of stroke. In: Barnett HJM, Mohr JP, Stein BM,

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Yatsu FM, eds. Stroke: Pathophysiology, Diagnosis, and Management, 2nd ed. New York: Churchill Livingstone, 1992:271–283. 2. National Stroke Association. Stroke remains a deadly mystery to many Americans: Gallup Study shows symptoms, causes often misunderstood by persons most at risk [press release]. Inverness, Colorado: National Stroke Association, June 5, 1996. 3. Anonymous. Activase approved for stroke in U.S. Scrip 2140; June 25, 1996:21. 4. Lassen NA. Pathophysiology of brain ischemia as it relates to the therapy of acute ischemic stroke. Clin Neuropharmacol 1990;13(suppl 3):1– 8. 5. Hossmann KA. Viability thresholds and the penumbra of focal ischemia. Ann Neurol 1994;36:557–565. 6. National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995;333:1581–1587. 7. Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R, Boysen G, Bluhmki E, Hoxter G, Mahagne MH. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke: the European Cooperative Acute Stroke Study (ECASS). JAMA 1995;274:1017–1025. 8. Multicenter Acute Stroke Trial–Europe Study Group. Thrombolytic therapy with streptokinase in acute ischemic stroke. N Engl J Med 1996;335:145–150. 9. Multicentre Acute Stroke Trial–Italy (MAST-I) Group. Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic stroke. Lancet 1995;346:1509 –1514. 10. Donnan GA, Davis SM, Chambers BR, Gates PC, Hankey GJ, McNeil JJ, Rosen D, Stewart-Wynne EG, Tuck RR, for the Australian Streptokinase (ASK) Trial Study Group. Streptokinase for acute ischemic stroke with relationship to time of administration. JAMA 1996;276:961–966. 11. Genentech, Inc. Activase Product Information. In: Physicians’ Desk Reference, 51st ed. Montvale, NJ: Medical Economics Company, Inc., 1997:1045–1049. 12. 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Scrip 2150;July 30, 1996:19. 20. Woodward RM, Huettner JE, Guastella J, Keana JFW, Weber E. In vitro pharmacology of ACEA-1021 and ACEA-1031: systemically active quinoxalinediones with high affinity and selectivity for N-methyl-D-aspartate receptor glycine sites. Mol Pharmacol 1995;47:568 –581. 21. Anonymous. CoCensys stroke therapy in clinical trials. Scrip 1997;February 7, 1995:27. 22. Kulagowski JJ, Leeson PD. Glycine-site NMDA receptor antagonists. Exp Opin Ther Patents 1995;5:1061–1075. 23. Warner DS, Martin H, Ludwig P, McAllister A, Keana JFW, Weber E. In vivo models of cerebral ischemia: effects of parenterally administered NMDA receptor glycine site antagonists. J Cereb Blood Flow Metab 1995;15:188 –196. 24. Newell DW, Barth A, Malouf AT. Glycine site NMDA receptor antagonists provide protection against ischemia-induced neuronal damage in hippocampal slice cultures. Brain Res 1995;675:38 – 44. 25. Anonymous. Clinical trials update. Scrip 2182;November 19, 1996:27. 26. Faraci FM, Brian JE. Nitric oxide and the cerebral circulation. Stroke 1994;25:692–703. 27. Lesage AS, Peeters L, Leysen JE. Lubeluzole, a novel long-term neuroprotectant, inhibits the glutamate-activated nitric oxide synthase pathway. J Pharmacol Exp Ther 1996;279:749 –766. 28. De Ryck M, Keersmaekers R, Duytschaever H, Claes C, Clincke G, Janssen M, Van Reet G. Lubeluzole protects sensorimotor function and reduces infarct size in a photochemical stroke model in rats. J Pharmacol Exp Ther 1996;279: 748 –758. 29. Buchkremer-Ratzmann I, Witte OW. Periinfarct and transhemispheric diaschisis caused by photothrombotic infarction in rat neocortex is reduced by lubeluzole but not MK-501. (Abstr.) J Cereb Blood Flow Metab 1995;15(suppl 1):S381. 30. De Ryck M, De Prins E, Nolten C, Marrannes R, Clincke G. Lubeluzole improves ischemic penumbra measured by cortical spreading depression in rats. Soc Neurosci Abstr. 1995;21:1031. 31. 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