AUTHOR AND EDITOR INFORMATION

Section 1 of 6  

• Authors and Editors
• Introduction
• Prevention of Early Ischemic Injury
• Prevention of Reperfusion Injury
• Conclusions
• References

INTRODUCTION

Section 2 of 6  

• Authors and Editors
• Introduction
• Prevention of Early Ischemic Injury
• Prevention of Reperfusion Injury
• Conclusions
• References

Stroke is the third leading cause of death in the United States and the most common cause of adult disability. An ischemic stroke occurs when a cerebral vessel occludes, obstructing blood flow to a portion of the brain.

The only currently approved medical stroke therapy, tissue plasminogen activator (tPA), is a thrombolytic that targets the thrombus within the blood vessel. Neuroprotective agents, another approach to stroke treatment, have generated as much interest as thrombolytic therapies.

Using various mechanisms, neuroprotective agents attempt to save ischemic neurons in the brain from irreversible injury. Studies in animals indicate a period of at least 4 hours after onset of complete ischemia in which many potentially viable neurons exist in the ischemic penumbra. In humans, the ischemia may be less complete, and the time window may be longer, but human patients also tend to be older with comorbidities that may limit benefit. As many neuroprotective drugs reduce ischemic damage in animal models of stroke, this line of pharmaceutical research holds great promise. Many are searching for a safe agent that can limit ischemic damage in human stroke.

One action of neuroprotective agents limits acute injury to neurons in the penumbra region or rim of the infarct after ischemia. Neurons in the penumbra are less likely to suffer irreversible injury at early time points than are neurons in the infarct core. Many of these agents modulate neuronal receptors to reduce release of excitatory neurotransmitters, which contribute to early neuronal injury.

Other neuroprotective agents prevent potentially detrimental events associated with return of blood flow. Although return of blood flow to the brain is generally associated with improved outcome, reperfusion may contribute to additional brain injury. Returning blood contains leukocytes that may occlude small vessels and release toxic products.

This article discusses 2 types of neuroprotective agents, one that prevents early ischemic injury and another that prevents reperfusion injury. Clinical trial results of these agents are summarized.

For excellent patient education resources, visit eMedicine's Stroke Center. Also, see eMedicine's patient education article Stroke.

PREVENTION OF EARLY ISCHEMIC INJURY

Section 3 of 6  

• Authors and Editors
• Introduction
• Prevention of Early Ischemic Injury
• Prevention of Reperfusion Injury
• Conclusions
• References

Ischemia leads to excessive activation of excitatory amino acid receptors, accumulation of intracellular calcium, and release of other toxic products that cause cellular injury. By preventing excitatory neurotransmitter release, neuroprotective agents may reduce deleterious effects of ischemia on cells.

N-methyl-D-aspartate Receptor Antagonists

The most commonly studied neuroprotective agents for acute stroke block the N-methyl-D-aspartate (NMDA) receptor. Dextromethorphan, a noncompetitive NMDA antagonist and metabolite of cough suppressant, was the first NMDA antagonist studied in human stroke patients. Unfortunately, dextrorphan caused hallucinations and agitation; it also produced hypotension, which limited use.

Selfotel, a competitive NMDA antagonist, showed trends toward higher mortality within treated patients than within placebo-treated cohorts, thus trials were stopped prematurely. A trial of another NMDA receptor antagonist, aptiganel HCl (Cerestat), was terminated because of concerns regarding benefit-to risk-ratios.

In patients treated with NMDA antagonists, the adverse effects of hallucinations and agitation mimic those seen with phencyclidine, which binds at a similar site. To avoid these phencyclidinelike effects, indirect NMDA receptor antagonists that work at the glycine site of the receptor were developed. These agents prevent glycine from binding, which in turn prevents glutamate from activating the receptor. Early clinical studies suggest that psychomimetic side effects occur less frequently in these glycine site NMDA antagonists. A large, 1367-patient, efficacy trial with the agent GV150526 was completed in 2000. Although the drug was reported to be safe and well tolerated, no improvement was observed in any of the 3-month outcome measures. No further trials are planned.

Magnesium is another agent with actions on the NMDA receptor and a low incidence of side effects. It may reduce ischemic injury by increasing regional blood flow, antagonizing voltage-sensitive calcium channels, and blocking the NMDA receptor. In myocardial infarction and small stroke studies, patients tolerated the drug. A phase III trial investigating the efficacy of magnesium in stroke, the Intravenous Magnesium Efficacy Study, which treated patients within 12 hours of symptom onset, did not show efficacy. The ongoing Field Administration of Stroke Therapy - Magnesium Phase III (FAST-MAG) Trial is trying a new approach: the delivery of magnesium in the field by paramedics, to greatly reduce the time to treatment (for more information, see The Internet Stroke Center, Stroke Trials, FAST-MAG).

Modulation of Non-NMDA Receptors

Nalmefene

Modulating other non-NMDA receptors and channels also can reduce excitatory neurotransmitter release. Nalmefene (Cervene) is a narcotic receptor antagonist that reduces levels of excitatory neurotransmitters contributing to cellular injury in early ischemia. Unlike NMDA receptor antagonists, this drug causes minimal side effects. Post hoc analyses of early studies suggest that the drug may have more benefit in patients younger than 70 years. However, no clinical benefit was found in a phase III clinical trial in which the drug was administered intravenously (IV) within 6 hours of symptom onset. No further trials are planned.

Lubeluzole

The exact mechanism of action of lubeluzole, a drug effective in animal models, is unclear. The drug may block sodium channels in cells. In addition, it may reduce the release of nitric oxide, a neurotransmitter generated by activation of the NMDA receptor. Although stroke severity and patient age appeared to influence outcome in early studies, a later trial was unable to confirm that lubeluzole was efficacious in these subsets of acute stroke patients. Clinical stroke research with this drug has been abandoned.

Clomethiazole

Clomethiazole, a g-aminobutyric acid agonist, decreases excitatory neurotransmission by increasing activity of inhibitory pathways.

In Europe, clomethiazole's central nervous system inhibitory properties have been used for anticonvulsant and sedative effects. The potential efficacy of clomethiazole as a neuroprotective agent in ischemia was first investigated in Europe as part of the Clomethiazole Acute Stroke Study. Patients received a 24-hour IV infusion of clomethiazole or placebo within 12 hours of symptom onset. As predicted by the drug's inhibitory effects, its primary side effect was sedation. Overall, the study was negative. Clomethiazole did not show improved functional outcome, the primary endpoint, compared to placebo at 3 months. In a subgroup of patients with large strokes, the study showed 37% relative improvement.

A large, 1198-patient, phase III trial was then done, focusing on patients with large strokes, which were defined by the presence of higher cortical dysfunction, limb weakness, and visual field disturbances. The results were negative, with 42% of the clomethiazole group and 46% of the placebo group showing a good outcome.

Additional drugs

Calcium channel blockers were extensively evaluated in acute stroke with the hope that stemming excessive cellular calcium influx caused by ischemia may prevent neuronal injury. Studies of calcium channel blockers did not show efficacy in stroke treatment. The most recent clinical trial, which assessed the usefulness of oral nimodipine given within 6 hours of symptom onset, was terminated early after analysis of the first 439 patients predicted no beneficial effect of the drug.

Several drugs with novel mechanisms to modulate neurotransmission or ion channels have recently completed clinical trials. These treatments included an a-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid antagonist developed by Yamanouchi, USA, Inc; a serotonin agonist, repinotan, developed by Bayer Corporation; and a transmembrane potassium channel modulator developed by Bristol-Myers Squibb. Unfortunately, none of the clinical trials showed efficacy for the investigational treatment. The serotonin agonist, repinotan, was given early, after only 4.5 hours of symptom onset. ONO 2506, a novel neuroprotectant developed by Ono Pharmaceutical Co, Ltd that inhibits astrocyte activation, was administered within 6 hours of stroke onset. A futility analysis performed in May 2005 led to discontinuation of the trial in the United States.

Another target of neuroprotective therapy in acute ischemic stroke is free-radical generation, which leads to further release of calcium and excitatory neurotransmitters. The free-radical scavenger tirilazad did not show benefit in an acute stroke trial. The drug also was investigated in subarachnoid hemorrhage and in traumatic brain injury, without convincing evidence of benefit. The free-radical trapping agent NXY-059 is currently being investigated in stroke efficacy trials (see below).

Phase 3 trials are still ongoing for certain agents. In addition to assessments of NXY-059, a trial is investigating albumin within 5 hours of symptom onset. In preclinical studies, albumin appears to have both antioxidant properties and the ability to increase blood flow to the penumbra. Hypothermia is also being evaluated for its neuroprotective capabilities. One study is evaluating hypothermia (treatment within 300 min) in conjunction with a combination of caffeine and ethanol (caffeinol) (treatment within 240 min).

Agents in earlier acute stroke trials include SUN N4057 or piclozotan, a serotonin agonist (Daiichi, Asubio Pharmaceuticals); TS-011 (Taisho Pharmaceutical Co. Ltd), which blocks the synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE), a potent vasoconstrictor; lovastatin, a statin agent; and normobaric oxygen.

One positive trial - NXY-059

The free-radical trapping agent NXY-059 is the first neuroprotectant to show efficacy in an acute stroke treatment trial. The trial, called Stroke-Acute Ischemic NXY Treatment (SAINT I), was the first of 2 efficacy trials. The drug was delivered intravenously over 72 hours in patients within 6 hours of stroke symptom onset, although a forced allocation scheme maintained an average treatment time of less than 4 hours. Patients were required to have limb weakness and a score of at least 6 on the National Institutes of Health Stroke Scale (NIHSS).

Patients who received treatment had significantly better outcomes (P = .038) on the primary endpoint, the distribution of scores on the modified Rankin scale that assessed disability at 90 days. The co-primary endpoint, the change from baseline on the NIHSS, did not show a difference between treatment groups. Of interest, post hoc analyses in patients treated with tPA showed that patients who received NXY-059 and tPA had significantly fewer hemorrhagic transformations than those who received placebo and tPA (P = .001) and symptomatic hemorrhagic transformations also occurred less frequently in this group (P = .036).

The second efficacy trial, SAINT II, completed enrollment in the summer of 2006. Results are expected by early 2007. Because the drug has demonstrated safety in a previous trial of patients with hemorrhagic strokes, in the future it could potentially be administered before head imaging is performed should SAINT II confirm the results of SAINT I. NXY-059 also holds promise as a vasoprotective agent in patients treated with tPA, although its putative preventative effects on hemorrhagic transformation need to be confirmed.

PREVENTION OF REPERFUSION INJURY

Section 4 of 6  

• Authors and Editors
• Introduction
• Prevention of Early Ischemic Injury
• Prevention of Reperfusion Injury
• Conclusions
• References

Despite the good outcome generally associated with reopening a blood vessel, additional brain injury may result when reperfusion occurs. When white blood cells reenter a previously hypoperfused region via returning blood, they can occlude small vessels, producing additional ischemia. Leukocytes release toxic products that can lead to free radical and cytokine formation.

Agents that prevent white blood cells from adhering to vessel walls, limit formation of free radicals, or promote neuronal repair may protect the brain from additional injury during reperfusion. Neuroprotective agents that work primarily during reperfusion may have a longer window of therapeutic effect than drugs that work earlier in the ischemic cascade.

Antiadhesion Antibodies

Enlimomab

Monoclonal antibodies can block an intercellular adhesion molecule (ICAM) on the endothelium to prevent adhesion of white blood cells to the vessel wall. Because anti-ICAM antibodies appear to block an early step in reperfusion-related injury, they present a hopeful mechanism for preserving neuronal function.

A large multicenter trial assessed clinical efficacy of anti-ICAM-1. More than 600 patients received either IV boluses of murine monoclonal antibody to ICAM-1 (enlimomab) or placebo for 5 days, beginning within 6 hours after symptom onset. Treated subjects were found to have higher mortality rates and worse outcomes than subjects in the placebo group. A marked increase in fevers occurred in patients who received enlimomab. Elevated temperatures previously were found to worsen stroke outcome. A viable explanation for the adverse effects seen in the anti-ICAM-1 trial is that the patients who were treated developed an immune response to the murine antibody. Although enlimomab was not clinically useful in the treatment of stroke, researchers hoped that its mechanism of action still could have a role in limiting neuronal injury.

Hu23F2G

A phase III trial was then done by using a human antileukocytic antibody, Hu23F2G, developed by ICOS Corporation. Because the antibody is humanized and not murine, this agent hopefully avoids the unwanted effects of enlimomab. This agent did not appear to produce the immune response seen with enlimomab. However, no clinical benefit was seen with Hu23F26 on any of the planned measures. No further studies with this agent are planned, though smaller antibodies that target specific leukocyte receptors may still have potential.

Antiplatelet antibodies

Another antiadhesion monoclonal antibody strategy targets platelets. These antibodies inhibit platelet aggregation, potentially preventing additional ischemic injury during reperfusion as well as promoting thrombolytic action. Such an antiplatelet drug, abciximab (ReoPro), was in phase 3 clinical stroke treatment trials, but an increased rate of intracranial hemorrhage led to discontinuation of all trials.

Membrane Stabilization

Citicoline is an exogenous form of cytidine-5'-diphosphocholine (CDP-choline) used in membrane biosynthesis. Citicoline may reduce ischemic injury by stabilizing membranes and decreasing free radical formation. A phase II trial showed improved outcome in stroke patients treated with either a 500- or 2000-mg/d dose of citicoline. A phase III trial then randomized patients in a 2:1 fashion to receive either 500 mg of citicoline or placebo orally in capsule form every day for 6 weeks. Treatment began within 24 hours of symptom onset.

There were 267 patients in the citicoline-treated group and 127 patients in the placebo group. After 3 months, the citicoline-treated and placebo-treated groups showed no significant differences on selected assessments of functional outcome. There were no significant side effects. Despite similar mean baseline neurologic stroke scale scores, a higher percentage of placebo patients had mild strokes. A post hoc subgroup analysis suggested that patients with more severe strokes (National Institutes of Health Stroke Scale >8) had better functional outcome with citicoline.

Another phase 3 trial assessed infarct size on magnetic resonance imaging (MRI) in patients with mild, moderate, and severe strokes. Although this study also failed to show a significant difference between treated and untreated groups, there was a trend toward smaller infarct volumes in treated patients. A phase III trial was then done, involving only moderate-to-large strokes. The drug showed no adverse effects. Unfortunately, the company chose a novel endpoint (NIHSS score improvement > 7 points), and the trial was negative. If the company had instead used more conventional endpoints (eg, NIHSS = 0 or 1, Rankin = 0 or 1), the trial would have been positive. In a pooled analysis of multiple trials, citicoline appears to have a modest benefit. Interestingly CDP-choline is available as a supplement (Jarrow Formulas, Inc.). A large international trial, ICTUS Study: International Citicoline Trial on acUte Stroke, is enrolling patients within 24 hours of stroke onset.

Neuronal Healing

Fiblast, a basic fibroblast growth factor, could help regulate neuronal healing after ischemia. In a phase II safety trial, Fiblast was administered IV for up to 24 hours in acute stroke patients. Although it was associated with transient leukocytosis, the drug otherwise appeared to be well tolerated and safe. A large trial was begun to evaluate the efficacy of Fiblast in stroke patients presenting within 6 hours of symptom onset. However, the trial was terminated because of poor risk-to-benefit ratios.

CONCLUSIONS

Section 5 of 6  

• Authors and Editors
• Introduction
• Prevention of Early Ischemic Injury
• Prevention of Reperfusion Injury
• Conclusions
• References

Until the NXY-059 trial, the past decade had produced a plethora of negative neuroprotective trial results. This is frustrating because all of these agents seemed effective in animal trials. The ischemic cascade appears to be so complex that targeting a single pathway may be ineffective.

A pattern of potential benefit in particular subgroups of patients, such as younger patients or those with large strokes, has emerged in several trials. The pathophysiology underlying subgroup efficacy effects may be complex. Older patients tend to show poorer stroke outcomes both in treated and in placebo groups, which may narrow margins of efficacy. Patients with mild strokes may not show treatment effects, because the placebo group achieves high levels of spontaneous recovery. Mild strokes also are less likely to involve cortical structures and gray matter. If an agent has a primary effect on such highly metabolic gray matter structures, it may not show efficacy in smaller strokes.

Ongoing studies will determine whether these treatments are indeed effective in their targeted subgroups. In agents hampered by side effects, such as NMDA receptor antagonists, modifications in structure may improve benefit-to-risk ratios. Finally, novel agents that have not yet completed clinical trials still hold promise of potential efficacy.

In the future, optimal therapy may be achieved by combining neuroprotective agents with complementary mechanisms in a "stroke cocktail." Because these drugs most likely will not display adverse effects in patients with hemorrhagic stroke, ambulance crews could begin administering this stroke cocktail in the field. Upon arrival at the hospital, the patient would undergo imaging studies of the head, and assessment for potential administration of a medical or mechanical thrombolytic would take place. The final step of therapy would be participation in a state-of-the-art rehabilitation program.

To reduce the devastating impact on society, physicians must achieve better functional recovery in stroke patients.

REFERENCES

Section 6 of 6

• Authors and Editors
• Introduction
• Prevention of Early Ischemic Injury
• Prevention of Reperfusion Injury
• Conclusions
• References

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Article Last Updated: Nov 2, 2006