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Neuroprotection for ischemic stroke. (Pharmacology Update).

Stroke, or brain attack, is a leading cause of death and disability in many developed nations. In the United States approximately 400,000 individuals have an acute ischemic stroke each year (National Stroke Association, 2000). Ischemic stroke costs the United States an estimated $71.8 billion each year (Matchar & Samsa, 2000). With more than 3 million stroke survivors in the United States, it is beneficial to limit the amount of brain damage from the initial insult.

Neurons and support cells require a careful balance of variables such as temperature, pH, nutrition, and waste removal in their environment to function optimally (Reed, 2000). Recent intensive basic science research has given healthcare professionals an increased understanding of the precise environmental alterations that are involved in the pathophysiology of ischemic injury. Fig 1 provides an overview of these alterations, referred to as the ischemic cascade. Improved understanding of this pathophysiology has led basic science researchers to investigate new treatments for ischemic injury.

[FIGURE 1 OMITTED]

The term neuroprotection is quite broad and refers to pharmacological and nonpharmacological treatments used to halt the sequence of events in the ischemic cascade. Neuroprotective drugs are mostly still in clinical trials. Methods of averting the entire ischemic cascade can be considered to be neuroprotective in a more global manner. This article briefly reviews current and experimental drug therapy for acute ischemic stroke and then focuses on investigational neuroprotective drugs and strategies.

Current Drug Therapy for Ischemic Stroke

Ischemic stroke occurs most commonly in older individuals with underlying atherosclerosis (Alberts, 1999). A thrombus or emboli from the heart, aorta, or carotid or vertebral arteries lodges in the intracranial circulation of the brain, blocking blood flow to the distal portion of the affected vessel.

The first window of opportunity for intervention occurs in the beginning of the ischemic cascade (Fig 1), where key variables for cell metabolism are adequate glucose and oxygen supplied by cerebral blood flow (CBF). Following an acute ischemic stroke, with a decrease in CBF to below 20 ml/100 g brain tissue/ minute, an infarcted core with an ischemic penumbra forms (Warlow et al., 2001). This step in the cascade provides an important opportunity to restore CBF and prevent further damage. The only standard treatment available to accomplish this currently is the administration of tissue plasminogen activator (t-PA) (Activase).

The drug, t-PA, lyses the clot and restores blood flow to the ischemic penumbra (Alberts, 1999; Kongable, 1997). Administration of t-PA has been approved for use by the Food and Drug Administration (FDA) within 3 hours of symptom onset. The dose is 0.9 mg/kg total or maximum of 90 mg. Ten percent of the dose is administered as an intravenous (IV) bolus over 1 minute, and the remaining 90% is given intravenously over the next hour (Bonnono et al., 2000; Kongable; National Institute of Neurological Disease and Stroke rt-PA Study [NINDS] Group, 1995). Most healthcare professionals are aware of the many inclusion and exclusion criteria for t-PA administration, which are discussed in detail elsewhere (Bonnono et al.; Kongable; NINDS Group).

The administration of t-PA does not affect the infarcted core but can revitalize the ischemic penumbra. Thus, t-PA restores blood flow and limits the extent of the secondary brain damage caused by an ischemic stroke and improves function (NINDS Group, 1995). Although t-PA is currently the only FDA-approved therapy for acute ischemic stroke in the United States, other emerging therapies are being investigated.

Emerging Therapies

Delivering a thrombolytic agent directly through the intra-arterial (IA) route is an emerging therapy that appears to have many advantages over IV administration (Saver, 2001). Advantages include delivering the agent directly to the clot, reducing systemic exposure, gentle mechanical disruption of the clot with the catheter and wire, and visualization of the recanalization (Saver, 2001). A major advantage is the longer time frame (6 hours) for intervention compared to the current 3-hour window allowed by the FDA for IV t-PA (Saver). Drugs used for IA thrombolysis or under investigation include urokinase, recombinant pro-urokinase (rpro-UK), and t-PA (Saver; Schellinger et al., 2001). The major disadvantage, similar to IV t-PA administration, is the occurrence of intracerebral hemorrhage (Saver).

Prolyse in Acute Cerebral Thromboembolism (PROACT) I and II were randomized in clinical trials of IA therapy using rpro-UK (Saver, 2001; Schellinger et al., 2001). These trials showed that IA therapy; delivered within 6 hours of symptom onset, is a safe, effective, and promising treatment strategy for acute ischemic stroke. PROACT III is in international drug trial, with participating sites in the United States and Canada, evaluating safety and efficacy of rpro-UK administered within 6 hours of symptom onset (Schellinger et al., 2001).

Investigational Neuroprotective Drugs

Glutamate antagonists, gamma-aminobutytic aminobutyric acid (GABA) agonists, calcium channel blockers, and free-radical scavengers are other neuroprotective strategies currently under investigation for acute ischemic stroke. Many agents have shown promise in laboratory experiments and some are moving into human trials.

Glutamate Antagonists

The neurotransmitter, glutamate, is important in the ischemic cascade (Fig 1). It helps neurons communicate with each other and is present in the normal axon terminal in very small amounts. Neurons are particularly sensitive to glutamate. When there is ischemic injury, excessive amounts of glutamate are released. Glutamate opens the calcium channels in the neurons, allowing calcium to move into the cell. This calcium entry is toxic to the cell.

Glutamate can only attach itself to neurons that have glutamate receptors. There are several different glutamate receptors, including the N-methyl-D-aspartate (NMDA) receptor and the a-amino-3-hydroxy -5-methylisoxazole-4-propionis acid (AMPA) receptor (During et al., 2000; Zipfel, Lee, & Chio, 1999). In animal models, neuroprotective agents, known as glutamate antagonists, minimize brain cell death by inhibiting glutamate release, or blocking glutamate binding at NMDA or AMPA receptor sites.

NMDA trials. Overwhelmingly, to date, the results of NMDA antagonists in human trials have been negative. Aptiganel hydrochloride, for example, showed great promise in animal experiments but the results of a randomized controlled clinical trial for this agent showed it was not efficacious in 628 patients with acute ischemic stroke (Albers, Goldstein, Hall, & Lesko, 2001). Using the Modified Rankin Scale at 90 days, two doses of the drug did not improve outcome compared with placebo. In addition, the placebo group had a lower mortality rate (Albers et al.).

Another NMDA compound, gelsolin, has shown promise in animal models by reducing the calcium influx and inhibiting neuronal death (Zipfel et al., 1999). Research efforts in animal models and in clinical trials continue on NMDA antagonists (Reed, 2000; Warlow et al., 2001).

AMPA trials. Several AMPA antagonists, identified by numbers so far, are in animal and human testing (Reed, 2000; Warlow et al., 2001). For example, YM872 is in phase II clinical trial (Pharmaceutical Research and Manufacturers of America, 2001). Other AMPA antagonists, such as YM90K and ZK-200775, are under investigation (Warlow et al.).

IMAGES trial. Magnesium is an inexpensive and commonly used compound thought to be an NMDA antagonist (Charlton, 1998; Warlow et al., 2001). The Intravenous Magnesium Efficacy in Stroke (IMAGES) trial is a randomized, double-blind, placebo-controlled, multicenter international collaborative trial designed to test the efficacy of magnesium sulfate (MgS[O.sub.4]) given within 12 hours of acute stroke (Lees & Muir, 2002). An IV dose of 16 mmol of MgS[O.sub.4] is given over 15 minutes followed by 65 mmol over the next 24 hours (Charlton). Enrollment of 2,700 patients is planned; entry and exclusion criteria can be found on IMAGES Web site (Charlton).

Estrogens. It has been known for some time that estrogens are glutamate antagonists (Roof & Hall, 2000), but the hormonal side effects have limited their clinical application. A recent study showed that an estrogen analogue, ZYC3, decreased infarct volume in rats (Liu et al., 2002). This suggests that estrogen analogues have possible clinical applications for neuroprotection in stroke without the hormonal side effects of estrogen.

GABA Agonists

GABA agonists such as domethiazole and diazepam (Valium) have had positive results in basic research with animal models (Reed, 2000; Warlow et al., 2001). These agents are thought to counteract membrane depolarization in the ischemic cascade and provide neuroprotection in this manner.

EGASIS trial. The early GABA-ergic activation study in stroke (EGASIS) is an international multicenter, randomized, placebo-controlled, double-blind trial being coordinated in the Netherlands (Lodder, 2002). This trial will enroll 5,000 acute stroke patients to evaluate the efficacy of diazepam (Valium) as a GABA agonist type of neuroprotective agent (Lodder). A dose of 10 mg rectal diazepam is administered as soon as possible following admission to the hospital for acute stroke (preferably within 3 hours and at least within 12 hours) followed by five oral doses of 10 mg every 12 hours (Raak, Hilton, Kessels, & Lodder, 2002). The modified Rankin Scale will be used to measure outcome at 3 months after stroke (Raak et al.).

Calcium Channel Blockers

In the middle of the ischemic cascade are a number of important cellular events that present windows of opportunity for therapeutic intervention. At this middle point the name "cascade" is not entirely correct, because the flow of events is not strictly linear (Fig 1). Some events are simultaneous, sideways, or even circular. One important event is membrane depolarization, and it has a number of trigger events. When a neuronal membrane is destabilized by depolarization, this leads to subsequent events, including an increase in intracellular calcium (Reed, 2000). Calcium, in abnormal amounts, can activate a number of damaging pathways. Because calcium is so important, much research time and effort have focused on calcium channel antagonists that stop the influx of intracellular calcium and thus the course of events in this middle section of the ischemic cascade.

Nimodipine. The drug nimodipine (Nimotop) is perhaps the best-known calcium channel blocker due to its therapeutic efficacy in patients with subarachnoid hemorrhage. It has proven much less effective in clinical trials for acute ischemic stroke, yielding mostly negative results due to hypotension and delays of up to 48 hours in initial treatment (Reed, 2000). Other calcium channel antagonists, such as flunarizine and ziconotide, are under investigation (Reed; Warlow et al., 2001).

Free-Radical Scavengers

An important step toward the end of the ischemic cascade is the formation of free radicals (Fig 1). As a result of membrane depolarization and calcium influx, amongst other events, molecules with an unpaired electron form and are referred to as free radicals (Reed, 2000). Free radicals are toxic to neurons; compounds that trap them are called free radical scavengers. By trapping the free radicals, the scavengers decrease cellular toxicity at this point in the ischemic cascade.

NXY-059 trial. The compound NXY-059 is a free radical scavenger in development by Astra Zeneca (Lees et al., 2002). It has been tested in a double-blind, placebo-controlled, international multicenter dose-escalation study with 135 acute stroke patients. Results showed that NXY-059 was well tolerated and safe in acute ischemic stroke patients at higher doses than had previously been tried (Lees et al.). Further studies are under way, because this study had insufficient patients enrolled to measure outcome with the modified Rankin Scale (Lees et al.).

Neuroprotective Strategies

Additional nonpharmacological neuroprotective strategies include hypothermia and the stroke vaccine.

Hypothermia

The temperature of the cellular environment, while not discussed in the ischemic cascade, is known to be an important variable following acute central nervous system (CNS) injury. Thus clinicians have investigated manipulation of body temperature as a means of minimizing secondary brain injury. Hypothermia is known to decrease the cerebral metabolic rate and in this manner can be neuroprotective (Correia, Silva, & Veloso, 2001).

Hypothermia is usually divided into mild, moderate, and deep levels depending on the core temperature achieved. Mild hypothermia (34[degrees]C), for example, is a neuroprotective treatment currenfiy trader investigation for the treatment of stroke patients (Bell, Kongable, & Steinberg, 1998). Moderate hypothermia (33[degrees] C) has been combined with hemicraniectomy to improve outcome in one series of 36 patients following severe ischemic stroke (Georgiadis, Schwarz, Aschoff, & Schwab, 2002). Deep hypothermia (15-22[degrees]C) is known to have serious adverse effects such as hemorrhagic, cardiac, and systemic complications and generally is not used.

The hypothermic state is achieved by chemical or physical means. Chemical agents include antipyretic drugs such as aspirin and acetaminophen (Correia et al., 2001). Physical cooling is achieved with devices such as cooling blankets, ice-water lavage, and air-cooling devices (Correia et al.).

Hypothermia is routinely used in patients undergoing neurosurgery and coronary artery bypass surgery (CABG) to protect against the effects of cerebral hypoxia (Correia et al., 2001). Lowering the body temperature appears to improve clinical outcome following severe head injury. Currently there is no evidence from randomized clinical trials to support the routine use of physical or chemical cooling therapy in acute stroke (Correia et al.; Liu et al., 2002). Further randomized, double-blind, placebo-controlled, multicenter collaborative trials are needed to test the efficacy of hypothermia in acute ischemic stroke.

The Stroke Vaccine

A unique global neuroprotective strategy is a stroke vaccine that can be given in advance to at-risk individuals, ready to protect the brain from secondary ischemic injury. The vaccine is in the very early stages of development (During et al., 2000). So far it has been given to 38 rats; 5 months after vaccination the rats were given a middle cerebral artery stroke in a controlled laboratory situation (During et al.). The size of the lesion in the vaccinated rats was reduced 70% compared with a control group (During et al.). Because the rats had such small strokes after being vaccinated, scientists are hopeful that further work in this area may one day lead to a vaccine against stroke for humans.

Summary

Many pharmacological and nonpharmacologic neuroprotective therapies are in various phases of animal or human testing. The future in acute ischemic stroke therapy most likely will consist of combination therapies (Bonnono et al., 2000; Schellinger et al., 2001). An IV thrombolytic agent may be combined with an IA agent and then followed up with a neuroprotective strategy early in treatment of acute ischemic stroke. A hemicraniectomy may be combined with hypothermia to improve outcome (Georgiadis et al., 2002). Many resources (Fig 2) are available to assist neuroscience nurses in keeping abreast of this fast-paced area of development.

References

Albers, G.W., Goldstein, L.B., Hall, D., & Lesko, L. (2001). Aptiganel hydrochloride in acute ischemic stroke, Journal of the American Medical Association, 286, 2673-2682.

Alberts, M.J. (1999). Diagnosis and treatment of ischemic stroke. The American Journal of Medicine, 106, 211-221.

Bell, T., Kongable, G., & Steinberg, G. (1998). Mild hypothermia: An alternative to deep hypothermia liar achieving neuroprotection. Journal of Cardiovascular Nursing, 13(1), 34-44.

Bonnono, C., Criddle, L.M., Lutsep, H.L., Stevens, P., Kearns, K., & Norton, R. (2000). Emergi-paths and stroke teams: An emergency department approach to acute ischemic stroke. Journal of Neuroscience Nursing, 32, 298-305.

Charlton, D. (1998, February 19). IMAGES Study Trial Summary [Web site}. Department of Medicine and Therapeutics, Western Infirmary, Glasgow. Retrieved August 30, 2002, from www.dcn.ed.ac.uk/posterm.htm

Correia, M., Silva, M., & Veloso, M. (2001). Cooling therapy for acute stroke. The Cochrane Database of Systematic Reviews. Retrieved March 6, 2001, from http://gateway2.ovid.com/ovidweb.cgi

During, M., Symes, C., Lawlor, P., Lin, J., Dunning, J., Fitzsimons, H., et al. (2000). An oral vaccine against NMDAR1 with efficacy in experimental stroke and epilepsy. Science, 287, 1453-1460.

Georgiadis, 13., Schwarz, S., Aschoff, A., & Schwab, S. (2002). Hemicraniectomy and moderate hypothermia in patients with severe ischemic stroke. Stroke, 33, 1584-1588.

Kongable, G. (1997). Code stroke: Using t-PA to prevent ischemic brain injury. American Journal of Nursing, 97(11), 16bb-16hh.

Lees, K., Barer, D.H., Ford, G.A., Hacke, W., Kostulas, V., Sharma, A.K., et al. (2002). Safety and tolerability of NXY-059 at higher target concentrations in acute stroke patients. Poster presented at the 27th International Stroke Conference, San Antonio, TX.

Lees, K., & Muir, K.W. (2002). Intravenous magnesium efficacy in stroke trial (IMAGES). Stroke, 33, 1733.

Liu, R., Yang, S., Perez, E., Yi, D., Wu, S., Eberst, K., et al. (2002). Neuroprotective effects of a novel non-receptor-binding estrogen analogue. Stroke, 33, 2485-2491.

Lodder, J. (2002). Early GABA-ergic activation study in stroke (EGASIS). Stroke, 33, 1731.

Matchar, D.B., & Samsa, G.P. (2000). Secondary and tertiary prevention of stroke. Patient outcomes research team (PORT) final report-phase 1 (AHRQ Pub. No. 00-N001). Rockville, MD: Agency for Healthcare Research and Quality.

National Institute of Neurological Disease and Stroke rt-PA Study (NINDS) Group. (1995). Tissue plasminogen activator for acute ischemic stroke. New England Journal of Medicine, 333, 1581-1587.

National Stroke Association. (2000). Brain attack statistics [Web page]. Retrieved January 14, 2002, from http://www. 0stroke.org/brain_stat.cfm

Pharmaceutical Research and Manufacturers of America. (2001). New medicines in development for heart disease and stroke. Retrieved August 30, 2002, from www.phrma.org/searchcures/newmeds/ heart2000/heart.pdf

Raak, L., Hilton, A., Kessels, F., & Lodder, J. (2002). Implementing the EGASIS trial, an international multicenter acute intervention trial in stroke. Controlled Clinical Trials, 23(1), 74-79.

Reed, S. (2000). Pharmacological therapy for acute stroke. Current Opinion in Investigational Drugs, 1, 329-339.

Roof, R.L., & Hall, E.D. (2000). Gender differences in acute CNS trauma and stroke: Neuroprotective effects of estrogen and progesterone. Journal of Neurotrauma, 17, 367-388.

Saver, J. (2001). Intra-arterial thrombolysis. Neurology, 57(Suppl. 2), S58-S60.

Schellinger, P., Fiebach, J., Mohr, A., Ringleg, P., Jansen, O., & Hacke, W. (2001). Thrombolytic therapy for ischemic stroke--A review. Part II-Intra-arterial thrombolysis, vertebrobasilar stroke, phase IV trails, and stroke imaging. Critical Care Medicine, 29, 1819-1825.

Warlow, C., Dennis, M., van Gign, J., Hankey, G.J., Sandercock, P., Bamford, J., & Wardlaw, J. (2001). Stroke: A practical guide to management (2nd ed.). London: Blackwell Science Inc.

Zipfel, G., Lee, J., & Choi, D. (1999). Reducing calcium overload in the ischemic brain. New England Journal of Medicine, 341, 1543-1544.

Fig. 2 Sources of information on neuroprotective agents in acute ishemic stroke

Stroke

Stroke, a monthly publication of the American Stroke Association, publishes a list of major ongoing studies in the February, June, and October issues.

Stroke Trial Directory

A list of ongoing and concluded stroke trial information organized alphabetically by study name. Links to publications are provided in the reference list for each therapeutic agent. Maintained by Washington University, St. Louis, School of Medicine, available at http://www.strokecenter.org/trials/

The Center Watch

A clinical trials listing service designed for both patients and researchers with a large collection of resources. Patient resources include background information on clinical research, research headlines, and an index of government-funded clinical research studies being conducted by the National Institutes of Health (NIH). E-mail notification that is available alerts subscribers to new postings in up to eight therapeutic areas. Available at http://www.centerwatch.com/

Cochrane Library

Provides systematic research reviews updated every 3 months and open to the public without charge. Available on CD-ROM or on the Internet at http://www.updatesoftware.com/cochrane/

Questions or comments about this article may be directed to: Janice L. Hinkle, PhD RN CNRN, by phone at 610/519-6819 or by e-mail at Janice. Hinkle@Villanova.edu. She is an assistant professor at Villanova University College of Nursing in Villanova, PA.

Lisa Bowman, BSN RN CNRN, is the clinical research coordinator in the division of cerebrovascular disease and neurological critical care at Thomas Jefferson University Hospital. She reports that she is a clinical research coordinator for trials involving some of the drugs discussed in this article.
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Title Annotation:neuroscience nursing research
Author:Hinkle, Janice L.; Bowman, Lisa
Publication:Journal of Neuroscience Nursing
Geographic Code:1USA
Date:Apr 1, 2003
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