Erythropoietin reduces experimental autoimmune encephalomyelitis severity via neuroprotective mechanisms.

BACKGROUND: Treatment with erythropoietin (Epo) in experimental autoimmune encephalomyelitis (EAE), the rodent model of multiple sclerosis (MS), has consistently been shown to ameliorate disease progression and improve overall outcome. The effect has been attributed to modulation of the immune response and/or preservation of the central nervous system (CNS) tissue integrity. It remains unclear, however, if (a) Epo acts primarily in the CNS or the periphery and if (b) Epo's beneficial effect in EAE is mainly due to maintaining CNS tissue integrity or to modulation of the immune response. If Epo acts primarily by modulating the immune system, where is this modulation required? In the periphery, the CNS or both? METHODS: To address these questions, we used two well-characterized transgenic mouse strains that constitutively overexpress recombinant human Epo (rhEpo) either systemically (tg6) or in CNS only (tg21) in a MOG-induced EAE model. We assessed clinical severity, disease progression, immunomodulation, and CNS tissue integrity, including neuronal survival. RESULTS: Although disease onset remained unaffected, EAE progression was alleviated in transgenic animals compared to controls with both lines performing equally well showing that expression of Epo in the periphery is not required; Epo expression in the CNS is sufficient. Immunomodulation was observed in both strains but surprisingly the profile of modulation differed substantially between strains. Modulation in the tg21 strain was limited to a reduction in macrophages in the CNS, with no peripheral immunomodulatory effects observed. In contrast, in the tg6 strain, macrophages were upregulated in the CNS, and, in the periphery of this strain, T cells and macrophages were downregulated. The lack of a consistent immunomodulatory profile across both transgenic species suggests that immunomodulation by Epo is unlikely to be the primary mechanism driving amelioration of EAE. Finally, CNS tissue integrity was affected in all strains. Although myelin appeared equally damaged in all strains, neuronal survival was significantly improved in the spinal cord of tg21 mice, indicating that Epo may ameliorate EAE predominantly by protecting neurons. CONCLUSIONS: Our data suggests that moderate elevated brain Epo levels provide clinically significant neuroprotection in EAE without modulation of the immune response making a significant contribution.

Attenuation of ketamine-induced impairment in verbal learning and memory in healthy volunteers by the AMPA receptor potentiator PF-04958242.

There is a need to develop treatments for cognitive impairment associated with schizophrenia (CIAS). The significant role played by N-methyl-d-aspartate receptors (NMDARs) in both the pathophysiology of schizophrenia and in neuronal plasticity suggests that facilitation of NMDAR function might ameliorate CIAS. One strategy to correct NMDAR hypofunction is to stimulate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) as AMPAR and NMDAR functioning are coupled and interdependent. In rats and nonhuman primates (NHP), AMPAR potentiators reduce spatial working memory deficits caused by the nonselective NMDAR antagonist ketamine. The current study assessed whether the AMPAR potentiator PF-04958242 would attenuate ketamine-induced deficits in verbal learning and memory in humans. Healthy male subjects (n=29) participated in two randomized treatment periods of daily placebo or PF-04958242 for 5 days separated by a washout period. On day 5 of each treatment period, subjects underwent a ketamine infusion for 75 min during which the effects of PF-04958242/placebo were assessed on ketamine-induced: (1) impairments in verbal learning and recall measured by the Hopkins Verbal Learning Test; (2) impairments in working memory on a CogState battery; and (3) psychotomimetic effects measured by the Positive and Negative Syndrome Scale and Clinician-Administered Dissociative Symptoms Scale. PF-04958242 significantly reduced ketamine-induced impairments in immediate recall and the 2-Back and spatial working memory tasks (CogState Battery), without significantly attenuating ketamine-induced psychotomimetic effects. There were no pharmacokinetic interactions between PF-04958242 and ketamine. Furthermore, PF-04958242 was well tolerated. 'High-impact' AMPAR potentiators like PF-04958242 may have a role in the treatment of the cognitive symptoms, but not the positive or negative symptoms, associated with schizophrenia. The excellent concordance between the preclinical (rat, NHP) and human studies with PF-04958242, and in silico modeling of AMPAR-NMDAR interactions in the hippocampus, highlights the translational value of this study.

Conversion of external fixation to open reduction and internal fixation for complex distal radius fractures.

INTRODUCTION: Distal radius fractures are common injuries treated in a multitude of ways. One treatment paradigm not extensively studied is initial treatment by external fixation (EF) followed by conversion to open reduction internal fixation (ORIF). Such a paradigm may be beneficial in damage control situations, when there is extensive soft tissue injury, or when appropriate personnel/hospital resources are not available for immediate internal fixation. HYPOTHESIS: There is no increased risk of infection when converting EF to ORIF in the treatment of complex distal radius fractures when conversion occurs early or if EF pin sites are overlapped by the definitive fixation. MATERIALS AND METHODS: Using an IRB approved protocol, medical records over nine years were queried to identify patients with distal radius fractures that had undergone initial EF and were later converted to ORIF. Charts were reviewed for demographic data, injury characteristics, operative details, time to conversion from EF to ORIF, assessment of whether the EF pin sites overlapped the definitive fixation, presence of infection after ORIF, complications, and occupational therapy measurements of range of motion and strength. RESULTS: In total, 16 patients were identified, only one of which developed an infection following conversion to ORIF. Fisher's exact testing showed that infection did not depend on open fracture, time to conversion of one week or less, presence of EF pin sites overlapping definitive fixation, fracture classification, high energy mechanism of injury, or concomitant injury to the DRUJ. DISCUSSION: Planned staged conversion from EF to ORIF for complex distal radius fractures does not appear to result in an increased rate of infection if conversion occurs early or if the EF pin sites are overlapped by definitive fixation. This treatment paradigm may be reasonable for treating complex distal radius fractures in damage control situations, when there is extensive soft tissue injury, or when appropriate personnel/hospital resources are not available for immediate internal fixation. LEVEL OF EVIDENCE: IV, retrospective case series.

Report of the task force on designing clinical trials in early (predementia) AD.

BACKGROUND: A large number of promising candidate disease-modifying treatments for Alzheimer disease (AD) continue to advance into phase II and phase III testing. However, most completed trials have failed to demonstrate efficacy, and there is growing concern that methodologic difficulties may contribute to these clinical trial failures. The optimal time to intervene with such treatments is probably in the years prior to the onset of dementia, before the neuropathology has progressed to the advanced stage corresponding to clinical dementia. METHOD: An international task force of individuals from academia, industry, nonprofit foundations, and regulatory agencies was convened to discuss optimal trial design in early (predementia) AD. RESULTS: General consensus was reached on key principles involving the scope of the AD diagnosis, the selection of subjects for trials, outcome measures, and analytical methods. CONCLUSION: A consensus has been achieved in support of the testing of candidate treatments in the early (predementia) AD population.

[Traumatic brain injuries--effects of alcohol and caffeine on intracranial pressure and cerebral blood flow]. / Traumatická poranení mozku--vliv alkoholu a kofeinu na intrakraniální tlak a prutok krve mozkem.

INTRODUCTION: Alcohol and caffeine is intermittently or regularly used by majority of people. These drugs may have acute or chronic effects on patients with traumatic brain injury. Alcohol intoxication increases cerebral blood flow from 8 to 24%. Caffeine decreases cerebral blood flow from 10 to 20%. These facts create a theoretical hypothesis that the decrease of CBF may reduce incranial pressure. The aim of this study was to investigate the effect of caffeine on intracranial pressure in rats following traumatic brain injury. METHODS: Ten Wistar male rats underwent weight drop closed head injury. The second stage of the experiment was done 12 to 18 hours later. Intracranial pressure, respiration, heart rate and the mean arterial pressure was monitored. Intraperitoneal injection of caffeine (20 mg/kg) was administered and repetitive measurement of vital signs and intracranial pressure was done. RESULTS: The baseline ICP after head injury was 8.5 +/- 2.9 mm Hg. Ten minutes after intraperitoneal caffeine administration ICP dropped to 7.6 +/- 3.1 mm Hg (p < 0.05). This represents a 11% decrease from baseline value. Mean arterial pressure, respiration and heart rate were stable. CONCLUSION: Intracranial pressure decrease of 11% from baseline value. This drop was compatible with our hypothesis. The exact dosage of caffeine, its form and rate, should be more precisely specified in further studies.

The effect of vasodilators on aspirin-induced antagonism of t-PA thrombolysis.

Although i.v. t-PA has proven successful in reducing neurologic deficits in acute ischemic stroke, the disadvantages of a narrow therapeutic time window and the failure of thrombolysis in more than 50% of patients treated have necessitated an examination of adjuvant therapies to improve the rate of thrombolysis. Experimentally, the combination of aspirin therapy with t-PA has resulted in a paradoxical antagonism of thrombolysis. Reversal of this antagonism with nitric oxide (NO) donors suggested that aspirin may inhibit/ antagonize NO-related mechanisms. Using this rabbit model of thromboembolic stroke, this hypothesis is now expanded to compare two clinically relevant anti-hypertensive agents, atenolol (NO-dependent) and hydralazine (NO-independent), for their ability to improve t-PA-mediated clot lysis following aspirin pre-treatment. Thirty rabbits (10 per group) were pre-treated with aspirin (20mg kg(-1), i.v.) and then randomized to receive either vehicle, atenolol (20 microg kg(-1) h(-1), i.v.) or hydralazine (10 microg kg(-1) min(-1), i.v.) beginning 30 min following autologous clot embolization. All rabbits then received t-PA (6.3 mg kg(-1), i.v.) beginning 1 h after embolization, with completion of the protocol 4 h after embolization. Aspirin therapy reduced regional cerebral blood flow (rCBF) from 82.8m +/- 4.7 to 62.5 +/- 6.6 (n = 30; p = 0.0005). In the aspirin control group only 30% (3 of 10) rabbits demonstrated complete clot lysis, whereas the combined atenolol (60%) and hydralazine (70%) groups experienced a clot lysis rate of 65% (13 of 20 rabbits), similar to clot lysis rates previously observed with t-PA alone. In a separate series of experiments, all agents able to reverse aspirin antagonism of thrombolysis demonstrated an improvement in rCBF, suggesting a common mechanism for this diverse group of agents in reversing aspirin's antagonism of thrombolysis.

A Phase I/II study of weekly paclitaxel and 3 days of high dose oral estramustine in patients with hormone-refractory prostate carcinoma.

BACKGROUND: The maximum tolerated dose (MTD) and efficacy of weekly 1-hour paclitaxel with 3 days of high dose oral estramustine were evaluated in patients with hormone-refractory prostate carcinoma. METHODS: Patients enrolled in cohorts of three received two cycles of six weekly treatments with 1 week of rest: Cohort I received paclitaxel 40 mg/m2 and estramustine 600 mg/m2, and Cohorts II-IV received paclitaxel 60 mg/m2, 75 mg/m2, or 90 mg/m2, respectively, and estramustine 900 mg/m2. Toxicity was assessed weekly, and response was measured by serum prostate specific antigen (PSA), abdominal computed tomography scans, and bone scans at Week 13. RESULTS: Eighteen patients were enrolled, with 12 in Cohorts III and IV. Four patients did not complete treatment. Grade 3 toxicity included one patient with nausea and diarrhea in Cohort III and one patient each with neutropenia and edema followed by Grade 4 thromboembolism in Cohort IV. Grade 1-2 anemia or myelotoxicity were not observed; 3 patients had neuropathy, 5 patients had hair loss, and 8 patients had gastrointestinal symptoms. A decline in the serum PSA level > or = 50% occurred in none of three patients, one of three patients, four of six patients, and four of six patients in Cohorts I-IV, respectively. An intent-to-treat analysis showed responses in 9 of 18 patients (50%) in Cohorts I-IV, with 9 of 15 responders (60%) in Cohorts II-IV. Seven patients achieved declines in serum PSA levels > 75%. The median duration of PSA response was 16.7 weeks. Response was observed in one of three patients with measurable disease. CONCLUSIONS: The MTD for 1-hour weekly paclitaxel was 90 mg/m2 with 3 days of 900 mg/m2 estramustine. Hematologic and neurotoxicity were reduced markedly, and gastrointestinal symptoms were ameliorated, but thromboembolic events were unaffected. PSA response rates were within the expected 60% range for these agents.

In vivo determination of available brachioradialis excursion during tetraplegia reconstruction.

The brachioradialis muscle is a common donor in tetraplegia reconstruction. The purpose of this study was to determine the available excursion of the brachioradialis during graduated release of its insertion sites. Fourteen extremities in 10 patients with cervical spine injuries underwent surgical reconstruction for restoration of hand function using the brachioradialis as a donor for one of the restored movements. At the time of surgery the brachioradialis was exposed along the forearm and a wire was inserted into the muscle followed by excitation with a biphasic, asymmetrical, charge-balanced waveform. A 12-Hz frequency and 20-mA current were used to stimulate the muscle while the pulse duration was varied between 0 and 200 milliseconds to achieve maximum contraction. Average brachioradialis excursion after incision of the radial styloid insertion site was 8 mm and 14 mm after mobilization to the musculotendinous junction. Further release of the fascial connections and mobilization of the muscle belly increased the excursion to an average of 61 mm. The increase in excursion after fascial release and muscle mobilization was significant and should be performed to obtain maximum available excursion.

The QT interval.

The effects of disease states and therapeutic drugs on the QT interval have been extensively studied in an attempt to understand the relationship between QT and the risk of torsade de pointes and sudden cardiac death. Differences in heart rate correction methods, electrocardiogram lead placement, and other internal (eg, genetic, physiologic) and external (eg, food, time of day) factors have confounded the interpretation of this relationship. A comprehensive review of the epidemiologic literature suggests that the corrected QT interval (QTc) is an important but imprecise marker of cardiovascular disease. The association between QTc prolongation and mortality has been identified in patients with cardiac disease but is unclear in patients without cardiac disease. Drug-related prolongation of QTc can clearly increase the risk of torsade de pointes, but this arrhythmia is rarely associated with a QTc of less than 500 ms. It also appears that noncardiac drugs that are associated with QTc prolongation are not identical in their proarrhythmic capacities and that increased exposure via clinically significant drug interactions is a major contributor to the liability of noncardiac drug-induced arrhythmia. Recognition of the aforementioned variables in conjunction with careful QTc measurements assists in establishing a more precise benefit-risk ratio for a specific drug therapy or for arrhythmia risk associated with various pathophysiologic or genetic states.

Peripheral neuropathy in the hands of diabetic patients with lower extremity amputations.

One hundred unilateral ambulatory lower extremity amputees underwent sensibility testing of their remaining foot and right hands to determine if the magnitude of peripheral neuropathy present in the feet of patients with diabetes was of greater magnitude than that in their hands. Testing was performed with a series of Semmes-Weinstein monofilaments. Ninety-one of the subjects were male, and 9 were female. Sixty-five were diabetic, 40 required insulin. The magnitude of peripheral neuropathy was compared between the hands and feet of patients with and without diabetes, and between insulin-dependent and non-insulin-dependent diabetics. There was a slight trend to a more severe degree of insensitivity in the feet as compared with the hands in each of the individual groups. There was no statistically significant difference when comparing hand and foot sensibility in any of the comparison groupings. The quantitative amount of peripheral neuropathy appears to affect the hands and feet of diabetics in a similar "stocking-glove" fashion. The results of this screening gives further support to the concept of prophylactic foot care programs in diabetics with peripheral neuropathy to decrease the risk for the development of foot ulcers, which are often the precursor of eventual lower extremity amputation.

16(R)-hydroxyeicosatetraenoic acid, a novel cytochrome P450 product of arachidonic acid, suppresses activation of human polymorphonuclear leukocyte and reduces intracranial pressure in a rabbit model of thromboembolic stroke.

OBJECTIVE: Activated polymorphonuclear leukocytes (PMNs) have been suggested to contribute to the development of increased intracranial pressure (ICP). We recently demonstrated that human PMNs produce a novel cytochrome P450-derived arachidonic acid metabolite, 1 6(R)-hydroxyeicosatetraenoic acid [16(R)-HETE], that modulates their function. It was thus of interest to examine this novel mediator in an acute stroke model. METHODS: 16-HETE was assessed initially in a variety of human PMN and platelet in vitro assays and subsequently in an established rabbit model of thromboembolic stroke. A total of 50 rabbits completed a randomized, blinded, four-arm study, receiving 16(R)-HETE, tissue plasminogen activator, both, or neither. Experiments were completed 7 hours after autologous clot embolization. The primary end point for efficacy was the suppression of increased ICP. RESULTS: In in vitro assays, 16(R)-HETE selectively inhibited human PMN adhesion and aggregation and leukotriene B4 synthesis. In the thromboembolic stroke model, animals that received 16(R)-HETE demonstrated significant suppression of increased ICP (7.7 +/- 1.2 to 13.1 +/- 2.7 mm Hg, baseline versus final 7-h time point, mean +/- standard error), compared with either the vehicle-treated group (7.7 +/- 0.9 to 15.8 +/- 2.6 mm Hg) or the tissue plasminogen activator-treated group (7.6 +/- 0.6 to 13.7 +/- 2.1 mm Hg). The group that received the combination of 16(R)-HETE plus tissue plasminogen activator demonstrated no significant change in ICP for the duration of the protocol (8.6 +/- 0.6 to 11.1 +/- 1.2 mm Hg). CONCLUSION: 16(R)-HETE suppresses the development of increased ICP in a rabbit model of thromboembolic stroke and may serve as a novel therapeutic strategy in ischemic and inflammatory pathophysiological states.

Stroke: antithrombin versus antiplatelet therapy.

The success of thrombolytic therapy for acute stroke has demonstrated that neurologic outcome can be improved with timely treatment. However, the severely restricted use of thrombolytics has reinforced the need to develop alternative and complementary therapies. Antithrombin and antiplatelet agents represent promising therapeutic approaches for stroke management. Antiplatelet therapy has modestly improved outcome in both acute stroke (aspirin) and in secondary stroke prevention (aspirin with or without dipyridamole; adenosine receptor antagonists), although bleeding and other adverse events associated with antithrombin therapy have largely negated their potential benefit. These findings have prompted innovative solutions to the pharmacokinetic and pharmacodynamic challenges that are crucial to advancing these strategies for acute, primary and secondary stroke therapy. Currently, inhibitors of the platelet surface glycoprotein IIb/IIIa (GP IIb/IIIa, fibrinogen) receptor are being examined in clinical trials while antithrombin therapies focus on thrombin antagonists and inhibitors as well as inhibitors of Factor Xa. Further advances in stroke treatment will include combination therapies. Additionally, the successful design of future drug therapies will result from a more complete understanding of the activity of these agents not only on platelet function and the coagulation cascade, but also for their effects on the endothelium and within the brain parenchyma. The sum of these activities will allow for the maintenance of cerebral blood flow, blood-brain barrier integrity and neuronal function.

16(R)-hydroxy-5,8,11,14-eicosatetraenoic acid, a new arachidonate metabolite in human polymorphonuclear leukocytes.

Intact human polymorphonuclear leukocytes (PMNL) incubated with substimulatory amounts of arachidonic acid in the absence of a calcium ionophore formed four metabolites that were isolated by reverse-phase HPLC and characterized structurally by GC/MS. A major metabolite eluting as the most abundant peak of radioactivity lacked UV chromophores above 215 nm, and its formation was sensitive to 2-diethylaminoethyl-2,2-diphenylvalerate hydrochloride (SKF525A) but not 3-amino-1-[m(trifluoromethyl)phenyl]-2-pyrazoline (BW755C), suggesting that it was likely to be a product of cytochrome P450. The GC/MS analysis revealed the presence of two components: 20-hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE) and 16-hydroxy-5,8,11,14-eicosatetraenoic acid (16-HETE) in an approximate ratio of 4:1. The minor metabolites were identified as 15-HETE and 5-HETE. Although 20-HETE has been observed previously as a product of arachidonic acid metabolism in PMNL, the occurrence of 16-HETE was a novel finding. The stereochemistry of the hydroxyl group in PMNL-derived 16-HETE was established by analysis of 1-pentafluorobenzyl-16-naphthoyl derivatives on a chiral-phase chromatographic column and comparison with authentic synthetic stereoisomers. The PMNL-derived radioactive metabolite co-eluted with the synthetic 16(R)-HETE stereoisomer. Analysis of the total lipid extracts from intact PMNL followed by mild alkaline hydrolysis resulted in detectable amounts of 16-HETE (108+/-26 pg/10(8) cells) and 20-HETE (341+/-69 pg/10(8) cells), which suggested that these HETEs were formed from endogenous arachidonic acid and esterified within PMNL lipids. Thus, in contrast to calcium ionophore-stimulated neutrophils that generate large amounts of 5-lipoxygenase products, the intact PMNL generate 20-HETE and 16(R)-HETE via a cytochrome P450 omega- and omega-4 oxygenase(s).

New formula for calculating antibiotic critical concentration by the disk diffusion method.

New formula was designed for calculation of the antibiotic critical concentration: Cc = (1/pi Bh)e-A/B where h is agar depth, B is the slope, A is the intercept. The formula is derived from the second Fick's law. Neither diffusion constant nor critical time data apply. Three or more disks containing varied concentrations of the same antibiotic are used. Regression analysis of square of zone of inhibition radii is performed and subsequently the critical concentration is computed.

DNA microarray technology and application.

DNA microarrays (collections of DNA probes arranged on a shared base) have recently enlarged the spectrum of commercially available laboratory-ready kits in molecular biology. They are powerful new tools for the investigation of global changes in gene expression profiles in cells and tissues. Their assembly process is automatized and the DNA microarrays are further miniaturized. The DNA microarrays are used in search for various specific genes (e.g. connected with an infectious agent) or in gene polymorphism and expression analysis. They will be widely used to investigate expression of various genes connected with various diseases in order to find causes of these diseases and to enable their accurate treatment. Since the DNA microarray assembly technology has been based on methods widely used in the semiconductor industry, we can expect a rapid onset of the routine use of this revolutionary device.

Aspirin reduces experimental cerebral blood flow in vivo.

Aspirin therapy for stroke prophylaxis in low risk patients has paradoxically demonstrated an increased risk of ischemic stroke in several studies. Moreover, the MAST-Italy trial reported a near doubling of mortality with the addition of aspirin to thrombolytics while experimentally, we have noted that aspirin antagonizes t-PA-mediated clot lysis. The mechanisms responsible for these observations is unclear. Of interest, few studies have examined the effect of aspirin on cerebral blood flow (CBF). The objective of this study was to examine the acute effect of high dose aspirin on CBF in a rabbit model. Mean arterial pressure, arterial blood gases, and core and brain temperature were controlled throughout the protocol. CBF, measured by the technique of hydrogen clearance using Platinum-Iridium flow probes, was measured before and 20 min following aspirin administration (20 mg kg-1 i.v.) in a cohort of 50 rabbits and compared to rabbits receiving vehicle (n = 19). Following aspirin therapy, CBF (cc/100 g-1 min-1) was reduced from 80.8 +/- 27.4 to 65.1 +/- 31.7 (mean +/- SD), a reduction to 80.4 +/- 21.3% of baseline (p < 0.00001, t-test), whereas CBF in the control group remained unchanged (81.0 +/- 25.4 vs. 77.5 +/- 24.0, mean +/- SD). Thus aspirin acutely reduced CBF by approximately 20% in a rabbit model, perhaps related to inhibitory effects on prostacyclin and/or nitric oxide. This result may help explain the possible increase in ischemic stroke seen in low risk patients on aspirin therapy. A reduction in CBF by aspirin may also assist in understanding the antagonism of t-PA-mediated clot lysis by aspirin seen in our rabbit model of thromboembolic stroke, particularly since all agents which share the ability to reverse this antagonism (nitric oxide donors, beta blockers, hydralazine, prostacyclin) also increase CBF by approximately 20%. Future strategies for 'antiplatelet' therapy may benefit from using agents which do not adversely affect CBF.

[Talc--a standard drug in the treatment of malignant pleural effusion]. / Talek--standardní lék v terapii maligních pleurálních výpotku.

Currently, talc is the most effective and widely-used agent for chemical pleurodesis in the treatment of both malignant pleural effusion and pneumothorax. Its popularity has been growing due to the low incidence of side effects, low cost and higher success rate in comparison with other agents (tetracyclines, bleomycin, Corynebacterium parvum). The guidelines for talc pleurodesis are summarized and the history of the Corynebacterium parvum as an agent for chemical pleurodesis is mentioned. Its production in the Czech Republic has been halted due to the increased interest in the talc as a chemical sclerosant.

Complement depletion does not reduce brain injury in a rabbit model of thromboembolic stroke.

The contribution of the complement system to cerebral ischemic and ischemia/reperfusion injury was examined in a rabbit model of thromboembolic stroke by delivery of an autologous clot embolus to the intracranial circulation via the internal carotid artery. A two-by-two factorial design was employed to study the impact of complement depletion via pretreatment with cobra venom factor (CVF, 100 U/kg i.v.) in the setting of permanent (without tissue plasminogen activator; t-PA) and transient (with t-PA) cerebral ischemia. Thirty-two New Zealand white rabbits were assigned to one of four groups (n=8, each group): control without t-PA, control with t-PA, CVF without t-PA and CVF with t-PA. In the complement intact animals, t-PA administration resulted in an approximate 30% reduction in infarct size when compared to the group not receiving t-PA (20.4+/-6.6% of hemisphere area vs. 30.1+/-7.2%; mean+/-SEM). However, infarct sizes in the complement depleted rabbits, with (30.7+/-8.2%) or without (30.2+/-7.9%) t-PA, were no different from the control group receiving no therapy. Similarly, no difference in regional cerebral blood flow or final intracranial pressure values was noted between any of the four groups. Complement activation does not appear to be a primary contributor to brain injury in acute thromboembolic stroke.

Antiplatelet therapy in acute cerebral ischemia.

BACKGROUND: Improved recognition of stroke signs and symptoms has paralleled the development of pharmacological strategies that may be examined to reduce stroke mortality and morbidity. Presently, tissue plasminogen activator is the only therapy that significantly improves outcome in acute stroke, with no agent demonstrating a significant reduction in mortality. SUMMARY OF REVIEW: Antiplatelet agents are a heterogenous class of drugs that have been successfully used for more than 2 decades in secondary stroke prevention. These agents include aspirin, with or without dipyridamole, and more recently, the adenosine antagonists ticlopidine and clopidogrel. However, studies of the use of antiplatelet agents within 48 hours of the ictus have examined only aspirin. Only 1 study, the Multicentre Acute Stroke Trial-Italy (MAST-I), entered patients within 6 hours of the ictus. These data suggest that an improvement in mortality may be related to the speed of administration. No significant adverse events were noted with early antiplatelet monotherapy. However, MAST-I did note a significant increase in early mortality in patients receiving aspirin plus streptokinase, a finding not adequately explained by an increase in the intracranial hemorrhage rate. CONCLUSIONS: The use of antiplatelet therapy in acute stroke, clinical or experimental, has only recently received attention. It is likely that the use of antiplatelet agents for acute stroke therapy will be less restrictive than that currently seen for thrombolytics. Future studies should include an examination of those agents that have previously demonstrated efficacy in secondary stroke prevention, most notably, aspirin. The recognition that all platelet stimuli share a final common pathway that is dependent on the surface glycoprotein IIb/IIIa (fibrinogen) receptor has resulted in the development of various agents which block this receptor and are currently the focus for clinical trials. The role of nitric oxide in stroke therapy will depend on minimizing the hypotensive side effects of this agent. Stroke models are needed to provide preliminary data on the efficacy of antiplatelet therapy, especially as relates to the interaction of antiplatelet agents with thrombolytics.