Published by American Heart Association
Online ISSN: 1524-4628
Print ISSN: 0039-2499
Sustained mass depolarization of neurons, termed cortical spreading depolarization, is one electrophysiological correlate of the ischemic injury of neurons. Cortical spreading depolarizations spread in the gray matter at a rate of approximately 3 mm/min and are associated with large infraslow extracellular potential changes (<0.05 Hz). Moreover, smaller infraslow potential changes accompany functional activation and might help to assess neuronal repair after stroke. The objective of the present pilot study was to investigate whether it is feasible to apply noninvasive near-DC-magnetoencephalography to detect and monitor infraslow field changes in patients with acute stroke. A simple motor condition was used to induce physiological cortical infraslow field changes. Five patients in a subacute state after ischemic stroke performed self-paced simple finger movements (30-second periods of finger movements, always separated by 30-second periods of rest, for a total of 15 minutes). Near-DC-magnetoencephalography signals were recorded over the contralateral primary motor cortex for the affected and unaffected hemisphere, respectively. In all patients, the time courses of the contralateral cortical field amplitudes in the infraslow frequency range followed closely the motor task cycles revealing statistically significant differences between finger movement and rest periods. In 4 of 5 patients, infraslow field amplitudes were significantly stronger over the unaffected hemisphere compared with the affected hemisphere. This study demonstrates that cortical infraslow activity can be recorded noninvasively in patients in the subacute state after ischemic stroke. It is suggested that near-DC-magnetoencephalography is a promising tool to also detect cortical spreading depolarization noninvasively.
We evaluated isovolumic hemodilution with hydroxyethyl starch 200/0.5 in a rat model of focal cerebral ischemia. This compound avoids the unfavorable viscosity and erythrocyte aggregation abnormalities of low molecular weight dextran during administration over a period of several days. Sprague-Dawley rats, anesthetized with 0.5-1% halothane and 70% N2O, were subjected to silicon cylinder (treated and control groups) or sham (sham group) embolization of the cerebral circulation. Thirty minutes after embolization, the treated group (n = 5) was infused with 11 ml/kg of 10% hydroxyethyl starch 200/0.5, and the control (n = 5) and sham (n = 4) groups were infused with saline for 1 hour. In the treated group, 7.1 ml/kg of blood was withdrawn. After 24 hours, the animals were reanesthetized, and cerebral blood flow was determined with [14C]iodoantipyrine. Alternative brain slices were either incubated with 2,3,5-triphenyltetrazolium chloride for infarct volume determination or frozen for ischemic volume and cerebral blood flow determination using autoradiography. The hematocrit in the treated group was reduced from (mean +/- SEM) 46 +/- 1% to 35 +/- 2% at 1.5 hours (p < 0.01). Cortical blood flow was within the normal range of 115-185 ml/min/100 g, except for the ischemic cortex in the embolized groups, treated and control. The ischemic and infarct volume of the treated group was reduced by 74% (p < 0.05) and 89% (p < 0.05), respectively, from the control group. The treated and sham ischemic and infarct volumes were not statistically different. These data suggest that hydroxyethyl starch 200/0.5 could be an effective treatment for ischemic stroke when administered early, because it reduces infarct and ischemic volumes from control values to levels indistinguishable from those of the sham group.
Based on previous studies comparing different recombinant tissue plasminogen activator (rt-PA) doses, we performed a clinical trial with 0.6 mg/kg, which is lower than the internationally approved dosage of 0.9 mg/kg, aiming to assess the efficacy and safety of alteplase in acute ischemic stroke for the Japanese. Our prospective, multicenter, single-arm, open-label trial was designed with a target sample size of 100 patients. The primary end points were the proportion of patients with a modified Rankin Scale (mRS) score of 0 to 1 at 3 months and the incidence of symptomatic intracranial hemorrhage (sICH) within 36 hours. Thresholds for these end points were determined by calculating 90% CIs of weighted averages derived from published reports. The protocol was defined according to the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA stroke study with slight modifications. Among the 103 patients enrolled, 38 had an mRS of 0 to 1 at 3 months; this proportion (36.9%) exceeded the predetermined threshold of 33.9%. sICH within 36 hours occurred in 6 patients; this incidence (5.8%) was lower than the threshold of 9.6%. In patients receiving 0.6 mg/kg alteplase, the outcome and the incidence of sICH were comparable to published data for 0.9 mg/kg. These findings indicate that alteplase, when administered at 0.6 mg/kg to Japanese patients, might offer a clinical efficacy and safety that are compatible with data reported in North America and the European Union for a 0.9 mg/kg dose.
Figure. Modified Mori grades. A–D, Baseline MRA; E–H, follow-up MRA. For details of the grades, see text under " MRA Protocol. " The arrow shows the occluded artery. 
The purpose of this study was to evaluate further the efficacy of 0.6 mg/kg intravenous alteplase on vascular and clinical outcomes in patients with middle cerebral artery occlusion in a postmarketing Phase IV trial of prospective cohort study design. Alteplase was given intravenously at 0.6 mg/kg to patients with ischemic stroke within 3 hours of onset with MR angiography-documented middle cerebral artery occlusion. Vascular outcome was evaluated by MR angiography at 6 and 24 hours after symptom onset based on the modified Mori grade. The primary end points also included a favorable outcome (modified Rankin Scale 0 to 1 at 3 months after onset) and incidence of symptomatic intracranial hemorrhage within 36 hours after treatment. The impact of recanalization on clinical outcome was assessed by stepwise logistic regression analysis. Fifty-eight patients were enrolled. Recanalization was noted in 51.7% on 6-hour MR angiography and 69.0% on 24-hour MR angiography. A favorable clinical outcome was achieved in 46.6%. None had symptomatic intracranial hemorrhage. In logistic regression models, recanalization on either 6-hour or 24-hour MR angiography was an independent predictor for clinical outcome as well as the baseline National Institutes of Health Stroke Scale score. Early recanalization of an occluded middle cerebral artery can be provoked by 0.6 mg/kg intravenous alteplase and may induce a favorable clinical outcome. The rates of recanalization and favorable outcome are comparable to that previously reported with the 0.9-mg/kg dose.
In Japan, alteplase at 0.6 mg/kg was approved in October 2005 for use within 3 hours of stroke onset by the Ministry of Health, Labor and Welfare (MHLW). The aim of the Japan post-Marketing Alteplase Registration Study (J-MARS), which was requested by MHLW at the time of approval, was to assess the safety and efficacy of 0.6 mg/kg alteplase in routine clinical practice for the Japanese. A total of 7492 patients from 942 centers were enrolled in the J-MARS, an open-label, nonrandomized, observational study, from October 2005 to October 2007. Primary outcome measures were symptomatic intracranial hemorrhage (a deterioration in NIHSS score >or=4 from baseline) and favorable outcome (modified Rankin Scale score, 0-1) at 3 months after stroke onset. The proportion of patients with symptomatic intracranial hemorrhage in 7492 patients (safety analysis) was 3.5% (95% confidence interval [CI], 3.1%-3.9%) within 36 hours and 4.4% (95% CI, 3.9%-4.9%) at 3 months. The overall mortality rate was 13.1% (95% CI, 12.4%-13.9%) and the proportion of patients with fatal symptomatic intracranial hemorrhage was 0.9% (95% CI, 0.7%-1.2%). The outcomes at 3 months were available for 4944 patients and the proportion of favorable outcome (efficacy analysis) was 33.1% (95% CI, 31.8%-34.4%). The subgroup analysis in patients between 18 and 80 years with a baseline NIHSS score <25 demonstrated that favorable outcome at 3 months was 39.0% (95% CI, 37.4%-40.6%). These data suggest that 0.6 mg/kg intravenous alteplase within 3 hours of stroke onset could be safe and effective in routine clinical practice for the Japanese.
The benefit of intravenous thrombolytic therapy in acute brain ischemia is strongly time dependent. The Get With the Guidelines-Stroke database was analyzed to characterize ischemic stroke patients arriving at hospital Emergency Departments within 60 minutes of the last known well time from April 1, 2003, to December 30, 2007. During the 4.75-year study period, among 253 148 ischemic stroke patients arriving directly by ambulance or private vehicle at 905 hospital Emergency Departments, 106 924 (42.2%) had documented, exact last known well times. Onset to door time was <or=60 minutes in 30 220 (28.3%), 61 to 180 minutes in 33 858 (31.7%), and >180 minutes in 42 846 (40.1%). Features most strongly distinguishing the patients arriving at <or=60, 61 to 180, and >180 minutes were greater stroke severity (median National Institutes of Health Stroke Scale score, 8.0 vs 6.0 vs 4.0, P<0.0001) and more frequent arrival by ambulance (79.0%. vs 72.2% vs 55.0%, P<0.0001). Compared with patients arriving at 61 to 180 minute, "golden hour" patients received intravenous thrombolytic therapy more frequently (27.1% vs 12.9%; odds ratio=2.51; 95% CI, 2.41-2.61; P<0.0001), but door-to-needle time was longer (mean, 90.6 vs 76.7 minutes, P<0.0001). A door-to-needle time of <or=60 minutes was achieved in 18.3% of golden hour patients. At Get With the Guidelines-Stroke hospital Emergency Departments, more than one quarter of patients with documented onset time and at least one eighth of all ischemic stroke patients arrived within 1 hour of onset, where they received thrombolytic therapy more frequently but more slowly than late arrivers. These findings support public health initiates to increase early presentation and shorten door-to-needle times in patients arriving within the golden hour.
White matter hyperintensities (WMH) are highly heritable and associated with small artery ischemic stroke, so they may be a useful trait for studying the genetics of small vessel disease. Many studies have attempted to find associations between polymorphisms in various candidate genes and WMH. We aimed to evaluate the evidence for these associations by performing a systematic review and series of meta-analyses. We used a comprehensive search strategy to identify studies of the association between any genetic polymorphism and WMH. For all polymorphisms in genes studied in >2000 subjects we performed meta-analyses, calculating pooled odds ratios or standardized mean differences. We identified 46 studies of polymorphisms in 19 genes in approximately 19 000 subjects. Most genes were involved in lipid metabolism, control of vascular tone, or blood pressure regulation. Polymorphisms in the apolipoprotein E, angiotensin-converting enzyme, methylenetetrahydrofolate reductase, and angiotensinogen genes had been studied in >2000 subjects and were evaluated by meta-analysis. There was no evidence for an association between apolipoprotein E (epsilon 4+/-), methylenetetrahydrofolate reductase (677 cytosine/thymine polymorphism [C/T]), or angiotensinogen (Met235Thr) and WMH. For the angiotensin-converting enzyme insertion/deletion polymorphism (I/D) there appeared to be a significant association (OR, 1.95; 95% CI, 1.09-3.48), but this may be partly attributable to the small study (mainly publication) and other biases. No genetic polymorphism has yet shown convincing evidence for an association with WMH. Much larger studies will be needed to detect and confirm genetic associations with this promising trait in the era of genome-wide association studies.
Despite previous investigations, substantial uncertainty remains about the relation between body mass index (BMI) and stroke, especially in populations with a relatively low BMI but a high stroke rate. A nationally representative prospective study of mortality included 212,000 Chinese men 40 to 79 years old without known cardiovascular disease in 1990 to 1991 who were followed up for 10 years. Standardized hazard ratios were calculated for stroke mortality by baseline systolic blood pressure (SBP) and BMI. Mean SBP and BMI were 124 mm Hg and 21.7 kg/m(2), respectively. During 10 years of follow-up, 5766 stroke deaths were recorded. There were strong, positive relations between BMI and SBP and between SBP and stroke mortality, with a 3-mm Hg higher baseline SBP associated with a 5.6% (95% CI, 5.3% to 6.0%; P<0.00001) higher stroke mortality. The association between BMI and stroke mortality was, however, not linear, with the hazard increasing substantially only for BMI >25 kg/m(2) (P<0.001 for nonlinearity). Approximately 90% of men had a baseline BMI <25 kg/m(2), and among them, BMI was not associated with stroke mortality despite its strong association with BP (which continued to a BMI <18 kg/m(2)). The relation with BMI was similar for ischemic and hemorrhagic stroke but appeared to be steeper among lifelong nonsmokers than among current smokers (P=0.01 for difference between slopes) despite similarly positive relations between BMI and SBP and between SBP and stroke risk in both smoking categories. High BMI was strongly associated with increased stroke mortality only among men who were overweight or obese.
Disease of the cardiovascular system is the main cause of long-term complications and mortality in patients with type I (insulin-dependent) and type II (non-insulin-dependent) diabetes. Cerebrovascular mortality rates have been shown to be raised in patients with type II diabetes but have not previously been reported by age and sex in patients with type I diabetes. A cohort of 23 751 patients with insulin-treated diabetes, diagnosed under the age of 30 years from throughout the United Kingdom, was identified during 1972 to 1993 and followed up for mortality until the end of December 2000. Age- and sex-specific mortality rates and standardized mortality ratios (SMRs) were calculated. There were 1437 deaths during the follow-up, 80 due to cerebrovascular disease. Overall, the cerebrovascular mortality rates in the cohort were higher than the corresponding rates in the general population, and the SMRs were 3.1 (95% CI, 2.2 to 4.3) for men and 4.4 (95% CI, 3.1 to 6.0) for women. When stratified by age, the SMRs were highest in the 20- to 39-year age group. After subdivision of cause of death into hemorrhagic and nonhemorrhagic origins, there remained a significant increase in mortality from stroke of nonhemorrhagic origin. Analyses of mortality from this cohort, essentially one of patients with type I diabetes, has shown for the first time that cerebrovascular mortality is raised at all ages in these patients. Type I diabetes is at least as great a risk factor for cerebrovascular mortality as type II diabetes.
The Paul Coverdell National Acute Stroke Registry is being developed to improve the quality of acute stroke care. This article describes key features of acute stroke care from 4 prototype registries in Georgia (Ga), Massachusetts (Mass), Michigan (Mich), and Ohio. Each prototype developed its own sampling scheme to obtain a representative sample of hospitals. Acute stroke admissions were identified using prospective (Mass, Mich) or retrospective (Ga, Ohio) methods. All prototypes used a common set of case definitions and data elements. Weighted site-specific frequencies were generated for each outcome. A total of 6867 admissions from 98 hospitals were included; the majority were ischemic strokes (range, 52% to 70%) with transient ischemic attack and intracerebral hemorrhage comprising the bulk of the remainder. Between 19% and 26% of admissions were younger than age 60 years, and between 52% and 58% were female. Black subjects varied from 7.1% (Mich) to 30.6% (Ga). Between 20% and 25% of admissions arrived at the emergency department within 3 hours of onset. Treatment with recombinant tissue plasminogen activator (rtPA) was administered to between 3.0% (Ga) and 8.5% (Mass) of ischemic stroke admissions. Of 118 subjects treated with intravenous rtPA, <20% received it within 60 minutes of arrival. Compliance with secondary prevention practices was poorest for smoking cessation counseling and best for antithrombotics. A minority of acute stroke patients are treated according to established guidelines. Quality improvement interventions, targeted primarily at the health care systems level, are needed to improve acute stroke care in the United States.
Using a model of embolic stroke, the present study tested the hypothesis that blockage of endothelin-1 with S-0139, a specific endothelin type A receptor (ET(A)) antagonist, enhances the neuroprotective effect of recombinant tissue plasminogen activator (rtPA) by suppressing molecules that mediate thrombosis and blood brain barrier (BBB) disruption induced by ischemia and rtPA. Rats (n=104) subjected to embolic middle cerebral artery (MCA) occlusion were randomly divided into 1 of 4 infusion groups with 26 rats per group: (1) the control group in which rats were administered saline, (2) the monotherapy rtPA group in which rtPA was intravenously administered at a dose of 10 mg/kg 4 hours after MCA occlusion, (3) the monotherapy S-0139 group in which S-0139 was intravenously given 2 hours after MCA occlusion, and (4) the combination of rtPA +S-0139 group in which S-0139 and rtPA were given 2 and 4 hours after MCA occlusion, respectively. Measurements of infarct volume and parenchymal hemorrhage, behavioral outcome, and immunostaining were performed on rats euthanized 1 and 7 days after stroke. The combination therapy of S-0139 and rtPA significantly (P<0.01) reduced infarct volume (24.8+/-0.9% versus 33.8+/-1.5% in control) and hemorrhagic area (7.1+/-6.1 microm(2) versus 36.5+/-19.2 microm(2) in control) and improved functional recovery compared with control saline-treated animals. Immunostaining analysis revealed that the combination therapy had the synergistically suppressed ischemia- and rtPA-induced ICAM-1, protease-activated receptor 1 (PAR-1), as well as accumulation of platelets in cerebral microvessels. Furthermore, the combination treatment synergistically reduced loss of laminin, ZO1, and occludin in cerebral vessels. These data suggest that S-0139 provides the neuroprotection by suppressing ischemia- and rtPA-triggered molecules that evoke thrombosis and BBB disruption.
The objective of this study was to examine the association of 2 nonsynonymous intercellular adhesion molecule 1 (ICAM1) gene variants (Lys56Met and Gly241Arg) with baseline plasma soluble ICAM1 concentrations and with risk of total and selected cardiovascular disease (CVD) events in a prospective cohort of 23 014 apparently healthy white American women followed for 10 years. ICAM1 variations have been associated with plasma soluble ICAM1 concentrations and inflammatory conditions, including atherosclerosis. However, to date, no large prospective, genetic-epidemiological data set is available that would allow evaluation of the degree of association of these gene variants with risk of CVD. ICAM1 genotypes and baseline plasma soluble ICAM1 concentrations were determined. The primary outcome measure was a composite CVD end point (incident ischemic stroke, myocardial infarction, or death due to ischemic CVD); other measures were incident ischemic stroke, myocardial infarction, and coronary revascularization. During follow-up, 751 total incident CVD events, 187 incident myocardial infarction cases, 203 incident ischemic stroke cases, and 433 coronary revascularization events occurred. All observed genotype frequencies were in Hardy-Weinberg equilibrium across the whole sample population. We found baseline plasma soluble ICAM1 concentrations to be significantly reduced among carriers of Met56 allele (P<0.0001) and Arg241 allele (P<0.0001) as compared with the respective noncarriers of these variants. However, the polymorphisms tested and the respective haplotypes were neither associated with overall risk nor with risk with risk for selected CVD events regardless of whether analyses were adjusted for traditional CVD risk factors/confounders (all P values >0.10). In this large prospective study, we found an association of the nonsynonymous gene variants tested with reduced baseline plasma soluble ICAM1 concentrations. However, no evidence was found for an association of the gene variants tested with the overall or selected CVD end points examined, suggesting that these variants may not add useful aids to current risk predictors for early assessment of cardiovascular events.
Time to stroke (fatal and nonfatal) in patients (a) with and (b) without previous stroke. 
Change From Baseline Laboratory and Blood Pressure Data 
Diabetes is an important risk factor for stroke. We conducted analyses in patients who had entered the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) with a history of stroke or without stroke. The prospective, double-blind PROactive (mean duration, 34.5 months) randomized 5238 patients with type 2 diabetes and a history of macrovascular disease to pioglitazone (titrated to 45 mg) or placebo, in addition to current diabetes and cardiovascular medications. Cardiovascular end-point events were independently adjudicated. This analysis evaluated the risk of stroke and other cardiovascular outcomes in patients with (n=984) and without (n=4254) prior stroke. In patients with previous stroke (n=486 in the pioglitazone group and n=498 in the placebo group), there was a trend of benefit with pioglitazone for the primary end point of all-cause death, nonfatal myocardial infarction, acute coronary syndrome, and cardiac intervention (including coronary artery bypass graft or percutaneous coronary intervention), stroke, major leg amputation, or bypass surgery or leg revascularization (hazard ratio[HR]=0.78, event rate=20.2% pioglitazone vs 25.3% placebo; 95% CI=0.60-1.02; P=0.0670) and for the main secondary end point of all-cause death, nonfatal myocardial infarction, or nonfatal stroke (HR=0.78, event rate=15.6% pioglitazone vs 19.7% placebo; 95% CI=0.58-1.06; P=0.1095). Pioglitazone reduced fatal or nonfatal stroke (HR=0.53, event rate=5.6% pioglitazone vs 10.2% placebo; 95% CI=0.34-0.85; P=0.0085) and cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (HR=0.72, event rate=13.0% pioglitazone vs 17.7% placebo; 95% CI=0.52-1.00; P=0.0467). Higher event rates were observed in patients with prior stroke compared with those without prior stroke. In patients without prior stroke, no treatment effect was observed for a first stroke. In a subgroup analysis from PROactive, pioglitazone reduced the risk of recurrent stroke significantly in high-risk patients with type 2 diabetes.
Thromboxane synthetase activity is selectively inhibited by (E)-3-[4-(1-imidazolylmethyl)phenyl]-2-propenoic acid hydrochloride monohydrate (OKY-046). A single dose of 100 mg OKY-046 was orally administered to patients with ischemic cerebrovascular disease and healthy volunteers. Platelet aggregation and thromboxane B2 (TXB2) generation of intact and homogenised platelets induced by 1.0 mM sodium arachidonate were measured before and at 1, 4, 6 and 8 h after dosing. OKY-046 inhibited arachidonate-induced aggregation in platelet rich plasma from some, but not all, individuals, whereas platelet TXB2 generation was almost completely inhibited by a single dose of 100 mg OKY-046, in all of the patients and healthy volunteers. Endogenous TXA2 and prostacyclin (PGI2) biosynthesis were assessed by measurement of urinary immunoreactive TXB2 (i-TXB2) and 6-keto-PGF1 alpha (i-6-keto-PGF1 alpha) before and at 0-3, 3-6, 6-9 h after dosing. OKY-046 increased the urinary i-6-keto-PGF1 alpha coincidently with a decrease of urinary i-TXB2, both in patients and healthy volunteers. These effects of a selective thromboxane synthetase inhibitor will improve a disturbed balance between TXA2 and PGI2, associated with the development of ischemic cerebrovascular disease.
To the Editor: Testing AstraZeneca’s nitrone drug NXY-059 against acute stroke, the SAINT-I phase-3 trial1 showed significant neuroprotectant activity.1 Moreover, looking at hemorrhagic progression secondary to the “clot-buster” tPA (alteplase) in a parallel trial, symptomatic hemorrhage more than halved in the NXY-059-treated group, to 2.5% versus 6.4% in the controls. Likewise, the rate of asymptomatic hemorrhage was significantly lower in the treatment group (12.9% versus 20.9%). Although the subjective modified Rankin Scale used in the main trial might be open to question, it is hard to dismiss …
The SAINT I trial demonstrated that the neuroprotective agent NXY-059 improves the distribution of acute stroke patient outcomes on the modified Rankin Scale (mRS) of global disability. Standard dichotomized number-needed-to-treat (NNT) analyses for the magnitude of treatment benefit range widely, from 22.7 to infinity, and each capture only a portion of the observed beneficial shift in outcomes. Derivation of an NNT value reflecting the treatment's benefit over the entire range of the mRS is required to describe the clinical import of the trial results. The minimum and maximum possible NNTs for benefit over the range of mRS global disability outcomes were calculated by completing a joint distribution outcome table for a model population of 1000 patients, shifting responders by the greatest and smallest possible increments, respectively. The biologically most plausible NNT within this range was derived by having 10 neurologist and emergency-physician acute stroke-care experts independently specify the joint distribution of outcomes in model samples of 1000 patients assigned to placebo and active therapy. The minimum possible NNT for benefit incorporating all mRS state transitions is 7.9 and the maximum is 16.7. The biologically most plausible NNT for 1 additional patient to have a better outcome by 1 or more grades on the mRS outcomes is 9.8 (95% CI, 8.7 to 10.9). Considering improvements in global disability over the entire outcome range, the SAINT I trial results indicate that for every 100 patients treated, approximately 10 will benefit and none be harmed as a result of treatment.
The neutral results of the SAINT II trial have again highlighted difficulties translating neuroprotective efficacy from bench to bedside. Animal studies are susceptible to study quality biases, which may lead to overstatement of efficacy. We report the impact of study quality on published estimates of the efficacy of NXY-059 in animal models of stroke. We conducted a systematic review and stratified meta-analysis of published studies describing the efficacy of NXY-059 in experimental focal cerebral ischemia. Overall, NXY-059 improved infarct volume by 43.3% (95% CI, 34.7 to 52.8). Only 2 of 9 publications reported randomization, concealment of treatment allocation, and blinded outcome assessment. Studies not reporting these quality items gave substantially higher estimates of efficacy than did higher-quality studies. The reported efficacy of NXY-059 in animal models of stroke is confounded by low study quality. The failure of SAINT II highlights the need for substantial improvements in the design, conduct, and reporting of animal studies; journals can play an important role in this by adopting standards for animal studies similar to those agreed over 10 years ago for clinical trials.
NXY-059 is a free radical-trapping neuroprotectant developed for use in acute ischemic stroke. To facilitate prompt administration of treatment, potentially before neuroimaging, we investigated the safety of NXY-059 in patients with intracerebral hemorrhage (ICH). We randomized 607 patients within 6 hours of acute ICH to receive 2270 mg intravenous NXY-059 over 1 hour and then up to 960 mg/h over 71 hours, or matching placebo, in addition to standard care. The primary outcome was safety: the mortality and the frequency of adverse events, and the change from baseline for a variety of serum, imaging, and electrophysiological measurements. We also studied the overall distribution of disability scores on the modified Rankin Scale (mRS) and the Barthel index. We treated 300 patients with NXY-059 and 303 with placebo. Treatment groups were well matched for prognostic variables including Glasgow Coma Scale, risk factors, and age. The mean National Institute of Health Stroke Scale score on admission was 14 in both groups. The baseline hemorrhage volume was 22.4+/-20.1 mL in the NXY-059 group and 23.3+/-22.8 mL in the placebo group (mean+/-SD). Most hemorrhages were related to hypertension or anticoagulant use. Mortality was similar in both groups: 20.3% for NXY-059 and 19.8% for placebo-treated patients. The proportion of patients who experienced an adverse event was the same for both groups, whereas for serious adverse events the proportion was slightly higher in the NXY-059 group. However, no pattern emerged to indicate a safety concern. Serum potassium fell transiently in both groups, lower in the NXY-059 group. There were no differences in 3-month function, disability, or neurological deficit scores. The odds ratio for an improved outcome in 3-month mRS scores in the NXY-059 group was 1.01 (95% CI 0.75, 1.35). NXY-059 given within 6 hours of acute ICH has a good safety and tolerability profile, with no adverse effect on important clinical outcomes.
A variety of primary end points have been used in acute stroke trials. We focus on the modified Rankin Scale, a reliable and valid ordinal outcome measure that assesses disability on a 7-point scale. We provide an abbreviated discussion of analytical methods for ordinal scales, and related effect size measures; we illustrate these methods and their interpretation with outcome data from the SAINT I study of NXY-059 in acute ischemic stroke. The nonparametric Mann-Whitney statistic provides a straightforward method for analysis of the modified Rankin Scale, and incorporates associated measures of effect size. These measures are directly related to the concepts of Number Needed to Treat and Number Needed to Harm. Our re-examination of the outcome data from the SAINT I study provides little evidence for the purported efficacy of NXY-059. More broadly, analysis and interpretation of ordinal outcome scales based on ascribed numerical values to the steps of the scale should be done cautiously. Statistical treatment of multiple primary outcome measures in acute stroke clinical trials should be established before analysis. Lastly, conflating statistical and clinical significance should be avoided.
In animal models of acute ischemic stroke (AIS), the free radical-trapping agent NXY-059 showed promise as a neuroprotectant. SAINT I and II were randomized, placebo-controlled, double-blind trials to investigate the efficacy of NXY-059 in patients with AIS. Patients with AIS received an infusion of intravenous NXY-059 or placebo within 6 hours from the onset of stroke symptoms. A pooled individual patient analysis was prespecified to assess the overall efficacy and to examine subgroups. The primary end point was the distribution of disability scores measured on the modified Rankin scale (mRS) at 90 days. Neurologic and activities of daily living scores were investigated as secondary end points. We also evaluated whether treatment with NXY-059 would reduce alteplase-related intracranial hemorrhages. Finally, we evaluated possible predictors of good or poor outcome. An intent-to-treat efficacy analysis was based on 5028 patients. Baseline parameters and prognostic factors were well balanced between treatment groups. The distribution of scores on the mRS was not different in the group treated with NXY-059 (n=2438) compared with the placebo group (n=2456): odds ratio for limiting disability=1.02; 95% CI, 0.92 to 1.13 (P=0.682, Cochran-Mantel-Haenszel test). Comparisons at each level of the mRS confirmed an absence of benefit. There was no evidence of efficacy in prespecified subgroups or from the secondary outcome analyses. Mortality was equal in the 2 groups (16.7% vs 16.5%), and adverse event rates were similar. Among patients treated with alteplase, there was no decrease in rates of symptomatic or asymptomatic hemorrhage associated with NXY-059 treatment versus placebo. Subgroup analyses identified National Institutes of Health Stroke Scale score, age, markers of inflammation, blood glucose, and right-sided infarct as predictors of poor outcome. NXY-059 is ineffective for treatment of AIS within 6 hours of symptom onset. This is also true for subgroups and the prevention of alteplase-associated hemorrhage.
Effect of Pharmacological Treatments on Blood Glucose Levels After Thromboembolic Stroke
Effect of Pharmacological Treatments on Infarct Rate and Volume After Thromboembolic Stroke
It has been proposed that the novel spin trap agent disodium-[(tert-butylimino)methyl]benzene-1,3-disulfonate N-oxide (NXY-059) may be useful in the treatment of ischemia and stroke. To date, there is little information concerning the safety of NXY-059 when administered in combination with the only Food and Drug Administration-approved pharmacological agent for the treatment of stroke, the thrombolytic tissue plasminogen activator (tPA). Thus, we determined the effects of NXY-059G, a generic form of NXY-059, on hemorrhage and infarct rate and volume when administered alone or in combination with tPA. In addition, we determined whether NXY-059G affected 2 physiological variables, blood glucose levels and body temperature. Male New Zealand White rabbits were embolized by injecting a large blood clot into the middle cerebral artery via a catheter. Five minutes after embolization, NXY-059G (100 mg/kg) was infused intravenously; control rabbits received infusions of saline, the vehicle required to solubilize NXY-059G. In tPA studies, the thrombolytic was administered intravenously starting 60 minutes after embolization (20% bolus injection/80% infusion over 30 minutes). Body temperature and blood glucose levels were measured throughout the study. Postmortem analysis included assessment of hemorrhage and infarct rate, size, and location. In the vehicle control group, the hemorrhage rate after a thromboembolic stroke was 52% (n=23), and this was increased by 67% if tPA was administered (n=15). The rabbits treated with NXY-059G in the absence of tPA had a 79% incidence of hemorrhage (n=19), an increase of 52% over the control group. In the combination drug-treated groups, the NXY-059G/tPA group had a 47% incidence of hemorrhage (n=15). There was a decrease of hemorrhage volume in the NXY-059G+tPA group compared with the other 3 groups included in the study. There was no significant effect of NXY-059G either alone or in combination with tPA on infarct rate or volume. NXY-059G did not significantly alter the physiological variables that were measured. This study suggests that NXY-059G may affect the integrity of the cerebral vasculature when administered immediately after an embolic stroke, as evidenced by an increase in hemorrhage rate. However, when NXY-059G is administered in combination with tPA, it may improve the safety of tPA by reducing the incidence of tPA-induced hemorrhage. The mechanism(s) involved in the NXY-059G-induced increase in hemorrhage rate and reduction of tPA-induced hemorrhage rate remains to be elucidated.
Section Editors: Marc Fisher MD Kennedy Lees MD The SAINT I article reports the results of a phase III trial of the free-radical-spin trap, neuroprotective agent, NXY-059 in acute ischemic stroke. The study had a statistically significant effect on the primary outcome measure, the range of 90-day outcomes on the modified Rankin Scale (mRS), a measure of functional outcome after stroke. The change in National Institutes of Health Stroke Scale (NIHSS) scores from baseline, the principal secondary outcome variable, was not effected by treatment with NXY-059. The primary outcome measure used in this trial is novel and has not to my knowledge been used in prior acute stroke trials. The observation in a post hoc analysis of a significant reduction of symptomatic and asymptomatic hemorrhage with NXY-059 in patients who were treated with IV tissue plasminogen activator (t-PA) is also encouraging. It suggests that NXY-059 could be a useful adjunct in stroke patients treated with IV recombinant t-PA to reduce hemorrhagic risk, if reproduced. The primary outcome measure of a shift in the mRS in a favorable direction …
The SAINT II Trial, a large randomized multicenter clinical trial of the putative neuroprotectant, NXY-059, failed to demonstrate a treatment benefit in acute ischemic stroke. The further development of this agent was suspended. The implications of this outcome are considered from several perspectives, including: (1) the marginally positive antecedent trial, SAINT I, and the critical commentary stimulated by it, which called attention to its interpretively challenging primary outcome measure--a shift in the full-scale modified Rankin scale score--and to other statistical shortcomings; (2) the cogency of the STAIR recommendations, to which the development of NXY-059 closely adhered; and (3) the inherent physiochemical shortcomings of NXY-059 as a neuroprotective agent--its polar, nonlipophilic nature, poor blood-brain barrier penetrability, nonphysiological oxidation potential, and low potency. Caution is urged, however, regarding the unwarranted adoption of a nihilistic view toward neuroprotection on the part of the stroke community in view of the abundant preclinical evidence demonstrating proof-of-principle of the feasibility of neuroprotection, as well as the multiplicity of biochemical and molecular neuroprotective targets. The author offers the personal example of a translational journey in which a promising neuroprotectant agent targeting multiple injury mechanisms, high-dose albumin therapy, has proceeded successfully from preclinical studies that established efficacy through a pilot clinical trial that demonstrated safety and offered strong suggestions of clinical efficacy, leading to a large multicenter clinical trial currently in progress.
Spontaneous rotation and head bias in saline-treated and NXY-059 –treated monkeys 3 and 10 weeks after pMCAO. a, Spontaneous rotation measured as number of complete (360°) right rotations minus left rotations in a 15-minute period. b, Head bias score. Open bars indicate saline-treated group; solid bars, NXY-059 –treated group. ANOVA analysis is presented in text; post hoc analysis is shown as difference between NXY-059 and control groups. * P Ͻ 0.05; ** P Ͻ 0.01. 
Time to find food reward hidden in 1 of 6 tubes positioned from the monkeys’ far right (tube 1) to their far left (tube 6) by saline-treated and NXY-059 –treated monkeys (a, 3 weeks; b, 10 weeks). Before pMCAO there was no significant difference in time to find the reward in each tube between the 2 groups and a similar time to find the reward in all tubes (range, 1.8 to 3.8 seconds; mean, 2.6 seconds). Open bars indicate saline- treated group; solid bars, NXY-059 –treated group. ANOVA analysis is presented in text; post hoc analysis is shown as difference between NXY-059 and control groups. ** P Ͻ 0.01. 
Histological studies of neuroprotective effect of NXY- 059. a, Area of tissue damage to ipsilateral hemisphere compared with contralateral hemisphere between stereotaxic levels A14.5 and A2.5 of saline-treated (open squares) and NXY-059 – treated ( fi lled diamonds) monkeys. b, Volume of damage to dif- ferent cerebral structures. Results were analyzed by ANOVA followed by post hoc Newman-Keuls analysis. ** P Ͻ 0.01, difference between groups. 
NXY-059 has substantial protective effects when administered immediately after the onset of ischemia in a primate model of stroke. This study examined the efficacy of this drug when administered 4 hours after onset, a more clinically relevant time point. Before surgery, marmosets were trained and tested on a number of neurological tests, which assessed general neurological function, motor ability, and spatial awareness. Four hours after permanent middle cerebral artery occlusion (pMCAO), marmosets received a bolus of saline (n=13) or NXY-059 (n=13), and osmotic minipumps were implanted, providing 48-hour saline or drug (85 micromol/kg per hour) infusion. The monkeys were retested 3 and 10 weeks after surgery. Finally, infarct size was evaluated with histological analysis. The unbound plasma NXY-059 concentration was 200+/-9 micromol/L after 24-hour infusion, a concentration well tolerated in stroke patients. Drug treatment ameliorated the long-term motor impairment produced by pMCAO; the marmosets were better at using their contralesional, stroke-affected arm than controls at both 3 and 10 weeks. Saline-treated animals had a debilitating spatial neglect at 3 weeks with residual signs evident at 10 weeks. NXY-059 treatment substantially attenuated neglect at 3 weeks, with no deficit being seen at 10 weeks. NXY-059 reduced the overall infarct size by 28% (saline, 324+/-46 mm3; NXY-059, 234+/-30 mm3) with protection to the cortex, white matter, and subcortical structures. NXY-059 is an effective neuroprotective agent when administered 4 hours after pMCAO in a primate species, attenuating both motor and spatial neglect. The compound also substantially lessened the volume of cerebral damage.
Increased free radical formation contributes to the damage caused to the brain by acute ischemia. NXY-059 is a nitrone-based free radical trapping agent in development for acute stroke. NXY-059 has neuroprotective efficacy when given 5 hours after onset of transient focal ischemia in the rat. This was a randomized, double-blind, placebo-controlled, parallel group, multicenter study that evaluated the safety and tolerability of 2 NXY-059 dosing regimens compared with placebo within 24 hours of acute stroke. NXY-059 was administered as either 250 mg over 1 hour followed by 85 mg/h for 71 hours or 500 mg over 1 hour followed by 170 mg/h for 71 hours; plasma concentrations were monitored. Neurological and functional outcomes were recorded up to 30 days. One hundred fifty patients were recruited, of whom 147 received study treatments and completed assessments (50 placebo, 48 lower-dose NXY-059, 49 higher-dose NXY-059). Mean (+/-SD) age was 68 (+/-10) years, and baseline National Institutes of Health Stroke Scale score was 7.9 (+/-6.2). Serious adverse events occurred in 16%, 23%, and 16% of patients, respectively, with deaths in 0%, 10%, and 4%, largely following the proportions with primary intracerebral hemorrhage (6%, 16%, and 8%). Hyperglycemia, headache, and fever were common but not related to treatment. The mean unbound steady state NXY-059 plasma concentrations were 25 and 45 micromol/L, respectively. Population pharmacokinetic analysis estimated clearance to be 4.6 L/h. NXY-059 was well tolerated in patients with an acute stroke. The testing of higher doses in future trials may be justified.
Six-tube search task, illustrated in a, with results shown as latency ( Ϯ SEM) to find food reward hidden in 1 of 6 tubes positioned from monkey’s far right (tube 1) to their far left (tube 6) by saline-treated (n ϭ 5, white bars) and NXY-059 – treated (n ϭ 6, gray bars) monkeys before pMCAO (b); 3 weeks after pMCAO (c); and (d) 10 weeks after pMCAO. Results were analyzed by ANOVA followed by post hoc Newman-Keuls analysis. * P Ͻ 0.05, ** P Ͻ 0.01, significant difference between groups. 
Photomicrographs of coronal sections stained with solochrome cyanine and cresyl violet. Sections from the stereotaxic level A 9.5 are from pair of twins; twin in a received saline; twin in b received NXY-059. Scale bar ϭ 5 mm. cd indicates caudate; put, putamen. 
Area (mm 2 SEM) of tissue damage to ipsilateral hemisphere compared with contralateral hemisphere between stereotaxic levels A 14.5 and A 2.5 of saline-treated (n5, ) and NXY-059-treated (n6, ) monkeys. Results were analyzed by ANOVA followed by post hoc Newman-Keuls analysis. *P0.05, **P0.01, difference between groups.
NXY-059 is a novel nitrone with free radical-trapping properties that has a considerable neuroprotective effect in rats. We have now examined the efficacy of this drug at reducing long-term functional disability in a primate model of stroke. Twelve monkeys were trained and tested on a variety of behavioral tasks used to dissociate and quantify motor and spatial deficits. Five minutes after permanent occlusion of the right middle cerebral artery, monkeys received a 1-mL intravenous infusion of either saline or NXY-059 (28 mg x kg(-1)), and osmotic minipumps, model 2001D, were implanted subcutaneously to provide continuous drug or saline infusion for 48 hours. Drug-filled pumps released NXY-059 at 16 mg x kg(-1) x h(-1). The monkeys were retested 3 and 10 weeks after surgery to assess functional disability. Surgery, behavioral testing, and histology were all done blinded to treatment condition. NXY-059-treated monkeys were significantly better at reaching with their hemiparetic arm than were saline-treated monkeys when retested 3 weeks (P:<0.01) and 10 weeks (P:<0.01) after surgery. Drug treatment also significantly lessened the degree of spatial perceptual neglect (P:<0.01), a debilitating though ameliorating consequence of this infarct. NXY-059 treatment reduced the overall amount of brain damage by >50% of saline-treatment values, with similar levels of protection afforded to both white and gray matter. This novel drug has a substantial protective effect, lessening the disability caused by an experimentally induced stroke in a primate species. These findings provide considerable encouragement for the clinical development of NXY-059.
Estimated ES 50 Values Measured in Embolized Rabbits
Percentage of rabbits behaviorally abnormal as a function of the weight of clots injected into the carotid artery system. The curve in the middle (solid) shows the response of vehicle-treated control rabbits to clot administration. It demonstrates that 50% of the animals treated with 1.040.31 mg of clots (ES 50 ) will be abnormal or dead 24 hours after injection of the clots. The curve in the middle (dashed) indicates that if tPA is administered 3 hours after embolization, the ES 50 was decreased to 0.630.35 mg (P0.05). The curve on the right (dotted) indicates that if NXY-059G is administered 5 minutes after embolization and tPA is administered 3 hours after embolization, the ES 50 is significantly increased to 2.660.82 mg (P0.05).
It has been proposed that the novel spin trap agent disodium-[(tert-butylimino)methyl]benzene-1,3-disulfonate N-oxide (NXY-059) may be useful in the treatment of ischemic stroke. However, there is little information concerning the neuroprotective properties of NXY-059 when administered after an embolic stroke. Moreover, there is no information available concerning the combination of NXY-059 with the only Food and Drug Administration-approved pharmacological agent for the treatment of acute stroke, the thrombolytic tissue plasminogen activator (tPA). Thus, we determined the effects of NXY-059G, a generic form of NXY-059, on behavioral outcome after an embolic stroke when administered alone or in combination with tPA. Male New Zealand White rabbits were embolized by injecting a suspension of small blood clots into cerebral circulation via a carotid catheter. NXY-059G (100 mg/kg) was infused intravenously 5 minutes or 3 hours after embolization, whereas control rabbits received infusions of the saline vehicle. In tPA studies, the thrombolytic was administered intravenously starting 60 minutes or 3 hours after embolization (3.3 mg/kg). In combination studies, NXY-059G was given 5 minutes after embolization, followed by the administration of tPA beginning either 60 minutes or 3 hours after embolization. Behavioral analysis was conducted 24 hours after embolization. In the vehicle control group, the ES50 value (calculated as the amount of microclots [milligrams] that produce neurological dysfunction [impairment] in 50% of the rabbits within a specific treatment group) measured 24 hours after embolism was 1.04+/-0.31 mg, and this was increased by 153% to 2.54+/-0.72 mg if NXY-059G was administered beginning 5 minutes after embolization. However, if NXY-059G was administered beginning 3 hours after embolization, the ES50 was 2.01+/-0.40 mg. The rabbits treated with tPA alone had an ES50 of 2.64+/-0.66 or 0.63+/-0.35 mg if tPA administration started 60 minutes or 3 hours after embolization, respectively. If tPA was administered after NXY-059G (started at 5 minutes), the ES50 values were 3.15+/-0.50 or 2.66+/-0.82 if tPA administration started 60 minutes or 3 hours after embolization, respectively. This study suggests that NXY-059G is neuroprotective and can increase behavioral ratings if administered early after an embolic stroke. In addition, the study shows that NXY-059G can be used in combination with tPA without negative side effects. The drug combination can improve behavioral function and increase ES50 values. However, during the short time course of the behavioral analysis, the combination was not statistically better than either drug alone.
The SAINT studies on NXY-0591,2 have reinvigorated debate over the momentous issues of neuroprotection and the development of novel stroke therapeutics. Some may argue there is little new ground that NXY-059 has unearthed and, in fact, the clinical trials merely confirm that as a strategy, neuroprotection has not been shown to be effective. Editorials in high-profile journals have sent out the clarion call to terminate research on neuroprotection given decades of work, which has uniformly led to failure after failure in clinical studies.3 These sentiments are premature and ignore studies showing that hypothermia improves outcome in patients after cardiac arrest, a major cause of global cerebral ischemia.4,5 Proof for the neuroprotection concept has therefore already been established. Despite decades of neutral clinical trials, there still remains optimism among the stroke academic community. A majority of university-affiliated stroke neurologists in the United States in a recent survey still believe neuroprotection is a viable therapeutic strategy, although admittedly, that survey was conducted between the SAINT I and SAINT II publications.6 However, the question whether neuroprotection will ever work in stroke has been overshadowed by the larger issue of whether animal studies, which serve as the foundation for the development of stroke therapeutics, are even relevant to our patients with acute stroke. In the discussion section of the SAINT II article, the authors write, “it is possible that the animal models of acute focal infarction are not relevant to the patient population; they certainly are insufficient to guarantee a positive clinical-trial result.” Have all prior neuroprotective agents failed in clinical studies because rodent stroke is not relevant to human stroke? This is a key question. Substantial reductions in infarct size in rodents with stroke treated with various types of purported neuroprotective agents would seem to support this view. There …
NXY-059 is a free radical-trapping neuroprotectant demonstrated to reduce disability from ischemic stroke. We conducted analyses on additional end points and sensitivity analyses to confirm our findings. We randomized 1722 patients with acute ischemic stroke to a 72-hour infusion of placebo or intravenous NXY-059 within 6 hours of stroke onset. The primary outcome was disability at 90 days, as measured by the modified Rankin Scale (mRS), a 6-point scale ranging from 0 (no residual symptoms) to 5 (bed-bound, requiring constant care). Additional and exploratory analyses included mRS at 7 and 30 days; subgroup interactions with final mRS; assessments of activities of daily living by Barthel index; and National Institutes of Health Stroke Scale (NIHSS) neurological scores at 7 and 90 days. NXY-059 significantly improved the distribution of the mRS disability score compared with placebo at 7, 30, and 90 days (Cochran-Mantel-Haenszel test P=0.002, 0.004, 0.038, respectively; 90-day common odds ratio 1.20; 95% CI, 1.01 to 1.42). The benefit was not attributable to any specific baseline characteristic, stratification variable or subgroup interaction. Neurological scores were improved at 7 days (odds ratio [OR], 1.46; 95% CI, 1.13, 1.89; P=0.003) and the Barthel index was improved at 7 and 30 days (OR, 1.55; 95% CI, 1.22, 1.98; P<0.0001; OR, 1.27; 95% CI, 1.01, 1.59; P=0.02). NXY-059 within 6 hours of acute ischemic stroke significantly reduced disability. Benefit on neurological scores and activities of daily living was detectable early but not significant at 90 days; however, our trial was underpowered to measure effects on the neurological examination. The benefit on disability is not confounded by interactions and is supported by other outcome measures.
NXY-059 is a nitrone-based free radical-trapping agent in development for acute stroke. In patients with acute stroke, NXY-059 is well tolerated at concentrations known to be associated with neuroprotection in animal models of transient cerebral ischemia; however, higher target concentrations appear necessary on the basis of animal models of permanent ischemia. This was a randomized, double-blind, placebo-controlled, parallel-group, dose-escalation, multicenter study that evaluated safety, tolerability, and plasma concentrations of 2 NXY-059 dosing regimens within 24 hours of acute stroke. NXY-059 was administered as either 915 mg over 1 hour followed by 420 mg/h for 71 hours or 1820 mg for 1 hour followed by 844 mg/h for 71 hours; plasma concentrations were monitored. Neurological and functional outcomes were recorded for up to 30 days. One hundred thirty-five patients were recruited, of whom 134 received study treatment and completed assessments (844 mg/h, n=39; 420 mg/h, n=48; placebo, n=47). Mean age was 69 years (range, 34 to 92 years), and baseline National Institutes of Health Stroke Scale score was 8.5 (SD, 6.6). Serious adverse events occurred in 3, 17, and 13 patients, respectively, with deaths in 0, 4, and 3 patients and treatment discontinuations because of adverse events in 0, 1, and 3 patients. Good outcome, defined by modified Rankin Scale score of 0 or 1, was seen in 53%, 29% and 40%, respectively. No safety concern was identified in analysis of body temperature, blood pressure, or other laboratory parameters. The unbound plasma concentration at steady state was 260+/-79 micromol/L, exceeding the target of 200 micromol/L in the high-dose group. NXY-059 was well tolerated in patients with an acute stroke at and above concentrations shown to be neuroprotective in an animal model when initiated 4 hours after onset of permanent focal ischemia.
Recent studies demonstrated a significant neuroprotective action of the selective peptide-based bradykinin B2 receptor antagonist CP-0597 after permanent middle cerebral artery (MCA) occlusion (MCAO) in the rat. We therefore evaluated the efficacy of this compound after reversible MCAO in the rat. Male Wistar rats underwent reversible MCAO by insertion of a nylon monofilament to the origin of the MCA. After 1 hour the filament was retracted and the ischemic tissue reperfused. Immediately after MCAO, primed miniosmotic pumps containing either vehicle or CP-0597 (300 ng/kg per minute) were implanted into the subcutaneous space (n = 14 per group). Twenty-four hours after surgery, animals were killed and brains fixed, and 4-micron sections were taken from five sequential tissue blocks labeled A through E and stained with hematoxylin and eosin. Clinical evaluation of rats was performed by neurological scoring and change in body weight. Treatment with CP-0597 significantly reduced percent increase in hemisphere size of the ischemic hemisphere in all brain sections (C section: vehicle, 40.6 +/- 4.3% versus CP-0597, 20.8 +/- 5.3%; P < 0.001), total infarct volume (vehicle, 206.5 +/- 7.7 mm3 versus CP-0597, 94.0 +/- 19.2 mm3; P < .001), cortical infarct volume (vehicle, 145.5 +/- 4.5 mm3 versus CP-0597, 64.0 +/- 15.1 mm3; P < .001), subcortical infarct volume (vehicle, 55.8 +/- 4.1 mm3 versus CP-0597, 27.5 +/- 4.5 mm3; P < .001), and the number of necrotic neurons (vehicle 42.9 +/- 3.8 versus CP-0597, 23.6 +/- 4.7 per field; P < .01). Neurological score (vehicle, 2.78 +/- 0.36 versus CP-0597, 6.29 +/- 0.87 P < .01) and change in body weight (vehicle, -28.7 +/- 2.0 g versus CP-0597, -18.2 +/- 2.8 g; P < .01) were also significantly improved. The present data demonstrate the significant overall efficacy profile of CP-0597 in a rat model of reversible MCAO and provide strong rationale for the use of such bradykinin B2 receptor antagonist in the treatment of stroke.
The protective properties of PY 108-068 against ischemic disturbances in the brain were investigated in vitro and in vivo. The calcium antagonistic effects were demonstrated on isolated, calcium-loaded arterial rings of feline cerebral arteries. Determination of brain tissue oxygenation with pO2 microelectrodes showed that PY 108-068 improved oxygen supply in the cortex of cats subjected to epicerebral arterial occlusion. In a model of cerebral vasospasm induced by autologous blood superfusion, PY 108-068 reversed the spastic state of cortical microvessels. In a chronic stroke model (microsphere embolization in rats) PY 108-068 led to a significant reduction in mortality and in the severity of neurological symptoms, whereby the peroral efficacy of the drug could be demonstrated. The efficacy of PY 108-068 in a variety of ischemic insults makes this drug a promising aid in the treatment of cerebrovascular accidents.
A double-blind, randomized, pilot trial of the calcium channel antagonist PY108-068 was completed in patients with acute ischemic cerebral infarction. Nine treated patients received PY108-068 orally (150 mg/day in divided doses) and 10 control patients received placebo within 48 hours of stroke onset for 21 days. The mean age of the treated patients (four men, five women) was 63.7 years and of the control patients (seven men, three women) 64.4 years. Most infarctions were in the territory of the middle cerebral artery. One treated patient died of sudden cardiac death on Day 12; one control patient died of cerebral herniation. Two treated patients had episodes of clinically insignificant hypotension during Day 1 of treatment. Two control patients had myocardial infarctions during the trial. The mean Toronto Stroke Scale scores at stroke onset were 67 and 90 and at Week 12 were 22.5 and 34.7 in the treated and control groups, respectively. There was parallel improvement in the two groups, with no significant difference between groups (p = 0.12). The mean Barthel Index functional scores at stroke onset were 32.8 and 33 and at Week 12 were 90 and 78.8 in the treated and control groups, respectively. There was a trend in favor of the treated group, but differences between groups did not reach significance. In this pilot trial, PY108-068 was found to be safe but not effective in patients with acute ischemic cerebral infarction.
Since stroke is a principal cause of death in elderly people, we analyzed the association between alcohol and stroke mortality in a cohort of 15,077 middle-aged and older men and women. Data on alcohol habits were obtained from a questionnaire in 1967. The subsequent 20 years yielded 769 deaths from stroke, of which 574 were ischemic. Relative mortality risks (RR) were estimated from logistic regression analyses with lifelong alcohol abstainers as a reference group. Adjustments were made for age and smoking. No association was found between alcohol intake and hemorrhagic stroke. An elevated risk of ischemic stroke was found for men who drank infrequently, that is, a few times a year or less often (RR, 2.0; 95% confidence interval [CI], 1.3 to 3.2), for those who were intoxicated now and then (RR, 1.8; 95% CI, 1.1 to 2.8), and for those who reported "binge" drinking a few times in the year or less often (RR, 1.6; 95% CI, 1.1 to 2.5). Among women only ex-drinkers had an elevated risk of dying of ischemic stroke (RR, 3.3; 95% CI, 1.5 to 7.2). The risk was reduced for women who had an estimated average consumption of 0 to 5 g pure alcohol per day (RR, 0.6; 95% CI, 0.5 to 0.8); for those who did not drink every day (RR, 0.7; 95% CI, 0.5 to 0.9); and for those who never "went on a binge" (RR, 0.6; 95% CI, 0.5 to 0.8) or became intoxicated (RR, 0.7; 95% CI, 0.5 to 0.9). Drinking habits were associated only with deaths from ischemic stroke, and the risk patterns were different for men and women. In analyses, ex-drinkers should not be included with lifelong abstainers, since the former tend to run high health risk.
Increased knowledge of stroke risk factors in the general population may lead to improved prevention of stroke. The objective of the present study was to assess knowledge of stroke risk factors and to determine factors associated with knowledge. In a population-based survey, we sent a questionnaire to randomly selected residents in Berlin who were > or =50 years of age enquiring about knowledge of stroke risk factors. Knowledge was assessed in an open-ended question. In addition, we enquired about the source of participants' information. Sociodemographic factors, including age, sex, educational level, and nationality, were also assessed. A total of 28,090 of 75,720 residents (response rate, 37%) responded to the questionnaire. Of all respondents, 68% were able to name > or =1 correct stroke risk factor, and 13% named 4 correct risk factors. The majority of respondents named mass media as source of information (82%), followed by family/friends (45%) and by general physicians (20%). In multivariable analysis, increased knowledge of stroke risk factors was significantly associated with younger age, a higher educational level, not living alone, a German nationality, and having received any information about stroke during the last year. However, characteristics of respondents using the respective sources of information varied significantly. Mass media was most frequently named as a source of information about stroke risk factors. Source of information used varied according to population characteristics. Health education programs should take this into account and be adapted accordingly.
We present epidemiologic, etiologic, and clinical data for 1,000 consecutive patients with a first stroke (cerebral infarction or hemorrhage) admitted to the Centre Hospitalier Universitaire Vaudois since 1982. The patients were evaluated using a standard protocol of tests (computed tomography, Doppler ultrasonography, and electrocardiography in all patients, as well as angiography and specific cardiac investigations in selected patients). Each case was coded prospectively into a computerized registry. We believe that the Lausanne Stroke Registry is the first registry with complete computed tomography and Doppler ultrasonography data on all patients, which allows correlation between clinical findings, presumed etiology, and stroke location. Although the Lausanne Stroke Registry is not population-based, it gives a good estimate of the stroke-related problems in patients admitted to a primary-care center since our hospital is the sole acute-care facility for stroke in the Lausanne area.
Location and Relative Incidence of 277 Ocdusive Lesions and Incidence of Pathologic Findings With Transcran- ial Doppler Sonography in 210 Patients
Correlation Between Doppler Findings and Angiog- raphy for Evaluating Collateral Flow in 39 Carotid Lesions
Correlation Between Transcranial Doppler Find- Ings and Aoglography in 93 Patients After Subarachnoid Hemorrhage Doppler sonography
Correlation Between Doppler Findings and Angiog- raphy for Identifying 20 Arteriovenous Malformation Feeder Arteries hi 14 Patients Doppler sonography Angiography ECA MCA ACA PCA Normal Total
Results from 1,039 combined cervical and transcranial Doppler examinations are reported. Satisfactory transcranial signals were not found in 2.7% of the cases. Compared with angiography, the accuracy of transcranial criteria in assessing collateral flow over the circle of Willis was 94 and 88% for anterior and posterior circulation, respectively. The method also appeared very promising for detection of lesions of the intracranial arteries although the number of such cases with angiographic verification was limited in the present series. Arterial narrowing due to cerebral vasospasm was diagnosed with a sensitivity of 80%. In patients with ruptured intracranial aneurysms, an incidence of 93% arterial narrowing in basal cerebral arteries was found. Patients with subarachnoid hemorrhage and no aneurysm on angiography also showed arterial narrowing with an incidence of 56%. It was possible to monitor the time course and severity of cerebral vasospasm. Arteriovenous malformations were characterized by Doppler findings of high velocities and low pulsatilities. These lesions were diagnosed with an accuracy of 95%.
Functional assessment of animals following experimental cerebral ischemia is often difficult due to the passive nature of many neurologic exams. We attempted to increase the objectivity of motor function evaluation by adapting quantifiable behavioral tests and actively testing rats' motor capability following a cerebral ischemic insult. It was hypothesized that active testing would reveal motor deficits which were not readily apparent upon casual observation and that such testing would provide a more sensitive means of experimental neurologic assessment. Wistar rats were exposed to reversible severe forebrain ischemia using the four-vessel occlusion technique. Motor function was evaluated using the total motor score (sum of scores for screen test, balance beam test, and prehensile-traction test) over the 48 hours which followed 20 minutes of cerebral ischemia. To manipulate neurologic outcome, rats were fed or fasted the day prior to ischemia and then pretreated with either 1,3-butanediol or saline. Fasted saline-treated animals demonstrated improved total motor performance compared with fed animals by 48 hours after ischemia. There was no improvement in motor performance by fasted vs. fed rats from among the butanediol-treated animals. Pretreatment with butanediol resulted in significantly better total motor performance among fasted rats 24 hours after ischemia; however, by 48 hours postischemia, no difference was detectable. This is the first demonstration of motor deficits produced by four-vessel occlusion in rats. The motor tests devised appear to be adequately sensitive to detect changes in motor function that are not apparent with passive observation in this model.
We assessed the effect of 1,3-butanediol on cerebral energy metabolism and edema after inducing multifocal brain infarcts in 108 rats by the intracarotid injection of 50-microns carbonized microspheres. An ethanol dimer that induces systemic ketosis, 25 mmol/kg i.p. butanediol was injected every 3 hours to produce a sustained increase in the plasma level of beta-hydroxybutyrate. Treatment significantly attenuated ischemia-induced metabolic changes by increasing the concentrations of phosphocreatine, adenosine triphosphate, and glycogen and by reducing the concentrations of pyruvate and lactate. Lactate concentration 2, 6, and 12 hours after embolization decreased by 13%, 44%, and 46%, respectively. Brain water content increased from 78.63% in six unembolized rats to 80.93% in 12 saline-treated and 79.57% in seven butanediol-treated rats 12 hours after embolization. (p less than 0.05). The decrease in water content was associated with significant decreases in the concentrations of sodium and chloride. The antiedema effect of butanediol could not be explained by an osmotic mechanism since equimolar doses of urea or ethanol were ineffective. Our results support the hypothesis that the beneficial effect of butanediol is mediated through cerebral utilization of ketone bodies arising from butanediol metabolism, reducing the rate of glycolysis and the deleterious accumulation of lactic acid during ischemia.
Treatment with the ketone body precursor 1,3-butanediol has been suggested to ameliorate hypoxic/ischemic brain damage. Butanediol could provide an alternative energy substrate for the brain, thereby decreasing the amount of glycolytically produced lactate. Hyperglycemia aggravates brain damage after brain ischemia and causes fatal postischemic seizures, probably by increasing the production of lactate and decreasing the pH. We studied whether butanediol treatment altered the adverse consequences following ischemia complicated by hyperglycemia. Hyperglycemic adult male rats were given 25 or 50 body wt butanediol intravenously 30 minutes before 10 minutes of transient forebrain ischemia. Morphological evaluation was performed following perfusion-fixation after 15 hours of recovery. Blood concentrations of beta-hydroxybutyrate, acetoacetate, glucose, and lactate and brain tissue concentrations of energy metabolites were measured before and after ischemia. Blood levels of ketone bodies increased in the butanediol-treated rats. Ischemia decreased the blood levels of acetoacetate but increased the levels of beta-hydroxybutyrate by a similar amount, resulting in unchanged high levels of total ketone bodies in the animals that received butanediol. Brain tissue levels of glucose, energy metabolites, and lactate showed no difference between butanediol- and saline-treated rats. Furthermore, compared with saline-treated animals butanediol-treated rats showed no decrease in brain damage and no attenuation in the development of postischemic seizures. The ketone body precursor 1,3-butanediol offers no protective effect in transient forebrain ischemia complicated by hyperglycemia.
Top-cited authors
Jeffrey L Saver
  • University of California, Los Angeles
s. Claiborne Johnston
  • University of Texas at Austin
Edward C. Jauch
  • Mission Hospital
Scott Kasner
  • University of Pennsylvania
Geoffrey A Donnan
  • University of Melbourne