(Stroke. 1996;27:76-81.)
© 1996 American Heart Association, Inc.
Articles |
Lubeluzole in Acute Ischemic Stroke
A Double-blind, Placebo-Controlled Phase II Trial
From Neurologische Universitätsklinik, Essen, Germany (H.C.D.); Neurologische Universitätsklinik, Heidelberg, Germany (W.H.); Neurologische Universitätsklinik, Mannheim, Germany (M.H.); Neurologische Universitetssjukhuset, Linköping, Sweden (J.R.); Janssen Research Foundation, Beerse, Belgium (L.H.); A.Z. Vrije Universiteit Brussel, Brussels, Belgium (J. De K.); for the Lubeluzole International Study Group (see Appendix for participants).
Correspondence to H.C. Diener, MD, Neurologische Universitätsklinik Essen, Hufelandstr 55, 45122 Essen 1, Germany.
 |
Abstract |
|---|
 Top Abstract IntroductionSubjects and Methods Results Discussion Appendix References |
|---|
Background and Purpose We aimed to assess the safety and efficacy of lubeluzole in patients with a clinical diagnosis of acute (<6 hours) ischemic stroke in the carotid artery territory.
Methods A randomized, double-blind, placebo-controlled multicenter trial was conducted in 232 patients. Because treatment was administered within 6 hours and a CT scan was not mandatory before the start of treatment, 39 patients with either an intracerebral hemorrhage or ischemic stroke in the vertebrobasilar circulation were excluded from the primary efficacy analysis as prespecified in the protocol. Of the 193 patients with acute ischemic stroke in the carotid artery territory (target population), 61 received placebo, 66 lubeluzole 7.5 mg over 1 hour followed by 10 mg/d for 5 days, and 66 lubeluzole 15 mg over 1 hour followed by 20 mg/d for 5 days.
Results The trial, initially aimed at a patient inclusion of 270, was terminated prematurely according to the advice of the Safety Committee because of an imbalance in mortality between the treatment groups. Mortality rates at the final follow-up of 28 days for placebo, lubeluzole 10 mg/d, and lubeluzole 20 mg/d were, respectively, 18%, 6%, and 35% in the target population, results that were confirmed in the intent-to-treat population. Multivariate logistic regression analysis showed that the lower mortality in the lubeluzole 10 mg/d group was significantly in favor of the 10 mg/d treatment (P=.019). The higher mortality rate in the 20 mg/d group could be explained, at least in part, by an imbalance at randomization that led to a higher number of patients in that group with severe ischemic stroke. A total of 26 of 66 patients (39%) who received lubeluzole 10 mg/d had a score on the Barthel Index of >70 at day 28, indicating no or mild disability, compared with 21 of 61 (34%) in the placebo group and 19 of 66 (29%) in the lubeluzole 20 mg/d group (P=NS).
Conclusions In patients with acute ischemic stroke, the dosage regimen of 7.5 mg over 1 hour followed by 10 mg/d of intravenous lubeluzole is safe and statistically significantly reduced mortality. Further clinical trials in a larger number of patients are ongoing to confirm efficacy.
Key Words: cerebral ischemia • neuroprotection • clinical trials • lubeluzole
|
Introduction |
|---|
|
TopAbstractIntroductionSubjects and Methods Results Discussion Appendix References |
|---|
Lubeluzole is a newly synthesized benzothiazole compound in clinical development for the treatment of acute ischemic stroke. The compound improved neurological outcome and reduced infarct volume in photochemically induced thrombotic cerebral infarcts in rats, even when administered up to 6 hours after infarct induction.1 It also significantly reduced infarct size in a middle cerebral artery occlusion model in spontaneous hypertensive rats (J. Grotta, unpublished data, 1995).
Lubeluzole prevents the increase in extracellular glutamate concentrations2 and normalizes neuronal excitability3 in the peri-infarct region. Experiments in embryonic hippocampal neuronal cultures indicate that the drug also inhibits glutamate-induced nitric oxide–related neurotoxicity.4 Therefore, it might be assumed that the neuroprotective action of lubeluzole in focal cerebral ischemia is based on interference with key mechanisms in the biochemical cascade that lead to irreversible tissue damage in the penumbral zone.5
Favorable results from animal experiments and early safety data in humans prompted us to initiate an international, multicenter, double-blind, randomized, placebo-controlled trial to evaluate the safety and efficacy of lubeluzole in patients with acute ischemic stroke in the carotid artery territory.
|
Subjects and Methods |
|---|
|
TopAbstractIntroductionSubjects and Methods Results Discussion Appendix References |
|---|
The trial was performed in accordance with the Declaration of Helsinki and its subsequent revisions. At each study center, Ethics Committee approval was obtained, and the patients or their legal representative gave written or witnessed informed consent to participate in the trial.
Patients
A total of 232 patients were enrolled at 34 centers
in 7
countries between January 1993 and April 1994. Patients with a clinical
diagnosis of acute ischemic stroke in the carotid artery
territory were eligible for inclusion in the trial if they (1) were
older than 50 years, (2) had a stable hemiparesis with the affected
outstretched arm unable to hold a 90° position for 10 seconds, (3)
were conscious, and (4) had presented for initiation of
treatment within 6 hours after the event. Patients who had experienced
a previous stroke with residual neurological impairment, suffered from
any other disorder interfering with neurological or functional
assessment, or had a life-threatening concurrent illness were
excluded from participation in the trial. Other exclusion criteria were
overt heart failure, myocardial infarction within the previous 6 weeks,
ECG findings of ventricular arrhythmia, second or
third degree atrioventricular block, a QTc
interval >450 milliseconds, or an intake of potassium-losing
diuretics without special measures to prevent hypokalemia. Most
sites had a cardiologist read the ECG at baseline, and all
participating centers received training in evaluating ECGs.
Treatment Regimen
Within 6 hours after the onset of stroke,
patients were assigned
according to a randomization code to receive intravenous
treatment with placebo or one of the two dosages of lubeluzole: either
a loading dose of 7.5 mg over 1 hour followed by a continuous infusion
of 10 mg/d for 5 days or a loading dose of 15 mg over 1 hour followed
by a continuous infusion of 20 mg/d for 5 days. Concomitant treatment
with calcium channel blockers and other experimental stroke drugs was
prohibited throughout the trial. Acetylsalicylic
acid, ticlopidine, and heparin were permitted for
prophylactic reasons. Heparin was allowed in low dose for
prevention of deep vein thrombosis or pulmonary embolism or
high dose for suspected cardiac source of embolism.
Assessments
Baseline assessments included a medical history,
general
physical and neurological examinations, ECG, and hematologic and
biochemical tests. A CT scan of the brain was performed either before
the start of treatment if results could be available within 30 minutes
after admission of the patient or after the start of treatment within
the first 24 hours. Neurological status was assessed by the NIH Stroke
Scale6 and the ESS,7 and functional status
was assessed by the Barthel Index.8 The ESS and NIH Scale
grades 14 and 15 neurological items, respectively; for the ESS the
maximal score is 100 (normal) and the minimal score is 0, and for the
NIH the best score is 0 (normal) and the worst score is 42. Patients
who died within the 28-day study period were included in the
analysis up to the time of death (observed case
analysis). The Barthel Index evaluates 10 activities of daily
living with a maximal value of 100 and a minimal value of 0; a score
from 0 to 45 corresponds to severe disability, 50 to 70 to moderate
disability, 75 to 95 to mild disability, and 100 to no
disability.9 10 11
Blood pressure, heart rate, ECG, and neurological assessments were repeated within 6 to 12 hours after the initiation of therapy and on days 3, 5, 7, 14, and 28. The Barthel Index was completed on days 7 and 28 of the study. Laboratory investigations and a CT scan of the brain were repeated on day 5 (including determination of plasma concentrations of lubeluzole) and on day 28. Mortality and adverse events were followed over the entire trial period of 28 days. Serious adverse events were reported within 24 hours. Safety was followed by the Safety Monitoring Committee, which reviewed all reports of death and serious adverse events.
Protocol-specified study end points were neurological outcome according to the NIH Stroke Scale and ESS and functional outcome according to the Barthel Index and mortality at day 28.
Statistical Analysis
Demographic and baseline disease
characteristics were compared
with the use of the Cochran-Mantel-Haenszel test for general
association for nominal categorical variables (eg, sex) and a
one-way ANOVA for continuous variables (eg, age).
One-sample t tests were performed with the use of
descriptive statistics for each ECG interval, heart rate, and blood
pressure to evaluate changes versus baseline values.
The primary efficacy analysis was performed on a target population basis as prespecified in the protocol, ie, on all patients with carotid artery territory ischemic stroke who were correctly included in the trial according to the inclusion and exclusion criteria. Safety analysis included all randomized patients (intent-to-treat).
Descriptive statistics and frequency distributions were generated for the study end point data. The Mann-Whitney U test was used for pairwise comparisons. Mortality rates and disability levels on the Barthel Index among the three treatment groups were compared with the use of Fisher's exact test. A multivariate logistic regression analysis was performed to detect the possible influence of several factors on mortality.
Because patients with mild stroke all showed good functional outcome, a post hoc subgroup analysis was performed on those patients who had suffered a moderate to severe stroke, defined as a baseline ESS total score <70. All statistical tests were interpreted at the 5% two-tailed significance level. To preserve the overall 5% type I error rate, a closed test procedure strategy was used when multiple comparisons were performed, and a comparison between the two groups was declared significant if both the overall and the pairwise comparisons were significant at the 5% level.
|
Results |
|---|
|
TopAbstractIntroductionSubjects and Methods Results Discussion Appendix References |
|---|
The trial initially aimed at inclusion of 270 patients but was terminated prematurely by the Safety Committee after 232 patients were recruited because of an imbalance in the 28-day mortality between the three treatment groups: 10 mg/d, 8 of 83 (10%); placebo, 13 of 69 (19%); and 20 mg/d, 25 of 80 (31%). After all data were entered and the target population (ie, patients with CT scan consistent with ischemic stroke in the carotid artery territory) was determined, the randomization code was broken. The target population consisted of 193 patients. Thirty-nine patients with either intracerebral hemorrhage or ischemic stroke in the vertebrobasilar territory were excluded from the primary efficacy analysis. The exclusion was blind regarding the treatment groups. The study protocol allowed a CT scan to be performed within 24 hours after the start of trial medication.
There were no significant differences between the treatment groups in
the target population with regard to demographic and baseline
characteristics, except for the baseline ESS and NIH scores. The mean
ESS and NIH baseline scores were significantly worse for the lubeluzole
20 mg/d group compared with the placebo and 10 mg/d groups, and
significantly more patients in the lubeluzole 20 mg/d group suffered
from severe stroke (ESS score 
30) compared with the placebo group and
the 10 mg/d group (Table 1
).
|
Compared with placebo, in both the target and the
intent-to-treat populations there was a higher mortality in the
20 mg/d group and a lower mortality in the 10 mg/d group (Table
2). The causes of death are also listed in Table
2. A
multivariate logistic regression analysis on
the mortality rate in the target population showed that patients with a
very low baseline ESS score (severe neurological impairment) had a
significantly higher risk of dying than those with higher scores (Table
3). The analysis further showed that none of the
following factors had a significant effect on mortality: high versus
normal glycemia, age 70 or >70 years, or the location of the insult
(left versus right side). While the analysis showed no
significant effect on mortality after treatment with the 20 mg/d dose
versus placebo, the analysis disclosed a significant effect of
treatment with the 10 mg/d dose versus placebo (P=.019)
(Figure).
|
|
|
Of the 155 patients in the target population who survived the 28-day follow-up period, there were 6 additional dropouts: 3 in the placebo group (2 patient withdrawals, 1 bradycardia), 2 in the 20 mg/d group (1 secondary intracerebral hemorrhage, 1 protocol violation), and 1 patient in the 10 mg/d group (symptomatic heart failure).
There was no significant difference between the treatment groups in
shifts from baseline at day 28 on the scores of both the ESS and NIH
Stroke Scale (Table 4). When outcome was evaluated with
the Barthel Index, the 10 mg/d group was found to have a higher
proportion of patients with good recovery (no or mild disability, ie, a
Barthel score >70) than the 20 mg/d and placebo groups. This effect
was more pronounced in the subgroup of 174 of the 193 patients with an
ESS score <70 at baseline, as the placebo group contained a higher
number of patients with an ESS score 
70. The differences between the
groups, however, did not reach statistical significance, except for
mortality (Table 5). The Barthel distribution for the
intent-to-treat study population (n=232) is shown in Table
6.
|
|
|
Mean±SD steady state plasma concentrations of lubeluzole at day 5 were 61.3±22.4 ng/mL in the 10 mg/d group and 106±34.0 ng/mL in the 20 mg/d group. During phase I studies, it was found that the QTc interval on the ECG tended to be prolonged with increasing lubeluzole plasma concentrations, starting from >100 ng/mL (Janssen Pharmaceutica Report, data on file). However, in the present study QTc shifts (which included increases as well as decreases) in both the lubeluzole groups remained in the same ranges as in the placebo group. Ventricular fibrillation was reported in 1 patient given placebo, 1 patient given the 10 mg/d dose (resuscitated), and 4 patients given the 20 mg/d dose. One patient in each group suffered cardiac arrest, and 1 placebo patient had ventricular tachycardia.
Overall, adverse events were reported in 84% of patients in the
placebo group, 89% of patients in the 10 mg/d group, and 86% of
patients in the 20 mg/d group, and there were no clinically relevant
differences among the three groups. The most commonly reported adverse
events are listed in Table 7. Neither dosage of
lubeluzole had an effect on blood pressure and heart rate. There were
no apparent differences between the groups with regard to biochemistry
and hematology values.
|
|
Discussion |
|---|
|
TopAbstractIntroductionSubjects and Methods Results Discussion Appendix References |
|---|
Based on successful posttreatment effects of lubeluzole in animal models of focal cerebral ischemia, the present study, a phase II trial, was initiated to investigate the safety and the ability of this neuroprotective drug to ameliorate the outcome of patients with ischemic stroke. It was hypothesized that the drug may offer more promise in rescuing the tissue in the ischemic penumbra than selective NMDA or AMPA receptor antagonists because of its ability to prevent an increase in extracellular glutamate concentrations, thereby inhibiting the damaging excitotoxic events in a more global way.5 Because the drug is not an NMDA antagonist, it is free of psychotic side effects and does not produce neuronal vacuolizations in rat brain (Janssen Pharmaceutica Report, data on file), as observed with some NMDA receptor antagonists.12 In addition, data from experiments in embryonic hippocampal neurons suggest that the drug also inhibits nitric oxide–related neurotoxicity.4 Further in vivo animal experiments are being performed to investigate whether this effect, occurring further downstream in the cascade of biochemical events leading to tissue damage in the penumbral zone, also contributes to the neuroprotective action of this agent in focal cerebral ischemia.
The lubeluzole 10 mg/d regimen resulted in a decreased mortality rate (6%) and a trend toward a better functional outcome on the Barthel Index, ie, a higher number of patients with no or mild disability (score >70). This effect was more pronounced when patients with a mild stroke (of which there was a higher number in the placebo group) were excluded because these patients were found to have a good functional outcome irrespective of their treatment. In both analyses this effect did not achieve statistical significance because the number of patients in the treatment groups was too small. No significant difference between the treatment groups in neurological recovery was seen by analyzing the shifts from baseline on the ESS and NIH Stroke Scale. However, a correct interpretation of neurological recovery assessed by a stroke scale is seriously hampered by the imbalance in mortality between the treatment groups, since patients who died were analyzed only up to the time of death.
The higher mortality rate in the 20 mg/d group (35%) may be explained, at least in part, by the higher number of patients with more severe stroke in this group at baseline. This finding was supported by a multivariate regression analysis. Ten patients in the 20 mg/d group died from cerebral edema and transtentorial herniation, typical complications of severe stroke. Unpublished results from animal experiments (A.M. Van der Linden, M. De Ryck, 1994) indicate that lubeluzole does not produce or increase preexisting brain edema. In general, adverse experiences were similar in the three groups.
With regard to cardiac safety, in phase I trials a plasma level–related QTc prolongation was observed in some healthy volunteers and patients with plasma concentrations >100 ng/mL (Janssen Pharmaceutica Reports, data on file). This plasma concentration was reached in the 20 mg/d group, but in the present study it was not possible to detect QTc interval changes in this group that were different from those observed in the placebo and 10 mg/d groups. Incidence of ventricular fibrillation was higher in the 20 mg/d group. Four patients in the 20 mg/d group died from ventricular fibrillation. However, in view of the imbalance in stroke severity at baseline, interpretation of the cardiovascular safety of the 20 mg/d dose is difficult. It is well recognized that stroke by itself may prolong the QT interval.13 There were fewer cardiac events in the 10 mg/d group compared with the placebo group, suggesting that this dosage regimen, resulting in a mean plasma concentration of 61 ng/mL, is safe.
A recently completed, double-blind, placebo-controlled study in 46 stroke patients showed that the 10 mg/d dose had no statistically significant effects on ECG parameters, including Qtc (Janssen Pharmaceutica Report, data on file). No ventricular tachycardia, ventricular fibrillation, or torsade de pointes were reported.
In conclusion, this trial suggests that patients with ischemic stroke in the carotid artery territory may benefit, in terms of reduction in mortality, from a treatment regimen of lubeluzole at a loading dose of 7.5 mg over 1 hour started within 6 hours after the event followed by a continuous infusion of 10 mg/d for 5 days. Further clinical trials in a large number of patients are ongoing.
|
Selected Abbreviations and Acronyms |
|---|
|
-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid
|
Acknowledgments |
|---|
This trial was sponsored by the Janssen Research Foundation, Beerse, Belgium. We thank the patients, physicians, nurses, clinical trial managers, study monitors, and members of the Steering and Safety Committees for their participation in this study.
|
Footnotes |
|---|
Reprint requests to Ludwig Hantson, PhD, Group Director, Clinical Research and Development, Janssen Pharmaceutica, 1125 Trenton-Harbourton Rd, Titusville, NJ 08560-0200.
|
Appendix |
|---|
|
TopAbstractIntroductionSubjects and Methods Results Discussion Appendix References |
|---|
The Lubeluzole International Study Group
Steering Committee: J. De Keyser (Brussels, Belgium), H.C. Diener (Essen, Germany), W. Hacke (Heidelberg, Germany), L. Hantson (Beerse, Belgium), M. Hennerici (Mannheim, Germany), J. Rådberg (Linköping, Sweden).
Safety Committee: P. Cras (Antwerp, Belgium), B. Nilsson (Lund, Sweden), J.P. Thijssen (Amsterdam, Netherlands).
Investigators: Belgium: H.H. Ziekenhuis, Roeselare: P. Bourgeois; O.-L. Vrouwziekenhuis, Aalst: M. Van Orshoven, J. Caeckebeke; St Luc (UCL), Brussels: A. Peeters, C. Delwaide; St-Andries Ziekenhuis, Tielt: P. Tack, D. De Maeyer; Stedelijk Ziekenhuis, Aalst: E. Fosselle; A.Z. Vrije Universiteit Brussel, Brussels: J. De Keyser, N. De Klippel, L. Herroelen, V. Bissay. Canada: Hamilton Civic Hospital, Hamilton, Ontario: R. Duke, W. Nolan, W. Oczkowski, J. Paulseth; St Joseph's Hospital, Hamilton, Ontario: S. Fawcett; St Luc Hospital, Montreal, Québec: L. Lebrun, N. Daneault; Hôpital de l'Enfant-Jésus, Québec City, Québec: D. Simard, C. Roberge, A. Mackey, M. Petitclerc, D. Rivest, S. Tremblay. Denmark: Bispebjerg Hospital, Copenhagen: H. Jespersen; KAS Gentofte, Hellerup: P. Thorvaldsen; Vejle Sygehus, Vejle: M. Tango, I. Zeeberg; Viborg Sygehus, Viborg: B. Sivertsen. France: Centre Hospitalier Universitaire Purpan, Toulouse: F. Chollet; Centre Hospitalier Universitaire de Caen: F. Vinder, V. De la Sayette. Germany: Krankenhaus Maria Hilf Mönchengladbach: J. Haan, S. Trabert, S. Telia, T. Simm, H. Schroers; Kreiskrankenhaus Lüdenscheid: U. Gallenkamp, C. Sulemann, H. Heusler, Y. Erim, E. Stolz, R. Martens; Neurologische Universitätsklinik, Mannheim: M. Hennerici, T. Kammer, J. Röther, J.C. Wöhrle, T. Els; Neurologische Universitätsklinik, Heidelberg: W. Hacke, W. Fogel, H. Hund, E. Jünger, L. Rosin, T. Steiner, M. Müller-Küppers; Neurologische Universitätsklinik, Essen: H.C. Diener, R. Malessa, R. van Schayck, G. Leonhardt, J. Nebe, C. Eichten; Neurologische Universitätsklinik, Düsseldorf: H. Steinmetz, M. Siebler, A. Nachtmann; Städtisches Krankenhaus Fulda: H.D. Langohr, T. Klitsch; Klinikum Minden: O. Busse, H. Griese, M. Hoffman. Netherlands: De Wever Ziekenhuis, Heerlen: A. Colon, A. Soeterboek, J. Van Der Plas; Sint Elisabeth Ziekenhuis, Tilburg: R. Schellens, G. Verheul. Sweden: Geriatrik och Rehabklin, Kungälv: G.B. Larsson, C. Lundbom, M. Andersson; Medicinklinik Falu lasarett, Falun: S.E. Eriksson; Medicinklinik Höglandssjukhuset, Eksjö: L. Hermodsson; Medicinklinik Kärnsjukhuset, Skövde: E. Bertholds, S. Håkansson, G. Hallgren, M. Gilleryd, K. Nylén; Medicinklinik Länssjukhuset, Jönköping: G. Hedman; Medicinklinik Norrköping lasarett: B. Stahre, C. Hallert, H. Nilsson; Neurolog Universitetssjukhuset, Linköping: J. Rådberg, J.E. Olsson; Neurolog Centralsjukhuset, Karlstad: O. Gatchev, B. Fure, R. Palm; Neurolog Länssjukhuset, Halmstad: P. Thomasson, J. Kinnman, H. Askmark.
Received June 26, 1995; revision received September 26, 1995; accepted October 9, 1995.
|
References |
|---|
|
TopAbstractIntroductionSubjects and Methods Results Discussion Appendix References |
|---|
1. De Ryck M, Keersmaekers R, Clincke G, Janssen M, Van Reet S. Lubeluzole, a novel benzothiazole, protects neurologic function after cerebral thrombotic stroke in rats: an apparent stereospecific effect. Soc Neurosci Abstr. 1994;20:185.
2. Scheller D, Kolb J, Szathmary S, Zacharias E, De Ryck M, Van Reempts J, Clincke B, Tegtmeier F. Extracellular changes of glutamate in the periinfarct zone: effect of lubeluzole. J Cereb Blood Flow Metab. 1995;15(suppl 1):S379.
3. Buchkremer-Ratzmann I, Witte OW. Periinfarct and transhemispheric diaschisis caused by photothrombotic infarction in rat neocortex is reduced by lubeluzole but not MK-801. J Cereb Blood Flow Metab. 1995;15(suppl 1):S38.
4. Lesage AS, De Loore KL, Osikowska-Evers B, Peeters L, Leysen JF. Lubeluzole, a novel neuroprotectant, inhibits the glutamate-activated NOS pathway. Soc Neurosci Abstr. 1994;20:185.
5. Heiss W-D, Graf R. The ischemic penumbra. Curr Opin Neurol. 1994;7:11-19. [Medline] [Order article via Infotrieve]
6.
Brott T, Adams HP Jr, Olinger CP, Marler JR, Barsan
WG, Biller J, Spilker J, Holleran R, Eberle R, Hertzberg V,
Rorick M, Moomaw CJ, Walker M. Measurements of acute cerebral
infarction: a clinical examination scale. Stroke. 1989;20:864-870.
7. Hantson L, De Weerdt W, De Keyser J, Diener HC, Franke C, Palm R, Van Orshoven M, Schoonderwalt H, De Klippel N, Herroelen L, Feys H. The European Stroke Scale. Stroke. 1994;25:2215-2219. [Abstract]
8. Mahoney FI, Barthel DW. Functional evaluation: the Barthel Index. Md State Med J. 1965;14:61-65. [Medline] [Order article via Infotrieve]
9. Granger CV, Albrecht GL, Hamilton BB. Outcome of comprehensive medical rehabilitation: measurement by PULSES Profile and the Barthel Index. Arch Phys Med Rehabil. 1979;60:145-154. [Medline] [Order article via Infotrieve]
10. Granger CV, Hamilton BR, Gresham GE, Kramer AA. The stroke rehabilitation outcome study, part II: relative merits of the total Barthel Index score and a four-item subscore in predicting patient outcomes. Arch Phys Med Rehabil. 1989;70:100-103. [Medline] [Order article via Infotrieve]
11. Taub NA, Wolfe CDA, Richardson E, Burney PGJ. Predicting the disability of first-time stroke sufferers at 1 year: 12-month follow-up of a population-based cohort in southeast England. Stroke. 1994;25:352-357. [Abstract]
12. Willets J, Balster RL, Leander JD. The behavioral pharmacology of NMDA receptor antagonists. Trends Pharmacol Sci. 1990;11:423-428. [Medline] [Order article via Infotrieve]
13. Oppenheimer SM, Hachinski VC. The cardiac consequences of stroke. Neurol Clin. 1992;10:167-176.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  H. P. Adams Jr, G. del Zoppo, M. J. Alberts, D. L. Bhatt, L. Brass, A. Furlan, R. L. Grubb, R. T. Higashida, E. C. Jauch, C. Kidwell, et al. Guidelines for the Early Management of Adults With Ischemic Stroke: A Guideline From the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Circulation, May 22, 2007; 115(20): e478 - e534. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. P. Adams Jr, G. del Zoppo, M. J. Alberts, D. L. Bhatt, L. Brass, A. Furlan, R. L. Grubb, R. T. Higashida, E. C. Jauch, C. Kidwell, et al. Guidelines for the Early Management of Adults With Ischemic Stroke: A Guideline From the American Heart Association/ American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists Stroke, May 1, 2007; 38(5): 1655 - 1711. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Bruno, C. Saha, and L. S. Williams Using Change in the National Institutes of Health Stroke Scale to Measure Treatment Effect in Acute Stroke Trials Stroke, March 1, 2006; 37(3): 920 - 921. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. P. Adams Jr, R. J. Adams, T. Brott, G. J. del Zoppo, A. Furlan, L. B. Goldstein, R. L. Grubb, R. Higashida, C. Kidwell, T. G. Kwiatkowski, et al. Guidelines for the Early Management of Patients With Ischemic Stroke: A Scientific Statement From the Stroke Council of the American Stroke Association Stroke, April 1, 2003; 34(4): 1056 - 1083. [Full Text] [PDF]
|
|
|
|
|
|
K. Uchino, D. Billheimer, and S. C. Cramer Entry Criteria and Baseline Characteristics Predict Outcome in Acute Stroke Trials Stroke, April 1, 2001; 32(4): 909 - 916. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. R. Lees, A. G. Dyker, A. Sharma, G. A. Ford, M. E. Ardron, and D. G. Grosset Tolerability of the Low-Affinity, Use-Dependent NMDA Antagonist AR-R15896AR in Stroke Patients : A Dose-Ranging Study Stroke, February 1, 2001; 32(2): 466 - 472. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. C. Diener, M. Cortens, G. Ford, J. Grotta, W. Hacke, M. Kaste, P. J. Koudstaal, and T. Wessel Lubeluzole in Acute Ischemic Stroke Treatment : A Double-Blind Study With an 8-Hour Inclusion Window Comparing a 10-mg Daily Dose of Lubeluzole With Placebo Stroke, November 1, 2000; 31(11): 2543 - 2551. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P. Broderick, M. Lu, R. Kothari, S. R. Levine, P. D. Lyden, E. C. Haley, T. G. Brott, J. Grotta, B. C. Tilley, J. R. Marler, et al. Finding the Most Powerful Measures of the Effectiveness of Tissue Plasminogen Activator in the NINDS tPA Stroke Trial Stroke, October 1, 2000; 31(10): 2335 - 2341. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.E. Arrowsmith, M.J.G. Harrison, S.P. Newman, J. Stygall, N. Timberlake, and W.B. Pugsley Neuroprotection of the Brain During Cardiopulmonary Bypass : A Randomized Trial of Remacemide During Coronary Artery Bypass in 171 Patients Stroke, November 1, 1998; 29(11): 2357 - 2362. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Management soon after a stroke DTB, July 1, 1998; 36(7): 51 - 54. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Grotta Lubeluzole Treatment of Acute Ischemic Stroke Stroke, December 1, 1997; 28(12): 2338 - 2346. [Abstract] [Full Text]
|
|
|
|
|
|
M. Haseldonckx, J. Van Reempts, M. Van de Ven, L. Wouters, M. Borgers, and J. A. Clemens Protection With Lubeluzole Against Delayed Ischemic Brain Damage in Rats: A Quantitative Histopathologic Study Stroke, February 1, 1997; 28(2): 428 - 432. [Abstract] [Full Text]
|
|
|
|
 |
|
 J. Grotta Rodent Models of Stroke Limitations: What Can We Learn From Recent Clinical Trials of Thrombolysis? Arch Neurol, October 1, 1996; 53(10): 1067 - 1070. [Abstract] [PDF]
|
|
|
|
|
|
J. Aronowski, R. Strong, J.C. Grotta, and H. A. Kontos Combined Neuroprotection and Reperfusion Therapy for Stroke: Effect of Lubeluzole and Diaspirin Cross-Linked Hemoglobin in Experimental Focal Ischemia Stroke, September 1, 1996; 27(9): 1571 - 1577. [Abstract] [Full Text]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||