Isradipine in patients with acute ischaemic cerebral infarction. An overview of the ASCLEPIOS Programme. Hydroxyethyl starch for hypervolemic hemodilution in patients with acute ischemic stroke: a randomized, placebo-controlled phase II safety study. Remacemide hydrochloride: a double-blind, placebo-controlled, safety and tolerability study in patients with acute ischemic stroke. Emergency administration of abciximab for treatment of patients with acute ischemic stroke: results of an international phase III trial: Abciximab in Emergency Treatment of Stroke Trial (AbESTT-II). Glycine antagonist (gavestinel) in neuroprotection (GAIN International) in patients with acute stroke: a randomised controlled trial. GAIN International Investigators. Effects of fasudil in acute ischemic stroke: results of a prospective placebo-controlled double-blind trial. Controlled trial of intravenous aminophylline in acute cerebral infarction. A pilot study with monosialoganglioside GM1 on acute cerebral ischemia. Emergency administration of abciximab for treatment of patients with acute ischemic stroke: results of a randomized phase 2 trial.
Calcium-related mechanisms are an integral part of metabolic reactions during acute cerebral infarction. In an animal model of stroke, the calcium antagonist isradipine was shown to protect neurons against ischaemia. In order to improve the neurological and functional outcome of human stroke patients, a randomised, double-blind, placebo-controlled multicentre study was started in up to 600 patients with acute ischaemic brain infarction. Since early treatment is considered to be of great importance, patients must be recruited no more than 12 hours after stroke onset. Medical, ECG, laboratory, neurological and functional evaluations are conducted for up to 90 days after stroke. Hypervolemic hemodilution (HH) with hydroxyethyl starch (HES) significantly increases cerebral blood flow and thus may reduce ischemic tissue damage in the penumbra zones when given within the therapeutic time window. The objective of this study was to investigate the safety of a 10% solution of HES 130/0.4 versus 0.9% saline solution in acute ischemic stroke by the incidence of adverse events (AEs).
                In a controlled, double-blind, randomized, multicenter, phase II, parallel-group study, 106 patients with acute ischemic stroke received high-dose HH with HES 130/0.4 or placebo within 6 h of symptom onset with a randomization ratio of 2:1 in favor of HES therapy.
                There were no significant differences between the groups with regard to the incidence of the specific AEs (cardiovascular events, bleeding complications, allergic reactions) assessed over days 1-30, or mortality over days 1-8. In addition, global tests of efficacy showed a trend towards a better functional outcome with HES therapy; however, the study was not designed to prove efficacy.
                High-dose HH with HES or NaCl was generally safe and well tolerated. Safety profiles were similar for the two treatment groups, and there was a nonsignificant trend towards a better functional outcome with HES therapy.
                Copyright 2002 S. Karger AG, Basel Remacemide hydrochloride and its principal active desglycinyl metabolite are low-affinity noncompetitive N-methyl-D-aspartate (NMDA)-receptor channel blockers. Remacemide hydrochloride has demonstrated neuroprotection in animal models of hypoxia and ischemic stroke. This study assessed the safety, tolerability, and pharmacokinetics of ascending doses of remacemide hydrochloride in patients with recent onset (within 12 hours) ischemic stroke.
                This was a placebo-controlled, dose escalating, parallel group study. Groups of 8 patients (6 active, 2 placebo) were planned to receive twice-daily treatment, with l00 mg, 200 mg, 300 mg, 400 mg, 500 mg, or 600 mg remacemide hydrochloride given as 2 intravenous infusions followed by 6 days' oral treatment. Patients who were unable to swallow discontinued study medication but continued to be monitored for safety; these patients were replaced. A CT or MRI scan was performed within 48 hours of admission to establish the cause of focal neurological deficit. Patients with ischemic stroke continued in the study. Patients with other causes of focal neurological deficit were withdrawn and replaced. Because the frequency of dysphagia after stroke in the first dose group (100 mg BID) was higher than had been anticipated, the protocol was amended so that subsequent dose groups received 6 intravenous infusions (2 doses per day for 3 days). Neurological and functional outcome data were collected, but the study was not powered to demonstrate drug efficacy. Patient safety was assessed by clinical observation, laboratory tests, and ECGs, while tolerability was assessed by recording adverse events. Blood sampling was included to determine plasma concentrations of remacemide and the desglycinyl metabolite at fixed points during the dosing period.
                The most common adverse events considered by the investigator to be possibly treatment related were related to the central nervous system (CNS), and these events appeared to increase with dose. Four patients were withdrawn from the study because of CNS-related events: 1 in the placebo group, 1 in the 500 mg BID group, and 2 in the 600 mg BID group. Infusion site reactions and gastrointestinal upset were also reported and considered to be treatment related. One patient in the placebo group and 4 patients in the 600 mg BID dose group experienced vomiting, whereas this event was not reported by patients in the other dose groups.
                On the evidence of this study, the maximum well-tolerated dose for remacemide hydrochloride in acute stroke is 400 mg BID. Doses of 200 mg BID or higher attained the putative neuroprotective plasma concentrations of remacemide predicted from animal models (250 to 600 ng/mL). The expected gradual accumulation of active metabolite might suggest that optimal neuroprotective concentrations are unlikely to be achieved within the early hours of treatment at this dose. However, plasma concentrations do not directly reflect brain concentrations, because studies in rats show that remacemide and the desglycinyl metabolite rapidly reach comparable brain concentrations within 1 hour, despite a lower plasma concentration of the metabolite. A previous randomized, placebo-controlled, double-blind study suggested that abciximab may be safe and effective in treatment of acute ischemic stroke. The current phase 3 study was planned to test the relative efficacy and safety of abciximab in patients with acute ischemic stroke with planned treatment within 5 hours since symptoms onset.
                An international, randomized, placebo-controlled, double-blind phase 3 trial tested intravenous administration of abciximab in 2 study cohorts using stratification variables of time since onset and stroke severity. The planned enrollment was 1800 patients. The primary cohort enrolled those patients who could be treated within 5 hours of onset of stroke. A companion cohort enrolled patients that were treated 5 to 6 hours after stroke as well as a smaller cohort of patients who could be treated within 3 hours of stroke present on awakening. The primary efficacy measure was the dichotomous modified Rankin Scale score at 3 months as adjusted to the baseline severity of stroke among subjects in the primary cohort. The primary safety outcome was the rate of symptomatic or fatal intracranial hemorrhage that occurred within 5 days of stroke.
                The trial was terminated prematurely after 808 patients in all cohorts were enrolled by recommendation of an independent safety and efficacy monitoring board due to an unfavorable benefit-risk profile. At 3 months, approximately 33% of patients assigned placebo (72/218) and 32% of patients assigned abciximab (71/221; P=0.944) in the primary cohort were judged to have a favorable response to treatment. The distributions of outcomes on the modified Rankin Scale were similar between the treated and control groups. Within 5 days of enrollment, approximately 5.5% of abciximab-treated and 0.5% of placebo-treated patients in the primary cohort had symptomatic or fatal intracranial hemorrhage (P=0.002). The trial also did not demonstrate an improvement in outcomes with abciximab among patients in the companion and wake-up cohorts. Although the number of patients was small, an increased rate of hemorrhage was noted within 5 days among patients in the wake-up population who received abciximab (13.6% versus 5% for placebo).
                This trial did not demonstrate either safety or efficacy of intravenous administration of abciximab for the treatment of patients with acute ischemic stroke regardless of end point or population studied. There was an increased rate of symptomatic or fatal intracranial hemorrhage in the primary and wake-up cohorts. Early treatment may improve acute ischaemic stroke outcome. Gavestinel is a selective antagonist at the glycine site of the N-methyl-D-aspartate (NMDA) receptor, and is neuroprotective in animal models of ischaemic stroke.
                We did a randomised, double-blind, placebo-controlled trial to test whether gavestinel could improve functional outcome after acute stroke in human beings. Conscious patients with stroke involving limb weakness received either gavestinel at an intravenous loading dose of 800 mg followed by 200 mg every 12 h for five doses, or matching placebo, within 6 h of stroke onset. Stratification variables were age and stroke severity. A computed tomography brain scan within 18 h of stroke onset identified the primary efficacy population with ischaemic stroke. Outcome was assessed by an independent observer with the Barthel index at 3 months. Three outcome categories were applied: good (Barthel index 95-100), moderate (60-90), and poor (0-55 or dead). Analysis was by intention to treat.
                Of 1804 patients randomised, 16 received no treatment, and 333 had primary intracranial haemorrhage. 891 patients received gavestinel and 897 received placebo. Outcome in 721 patients who received gavestinel and were analysed for the primary endpoint at 3 months was good in 246 (34.1%), moderate in 136 (18.8%), and poor in 339 (47.0%), compared with 256 (34.9%), 133 (18.1%), and 345 (47.0%), respectively, of 734 patients who received placebo (p=0.8). Mortality at 3 months was 147 (20.4%) in the gavestinel group and 138 (18.8%) in the placebo group. Outcomes within preplanned subgroup and secondary analyses were also neutral. There were no significant differences in serious side-effects between the groups.
                Treatment with gavestinel within 6 h of acute ischaemic stroke did not improve outcome. A multicenter, double-blind, placebo-controlled study was conducted to assess the efficacy and safety of fasudil, a Rho-kinase inhibitor (RKI), in the treatment of acute ischemic stroke.
                A total of 160 patients, who were able to receive drug treatment within 48 h of acute ischemic stroke onset were enrolled. Patients received either 60 mg fasudil or a placebo (saline) by intravenous injection over 60 min, twice daily for 14 days. The primary end points were neurological status at 2 weeks after the start of treatment, and clinical outcome at 1 month after the onset of symptoms.
                Fasudil treatment resulted in significantly greater improvements in both neurological functions (p=0.0013), and clinical outcome (p=0.0015). There were no serious adverse events reported in the fasudil group. The average trough value (12 h values) of active metabolite hydroxyfasudil, another RKI, in healthy elderly volunteers receiving 60 mg of fasudil was 0.077 microM-a concentration well above that needed to inhibit Rho-kinase (0.025-0.05 microM).
                Treatment with fasudil within 48 h of acute ischemic stroke onset significantly improved the patient's clinical outcome. This study found fasudil to be a useful and safe drug for patients with acute ischemic stroke. Further evaluations, for example, 3-month functional outcomes in a larger clinical trial, may help to define the efficacy of fasudil in acute ischemic stroke. In a double-blind trial intravenous aminophylline was compared with placebo in 79 patients with acute cerebral infarction. Immediate improvement in the neurological evaluation score was significantly more frequent in patients receiving aminophylline (38 per cent) than in those on placebo (15 per cent); only patients with mild or moderately severe strokes responded to the injection. After 3 weeks, however, the treated patients did not fare significantly better than the controls in terms of neurological score and residual disability. Survival rate, length of stay in hospital, and social readaptation were similar in the two groups. It is concluded that intravenous aminophylline in patients with ischaemic strokes can bring about an immediate symptomatic relief, but without appreciably influencing the ultimate recovery. Reported here are the results of an open controlled study on the use of GM1 in cases of ischemic strokes in its acute phase. A statistically significant improvement was observed in cases treated with GM1 for neurological deficits (assessed by Mathew's rating scale, modified by Fritz-Werner) at 21, 60 and 120 days and for disability at 120 days. Because of its success in treatment of acute cardiac ischemia, there is interest in the use of abciximab for treating patients with acute ischemic stroke. A previous dose-escalation study determined that abciximab could be given safely in a regimen of 0.25 mg/kg intravenous bolus followed by a 12-hour infusion at 0.125 microg/kg per minute (maximum 10 microg/min). This study was performed to obtain more information about the safety and potential efficacy of abciximab in patients with stroke.
                An international randomized, double-blind, placebo-controlled phase 2 trial enrolled 400 patients within 6 hours of onset of ischemic stroke. The primary safety outcome was the rate of symptomatic hemorrhage that occurred during the first 5 days after stroke. The primary efficacy measure was the distribution of outcomes at 3 months after stroke using the modified Rankin Scale (mRS) based on an ordinal regression model of outcomes, adjusting for baseline severity of stroke, age, and interval from stroke.
                Symptomatic intracranial hemorrhage within 5 days was diagnosed in 7 of 195 (3.6%) patients treated with abciximab and 2 of 199 (1%) patients given placebo (odds ratio [OR], 3.7; P=0.09; 95% confidence interval [CI], 0.7 to 25.9). Asymptomatic hemorrhagic transformation was detected by brain imaging in 24 patients administered abciximab and 33 patients receiving placebo (OR, 0.74; P=0.25; 95% CI, 0.4 to 1.3). Treatment with abciximab showed a nonsignificant shift in favorable outcomes as measured by mRS scores at 3 months (OR, 1.20; P=0.33; 95% CI, 0.84 to 1.70).
                Intravenously administered abciximab can be given to patients with a reasonable degree of safety. The trial also suggests that abciximab could improve outcomes at 3 months after stroke. A larger randomized, double-blind, placebo-controlled trial is necessary to test the efficacy of abciximab.
There is not enough evidence to assess adequately the effectiveness and safety of methylxanthines after acute ischaemic stroke.