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. Combination Therapy Stroke Trial: recombinant tissue-type plasminogen activator with/without lubeluzole. Glycine antagonist (GV150526) in acute stroke: a multicentre, double-blind placebo-controlled phase II trial. Safety and tolerability of GV150526 (a glycine site antagonist at the N-methyl-D-aspartate receptor) in patients with acute stroke. Phase II studies of the glycine antagonist GV150526 in acute stroke : the North American experience. The North American Glycine Antagonist in Neuroprotection (GAIN) Investigators. Safety and tolerability study of aptiganel hydrochloride in patients with an acute ischemic stroke. Aptiganel hydrochloride in acute ischemic stroke: a randomized controlled trial. Lubeluzole in acute ischemic stroke. A double-blind, placebo-controlled phase II trial. Lubeluzole International Study Group. Cardiovascular safety of lubeluzole (Prosynap(R)) in patients with ischemic stroke. Remacemide hydrochloride: a double-blind, placebo-controlled, safety and tolerability study in patients with acute ischemic stroke. Safety and tolerability of the glutamate antagonist CGS 19755 (Selfotel) in patients with acute ischemic stroke. Results of a phase IIa randomized trial. Dose escalation study of the NMDA glycine-site antagonist licostinel in acute ischemic stroke. Safety, tolerability, and pharmacokinetics of the N-methyl-D-aspartate antagonist dextrorphan in patients with acute stroke. Dextrorphan Study Group. Glycine antagonist in neuroprotection for patients with acute stroke: GAIN Americas: a randomized controlled trial. Glycine antagonist (gavestinel) in neuroprotection (GAIN International) in patients with acute stroke: a randomised controlled trial. GAIN International Investigators. Pharmacokinetics of 619C89, a novel neuronal sodium channel inhibitor, in acute stroke patients after loading and discrete maintenance infusions. Termination of Acute Stroke Studies Involving Selfotel Treatment. ASSIST Steering Committed. Dose optimization of intravenous magnesium sulfate after acute stroke. Tolerability of the low-affinity, use-dependent NMDA antagonist AR-R15896AR in stroke patients: a dose-ranging study. Phase II clinical trial of sipatrigine (619C89) by continuous infusion in acute stroke.
This trial was a double-blind, placebo-controlled, phase III trial with an 8-hour inclusion window to assess the efficacy and safety of an intravenous loading dose of 7.5 mg followed by a daily intravenous dose of 10 mg lubeluzole for 5 days in acute ischemic stroke patients.
                A total of 1786 patients were randomized: 901 to lubeluzole and 885 to placebo. Overall, 212 patients (23.5%) from the lubeluzole group and 213 (24.1%) from the placebo group discontinued the trial prematurely. In the lubeluzole group 201 patients (22.3%) discontinued because of adverse events compared with 193 patients (21.8%) in the placebo group.
                The primary population for the efficacy analysis comprised the core stroke patients (exclusion of older patients aged >75 years with severe stroke) in the 0- to 6-hour inclusion time window. The primary efficacy parameter was a 3-category functional status (Barthel Index 70 to 100/0 to 70/vegetative, dead) at week 12. In the lubeluzole group 207 patients (47.8%) were classified as mildly dependent/independent at week 12, 131 (30.3%) were moderately/severely dependent, and 95 (21.9%) were vegetative/dead. In the placebo group these numbers were 221 (54.4%), 112 (27.6%), and 73 (18.0%), respectively. Logistic regression analysis showed no statistically significant difference between the treatment groups (P:=0.162). Additionally, for none of the secondary efficacy parameters (mortality at week 12, modified Rankin score, total Barthel score) was a statistically significant difference between the lubeluzole and placebo groups obtained. There were no statistically significant differences between the 2 treatments for all treated patients, patients included within the 6- to 8-hour window, and patients with severe strokes aged >75 years. Overall, of all treated patients, 401 (22.5%) died: 203 (22.5%) in the lubeluzole group and 198 (22.4%) with placebo. Of all subjects treated, 853 (95%) on lubeluzole and 826 (93%) on placebo reported an adverse event during their treatment period or within the next 2 days after discontinuation of treatment. The most frequently observed adverse events were fever (25.9% lubeluzole; 23.4% placebo), constipation (20.2%; 19.7%), and headache (17.6%; 21.2%). Imbalances were found for atrial fibrillation (1.8% lubeluzole; 1.1% placebo) and QT prolongation (0.9%; 0.2%).
                This study failed to show an efficacy of lubeluzole in the treatment of acute stroke. On the other hand, lubeluzole treatment by the current dosage schedule was not associated with a significant safety problem. A neuroprotective drug may be safe and effective if given very early and in combination with recombinant tissue-type plasminogen activator (rt-PA) to acute stroke patients. No clinical trial has yet tested this hypothesis.
                To assess the feasibility, safety and efficacy of simultaneously combining the neuroprotective drug lubeluzole with rt-PA.
                Patients who qualified for and received rt-PA within 3 h of symptom onset were randomly allocated 1:1 to lubeluzole (7.5 mg i.v. over 1 h, then continuous 5-day infusion of 10 mg/day) or placebo. Infusion of the study medication was started before the end of the 1-hour rt-PA infusion. Inclusion criteria were the same as those of the FDA-approved guidelines for rt-PA, plus National Institutes of Health Stroke Scale (NIHSS) >5 and absence of serious ventricular arrhythmia, atrioventricular block or Q-T >450 ms. EKG was continuously monitored until 48 h after treatment. The primary outcomes were adverse events, especially hemorrhage and severe arrhythmia, and functionality as determined by the Barthel Index divided into >70,0-70 and dead.
                89 patients were randomized at 34 centers over 8 months. The study was terminated by the sponsor before the planned enrollment of 200 patients when a concurrent phase 3 trial of lubeluzole versus placebo given up to 8 h after stroke was negative. In our study, the mean NIHSS was 14.5, and the mean time from symptom onset to rt-PA was 2.5 h and to randomization to lubeluzole or placebo 3.2 h. Mortality was 26%, intracerebral hemorrhage occurred in 10% and serious adverse events in 51%. There were no differences between the two treatment groups in any of these variables, outcomes or in the Barthel Index or other measures of functionality.
                Combining neuroprotective drugs such as lubeluzole simultaneously with rt-PA is feasible and safe. The efficacy of this strategy, using a potentially more effective neuroprotective agent, should be evaluated in an adequately powered clinical trial.
                Copyright 2001 S. Karger AG, Basel GV150526 is a novel glycine antagonist at the NMDA receptor complex. It is a potent neuroprotective agent in animal models of acute stroke including permanent middle cerebral artery occlusion in the rat. GV150526 was very well tolerated in early human studies. The purpose of this randomised, double-blind, multicentre, placebo-controlled trial was to assess the safety and population pharmacokinetics of GV150526 in patients with a clinical diagnosis of acute stroke. Exploratory assessment of efficacy, quality of life and resource utilisation was also undertaken. Upon clinical diagnosis of acute stroke within 12 h of onset of symptoms, patients were treated with a loading dose of 800 mg GV150526 (or placebo), followed by 5 maintenance doses of 400 mg GV150526 (or placebo) given every 12 h over 3 days. Following observation of asymptomatic hyperbilirubinaemia, the maintenance dose was reduced mid-study to 200 mg. CT/MRI scanning was not mandatory prior to treatment. The study treated 128 patients (38 with GV 800 mg/400 mg, 48 with GV 800 mg/200 mg and 42 with placebo). Fewer patients with mild stroke (NIH scores < or =5) were enrolled in the GV150526-treated groups than in the placebo group (placebo 38%, GV 800 mg/400 mg 18%, GV 800 mg/200 mg 15%). There was also an imbalance in the proportion of patients with haemorrhagic strokes (placebo 5%, GV 800 mg/400 mg 3%, GV 800 mg/200 mg 15%). Mortality at 1 month was unbalanced between treatment groups, being 10, 18 and 17% in the placebo, GV 800 mg/400 mg and GV 800 mg/200 mg groups, respectively (no significant difference). Similarly, adverse events, though consistent with an acute stroke population, appeared more often in the GV 800 mg/200 mg group. Functional outcomes at 1 month also showed imbalances, the percentage of patients with a Barthel Index score of > or =95 at 1 month being 52, 39 and 27% in the placebo, GV 800 mg/400 mg and GV 800 mg/200 mg groups, respectively. These results probably reflect a prognostically significant baseline difference between the groups rather than the effect of GV150526. GV150526 was generally well tolerated in patients with a clinical diagnosis of acute stroke and formal efficacy studies were considered justified.
                Copyright 2001 S. Karger AG, Basel. GV150526 is a novel glycine site antagonist at the N-methyl-D-aspartate receptor complex. It is a potent neuroprotective agent in animal models of stroke, including permanent middle cerebral artery occlusion in the rat. Unlike antagonists at the glutamate ligand binding site, GV150526 appears to be free of hemodynamic and central nervous system adverse effects. The purpose of this study was to assess the safety, tolerability, and pharmacokinetics of loading and maintenance infusions of GV150526 in patients with acute stroke.
                This was a randomized, placebo-controlled, parallel-group, ascending-dose study conducted in 2 phases. In part A of the study, loading doses of 50, 100, 200, 400, or 800 mg were administered. In part B, the maximum loading dose from part A was followed by maintenance infusions (5 infusions at 12-hour intervals), aiming to maintain neuroprotective levels. Safety data were collected throughout. The study was not designed to test efficacy, but outcome data (Barthel Index and National Institutes of Health Stroke Scale) were collected.
                Sixty-six patients were recruited to the study over 11 months; 18 patients received placebo. GV150526 was well tolerated by the 48 patients who received it. There was no excess of central nervous system or hemodynamic adverse events compared with placebo. Minor abnormalities in liver function tests were observed in association with the higher maintenance doses tested. Four of 7 patients receiving the 800-mg loading dose followed by 400 mg BID and 1 of 6 patients who received the 200-mg BID maintenance dose showed a small rise in bilirubin, and 3 patients had increases in transaminases; the mean values at 72 hours remained under twice the upper limit of normal. These changes were asymptomatic and resolved within 10 days.
                GV150526 is an emerging neuroprotective agent, with no apparent significant central nervous system or hemodynamic effects. Dose-limiting effects appear to be restricted to mild transient and asymptomatic rises in bilirubin and/or transaminases, primarily observed at high maintenance doses, and there were no findings that should preclude further clinical development. GV150526, a selective glycine site antagonist, reduces infarct volume in rats with focal cerebral ischemia. Safety and efficacy in humans with acute stroke are being investigated. We sought to further explore the safety, pharmacokinetics, and preliminary outcome of GV150526 treatment in patients with a clinical diagnosis of acute stroke.
                Two trials were conducted in North America. The North American Glycine Antagonist in Neuroprotection trial (GAIN 1) (GLYA2001; United States only) was designed as a sequential dose escalation study. GAIN 2 (GLYA2005; United States and Canada) was designed to further assess the safety of the highest dose tolerated in GAIN 1. Both trials were randomized (2:1), double-blind, and placebo controlled. Treatment was started within 12 hours of symptom onset; patients with both ischemic stroke and primary intracerebral hemorrhage were included in both trials.
                The dose escalation study (GAIN 1) completed 3 dosing tiers. Enrollment was suspended before escalation to the fourth tier because of laboratory reports of transiently elevated bilirubin levels in a concurrent European study that employed the dose targeted for this tier. After review by an independent safety committee of the worldwide safety data, the second study (GAIN 2) commenced. One hundred nine patients were randomized and dosed with study drug, either an 800-mg loading dose followed by 200 mg every 12 hours for 3 days of GV150526 or placebo. The incidence of serious adverse events was similar in the drug and placebo groups. Mild irritation at the infusion site and symptoms suggestive of mild and reversible altered mentation were reported more frequently in the GV150526 group than in the placebo group. Hyperbilirubinemia was reported in 6% of GV150526-treated patients compared with 3% of placebo-treated patients. Outcome at 4 weeks after stroke was better in GV150526-treated patients, but the studies were not powered to show statistical significance, and the baseline neurological deficits in the GV150526-treated patients were less severe.
                These preliminary studies suggest that GV150526 is well tolerated by patients with suspected acute stroke. Further pivotal studies testing the efficacy and safety of GV150526 in acute stroke are ongoing. Aptiganel (CNS 1102) is a selective, noncompetitive antagonist that acts on the ion channel associated with the N-methyl-D-aspartate (NMDA) receptor and is neuroprotective in experimental focal cerebral ischemia models at a plasma concentration of 10 ng/mL. In human volunteers, dose-limiting effects of aptiganel are blood pressure increases and central nervous system (CNS) excitation or depression. This study assessed the safety and tolerability of non-weight-adjusted doses of aptiganel in patients with acute ischemic stroke.
                This was a double-blind, randomized, placebo-controlled multicenter study in patients presenting within 24 hours of acute ischemic stroke. Ascending single intravenous bolus doses of aptiganel (3, 4.5, 6, and 7.5 mg) were assessed in 21 patients with a 3:1 active drug:placebo randomization schedule. In 15 subsequent patients, selected bolus doses were followed by constant intravenous infusion for 6 to 12 hours (6 mg plus 1 mg/h, n=10; then 4.5 mg plus 0.75 mg/h, n=15) in a 4:1 randomization schedule. Prospectively collected pharmacokinetic data guided selection of infusion rates. Neurological and functional status were recorded at entry and after 1 week, although the study was not designed to test efficacy.
                Forty-six patients were randomized from 4 centers (3 in the United States and 1 in the United Kingdom): 36 received aptiganel HCl, and 10 were given placebo. Hypertension and CNS events were commonly reported after a bolus dose of 7.5 mg and after a 6-mg bolus followed by an infusion of 1 mg/h. The lower regimen of 4.5-mg bolus followed by infusion of 0.75 mg/h achieved plasma aptiganel concentrations of >10 ng/mL and was well tolerated by patients but still raised systolic blood pressure by approximately 30 mm Hg over baseline.
                A 4.5-mg intravenous bolus of aptiganel HCl followed by infusion of 0.75 mg/h for 12 hours is a tolerable dose that can produce plasma drug concentrations shown to be neuroprotective in animal models. However, increases in systolic blood pressure and an excess of CNS effects were both observed at this dose. Tissue plasminogen activator is the only thrombolytic agent approved in the United States for treatment of acute ischemic stroke, and has limitations. Aptiganel hydrochloride is a novel and selective ligand for the ion-channel site of the N-methyl-D-aspartate receptor-channel complex and a promising neuroprotective agent in animal models of focal brain ischemia.
                To determine whether aptiganel improves the clinical outcome for acute ischemic stroke patients.
                Nested phase 2/phase 3 randomized controlled trial conducted between July 1996 and September 1997.
                One hundred fifty-six medical centers in the United States, Canada, Australia, South Africa, England, and Scotland.
                A total of 628 patients with hemispheric ischemic stroke (50.3% male; mean age, 71.5 years).
                Patients were randomly assigned within 6 hours of stroke to receive 1 of 3 treatment regimens: high-dose aptiganel (5-mg bolus followed by 0.75 mg/h for 12 hours; n = 214); low-dose aptiganel (3-mg bolus followed by 0.5 mg/h for 12 hours; n = 200); or placebo (n = 214).
                The primary efficacy end point was the Modified Rankin Scale score at 90 days after stroke onset. Secondary end points included mortality and change in National Institutes of Health (NIH) Stroke Scale score at 7 days after stroke.
                The trial was suspended by the sponsor and the independent data and safety monitoring board because of both a lack of efficacy and a potential imbalance in mortality. There was no improvement in outcome for either aptiganel (low-dose or high-dose) group compared with the placebo group at 90 days (median Modified Rankin Scale score for all 3 treatment groups = 3; P =.31). At 7 days, placebo-treated patients exhibited slightly greater neurological improvement on the NIH Stroke Scale than high-dose aptiganel patients (mean improvement for placebo group, -0.8 points vs for high-dose aptiganel, 0.9 points; P =.04). The mortality rate at 120 days in patients treated with high-dose aptiganel was higher than that in patients who received placebo (26.3% vs 19.2%; P =.06). Mortality in the low-dose aptiganel group was 22.5% (P =.39 vs placebo).
                Aptiganel was not efficacious in patients with acute ischemic stroke at either of the tested doses, and m ay be harmful. The larger proportion of patients with favorable outcomes and lower mortality rate in the placebo group suggest that glutamate blockade with aptiganel may have detrimental effects in an undifferentiated population of stroke patients. 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.
                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.
                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).
                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. The cardiovascular safety of lubeluzole was evaluated in patients with ischemic stroke in a double-blind, placebo-controlled trial. Forty-six patients were randomized to receive a continuous daily infusion of lubeluzole 5 mg (loading dose 3.75 mg over 1 h), lubeluzole 10 mg (loading dose 7.5 mg over 1 h), or placebo for 5 days within 24 h of stroke onset. The primary measure of cardiovascular safety was the QTc interval, derived from the continuous electrocardiogram (ECG) and measured during treatment and a 2-day follow-up. Compared with placebo. Neither dosage of lubeluzole had any statistically or clinically relevant effects on the QTc. Neither were there any significant differences among the three treatment groups in the area under the curve for heart rate, QT interval, QT dispersion, or QTlc. Lubeluzole did not increase the frequency of ECG abnormalities. No ventricular fibrillation, ventricular tachycardia, or torsades de pointes were observed in any of the treatment groups. During this trial, 3 patients in the placebo group and 2 patients in the lubeluzole 5-mg group died. There were no deaths in the lubeluzole 10-mg group. Adverse experiences were similar in all three treatment groups except that superficial thrombophlebitis was more frequent in the lubeluzole 10-mg group. In doses to 10 mg/day, lubeluzole has a favorable cardiovascular safety profile, as demonstrated by the lack of clinically relevant effects on heart rate, QT, QTc, and QTlc, and it was well tolerated by patients with ischemic stroke. 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. CGS 19755 is a competitive N-methyl-D-aspartate (NMDA) receptor antagonist that limits neuronal damage in animal stroke models. The objectives of this multicenter (7 centers), randomized, double-blind, placebo-controlled, ascending-dose phase IIa study were to evaluate the safety and tolerability of CGS 19755 and obtain pharmacokinetic and preliminary data on its efficacious dose range in patients treated within 12 hours of hemispheric ischemic stroke.
                At each dose level, 6 patients were randomized to one or two intravenous bolus doses of CGS 19755, and 2 patients were randomized to placebo. An unblinded safety and monitoring committee-evaluated results at each dose before ascending to the next level. All patients at the first level (1 mg/kg) received two doses separated by 12 hours. The first 2 patients at 2 mg/kg received two doses, but adverse experiences occurred in both; subsequent patient groups received single doses of 2.0, 1.75, or 1.5 mg/kg.
                Adverse experiences (agitation, hallucinations, confusion, paranoia, and delirium) occurred in all 6 patients treated with 2 mg/kg, and in 3 of 5 at 1.75 mg/kg. Similar but milder adverse experiences were noted in 4 of 7 patients at 1.5 mg/kg and 1 of 6 patients at 1.0 mg/kg. Adverse experiences began between 20 minutes and 22 hours (mean, 8 hours) after treatment and lasted 2 to 60 hours (mean, 24 hours). Mortality was 1 of 8 in patients receiving placebo and 3 of 24 in treated patients. In treated survivors, median and mean percent improvement in National Institutes of Health Stroke Scale scores from baseline to terminal visit (mean, 86 days) was comparable at all doses, and 95% of treated patients had Barthel Index scores of > or = 70 at the terminal visit.
                We conclude that a single intravenous dose of 1.5 mg/kg CGS 19755 is safe and tolerable in patients with acute ischemic stroke. An efficacy trial is indicated. Licostinel (ACEA 1021; 5-nitro-6, 7-dichloro-2,3-quinoxalinedione), a competitive antagonist of glycine at the N-methyl-D-aspartate (NMDA) receptor, is an effective neuroprotective agent in animal models of cerebral ischemia. The purpose of this study was to assess the safety, tolerability, and pharmacokinetics of licostinel in patients with acute stroke.
                In this 5-center dose escalation trial, patients were enrolled within 48 hours of an ischemic stroke and treated with ascending doses of a short infusion of licostinel or a placebo. Adverse effects were assessed with clinical and laboratory measurements, and patient outcome was determined with the National Institutes of Health Stroke Scale.
                Sixty-four patients (44 treated with escalating doses of licostinel and 20 who received placebo) were treated. Lower doses of licostinel (0.03 to 0.60 mg/kg) were not associated with any significant adverse effects. Higher doses of licostinel (1.2 to 3.0 mg/kg) were associated with a variety of mild-to-moderate adverse effects including neurological and gastrointestinal complaints. No major psychotomimetic effects or significant safety concerns occurred. At the higher dose levels, peak plasma concentrations of licostinel were substantially higher than those required for neuroprotection in animal stroke models. A similar improvement in National Institutes of Health Stroke Scale scores over time was seen in both the placebo group and the licostinel-treated patients.
                A short infusion of licostinel in doses up to 3.0 mg/kg is safe and tolerable in acute stroke patients. Licostinel may be a safer and better tolerated neuroprotective agent than many of the previously evaluated NMDA antagonists. Dextrorphan hydrochloride is a noncompetitive N-methyl-D-aspartate antagonist that is neuroprotective in experimental models of focal brain ischemia. The purpose of this study was to determine the maximum loading dose and maintenance infusion of dextrorphan hydrochloride that are well tolerated in patients with an acute stroke.
                An intravenous infusion of dextrorphan or placebo was begun within 48 hours of onset of a mild-to-moderate hemispheric stroke. Initially, patients were treated with either placebo (n = 15) or dextrorphan (n = 22) using a 1-hour loading dose (60 to 150 mg) followed by a 23-hour ascending-dose maintenance infusion (maximum total dose, 3310 mg). Subsequently, 29 patients were treated with dextrorphan in an open trial using a 1-hour loading dose (145 to 260 mg) followed by an 11-hour constant rate (30 to 70 mg/h) infusion.
                Transient and reversible adverse effects, including nystagmus, nausea, vomiting, somnolence, hallucinations, and agitation, commonly occurred in dextrorphan-treated patients. Loading-dose escalation was stopped because of rapid-onset, reversible, symptomatic hypotension in 7 of 21 patients treated with doses of 200 to 260 mg/h. At the highest rates of maintenance infusion (> 90 mg/h), 3 patients developed deep stupor or apnea. The maximum tolerated loading dose was 180 mg/h, and the maximum tolerated maintenance infusion was 70 mg/h. Maximum plasma levels of 750 to 1000 ng/mL were obtained in 9 patients. There was no difference in neurological outcome at 48 hours between the dextrorphan-treated and placebo-treated patients.
                The highest doses of dextrorphan administered were associated with serious adverse experiences in some patients. Lower doses (loading doses of 145 to 180 mg, maintenance infusions of 50 to 70 mg/h) were better tolerated and rapidly produced potentially neuroprotective plasma concentrations of dextrorphan. These doses were associated with well-defined pharmacological effects compatible with N-methyl-D-aspartate receptor antagonism. Elucidation of the ischemic cascade has helped stimulate development of neuroprotective drugs aimed at limiting brain injury in the hours following an ischemic stroke. To date, none of these drugs has shown clinical efficacy.
                To examine the efficacy of gavestinel (GV150526), an antagonist of the glycine site of the N-methyl-D-aspartate receptor, as a neuroprotective therapy for acute ischemic stroke when administered within 6 hours of symptom onset.
                The Glycine Antagonist in Neuroprotection (GAIN) Americas trial, a randomized, double-blind placebo-controlled trial with enrollment from April 1998 to October 1999.
                One hundred thirty-two hospital centers across the United States and Canada.
                The primary efficacy population consisted of 1367 ischemic stroke patients with a predefined level of limb weakness and functional independence prior to stroke, stratified at randomization by age (</=75 vs >75 years) and initial stroke severity (National Institutes of Health [NIH] Stroke Scale scores of 2-5, 6-13, or >/=14).
                Patients were randomly assigned to receive an intravenous loading dose (800 mg) plus 5 maintenance doses (200 mg every 12 hours) of gavestinel (n = 701) or placebo (n = 666) for 3 days.
                Functional capability at 3 months, measured by the Barthel Index (BI), with scores trichotomized as dead/0-55, 60-90, and 95-100, compared between the gavestinel and placebo groups.
                Treatment groups were well matched for baseline characteristics. For each group, median NIH Stroke Scale was 12, median age was 72 years, and median time to treatment was 5.2 hours. No statistically significant improvement on the 3-month BI trichotomy was demonstrated for gavestinel (P =.79). The proportion who were functionally independent (BI score = 95-100) was 39% in the gavestinel group and 37% in the placebo group. No statistically significant difference in 3-month survival was observed using Kaplan-Meier curves (P =.11). No other secondary end point suggested an advantage for gavestinel. Among the 333 patients (24%) who received recombinant tissue-type plasminogen activator, there was also no benefit for gavestinel (P =.53). There were no serious safety issues.
                In this study, gavestinel administered up to 6 hours after an acute ischemic stroke did not improve functional outcome at 3 months. 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. 1. This was a multi-centre, placebo controlled, randomized, dose-escalating design study in which five dosing regimens of 619C89/placebo were evaluated in 48 stroke patients. Loading infusions of 0.5, 1, 1.5, 2 and 2.5 mg kg-1 over 1 h were followed by respective maintenance infusions of 0.25, 0.5, 0.75, 1 and 1.25 mg kg-1 over 30 min at 8 hourly intervals for 3 days. 2. Plasma concentrations of 619C89 and its N-oxide, 341C90, and N-demethylated, 78C90, metabolites were assayed using an LC-MS-MS method. Plasma concentration-time profiles after the final maintenance infusion were subjected to conventional noncompartmental pharmacokinetic analysis. 3. For 619C89, geometric CL means ranged between 0.71 and 0.99 1 h-1 kg-1 for maintenance infusions up to 1.25 mg kg-1 over 30 min, with an overall mean of 0.85 l h-1 kg-1 (95% CI: 0.70-1.04 l h-1 kg-1). Geometric Vss means ranged between 13.2 and 27.9 l kg-1 for the same doses, with an overall mean of 22.5 l kg-1 (95% CI: 16.4-30.9 l kg-1). The ANOVA results revealed that neither CL, Vss nor t1/2 were significantly different across the five dosing regimens (P values: 0.82, 0.54 and 0.61, respectively). 4. Average AUC for 341C90 was 270% and that for 78C90 was 62% of the AUC for 619C89. The AUCm/AUCp-ratios were similar at all dose levels for each metabolite. Values of t 1/2 for 341C90 were similar to those of 619C89 whereas t1/2 for 78C90 was about three-fold longer than that of parent drug. 5. In conclusion, the pharmacokinetics of 619C89 are independent of dose in acute stroke patients. The pharmacokinetics of 341C90 are probably formation rate-limited and those of 78C90 are elimination rate-limited and are also dose-independent. nan Parenterally administered MgSO4 is neuroprotective in standard animal models of focal cerebral ischemia and in many other paradigms of brain injury. Previous small clinical trials in stroke patients have explored the safety and tolerability of different infusion regimens. This study was undertaken to optimize the regimen for a multicenter trial.
                Within 24 hours of the onset of clinically diagnosed stroke, patients were randomized to receive placebo or one of three intravenous MgSO4 infusions: a loading infusion of 8, 12, or 16 mmol, followed by 65 mmol over 24 hours. Cardiovascular parameters, serum magnesium concentrations, and blood glucose concentrations were determined. Outcome at 30 and 90 days was recorded.
                Twenty-five patients were recruited and treated at a mean time of 20 hours after stroke. No tolerability problems were identified. No effects of magnesium on heart rate, blood pressure, or blood glucose were evident. Serum magnesium concentrations rose to target levels most rapidly in the highest loading infusion group and were maintained in all groups for at least 24 hours.
                MgSO4 infusions that rapidly elevate the serum magnesium concentration to potentially therapeutic levels are well tolerated and have no major hemodynamic effects in patients with acute stroke. The 16-mmol loading infusion achieved target serum concentrations most rapidly and has been chosen for further trials. AR-R15896AR is a use-dependent, low-affinity blocker of the NMDA ion channel with neuroprotective effects in animal models of focal cerebral ischemia. This study aimed to establish the highest safe and tolerated loading and maintenance dosing regimen of AR-R15896AR in acute ischemic stroke patients and to determine the associated plasma concentrations of AR-R15896AR.
                This was a 4-part, multicenter, randomized, double-blind, placebo-controlled study in 175 patients (mean age, 69 years) within 24 hours of acute stroke symptom recognition. Ascending 60-minute intravenous infusion loading doses of AR-R15896AR were initially examined (100, 150, 200, 250, or 300 mg or placebo in 3:1 randomization, n=36 treated); in part 2, 250, 275, or 300 mg was compared with placebo (n=33). In part 3, a 250-mg loading dose was followed by 9 maintenance doses of 60, 75, 90, 105, or 120 mg every 8 hours versus placebo in 3:1 randomization (n=59); subsequently, in part 4, maintenance doses of 90, 105, and 120 mg after the 250-mg loading dose were directly randomized against placebo (n=42). Safety, tolerability, and pharmacokinetics were the primary end points; NIHSS at 1 week and Barthel and modified Rankin scores at 1 month were also recorded, but the study was neither designed nor powered to assess efficacy.
                Rates for mortality and serious adverse events (SAE) were similar in active and placebo groups (9% mortality and 23% SAE for all active combined versus 11% mortality and 33% SAE for placebo). Adverse events associated with AR-R15896AR were dizziness, vomiting, nausea, stupor, and some agitation/hallucination. Withdrawal from treatment occurred only in response to loading doses with AR-R15896AR: placebo, 3 of 46 (7%); 250 mg, 11 of 89 (12%); 275 mg, 1 of 8 (12.5%); and 300 mg, 3 of 15 (20%). No significant difference in outcome was observed between groups. Plasma concentrations of AR-R15896AR were 1524+/-536 ng/mL at the end of the 250-mg loading infusion and were 1847+/-478 ng/mL at steady state after the 9 maintenance doses of 120 mg.
                The maximum tolerated loading infusion of AR-R15896AR in this study was 250 mg over a period of 1 hour. Subsequent maintenance infusions of 120 mg every 8 hours were well tolerated. With these doses, putative neuroprotective concentrations of 1240 ng/mL are attained by the loading dose and are satisfactorily maintained thereafter. The loading dose may be improved further by adjustment on an individual patient basis, but tolerability issues remain. The sodium channel blocker sipatrigine (619C89) prevents ischemia-induced glutamate release and is neuroprotective in animal models of stroke. Previous clinical experience found neuropsychiatric effects attributed to sipatrigine that may have been related to peak plasma concentrations of the drug.
                Patients within 12 h of clinically diagnosed stroke were randomized to placebo or sipatrigine at total doses of 10, 18, 27, or 36 mg/kg by continuous intravenous infusion over 65 h. Pharmacokinetic and routine laboratory analyses were undertaken. The outcome at 30 days or 3 months was assessed by Barthel and Rankin scores.
                Twenty-seven patients were recruited: 7 of 21 patients stopped the sipatrigine infusion early due to adverse events as compared with none of 6 placebo patients. Neuropsychiatric effects (reduced consciousness, agitation, confusion, visual perceptual disturbance, or frank hallucinations) occurred in 16 of 21 patients receiving sipatrigine and in no placebo patients. Nausea, vomiting, infusion site reactions, and hyponatremia were also commoner in sipatrigine patients. Pharmacokinetic parameters were similar to those observed previously. No effects on outcome measures were demonstrated.
                Continuous infusion of sipatrigine is associated with neuropsychiatric effects. No difference in the nature of these events was evident between this regimen and repeated short infusions, but it was possible to administer higher doses.
                Copyright 2000 S. Karger AG, Basel
There was no evidence of significant benefit or harm from drugs modulating excitatory amino acid action. Reduction of death or dependence by 8% or more has been excluded for gavestinel and lubeluzole, which contribute most of the data for this review. However, mechanistic understanding of neuroprotection is too poor to extrapolate from these two failed development plans to all glutamate modulators. Further clinical trials of neuroprotective agents remain justified, since confidence limits around estimates of effect remain wide for most agents, and cannot reliably exclude benefit. Although numbers of patients are too small to confirm or refute a trend towards increased mortality with some NMDA antagonists, further commercial development of these agents is exceedingly unlikely.