Keith W. Muir

Clinical Experience With Excitatory Amino Acid Antagonist Drugs

BACKGROUND Excitotoxic damage due to excess release of neuronal glutamate is hypothesized to play a pivotal role in the pathogenesis of focal cerebral ischemia. Drugs that antagonize excitatory amino acid function are consistently neuroprotective in preclinical models of stroke, and many are now entering clinical trials. SUMMARY Antagonists of the N-methyl-D-aspartate (NMDA) receptor are furthest advanced in clinical development for stroke. Both noncompetitive (aptiganel hydrochloride, dextrorphan) and competitive (selfotel, d-CPPene) antagonists have undergone tolerability studies in acute stroke and traumatic brain injury. These agents all cause a similar spectrum of neuropsychological symptoms, and several have important cardiovascular effects. Other modulatory sites on the NMDA receptor complex, notably the polyamine and magnesium ion sites, are also the subject of clinical trials. Glycine site antagonists are in early clinical development. Non-NMDA glutamate receptor antagonists remain in preclinical study. Neuroprotection by agents that block glutamate release in vitro may be due to sodium channel blockade in vivo, but some agents (619C89) exhibit neurological effects similar to NMDA antagonists in stroke. The therapeutic index is unknown for different drugs but may be determined by cardiovascular effects, especially hypotension, which may be detrimental after stroke. CONCLUSIONS Excitatory amino acid antagonists are in advanced development in the treatment of stroke and traumatic brain injury. A similar pattern of side effects is apparent with the majority of agents. However, cardiovascular effects may ultimately define therapeutic index for each drug.

A Randomized, Double-Blind, Placebo-Controlled Pilot Trial of Intravenous Magnesium Sulfate in Acute Stroke

BACKGROUND AND PURPOSE Magnesium ions act as endogenous vasodilators of the cerebral circulation and act pharmacologically as noncompetitive antagonists of the N-methyl-D-aspartate receptor by virtue of their role as endogenous voltage-sensitive blockers of the ion channel. The preclinical efficacy of magnesium has been demonstrated in standard models of stroke. METHODS Sixty patients were randomized to magnesium sulfate (8 mmol IV over 15 minutes and 65 mmol over 24 hours) or placebo within 12 hours of clinically diagnosed middle cerebral artery stroke. Pulse, blood pressure, and serum magnesium levels were monitored. Primary outcome was death or significant functional impairment (Barthel Index score < 60) at 3 months. RESULTS Magnesium was well tolerated, with no significant adverse effects and no change in blood pressure or pulse rate. Laboratory and electrocardiographic variables did not differ significantly between placebo- and magnesium-treated groups. Serum magnesium rose from 0.76 mmol/L to 1.42 mmol/L over 24 hours and remained significantly higher than in the placebo group at 48 hours. Thirty percent of magnesium-treated and 40% of placebo-treated patients were dead or disabled (Barthel Index score < 60) at 3 months (P = .42). There was a decrease in the number of early deaths in the magnesium-treated group (P = .066, log-rank test). CONCLUSIONS Magnesium sulfate is well tolerated after acute stroke and has no deleterious hemodynamic effects at this dose. Further trials are required to determine efficacy.

Dose Optimization of Intravenous Magnesium Sulfate After Acute Stroke

BACKGROUND AND PURPOSE 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

Phase II Clinical Trial of Sipatrigine (619C89) by Continuous Infusion in Acute Stroke

Background: 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. Methods: 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. Results: 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. Conclusions: 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.

Perihematomal Edema and Functional Outcomes in Intracerebral Hemorrhage Influence of Hematoma Volume and Location

Background and Purpose— Perihematomal edema (PHE) is associated with poor outcomes after intracerebral hemorrhage (ICH). PHE evolves in the early period after ICH, providing a therapeutic target and window for intervention. We studied the effect of PHE volume expansion in the first 72 hours (iPHE) and its relationship with functional outcomes. Methods— We used data contained in the Virtual International Stroke Trials Archive. We included patients who presented within 6 hours of symptom onset, had baseline clinical, radiological, and laboratory data, and further computed tomographic scan data at 72 hours and 90-day functional outcomes. We calculated iPHE and used logistic regression analysis to assess relationships with outcome. We adjusted for confounding variables and the primary outcome measure poor day-90 outcome (defined as modified Rankin Scale score of ≥3. We performed subgroup analyses by location and by volume of ICH. Results— We included 596 patients with ICH. Median baseline hematoma volume was 15.0 mL (IQR, 7.9–29.2) and median baseline PHE volume was 8.7 mL (IQR, 4.5–15.5). Hematoma expansion occurred in 122 (34.9%) patients. Median iPHE was 14.7 mL (IQR, 6.6–30.3). The odds of a poor outcome were greater with increasing iPHE (OR, 1.78; CI, 1.12–2.64 per mL increase). Subgroup analyses showed that iPHE was only related to poor functional outcomes in basal ganglia and small (<30 mL) ICH. Conclusions— Absolute increase in PHE during 72 hours was associated with worse functional outcomes after ICH, particularly with basal ganglia ICH and hematomas <30 mL.

Safety and Tolerability of 619C89 after Acute Stroke

Background: 619C89 is a use-dependent sodium channel blocker which reduces hemispheric infarction volume by up to 60% after permanent middle cerebral artery occlusion in rats. Intravenous doses of up to 1 mg/kg have been well tolerated by healthy young and elderly volunteers. This study sought to assess safety and tolerability of 619C89 in the treatment of acute stroke. Methods: Patients were randomised within 12 h of onset of stroke to receive 619C89 or placebo as an intravenous loading dose, followed by maintenance doses given 8 hourly for 64 h in a double-blind, ascending-dose tolerance study. Dosing commenced at 0.5 mg/kg loading plus 0.25 mg/kg/8 h maintenance for the first group and increased in increments of 0.5 mg/kg loading +0.25 mg/kg/8 h maintenance thereafter. Safety evaluation was continued for 3 months. Results: 48 patients were recruited. 12 received placebo and 36 received 619C89 in doses up to 2.5 mg/kg loading plus 1.25 mg/kg/8 h. Dose escalation was stopped after the occurrence of hallucinations in 5 of 18 patients who received 2 mg/kg +1 mg/kg/8 h or more. Gastro-intestinal upset and confusion were also possibly drug related. No drug-related effects on cardiovascular function were found. Conclusions: 619C89 was associated with significant central nervous system side-effects at doses of 2 mg/kg +1 mg/kg/8 h or greater as discrete intravenous infusions within 12 h of stroke onset. It may also cause gastro-intestinal side-effects. Doses below this are well tolerated in patients. No adverse cardiovascular effects were seen.

Interconversion of Stroke Scales Implications for Therapeutic Trials

Background and Purpose Stroke scales are intended to measure stroke severity for the purpose of clinical trials. Scores have been used to determine trial entry, to compare patient groups within or between trials, or as a secondary end point. The use of scores as an end point in meta‐analysis has not been validated, but such analyses have nevertheless been performed when equivocal results have been obtained using the main outcome measure. The different scale designs suggest that conversion of scores may not be possible. We sought to determine whether scores on different scales could be interconverted. Methods A single observer scored 433 consecutive admissions to an acute stroke unit on the Canadian Neurological Scale, the middle cerebral artery Neurological Score (or Orgogozo scale), and the National Institutes of Health stroke scale. Data were separated into training and test sets, and linear regression was used to model conversion between scales. Prediction errors were calculated. Strokes were subdivided according to the Oxfordshire Community Stroke Project classification, and coefficients of determination were calculated for different subtypes. Results Conversion between Canadian and middle cerebral artery Neurological scales was satisfactory (R2=94.7%), and prediction errors were acceptable (absolute prediction error, 5.0±5). Conversion from the National Institutes of Health scale was worse (R2=87.5% to Canadian and 89.0% to Neurological Score), and prediction errors were significantly greater (Neurological Score error, 8.7±7; Canadian Neurological Scale error, 8.5±7.3; P<.005 for both). Coefficients of determination for interconversion were significantly worse for dysphasic patients with total anterior circulation strokes than for other stroke types (P<.01). Reweighting the motor component of the National Institutes of Health scale improved coefficients of determination and reduced prediction errors, but prediction error for conversion to the Canadian scale remained significantly greater than other conversions (P=.001). Conclusions The Canadian Neurological Scale and the middle cerebral artery Neurological Score may reliably be converted. The National Institutes of Health scale cannot be used to predict these scores reliably, even with reweighting of the motor score. Interconversion is poorest for patients with dysphasia and total anterior circulation strokes. These results suggest that there will be more general difficulty in interconverting scales that use different test items and weighting. Meta‐analysis using sequential changes in averaged scores from various stroke scales is not valid. (Stroke. 1994;25:1366‐1370.)

National Institutes of Health Stroke Scale Item Profiles as Predictor of Patient Outcome External Validation on Independent Trial Data

Background and Purpose— National Institutes of Health Stroke Scale (NIHSS) item profiles that were recently proposed may prove useful both clinically and for research studies. We aimed to validate the NIHSS item profiles in an acute cohort. Methods— We conducted a retrospective analysis on pooled data from randomized clinical trials. We applied the latent class analysis probabilities of profile membership developed from the derivation study to obtain symptom grouping, a-NIHSS item profiles. We implemented an independent latent class analysis to derive secondary symptom grouping, b-NIHSS item profiles. Validation was performed by assessing the associations with outcomes and evaluating both sets of NIHSS item profiles’ discrimination and calibration to the data. The outcomes evaluated included modified Rankin Scale (mRS; using the full distribution and dichotomized, mRS, 0–1) at day 90 and mortality by 90 days. Results— We identified 10 271 patients. Ordinal analysis of mRS confirmed increased odds of better outcome across the profiles in a stepwise manner, adjusted for age and thrombolysis treatment, for each set of NIHSS item profiles. Similar patterns were observed for mRS 0 to 1, and inverse patterns were seen for mortality. The c-statistics of a-NIHSS and b-NIHSS item profiles for mRS 0 to 1 were similar at 0.71 (95% confidence interval, 0.70–0.72) and for mortality, 0.74 (0.73–0.75) and 0.75 (0.73–0.76), respectively. Calibration was good. Conclusions— These NIHSS item profiles identified using latent class analysis offer a reliable approach to capture the true response patterns that are associated with functional and outcome and mortality post stroke. This approach has the potential to enhance the clinical value of the overall NIHSS score.

Clinical Pharmacology of CNS 1102 in Volunteers

The high affinity noncompetitive N-methyl-D-aspartate receptor antagonist CNS 1102 (aptiganel hydrochloride, Cambridge NeuroScience, Cambridge, MA.) is neuroprotective in preclinical models of stroke when administered as pretreatment or up to 60 minutes postischemia, and has potential for treatment of acute stroke or traumatic brain injury in man. A total of 55 healthy male subjects have participated in three separate studies to determine the clinical pharmacology of CNS 1102, 43 of whom have received CNS 1102 in doses of up to 100 micrograms/kg. Administration of CNS 1102 has been studied as a 15-minute intravenous infusion, as a 15-minute loading intravenous infusion followed by a 4-hour maintenance infusion, or as a fixed-dose intravenous bolus over 90 seconds. CNS 1102 in normal volunteers is well tolerated in total doses up to 32 micrograms/kg whether as a bolus injection, 15-minute infusion or 4-hour infusion. Central nervous system affects are evident within minutes of administration, implying rapid drug penetration. CNS 1102 has a large and variable volume of distribution (mean +/- standard deviation, 6.2 +/- 1.9 l/kg), variable clearance (115 +/- 77 l/h), and plasma half-life of approximately 4.5 hours. Adjustment of doses by subject weight does not improve variability of these parameters, and fixed doses may thus be administered. CNS 1102 causes dose-dependent elevation of blood pressure, accompanied by clinical evidence of vasoconstriction. Global cerebral blood flow is maintained, whilst middle cerebral artery flow velocity increases. Symptoms of light-headedness, disorientation and paresthesia progress through euphoria, disinhibition, and hallucinations to psychomotor retardation, paranoia and catatonia as total administered dose increases.

Clinical Aspects of Stroke and Therapeutic Strategies

“Stroke” is defined by the World Health Organization as “rapidly developing clinical signs of focal (or global) disturbance of cerebral function, with symptoms lasting 24 h or longer or leading to death, with no apparent cause other than of vascular origin.” Ultimately, stroke results from the death of neurons in the central nervous system (CNS), and improved understanding of the pathological processes that mediate neuronal death at the cellular and neurochemical level has led to the development of therapeutic strategies that promise to improve the outcome after acute stroke. Many pathological processes may cause stroke, and many disease processes may mimic stroke. Advances in the therapeutic possibilities in stroke require physicians and clinical trialists alike to appreciate the clinical spectrum of stroke disease, and the problems that are peculiar to it.