Tomas Odergren

Animal models of stroke: do they have value for discovering neuroprotective agents?

There has been a series of high-profile failures of drugs in clinical trials of acute ischaemic stroke that were designed to meet criteria necessary for drug regulatory approval. This has, again, called into question the value of animal models for identifying effective neuroprotective agents. Here, we review evidence that physiological changes (reperfusion, hyperglycaemia, hypothermia and blood pressure) produce comparable changes in outcome in both animal models and human stroke patients, which indicates that the models should identify clinically effective neuroprotective agents. We suggest that most clinical failures have occurred because compounds were administered differently in animal and clinical studies. We review earlier guidelines on the information that is necessary from preclinical studies before a compound enters clinical trials, and propose modifications to these guidelines.

Early impairment in consciousness predicts mortality after hemispheric ischemic stroke.

ObjectiveEarly predictors of poor outcome after acute ischemic stroke may be useful in selecting patients for potentially beneficial but high-risk interventions. DesignCohort study of patients given placebo in a randomized clinical trial. SettingMulticenter trial at 139 U.S. and 14 Canadian hospitals. PatientsA cohort of 564 placebo-treated patients with major anterior circulation ischemic stroke enrolled in the Clomethiazole in Acute Stroke Study-Ischemic Stroke (CLASS-I) trial. Patients did not have significant impairment in consciousness at baseline and were enrolled within 12 hrs of symptom onset. InterventionsProspective data collection of a number of clinical variables including use of a 6-point level of consciousness scale (1 = awake, 6 = no reaction to pain) to measure patients’ level of consciousness at enrollment and 12 additional times during the first 24 hrs after enrollment. The ability of level of consciousness score and additional clinical data to predict 30-day mortality was assessed. Measurements and Main ResultsAt 1 month, 114 of 564 patients (20%) had died. In univariate analysis, factors significantly associated with mortality included older age, white race, higher National Institutes of Health Stroke Scale score, higher serum glucose, atrial fibrillation, and any impairment in level of consciousness (p < .05). After controlling for these factors, increasing level of consciousness score at 3 hrs after enrollment and at all but one subsequent time point was significantly associated with increased mortality (odds ratio, 1.8 per point; 95% confidence interval, 1.2–2.6; p = .003 at 3-hr time point). Maximum level of consciousness score during the initial 24 hrs of monitoring also predicted mortality (odds ratio, 1.9 per point; 95% confidence interval, 1.4–2.5; p < .001). ConclusionThe development of a decreased level of consciousness within the initial hours after stroke onset, as evaluated by a simple six-point scale, is a powerful independent predictor of mortality after major anterior circulation ischemic stroke.

The clomethiazole acute stroke study in ischemic, hemorrhagic, and t-PA treated stroke: Design of a phase III trial in the united states and canada

Clomethiazole is a drug with sedative properties effective in laboratory studies of brain ischemia. A large European multicenter trial of clomethiazole in acute stroke patients showed no benefit overall, but subgroup analysis indicated that patients with large infarctions may have benefited from treatment. To confirm this preliminary finding, we have designed CLASS-IHT, the Clomethiazole for Acute Stroke Study in Ischemic, Hemorrhagic and TPA Treated Patients, to be conducted in North America. Patients who suffer large cerebral infarctions and present within 12 hours of symptom onset are eligible. Patients will be randomized to receive clomethiazole 68 mg/kg over 24 hours or vehicle, using a dosing scheme based on the pharmacokinetics measured in the first trial. Outcome assessments include stroke scales, the Barthel Index, and lesion volume. An additional study of health economic outcomes is planned. The primary endpoint for CLASS-I will be the Barthel Index 90 days after stroke. A total of 1,200 patients will be randomized to CLASS-I, and in safety-only trials, 200 patients with cerebral hemorrhage will be randomized into CLASS-H and another 100 to 200 patients will be randomized into CLASS-T. The details of the protocols for all three studies are presented.

Lack of hemispheric dominance for consciousness in acute ischaemic stroke

Background: Previous reports have suggested left hemispheric dominance for maintaining consciousness, although there is controversy over this claim. Objective: To compare early impairment of level of consciousness between patients with right and left hemispheric stroke. Methods: Data from 564 patients with ischaemic stroke enrolled in the placebo arm of a trial of a putative neuroprotectant were analysed. All patients had major hemispheric stroke with cortical dysfunction, visual field deficit, and limb weakness, with symptom onset within 12 hours of enrolment. Patients were prospectively evaluated on a predefined scale (1–6; 1 = fully awake, higher scores representing greater impairment) to measure level of consciousness at multiple time points over the initial 24 hours after presentation. The National Institutes of Health (NIH) stroke scale score at presentation and infarct volume at 30 days were determined. Results: Some degree of impairment in level of consciousness was observed in 409 of the 564 patients (73%). Median maximum sedation score was 2 for both right and left hemispheric stroke (p = 0.91). Mean sedation score over 24 hours was 1.5 for both right and left stroke (p = 0.75). There was no difference between level of consciousness scores in right and left stroke at any individual time point during the 24 hour monitoring period. No association between side and impairment in level of consciousness was seen after adjustment for stroke severity and infarct volume. Conclusions: In contrast to previous reports, there was no evidence for hemispheric dominance for consciousness in the setting of a major hemispheric stroke.

Population Pharmacokinetic Modelling and Estimation of Dosing Strategy for NXY-059, a Nitrone Being Developed for Stroke

Background and objectivesNXY-059 (disufenton sodium, Cerovive®), a nitrone with neuroprotective and free radical trapping properties (in experimental stroke) is under development for the treatment of acute stroke. The objectives of this study were to develop a population pharmacokinetic model for NXY-059 in acute stroke patients and to estimate individualised dosing strategies for NXY-059 using preclinical pharmacological and clinical pharmacokinetic information and knowledge of characteristics of the patient population.MethodsNXY-059 was given as a continuous intravenous infusion for 72 hours, including a 1-hour loading infusion. Maintenance infusion rates were individualised based on creatinine clearance (CLCR). Population pharmacokinetic models were derived using NONMEM software. Optimal dosing strategies, individualised based on CLCR or bodyweight, were estimated using the population pharmacokinetic models, empirical covariate distributions relevant for the target population, and a target definition. Dosing strategies were selected based on target fulfilment criteria and parsimony.PatientsPharmacokinetic data from 179 patients with acute ischaemic or haemorrhagic stroke, included in two clinical studies, were used for the analyses. Patients were aged 34–92 years with varying degrees of renal impairment (estimated CLCR 20–143 mL/min).Main outcome measures and resultsThe final population model based on data from both studies comprised a two-compartment model with unexplained interpatient variability for clearance (23% coefficient of variation [CV]) and central volume of distribution (40% CV). Part of the variability in clearance and volume of distribution was explained by CLCR and bodyweight, respectively. Typical clearance was estimated to 4.54 L/h in a patient with CLCR of 70 mL/min. The preferred dosing strategy for NXY-059 comprised an initial loading infusion (the same for all patients) followed by an individualised maintenance infusion on the basis of CLCR (three dosing categories) with cut-off values (at which infusion rates are incremented or decremented) of 50 and 80 mL/min.ConclusionThe results illustrate how an individualised dosing strategy, given a pharmacokinetic target, for NXY-059 was successfully optimised through estimation using the increasing pharmacokinetic and pharmacodynamic knowledge during a clinical drug development programme. The chosen dosing strategy of NXY-059 provides an easily adapted treatment regimen for acute stroke, resulting in early achievement of target plasma concentrations.

Response to Letter by Proctor and Tamborello

Response It is premature to comment on SAINT II before any manuscript is published. However, the suggestion that different products were used for the 2 SAINT trials can be discounted. Relevant knowledge contained in the patent application was applied identically to …