Biomedical subjects

Tim Ashwood

Publications and source records attributed to Tim Ashwood.

9 recordsLinked to original sources

PubMed2006

Additional outcomes and subgroup analyses of NXY-059 for acute ischemic stroke in the SAINT I trial.

BACKGROUND AND PURPOSE: NXY-059 is a free radical-trapping neuroprotectant demonstrated to reduce disability from ischemic stroke. We conducted analyses on additional end points and sensitivity analyses to confirm our findings. METHODS: We randomized 1722 patients with acute ischemic stroke to a 72-hour infusion of placebo or intravenous NXY-059 within 6 hours of stroke onset. The primary outcome was disability at 90 days, as measured by the modified Rankin Scale (mRS), a 6-point scale ranging from 0 (no residual symptoms) to 5 (bed-bound, requiring constant care). Additional and exploratory analyses included mRS at 7 and 30 days; subgroup interactions with final mRS; assessments of activities of daily living by Barthel index; and National Institutes of Health Stroke Scale (NIHSS) neurological scores at 7 and 90 days. RESULTS: NXY-059 significantly improved the distribution of the mRS disability score compared with placebo at 7, 30, and 90 days (Cochran-Mantel-Haenszel test P=0.002, 0.004, 0.038, respectively; 90-day common odds ratio 1.20; 95% CI, 1.01 to 1.42). The benefit was not attributable to any specific baseline characteristic, stratification variable or subgroup interaction. Neurological scores were improved at 7 days (odds ratio [OR], 1.46; 95% CI, 1.13, 1.89; P=0.003) and the Barthel index was improved at 7 and 30 days (OR, 1.55; 95% CI, 1.22, 1.98; P<0.0001; OR, 1.27; 95% CI, 1.01, 1.59; P=0.02). CONCLUSIONS: NXY-059 within 6 hours of acute ischemic stroke significantly reduced disability. Benefit on neurological scores and activities of daily living was detectable early but not significant at 90 days; however, our trial was underpowered to measure effects on the neurological examination. The benefit on disability is not confounded by interactions and is supported by other outcome measures.

Aged↗

PubMed2006

NXY-059 for acute ischemic stroke.

BACKGROUND: NXY-059 is a free-radical-trapping agent that is neuroprotective in animal models of stroke. We tested whether it would reduce disability in humans after acute ischemic stroke. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 1722 patients with acute ischemic stroke who were randomly assigned to receive a 72-hour infusion of placebo or intravenous NXY-059 within 6 hours after the onset of the stroke. The primary outcome was disability at 90 days, as measured according to scores on the modified Rankin scale for disability (range, 0 to 5, with 0 indicating no residual symptoms and 5 indicating bedbound, requiring constant care). RESULTS: Among the 1699 subjects included in the efficacy analysis, NXY-059 significantly improved the overall distribution of scores on the modified Rankin scale, as compared with placebo (P=0.038 by the Cochran-Mantel-Haenszel test). The common odds ratio for improvement across all categories of the scale was 1.20 (95 percent confidence interval, 1.01 to 1.42). Mortality and rates of serious and nonserious adverse events were each similar in the two groups. NXY-059 did not improve neurologic functioning as measured according to the National Institutes of Health Stroke Scale (NIHSS): the difference between the two groups in the change from baseline scores was 0.1 point (95 percent confidence interval, -1.4 to 1.1; P=0.86). Likewise, no improvement was observed according to the Barthel index (P=0.14). In a post hoc analysis of patients who also received alteplase, NXY-059 was associated with a lower incidence of any hemorrhagic transformation (P=0.001) and symptomatic intracranial hemorrhage (P=0.036). CONCLUSIONS: The administration of NXY-059 within six hours after the onset of acute ischemic stroke significantly improved the primary outcome (reduced disability at 90 days), but it did not significantly improve other outcome measures, including neurologic functioning as measured by the NIHSS score. Additional research is needed to confirm whether NXY-059 is beneficial in ischemic stroke. (ClinicalTrials.gov number, NCT00119626.).

Acute Disease↗

PubMed2006

Brain penetration of the novel free radical trapping neuroprotectant NXY-059 in rats subjected to permanent focal ischemia.

The penetration of the free radical trapping neuroprotectant NXY-059 into the brain has been examined in rats subjected to permanent middle cerebral artery occlusion (pMCAO). NXY-059 (125 mg/kg bolus followed by 125 mg/kg/h) was infused for 4 h 45 min starting 15 min after right pMCAO or sham operation. At 5 h, there was a similar plasma total NXY-059 concentration (micromol/L) in both groups [sham: 623 +/- 44 (6); pMCAO: 605 +/- 43 (5)] and a similar drug concentration (nmol/g) in the right cortex [sham: 6.92 +/- 1.05 (6); pMCAO: 6.14 +/- 2.18 (6)]. A subsequent experiment in normal rats, infusing NXY-059 at both a similar and higher concentration (252 mg/kg bolus and 252 mg/kg/h), demonstrated that the concentration of NXY-059 in cortex increased linearly with respect to the plasma concentration. These data demonstrate that NXY-059 does penetrate brain tissue in control animals and ischemic tissue of animals subjected to pMCAO.

Animals↗

PubMed2005

Free radical trapping as a therapeutic approach to neuroprotection in stroke: experimental and clinical studies with NXY-059 and free radical scavengers.

There is substantial experimental evidence that free radicals are produced in the brain during ischemia, during reperfusion and during intracranial hemorrhage. Removal of pathologically produced free radicals is therefore a viable approach to neuroprotection. Four compounds with free radical scavenging activity (tirilazad, ebselen, edaravone) or free radical trapping properties (NXY-059) have been examined in experimental models of stroke and evaluated clinically as neuroprotective agents. Both experimental and clinical results are reviewed in this article. Ebselen was a modestly effective neuroprotectant in a rat transient middle cerebral artery occlusion (MCAO) model when given before the start of ischemia, but not when the insult was severe. Data from the permanent MCAO model and an embolic stroke model suggested a bell shaped dose-response curve. The weak preclinical profile may explain the lack of success in clinical trials. Preclinical data on tirilazad in animal models of acute ischemic stroke are neither comprehensive nor consistent. There was little evidence of efficacy in permanent MCAO or when the drug was given several hours post-occlusion. This may explain the negative clinical trials as these did not target patients likely to reperfuse and treatment started several hours after stroke onset. While preclinical data on subarachnoid hemorrhage demonstrated an attenuation of vasospasm the clinical data were inconsistent. There is very limited published preclinical data on edaravone but it has been approved in Japan as a neuroprotectant for the treatment of stroke. Evidence is based on a single placebo controlled trial in a relatively small number of patients. The status of possible development of edaravone outside of Japan is not known. NXY-059 has been found to be a very effective agent in transient and permanent MCAO and thromboembolic models of acute ischemic stroke. Its preclinical development has been governed by adherence with the recommendations of the Stroke Therapy Academic Industry Roundtable (STAIR) group and is now being investigated in Phase III clinical trials using a therapeutic time window and plasma concentrations that are effective in rat and primate models of stroke.

Animals↗

PubMed2004

Factor analysis of the National Institutes of Health Stroke Scale in patients with large strokes.

BACKGROUND: The National Institutes of Health Stroke Scale (NIHSS) was created to detect treatment-related differences in clinical trials and was designed to measure right- and left-sided cerebral hemispheric function. OBJECTIVE: To validate the original design in patients with very large strokes. DESIGN: A previously published factor structure was fit to the data. Then, a new analysis was conducted to explore the underlying structure of the scale in this population. Finally, NIHSS scores and infarction volumes were compared. SETTING: The Clomethiazole for Acute Stroke Study-Ischemic, conducted in academic and community hospitals. PATIENTS: Individuals with acute stroke seen within 12 hours of onset. Of 1191 records available, 98% had complete NIHSS scores. MAIN OUTCOME MEASURE: Goodness-of-fit statistic (Bentler) for each factor solution. RESULTS: Two factors were found underlying the NIHSS, corresponding to the left and right hemispheres (goodness of fit = 0.97), using the previously published factor analysis. The new exploratory analysis also suggested 2 factors representing left and right brain function. The median (range) NIHSS scores were 15 (5-25) for right brain strokes and 19 (6-32) for left brain strokes (P<.001). The median (range) infarction volumes were 56.2 mL (0.1-381.5 mL) for right brain strokes and 37.8 mL (0.2-255.1 mL) for left brain strokes (P<.001). The correlation coefficient between NIHSS score and lesion volume was 0.37 (P<.001). CONCLUSIONS: The underlying structure of the NIHSS conforms to cerebral hemispheric lateralization, confirming previous findings in a new population of large hemispheric strokes. Left- brain strokes score 4 points higher on the NIHSS than right brain strokes of larger volume.

Acute Disease↗

PubMed2004

Early impairment in consciousness predicts mortality after hemispheric ischemic stroke.

OBJECTIVE: Early predictors of poor outcome after acute ischemic stroke may be useful in selecting patients for potentially beneficial but high-risk interventions. DESIGN: Cohort study of patients given placebo in a randomized clinical trial. SETTING: Multicenter trial at 139 U.S. and 14 Canadian hospitals. PATIENTS: A 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. INTERVENTIONS: Prospective 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 RESULTS: At 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). CONCLUSION: The 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.

Age Distribution↗

PubMed2003

Nitrones as neuroprotective agents in cerebral ischemia, with particular reference to NXY-059.

Stroke is a major clinical problem, and acute pharmacological intervention with neuroprotective agents has so far been unsuccessful. Recently, there has been considerable interest in the potential therapeutic benefit of nitrone-derived free radical trapping agents as neuroprotective agents. Nitrone compounds have been shown to be beneficial in animal models of various diseases, and the prototypic compound alpha-phenyl-N-tert-butylnitrone (PBN) has been extensively demonstrated to be neuroprotective in rat models of transient and permanent focal ischemia. The nitrone radical trapping agent disodium 2,4-disulfophenyl-N-tert-butylnitrone (NXY-059) has also been shown to be neuroprotective in these models. Furthermore, it has recently been shown to improve neurological function and reduce infarct volume in a primate model of permanent focal ischemia even when given 4 hr postocclusion. While radical trapping activity is demonstrable with NXY-059 and other nitrone compounds such as PBN, this activity is weak. Arguments for and against ascribing radical trapping as the therapeutic mechanism of action are discussed. This compound is well tolerated in human stroke patients and can be administered to produce plasma concentrations exceeding those effective in animal models; crucially, at the same time, it has also been shown to be effective in animal models. NXY-059 may thus be the first compound to be examined in stroke patients using drug exposure and time to treatment that have been shown to be effective in animal models of stroke.

Aged↗

PubMed2003

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.

Animals↗

PubMed2003

Population pharmacokinetics of clomethiazole and its effect on the natural course of sedation in acute stroke patients.

AIMS: This analysis was performed to investigate the population pharmacokinetics of clomethiazole and its effect on the natural course of sedation in acute stroke patients using a nonlinear mixed effects modelling approach. METHODS: One thousand five hundred and forty-six acute stroke patients (774 on active treatment) from 166 centres were included in three randomized, double-blind, placebo-controlled phase III efficacy and safety studies. A total dose of 68 mg kg(-1) clomethiazole edisilate was given as a three-phase i.v.-infusion over 24 h. Three blood samples were drawn from all patients to characterize the pharmacokinetics. Sedation was monitored throughout the entire treatment period and the degree of sedation was measured on a discrete ordinal scale with six levels. Models were fitted to the data using the software NONMEM. RESULTS: Clomethiazole was characterized by a two-compartment pharmacokinetic model with interindividual variability in all structural parameters. For a patient weighing 75 kg, the average CL, V1, Q, and V2 was estimated to be 52.7 l h(-1), 82.5 l, 167 l h(-1) and 335 l, respectively. The interindividual variability in CL, V1, Q and V2 was estimated to be 48%, 53%, 42% and 54%, respectively. Increasing body weight and concomitant administration of liver enzyme inducing drugs were found to increase clearance (by 0.5 l h(-1) kg(-1) and 40%, respectively). Increasing weight also increased the volume of distribution (1.1 l kg(-1) for V1 and 4.7 l kg(-1) for V2). A six-category proportional odds model with a component including the natural course of sedation following placebo administration, a drug component (present or absent) and an interindividual variability component described the degree of sedation. Stroke severity as measured on the NIH-stroke scale on admission and drug treatment were the most important predictors of sedation, but a nonlinear increase in sedation with increasing age was also found. Increasing body weight increased the sedative drug effect. CONCLUSIONS: The pharmacokinetics of clomethiazole were characterized in acute stroke patients and the analysis excluded several possible covariates of interest in drug development. The time course of sedation could be quantitatively described during the first 24 h following an acute stroke in the presence or absence of clomethiazole treatment.

Adult↗