Tolerability of NXY-059 at Higher Target Concentrations in Patients With Acute Stroke
| Autor: | Kennedy R. Lees, David Barer, A K Sharma, Werner Hacke, Gary A. Ford, V. Kostulas, Tomas Odergren |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Adult
Male Randomization medicine.medical_treatment Ischemia Severity of Illness Index Double-Blind Method Pharmacokinetics medicine Humans Dosing Stroke Aged Aged 80 and over Advanced and Specialized Nursing Chemotherapy Dose-Response Relationship Drug business.industry Benzenesulfonates Free Radical Scavengers Middle Aged medicine.disease Magnetic Resonance Imaging Survival Rate Neuroprotective Agents Treatment Outcome Tolerability Anesthesia Toxicity Drug Evaluation Female Nitrogen Oxides Neurology (clinical) Tomography X-Ray Computed Cardiology and Cardiovascular Medicine business |
| Zdroj: | Stroke. 34:482-487 |
| ISSN: | 1524-4628 0039-2499 |
| Popis: | Background and Purpose— NXY-059 is a nitrone-based free radical–trapping agent in development for acute stroke. In patients with acute stroke, NXY-059 is well tolerated at concentrations known to be associated with neuroprotection in animal models of transient cerebral ischemia; however, higher target concentrations appear necessary on the basis of animal models of permanent ischemia. Methods— This was a randomized, double-blind, placebo-controlled, parallel-group, dose-escalation, multicenter study that evaluated safety, tolerability, and plasma concentrations of 2 NXY-059 dosing regimens within 24 hours of acute stroke. NXY-059 was administered as either 915 mg over 1 hour followed by 420 mg/h for 71 hours or 1820 mg for 1 hour followed by 844 mg/h for 71 hours; plasma concentrations were monitored. Neurological and functional outcomes were recorded for up to 30 days. Results— One hundred thirty-five patients were recruited, of whom 134 received study treatment and completed assessments (844 mg/h, n=39; 420 mg/h, n=48; placebo, n=47). Mean age was 69 years (range, 34 to 92 years), and baseline National Institutes of Health Stroke Scale score was 8.5 (SD, 6.6). Serious adverse events occurred in 3, 17, and 13 patients, respectively, with deaths in 0, 4, and 3 patients and treatment discontinuations because of adverse events in 0, 1, and 3 patients. Good outcome, defined by modified Rankin Scale score of 0 or 1, was seen in 53%, 29% and 40%, respectively. No safety concern was identified in analysis of body temperature, blood pressure, or other laboratory parameters. The unbound plasma concentration at steady state was 260±79 μmol/L, exceeding the target of 200 μmol/L in the high-dose group. Conclusions— NXY-059 was well tolerated in patients with an acute stroke at and above concentrations shown to be neuroprotective in an animal model when initiated 4 hours after onset of permanent focal ischemia. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|