Brain or Vessel Protection

NXY-059 is a nitrone compound with free radical trapping properties that appears to be neuroprotective in some animal models of stroke.1,2 The publication this month of SAINT-I trial in the New England Journal of Medicine3 demonstrates a small but statistically significant improvement of the primary outcome by NXY-059 treatment. The authors observed reduced disability at 90 days as assessed by a shift in the modified Rankin scale. Patients were treated within 4 hours from stroke onset with doses of NXY-059 compatible with the neuroprotective effects seen in some animal models.1,2 The development of the drug is to be commended in that a number of the STAIR criteria4 were followed, but there are questions that are being discussed. Critically, the site of action of NXY-059 has still not been conclusively determined, and this dispute originates from the poor permeability of NXY-059 across the blood–brain barrier.2,5 Therefore, the question is if NXY-059 eventually exhibits any pharmacological protection by scavenging free radicals in the brain tissue. Alternatively, its mechanism of action might be a manifestation of physiological protection, mediated probably by improving cerebral blood flow. Another consideration is whether the benefit of NXY-059 at 90 days, after stroke onset, is not a long-term effect, but rather a postponement of the injury. This is supported by the reduction of the odds for improved outcome by NXY-059 compared with placebo, from 7 to 30 to 90 days. Another criticism of the SAINT-I trial is that the modified Rankin scale is used in a nonconventional way, which is a nonvalidated concept. Finally, an important caveat of the study was that NXY-059 did not result in any significant National Institutes of Health Stroke Scale (NIHSS) score improvement.