Life after cerovive: a personal perspective on ischemic neuroprotection in the post-NXY-059 era.
The SAINT II Trial, a large randomized multicenter clinical trial of the putative neuroprotectant, NXY-059, failed to demonstrate a treatment benefit in acute ischemic stroke. The further development of this agent was suspended. The implications of this outcome are considered from several perspectives, including: (1) the marginally positive antecedent trial, SAINT I, and the critical commentary stimulated by it, which called attention to its interpretively challenging primary outcome measure--a shift in the full-scale modified Rankin scale score--and to other statistical shortcomings; (2) the cogency of the STAIR recommendations, to which the development of NXY-059 closely adhered; and (3) the inherent physiochemical shortcomings of NXY-059 as a neuroprotective agent--its polar, nonlipophilic nature, poor blood-brain barrier penetrability, nonphysiological oxidation potential, and low potency. Caution is urged, however, regarding the unwarranted adoption of a nihilistic view toward neuroprotection on the part of the stroke community in view of the abundant preclinical evidence demonstrating proof-of-principle of the feasibility of neuroprotection, as well as the multiplicity of biochemical and molecular neuroprotective targets. The author offers the personal example of a translational journey in which a promising neuroprotectant agent targeting multiple injury mechanisms, high-dose albumin therapy, has proceeded successfully from preclinical studies that established efficacy through a pilot clinical trial that demonstrated safety and offered strong suggestions of clinical efficacy, leading to a large multicenter clinical trial currently in progress.
Ginsberg
Myron D
MD
Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33101, USA. mginsberg@med.miami.edu
D000818:Animals; D001557:Benzenesulfonates / Q000627:therapeutic use*; D002545:Brain Ischemia / Q000453:epidemiology / Q000517:prevention & control*; D004353:Drug Evaluation, Preclinical / Q000639:trends; D006801:Humans; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D020521:Stroke; D013997:Time Factors
D001557:Benzenesulfonates; D018696:Neuroprotective Agents; C120851:disufenton sodium