The effect of the selective NMDA receptor antagonist traxoprodil in the treatment of traumatic brain injury.
Traumatic brain injury (TBI) remains a major public health problem, and there is a great medical need for a pharmacological treatment that could improve long-term outcome. The excitatory neurotransmitter, glutamate, has been implicated in processes leading to neurodegeneration. Traxoprodil (CP-101,606) is a novel and potent glutamate receptor antagonist that is highly selective for the NR2B subunit of the NMDA receptor; it has been shown to be neuroprotective in animal models of brain injury and ischemia. A randomized, double-blind, placebo-controlled study was therefore conducted to assess the efficacy and safety of a 72-h infusion of traxoprodil compared to placebo in subjects with computed tomography scan evidence of severe TBI (GCS 4-8). A total of 404 males and non-pregnant females, aged 16-70, were treated within 8 h of injury. At baseline, subjects were stratified by motor score severity. The results showed that a greater proportion of the traxoprodil-treated subjects had a favorable outcome on the dichotomized Glasgow Outcome Scale (dGOS) at 6 months (delta 5.5%, OR 1.3, p = 0.21, 95% CI:[0.85, 2.06]) and at last visit (delta 7.5%, OR 1.47, p = 0.07, 95% CI:[0.97, 2.25]). The mortality rate with traxoprodil treatment was 7% less than with placebo treatment (OR 1.45, p = 0.08, 95% CI:[0.96, 2.18]). Differences between treatment groups were more pronounced in the severest subset (delta 11.8% for the dGOS at last visit and delta 16.6% for mortality). Traxoprodil was well tolerated. Although these results are intriguing, no definitive claim of efficacy can be made for traxoprodil for the treatment of severe TBI.
Yurkewicz
Lorraine
L
CNS, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA. lorraine.yurkewicz@pfizer.com
Weaver
Jerry
J
Bullock
M Ross
MR
Marshall
Lawrence F
LF
D000293:Adolescent; D000328:Adult; D000368:Aged; D001930:Brain Injuries / Q000188:drug therapy* / Q000401:mortality; D018691:Excitatory Amino Acid Antagonists / Q000097:blood / Q000627:therapeutic use*; D005260:Female; D023261:Glasgow Outcome Scale; D006801:Humans; D008297:Male; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000097:blood / Q000627:therapeutic use*; D010880:Piperidines / Q000097:blood / Q000627:therapeutic use*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D020127:Recovery of Function; D016019:Survival Analysis; D015996:Survival Rate; D016896:Treatment Outcome
D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; C095106:traxoprodil mesylate