The Effect of the Selective NMDA Receptor Antagonist Traxoprodil in the Treatment of Traumatic Brain Injury

Abstract

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.

Clinical Trials in Traumatic Brain Injury: Past Experience and Current Developments

“…22 The Pfizer study had a decrease of mortality of 7% and an increase in favorable outcome in the treated group. 23 Therefore, it would appear that at least some trials show an indication of efficacy, and this may be interpreted as further evidence in support of the concept that TBI trials have been underpowered. Other factors, such as confounding effects of heterogeneity of TBI populations, overly optimistic expectations, and insensitive methodology have also contributed to the difficulties experienced in demonstrating benefit of investigational treatments.…”

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

“…These data supported the clinical investigation for utility in preventing death and long term disability after stroke and TBI in man. Several large clinical trials have been undertaken (Dyker et al, 1999;Lees et al, 2000;Albers et al, 2001;Sacco et al, 2001;Yurkewicz et al, 2005). Unfortunately, all clinical tests of glutamate antagonists for neuroprotection have failed.…”

“…In particular, deleterious effects can be mediated by extrasynaptic receptors containing GluN2B subunits (Tu et al, 2010). However, the GluN2B-selective antagonist CP-101,606 was apparently insufficient to achieve efficacy in severe TBI (Yurkewicz et al, 2005).…”

Ionotropic GABA and Glutamate Receptor Mutations and Human Neurologic Diseases

“…NMDA receptors participate in the development of the CNS (Colonnese et al, 2005;Colonnese and Constantine-Paton, 2006;Kelsch et al, 2012). In addition, overactivation of NMDA receptors can promote seizures and cell death (Choi, 1994;Rothman and Olney, 1995;Obrenovitch et al, 1997;Dirnagl et al, 1999;Yurkewicz et al, 2005), and NMDA receptor hypofunction is a leading hypothesis for schizophrenia (Coyle, 2012;Menniti et al, 2013). Thus, there is considerable interest in factors that control NMDA receptor expression and function.…”