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Traumatic Brain Injury Research in Europe: The Quest for a Pharmacologic Intervention Goes On – NOSTRA Phase III Trial By Raimund Helbok, MD, and Ronny Beer, MD Traumatic brain injury (TBI) constitutes a major health and socioeconomic problem throughout the world. Still representing the leading cause of death and disability in young adults in the United States and Europe, TBI has also become a huge burden of disease in countries with emerging economies. Noteworthy, in several regions of Europe, middle aged and elderly persons are more and more affected by this devastating condition, meaning that the frequent comorbidities seen in this patient cohort pose an additional challenge to the critical care management. A major constraint of clinical research activities in the field of TBI is the heterogeneity of injury patterns strongly arguing for an individualized treatment approach. Unfortunately, little progress has been made in developing new therapeutics for TBI. Despite the tremendous efforts that have been devoted to TBI research to identify an effective pharmacological and/ or non-pharmacological treatment, none of the recently conducted intervention trials have shown efficacy. For example, neither randomized clinical trials examining decompressive nor studies on early hypothermia for neuroprotection after TBI did hold promise for a treatment that could significantly improve neurological outcome. Further, pharmacological interventions with neuroprotective agents that provided hope for a potentially effective treatment of acute TBI in experimental and phase II clinical investigations, such as progesterone and erythropoietin, failed to convincingly show benefit. So, is there still a perspective for another neuroprotection trial in TBI? Pathophysiological mechanisms of TBI are complex as secondary brain injury cascades that substantially contribute to morbidity and mortality are triggered by the primary impact. Contemporary basic and clinical research has identified the gaseous neurotransmitter NO as one of the key factors in the development of secondary injury after TBI. Under pathological conditions, NO is generated by the inducible isoform of the enzyme NO synthase (iNOS). Importantly, induction of NOS with concomitant overproduction of NO has been demonstrated in TBI and increased levels of NO have been found to correlate with the elevation of intracranial pressure. The antipterin compound VAS203 (4-Amino-(6R,S)-5,6,7,8-tetrahydro-L-biopterin dihydrochloride dihydrate) is a structural analogue of the endogenous NOS cofactor and one of the most potent, and in vivo selective, inhibitors of iNOS known so far. Following experimental and a phase I clinical study, the compound was tested in an exploratory randomized, placebo-controlled phase II clinical trial including 32 patients with TBI in six European centers1. The innovative part of this trial was the inclusion of cerebral microdialysis in the monitoring protocol. Exploratory analysis of the cerebral microdialysis samples proved the detection of VAS203-metabolites in the brain extracellular fluid of TBI patients; microdialysis analysis also showed a tendency by VAS203 to increase the arginine/citrulline ratio, an indirect marker of NOS activity. Exploratory outcome analysis after six months showed significant improvement by VAS203 compared to placebo in the extended Glasgow Outcome Scale Interview (eGOS-I). Raimund Helbok, MD Ronny Beer, MD 10


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