Pharmacological treatment of traumatic brain injury - A review of agents in development

Successful treatment strategies for patients with traumatic brain injury (T BI) remain elusive despite standardised clinical treatment guidelines, impr oved understanding of mechanisms of cellular response to trauma, and a deca de of clinical trials aimed at identifying therapeutic agents targeted at m ediators of secondary injury. The information explosion relative to mechanisms of secondary injury has id entified several potential targets for intervention. Depending on the type of injury to the brain and the intensity and the success of resuscitation, necrosis, apoptosis, inflammatory and excitotoxic cellular damage can be se en. These, same processes may continue postinjury, depending on the adequac y of clinical care. Each of these mechanisms of cellular damage can initiat e a cascade of events mediated by endogenous signals that lead to secondary neurological injury. Several factors contributed to the failure of earlier clinical trials. Now that these have been recognised, a positive impact on future drug developme nt in TBI has been realised. Both the US and Europe have organised brain in jury consortiums where experts in the treatment of TBI provide insight into study design, implementation, conduct and oversight in conjunction with th e pharmaceutical industry. Consequently, future clinical trials of new inve stigational treatments have greater potential for identifying therapies of merit in specific populations of patients with TBI. Pharmacological strategies under investigation are targeting sites involved in the secondary cascade that contribute to overall poor outcome following the primary injury. These treatments include ion channel antagonists inclu ding Calcium channel antagonists, growth factors, antioxidants, stem cells, apoptosis inhibitors, and inhibitors of other signal modulators. In conclusion, the complexity of TBI pathology and the mechanisms contribut ing to secondary injury present unique therapeutic challenges. Appropriate research targets for intervention continue to be investigated, however, the likelihood of improving outcomes with a single approach is extremely small . There is a need for collaborative efforts to investigate the optimal time for drug administration and the logical sequence or combination of treatme nts that will ultimately lead to improved neurological outcomes in this pop ulation.