Peptidergic Drugs for Treatment of Traumatic Brain Injury
Traumatic brain injury (TBI) is a devastating medical condition that has an enormous socioeconomic impact because it affects more than 10 million people annually worldwide and is associated with high rates of hospitalization, mortality and disability. Although TBI survival has improved continuously for decades, particularly in developing countries, implementation of an effective drug therapy for TBI represents an unmet clinical need. All confirmatory trials conducted to date with drugs targeting a single TBI pathological pathway failed to show clinical efficacy, probably because TBI pathophysiology involves multiple cellular and molecular mechanisms of secondary brain damage. According to current scientific evidence of the participation of peptide-mediated mechanisms in the processes of brain injury and repair after TBI, peptidergic drugs represent a multimodal therapy alternative to improve acute outcome and long-term recovery in TBI patients. Preliminary randomized-controlled clinical trials and open-label studies conducted to date with the peptidergic drug Cerebrolysin® (Ever Neuro Pharma GmbH, Unterach, Austria) and with the endogenous neuropeptides progesterone and erythropoietin, showed positive clinical results. Cerebrolysin-treated patients had a faster clinical recovery, a shorter hospitalization time and a better long-term outcome. Treatment with progesterone showed advantages over placebo regarding TBI mortality and clinical outcome, whereas erythropoietin only reduced mortality. Further validation of these promising findings in confirmatory randomized-controlled clinical trials is warranted. This article reviews the scientific basis and clinical evidence on the development of multimodal peptidergic drugs as a therapeutic option for the effective treatment of TBI patients.
Traumatic brain injury (TBI) affects 10 million individuals annually worldwide and represents a major health and socioeconomic problem. The highest incidence of TBI is among young (15–25 years old) and old (75 years and older) individuals, and it is the first cause of injury-related death and disability in children and young adults; it accounts for the hospitalization of approximately 100 cases per 100,000 population/year and for an annual death rate of 18 deaths/100,000 population, which is even greater in low-income countries. Furthermore, it enhances the risk of death for at least 7 years after hospitalization and causes long-term disabilities in more than 1% of the population.
Although the survival rate of TBI cases has improved continuously for decades, particularly in developing countries, there has been no real progress in the prevention and management of the lifelong impairments induced by TBI on physical, cognitive and psychosocial functioning. Apart from reducing the high mortality in severe cases and in elderly patients, the main goal of TBI treatment is the secondary prevention of long-lasting disabilities by enhancing brain recovery after TBI. Recent advances in the characterization of the cellular and molecular mechanisms involved in TBI pathophysiology has allowed novel therapeutic targets to be identified, but almost all drug trials conducted to date have failed to demonstrate clinical efficacy. Therefore, at present, there is no specific drug therapy approved for TBI.
In this article, the authors reviewed recent pharmacological and clinical studies supporting the development of peptidegic drugs as a promising option for TBI treatment.
Abstract and Introduction
Abstract
Traumatic brain injury (TBI) is a devastating medical condition that has an enormous socioeconomic impact because it affects more than 10 million people annually worldwide and is associated with high rates of hospitalization, mortality and disability. Although TBI survival has improved continuously for decades, particularly in developing countries, implementation of an effective drug therapy for TBI represents an unmet clinical need. All confirmatory trials conducted to date with drugs targeting a single TBI pathological pathway failed to show clinical efficacy, probably because TBI pathophysiology involves multiple cellular and molecular mechanisms of secondary brain damage. According to current scientific evidence of the participation of peptide-mediated mechanisms in the processes of brain injury and repair after TBI, peptidergic drugs represent a multimodal therapy alternative to improve acute outcome and long-term recovery in TBI patients. Preliminary randomized-controlled clinical trials and open-label studies conducted to date with the peptidergic drug Cerebrolysin® (Ever Neuro Pharma GmbH, Unterach, Austria) and with the endogenous neuropeptides progesterone and erythropoietin, showed positive clinical results. Cerebrolysin-treated patients had a faster clinical recovery, a shorter hospitalization time and a better long-term outcome. Treatment with progesterone showed advantages over placebo regarding TBI mortality and clinical outcome, whereas erythropoietin only reduced mortality. Further validation of these promising findings in confirmatory randomized-controlled clinical trials is warranted. This article reviews the scientific basis and clinical evidence on the development of multimodal peptidergic drugs as a therapeutic option for the effective treatment of TBI patients.
Introduction
Traumatic brain injury (TBI) affects 10 million individuals annually worldwide and represents a major health and socioeconomic problem. The highest incidence of TBI is among young (15–25 years old) and old (75 years and older) individuals, and it is the first cause of injury-related death and disability in children and young adults; it accounts for the hospitalization of approximately 100 cases per 100,000 population/year and for an annual death rate of 18 deaths/100,000 population, which is even greater in low-income countries. Furthermore, it enhances the risk of death for at least 7 years after hospitalization and causes long-term disabilities in more than 1% of the population.
Although the survival rate of TBI cases has improved continuously for decades, particularly in developing countries, there has been no real progress in the prevention and management of the lifelong impairments induced by TBI on physical, cognitive and psychosocial functioning. Apart from reducing the high mortality in severe cases and in elderly patients, the main goal of TBI treatment is the secondary prevention of long-lasting disabilities by enhancing brain recovery after TBI. Recent advances in the characterization of the cellular and molecular mechanisms involved in TBI pathophysiology has allowed novel therapeutic targets to be identified, but almost all drug trials conducted to date have failed to demonstrate clinical efficacy. Therefore, at present, there is no specific drug therapy approved for TBI.
In this article, the authors reviewed recent pharmacological and clinical studies supporting the development of peptidegic drugs as a promising option for TBI treatment.
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