Novel therapies in development for the treatment of traumatic brain injury

In industrialised countries, the mean per capita incidence of traumatic brain injury (TBI) that results in a hospital presentation is 250 per 100,000. In Europe and North America alone, this translates to > 2 million TBI presentations annually. Approximately 25% of these presentations are admitted for hospitalisation. Despite the significance of these figures, there is no single interventional pharmacotherapy that has shown efficacy in the treatment of clinical TBI. This lack of efficacy in clinical trials may be due, in part, to the inherent heterogeneity of the traumatic brain injury population. However, it is the multifactorial nature of secondary injury that also poses a major hurdle, particularly for those therapies that have been designed to specifically target an individual injury factor. It is now becoming increasingly recognised that any successful TBI therapy may have to simultaneously affect multiple injury factors, somewhat analogous to other broad spectrum interventions. Recent efforts in experimental TBI have therefore focussed on developing novel pharmacotherapies that may affect multiple injury factors and thus improve the likelihood of a successful outcome. While a number of interventions are noteworthy in this regard, this review will focus on three novel compounds that show particular promise: magnesium, substance P antagonists and cyclosporin A.     

Recent advances in the development of multifactorial therapies for the treatment of traumatic brain injury

Traumatic brain injury (TBI) is one of the leading causes of death and disability in the industrialised world and remains a major health problem with serious socioeconomic consequences. So far, despite encouraging preclinical results, almost all neuroprotection trials have failed to show any significant efficacy in the treatment of clinical TBI. This may be due, in part, to the fact that most of the therapies investigated have targeted an individual injury factor. It is now recognised that TBI is a very heterogeneous type of injury that varies widely in its aetiology, clinical presentation, severity and pathophysiology. The pathophysiological sequelae of TBI are mediated by an interaction of acute and delayed molecular, biochemical and physiological events that are both complex and multifaceted. Accordingly, a successful TBI treatment may have to simultaneously attenuate many injury factors. Recent efforts in experimental TBI have, therefore, focused on the development of neuropharmacotherapies that target multiple injury factors and thus improve the likelihood of a successful outcome. This review will focus on three such novel compounds that are currently being assessed in clinical trials; progesterone, dexanabinol and dexamethasone, and provide an update on the progress of both magnesium and cyclosporin A.     

Recent advances in the development of multifactorial therapies for the treatment of traumatic brain injury

Traumatic brain injury (TBI) is one of the leading causes of death and disability in the industrialised world and remains a major health problem with serious socioeconomic consequences. So far, despite encouraging preclinical results, almost all neuroprotection trials have failed to show any significant efficacy in the treatment of clinical TBI. This may be due, in part, to the fact that most of the therapies investigated have targeted an individual injury factor. It is now recognised that TBI is a very heterogeneous type of injury that varies widely in its aetiology, clinical presentation, severity and pathophysiology. The pathophysiological sequelae of TBI are mediated by an interaction of acute and delayed molecular, biochemical and physiological events that are both complex and multifaceted. Accordingly, a successful TBI treatment may have to simultaneously attenuate many injury factors. Recent efforts in experimental TBI have, therefore, focused on the development of neuropharmacotherapies that target multiple injury factors and thus improve the likelihood of a successful outcome. This review will focus on three such novel compounds that are currently being assessed in clinical trials; progesterone, dexanabinol and dexamethasone, and provide an update on the progress of both magnesium and cyclosporin A.     

Investigational agents for treatment of traumatic brain injury

Introduction: Traumatic brain injury (TBI) is a major cause of death and disability worldwide. To date, there are no pharmacologic agents proven to improve outcomes from TBI because all the Phase III clinical trials in TBI have failed. Thus, there is a compelling need to develop treatments for TBI.

Areas covered: The following article provides an overview of select cell-based and pharmacological therapies under early development for the treatment of TBI. These therapies seek to enhance cognitive and neurological functional recovery through neuroprotective and neurorestorative strategies.

Expert opinion: TBI elicits both complex degenerative and regenerative tissue responses in the brain. TBI can lead to cognitive, behavioral, and motor deficits. Although numerous promising neuroprotective treatment options have emerged from preclinical studies that mainly target the lesion, translation of preclinical effective neuroprotective drugs to clinical trials has proven challenging. Accumulating evidence indicates that the mammalian brain has a significant, albeit limited, capacity for both structural and functional plasticity, as well as regeneration essential for spontaneous functional recovery after injury. A new therapeutic approach is to stimulate neurovascular remodeling by enhancing angiogenesis, neurogenesis, oligodendrogenesis, and axonal sprouting, which in concert, may improve neurological functional recovery after TBI.     

Pharmacological treatment of traumatic brain injury: a review of agents in development

Successful treatment strategies for patients with traumatic brain injury (TBI) remain elusive despite standardised clinical treatment guidelines, improved understanding of mechanisms of cellular response to trauma, and a decade of clinical trials aimed at identifying therapeutic agents targeted at mediators of secondary injury. The information explosion relative to mechanisms of secondary injury has identified 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 seen. These same processes may continue postinjury, depending on the adequacy of clinical care. Each of these mechanisms of cellular damage can initiate 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 development in TBI has been realised. Both the US and Europe have organised brain injury consortiums where experts in the treatment of TBI provide insight into study design, implementation, conduct and oversight in conjunction with the pharmaceutical industry. Consequently, future clinical trials of new investigational 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 including 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 contributing 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 treatments that will ultimately lead to improved neurological outcomes in this population.     

Medical treatment and neuroprotection in traumatic brain injury

The goal of this article is to give an overview about the established current treatment concepts of traumatic brain injury, as well as an outlook on possible future developments in pharmacological neuroprotection. Modern medical treatment modalities of traumatic brain injury (TBI), including the preclinical management of severely head-injured patients, are reviewed. Since an increased intracranial pressure represents the most common complication of severe traumatic brain injury, frequently associated with the development of secondary brain damage, special emphasis was given to an updated treatment algorithm for this important condition. New insight into the pathophysiology of severe traumatic brain injury, especially the realization that brain damage develops sequentially, initiated several new treatment approaches aiming at the interruption of pathophysiological mechanisms leading to secondary brain injury. A high number of pharmacological substances have been tested for their ability to ameliorate secondary damage after TBI, or are currently under clinical trial. Although no drug has achieved this goal so far, the most promising of these therapeutical approaches, glutamate receptor antagonists, calcium channel antagonists, free radical scavengers, and cyclosporin A will be discussed in this review. Although a "magical bullet" for the treatment of traumatic brain injury has not been developed yet, several of the currently investigated neuroprotective strategies seem to be encouraging. A promising future approach might be to evaluate treatment strategies that combine several pharmacological agents, and possibly other treatment modalities, such as mild hypothermia, "tailored" according to the special pathology of patient subgroups, or even to every single patient in order to achieve an improvement in outcome after TBI.     

外伤性重型颅脑损伤急救阶段护理体会分析

目的对比不同护理手段对外伤性重型颅脑损伤患者急救阶段的护理效果。方法将我院收治的126例外伤性重型颅脑损伤患者依据急救阶段护理方式差异分组,对比两组护理效果。结果观察组入院抢救时间与抢救费用、并发症率与死亡率均远低于对照组(P0.05);观察组病情稳定率远高于对照组(P0.05);观察组护理态度、护理技术、心理护理与健康教育满意率均较对照组更理想(P0.05)。结论临床予以外伤性重型颅脑损伤患者急救阶段临床护理路径,可有效降低抢救时间、费用与并发症率,同时对患者的病情稳定与生存率均具明显提升作用,该法深受临床欢迎,值得推广。     

Evaluation of pharmacological treatment strategies in traumatic brain injury

Traumatic brain injury (TBI) is a devastating disease, predominately affecting young people. Although the prognosis for TBI victims has improved in recent years, many survivors of TBI suffer from emotional, cognitive and motor disturbances and a decreased quality of life. In recent years, there has been a rapid increase in the number of pharmacological targets evaluated in clinically-relevant experimental TBI models, showing improved cognitive and motor outcome and decreased loss of brain tissue. Despite the completion of several recent clinical trials using compounds showing neuroprotection in preclinical studies, pharmaceutical treatment strategies with proven clinical benefit are still lacking. This paper reviews the preclinical pharmacological treatment studies evaluated to date in experimental models of TBI. Although human TBI is a complex and multifaceted disease, these studies provide encouraging translational data suggesting that pharmacological compounds, delivered in a clinically-relevant time window, may improve the outcome of TBI patients.     

A review of neuroprotection pharmacology and therapies in patients with acute traumatic brain injury

Traumatic brain injury (TBI) affects 1.6 million Americans annually. The injury severity impacts the overall outcome and likelihood for survival. Current treatment of acute TBI includes surgical intervention and supportive care therapies. Treatment of elevated intracranial pressure and optimizing cerebral perfusion are cornerstones of current therapy. These approaches do not directly address the secondary neurological sequelae that lead to continued brain injury after TBI. Depending on injury severity, a complex cascade of processes are activated and generate continued endogenous changes affecting cellular systems and overall outcome from the initial insult to the brain. Homeostatic cellular processes governing calcium influx, mitochondrial function, membrane stability, redox balance, blood flow and cytoskeletal structure often become dysfunctional after TBI. Interruption of this cascade has been the target of numerous pharmacotherapeutic agents investigated over the last two decades. Many agents such as selfotel, pegorgotein (PEG-SOD), magnesium, deltibant and dexanabinol were ineffective in clinical trials. While progesterone and ciclosporin have shown promise in phase II studies, success in larger phase III, randomized, multicentre, clinical trials is pending. Consequently, no neuroprotective treatment options currently exist that improve neurological outcome after TBI. Investigations to date have extended understanding of the injury mechanisms and sites for intervention. Examination of novel strategies addressing both pathological and pharmacological factors affecting outcome, employing novel trial design methods and utilizing biomarkers validated to be reflective of the prognosis for TBI will facilitate progress in overcoming the obstacles identified from previous clinical trials.     

Emerging treatments for traumatic brain injury

Background: This review summarizes promising approaches for the treatment of traumatic brain injury (TBI) that are in either preclinical or clinical trials. Objective: The pathophysiology underlying neurological deficits after TBI is described. An overview of select therapies for TBI with neuroprotective and neurorestorative effects is presented. Methods: A literature review of preclinical TBI studies and clinical TBI trials related to neuroprotective and neurorestorative therapeutic approaches is provided. Results/conclusion: Nearly all Phase II/III clinical trials in neuroprotection have failed to show any consistent improvement in outcome for TBI patients. The next decade will witness an increasing number of clinical trials that seek to translate preclinical research discoveries to the clinic. Promising drug- or cell-based therapeutic approaches include erythropoietin and its carbamylated form, statins, bone marrow stromal cells, stem cells singularly or in combination or with biomaterials to reduce brain injury via neuroprotection and promote brain remodeling via angiogenesis, neurogenesis, and synaptogenesis with a final goal to improve functional outcome of TBI patients. In addition, enriched environment and voluntary physical exercise show promise in promoting functional outcome after TBI, and should be evaluated alone or in combination with other treatments as therapeutic approaches for TBI.     

Novel systemic therapies for the treatment of psoriasis

Introduction: The immunopathogenesis of psoriasis has led to the discovery and development of several promising treatment options for psoriasis, including those that target the IL-17 and IL-23 pathways as well as small molecules that act on intracellular signaling pathways including the Janus kinase inhibitor and phosphodiesterase-4 inhibitor. Studies have demonstrated efficacy although long-term risks are not fully known. This review looks at novel systemic therapies for psoriasis that have emerged recently.

Areas covered: Systemic treatments for psoriasis that are in the late phase of development were reviewed, with the main focus on the efficacy and adverse effects of individual treatments.

Expert opinion: The future of psoriasis treatment is likely to be based on clinical, genetic and immune biomarkers that will individualize treatment and may potentially optimize disease outcome.     

Neuroprotection in traumatic brain injury

The management of traumatic brain injury (TBI) is challenging and there is a need for neuroprotective therapies. A better understanding of the pathomechanism of TBI, particularly of the evolution of secondary damage, is providing targets for new approaches and selected ones in clinical development are described. Clinical trials that have been discontinued in the past for lack of efficacy or other reasons are also listed. One of the problems has been the translation of promising animal experimental results into clinically successful therapies. The complexity of sequelae of TBI requires a multifaceted approach. In addition to the investigation of drugs for neuroprotective effect in TBI, new technologies based on cell/gene therapies, biomarkers and nanobiotechnology are being employed for the integration of neuroprotection with neuroregeneration and are promising.     

Novel therapies in the treatment of spondyloarthritis

Spondyloarthritis represents one of the commonest groups of inflammatory arthritides with onset in the third and fourth decades and primarily affecting the axial skeleton. Current treatment is primarily symptomatic, non-steroidal anti-inflammatory drugs being used most commonly. No therapeutics have been shown to prevent structural damage. The development of validated and standardised outcome instruments and a composite criterion of response should encourage evaluation of new therapeutics. Anti-TNF-α-directed therapeutics have been shown to be dramatically effective in short-term (12 week) placebo-controlled trials in both ankylosing spondylitis and psoriatic arthritis whilst observational cohorts describe efficacy that is maintained for over one year. Treatment has been well-tolerated, with mycobacterial infections being the primary concern. Significant costs and the requirement for continuous therapy are likely to spur the development of orally bioavailable agents targeting TNF-α expression.     

Novel therapies in the treatment of spondyloarthritis

Spondyloarthritis represents one of the commonest groups of inflammatory arthritides with onset in the third and fourth decades and primarily affecting the axial skeleton. Current treatment is primarily symptomatic, non-steroidal anti-inflammatory drugs being used most commonly. No therapeutics have been shown to prevent structural damage. The development of validated and standardised outcome instruments and a composite criterion of response should encourage evaluation of new therapeutics. Anti-TNF- alpha -directed therapeutics have been shown to be dramatically effective in short-term (12 week) placebo-controlled trials in both ankylosing spondylitis and psoriatic arthritis whilst observational cohorts describe efficacy that is maintained for over one year. Treatment has been well-tolerated, with mycobacterial infections being the primary concern. Significant costs and the requirement for continuous therapy are likely to spur the development of orally bioavailable agents targeting TNF- alpha expression.     

Pharmacological strategies for neuroprotection in traumatic brain injury

Traumatic brain injury affects over a million Americans annually, but pharmacological therapy remains limited. Current standards of care in acute, subacute and chronic phases of injury are primarily supportive. This review discusses pharmacological strategies and future directions in patient treatment emphasizing pleiotropic agents targeting inflammation, oxidative damage, and glutamate excitotoxicity.     

Diffuse traumatic brain injury and the sensory brain

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