Multifunctional drugs for head injury

Traumatic brain injury (TBI) remains one of the leading causes of mortality and morbidity worldwide in individuals under the age of 45 years, and, despite extensive efforts to develop neuroprotective therapies, there has been no successful outcome in any trial of neuroprotection to date. In addition to recognizing that many TBI clinical trials have not been optimally designed to detect potential efficacy, the failures can be attributed largely to the fact that most of the therapies investigated have been targeted toward an individual injury factor. The contemporary view of TBI is that of a very heterogenous type of injury, one that varies widely in etiology, clinical presentation, severity, and pathophysiology. The mechanisms involved in neuronal cell death after TBI involve an interaction of acute and delayed anatomic, molecular, biochemical, and physiological events that are both complex and multifaceted. Accordingly, neuropharmacotherapies need to be targeted at the multiple injury factors that contribute to the secondary injury cascade, and, in so doing, maximize the likelihood of a successful outcome. This review focuses on a number of such multifunctional compounds that have shown considerable success in experimental studies and that show maximum promise for success in clinical trials.     

Disease-modifying therapy for spinal and bulbar muscular atrophy (SBMA)

Neurodegenerative diseases have long been construed as incurable disorders. However, therapeutic developments for these diseases are now facing a turning point, that is, analyses of cellular and animal models have provided insights into the pathogenesis of neurodegenerative diseases and have indicated rational therapeutic approaches. Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease characterized by slowly progressive muscle weakness and atrophy. This disease is caused by the expansion of a trinucleotide CAG repeat within the androgen receptor (AR) gene. The results of animal studies suggest that testosterone-dependent nuclear accumulation of the pathogenic AR protein is a fundamental step in the neurodegenerative process. Androgen deprivation with a luteinizing hormone-releasing hormone (LHRH) analogue suppresses the toxicity of the mutant AR in animal models of SBMA. In a phase 3 trial, 48 weeks of treatment with leuprorelin acetate, an LHRH analogue, tended to improve swallowing function in a subgroup of SBMA patients with disease duration less than 10 years but did not significantly affect the total population. Disease duration might influence the efficacy of leuprorelin acetate, and therefore, a further clinical trial that involves sensitive outcome measures is in progress. Advances in basic and clinical research on SBMA are now paving the way for the clinical application of pathogenesis-targeting therapies. To optimize translational research related to the process of testing candidate therapies in humans, it is important to identify biomarkers that can be used as surrogate endpoints in clinical trials for neurodegenerative diseases.     

An Update on Monoclonal Gammopathy and Neuropathy

Peripheral neuropathy associated with monoclonal gammopathy is a rare but important cause of neuropathy that can herald serious underlying disease. IgM monoclonal gammopathy of undetermined significance (MGUS) is the most commonly found monoclonal gammopathy associated with neuropathy, with characteristic clinical, electrophysiologic, and pathologic features. The IgG and IgA monoclonal gammopathies are rarely associated with specific neuropathies. Standard immunomodulatory agents including steroids, intravenous immunoglobulin, and plasmapheresis have shown limited efficacy in IgM MGUS. Neuropathies associated with specific lymphoproliferative disorders may not respond to treatments aimed at that disorder. Case series had shown promising results with rituximab, a monoclonal antibody that targets the B cell surface antigen CD20 and results in a rapid and sustained depletion of B cells; however, two recent randomized controlled trials with rituximab failed to provide evidence of efficacy in primary outcome measures, despite reduction in antibody levels. Long-term studies looking at the association between specific immunologic markers and disease recurrence are needed to ultimately develop targeted therapies.     

Systematic review of paramedical therapies for Parkinson's disease.

We evaluated the efficacy of physiotherapy, occupational therapy, and speech and language therapy in Parkinson's disease by synthesizing six Cochrane systematic reviews. All randomised, controlled trials examining the efficacy of a paramedical therapy versus control intervention and all those comparing the efficacy of two forms of active therapy in Parkinson's disease were included. Trials were identified by searching biomedical databases, reference lists, hand searching, and contacting investigators. The main outcome measures were quality of life, speech intelligibility, activities of daily living, and individual measures of motor and speech impairment. We identified 16 physiotherapy randomised controlled trials (399 patients), two occupational therapy trials (84 patients), and five speech and language therapy for dysarthria trials (154 patients). None of these studies examined nonpharmacological swallowing therapy for dysphagia. We were unable to perform meta-analysis of the results because the trials used heterogeneous therapy methods and outcome measures. The trials also had marked methodological flaws that could have introduced bias. In summary, we failed to find conclusive evidence of benefit for any form of paramedical therapy sufficient to recommend them in routine clinical practice. However, this lack of evidence is not proof of a lack of effect. Further large pragmatic randomised controlled trials are required to determine the effectiveness of paramedical therapies in Parkinson's disease.     

Translational research in neurology: dementia

Dementia disorders are characterized by clinicopathological criteria. Molecular understandings of these disorders, based on immunohistochemical studies, biochemical investigations, genetic approaches, and animal models, have resulted in advances in diagnosis. Likewise, translational research has allowed us to apply our increasing basic scientific knowledge of neurodegeneration to the rational development of new investigational therapies based on our current understanding of disease pathogenesis. This review discusses the application of translational research to both diagnosis and treatment of dementia disorders. The development of biomarkers has yielded imaging and biochemical methods that assist the physician more than ever in the diagnosis of neurodegenerative dementias, especially Alzheimer disease. New diagnostic criteria for disease are based on these molecular-based techniques. And these biomarkers are of potential use in monitoring disease activity during therapeutic trials. Translational investigations likewise have led toward new avenues in targeted dementia research. This is particularly so in the development and testing of disease-modifying treatments that might slow or deter progressive deterioration. Recent clinical trials have not been based on empirical trials of established drugs but, rather, on trials of drugs shown, through experiments in biochemical, cell culture, and animal models, to interfere with known elements of the pathogenetic cascade of Alzheimer disease.     

The rocky road to translation in spinal cord repair

Over the past 2 decades, the biological understanding of the mechanisms underlying structural and functional repair of the injured central nervous system has strongly increased. This has resulted in the development of multiple experimental treatment strategies with the collective aim of enhancing and surpassing the limited spontaneous recovery occurring in animal models and ultimately humans suffering from spinal cord or brain injuries. Several of these experimental treatments have revealed beneficial effects in animal models of spinal cord injury. With the exception of neurorehabilitative therapies, however, therapeutic interventions that enhance recovery are currently absent within the clinical realm of spinal cord injury. The present review surveys the prospects and challenges in experimental and clinical spinal cord repair. Major shortcomings in experimental research center on the difficulty of closely modeling human traumatic spinal cord injury in animals, the small number of investigations done on cervical spinal injury and tetraplegia, and the differences in lesion models, species, and functional outcome parameters used between laboratories. The main challenges in the clinical field of spinal cord repair are associated with the standardization and sensitivity of functional outcome measures, the definition of the inclusion/exclusion criteria for patient recruitment in trials, and the accuracy and reliability of an early diagnosis to predict subsequent neurological outcome. Research and clinical networks were recently created with the goal of optimizing animal studies and human trials. Promising clinical trials are currently in progress. The time has come to translate the biologic–mechanistic knowledge from basic science into efficacious treatments able to improve the conditions of humans suffering from spinal cord injury. ANN NEUROL 2012;72:491–501     

Designing Clinical Trials for Dystonia

With advances in the understanding of the pathophysiology of dystonia, novel therapeutics are being developed. Such therapies will require clinical investigation ranging from exploratory studies to examine safety, tolerability, dosage selection, and preliminary efficacy to confirmatory studies to evaluate efficacy definitively. As dystonia is a rare and complex disorder with clinical and etiological heterogeneity, clinical trials will require careful consideration of the trial design, including enrollment criteria, concomitant medication use, and outcome measures. Given the complexities of designing and implementing efficient clinical trials, it is important for clinicians and statisticians to collaborate closely throughout the clinical development process and that each has a basic understanding of both the clinical and statistical issues that must be addressed. To facilitate designing appropriate clinical trials in this field, we review important general clinical trial and regulatory principles, and discuss the critical components of trials with an emphasis on considerations specific to dystonia. Additionally, we discuss designs used in early exploratory, late exploratory, and confirmatory phases, including adaptive designs.     

Somatic treatment of bipolar disorder in children and adolescents.

The currently available data from randomized, controlled trials and a considerable amount of open clinical data suggest that adolescent-onset bipolar disorder probably responds to the same agents as adult-onset bipolar disorder. Research examining psychopharmacologic treatment approaches in the early-onset bipolar disorder is limited, however. Methodologic problems include small sample sizes, lack of comparison groups, retrospective designs,and lack of standardized measures. In addition, sometimes no clear differentiation is made between mania and bipolar disorder, the latter term being used broadly in the literature. Often the studies show that symptoms improve because of treatment, but the functioning of the patients does not improve significantly. More research is clearly needed in all aspects of this disorder but especially in examining the efficacy of various types of treatment, its longitudinal course, and diagnostic issues. The indications for, and the overall duration of, long-term maintenance therapy need further study.Many adolescents and children with bipolar disorder do not respond to any of the first-line pharmacologic treatments; therefore, studies with novel agents should be extended to patients in this age range. Furthermore, physicians will probably continue to use combination therapies when confronted by either lack of efficacy or delayed onset of efficacy with a single agent. Thus, such resultant drug-drug interactions also should also be systematically studied [97].     

Somatic treatment of bipolar disorder in children and adolescents

The currently available data from randomized, controlled trials and a considerable amount of open clinical data suggest that adolescent-onset bipolar disorder probably responds to the same agents as adult-onset bipolar disorder. Research examining psychopharmacologic treatment approaches in the early-onset bipolar disorder is limited, however. Methodologic problems include small sample sizes, lack of comparison groups, retrospective designs, and lack of standardized measures. In addition, sometimes no clear differentiation is made between mania and bipolar disorder, the latter term being used broadly in the literature. Often the studies show that symptoms improve because of treatment, but the functioning of the patients does not improve significantly. More research is clearly needed in all aspects of this disorder but especially in examining the efficacy of various types of treatment, its longitudinal course, and diagnostic issues. The indications for, and the overall duration of, long-term maintenance therapy need further study. Many adolescents and children with bipolar disorder do not respond to any of the first-line pharmacologic treatments; therefore, studies with novel agents should be extended to patients in this age range. Furthermore, physicians will probably continue to use combination therapies when confronted by either lack of efficacy or delayed onset of efficacy with a single agent. Thus, such resultant drug-drug interactions also should also be systematically studied [97].     

Therapeutics development in myotonic dystrophy type 1

Myotonic dystrophy (DM1), the most common adult muscular dystrophy, is a multisystem, autosomal dominant genetic disorder caused by an expanded CTG repeat that leads to nuclear retention of a mutant RNA and subsequent RNA toxicity. Significant insights into the molecular mechanisms of RNA toxicity have led to the previously unforeseen possibility that treating DM1 is a viable prospect. In this review, we briefly present the clinical picture in DM1, and describe how the research in understanding the pathogenesis of RNA toxicity in DM1 has led to targeted approaches to therapeutic development at various steps in the pathogenesis of the disease. We discuss the promise and current limitations of each with an emphasis on RNA-based therapeutics and small molecules. We conclude with a discussion of the unmet need for clinical tools and outcome measures that are essential prerequisites to proceed in evaluating these potential therapies in clinical trials.     

Translating the basic and clinical cognitive neuroscience of schizophrenia to drug development and clinical trials of antipsychotic medications.

Neurocognitive deficits have become increasingly important defining features of schizophrenia and its treatment. Multiple domains of neurocognitive functions are impaired in schizophrenia patients, and these impairments are considered to be core features of the disorder. Many recent reports support the importance of the relationship of these neurocognitive deficits to measures of "functional outcome" such as social skills acquisition, social problem solving, and community outcome. Neurocognitive deficits appear to be improved with newer (atypical) antipsychotic medications across a broad range of domains in schizophrenia patients. Together with clinical neuroscience advances, basic research in cognitive neuroscience ranging from animal models of gating functions to early gene expression induced by antipsychotic medications has illuminated the specific neural basis of neurocognitive deficits in schizophrenia and the neurobiology of antipsychotic actions. These translational basic and clinical studies provide powerful screening tools and strategies for drug development and the subsequent assessment of the clinical efficacy of new antipsychotic medications. These interlocking clinical and basic research findings have substantial implications for improving both drug development and improving clinical trials methodology for antipsychotic medications. Thus, there is an informed translation and cross-fertilization between basic and clinical research focused on the development and assessment of putative new antipsychotic compounds.     

Charcot–Marie–Tooth neuropathies: Current gene therapy advances and the route toward translation

Charcot–Marie–Tooth (CMT) neuropathies are a group of genetically and phenotypically heterogeneous disorders that predominantly affect the peripheral nervous system. Unraveling the genetic and molecular mechanisms, as well as the cellular effects of CMT mutations, has facilitated the development of promising gene therapy approaches. Proposed gene therapy treatments for CMTs include virally or non-virally mediated gene replacement, addition, silencing, modification, and editing of genetic material. For most CMT neuropathies, gene- and disease- and even mutation-specific therapy approaches targeting the neuronal axon or myelinating Schwann cells may be needed, due to the diversity of underlying cellular and molecular-genetic mechanisms. The efficiency of gene therapies to improve the disease phenotype has been tested mostly in vitro and in vivo rodent models that reproduce different molecular and pathological aspects of CMT neuropathies. In the next stage, bigger animal models, in particular non-human primates, provide important insights into the translatability of the proposed administration and dosing, demonstrating scale-up potential and safety. The path toward clinical trials is faced with further challenges but is becoming increasingly feasible owing to the progress and knowledge gained from clinical applications of gene therapies for other neurological disorders, as well as the emergence of sensitive outcome measures and biomarkers in patients with CMT neuropathies.     

Temperature management in stroke - an unsolved, but important topic

Clinical data clearly show that elevated body temperature contributes to an unfavorable outcome after ischemic and hemorrhagic stroke. Two promising therapeutic strategies arise from this observation: (1) treatment of fever aiming to sustain normothermia and (2) induced hypothermia, targeting core body temperatures below 36.5°C. A limited number of studies investigated antipyretic strategies after acute stroke and their results were rather disappointing in terms of clinical efficacy. For that reason, it remains unproven, whether sufficient fever treatment improves functional outcome. On the other hand, strong experimental evidence supports neuroprotective effects of induced hypothermia after stroke. Yet, clinical data on this topic remain preliminary and rely on a limited number of patients, mostly enrolled in nonrandomized trials. Therefore, induced hypothermia may be considered safe and feasible after ischemic stroke, but little can be said regarding efficacy. This review summarizes the data, both on fever treatment and induced hypothermia following stroke, starting with a synopsis of the most important experimental investigations, leading to the latest clinical trials. Given the promising data and the lack of successful acute neuroprotective therapies available thus far, suggestions are given for future investigation on both topics.     

Novel approaches and challenges to treatment of central nervous system viral infections

Existing and emerging viral central nervous system (CNS) infections are major sources of human morbidity and mortality. Treatments of proven efficacy are currently limited predominantly to herpesviruses and human immunodeficiency virus (HIV). Development of new therapies has been hampered by the lack of appropriate animal model systems for some important viruses and by the difficulty in conducting human clinical trials for diseases that may be rare, or in the case of arboviral infections, often have variable seasonal and geographic incidence. Nonetheless, many novel approaches to antiviral therapy are available, including candidate thiazolide and pyrazinecarboxamide derivatives with potential broad‐spectrum antiviral efficacy. New herpesvirus drugs include viral helicase‐primase and terminase inhibitors. The use of antisense oligonucleotides and other strategies to interfere with viral RNA translation has shown efficacy in experimental models of CNS viral disease. Identifying specific molecular targets within viral replication cycles has led to many existing antiviral agents and will undoubtedly continue to be the basis of future drug design. A promising new area of research involves therapies based on enhanced understanding of host antiviral immune responses. Toll‐like receptor agonists and drugs that inhibit specific cytokines as well as interferon preparations have all shown potential therapeutic efficacy. Passive transfer of virus‐specific cytotoxic T lymphocytes has been used in humans and may provide an effective therapy for some herpesvirus infections and potentially for progressive multifocal leukoencephalopathy. Humanized monoclonal antibodies directed against specific viral proteins have been developed and in several cases evaluated in humans in settings including West Nile virus and HIV infection and in pre‐exposure prophylaxis for rabies. Ann Neurol 2013;74:412–422     

Efficacy and safety of herbal medicines for idiopathic Parkinson's disease: a systematic review.

The objective of this study is to assess the efficacy and safety of herbal medicines (HMs), as a monotherapy or adjunct therapy, compared to placebo or conventional approaches in the treatment of idiopathic Parkinson's disease (PD). We conducted a systematic review of randomized controlled trials from both conventional and alternative medicine sources. Outcome measures were overall improvement, quality of life, reduction of levodopa dose, and adverse events. Nine studies were included, each testing a different HM. Six of the trials had limited internal validity due to major flaws in design, including the lack of proper randomization; insufficient blinding; unclear inclusive criteria in terms of diagnostic criteria, baseline staging, and duration of disease; lack of proper sample size calculation; and insufficient data analysis. Imbalances in gender and ethnicity among the patients in the included trials were observed. No major adverse events emerged, and no specific pattern was detected from the trials describing such data. In addition to major methodological defects, heterogeneity in (1) HM tested, (2) control treatment, and (3) outcome measure hindered in-depth data analysis and synthesis. Current evidence is insufficient to evaluate the efficacy and safety of various HMs. Further studies with improved trial design and reporting, with assessment on cost-effectiveness, quality of life, and qualitative data are warranted.     

Neuroprotective agents for the treatment of acute ischemic stroke

Neuroprotective treatments are therapies designed to interrupt the cellular, biochemical, and metabolic elaboration of injury during or following exposure to ischemia; they encompass a rapidly expanding array of pharmacologic interventions. Various classes of neuroprotective agents have reached phase III efficacy trials in focal ischemic stroke, but none has proven effective, despite successful preceding animal studies. This notwithstanding, recent favorable results of hypothermia in human cardiac arrest trials have validated the general concept of neuroprotection. In addition, the promise of neuroprotective therapy for focal acute ischemic stroke has been renewed by innovations in strategies of preclinical drug development and clinical trial design that rectify past defects, including trial testing of combination therapies rather than single agents and novel approaches to accelerating time to initiation of experimental treatment.     

Psychosocial treatments for bipolar disorders.

Psychosocial problems may be causes or consequences of BP relapses,and adding psychologic therapies to usual-treatment approaches may improve the prognosis of those at risk of persistent symptoms or frequent episodes. The three core individual manualized therapies (IPSRT, cognitive therapy, and FFT) have all developed specific models for use in BP. Colom et al's group psychoeducation model also has a clearly developed rationale and format, and it allows individuals to share their views of BP with others, to learn adaptive coping strategies from the other 8 to 12 members of the group, and to have regular contact with an expert therapist. Careful review of the four more extended and comprehensive approaches and the brief technique-driven interventions demonstrates that the effective therapies incorporate one or more of the modules show in Box 1. At present,the choice between the four extended models is more likely to be dictated by patient choice or the availability of a trained therapist. The technique-driven interventions are briefer than the specific therapies (about 6-9 sessions compared with about 20-22 sessions) and usually offer a generic, fixed treatment package targeted at a circumscribed issue such as medication adherence or managing early symptoms of relapse. These brief interventions can be delivered by a less-skilled or less-experienced professional than the specific model. They potentially seem to be useful in day-to-day clinical practice in general adult psychiatry settings; additional larger-scale, randomized trials should be encouraged. Given the reduction in relapse rates and hospitalizations associated with the use of psychologic therapy as an adjunct to medication, it is likely that these approaches will prove to be clinically and cost effective. They may provide a significant improvement in the quality of life of individuals with BP (and indirectly to that of their partners and family members). Brief,evidence-based therapies represent an important component of good clinical practice in the management of BP. Studies of a comprehensive, whole-system approach to the collaborative psychobiosocial management of BP are being undertaken in the United States. If these approaches improve the quality and continuity of care for individuals with BP, they will have further implications for the delivery and organization of mental health services. The number and variety of trials of psychosocial interventions is exciting for researchers and clinicians interested in BP. Enthusiasm for advocating these approaches should be tempered by an acknowledgment that the trials undertaken so far largely demonstrate efficacy in selected samples of patients treated at specialist BP clinics or psychologic treatment research centers. Translating efficacy into effectiveness requires evidence that the approaches used in the treatment trials are equally beneficial when used by the wider therapist community treating patients seen routinely in non-specialist or nonresearch centers. These patients often have multiple problems or complex presentations that preclude their involvement in pharmacologic or psychologic treatment studies, but monitoring the outcomes of these representative samples will be important in determining the true place of psychologic approaches in the management of BP. Large-scale studies are now underway on both sides of the Atlantic (the Medical Research Council study in the United Kingdom and the STEP-BD project in the United States).These trials are likely to answer basic questions about the benefits and limitations of psychologic therapies in the acute and maintenance treatment of BP in the clinical realm and will increase understanding of the effectiveness-versus-efficacy question.     

The role of MRI as a surrogate outcome measure in multiple sclerosis

The need for more specific and more sensitive outcome measures for use in testing new therapies in multiple sderosis (MS) is generally accepted. This need has been accentuated by the realization that the ability to conduct large placebo-controlled trials will be limited in the future. From the first use of magnetic resonance imaging (MRI) to study MS, the ability of this imaging technique to identify areas of the central nervous system damage by the disease process in MS has been impressive. Thus, the possibility that MRI could serve as a surrogate outcome measure in clinical trials in MS has been attractive. The use of MRI as a surrogate outcome measure has been examined by an international group of investigators with expertise in clinical aspects of MS, the use of MRI in MS, and in experimental therapeutics. The group agreed that MRI does not represent a validated surrogate in any clinical form of MS. It was also agreed, however, that MRI does provide a reflection of the underlying pathology in the disease, but no single MRI measurement in isolation was seen as sufficient to monitor disease. The use for multiple imaging techniques, especially new, emerging techniques that may better reflect the underlying pathology, was seen as particularly important in monitoring studies of patients with either secondary or primary progressive MS. The choice of MRI techniques used to monitor new therapies needs to be consistent with the proposed mechanisms of the new therapy and phase of the disease. It was also noted, however, that additional validation is required for nonconventional imaging techniques. Finally, the participants noted that clinical trials using MRI as a primary outcome measure may fail to fully identify the effects of the therapy on dinical measures and that the risk and cost-benefit ratio of the treatment might be unresolved. Thus, before MRI is used as a primary outcome measure, new approaches to trial design must be given careful consideration.     

Neuroimmunotherapies Targeting T Cells: From Pathophysiology to Therapeutic Applications

Therapeutic options for multiple sclerosis (MS) have significantly increased over the last few years. T lymphocytes are considered to play a central role in initiating and perpetuating the pathological immune response. Currently approved therapies for MS target T lymphocytes, either in an unspecific manner or directly by interference with specific T-cell pathways. While the concept of “T-cell-specific therapy” implies specificity and selectivity, currently approved approaches come from a general shaping of the immune system towards anti-inflammatory immune responses by non-T-cell-selective immune suppression or immune modulation (e.g., interferons—immune modulation approach) to a depletion of immune cell populations involving T cells (e.g., anti-CD52, alemtuzumab—immune selective depletion approach), or a selective inhibition of distinct molecular pathways in order to sequester leucocytes (e.g., natalizumab—leukocyte sequestration approach). This review will highlight the rationale and results of different T-cell-directed therapeutic approaches coming from basic animal experiments to clinical trials. We will first discuss the pathophysiological rationale for targeting T lymphocytes in MS leading to currently approved treatments acting on T lymphocytes. Furthermore, we will disuss previous promising concepts that have failed to show efficacy in clinical trials or were halted as a result of unexpected adverse events. Learning from the discrepancies between expectations and failures in practical outcomes helps to optimize future research approaches and clinical study designs. As our current view of MS pathogenesis and patient needs is rapidly evolving, novel therapeutic approaches targeting T lymphocytes will also be discussed, including specific molecular interventions such as cytokine-directed treatments or strategies enhancing immunoregulatory mechanisms. Based on clinical experience and novel pathophysiological approaches, T-cell-based strategies will remain a pillarstone of MS therapy.