Robert E. Becker

Incretin mimetics as pharmacologic tools to elucidate and as a new drug strategy to treat traumatic brain injury

Traumatic brain injury (TBI), either as an isolated injury or in conjunction with other injuries, is an increasingly common event. An estimated 1.7 million injuries occur within the USA each year and 10 million people are affected annually worldwide. Indeed, nearly one third (30.5%) of all injury‐related deaths in the USA are associated with TBI, which will soon outpace many common diseases as the major cause of death and disability. Associated with a high morbidity and mortality and no specific therapeutic treatment, TBI has become a pressing public health and medical problem. The highest incidence of TBI occurs in young adults (15–24 years age) and in the elderly (≥75 years of age). Older individuals are particularly vulnerable to these types of injury, often associated with falls, and have shown increased mortality and worse functional outcome after lower initial injury severity. In addition, a new and growing form of TBI, blast injury, associated with the detonation of improvised explosive devices in the war theaters of Iraq and Afghanistan, are inflicting a wave of unique casualties of immediate impact to both military personnel and civilians, for which long‐term consequences remain unknown and may potentially be catastrophic. The neuropathology underpinning head injury is becoming increasingly better understood. Depending on severity, TBI induces immediate neuropathologic effects that, for the mildest form, may be transient; however, with increasing severity, these injuries cause cumulative neural damage and degeneration. Even with mild TBI, which represents the majority of cases, a broad spectrum of neurologic deficits, including cognitive impairments, can manifest that may significantly influence quality of life. Further, TBI can act as a conduit to longer term neurodegenerative disorders. Prior studies of glucagon‐like peptide‐1 (GLP‐1) and long‐acting GLP‐1 receptor agonists have demonstrated neurotrophic/neuroprotective activities across a broad spectrum of cellular and animal models of chronic neurodegenerative (Alzheimers and Parkinsons diseases) and acute cerebrovascular (stroke) disorders. In view of the mechanisms underpinning these disorders as well as TBI, we review the literature and recent studies assessing GLP‐1 receptor agonists as a potential treatment strategy for mild to moderate TBI.

A new roadmap for drug development for Alzheimer's disease

An article in Nature Reviews Drug Discovery (Nature Rev. Drug Discov. 11, 657–660; 2012)1 reported that three prevention trials (known as API, DIAN and A4) in patients with asymptomatic Alzheimer’s disease (AD) hope, with biomarker and cognitive changes, to validate the amyloid hypothesis and set the stage for AD drug approvals. A response (Nature Rev. Drug Discov. 12, 324; 2013)2 endorsed the plans in this earlier report. n nHere, we question the wisdom of this step for these trials and another proposed study (known as DSBI) (TABLE 1). As currently designed, we consider that AD drug development trials have four important deficiencies. First, without the addition of aims to test specific mechanistic hypotheses that are able to explain the conditions necessary to modify the course of AD, these clinical trials will not advance our knowledge of AD neuropathologies and their roles in progression to symptomatic AD. Second, knowledge of how the timing of neuropathologies may affect the successful use of agents that target the 42-amino-acid form of the amyloid-β peptide (Aβ42) or other AD drugs will not advance. Third, a potentially useful drug may be abandoned owing to lack of clinical efficacy. Fourth, drug effects on symptoms may be misinterpreted as evidence for disease modification. n n n nTable 1 n nSelected trials of amyloid-β (Aβ)-targeted interventions for Alzheimer’s disease (AD)*

Alzheimers Disease Drug Development: Old Problems Require New Priorities

Alzheimers disease (AD) clinical drug development and patient care depend on rating instruments, research designs and methods, and translations of clinical trial (CT) results into the clinic without support from standardized protocols able to control (i) random measurement error intrusions into observations, (ii) inaccuracy and bias introduced by clinical evaluators, (iii) conformity of research sites to conditions of research protocols, (iv) the ability of the CT to model for practitioners the most effective use of the drug with individual patients, and (v) other factors able to invalidate research and patient care data. This relaxed attitude with regard to AD methods may be changing now with Alzheimers Disease Neuroimaging Initiative (ADNI) evidence that carefully standardized protocols are needed to validate biomarkers for use in AD diagnosis, drug development, and patient care. In the fields of psychiatry and AD, recent studies have detected serious inaccuracies, imprecision, biases and compromises of study protocols able to invalidate CT outcome data and conclusions drawn from these data. This limited but troubling evidence reinforces ADNI calls for more detailed methodological protocols. Based on the limits to precision and accuracy associated with rated outcomes in CTs and patient care, we call for priority to be given to the qualification and use of biomarkers as outcome variables in AD drug development and patient care and, to insure effective uses of biomarkers, to development of protocol guided practices being modeled in ADNI research. To meet clinical pharmacologys therapeutic aims we conclude that AD CTs need to set for clinicians the conditions of use of drugs shown efficacious, biomarker surrogate endpoints as drug targets, and not to function merely as tests for efficacy conducted under field conditions determined by current clinical practices.

Defining the brain circuits involved in psychiatric disorders: IMI-NEWMEDS.

Despite the vast amount of research on schizophrenia and depression in the past two decades, there have been few innovative drugs to treat these disorders. Precompetitive research collaborations between companies and academic groups can help tackle this innovation deficit, as illustrated by the achievements of the IMI-NEWMEDS consortium.

Lessons from Darwin: 21st century designs for clinical trials.

What are the resources needed by clinical pharmacology to test drugs in ways that model how the practitioner achieves optimal effectiveness and safety with each patient? I describe the applications of test-retest standard error of measurement, clinical decision rules, means or other statistical summaries of observations, clinical trial designs that use each patient as her own control, and methods to control observer and site variance as steps for developing a CT tested model for optimal clinical uses of an Alzheimers drug by a practitioner. Many investigators and clinicians have been concerned with clinical judgments being scientifically uncontrolled and unsystematic. The methods I describe demonstrate how clinical trials can be used to overcome these limitations in current patient care. Darwin showed that one simply could not understand evolution as long as one accepted essentialism. Species and populations are not types, they are not essentialistically defined classes, but rather are biopopulations composed of genetically unique individuals E. Mayr.

(−)-Phenserine inhibits neuronal apoptosis following ischemia/reperfusion injury

Stroke commonly leads to adult disability and death worldwide. Its major symptoms are spastic hemiplegia and discordant motion, consequent to neuronal cell death induced by brain vessel occlusion. Acetylcholinesterase (AChE) is upregulated and allied with inflammation and apoptosis after stroke. Recent studies suggest that AChE inhibition ameliorates ischemia-reperfusion injury and has neuroprotective properties. (-)-Phenserine, a reversible AChE inhibitor, has a broad range of actions independent of its AChE properties, including neuroprotective ones. However, its protective effects and detailed mechanism of action in the rat middle cerebral artery occlusion model (MCAO) remain to be elucidated. This study investigated the therapeutic effects of (-)-phenserine for stroke in the rat focal cerebral ischemia model and oxygen-glucose deprivation/reperfusion (OGD/RP) damage model in SH-SY5Y neuronal cultures. (-)-Phenserine mitigated OGD/PR-induced SH-SY5Y cell death, providing an inverted U-shaped dose-response relationship between concentration and survival. In MCAO challenged rats, (-)-phenserine reduced infarction volume, cell death and improved body asymmetry, a behavioral measure of stoke impact. In both cellular and animal studies, (-)-phenserine elevated brain-derived neurotrophic factor (BDNF) and B-cell lymphoma 2 (Bcl-2) levels, and decreased activated-caspase 3, amyloid precursor protein (APP) and glial fibrillary acidic protein (GFAP) expression, potentially mediated through the ERK-1/2 signaling pathway. These actions mitigated neuronal apoptosis in the stroke penumbra, and decreased matrix metallopeptidase-9 (MMP-9) expression. In synopsis, (-)-phenserine significantly reduced neuronal damage induced by ischemia/reperfusion injury in a rat model of MCAO and cellular model of OGD/RP, demonstrating that its anti-apoptotic/neuroprotective/neurotrophic cholinergic and non-cholinergic properties warrant further evaluation in conditions of brain injury.

Razoxane and dexrazoxane - Two multifunctional agents

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Lessons from Darwin: Evolutionary Biologys Implications for Alzheimers Disease Research and Patient Care

What are the aims appropriate for a science of clinical pharmacology and clinical trials: to test drugs for efficacy and safety in the clinic, to establish the optimal effectiveness and safety of drugs in patient care or both? Current designs of clinical trials test drugs for efficacy and safety in clinical settings-they do not address the clinicians problems adequately. Clinical trials better address the effectiveness of drugs in patient care with analyses to determine drug effects for each individual in the trial. We use current standards and designs for clinical trails supplemented to control random error effects for the individuals in the trials. Test-retest standard error of measurement can control random error effects for individuals. This allows individual clinical courses to be plotted with known precision and certainty. For individuals in a clinical trial the clinical course of surrogate outcome variables can be associated with long-term health outcomes in followup to develop clinical decision rules. Clinical courses on surrogate outcome variables during patient care can be interpreted using these clinical decision rules. In this Age of the Internet, Computers and Handhelds, electronic records and interpretations of clinical examinations and tests can be a part of decision making for every patient. We conclude that practical methods are available for making clinical trials more informative for clinical practice. This modification replaces unsystematic clinical judgments with statistically characterized data and interpretations for individuals available as care is delivered in the doctors office. An AD demonstration can be viewed at www.healthpragmatics.com.

Neuronal Enriched Extracellular Vesicle Proteins as Biomarkers for Brain Traumatic Injury

Traumatic brain injury (TBI) is a major cause of injury-related death throughout the world and lacks effective treatment. Surviving TBI patients often develop neuropsychiatric symptoms, and the molecular mechanisms underlying the neuronal damage and recovery following TBI are not well understood. Extracellular vesicles (EVs) are membranous nanoparticles that are divided into exosomes (originating in the endosomal/multi-vesicular body [MVB] system) and microvesicles (larger EVs produced through budding of the plasma membrane). Both types of EVs are generated by all cells and are secreted into the extracellular environment, and participate in cell-to-cell communication and protein and RNA delivery. EVs enriched for neuronal origin can be harvested from peripheral blood samples and their contents quantitatively examined as a window to follow potential changes occurring in brain. Recent studies suggest that the levels of exosomal proteins and microRNAs (miRNAs) may represent novel biomarkers to support the clinical diagnosis and potential response to treatment for neurological disorders. In this review, we focus on the biogenesis of EVs, their molecular composition, and recent advances in research of their contents as potential diagnostic tools for TBI.

Does traumatic brain injury hold the key to the Alzheimer's disease puzzle?

Neurodegenerative disorders have been a graveyard for hundreds of well‐intentioned efforts at drug discovery and development. Concussion and other traumatic brain injuries (TBIs) and Alzheimers disease (AD) share many overlapping pathologies and possible clinical links.