NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics最新文献

{"title":"The Quest for Market Exclusivity in Biotechnology: Navigating the Patent Minefield","authors":"Judge David M. Gersten","doi":"10.1602/neurorx.2.4.572","DOIUrl":"10.1602/neurorx.2.4.572","url":null,"abstract":"<div><p>A patent is a legal device that grants an inventor market exclusivity over a new invention or medication. Market exclusivity can mean tremendous economic rewards for the patent holder because it provides the inventor with a monopoly over the invention for the 20-year patent term. Obtaining a patent and retaining market exclusivity can be a treacherous process, especially in the arena of biotechnology patents. Scientific, legal, and practical considerations must be carefully weighed to best protect an inventor's rights. This article explores some common patenting pitfalls as well as emerging issues that are specific to the area of biotechnology patenting.</p></div>","PeriodicalId":87195,"journal":{"name":"NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics","volume":"2 4","pages":"Pages 572-578"},"PeriodicalIF":0.0,"publicationDate":"2005-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1602/neurorx.2.4.572","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25864775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Translational Research in Central Nervous System Drug Discovery","authors":"Orest Hurko (Assistant Vice-President),&nbsp;John L. Ryan","doi":"10.1602/neurorx.2.4.671","DOIUrl":"10.1602/neurorx.2.4.671","url":null,"abstract":"<div><p>Of all the therapeutic areas, diseases of the CNS provide the biggest challenges to translational research in this era of increased productivity and novel targets. Risk reduction by translational research incorporates the “learn” phase of the “learn and confirm” paradigm proposed over a decade ago. Like traditional drug discovery <em>in vitro</em> and in laboratory animals, it precedes the traditional phase 1–3 studies of drug development. The focus is on ameliorating the current failure rate in phase 2 and the delays resulting from suboptimal choices in four key areas: initial test subjects, dosing, sensitive and early detection of therapeutic effect, and recognition of differences between animal models and human disease. Implementation of new technologies is the key to success in this emerging endeavor.</p></div>","PeriodicalId":87195,"journal":{"name":"NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics","volume":"2 4","pages":"Pages 671-682"},"PeriodicalIF":0.0,"publicationDate":"2005-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1602/neurorx.2.4.671","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25864693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Medicinal Chemical Properties of Successful Central Nervous System Drugs","authors":"Hassan Pajouhesh Ph.D. ,&nbsp;George R. Lenz","doi":"10.1602/neurorx.2.4.541","DOIUrl":"10.1602/neurorx.2.4.541","url":null,"abstract":"<div><p>Fundamental physiochemical features of CNS drugs are related to their ability to penetrate the blood-brain barrier affinity and exhibit CNS activity. Factors relevant to the success of CNS drugs are reviewed. CNS drugs show values of molecular weight, lipophilicity, and hydrogen bond donor and acceptor that in general have a smaller range than general therapeutics. Pharmacokinetic properties can be manipulated by the medicinal chemist to a significant extent. The solubility, permeability, metabolic stability, protein binding, and human ether-ago-go-related gene inhibition of CNS compounds need to be optimized simultaneously with potency, selectivity, and other biological parameters. The balance between optimizing the physiochemical and pharmacokinetic properties to make the best compromises in properties is critical for designing new drugs likely to penetrate the blood brain barrier and affect relevant biological systems. This review is intended as a guide to designing CNS therapeutic agents with better drug-like properties.</p></div>","PeriodicalId":87195,"journal":{"name":"NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics","volume":"2 4","pages":"Pages 541-553"},"PeriodicalIF":0.0,"publicationDate":"2005-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1602/neurorx.2.4.541","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25864774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Developing Therapeutics for the Treatment of Multiple Sclerosis","authors":"David J. Virley Ph.D.","doi":"10.1602/neurorx.2.4.638","DOIUrl":"10.1602/neurorx.2.4.638","url":null,"abstract":"<div><p>Multiple sclerosis (MS) is both a complex and chronic neurological disease of the CNS. This poses unique challenges for drug discovery in terms of delineating specific targets related to disease mechanisms and developing safe and effective molecules for clinical application. Preclinical animal models of MS provide the necessary test bed for evaluating the effects of novel therapeutic strategies. Because the clinical manifestations and pathological consequences of disease vary dramatically from individual to individual, as well as treatment response to existing therapies, this creates a significant research endeavor in terms of translating preclinical methodologies to the clinical domain. Potentially exciting treatments have emerged in the form of natalizumab (Tysabri), an α4 integrin antagonist, and more recently FTY720, a sphinogosine-1 phosphate receptor modulator, providing a compelling proof-of-principle from bench to bedside. However, further research is required to discharge safety concerns associated with these therapeutic avenues. Future prospects in the guise of disease-modifying therapies that target the inflammatory and neurodegenerative components of disease have come to the forefront of preclinical research with the sole aim of reducing the underlying irreversible progressive disability of MS. Significant progress with novel therapies will be made by implementing biomarker strategies that extrapolate robustly from animal models to the divergent patient populations of MS. The future therapeutic options for MS will depend on improvements in understanding the precise factors involved in disease onset and progression and subsequently the development of oral therapeutics that translate sustained benefit from the preclinical context into clinical reality.</p></div>","PeriodicalId":87195,"journal":{"name":"NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics","volume":"2 4","pages":"Pages 638-649"},"PeriodicalIF":0.0,"publicationDate":"2005-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1602/neurorx.2.4.638","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25864690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drug Discovery for Disorders of the Central Nervous System","authors":"Menelas N. Pangalos Ph.D. (Guest Editors, Vice President),&nbsp;Christopher C. Gallen M.D., Ph.D. (Guest Editors)","doi":"10.1602/neurorx.2.4.539","DOIUrl":"10.1602/neurorx.2.4.539","url":null,"abstract":"Never in the history of science and medicine have we had a better understanding of brain function and the diseases that lead to its ultimate destruction and dysfunction. We have teased apart much detail concerning pathological cascades, genetic mutations, and environmental influences leading to some of the most devastating illnesses afflicting mankind in the post-vaccination world. Nevertheless, the majority of neurotherapeutics developed over the past three decades have been derived from serendipitous observations or oversimplified neurochemical hypotheses; the dopaminergic dysfunction of Parkinson’s disease, the acetylcholine deficit observed in the basal forebrain of Alzheimer’s disease patients, and the dopaminergic hyperfunction of schizophrenia are three such examples. Such hypotheses have led to the development and commercialization of medicines that, although providing clear benefit to patients, have still left much room for improvement in terms of both efficacy and tolerability. These therapies also help to highlight many of the limitations of our disease understanding because they are fairly uniformly unable to address the underlying etiology of any of the devastating diseases they are aimed to treat. Moreover, despite the increasing knowledge of the underlying substrates of neurological and psychiatric disease, despite dramatic increases in our ability to use biomarkers and imaging to mechanistically assess the potential actions of new therapeutics, and despite massive industrial investments in the development of new therapies for CNS diseases, success rates for pharmaceutical development have reached historical lows over the past several years. In this issue of NeuroRx®, better understanding of the characteristics of successful therapeutics (Pajouhesh and Lenz) and better strategies to adapt to emerging legal processes and standards needed to protect intellectual property (Gersten) are both seen as needed to improve the possibility for successful commercial development of new therapies. \u0000 \u0000The era of the human genome has now revealed a bountiful supply of innovative and exciting drug discovery targets filled with potential for treating not only the symptoms but perhaps even the underlying causes of seemingly incurable neurological and neuropsychiatric diseases. Furthermore, the advent of exponential improvements in areas such as high-throughput screening, robotics, molecular modeling, and data handling, coupled with the large advances in medicinal chemistry capacity and output, have meant that the number of targets now available for drug discovery efforts is at an all-time peak. Although the hopes and expectations of the world for breakthrough therapies may be high, never before have the challenges facing drug discovery scientists been harder. In fact, it is clear that the more we discover and understand about diseases of the CNS, the more surprises we find and the more we realize that there is much we do not understand. Whereas clini","PeriodicalId":87195,"journal":{"name":"NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics","volume":"2 4","pages":"Pages 539-540"},"PeriodicalIF":0.0,"publicationDate":"2005-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1602/neurorx.2.4.539","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67391003","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drug Metabolism and Pharmacokinetics, the Blood-Brain Barrier, and Central Nervous System Drug Discovery","authors":"Mohammad S. Alavijeh,&nbsp;Mansoor Chishty,&nbsp;M. Zeeshan Qaiser,&nbsp;Alan M. Palmer","doi":"10.1602/neurorx.2.4.554","DOIUrl":"10.1602/neurorx.2.4.554","url":null,"abstract":"<div><p>The worldwide market for therapies for CNS disorders is worth more than $50 billion and is set to grow substantially in the years ahead. This is because: 1) the incidence of many CNS disorders (e.g., Alzheimer's disease, stroke, and Parkinson's disease) increase exponentially after age 65 and 2) the number of people in the world over 65 is about to increase sharply because of a marked rise in fertility after World War II. However, CNS research and development are associated with significant challenges: it takes longer to get a CNS drug to market (12–16 years) compared with a non-CNS drug (10–12 years) and there is a higher attrition rate for CNS drug candidates than for non-CNS drug candidates. This is attributable to a variety of factors, including the complexity of the brain, the liability of CNS drugs to cause CNS side effects, and the requirement of CNS drugs to cross the blood-brain barrier (BBB). This review focuses on BBB penetration, along with pharmacokinetics and drug metabolism, in the process of the discovery and development of safe and effective medicines for CNS disorders.</p></div>","PeriodicalId":87195,"journal":{"name":"NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics","volume":"2 4","pages":"Pages 554-571"},"PeriodicalIF":0.0,"publicationDate":"2005-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1602/neurorx.2.4.554","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25864776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Current Concepts in Therapeutic Strategies Targeting Cognitive Decline and Disease Modification in Alzheimer's Disease","authors":"J. Steven Jacobsen,&nbsp;Peter Reinhart,&nbsp;Dr. Menelas N. Pangalos","doi":"10.1602/neurorx.2.4.612","DOIUrl":"10.1602/neurorx.2.4.612","url":null,"abstract":"<div><p>Alzheimer's disease is a progressive neurodegenerative disorder and the leading cause of dementia in the Western world. Postmortem, it is characterized neuropathologically by the presence of amyloid plaques, neurofibrillary tangles, and a profound gray matter loss. Neurofibrillary tangles are composed of an abnormally hyperphosphorylated intracellular protein called tau, tightly wound into paired helical filaments and thought to impact microtubule assembly and protein trafficking, resulting in the eventual demise of neuronal viability. The extracellular amyloid plaque deposits are composed of a proteinacious core of insoluble aggregated amyloid-β (Aβ) peptide and have led to the foundation of the amyloid hypothesis. This hypothesis postulates that Aβ is one of the principal causative factors of neuronal death in the brains of Alzheimer's patients. With multiple drugs now moving through clinical development for the treatment of Alzheimer's disease, we will review current and future treatment strategies aimed at improving both the cognitive deficits associated with the disease, as well as more novel approaches that may potentially slow or halt the deadly neurodegenerative progression of the disease.</p></div>","PeriodicalId":87195,"journal":{"name":"NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics","volume":"2 4","pages":"Pages 612-626"},"PeriodicalIF":0.0,"publicationDate":"2005-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1602/neurorx.2.4.612","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25864689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting Chronic and Neuropathic Pain: The N-type Calcium Channel Comes of Age","authors":"Dr. Terrance P. Snutch","doi":"10.1602/neurorx.2.4.662","DOIUrl":"10.1602/neurorx.2.4.662","url":null,"abstract":"<div><p>The rapid entry of calcium into cells through activation of voltage-gated calcium channels directly affects membrane potential and contributes to electrical excitability, repetitive firing patterns, excitation-contraction coupling, and gene expression. At presynaptic nerve terminals, calcium entry is the initial trigger mediating the release of neurotransmitters via the calcium-dependent fusion of synaptic vesicles and involves interactions with the soluble <em>N</em>-ethylmaleimide-sensitive factor attachment protein receptor complex of synaptic release proteins. Physiological factors or drugs that affect either presynaptic calcium channel activity or the efficacy of calcium-dependent vesicle fusion have dramatic consequences on synaptic transmission, including that mediating pain signaling. The N-type calcium channel exhibits a number of characteristics that make it an attractive target for therapeutic intervention concerning chronic and neuropathic pain conditions. Within the past year, both U.S. and European regulatory agencies have approved the use of the cationic peptide Prialt for the treatment of intractable pain. Prialt is the first N-type calcium channel blocker approved for clinical use and represents the first new proven mechanism of action for chronic pain intervention in many years. The present review discusses the rationale behind targeting the N-type calcium channel, some of the limitations confronting the widespread clinical application of Prialt, and outlines possible strategies to improve upon Prialt's relatively narrow therapeutic window.</p></div>","PeriodicalId":87195,"journal":{"name":"NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics","volume":"2 4","pages":"Pages 662-670"},"PeriodicalIF":0.0,"publicationDate":"2005-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1602/neurorx.2.4.662","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25864692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Central Nervous System Drug Development: An Integrative Biomarker Approach toward Individualized Medicine","authors":"B. Gomez-Mancilla M.D., Ph.D.,&nbsp;E. Marrer,&nbsp;J. Kehren,&nbsp;A. Kinnunen,&nbsp;G. Imbert,&nbsp;R. Hillebrand,&nbsp;M. Bergström,&nbsp;M.E. Schmidt","doi":"10.1602/neurorx.2.4.683","DOIUrl":"10.1602/neurorx.2.4.683","url":null,"abstract":"<div><p>Drug development for CNS disorders faces the same formidable hurdles as other therapeutic areas: escalating development costs; novel drug targets with unproven therapeutic potential; and health care systems and regulatory agencies demanding more compelling demonstrations of the value of new drug products. Extensive clinical testing remains the core of registration of new compounds; however, traditional clinical trial methods are falling short in overcoming these development hurdles. The most common CNS disorders targeted for drug treatment are chronic, slowly vitiating processes manifested by highly subjective and context dependent signs and symptoms. With the exception of a few rare familial degenerative disorders, they have ill-defined or undefined pathophysiology. Samples selected for treatment trials using clinical criteria are inevitably heterogeneous, and dependence on traditional endpoints results in early proof-of-concept trials being long and large, with very poor signal to noise. It is no wonder that pharmaceutical and biotechnology companies are looking to biomarkers as an integral part of decision-making process supported by new technologies such as genetics, genomics, proteomics, and imaging as a mean of rationalizing CNS drug development. The present review represent an effort to illustrate the integration of such technologies in drug development supporting the path of individualized medicine.</p></div>","PeriodicalId":87195,"journal":{"name":"NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics","volume":"2 4","pages":"Pages 683-695"},"PeriodicalIF":0.0,"publicationDate":"2005-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1602/neurorx.2.4.683","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25864118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New Prospects and Strategies for Drug Target Discovery in Neurodegenerative Disorders","authors":"Brian S. Hilbush ,&nbsp;John H. Morrison ,&nbsp;Warren G. Young ,&nbsp;J. Gregor Sutcliffe ,&nbsp;Floyd E. Bloom M.D.","doi":"10.1602/neurorx.2.4.627","DOIUrl":"10.1602/neurorx.2.4.627","url":null,"abstract":"<div><p>The future of neurodegenerative therapeutics development depends upon effective disease modification strategies centered on carefully investigated targets. Pharmaceutical research endeavors that probe for a much deeper understanding of disease pathogenesis, and explain how adaptive or compensatory mechanisms might be engaged to delay disease onset or progression, will produce the needed breakthroughs. Below, we discuss the prospects for new targets emerging out of the study of brain disease genes and their associated pathogenic pathways. We describe a general experimental paradigm that we are employing across several mouse models of neurodegenerative disease to elucidate molecular determinants of selective neuronal vulnerability. We outline key elements of our target discovery program and provide examples of how we integrate genomic technologies, neuroanatomical methods, and mouse genetics in the search for neurodegenerative disease targets.</p></div>","PeriodicalId":87195,"journal":{"name":"NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics","volume":"2 4","pages":"Pages 627-637"},"PeriodicalIF":0.0,"publicationDate":"2005-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1602/neurorx.2.4.627","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25864688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}