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Neurogenomics and Neurotherapeutic Strategies: New Directions in Platforms, Targets, and Therapeutic ApproachesPublished by: CHI Insight Pharma Reports Published: Mar. 1, 2005 - 296 Pages Table of ContentsChapter 1. Introduction 1.1 Alzheimer’s Disease 1.2 Parkinson’s Disease 1.3 Amyotrophic Lateral Sclerosis 1.4 Schizophrenia 1.5 Depression 1.6 Bipolar Disorder 1.7 Conclusion Part 1. Neurological Diseases Chapter 2. Alzheimer's Disease 2.1 Epidemiology of Alzheimer’s Disease 2.2 Types of Dementia Parkinson’s Disease Diffuse Lewy Body Disease Vascular Dementia Multi-Infarct Dementia Subcortical Vascular Dementia Frontal Lobe Dementia and Pick’s Disease Huntington’s Disease 2.3 Etiology and Pathophysiology: How the AD Brain Works 2.4 The Genetics of AD Classification of AD Types Based on Genetic Inheritance Genes Involved in Early- and Late-Onset AD The Apolipoprotein E (APOE) Gene The GSTO1 Gene and Age of Onset of AD 2.5 AD Therapeutics Cholinesterase Inhibitors: The Gold Standard for Mild-to-Moderate AD Treatment for Moderate to Severe AD: The Glutamate Pathway Investigative Therapies for AD Axonyx’s Phenserine Cortex Pharmaceuticals’ CX516 CeregeneR 17's Nerve Growth Factor (NGF) Neurochem’s Alzhemed Targacept’s NNRs Memory Pharmaceuticals’ Compounds Myriad Genetics’ Compounds Eunoe’s COGNIShunt: A Medical Device Prana Biotechnology’s PTB-1 Compound Praecis Pharmaceuticals’ Apan ReGen Therapeutics’ Colostrinin Acumen Pharmaceuticals’ ADDL Mechanism Sanofi-Synthélabo GlaxoSmithKline Wyeth Bristol-Myers Squibb Forest Laboratories Boehringer-Ingelheim Pharmaceuticals Hoffmann-La Roche Alternative Treatments for Alzheimer’s Disease Coenzyme Q10 or Ubiquinone Ginkgo biloba Huperzine A Phosphatidylserine Vitamin E Other Naturopathic Treatments 2.6 Early-Stage Tools and Approaches Used in Alzheimer’s R&D A Urine Test to Detect AD The Trojan Horse Strategy Notch-Protein Signaling Cascade Transthyretin Protein Samaritan Pharmaceuticals’ Neuroprotective Compound SP-33 Biomarkers for AD CCR1 As a Biomarker The M266 Biomarker for Amyloid in the Blood A Biomarker Panel for AD Detection Vaccines for AD Elan’s AN-1792 Vaccine (Suspended) Oral Vaccine Developed Repurposing Other Drugs for AD Clioquinol: An Antibiotic Lithium Shows Promise in AD Mouse Model Lipitor and Other Statins Cell Therapy In Vitro Brain Slice Techniques The Role of Fyn in Synaptic Impairment 2.6 R&D Platforms Molecular Imaging Positron Emission Tomography (PET) Pittsburgh Compound B FDDNP Applications of PET in Drug Efficacy Testing Selected Imaging Initiatives Focusing on AD The NIA’s Neuroscience and Neuropsychology of Aging Program The Alzheimer’s Disease Neuroimaging Initiative The UCLA Neuroimaging Lab Li-Cor Biosciences’ Odyssey Infrared Imaging System for AD Animal Models of AD APP Models PS1 Models Transgenic Mice Transgenic Flies Companies and Organizations and Their AD Animal Models Tranzyme Pharma’s TranzExpression Technology Neurome’s Analysis of Elan’s Mouse Model of AD Baylor College of Medicine’s VGLUT1 Knockout Mice Harvard Medical School’s p25 and Cdk5 mouse model Johns Hopkins University’s Mouse Model of BACE1 Inhibition University of California at Irvine’s Triple Transgenic Mice Chapter 3. Parkinson's Disease 3.1 Epidemiology of PD 3.2 Etiology and Pathology of PD 3.3 Symptoms of PD Tremor Rigidity Bradykinesia Postural Instability 3.4 The Genetics of PD Genetic Risk Factors Mitochondrial Impairment Genes for Early-Onset PD Genes for Late-Onset PD 3.5 Other Theories of Etiology Oxidative Neuronal Damage Smoking and Coffee Free-Radical Theory Endogenous and Exogenous Toxins 3.6 Parkinsonism: Conditions That Mimic PD Postencephalitic Parkinsonism Drug-Induced Parkinsonism Striatonigral Degeneration Arteriosclerotic Parkinsonism Toxin-Induced Parkinsonism Parkinsonism-Dementia Complex of Guam Parkinsonism Accompanying Other Conditions 3.7 Parkinson’s Disease Therapeutics Levodopa-Carbidopa: The Gold-Standard Treatment Other Leading Therapeutic Classes Dopamine Agonists Selegiline Anticholinergic Drugs Amantadine COMT Inhibitors Improvements on Current Therapies Tolcapone Combination Therapy Parcopa Orally Disintegrating Tablets Investigational Treatments for Parkinson’s Disease Newron Pharmaceuticals’ Safi namide Aderis Pharmaceuticals’ SPM-962 (Rotigotine) Avigen’s AV-201 Gene Therapy Approach Ceregene’s GDNF Gene Delivery Approach Acadia Pharmaceuticals’ ACP-103 Boston Life Sciences’ Altropane Imaging Agent Cephalon’s CEP-1347 Neurologix’s NLX-P101 Gene Therapy Schering-Plough’s Adenosine-2a Antagonist Teva Neuroscience/Eisai’s Agilect (Rasagiline mesylate) Titan Pharmaceuticals’ Speramine Guilford Pharmaceuticals’ Neuroimmunophilin Ligands GlaxoSmithKline’s ReQuip 3.8 Surgical Procedures to Treat Parkinson’s Disease Lesioning Techniques Deep-Brain Stimulation Activa Tremor Control System 3.9 Investigative Pathways and Techniques The Dopamine Degeneration Theory of PD MPTP As an Investigative Tool Dopamine Transporter Malfunction Novel Dopamine Receptors Dopamine Implants PET Scanning of Dopamine Receptors Controlled-Release Formulas and Implantable Pumps Cellular Implant Therapies Nerve Cell Implantation LEAPS: Encapsulated Cell Delivery of GDNF Stem-Cell Approaches The Inflammation Model of PD Sonic Hedgehog and Gli-1 Proteins 3.10 Animal Models Platforms in PD Transgenic Mice and Other Nonprimate Models: Applications and Limitations Nonhuman Primate Models Toxin Models MPTP 6-OHDA Rotenone Gene-Knockout and Transgenic Animals Chapter 4. Amyotrophic Lateral Sclerosis 4.1 Epidemiology of ALS 4.2 Etiology, Pathophysiology, and Genetic Components of ALS SOD1: The First ALS Gene ALS2 ALS4 Linkage to Chromosome 16 Other ALS Gene Mutations Neurofilament Gene Mutations in Sporadic ALS 4.3 ALS Therapeutics Riluzole: The Gold-Standard Treatment for ALS Other Treatments for ALS Colchicine Fluorouracil (Pfizer’s Adrucil) Investigational Treatments for ALS CytRx’s RNAi Gene-Silencing Technology Ceregene and Chiron’s IGF-1 Gene Therapy Programs Ceftriaxone, Promethazine, and Ebselen Compounds Under Investigation at the ALS Therapy Development Foundation Lantus Insulin ICV Long-Acting IGF-1 Trehalose Nelfinavir Guanidine hydrochloride TNF-alpha Polyamines Counting N eurons 4.4 Early-Stage Approaches in ALS R&D The Oxidative Stress Model The SOD1 Toxin Model Regenerating Axons via Nogo Inhibition SOD1 Mutations: Neuronal Aggregates and Abnormal Protein Folding 4.5 Tools and Platforms for Discovery Biomarkers Stem Cells The Challenge to the Use of Stem Cells in ALS Olfactory Bulb Stem Cells Olfactory Neural Stem Cells in the Mouse Model for ALS Spinal Cord Stem Cells The Role of Astrocytes in Neuronal Degeneration Peripherin and the Role of Toxic Splice Variants in ALS Gene Therapy Trophic Factors IGF-1 Autoimmunity and IgG VEGF Animal Models The SOD1 Transgenic Mouse Model of ALS The Wobbler Mouse Candida albicans Reintroduction of Stem-Cell-Generat ed Motor Neurons into an ALS Rat Model The SOD1 C. elegans Model Zebrafish Model Part 2. Psychiatric Disorders Chapter 5. Schizophrenia 5.1 Epidemiology of Schizophrenia 5.2 Types of Schizophrenia and Related Illnesses Paranoid Schizophrenia Disorganized (Hebephrenic) Schizophrenia Catatonic Schizophrenia Residual Schizophrenia. Schizoaffective Disorder Undifferentiated Schizophrenia. Differential Diagnosis: Bipolar Disorder (Manic Depression) 5.3 Pathophysiology of Schizophrenia 5.4 Manifestations and Symptoms Manifestations Symptomatology Distorted Perceptions of Reality Hallucinations and Illusions Delusions Disordered Thinking Emotional Expression 5.5 Genetic Basis of Schizophrenia Genetic Predisposition-Familial Linkage Genes Discovered Key Genes Involved Dysbindin-1 Neuregulin-1 (NRG1) ERBB3 G30, G72, and DAO RGS4 COMT PRODH Conclusion 5.6 Schizophrenia Therapeutics Currently Marketed Antipsychotic Drugs Companies with Therapeutics Under Investigation GlaxoSmithKline Wyeth Targacept American Biogenetic Sciences NPS Pharmaceuticals Cortex Pharmaceuticals deCODE genetics Acadia Pharmaceuticals Potomac Pharma and the Stanley Medical Research Institute 5.7 Mechanisms of Action and Pathways Under Investigation Glutamate and Dopamine Neurotransmitter Systems Glutamate Receptor: GRM Linkage Mapping Studies Research at the Mental Health Research Institute Brain Scans The Muscarinic Receptors Serotonin Receptors Benzodiazepine Binding Sites Role of Apolipoproteins Protein S100b High-Throughput Screening to Identify Genes Involved in Schizophrenia Pathology Brain Serotonin Abnormal Eye Movements Unraveling Endophenotypes New Dynamic Imaging Techniques for Studying Schizophrenia Brain Imaging The Endocannabinoid Syst em PKC Overactivation Glycine Transporters Prenatal Evidence of Schizophrenia As a Developmental Disorder Early Biochemical Changes 5.8 Animal Models Prepulse Inhibition in Mice and Rats Administration of Hallucinogens in Animal Models Blocking NMDA Receptors in Animal Models Mice Lacking the Brain Protein Calcineurin Chapter 6. Major Depression 6.1 Epidemiology 6.2 Types of Depression Dysthymia Bipolar Depression Seasonal Affective Disorder 6.3 Symptoms 6.4 Causes of Major Depression The Monoamine Theory 6.5 Therapeutic Classes for Depression Marketed Therapeutic Treatments Tricyclic Antidepressants Monoamine Oxidase Inhibitors Selective Serotonin Reuptake Inhibitors Serotonin and Norepinephrine Reuptake Inhibitors Bupropion Therapeutics Under Investigation Neurocrine Biosciences: Corticotropin-Releasing Factor Pherin Pharmaceuticals Targacept Wyeth GlaxoSmithKline Pfizer Sanofi-Synthélabo AstraZeneca Aventis Pharmaceuticals Eli Lilly Forest Laboratories Lexicon Genetics Somerset Pharmaceuticals Alternative Treatments Psychothe rapy Cognitive-Behavioral Therapy Interpersonal Therapy Electroconvulsive Therapy 6.6 New Genes Discovered TPH2 Isoform A New Gene Discovery: CHRM2 NIMH Research Efforts University of Pittsburgh Research Efforts: Locating Chromosomal Regions CREB1 Gene Susceptibility Gene 6.7 Mechanisms of Action and Pathways Under Investigation Fibroblast Growth Factors Blocking Neuron Formation 6.8 Tools and Platforms Used to Study Depression Imaging Technologies Brain Imaging PET Technology Animal Models Catecholamine Deficiency Learned Helplessness Behavioral Despair Chapter 7. Bipolar Disorder 7.1 Epidemiology 7.2 Symptoms Hypomania Psychosis 7.3 Types of Bipolar Disorder 7.4 Causes of Bipolar Disorder 7.5 Bipolar Disorder Treatments Currently Marketed Treatments Mood Stabilizers Antiseizure Medications Antidepressants Atypical Antipsychotics Psychotropics Psychosocial Interventions Alternative Treatments Electroconvulsive Therapy Herbal Remedies 7.6 Genetic Elements and Investigational Meth ods and Approaches DARPP-32, PENK, and TAC1 G-Protein Receptor Kinase 3 Other GRK3 Gene Evidence GSK-3 Inhibition Brain-Imaging Studies Benzodiazepine Binding Sites Protein S100b LifeShirt System for Monitoring Cardiopulmonary Parameters Fine Mapping in Candidate Chromosomal Regions Scanning Genes for Variation Part 3. Companies and Pipelines Chapter 8. Therapeutics in Development 8.1 Company Profiles: Company Focus; Targets and Technology; In the Pipeline Acadia Pharmaceuticals Avigen Cephalon Ceregene Cortex Pharmaceuticals CytRx deCODE genetics Lexicon Genetics Neurochem Neurocrine Biosciences Neurologix Newron Pharmaceuticals NPS Pharmaceuticals Prana Biotechnology Targacept Chapter 9. Business Outlook 9.1 Expert Commentaries Raymond T. Bartus (Ceregene) Uli Hacksell (Acadi Pharmaceuticals) Michael Sorell (Neurologix) Wendell Wierenga (Neurocrine Biosciences) 9.2 Overvivew of Unmet R& amp;D Needs Animal Model Considerations The Search for more effective Treatments 9.3 Clinical Trial Considerations Issues in Endpoint Selection 9.4 Advances in Molecular Diagnostics AD, PD, ALS 9.5 Competitive Considerations Tables and Figures Table 2.1: Genes Associated with Alzheimer’s Disease Table 2.2: Drugs Marketed for Alzheimer’s Disease Table 2.3: Compounds in Development for Alzheimer’s Disease Table 3.1: Genes Associated with Parkinson’s Disease Table 3.2: Drugs Marketed for Parkinson’s Disease Table 3.3: Drugs in Development for Parkinson’s Disease Table 4.1: Genes Associated with Amyotrophic Lateral Sclerosis Table 4.2: Marketed Drugs for Amyotrophic Lateral Sclerosis Table 4.3: Drugs in Development for Amyotrophic Lateral Sclerosis Table 5.1: Genes Associated with Schizophrenia Table 5.2: Drugs Approved for Schizophrenia Table 5.3: Selected Compounds under Investigation for Schizophrenia Table 6.1: TCA Class of Compounds Table 6.2: MAOI Class of Compounds Table 6.3: SSRI Class of Compounds Table 6.4: SNRI Class of Compounds Table 6.5: Dopamine Transporter Blocker Class of Compounds Table 6.6: Mixed-Action 5-HT Class of Compounds Table 6.7: Selected Compounds in Development for Depression Table 6.8: Genes Associated with Depression Table 7.1: Marketed Drugs for Bipolar Disorder Table 7.2: Selected Compounds in Development for Bipolar Disorder Table 7.3: Genes Associated with Bipolar Disorder Figure 2.1: Prevalence of Alzheimer’s Disease in the United States, 1980-2050 Figure 2.2: From APP to Beta-Amyloid Figure 2.3: Preclinical, Mild-to-Moderate, and Severe Alzheimer’s Disease Figure 2.4: Acetylcholine Is Diminished in the AD Brain Figure 2.5: PET Scans of Normal and AD Brains Figure 3.1: Parkinson’s Disease Prevalence in the United States, 1980-2010 Figure 4.1: Neuronal Degeneration Points in Amyotrophic Lateral Sclerosis Figure 4.2: Comparison of Normal Nerve Cell with ALS Nerve Cell Figure 5.1: The Genetic Risk of Developing Schizophrenia Figure 5.2: Cellular Disarray in Hippocampus of Schizophrenic Brain Figure 7.1: The Spectrum of Mood States in Bipolar Disorder AbstractNeurogenomics and Neurotherapeutic Strategies: New Directions in Platforms, Targets, and Therapeutic Approaches evaluates drug development efforts in six major CNS diseases:
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