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Basic aspects of catechol-O-methyltransferase and the clinical applications of its inhibitors / edited by Erkki Nissinen. — Amsterdam : Elsevier, c2010. – (59.58/P526/v.95)

Contents

        CONTENTS
    
    CONTRIBUTORS
    PREFACE
    Introductory Remarks: Catechol-O-Methyltransferase Inhibition-An Innovative Approach to Enhance L-dopa Therapy in Parkinson's Disease with Dual Enzyme Inhibition
    I. Introductory Remarks: Catechol-O-Methyltransferase Inhibition: An Innovative Approach to Enhance L-dopa Therapy in Parkinson's Disease with Dual Enzyme Inhibition
    References
    The Catechol-O-Methyltransferase Gene: its Regulation and Polymorphisms
    I. Introduction
    II. The COMT Gene
    III. Localization of COMT mRNA in the Brain
    IV. The Regulation of the COMT Gene
    V. Polymorphic Variants of COMT
    VI. Conclusions
    Acknowledgments
    References
    Distribution and Functions of Catechol-O-Methyltransferase Proteins: Do Recent Findings Change the Picture?
    I. Introduction: One Catechol-0-Methyltransferase Gene and Two mRNAs and Proteins
    II. Distribution of COMT in the Brain
    III. Distribution of COMT in the Peripheral Tissues
    IV. Distribution and Proposed Function of the Two COMT Isoforms.
    V. Recent Findings of COMT Distribution: A Study with S-COMT-Deficient Mouse
    VI. Functional Discussion
    VII. Concluding Remarks
    Acknowledgments
    References
    Catechol-O-Methyltransferase Enzyme: Cofactor S-Adenosyl-L-Methionine and Related Mechanisms
    I. Introduction
    II. Levodopa-Oral Administration Modes
    III. Homocysteine and Levodopa/DDI Application
    IV. Homocysteine Elevation
    V. Homocysteine Metabolism: A Link Between Chronic Neurodegeneration and Arteriosclerosis?
    VI. Consequences of Altered Met and SAM Levels on Motor Behavior in PD Patients?
    VII. Cysteine and PD
    VIII. Therapeutic Approaches for Homocysteine Decline in PD Patients
    IX. Conclusions
    References
    Biochemistry and Pharmacology of Catechol-O-Methyltransferase Inhibitors
    I. Introduction
    II. Kinetic Reaction Mechanism of COMT
    III. Other Enzymological Aspects
    IV. COMT Inhibitors
    V. Comparative Notes of the Properties of COMT Inhibitors at the Market
    VI. Other Effects of COMT Inhibitors
    VII. Physicochemical Properties and Animal Pharmacokinetics
    VIII. Transgenic Mice
    IX. Conclusions from Animal Studies with COMT Inhibitors
    References
    The Chemistry of Catechol-O-Methyltransferase Inhibitors
    I. Catechol-O-Methyltransferase (COMT) Physiological Role
    II. COMT Inhibitors
    III. Future Direction
    References
    Toxicology and Safety of COMT Inhibitors
    I. Introduction
    II. First-Generation COMT Inhibitors
    III. Safety Concerns of First-Generation Agents
    IV. Second-Generation COMT Inhibitors
    V. Regulatory Safety Studies with Entacapone and Tolcapone
    VI. General Safety Aspects in Clinical Trials of Second-Generation Inhibitors
    VII. Second-Generation Inhibitors in Clinical Use: Safety Concerns Associated with the Liver
    VIII. Mechanisms of Hepatotoxicity
    IX. Uncoupling of Mitochondrial Membrane Potential
    X. COMT Inhibition and Uncoupling in Relation to Protein Binding
    XI. Oxidative Stress Induced by COMT Inhibitors Does It Exist?
    XII. New Inhibitors in Development
    XIII. Are There Any Safety Concerns Connected to COMT Inhibition?
    XIV. Conclusions
    References
    Catechol-O-Methyltransferase Inhibitors in Preclinical Models as Adjuncts of L-dopa Treatment
    I. Introduction
    II. Effect of COMT Inhibition on t-dopa-Induced Long-Duration Response
    III. Effect of COMT Inhibition on L-dopa-Induced Motor Fluctuations
    IV. Effect of COMT Inhibition in L-dopa-Induced Dyskinesias
    V. Effect of COMT Inhibition in L-dopa-Induced Changes in Molecular Markers in Basal Ganglia Nuclei
    VI. Conclusions
    References
    Problems with the Present Inhibitors and a Relevance of New and Improved COMT Inhibitors in Parkinson's Disease
    I. Introduction
    II. Pharmacokinetic Problems
    III. Pharmacodynamic Problems
    IV. Efficacy Problems
    V. Safety Problems
    VI. New COMT Inhibitors
    VII. What Would Be an "Optimal" COMT Inhibitor/Inhibition and Levodopa/DDC Combination?
    VIII. Conclusion
    References
    Catechol-O-Methyltransferase and Pain
    I. Introduction
    II. Animal Studies
    III. COMT Polymorphisms in Acute Clinical and Experimental Pain in Humans
    IV. General Mechanistic Discussion
    Acknowledgments
    References
    INDEX
    CONTENTS OF RECENT VOLUMES