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