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Drug Discovery and Development Michael Williams

Drug Discovery and Development By Michael Williams

Drug Discovery and Development by Michael Williams


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Drug Discovery and Development Summary

Drug Discovery and Development by Michael Williams

The conceptual process of drug discovery is one that is often the result of an identified need in a defined disease area. This need represents a mandate from the marketing department of a phar- maceutical company or a breakthrough at the research level that has agreed applicability in response to a valid therapeutic demand. Although the intelligent design and development of new thera- peutic entities, as evidenced by Sir James Black's H -receptor an- 2 tagonist cimetidine (Tagamet), is intellectually satisfying, many novel drugs arise from serendipity, from the chance observation of the research scientist or the clinician, that a compound has unex- pected actions of use for the treatment of human disease states. Drugs that have been identified by this route include the antipsy- chotic chlorpromazine and the putative anxiolytic buspirone. The events surrounding the process of drug discovery and de- velopment are the theme of the present volume, which attempts to present, in a logical and lucid manner, the complexity of a process that is often naively assumed to represent nothing more than the identification of a new compound and its rapid introduction into humans, free of such complications as efficacy, selectivity, safety, bioavailability, toxicity, and need.

Table of Contents

Overview.- Drug Discovery and Development: Reflections and Projections.- 1. Introduction.- 2. Drug Discovery.- 2.1. General Issues.- 2.2. Compound Sources.- 2.3. Goal Identification.- 3. The Project Team.- 4. The Flow Chart.- 4.1. The Primary Screen.- 4.2. The Secondary Screen.- 4.3. The Tertiary Screen.- 4.4. Networking.- 4.5. Backup Compounds.- 5. Toxicological Evaluation.- 6. Clinical Evaluation.- 7. Newer Aspects Of Drug Development.- 7.1. The Mechanistic Approach.- 7.2. Drug Delivery.- 8. The Future.- 8.1. The Industry.- 8.2. ... and Society.- References.- Compound Discovery.- Drug Design.- 1. Drug Design.- 2. Lead Discovery by Design.- 3. Lead Discovery by Random and Directed Screening.- 4. Quantitative Structure-Activity Relationships.- 5. Pattern Recognition.- 6. Lead Development.- 6.1. Systematic Empirical Approach.- 6.2. Hypothesis-Based Lead Development.- 7. Conclusion.- References.- Computer-Based Approaches to Drug Design.- 1. Introduction.- 2. Theoretical Calculations.- 2.1. Molecular Mechanics-Based Approaches.- 2.2. General Limitations of Theoretical Calculations.- 2.3. Quantum Mechanics-Based Approaches.- 3. Graphical Displays of Molecular Geometry and Steric Volume.- 4. Display of Electronic Properties.- 4.1. Limitations of Partial Charges in Modeling Electronic Interactions.- 4.2. Electrostatic Potential Displays.- 4.3. Qualitative Nature of Electrostatic Potential Displays.- 4.4 Isopotential Surface Displays.- 5. Macromolecular Systems.- References.- Use of Intact Tissue Preparations in the Drug Discovery Process.- 1. Introduction.- 2. General Concepts.- 2.1. Receptors.- 2.2. Dose-Response.- 3. Relevance to Drug Development.- 3.1. Calcium Antagonists.- 3.2. H2 Antagonists.- 3.3. Leukotriene Antagonists.- 4. Summary.- References.- Neuropsychopharmacological Drug Development.- 1. Introduction.- 2. Anxiolytic Drug Discovery and Development.- 2.1. Antianxiety Activity.- 2.2. Anticonvulsant Activity.- 2.3. Muscle Relaxant Potential.- 2.4. Assessment of Sedation and Neuromuscular Impairment.- 2.5. Evaluation of Drug-Interaction Liabilities.- 2.6. Dependence Liability.- 2.7. Behavioral Assessment of Benzodiazepine Antagonist Activity.- 2.8. Behavioral Differentiation of Benzodiazepine Displacer and Nondisplacer Anxiolytics.- 2.9. Potential False Positives.- 3. Summary.- References.- Biochemical Approaches for Evaluating Drug-Receptor Interactions.- 1. Introduction.- 2. Neurotransmitter Receptor Binding.- 2.1. Criteria for Identification of a Receptor Binding Site.- 2.2. Analysis of Binding Data.- 2.3. Drug-Binding Site Interactions.- 3. Receptor-Mediated Responses.- 3.1. Cyclic AMP.- 3.2. Phosphatidylinositol Metabolism.- 4. Drug Screening.- References.- Drug Discovery at the Enzyme Level.- 1. Introduction.- 2. Enzyme Assays In Vitro.- 2.1. Detecting Substrate Disappearance or Product Formation.- 2.2. Reaction Conditions.- 3. Sources of Inhibitors.- 3.1. Chemical Synthesis.- 3.2. Natural Products.- 4. Characterization of Inhibitors In Vitro.- 4.1. Reversible or Irreversible.- 4.2. Competitive, Noncompetitive, or Uncompetitive Inhibitors.- 4.3. Specificity.- 5. Demonstration of Enzyme Inhibition In Vivo.- 5.1. Ex Vivo Inhibition.- 5.2. Substrate Conversion In Vivo.- 5.3. Antagonism of Mechanism-Based Inactivation.- 5.4. Substrate Accumulation or Product Depletion.- 5.5. Functional Effects.- 6. Specific Examples of Enzyme Inhibitors Used as Drugs.- 6.1. Monoamine Oxidase Inhibitors.- 6.2. Xanthine Oxidase Inhibitors.- 6.3. Carbidopa.- 7. Summary.- References.- EEG, EEG Power Spectra, and Behavioral Correlates of Opioids and Other Psychoactive Agents.- 1. Electroencephalography (EEG) - An Overview.- 2. Use of EEG and EEG Power Spectra in Drug Classification.- 2.1. Clinical Use of EEG Quantification in the Study of Psychoactive Drugs.- 2.2. Pharmaco-EEG Correlates of Psychoactive Agents in Experimental Animals.- 3. Delineation of Opioid Pharmacodynamic Properties with EEG and Behavior.- 3.1. Introduction.- 3.2. Differential Effects of Mu, Kappa, and Sigma Agonists on EEG, EEG Power Spectra, and Behavior.- 3.3. Tolerance and Cross-Tolerance Among Opioids.- 3.4. Differential Abstinence Syndromes Between Rats Chronically Treated with Mu and Kappa Opioid Agonists.- 3.5. Characteristic Changes in REM Sleep EEG Frequencies During Opioid Self-Administration.- 4. Pharmacodynamics of Other Psychotropic Drugs.- 4.1. EEG and Behavioral Effects of Ethanol.- 4.2. EEG and Behavioral Effects of Cannabinoids.- 5. Use of EEG Power Spectra in Neurotoxicology Studies.- 6. Summary and Conclusions.- References.- Immunopharmacological Approaches to Drug Development.- 1. Introduction.- 2. The Immune System.- 2.1. Anatomy.- 2.2. Cellular Components and Their Functions.- 2.3. Role of Cytokines in Immunity.- 3. Potential Therapeutic Targets for Immunomodulatory Drugs.- 3.1. Immunodeficiency Diseases.- 3.2. Autoimmune Diseases.- 3.3. Allergic Disorders.- 4. Immunomodulatory Agents.- 4.1. General Considerations.- 4.2. Classification.- 4.3. Biological Testing Procedures for Identifying Immunomodulatory Drugs.- 4.4. Immunomodulatory Agents in Current Use or Under Development.- 5. New Approaches Under Development.- 5.1. Monoclonal Antibodies.- 5.2. Cytokines.- 6. Summary.- References.- Toxicological Evaluation and Clinical Aspects.- Toxicological Evaluation of Drugs.- 1. Introduction.- 1.1. The Drug.- 1.2. The Test System.- 1.3. The Regimens.- 2. Toxicity Data Requirements.- 2.1. Acute Toxicity Studies.- 2.2. Subacute or Subchronic Toxicity (Short-Term Studies).- 2.3. Chronic Toxicity (Long-Term Studies).- 2.4. Carcinogenicity.- 2.5. Mutagenicity Studies.- 2.6. Reproduction and Teratology Studies.- 2.7. Metabolism Studies.- 2.8. Immunotoxicity Studies.- 2.9. Behavioral Toxicity Studies.- 3. Alternatives to Animal Testing.- 3.1. Short-Term In Vivo Studies.- 3.2. In Vitro Studies.- 3.3. Structure-Activity Models.- 4. Good Laboratory Practices.- 5. Future Trends in Toxicity Studies - The Age of Biotoxicology.- References.- Drug Delivery Systems.- 1. Introduction.- 2. Rationale for Selecting a Drug Delivery System.- 2.1. Terminology.- 3. Matrix Control of Drug Release.- 3.1. Theory.- 3.2. Oral Matrix Release Systems.- 3.3 Matrix Implants.- 3.4. Vaginal Inserts.- 3.5. Intrauterine Devices.- 3.6. Matrix Transdermal Delivery.- 3.7. Slow-Release Pesticide Generators.- 3.8. Nanoparticles.- 4. Membrane Control of Drug Release.- 4.1. Theory.- 4.2. Oral Dosage Forms.- 4.3. Ocular Systems.- 4.4. Transdermal Systems.- 4.5. Pesticide Generators.- 5. Ion Exchange.- 6. Biodegradable Polymers.- 6.1. Chemical Biodegradation - Matrix Release.- 6.2. Biodegradable Drug Carrier Complexes.- 7. Cellular Methods.- 7.1. Artificial/Naturally Occurring Cellular Methods.- 7.2. Liposomes.- 8. Mechanical Pumps.- 9. Conclusions.- References.- Clinical Evaluation of Drug Candidates.- 1. Introduction.- 2. Requirements and Timing for Proceeding to Human Trials.- 3. Definition and Scope of the Phases of Drug Development.- 3.1. Phase I.- 3.2. Phase II.- 3.3. Phase III.- 3.4. Phase IV.- 3.5. Phase V.- 4. Clinical Assessment of Safety.- 5. Assessment of Efficacy.- 6. Clinical Trial Methodology.- 6.1. Study Design.- 6.2. Randomization.- 6.3. Study Duration and Schedule of Observations.- 6.4. Patient Selection.- 6.5. Number of Subjects (Sample Size).- 6.6. Case Report Forms.- 6.7. Conduct and Monitoring of Clinical Trials.- 7. Ethical and Legal Considerations.- 8. New Drug Registration.- 8.1. Preparation of the New Drug Application in the US.- 8.2. NDA Review in the US.- 8.3. International Drug Registration.- References.- Therapeutic Entities-From Discovery to Human Use.- Cimetidine and Other Histamine H2-Receptor Antagonists.- 1. Peptic Ulcer Disease.- 2. Chemical Messengers and the Search for New Antiulcer Drugs.- 3. Pharmacological Characterization of Histamine Receptors.- 4. Discovery of H2-Receptor Antagonists.- 4.1. Background to Cimetidine.- 4.2. Development of Newer H2-Receptor Antagonists.- 5. Toxicology of Burimamide, Metiamide, and Cimetidine and More Recently Developed H2-Receptor Antagonists.- 6. Safety and Efficacy of Cimetidine in Widespread Clinical Use.- 7. Therapeutic Use of H2-Receptor Antagonists - Lessons Learned.- 8. Therapeutic Use of H2-Receptor Antagonists in Indications Unrelated to Hypersecretion of Gastric Acid.- References.- Atypical Psychotropic Agents: Trazodone and Buspirone.- 1. Introduction: Identifying Atypical Agents.- 2. Antidepressants.- 2.1. An Atypical Antidepressant: Trazodone.- 2.2. Discovery and Development of Nefazodone.- 3. Anxiolytics.- 3.1. Discovery and Development of Buspirone.- 3.2. Novel Mechanisms of Action.- 3.3. Second-Generation Compounds: Gepirone.- 4. Conclusions.- References.- Calcium Channel Antagonists.- 1. Introduction.- 1.1. Calcium and Cellular Function.- 1.2. Therapeutic Utility of Blocking Calcium Entry.- 2. Discovery and Physiological Effects of Calcium Channel Blockers.- 2.1. Historical Perspective.- 2.2. Physiological Effects.- 3. Biochemical Characterization.- 3.1. 3H-Dihydropyridines and Novel Antagonists.- 3.2. 3H-Phenylalkylamines.- 3.3. 3H-Diltiazem.- 4. Summary.- References.

Additional information

NLS9781461291800
9781461291800
1461291801
Drug Discovery and Development by Michael Williams
New
Paperback
Humana Press Inc.
2011-09-30
448
N/A
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