Drug Studies in the Elderly

I Research Determinants in Aging.- 1 Epidemiology and Demography of Aging: Some Lessons in Shortsightedness.- 1. Introduction.- 2. Demographic Trends in Aging.- 2.1. Migration of the Elderly.- 2.2. Patterns of Life Changes.- 2.3. Life Expectancy.- 3. Epidemiology of Health and Illness among the Elderly.- 3.1. Prevalence of Various Medical Conditions in the Elderly.- 3.2. Cardiovascular Disease among the Elderly.- 3.3. Aging and Dementia.- 3.4. Injuries and the Elderly.- 3.5. Well-Being and the Elderly.- 3.6. Suicide.- 3.7. Disability.- 4. Drugs and the Elderly.- 5. Overview.- References.- 2 Age: A Complex Variable.- 1. Introduction.- 2. Defining the Age Variable: Does It Describe Aging?.- 2.1. Biological Age.- 2.2. Functional Age.- 2.3. Pitfalls of Age Concepts.- 3. Clinical Trials in Geriatrics: Pharmacological Basis.- 4. Conclusions.- References.- 3 Physiological Changes with Aging: Relevance to Drug Study Design.- 1. Introduction.- 2. Drug Absorption.- 2.1. Reduced Gastric Motility.- 2.2. Increased Gastric pH.- 2.3. Reduced Small Intestinal Absorptive Surface Area.- 2.4. Reduced Portal Circulation.- 3. Drug Distribution.- 3.1. Plasma Protein Levels.- 3.2. Plasma Volume.- 3.3. Lean-to-Fat Ratio.- 3.4. Red-Blood-Cell Changes.- 3.5. Distribution into Urine.- 4. Drug Metabolism.- 4.1. Liver Blood Flow.- 4.2. Liver Size.- 4.3. Number and Function of Individual Hepatocytes.- 4.4. Hepatic Metabolizing Capacity.- 4.5. Enzyme Induction.- 5. Renal Drug Excretion.- 6. Drug Response.- 7. Conclusion.- References.- 4 Immunity and Aging.- 1. Introduction.- 2. Thymus Gland and Aging.- 3. Immunosenescence at the Cellular Level.- 4. Methodological Concerns for Basic Immunological Research in Aging.- 5. Clinical Consequences.- 6. Methodological Concerns for Clinical Research in Immunology and Aging.- References.- 5 Cardiovascular Changes with Aging.- 1. Introduction.- 2. Pathological Changes.- 3. Physiological and Biochemical Changes.- 4. Abnormalities of Blood Pressure.- 5. Maximal Work Performance.- 6. Invasive Procedures.- 7. Echocardiography.- 8. Radionuclide Techniques—Thallium 201.- 9. Radionuclide Techniques—Equilibrium Angiography.- 10. Electrocardiographic Changes.- 11. Conclusions.- References.- 6 The Effects of Age on Hepatic Drug Metabolism.- 1. Introduction.- 1.1. Hepatic Anatomical Changes with Age.- 1.2. Hepatic Physiological Changes with Age.- 2. Physiological Model of Hepatic Drug Metabolism.- 2.1. Clearance Concept.- 2.2. Intrinsic Clearance.- 2.3. Drug Binding.- 2.4. Classification of Drugs According to Extraction Ratio.- 2.5. Systemic Total Drug Clearance and Apparent Oral Drug Clearance.- 2.6. First-Pass Metabolism.- 2.7. Estimation of Hepatic Blood Flow and Intrinsic Clearance.- 3. Physiological Changes in the Liver with Age.- 3.1. Liver Blood Flow.- 3.2. Drug-Metabolizing Enzyme Activity.- 3.3. Drug Binding.- 4. Methodological Considerations.- 4.1. Subject Selection.- 4.2. Study Design.- 4.3. Protocol Selection.- 4.4. Data Analysis.- 5. Conclusions.- References.- 7 Hematological Effects of Aging: Considerations for Clinical Trials.- 1 Introduction.- 2. Effects of Aging on Blood Cells and Bone Marrow.- 2.1. Red Blood Cells.- 2.2. Leukocyte s.- 2.3. Platelets.- 2.4. Bone Marrow: Cellularity, Cytogenetics, and Function.- 3. Effects of Drugs on the Blood and Bone Marrow.- 3.1. General Considerations.- 3.2. Are the Elderly More Susceptible to Drug Effects on the Blood and Bone Marrow?.- 4. Methodological Considerations for Clinical Drug Trials in the Elderly.- References.- 8 The Aging Brain.- 1. Introduction.- 2. Brain Metabolism and Aging in the Rat.- 3. The Stressed Nervous System.- 4. Cerebral Metabolic Function and Aging in Humans.- 5. Cerebral Metabolic Function and Alzheimer’s Disease.- 6. Receptor Function and the Aging Brain.- 7. Summary.- References.- II Pharmacokinetics and Pharmacodynamics in the Elderly.- 9 The Tricyclic Antidepressants.- 1. Introduction.- 2. Diagnosis.- 3. Pharmacokinetic Factors.- 3.1. Drug Interactions.- 3.2. Coexisting Organic Pathology.- 4. Pharmacodynamic Factors.- 4.1. Intrinsic Drug Actions.- 4.2. Coexisting Organic Pathology.- 4.3. Additive Drug Effects.- References.- 10 Methodological Concerns for Clinical Trials in Geriatrics: Benzodiazepines.- 1. Introduction.- 2. Pharmacokinetic Trials.- 2.1. Selection of Subject Populations.- 2.2. Design of the Pharmacokinetic Study.- 3. Benzodiazepine Pharmacodynamic Studies in Geriatrics.- 3.1. Drug-Sensitive Pharmacodynamic Measures.- 3.2. Review of Benzodiazepine Pharmacodynamics in the Elderly.- 3.3. Pharmacodynamics in Elderly Patients with Underlying Disease.- 4. Conclusion.- References.- 11 Effect of Age on the Clinical Pharmacokinetics of Antiarrhythmic Drugs.- 1. Introduction.- 2. Major Antiarrhythmic Agents.- 2.1. Disopyramide.- 2.2. Lidocaine.- 2.3. Procainamide.- 2.4. Quinidine.- 3. New Antiarrhythmic Agents.- 3.1. Amiodarone.- 3.2. Cibenzoline.- 3.3. Encainide.- 3.4. Flecainide.- 3.5. Lorcainide.- 3.6. Mexiletine.- 3.7. Pirmenol.- 3.8. Propafenone.- 3.9. Tocainide.- 4. Commentary.- References.- 12 Beta Blockers in the Elderly.- 1. Introduction.- 2. Pharmacokinetics of Beta Blockers in the Elderly.- 3. Systemic Bioavailability.- 4. Distribution.- 5. Clearance.- 6. Sensitivity of Beta Blockers.- 7. Beta-Blocker Efficacy.- 8. Beta-Blocker Toxicity.- 9. Suggestions Regarding Pharmacokinetic Study Design.- 10. Concerns for Future Investigations.- References.- 13 Antiepileptic Drugs in the Elderly.- 1. Introduction.- 2. Studies of Antiepileptic Drug Efficacy and Toxicity.- 3. AED Pharmacology in the Elderly.- References.- 14 Pharmacokinetics and Bioavailability of Corticosteroids in the Treatment of Neurological Diseases of the Elderly.- 1. Introduction.- 2. Factors That Influence Clinical Responses to Administered Steroids.- 2.1. Normal Bioavailability and Pharmacokinetics.- 2.2. Pharmacokinetic Considerations of Steroids Administered in Geriatric Patients.- 3. Administration of Corticosteroids in Neuromuscular Diseases of the Elderly.- 3.1. The Aging Neuromuscular System.- 3.2. Common Neuromuscular Problems in the Aged That Need Steroid Therapy.- 3.3. Incidence of Side Effects from Therapeutic Doses of Corticosteroids in the Elderly.- 4. Conclusions.- References.- 15 Pharmacological Treatment of Parkinson’s Disease.- 1. Introduction.- 2. Levodopa.- 3. Extracerebral Decarboxylase Inhibitors.- 4. Artificial Dopamine Agonists.- 5. Monoamine Oxidase Inhibitors.- 6. Anticholinergics.- 7. Amantadine.- 8. Conclusions.- References.- 16 Cognitive Enhancers in Alzheimer’s Disease.- 1. Introduction.- 2. Empirical Therapy.- 3. Pharmacological Basis for Neurochemical Investigations.- 3.1. Cholinergic System.- 3.2. Noradrenergic System.- 3.3. Dopaminergic/GABAergic Systems.- 3.4. Serotoninergic System.- 3.5. Neuropeptidergic Systems.- 3.6. Glycolytic Enzymes.- 4. Brain Transplantation.- 5. Methodological Concerns.- 5.1. Subject Description.- 5.2. Description of Severity.- 5.3. Screening.- 5.4. Duration of a Therapeutic Trial.- 5.5. Role of Pilot Studies.- 5.6. Neuropsychological Measures.- 5.7. End-Organ Measures.- 6. Conclusion.- References.- III General Perspectives.- 17 Dosage Form Considerations in Clinical Trials Involving Elderly Patients.- 1. Introduction.- 2. Dosage Control and Flexibility.- 3. Compliance.- 4. Dosage Form Performance in Elderly Patients.- 5. Conclusions.- References.- 18 Clinical Trial Design—Industry Perspective.- 1. Introduction.- 2. Industry-Sponsored Drug Studies.- 3. Elderly Issues.- 4. Phase I: Pharmacokinetics.- 5. Phase II.- 6. Subject Selection.- 7. Phase III.- 8. New Therapeutic Objectives.- 9. Conclusions.- References.- 19 Methodological Issues: A Regulatory Perspective.- 1. Introduction.- 2. Domestic Drug Regulation: Its Aims and Requirements.- 3. Drug Development Program Design.- 4. Safety, Efficacy, and Directions for Use.- 4.1. Efficacy Issues.- 4.2. Outcome Assessment Measures.- 4.3. Safety.- 5. Special Studies.- 6. Conclusion.- References.- 20 Statistical Analysis of Drug Disposition Data.- 1. Introduction.- 2. Deterministic Approach.- 2.1. Model Development.- 2.2. Data Analysis.- 2.3. Parameter Estimation.- 2.4. Weighting of Data.- 2.5. Model Validity.- 2.6. Model Discrimination and Selection.- 2.7. Variance Estimates for Model Parameters.- 2.8. Correlation of Model Parameters.- 3. Nondeterministic Approach.- 3.1. Markovian Approach.- 3.2. Population Statistics.- 3.3. Kalman Filtering.- References.- 21 Analytical Methods.- 1. Introduction.- 2. Instrumentation.- 3. Method Development.- 4. Quality Control.- 5. Specimen Collection and Storage.- 6. Metabolite Measurement.- 7. Plasma Protein Binding.- References.- 22 Nursing Perspectives on Clinical Trials in Geriatrics.- 1. Introduction.- 2. Planning the Protocol.- 3. In-Service Education.- 4. Subject Screening.- 5. Informed Consent.- 6. Preservation of Patient Comfort and Safety.- 7. Administration of the Investigational Agent.- 8. Scheduling and Collection of Data.- 9. Documentation.- 10. Controlling Variables.- 11. Compliance.- 12. Discharge Planning and Follow-Up.- 13. Patient Teaching and Counseling.- 14. Clinical Nurse Specialist.- 15. The Nursing Administrator.- 16. Conclusion.- References.