Drug Studies in the Elderly

Clinical trials are the most definitive tool for evaluation of the applica­ bility of clinical investigations. The main objective of clinical investiga­ tions is to assess the potential value of a therapeutic entity in the treat­ ment or prophylaxis of a disease or a condition. It is also deemed necessary at this stage to obtain information regarding the undesirable side effects, associated risks, and their interrelationship with clinical assessments. Most of these clinical investigations conform, in some form or fashion, to the guidelines adopted by the Food and Drug Administration (FDA) for a given class of compounds. Clinical investigations in the past have not included specific studies in special or subpopulations, e.g., the elderly. Because of an ever-increasing elderly population, newer policies for clinical investigations are now being debated with the recognition of enhanced drug sensitivity in this special population. This key research activity can lead not only to improved health care in the elderly but also to control of its costs.

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.