AGE AND GENDER RELATED DIFFERENCES IN THE SENSITIVITY TO ETHENOL IN HUMANS
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A trial to determine if the elderly are more sensitive to the intoxicating effects of ethanol (alcohol) than younger people regardless of their ages. Increasing evidence shows that the elderly are more sensitive to the intoxicating effects of ethanol than young adults, but few studies have examined the relationship of pharmacokinetics (PK-the way the body absorbs, distributes, metabolizes, and excretes a chemical) and pharmacodynamics (PD-the reaction between drugs and a living system) for ethanol among people of different ages. Studies have been done indicating that the elderly are more sensitive, but lacked detailed PK and PD analysis, had small sample sizes, limited age ranges, exclusion of females, and lacked objective intoxication measures. This trial will attempt to provide more conclusive evidence regarding the effects of age and gender on sensitivity to ethanol by performing PK and PD analysis with a sufficient sample size in subjects of the advanced ages of more than 70 years old and by using objective measures to determine ethanol effects. This study will also provide data needed to plan future studies examining potential mechanisms of the different sensitivities to ethanol in young and old alcoholics. The elderly are a growing segment of the population and research is needed to provide data for possible frequent health problems. The study will involve eight healthy male and eight healthy female volunteers, ages 70-99, not deviating more than 15% above or below ideal weight. They must pass a physical exam with no evidence of active diseases with normal blood pressure, taking no medications that will interact with alcohol, drinking alcohol lightly or moderately, having a normal electrocardiogram (tracing of the heart), and with no history of liver, kidney, heart, lung, stomach, nerve or blood diseases. When subjects enter the Clinical Research Center, they will have a urinalysis testing for drug use and a breath alcohol test. They will complete a questionnaire concerning recent medical history and use of medications. Before dosing, volunteers will receive a snack and then fast for 10 hours. Meals will be served after dosing. Subjects will receive an intravenous infusion of ethanol. Blood samples taken periodically will be used to determine ethanol concentration and other important factors. Blood pressure will be taken and the subjects will be observed for signs of intolerance to the drug or to the procedure. Adverse effects will be reported by the subjects.
An attempt to set up a clear example for the use of cholinergic agents in the elderly by using scopolamine to impair the central nervous system. Central nervous system impairment induced by scopolamine in healthy volunteers has been advanced as a model of Alzheimer's Disease to assist in choosing doses of new cholinergic agents to be used in clinical efficacy trials in dementia patients. The hypothesis guiding this research is that the utility of the model will be improved by 1) extending it to healthy elderly volunteers to incorporate age-associated physiologic changes that can alter the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs under investigation, and 2) using PK-PD modelling approaches to examine the time course of drug concentrations and effects. The specific aims of this study are to: 1) characterize the magnitude and time course of the central and peripheral effects of scopolamine in a healthy elderly population, 2) estimate the variability in PK and PD of scopolamine in the elderly population, 3) examine the relationship between central and peripheral effects of scopolamine to generate hypothesis about surrogate markers of cognitive functions, and 4) recommend a clinical protocol for evaluating cholinergic agents for use in the treatment of Alzheimer's Disease (AD). Evidence indicates that dysfunction of the central nervous system is an early and prominent feature of Alzheimer's Disease . It is suggested that increasing the cholinergic (nerve responses) function will improve the cognitive and perhaps some of the behavioral impairment associated with AD. In addition, recent findings indicate that augmenting cholinergic neurotransmission may have disease-modifying effects by stimulating the production of nerve growth factor and inhibiting neurotoxic B-amyloid deposition. The subjects of this study will be healthy elderly people between the ages of 65 and 99 years old and must not deviate more than 15% from ideal body weight. They must pass a physical exam with no evidence of active disease. They must have a negative urine drug test and breath alcohol test. EKG, blood pressure, heart rate, oral body temperature , and an orthostatic test (supine/standing) will be done and must be within acceptable limits. They must be on no medications that are known to interact with scopolamine, known to have anticholinergic effects, or known to affect the CNS; must have a usual daily caffeine intake equal to or less than two cups of coffee; and must take no medications excluded above, alcohol, or caffeine beginning 72 hours before the study day and they must be non-smokers. After negative urine and breath tests, the subject will fill out a questionnaire concerning recent medical history and medication use, complete the Tridimentional Personality Questionnaire, and practice the psychometric test battery that is used to measure PD four times. A dose of scopolamine will be given. Blood samples will be taken through a catheter numerous times to measure PK and several will be taken to measure PD. Saliva flow measurements will be taken, heart rate will be measured and additional EKG (electrocardiogram) monitoring will be done. Safety measurements will be done to assure that there are no signs of intolerance to drugs or procedures. When measurements are scheduled for the same time, they will be conducted in the following sequence: 1) EKG, 2) blood sampling, 3) sedation scales, 4) saliva flow, 5) psychometric tests, and 6) vital signs, with blood samples being collected at exactly the scheduled time.
