The medical legal and political systems have emphasized the importance of detection and measurement of blood drug concentrations for the evaluation of intoxication under conditions of driving and in the workplace. Yet, it is well known that blood concentrations, most often, do not correlate well with behavioral impairment because of many factors including acute and chronic tolerance. Understanding the rate limiting mechanisms that mediate the changing relation between blood drug concentrations and behavioral impairment provides a more rational basis for evaluation of intoxication. Over the years, the major goal of this proposal has been to continue to develop a rational approach for benzodiazepine cognitive-neuromotor, toxicity, assessment. This assessment approach measures operationally defined pharmacodynamic variables (characterizing side effects), while controlling for, or systematically manipulating pharmacokinetic parameters. Specific objectives include the delineation of the relative contribution to the impairment-effect time course of: 1) benzodiazepine pharmacokinetics, 2) receptor kinetics, 3) B(Z1)-B(Z2) receptor specificity of the drug. Included in these objectives are the development of model and analysis means for assessing these components. We propose to contrast the impairment effect offset rates for an ultra-short t(1/2beta) benzodiazepine following manipulation of drug infusions to achieve different drug concentration offset rates including a plateau steady state. The rapid achievement of steady state will allow for discounting certain pharmacokinetic and receptor kinetic variables in the elucidation of mechanisms involved in acute tolerance. We will also compare two ultra-short half-life benzodiazepine agonists; one a B(Z1) specific the other B(Z1)-B(Z2) non-specific, for the further evaluation of receptor typology contribution to drug impairment profile. Insomniacs will be used to assess the effects of daily dosing on chronic tolerance and its effect on acute tolerance. We will also assess the standard hallmark of intoxication, i.e., alcohol, utilizing our newer behavioral tasks and in a subject population with a wide age range in order to better establish a normative range. This normative data base will provide a descriptive """"""""legal yardstick"""""""" for comparing our impairment levels induced by drugs. A long term goal of this project is to further refine a cognitive-neuromotor task battery for its utilization as: 1) evaluation and prediction of dangerous vs. safer sedative-anxiolytic drugs for clinical use and 2) a battery used in the physicians office to facilitate more discriminatory prescribing practices. An ideal battery would lead to a reduction in morbidity and mortality of occupational and driving accidents.
Showing the most recent 10 out of 11 publications
