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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA001883-10A1
Application #
3207024
Study Section
Special Emphasis Panel (SRCD (26))
Project Start
1977-12-01
Project End
1994-05-31
Budget Start
1990-06-01
Budget End
1991-05-31
Support Year
10
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Duke University
Department
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
Tupler, L A; Hege, S; Ellinwood Jr, E H (1995) Alcohol pharmacodynamics in young-elderly adults contrasted with young and middle-aged subjects. Psychopharmacology (Berl) 118:460-70
Wilson, W H; Ellinwood, E H; Mathew, R J et al. (1994) Effects of marijuana on performance of a computerized cognitive-neuromotor test battery. Psychiatry Res 51:115-25
Gupta, S K; Ellinwood, E H; Nikaido, A M et al. (1990) Simultaneous modeling of the pharmacokinetic and pharmacodynamic properties of benzodiazepines. II. Triazolam. Pharm Res 7:570-6
Nikaido, A M; Ellinwood Jr, E H; Heatherly, D G et al. (1990) Age-related increase in CNS sensitivity to benzodiazepines as assessed by task difficulty. Psychopharmacology (Berl) 100:90-7
Gupta, S K; Ellinwood, E H; Nikaido, A M et al. (1990) Simultaneous modeling of the pharmacokinetic and pharmacodynamic properties of benzodiazepines. I: Lorazepam. J Pharmacokinet Biopharm 18:89-102
Gupta, S K; Ellinwood, E H (1990) Liquid chromatographic assay and pharmacokinetics of halazepam and its metabolite in humans. J Pharm Sci 79:822-5
Nikaido, A M; Ellinwood Jr, E H (1987) Comparison of the effects of quazepam and triazolam on cognitive-neuromotor performance. Psychopharmacology (Berl) 92:459-64
Ellinwood Jr, E H; Nikaido, A M; Heatherly, D G (1987) Comparative pharmacodynamics of benzodiazepines. Psychopharmacol Ser 3:77-82
Ellinwood Jr, E H; Nikaido, A M; Heatherly, D G et al. (1987) Benzodiazepine pharmacodynamics: evidence for biophase rate limiting mechanisms. Psychopharmacology (Berl) 91:168-74
Ellinwood Jr, E H; Heatherly, D G; Nikaido, A M et al. (1985) Comparative pharmacokinetics and pharmacodynamics of lorazepam, alprazolam and diazepam. Psychopharmacology (Berl) 86:392-9

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