The major goal of this proposal is to develop an approach for benzodiazepine behavioral toxicity assessment that measures operationally defined pharmacodynamic contributions to the side effects, particularly neuromotor-cognitive impairment, while controlling for pharmacokinetic parameters. To determine the factors contributing to alterations in pharmacodynamic profiles, we will compare several benzodiazepines of differing pharmacological properties in terms of the following aspects of the behavioral drug effect: (1) de novo sensitivity-potency; (2) acute tolerance; (3) characteristics of de novo sensitivity-potency and acute tolerance for different neuromotor-cognitive functions. An important underlying premise in this proposal is that our recent findings demonstrating comparative benzodiazepine differences in potency and acute tolerance are in part based on differential receptor kinetics. To delineate further the contribution of receptor kinetics to the development of acute tolerance for different benzodiazepines, we propose the following objectives: (1) To elucidate the pharmacodynamic nature of the potentially unique high affinity binding by benzodiazepines with ortho Cl- on the """"""""C"""""""" ring in both a young and an elderly sample. (2) To elucidate the contribution of Bz1 and Bz2 receptors to benzodiazepine impairment by assessing the differential effect of a Bz1 specific drug vs. a Bz1, Bz2 nonspecific drug for coordination tasks vs. cognitive or learning-memory tasks in a young and an old population. (3) To explore the relationship between acute and chronic benzodiazepine tolerance. A long-term goal of this project is to develop a neuromotor-cognitive task battery that can be used to evaluate different sedative-anxiolytic drugs for the type, intensity and time course of impairment in order to predict expected levels of clinical impairment. Such a battery could be utilized in a physician's office to facilitate more discriminating prescribing practices as well as in the research laboratory to assess more systematically sedative-anxiolytic behavioral toxicity, especially for predicting drugs with the greatest potential for facilitating fatal traffic accidents.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA001883-07
Application #
3207022
Study Section
Drug Abuse Clinical and Behavioral Research Review Committee (DACB)
Project Start
1977-12-01
Project End
1988-08-31
Budget Start
1985-09-01
Budget End
1986-08-31
Support Year
7
Fiscal Year
1985
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

Showing the most recent 10 out of 11 publications