A series of clinical and experimental studies is proposed to evaluate the influence of the aging process on the consequences of chronic sedative-hypnotic drug administration and withdrawal. Healthy young and elderly volunteers will receive single 15-mg nightly doses of flurazepam (or placebo), used to represent the group of long half-life accumulating benzodiazepines. Prior to, during, and following 14 days of therapy, subjects will receive a test-dose challenge with a short half-life benzodiazepine (intravenous midazolam, 0.04 mg/kg, oral triazolam, 0.25 mg, or placebo). Following each test dose, plasma levels and pharmacokinetics of the test drugs are assessed in relation to changes in sedation and mood, impairment of psychomotor performance, impairment of memory, and quantitative alterations in the EEG. In analogous experimental studies, 3 groups of male CD-1 mice (young, middle-aged, and old) receive two weeks of continuous infusion (via implantable osmotic pumps) of lorazepam, clonazepam, or vehicle placebo, with infusion rates chosen to produce steady-state plasma concentrations similar to those achieved in humans. During and after the period of infusion, the following variables are quantitated: plasma and cortex drug levels, behavioral activity based on computerized monitoring, in vivo enzodiazepine receptor binding, and in vitro measures of receptor binding and function. An additional series of studies on young, middle- aged, and old CD-1 mice will assess age effects on chronic exposure to tolerance-producing and dependence-producing does of ethanol, as provided in animals' diet. After 30 days of acute withdrawal, and during long-term recovery. A clinical study of the pharmacotherapy of anxiety in abstinent alcoholics is proposed in male patients up to age 70. The effects of a single test-dose challenge of the medications to be used (halazepam, alprazolam, or buspirone) is followed by a period of long-term double-blind treatment. Plasma levels and clinical effects of the study drugs are monitored during the treatment period and the withdrawal phase.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37MH034223-15
Application #
3486500
Study Section
Treatment Development and Assessment Research Review Committee (TDA)
Project Start
1979-09-15
Project End
1994-08-31
Budget Start
1993-09-01
Budget End
1994-08-31
Support Year
15
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Tufts University
Department
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02111
Warrington, Jill S; Greenblatt, David J; von Moltke, Lisa L (2004) Age-related differences in CYP3A expression and activity in the rat liver, intestine, and kidney. J Pharmacol Exp Ther 309:720-9
Greenblatt, David J; Von Moltke, Lisa L; Giancarlo, Gina M et al. (2003) Human cytochromes mediating gepirone biotransformation at low substrate concentrations. Biopharm Drug Dispos 24:87-94
Bertelsen, Kirk M; Venkatakrishnan, Karthik; Von Moltke, Lisa L et al. (2003) Apparent mechanism-based inhibition of human CYP2D6 in vitro by paroxetine: comparison with fluoxetine and quinidine. Drug Metab Dispos 31:289-93
Tran, Thanh Huu; Von Moltke, Lisa L; Venkatakrishnan, Karthik et al. (2002) Microsomal protein concentration modifies the apparent inhibitory potency of CYP3A inhibitors. Drug Metab Dispos 30:1441-5
Stormer, Elke; von Moltke, Lisa L; Perloff, Michael D et al. (2002) Differential modulation of P-glycoprotein expression and activity by non-nucleoside HIV-1 reverse transcriptase inhibitors in cell culture. Pharm Res 19:1038-45
Perloff, Michael D; von Moltke, Lisa L; Greenblatt, David J (2002) Fexofenadine transport in Caco-2 cells: inhibition with verapamil and ritonavir. J Clin Pharmacol 42:1269-74
Olubodun, Joel O; Ochs, Hermann R; Truten, Volker et al. (2002) Zolpidem pharmacokinetic properties in young females: influence of smoking and oral contraceptive use. J Clin Pharmacol 42:1142-6
Laurijssens, Bart E; Greenblatt, David J (2002) Effect of 7-day exposure to midazolam on electroencephalogram pharmacodynamics in rats: a model to study multiple pharmacokinetic-pharmacodynamic relationships in individual animals. J Pharm Pharmacol 54:77-86
Warrington, Jill S; Von Moltke, Lisa L; Shader, Richard I et al. (2002) In vitro biotransformation of sildenafil (Viagra) in the male rat: the role of CYP2C11. Drug Metab Dispos 30:655-7
Venkatakrishnan, Karthik; Von Moltke, Lisa L; Greenblatt, David J (2002) Evaluation of Supermix as an in vitro model of human liver microsomal drug metabolism. Biopharm Drug Dispos 23:183-90

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