Management of HIV disease involves combination regimens of antiretroviral drugs including the protease inhibitors. Pharmacologically these compounds are of interest and a number of questions remain as to how best assure their optimal use. Pharmacokinetically, the protease inhibitors are prone to drug interactions as these drugs are complex metabolically being primarily metabolized by cytochrome P450 isozymes. In addition, issues relation to overall drug exposure and how this correlates with clinical outcome (pharmacodynamics) is of importance as suboptimum exposure (e.g. low drug levels and/or poor adherence) can result in the development of drug resistance while excessive exposure (e.g. high drug levels) may lead to toxicity. Both pharmacokinetic changes as well as variability in adherence to prescribed regimens (two separate components) can impact on exposure of these drugs and their insulting clinical effect. Ethanol is a substance of abuse for HIV infected patients and it may alter the pharmacokinetics of these drugs either by inducing drug metabolism as observed in the present of acutely high ethanol levels. This project will investigate these potential ethanol effects and determine the pharmacokinetics and pharmacodynamics of these antivirals in chronic ethanol users as compared to light/non-drinkers. The pharmacokinetic component of this project will include pharmacokinetic evaluations of the protease inhibitors in chronic ethanol users during acute co- administration with ethanol, as well as in the absence of acutely high levels of ethanol, to investigate the potential metabolic inhibiting and inducing effects of ethanol respectively. The data will be compared to results obtained in light/nondrinkers, using both population pharmacokinetic measurements as well as information on adherence so that overall drug exposure can be estimated. This in turn will be correlated in the Program Project with measures of clinical response (relating to the CNS and PNS morbidity of HIV disease). Finally, the disposition of these drugs in the CSF will be investigated. This project will provide important data on the effect of chronic heavy ethanol use on the metabolism and efficacy of anti-retroviral agents for HIV disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Program Projects (P01)
Project #
5P01AA011493-02
Application #
6200915
Study Section
Project Start
1999-09-01
Project End
2000-08-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Northern California Institute Research & Education
Department
Type
DUNS #
City
San Francisco
State
CA
Country
United States
Zip Code
94121
Cardenas, Valerie A; Durazzo, Timothy C; Gazdzinski, Stefan et al. (2011) Brain morphology at entry into treatment for alcohol dependence is related to relapse propensity. Biol Psychiatry 70:561-7
Van Boven, Robert W; Harrington, Greg S; Hackney, David B et al. (2009) Advances in neuroimaging of traumatic brain injury and posttraumatic stress disorder. J Rehabil Res Dev 46:717-57
Pa, Judy; Boxer, Adam; Chao, Linda L et al. (2009) Clinical-neuroimaging characteristics of dysexecutive mild cognitive impairment. Ann Neurol 65:414-23
Cardenas, V A; Meyerhoff, D J; Studholme, C et al. (2009) Evidence for ongoing brain injury in human immunodeficiency virus-positive patients treated with antiretroviral therapy. J Neurovirol 15:324-33
Studholme, Colin (2008) Dense feature deformation morphometry: Incorporating DTI data into conventional MRI morphometry. Med Image Anal 12:742-51
Gazdzinski, Stefan; Durazzo, Timothy C; Weiner, Michael W et al. (2008) Are treated alcoholics representative of the entire population with alcohol use disorders? A magnetic resonance study of brain injury. Alcohol 42:67-76
Gazdzinski, Stefan; Kornak, John; Weiner, Michael W et al. (2008) Body mass index and magnetic resonance markers of brain integrity in adults. Ann Neurol 63:652-7
Durazzo, Timothy C; Cardenas, Valerie A; Studholme, Colin et al. (2007) Non-treatment-seeking heavy drinkers: effects of chronic cigarette smoking on brain structure. Drug Alcohol Depend 87:76-82
Durazzo, Timothy C; Gazdzinski, Stefan; Meyerhoff, Dieter J (2007) The neurobiological and neurocognitive consequences of chronic cigarette smoking in alcohol use disorders. Alcohol Alcohol 42:174-85
Studholme, Colin (2007) Incorporating DTI data as a constraint in deformation tensor morphometry between T1 MR images. Inf Process Med Imaging 20:223-32

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