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Clinical pharmacology of tobacco alkaloids

Institution: University of California, San Francisco
Investigator(s): Peyton Jacob, Ph.D.
Award Cycle: 2001 (Cycle 10) Grant #: 10RT-0215 Award: $373,408
Subject Area: General Biomedical Science
Award Type: Research Project Awards

Initial Award Abstract
The objective of this project is to develop methods for measuring human exposure to toxic substances present in tobacco and tobacco smoke. Despite advances in smoking cessation research and new pharmacotherapies for tobacco addiction, many people who want to quit are unable to do so. Consequently, there is considerable interest in “harm reduction,” the possibility of reducing the harmful effects of continued tobacco use in persons who are unable to quit. Tobacco companies are developing products that are claimed to deliver lower levels of toxic substances to the user than do conventional cigarettes. Tobacco addiction treatment researchers are investigating the possibility that smokers’ cigarette consumption can be reduced (for example, with nicotine gum or patches) and that this may lead to reduced health risk.

A major issue is how to determine whether significant reduction in exposure to toxic substances has occurred. For example, smokers who reduce the number of cigarettes that they smoke may smoke them more intensively, thereby extracting more nicotine and other toxic substances from each cigarette, and not significantly reduce their daily intake. On the other hand, smokers using nicotine patches may inhale less smoke from their cigarettes, thereby reducing their daily exposure. Therefore, simply counting cigarettes is not a reliable method for estimating exposure to toxic substances. Methodology for determining intake of specific substances is needed to evaluate these possibilities.

Tobacco and tobacco smoke contain numerous toxic substances (for example, about 50 carcinogens have been identified), and measuring exposure to each individually would not be practical. Our approach is to develop methods for measuring specific toxic substances, or metabolic breakdown products, or other tobacco-derived substances in biologic fluids of smokers, such as blood or urine. Concentrations of these substances, called “biomarkers” can be used as a measure of exposure. For example, previous studies of ours, funded by TRDRP, demonstrated that the minor tobacco alkaloids anabasine and anatabine can be used as biomarkers to measure tobacco consumption in persons using nicotine gum or patches. In collaborative projects with other investigators, concentrations of these alkaloids in urine are being used as an outcome measure to test the efficacy of tobacco cessation programs that use nicotine gum or patches as part of the therapy.

A major goal of this proposal is to develop analytical methods for measuring concentrations of biomarkers that will be practical for large-scale clinical studies. Therefore, we are focusing our efforts on the use of a very sensitive, yet very fast, technique called liquid chromatography-tandem mass spectrometry that is suitable for analysis of large numbers of biological samples. Studies will be carried out to correlate measures of tobacco smoke exposure with biomarker concentrations in smokers of conventional cigarettes and smokers of new products claimed to be less harmful.

Some anticipated applications of the proposed methodology are: (1) monitoring human exposure to toxic substances from different types of cigarettes (such as low nicotine-content cigarettes that have been proposed to be non-addictive); (2) evaluating the health risks of new, potentially less harmful tobacco-based products (such as R. J. Reynolds’ Eclipse or Philip Morris’ Accord, products that heat rather than burn tobacco); (3) evaluating potential harm reduction in tobacco treatment programs (for example, in programs that seek to reduce health risks by reducing cigarette consumption in smokers who are unable to quit, perhaps in conjunction with nicotine maintenance therapy), and (4) assessing the risks of developing tobacco-related diseases in different populations of smokers.

Anabasine and anatabine levels in urine: Biomarkers for tobacco use during nicotine replacement therapy.
Periodical: Cancer Epidemiology Biomarkers and Prevention Index Medicus:
Authors: Jacob P, Hatsukami DK, Severson H, Hall S, Yu L, and Benowitz NL ART
Yr: 2005 Vol: 14(6):1376 Nbr: Abs: Pg:

Determination of nicotine, its major metabolites, and deuterium-labeled isotopomers in human urine using LC-MS/MS
Periodical: Drug Metabolism Reviews Index Medicus:
Authors: Jacob P, Yu L, Benowitz N ABS
Yr: 320 Vol: 34 Nbr: supp. 1 Abs: 320 Pg: 160

Carcinogen Exposure During Short-Term Switching From Regular to Light cigarettes. Cancer Epidemioly, Biomarkers and Prevention, in press.
Periodical: Cancer, Epidemiology, Biomarkers and Prevention Index Medicus:
Authors: Neal L. Benowitz, Peyton, Jocob III ART
Yr: 2005 Vol: 14(6):1376 Nbr: Abs: Pg:

Occupational Physical activity and risk of adenocarcinoma of the esophagus and stomach
Periodical: International Journal of Cancer Index Medicus:
Authors: Vigen C, Bernstein L, Wu AH ART
Yr: 2006 Vol: 118 Nbr: Abs: Pg: 1004-1009