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University of Minnesota

The overall goal of this center is to stimulate integrated research across scientific disciplines in order to significantly advance our understanding of tobacco use, nicotine addiction, and tobacco harm reduction.

TTURC Principal Investigator: Dorothy Hatsukami, Ph.D.

Overall Abstract

Project Principal Investigator: Dorothy K. Hatsukami, Ph.D.

The purpose of this TTURC proposal is to examine tobacco exposure reduction methods to treat smokers who have been resistant to conventional methods of intervention or who have not been previously targeted. Reduction of tobacco use will be examined both as a potential transitional goal toward cessation, or as an endpoint for refractory smokers. The center proposal involves four research projects and three cores. The four projects vary from animal studies to human clinical trials. Dr. Paul Pentel will use animal models of nicotine self-administration to study the use of high dose nicotine (doses producing plasma nicotine concentrations exceeding those experienced by smokers) as a treatment strategy. The combined use of high dose nicotine and the antagonist mecamylamine, and the effects of high dose nicotine on tobacco carcinogen activation will also be evaluated. Dr. Dorothy Hatsukami will conduct short-term, tightly controlled human behavioral pharmacology studies that examine different methods of reducing toxic exposure to tobacco. These methods include nicotine replacement products and behavioral methods to reduce the amount of cigarettes smoked. Drs. Larry An, Harry Lando and Anne Joseph will examine exposure reduction treatment methods in targeted populations unable or unwilling to become abstinent or who are on the trajectory towards nicotine dependence. The targeted populations to be examined will vary across the life span including mothers who smoke, adolescent experimental smokers and medically compromised smokers. Research on each population will have unique as well as common methods for assessment and treatment with the primary outcome measures being the reduction in tobacco use and toxicity, the degree to which these treatments facilitate abstinence, and the cost-effectiveness of these approaches. The Core facilities will include Biomarker, Administrative, and Design and Analysis Cores. Drs. Stephen Hecht and Sharon Murphy will be co-directors of the Biomarker Core. This Core will provide measurement of biomarkers for tobacco, nicotine and carcinogen exposure and the capability to phenotype individuals according to their metabolism of nicotine. The Design and Analysis Core will be responsible for data input, monitoring and statistical analyses and for performing the economic and policy analyses for each of the clinical studies. The Administrative Core will be responsible for the smooth and coordinated operation of the studies, the training and career development of students and faculty, and the dissemination of information. In summary, the goal of this highly interdisciplinary center grant is to systematically examine tobacco exposure reduction methods that will decrease mortality and morbidity associated with tobacco use.

Project 1: Tobacco Reduction Strategies for Patients with Cardiac Disease

Project Principal Investigator: Anne Joseph, M.D., M.P.H

Cigarette smoking promotes atherosclerosclerotic cardiovascular disease (ACVD), and cessation confers significant health benefits to patients with heart disease. Total abstinence is the goal of current tobacco dependence treatment models, however, it is not accessible to many patients. There is a strong dose-response relationship between the amount smoked and risk for ASCVD, suggesting that for those patients who cannot stop, reducing smoking may be of benefit. Nicotine replacement therapy (NRT) is safe in patients with cardiovascular disease, and limited data suggest that long term NRT is effective at reducing tobacco use and carbon monoxide (CO) exposure. We propose a randomized controlled clinical trial in 180 patients with ASCVD to test the hypothesis that a combined behavioral and pharmacological intervention designed to reduce smoking by at least 50% will 1) reduce cigarette consumption, 2) improve smoking cessation rates, 3) reduce signs and symptoms of ASCVD, 4) improve risk factors for ASCVD, and 5) prove to be cost-effective in terms of cost per quality adjusted life year gained. We will randomly assign subjects from two ambulatory care sites to the smoking reduction (SR) treatment group (including a standardized approach to transdermal nicotine, or nicotine gum if not successful reducing using patch) or the control group. Subjects will be followed for a two year period, and will be encouraged to quit at any time if they are ready. We will collect data regarding smoking behavior, exercise tolerance, angina, quality of life, and adverse events; and measure nicotine, cotinine, CO, lipids, and fibrinogen. We will contribute samples to the Biomarker Core project to assess the effect of smoking reduction on other toxin levels. We will conduct an economic analysis of the potential cost-effectiveness of this approach. This study will test whether a long term strategy to reduce cigarette consumption in a medically ill population is safe, effective, and improves health outcomes for smokers who cannot quit.

Project 2: Strategies for Tobacco Exposure Reduction

Project Principal Investigator: Dorothy K. Hatsukami, Ph.D.

Abstinence from tobacco use has been a common goal for many treatment programs. However, only a relatively small number of smokers are willing to quit tobacco use in the immediate future. Furthermore, of those who try to quit tobacco use, many are not successful in achieving abstinence. Tobacco reduction may be an important transitional goal for these individuals prior to abstinence or possibly even a treatment endpoint. However, relatively limited information is available on the effectiveness or consequences of recommending reduced tobacco use either by using nicotine replacements or behavioral methods. The primary goals of this research proposal are to systematically examine and compare the effects of different approaches for reducing tobacco use in tightly-controlled, short-term, outpatient, clinical studies. Subjects will be cigarette smokers who are interested in reducing cigarette smoking and not seriously interested in quitting within the next 30 days. Three studies are proposed. In each of these studies, reduction in smoking will occur over the course of 6 weeks, in which smokers are encouraged to reduce by 25% increments every two weeks. The aim is to reduce consumption of cigarettes by at least 75%. The first study will examine the effects of different instructional methods for nicotine gum use to reduce cigarette consumption. The instructional method that produces the greatest reduction in cigarette use will be selected for the subsequent studies. The second study will examine various nicotine replacement and behavioral methods for cigarette reduction to determine which approach produces the greatest reduction in tobacco use. The third study will focus on the most effective treatment selected from Study 2 and compare this condition with a placebo control. In addition, a combination of approaches (e.g., nicotine patch plus another nicotine replacement agent or behavioral treatment) will be examined to determine whether combining treatments will lead to a significantly greater reduction of tobacco exposure and toxicity compared to a placebo control condition and to the single method approach. These studies should determine whether these approaches are effective in reducing tobacco exposure and toxicity, enhancing motivation to quit, or increasing number of quit attempts. The cost-effectiveness of these treatments will also be determined. The results from these studies can be used to direct treatments in the other research projects proposed in this center grant.

Project 3: Reducing Children's Exposure to Tobacco Smoke Pollution

Project Principal Investigator: Deborah Henrikkus, Ph.D.

Tobacco smoke pollution is a major cause of disease and death for children in this country. While there have been some progress limiting tobacco smoking pollution (TSP) in public and work places, relatively little attention has focused on improving air quality in homes and private spaces where children receive their greatest exposure to TSP. As a result in the United States each year, children continue to suffer more than 5 million additional episodes of illness leading to nearly 4,000 preventable deaths due to the effects of tobacco smoke pollution (Aligne, 1997; US EPA, 1993; California EPA, 1997; DiFranza, 1996).

This proposal represents a developing collaboration between the U.S. Environmental Protection Agency, a large regional health maintenance organization (Health Partners, Minnesota), and an international team of researchers in an innovative effort to change parental smoking behavior in order to reduce children's exposure to TSP. Parental, and especially maternal, smoking in the home is the major source of children's exposure to TSP. All smoking parents should be advised and assisted in quitting. For the majority of smoking parents initially unable or unwilling to quit, efforts should focus on helping them limit their children's exposure to TSP. Promising counseling interventions have been developed to help parents create reduced-smoke and smoke-free environments for their children. Unfortunately, parents' continued smoking commonly results in continued exposure for the child and parents may need additional assistance to create truly smoke-free environments. Since nicotine addiction is often a major force driving continued cigarette use, providing smoking parents an alternative non-polluting source of nicotine (i.e. nicotine gum) for use in the home may help reduce their dependence on cigarettes and their children's TSP exposure.

Through a population-based environmental assessment survey of a large health plan's youngest members, we will identify families with infant children exposed to maternal smoking in the home (a marker for higher levels of overall TSP exposure). Smoking mothers will be recruited into a prospective 3 group randomized clinical trial to determine the ability of (1) individualized counseling and (2) individualized counseling plus access to nicotine gum as a substitute for cigarettes in the home to help mothers create smoke-free environments for their children. Specifically, we hypothesize that compared to usual care (advice to quit and written materials promoting a smoke-free environment for children):

1. Providing smoking mothers with individualized counseling focused on TSP reduction will reduce children's exposure to TSP.

2. Providing smoking mothers with individualized counseling focused on TSP reduction plus access to nicotine gum as a substitute for cigarettes in the home will further reduce children's exposure to TSP.

3. Engaging smoking mothers in interventions to reduce children's exposure to TSP will reduce maternal cigarette consumption and increase maternal smoking cessation.

In addition, we will explore a secondary set of hypotheses on the relative economic costs and benefits of the study interventions. Specifically, we hypothesize that, if sufficiently effective, the study interventions: (a) will also be a cost-effective (in terms of cost per life year gained) when compared to widely prescribed medical treatments; and (b) will lead to reductions in medical, mortality and morbidity costs that fully or partially offset the costs of the intervention.

Project 4: High Dose Nicotine Effects in Rats

Project Principal Investigator: Paul Pentel, Ph.D.

The aim of the proposed study is to evaluate the effects of high dose nicotine (HDN) infusion on nicotine self-administration (NSA) in rats. HDN safety and pharmacokinetics will also be studied. The long term goal of this work is to evaluate the potential of HDN as an adjunct to smoking cessation in patients refractory to standard therapies. Nicotine replacement therapy enhances smoking cessation rates, but most quit attempts are still unsuccessful. However, nicotine replacement therapy typically provides venous plasma nicotine concentrations that are substantially lower than those associated with smoking. Higher than usual doses of nicotine replacement, e.g. 2 nicotine patches at once, have been only equivocally successful in enhancing quit rates compared to usual doses, but even these higher doses do not provide the very high arterial nicotine concentrations associated with cigarette smoking. Whether even higher doses of nicotine (providing smokers with venous and arterial nicotine concentrations exceeding those experienced during normal smoking) would confer additional benefit is not known. Potential advantages of this level of HDN include more complete suppression of withdrawal, craving, and the rewarding effects of smoking. Hypotheses to be tested are that 1) HDN suppresses the maintenance and reinstatement of NSA, 2) HDN is safe owing to the rapid development of tolerance to its adverse effects, 3) HDN efficacy can be augmented by combining it with the nicotinic antagonist mecamylamine, 4) the pharmacokinetics of HDN is similar to that of usual replacement doses, and 5) HDN reduces the formation of some carcinogens from tobacco. Studies will be performed in rats because the safety of administering HDN at the proposed doses to humans is untested. The effects of HDN on the maintenance of ongoing NSA and the reinstatement of nicotine responding will be examined. A range of both HDN doses and NSA doses will be used to establish dose-response relationships. The physiologic effects and safety of these treatments will be evaluated. HDN will be combined with the nicotinic antagonist mecamylamine to determine whether this combination is more effective than HDN alone, or better tolerated. The pharmacokinetics of HDN compared to usual nicotine replacement doses will be studied to aid in HDN dose selection. The formation of carcinogenic metabolites from the tobacco mitrosamine NNK will be studied to determine whether this rate is altered when HDN and NNK are co-administered. Taken together, these studies will address the feasibility of using HDN as an adjunct to the initiation or maintenance of smoking cessation, and whether it is safe enough for testing in humans.

Communications Abstract: Communications Plan For The Robert Wood Johnson Foundation Transdisciplinary Tobacco-Use Research Center

Project Principal Investigator: Dorothy K. Hatsukami, Ph.D.

This project will establish a communications component to University of Minnesota's NIH-funded Transdisciplinary Tobacco Use Research Center (TTURC). The focus of this component will be to inform practitioners, public policy makers, academics, and scientist of the science relevant to the treatment of recalcitrant tobacco users, with particular emphasis on effective methods for tobacco exposure reduction. Initial efforts of this project are to develop the infrastructure and liaisons necessary to enhance communication among various constituents engaged in work relevant to this TTURC. Communication efforts will be directed within the Minnesota TTURC, across the seven TTURC centers, and to tobacco control organizations and advocates, policy makers, and health care providers. Once the infrastructure and liaisons are developed, subsequent years of the project will be devoted to the actual delivery of information to the above end users of information, as well as to national researchers and policy makers. Communications services and products that will be produced through this project include: list-serves, internal and external research newsletters, conference calls, travel to meet with other TTURC researchers, meetings with major stakeholders, semi-annual conferences/meetings, health provider training sessions, medical school curriculum development, materials for community members, expert panels, national conferences, publications, and presentations at scientific meetings.