WINSTON-SALEM, N.C. – If Pradeep K. Garg, Ph.D., of Wake Forest University Baptist Medical Center figures out why some smokers are more addicted to nicotine than others, it could lead to more successful smoking cessation treatments.
Backed by a $2.5 million grant from the National Institutes of Health, Garg and research colleagues at Wake Forest Baptist and Duke University Medical Center are conducting research to improve the effectiveness of nicotine vaccination for cigarette smokers. Using positron emission topography (PET) imaging, he will be able to see the dynamics of nicotine distribution in human body organs during actual cigarette smoking. The research, published recently by Proceedings of the National Academy of Sciences (PNAS), looked at how long it takes nicotine to reach peak levels in cigarette smokers’ brains.
“The bottom line is that if we can effectively block nicotine entry in the brain, we will have effective therapy,” Garg said. “Having an accurate understanding of the mechanism of anti-nicotine immunotherapy will help us improve its treatment efficacy and could lead to better patient management and may help develop better vaccines in the future.”
Injectable nicotine vaccines have proven to be effective in clinical trials, reducing the incidence of relapse in smokers who have recently quit. Many researchers believe the vaccines do this by producing antibodies that attach themselves to nicotine, thus preventing it from reaching the brain, making smoking less pleasurable and easier to give up. That’s where Garg and his team are focusing their research, using PET to scan smokers before and after vaccination.
“We propose a new model to explain how the anti-nicotine antibodies affect nicotine pharmacokinetics and how they might be beneficial for smoking cessation,” Garg said. “The success in smoking cessation after anti-nicotine vaccination is associated with the effectiveness of reducing brain nicotine accumulation.”
Garg said anti-nicotine immunotherapy is a relatively new approach that directly targets the absorption and distribution of nicotine in the body. It is widely believed that anti-nicotine antibodies produced through vaccination would bind to nicotine inhaled through cigarette smoking and would only release it slowly into the blood. Garg questions the validity of this approach because the amount of antibodies present in the body is inadequate to bind all the free nicotine absorbed during smoking. Garg and his team suggest that the anti-nicotine antibodies are nearly saturated by nicotine after passing through the lungs, but will lose bound nicotine in the peripheral tissues which have relatively low blood perfusion. After depositing nicotine in these tissues, the free antibody circulates back to the lungs to sequester more free nicotine and continues the absorption-deposition cycle. Such “recycling” allows the antibodies to reduce and even deplete lungs of free nicotine and dramatically slows nicotine accumulation in the brain.
Understanding why some people are more addicted to nicotine than others will lead to better treatment options. It’s an important question to answer when, in the United States alone, approximately 47 million adults are current cigarette smokers and smoking-attributable health care expenditures and productivity losses exceed $190 billion annually.
Previous research and collaboration between Garg and researchers at Duke has been supported by a grant from Phillip Morris USA and Phillip Morris International. Their research project looked at nicotine pharmacokinetics in addicted smokers and in casual smokers and found significant differences in how the nicotine is deposited in lungs and brain among these two groups of smokers. Armed with that knowledge, the research group proposes to enhance the efficacy of smoking cessation treatments.
“If successful, this study may help in combining current nicotine replacement therapies with immunotherapy for an enhanced and rapid response to smoking cessation,” Garg said.
Research collaborators also include Sudha Garg, Ph.D., of Wake Forest Baptist, and Jed Rose, Ph.D., Alexey G. Mukhin, M.D., Ph.D., Stephen J. Lokitz, Ph.D., Timothy G. Turkington, Ph.D., Joseph Herskovic, Ph.D., and Frédérique M. Behm, C.R.A., all from Duke University Medical Center.
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