TORONTO--Two new interventions for tobacco dependence are being investigated, and the preliminary findings look promising. One is a pill that blocks nicotine metabolism, thereby lowering smoking rates; the other is a vaccine that prevents nicotine from reaching the brain, thus reducing its effects and avoiding addiction. Both of these pharmacokinetic interventions are interesting because their mechanism of action differs completely from the existing methods of smoking cessation.

"Rather than modify the action of nicotine, these methods modify how much nicotine reaches the brain and how long it stays there. These methods have some similarities and may be complementary. The antibody [vaccine] slows nicotine elimination, which is similar to what the pill does," said Paul R. Pentel, MD, one of the vaccine's researchers, in an interview with PULMONARY REVIEWS.

The need for such smoking cessation tools is obvious. "The clinical morbidity and mortality from smoking are huge. The response to nicotine replacement therapy is not very good, with a one-year abstinence rate of only 6% to 10%," said Edward Sellers, MD, who is investigating methoxsalen, the pill that reduces smoking rates. (Methoxsalen is also used in the treatment of psoriasis.) "Clearly, we need to have a much wider range of options for treatment. Our study offers proof of an entirely new approach to helping people cut down on and stop smoking. What we've done opens up some new doors," added Dr. Sellers, who is a Professor of Pharmacology, Medicine, and Psychiatry at the Centre for Research in Women's Health at the University of Toronto, in Ontario, Canada.

TARGETING ENZYMES

During their research on drug addiction, Dr. Sellers and his colleagues at the University of Toronto identified the enzyme that metabolizes nicotine. They also discovered genetic defects in the enzyme that were associated with changes in smoking pattern.[1] "Some people who lack the enzyme either don't smoke or smoke very little," said Dr. Sellers. The researchers theorized that if they could block the enzyme from being produced or prevent its activity, it would reduce a person's desire to smoke.

To test this theory, Dr. Sellers et al investigated the effects of methoxsalen in tobacco-dependent subjects.[2] They found that the drug inhibited the metabolism of orally administered nicotine and reduced smoking levels in study subjects (Figure 1). "[The pill] indirectly decreases the desire to smoke by slowing the removal of nicotine from the body, so people have to smoke less and therefore they have less exposure to [the harmful effects of tobacco]," explained Dr. Sellers.

"We're quite optimistic this will be a useful treatment approach," he said. "The other thing that's interesting about this enzyme is that it's the same enzyme that activates procarcinogens, so blocking the enzyme may not only decrease smoking but also make cigarette smoke safer because there would be less activation of these procarcinogens," he added. However, the research is still in its early phase. According to Dr. Sellers, long-term safety and efficacy studies are needed.

Figure 1 EFFECTS OF METHOXSALEN ON NICOTINE CONCENTRATION AND SMOKING DESIRE

Adapted from Sellers et al. Clin Pharmacol Ther. 2000.

A NICOTINE VACCINE

With the help of the National Institute on Drug Abuse, other researchers are investigating the role of a smoking vaccine in combating tobacco addiction. Unlike methoxsalen, the vaccine, which consists of a nicotine derivative attached to a large protein, works by preventing nicotine from reaching the brain.

"The vaccine works by stimulating the immune system to produce antibodies, which combine with nicotine and keep it from reaching the brain, or at least reduce the amount of nicotine that reaches the brain," explained Dr. Pentel. "The hope is that it will reduce the reinforcing effects that someone gets from smoking and in that way reduce the drive to smoke," added Dr. Pentel, the Division Chief of the Department of Clinical Pharmacology and Toxicology at Hennepin County Medical Center, in Minneapolis.

Although the research is exciting, it is still in its early phase, Dr. Pentel noted. "We're not quite sure who the target audience will be. Theoretically, the vaccine might be useful for [smoking] cessation and particularly for preventing relapse," said Dr. Pentel. "The hope is that it will be possible to vaccinate smokers while they're still smoking so that when they do quit, the antibodies are already present to help prevent relapse," he added.

However, how effective the vaccine will be will likely depend on the amount of antibody there is relative to how much nicotine is present in a person's system. Therefore, the vaccine may be most effective in preventing relapse, according to Dr. Pentel. "When someone relapses after stopping smoking, they generally start with one puff or one cigarette. If vaccination could reduce the positive effects of that one puff or cigarette, it might make relapse less likely," Dr. Pentel suggested.

STUDIES SHOW PROMISING RESULTS

In laboratory studies, rats vaccinated with nicotine-specific antibodies and then injected with a single dose of nicotine had about a 65% reduction in the amount of nicotine that reached the brain.[3]

Another animal study found that even continuous nicotine dosing did not compromise the efficacy of the vaccine.[4] Clinical trials with the vaccine are slated to begin in one to two years, depending on the results of ongoing safety studies, Dr. Pentel said.

One of the advantages the vaccine has over medications like methoxsalen is that antibodies are very specific and bind only to nicotine, thereby minimizing the risk of side effects. "Because antibodies act outside of the brain, there should be no central nervous system–related side effects," Dr. Pentel said.

A NEW TOOL, NOT A CURE

The smoking vaccine is very different from vaccines for infectious diseases, which are designed for prevention.

"A vaccine for smoking would be much more analogous to a medication. It is not going to be a cure for smoking; nor is it going to prevent or wipe out smoking," emphasized Dr. Pentel. Rather, "the hope is that it will be another tool that can be used, along with other existing medications and counseling, for smoking cessation.”

"The vaccine is interesting theoretically, but whether enough antibody can be produced in vivo to modify smoking behavior sufficiently still has to be shown. Whether the vaccine can achieve as large an effect as the pill has yet to be seen," said Dr. Sellers.

--Deborah L. O'Connor

References
1. Rao Y, Hoffmann E, Zia M, et al. Duplications and defects in the CYP2A6 gene: identification, genotyping, and in vivo effects on smoking. Mol Pharmacol. 2000;58:747-755.

2. Sellers EM, Kaplan HL, Tyndale RF. Inhibition of cytochrome P450 2A6 increases nicotine's oral bioavailability and decreases smoking. Clin Pharmacol Ther. 2000;68:35-43.

3. Pentel PR, Malin DH, Ennifar S, et al. A nicotine conjugate vaccine reduces nicotine distribution to brain and attenuates its behavioral and cardiovascular effects in rats. Pharmacol Biochem Behav. 2000;65:191-198.

4. Hiedaa Y, Keylerac DE, Ennifarb S, et al. Vaccination against nicotine during continued nicotine administration in rats: immunogenicity of the vaccine and effects on nicotine distribution to brain. Int J Immunopharmacol. 2000; 10:809-819.

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