raise questions about its effect on atherogenesis during long-term use (Chalon et al., 2000; Gairola and Daugherty, 1999; Sabha et al., 2000). Such an effect may take many years to emerge and highlights the importance of continued postmarketing surveillance of NRT. Although existing data do not suggest that nicotine is carcinogenic in humans, it would be prudent to have continued surveillance of the incidence of cancer among users of NRT.

Studies of long-term nicotine administration on surrogate variables that more closely resemble the mechanism under consideration (e.g., imaging of plaque progression) and attendant studies in animal models seem timely. Increasingly, the application of genomic and proteomic approaches will help clarify the differential effects of smoking and NRT on the expression and translation of genes related to the development of smoking-related diseases. Finally, the understanding of nicotine’s effect on inflammation and the immune response is confused and limited (Sopori et al., 1998). More research is needed to clarify its effects on cytokine generation, the formation of nitric oxide (NO) and eicosanoids, and oxidative injury. Research should continue to explore other potential therapeutic efficacies of NRT, including for ulcerative colitis, analgesia, weight reduction, Parkinson’s disease, and cognitive disorders associated with aging and schizophrenia.

The continued use of NRT in conjunction with continued, albeit reduced, smoking prompts additional questions. For example, the constituents of cigarette smoke that mediate tissue injury are not all precisely known, and it is also not known if modulating the coincident nicotine level might influence their absorption, metabolic disposition, mechanism of action, or elimination. Design of such studies will rely upon the development of more refined and tractable methodology to investigate the in vivo kinetics and dynamics of other constituents of cigarette smoke and their interactions with nicotine.

Finally, although ethnicity has been shown to be relevant (Sabha et al., 2000), the factors that determine interindividual differences in nicotine efficacy, safety, and addictive potential remain largely unexplored. Particular attention might be paid to genetic variation in proteins relevant to nicotine pharmacokinetics and dynamics and their interaction with environmental variables. As with other drugs, one anticipates increasing individualization of nicotine dosage and/or delivery when given as a therapeutic agent. Insight into the interaction of genetic and environmental factors which influence initiation (Gynther et al., 1999; Heath et al., 1999) of cigarette smoking, latency until the practice becomes habitual (Stallings et al., 1999), and the quantity that is then smoked (Koopmans et al., 1999) has been increasing. Clarification of how these factors interact is also likely to afford insights of value in predicting the individual likelihood



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