Drs. Mogadam, Ando, and Guslandi and Tittobello raise many interesting points. Dr. Mogadam states that a 30% response (39% for nicotine compared with 9% for placebo) is not clinically meaningful. We strongly disagree. Studies of drugs that we accept as efficacious for ulcerative colitis and that led to U.S. Food and Drug Administration approval had very similar response rates. For example, Asacol (mesalamine, Procter & Gamble, Inc., Cincinnati, Ohio) at 2.4 g/d showed 26% clinical improvement (49% for Asacol and 23% for placebo) [1], and Pentasa (mesalamine, Hoechst Marion Roussel, Kansas City, Missouri) at 4.0 g/d showed 23% treatment success, defined as marked improvement of symptoms (59% for Pentasa and 36% for placebo) [2]. We believe that the 30% beneficial effect of nicotine compares favorably to the effects of these other drugs and is clinically meaningful. We also believe that it is reasonable to define first-line therapy as sulfasalazine, rectal or oral 5-aminosalicylate, and rectal or low-dose oral corticosteroids and to designate other, more toxic therapies (such as high-dose oral corticosteroids, 6-mercaptopurine, and azathioprine) as second-line agents.

Dr. Ando states that N-nitrosamines are synthesized from nicotine and that these carcinogens would increase the risk for cancer. Nicotine itself is not a carcinogen but is a precursor of N-nitrosamines, such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, which are believed to contribute to tobacco-induced cancer [3]. Whether there is endogenous formation of these N-nitrosamines in humans exposed to nontobacco sources of nicotine is unknown [4]. Dr. Ando's note of caution seems reasonable. Further research is warranted to analyze the urine of nonsmoking persons who use transdermal patches for evidence of endogenous production of N-nitrosamines. In addition, long-term treatment studies that address the safety (that is, risks for cancer and cardiovascular disease) of transdermal nicotine are needed for diseases in which smoking is protective and nicotine may be efficacious. These diseases include ulcerative colitis, Alzheimer disease, the Tourette syndrome, and Parkinson disease. To further improve the safety of nicotine, we are developing rectal enema and delayed-release oral nicotine formulations that provide a "topical" therapeutic effect in the colon while significantly reducing blood concentrations of nicotine [5].

Drs. Guslandi and Tittobello report that transdermal nicotine may be of benefit for steroid-sparing and remission maintenance treatment in patients with ulcerative colitis. We have had the same experience on an anecdotal basis. These potential treatment indications should be evaluated in randomized, double-blind, placebo-controlled, dose-ranging clinical trials.