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We should like to thank Kleinjans et al. for their interest in our paper.1Fiorucci S. Santucci L. Gresele P. Maffei Faccino R. Del Soldato P. Morelli A. Gastrointestinal safety iof NO-Aspirin (NCX-4016) in healthy human volunteers a proof of concept endoscopic study.Gastroenterology. 2003; 124: 600-607Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar In their letter, Kleinjans et al. raises the question of the collateral risk of endogenous formation of N-nitroso compounds after administration of NCX-4016, a NO-releasing derivative of acetyl salicylic acid. While the matter is of potential interest, Kleinjans et al. build up their argument using the 12-hour concentration of nitrite and nitrate (NOx) measured in the plasma of volunteers taking 1600 mg/day NCX-4016 for 7 days. Regarding this point, however, we would like to underline that this measure was used as qualitative evidence of NCX-4016 absorption, but it cannot be taken as quantitative measure of integrated NOx burden. Indeed, the mean of 24-hour urinary excretion of NOx (a more reliable index of the overall NOx load), measured after 7-day treatment with 800 mg bid NCX4016 in healthy human volunteers is ≈ 78 mg (Nicox SA, data on file). Taking into account that the 24-hour urinary excretion of NOx after a nitrate-rich meal is 59–135 mg2van Maanen J.M. Pachen D.M. Dallinga J.W. Kleinjans J.C. Formation of nitrosamines during consumption of nitrate- and amine-rich foods, and the influence of the use of mouthwashes.Cancer Detect Prev. 1998; 22: 204-212Crossref PubMed Scopus (50) Google Scholar it appears that NOx generated in response to NCX-4016 administration overlaps the dietary intake. Consistent with this view, increased plasma levels of NOx in volunteers taking NCX-4016 can be detected, as in our study, only if subjects were administered a nitrogen-free diet. The Acceptable Daily Intake (ADI) established by WHO in terms of nitrate, ranges between 0–3.7 mg/kg body weight, which corresponds to ≈259 mg for a 70-kg person.3WHOEvaluation of certain food additives and contaminants. World Health Organization, Joint FAO/WHO Expert Committee on Food Additives, Geneva1995Google Scholar, 4Guidelines for drinking water quality. 2nd ed. WHO, Geneva1998Google Scholar In this context, assuming a 70%–80% absorption and a 70%–80% biotransformation of the NO carrying moiety of NCX-4016 to nitrate (that is really unlikely), a daily dose of 1600 mg NCX4016 would give rise to ≈200 mg nitrates, i.e., a value that fit in the ADI. Confirming this view, 28-day treatment of patients with peripheral vasculopathy with 1600 mg/day NCX4016, increases the urinary excretion of NOx (in comparison with aspirin-treated patients) of 15%–20%, with a standard deviation of 20%, further indicating that the amount of NOx generated by NCX-4016 can hardly be distinguished from the dietary intake (Nicox SA, data on file). Finally, the NOAEL (No Observed Adverse Effect Level) for nitrite and nitrate determined in the long-term toxicology studies in rats is 370 mg of nitrate/kg.3WHOEvaluation of certain food additives and contaminants. World Health Organization, Joint FAO/WHO Expert Committee on Food Additives, Geneva1995Google Scholar, 4Guidelines for drinking water quality. 2nd ed. WHO, Geneva1998Google Scholar In conclusion, the above-mentioned data indicate that the amount of NOx generated after NCX 4016 administration is well within the range recommended by the WHO and overlaps the dietary intake. Risk assessment of endogenous formation of carcinogenic N-nitroso compounds in response to intake of NO-AspirinGastroenterologyVol. 127Issue 3PreviewWe read with interest the study on gastrointestinal safety of NO-Aspirin (NCX-4016) in human volunteers that was published with its corresponding editorial in the March 2003 issue of Gastroenterology.1,2 As the authors report a substantial increase of plasma nitrate levels upon administration of 400 or 800 mg of NO-Aspirin twice daily for 7 days in comparison to placebo control, it caught our attention that they did not discuss the collateral risk of endogenous formation of N-nitroso compounds (NOC). Full-Text PDF