Effect of Ketoprofen and ATB-352 on the Immature Human Intestine: Identification of Responders and Non-Responders

Background and Objective: The use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a broad spectrum of life-threatening adverse effects on the immature gastrointestinal tract. NSAID derivatives exploiting the beneficial effects of biologically active gases, such as hydrogen sulfide (H2S), have been developed. Herein, we determined the effects of ketoprofen and ATB-352, a H2S-releasing ketoprofen derivative, on selected metabolic pathways previously identified to be significantly altered by indomethacin in the human immature intestine. Methods: Ketoprofen and ATB-352 were tested on human mid-gestation small intestinal explants maintained in a serum-free organ culture system for 48 h. The expression levels of the representative genes involved in selected metabolic pathways were measured by real-time PCR after a treatment of 48 hours. Results: Tested at a concentration that allows more than 80% inhibition of PGE2 production, ketoprofen was found to be less damaging than indomethacin at an equivalent dosage. However, based on the inducibility of cyclooxygenase-2 transcript expression, we were able to discriminate between responder individuals in which the deleterious effects observed with indomethacin were attenuated, and non-responder specimens in which the effects were similar to those observed with indomethacin. ATB-352 did not induce significant changes compared to ketoprofen on these metabolic pathways. Conclusions: These results show less damaging effects of ketoprofen compared to indomethacin on the immature intestine and indicate that the intestinal response to this NSAID significantly varies between individuals. However the results did not allow us to demonstrate a specific beneficial effect of H2S release in organ culture. Address correspondence and reprint requests to Jean-François Beaulieu, Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada J1H 5N4 (. e-mail: Jean-Francois.Beaulieu@USherbrooke.ca). This is an open-access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. https://ift.tt/1eRPUFd Received 17 July, 2018 Accepted 15 January, 2019 Supplemental digital content is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal's Web site (www.jpgn.org). Conflicts of Interest and Source of Funding: This work was supported by grants from the Canadian Institutes of Health Research and the Star Foundation. JFB was the recipient of the Canada Research Chair in Intestinal Physiopathology. JLW is Chief Scientific Officer for Antibe Therapeutics Inc. JLW's research is supported by an operating grant from the Canadian Institutes of Health Research. Author list and roles: Marie-Pier Thibault conducted a significant part of the work and to the drafting of the manuscript and contributed to the design of the study and interpretation of the data. Éric Tremblay contributed to the design of the study, interpretation of the data and revision of the manuscript. John L. Wallace contributed to specific aspects of the design of the study and revision of the manuscript. Jean-François Beaulieu contributed to the design of the study, interpretation of the data, and revising the manuscript. All authors approved the final version of the manuscript to be published. © 2019 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,

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