Clinical and pharmacogenetic features of patients with upper gastrointestinal lesions at a multidisciplinary hospital: the role of nonsteroidal anti-inflammatory drugs

Natalia P. Denisenko; Anna S. Zhiryakova; Ivan V. Sychev; Alexander V. Kryukov; Svetlana N. Tuchkova; Olga Y. Vakulenko; Oleg V. Averkov; Valery I. Vechorko; Karin B. Mirzaev; Dmitry A. Sychev

doi:10.1515/dmpt-2024-0040

Article

Clinical and pharmacogenetic features of patients with upper gastrointestinal lesions at a multidisciplinary hospital: the role of nonsteroidal anti-inflammatory drugs

Natalia P. Denisenko , Anna S. Zhiryakova , Ivan V. Sychev , Alexander V. Kryukov , Svetlana N. Tuchkova , Olga Y. Vakulenko , Oleg V. Averkov , Valery I. Vechorko , Karin B. Mirzaev and Dmitry A. Sychev

Published/Copyright: July 15, 2024

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From the journal Drug Metabolism and Personalized Therapy Volume 39 Issue 2

Abstract

Objectives

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed medications, but their use can be associated with a number of adverse reactions, including upper gastrointestinal lesions. The aim of the study was to identify clinical and pharmacogenetic factors associated with upper gastrointestinal lesions, including those linked to NSAIDs, in patients at a multidisciplinary hospital.

Methods

The study included 92 patients (mean age 59.4±16.5 years; 47 women), who underwent esophagogastroduodenoscopy during inpatient treatment. Patients’ intake of NSAIDs and gastroprotectors during the year before hospitalization was considered. Demographic, clinical, laboratory data of patients were compared between groups, including genotyping for CYP2C9*2 rs179985, CYP2C9*3 rs1057910, CYP2C8*3 rs11572080, CYP2C8*3 rs10509681, PTGS-1 rs10306135, PTGS-1 rs12353214, and PTGS-2 rs20417 using real-time PCR.

Results

In NSAIDs⁺ patients, PTGS1 rs10306135 AT+TT genotypes increased the chance of developing gastrointestinal complications by 5.4 times (95 % CI=1.30–22.27). In total sample, smoking (OR=3.12, 95 % CI=1.15–8.46), and alcohol intake (OR=4.09, 95 % CI=1.05–15.87) increased odds of gastrointestinal damage. In NSAIDs⁺ patients omeprazole, famotidine and both famotidine and omeprazole during the last year were as ineffective as not taking gastroprotectors; in total sample famotidine (OR=0.19, 95 % CI=0.04–0.93) and two gastroprotectors (OR=0.13, 95 % CI=0.02–0.75) reduced the chance of upper gastrointestinal lesions.

Conclusions

Pharmacogenetic features of patients may significantly contribute to the development NSAIDs-induced upper gastrointestinal injuries.

Keywords: adverse reactions; SNP; COX-1; NSAIDs-induced gastropathy; PTGS1; ulcers

Corresponding author: Natalia P. Denisenko, Research Institute of Molecular and Personalized Medicine, Russian Medical Academy of Continuous Professional Education, Barrikadnaya St., 2/1, 1, 123242, Moscow, Russian Federation, E-mail: natalypilipenko3990@gmail.com

Funding source: Russian Science Foundation

Award Identifier / Grant number: No. 23-75-01137

Research ethics: Research involving human subjects complied with all relevant national regulations, institutional policies and is in accordance with the tenets of the Helsinki Declaration and was approved by the Ethics Committee of the Russian Medical Academy of Continuing Professional Education of the Ministry of Health of Russia (protocol #14 of September 29, 2022).
Informed consent: Informed consent was obtained from all individuals included in this study.
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Competing interests: The authors state no conflict of interest.
Research funding: This study was carried out with the financial support of the Russian Science Foundation, project No. 23-75-01137 (https://rscf.ru/en/project/23-75-01137).
Data availability: The raw data can be obtained on request from the corresponding author.

References

1. Karateev, AE, Nasonov, EL, Ivashkin, VT, Martynov, AI, Yakhno, NN, Arutyunov, GP, et al.. Rational use of nonsteroidal anti-inflammatory drugs. Clinical guidelines. Rheumatol Sci Pract 2018;56:1–29. https://doi.org/10.14412/1995-4484-2018-1-29.Search in Google Scholar

2. Keshwani, S, Grande, I, Maguire, M, Goodin, A, Vouri, SM, Hincapie-Castillo, JM. Trends in use of prescription nonsteroidal anti-inflammatory medications before vs. after implementation of a Florida law restricting opioid prescribing for acute pain. JAMA Netw Open 2021;4:e2113383. https://doi.org/10.1001/jamanetworkopen.2021.13383.Search in Google Scholar PubMed PubMed Central

3. Bhala, N, Emberson, J, Merhi, A, Abramson, S, Arber, N, et al.; Coxib and traditional NSAID Trialists’ (CNT) Collaboration. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet 2013;382:769–79. https://doi.org/10.1016/S0140-6736(13)60900-9.Search in Google Scholar PubMed PubMed Central

4. Singh, G. Gastrointestinal complications of prescription and over-the-counter nonsteroidal anti-inflammatory drugs: a view from the ARAMIS database. Arthritis, Rheumatism, and Aging Medical Information System. Am J Ther 2000;7:115–21.10.1097/00045391-200007020-00008Search in Google Scholar PubMed

5. Ramiro, S, Nikiphorou, E, Sepriano, A, Ortolan, A, Webers, C, Baraliakos, X, et al.. ASAS-EULAR recommendations for the management of axial spondyloarthritis: 2022 update. Ann Rheum Dis 2023;82:19–34. https://doi.org/10.1136/ard-2022-223296.Search in Google Scholar PubMed

6. Vane, JR, Botting, RM. Mechanism of action of nonsteroidal anti-inflammatory drugs. Am J Med 1998;104:2S–8. https://doi.org/10.1016/s0002-9343(97)00203-9.Search in Google Scholar PubMed

7. García-Rayado, G, Navarro, M, Lanas, A. NSAID induced gastrointestinal damage and designing GI-sparing NSAIDs. Expet Rev Clin Pharmacol 2018;11:1031–43. https://doi.org/10.1080/17512433.2018.1516143.Search in Google Scholar PubMed

8. Bindu, S, Mazumder, S, Bandyopadhyay, U. Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: a current perspective. Biochem Pharmacol 2020;180:114147. https://doi.org/10.1016/j.bcp.2020.114147.Search in Google Scholar PubMed PubMed Central

9. Brooks, J, Warburton, R, Beales, IL. Prevention of upper gastrointestinal haemorrhage: current controversies and clinical guidance. Ther Adv Chronic Dis 2013;4:206–22. https://doi.org/10.1177/2040622313492188.Search in Google Scholar PubMed PubMed Central

10. Gel’fand, BR, Protsenko, DN, Babayants, AV, Karateev, AE. Severe bleeding from the upper parts of the gastrointestinal tract: from epidemiology to the formation of the concept of conservative therapy. Infektsii v Khirurgii 2013:11–7. (In Russ.).Search in Google Scholar

11. Bordin, DS, Livzan, MA, Gaus, OV, Mozgovoi, SI, Lanas, A. Drug-associated gastropathy: diagnostic criteria. Diagnostics 2023;13:2220. https://doi.org/10.3390/diagnostics13132220.Search in Google Scholar PubMed PubMed Central

12. Theken, KN, Lee, CR, Gong, L, Caudle, KE, Formea, CM, Gaedigk, A, et al.. Clinical pharmacogenetics implementation Consortium guideline (CPIC) for CYP2C9 and nonsteroidal anti-inflammatory drugs. Clin Pharmacol Ther 2020;108:191–200. https://doi.org/10.1002/cpt.1830.Search in Google Scholar PubMed PubMed Central

13. McEvoy, L, Carr, DF, Pirmohamed, M. Pharmacogenomics of NSAID-induced upper gastrointestinal toxicity. Front Pharmacol 2021;12:684162. https://doi.org/10.3389/fphar.2021.684162.Search in Google Scholar PubMed PubMed Central

14. Macías, Y, Gómez Tabales, J, García-Martín, E, Agúndez, JAG. An update on the pharmacogenomics of NSAID metabolism and the risk of gastrointestinal bleeding. Expert Opin Drug Metab Toxicol 2020;16:319–32. https://doi.org/10.1080/17425255.2020.1744563.Search in Google Scholar PubMed

15. Resar, RK, Griffin, FA. Institute for Healthcare improvement: IHI global trigger tool for measuring adverse events, 2nd ed. Cambridge, MA: Institute for Healthcare Improvement; 2009. Available from: www.IHI.org.Search in Google Scholar

16. Lanza, FL, Nelson, RS, Rack, MF. A controlled endoscopic study comparing the toxic effects of sulindac, naproxen, aspirin, and placebo on the gastric mucosa of health volunteers. J Clin Pharmacol 1984;24:89–95. https://doi.org/10.1002/j.1552-4604.1984.tb02770.x.Search in Google Scholar PubMed

17. Tsujimoto, S, Mokuda, S, Matoba, K, Yamada, A, Jouyama, K, Murata, Y, et al.. The prevalence of endoscopic gastric mucosal damage in patients with rheumatoid arthritis. PLoS One 2018;13:e0200023. https://doi.org/10.1371/journal.pone.0200023.Search in Google Scholar PubMed PubMed Central

18. Pratt, VM, Cavallari, LH, Del Tredici, AL, Hachad, H, Ji, Y, Moyer, AM, et al.. Recommendations for clinical CYP2C9 genotyping allele selection: a joint recommendation of the Association for Molecular Pathology and College of American Pathologists. J Mol Diagn 2019;21:746–55. https://doi.org/10.1016/j.jmoldx.2019.04.003.Search in Google Scholar PubMed PubMed Central

19. St Germaine, CG, Bogaty, P, Boyer, L, Hanley, J, Engert, JC, Brophy, JM. Genetic polymorphisms and the cardiovascular risk of non-steroidal anti-inflammatory drugs. Am J Cardiol 2010;105:1740–5. https://doi.org/10.1016/j.amjcard.2010.01.352.Search in Google Scholar PubMed

20. Lee, YS, Kim, H, Wu, TX, Wang, XM, Dionne, RA. Genetically mediated interindividual variation in analgesic responses to cyclooxygenase inhibitory drugs. Clin Pharmacol Ther 2006;79:407–18. https://doi.org/10.1016/j.clpt.2006.01.013.Search in Google Scholar PubMed

21. Lucena, MI, García-Martín, E, Daly, AK, Blanca, M, Andrade, RJ, Agúndez, JAG. Next-generation sequencing of PTGS genes reveals an increased frequency of non-synonymous variants among patients with nsaid-induced liver injury. Front Genet 2019;10:134. https://doi.org/10.3389/fgene.2019.00134.Search in Google Scholar PubMed PubMed Central

22. Hunt, R, Lazebnik, LB, Marakhouski, YC, Manuc, M, Ramesh, GN, Aye, KS, et al.. International consensus on guiding recommendations for management of patients with nonsteroidal anti-inflammatory drugs induced gastropathy-ICON-G. Euroasian J Hepato-Gastroenterol 2018;8:148–60. https://doi.org/10.5005/jp-journals-10018-1281.Search in Google Scholar PubMed PubMed Central

23. Lanas, A, Tornero, J, Zamorano, JL. Assessment of gastrointestinal and cardiovascular risk in patients with osteoarthritis who require NSAIDs: the LOGICA study. Ann Rheum Dis 2010;69:1453–8. https://doi.org/10.1136/ard.2009.123166.Search in Google Scholar PubMed

24. Brun, J, Jones, R. Nonsteroidal anti-inflammatory drug-associated dyspepsia: the scale of the problem. Am J Med 2001;110:12–3. https://doi.org/10.1016/s0002-9343(00)00629-x.Search in Google Scholar PubMed

25. Freedberg, DE, Kim, LS, Yang, YX. The risks and benefits of long-term use of proton pump inhibitors: expert review and best practice. Advice from the American Gastroenterological Association. Gastroenterology 2017;152:706–15. https://doi.org/10.1053/j.gastro.2017.01.031.Search in Google Scholar PubMed

26. Scheiman, JM, Yeomans, ND, Talley, NJ, Vakil, N, Chan, FK, Tulassay, Z, et al.. Prevention of ulcers by esomeprazole in at-risk patients using non-selective NSAIDs and COX-2 inhibitors. Am J Gastroenterol 2006;101:701–10. https://doi.org/10.1111/j.1572-0241.2006.00499.x.Search in Google Scholar PubMed

27. Chan, FK, Wong, VW, Suen, BY, Wu, JC, Ching, JY, Hung, LC, et al.. Combination of a cyclo-oxygenase-2 inhibitor and a proton-pump inhibitor for prevention of recurrent ulcer bleeding in patients at very high risk: a double-blind, randomised trial. Lancet 2007;369:1621–26. https://doi.org/10.1016/s0140-6736(07)60749-1.Search in Google Scholar PubMed

28. Lanas, A, Ferrandez, A. Inappropriate prevention of NSAID-induced gastrointestinal events among long-term users in the elderly. Drugs Aging 2007;24:121–31. https://doi.org/10.2165/00002512-200724020-00004.Search in Google Scholar PubMed

29. Rostom, A, Dube, C, Wells, G, Tugwell, P, Welch, V, Jolicoeur, E, et al.. Prevention of NSAID-induced gastroduodenal ulcers. Cochrane Database Syst Rev 2002;2021:CD002296. https://doi.org/10.1002/14651858.cd002296.Search in Google Scholar PubMed PubMed Central

30. Li, LF, Chan, RL, Lu, L, Shen, J, Zhang, L, Wu, WK, et al.. Cigarette smoking and gastrointestinal diseases: the causal relationship and underlying molecular mechanisms (review). Int J Mol Med 2014;34:372–80. https://doi.org/10.3892/ijmm.2014.1786.Search in Google Scholar PubMed

31. Stermer, E. Alcohol consumption and the gastrointestinal tract. Isr Med Assoc J 2002;4:200–2.Search in Google Scholar

32. Burbige, EJ, Lewis, DRJr, Halsted, CH. Alcohol and the gastrointestinal tract. Med Clin North Am 1984;68:77–89. https://doi.org/10.1016/s0025-7125(16)31242-1.Search in Google Scholar PubMed

33. Lee, CR, Bottone, FGJr, Krahn, JM, Li, L, Mohrenweiser, HW, Cook, ME, et al.. Identification and functional characterization of polymorphisms in human cyclooxygenase-1 (PTGS1). Pharmacogenet Genom 2007;17:145–60. https://doi.org/10.1097/01.fpc.0000236340.87540.e3.Search in Google Scholar PubMed PubMed Central

34. Forgerini, M, Urbano, G, de Nadai, TR, Batah, SS, Fabro, AT, Mastroianni, PC. Genetic variants in PTGS1 and NOS3 genes increase the risk of upper gastrointestinal bleeding: a case-control study. Front Pharmacol 2021;12:671835. https://doi.org/10.3389/fphar.2021.671835.Search in Google Scholar PubMed PubMed Central

35. Figueiras, A, Estany-Gestal, A, Aguirre, C, Ruiz, B, Vidal, X, Carvajal, A, et al.. CYP2C9 variants as a risk modifier of NSAID-related gastrointestinal bleeding: a case-control study. Pharmacogenet Genom 2016;26:66–73. https://doi.org/10.1097/fpc.0000000000000186.Search in Google Scholar

36. Hamilton, WG, Gargiulo, JM, Reynolds, TR, Parks, NL. Prospective randomized study using pharmacogenetics to customize postoperative pain medication following hip and knee arthroplasty. J Arthroplasty 2022;37:76–81. https://doi.org/10.1016/j.arth.2022.02.037.Search in Google Scholar PubMed

Received: 2024-05-17

Accepted: 2024-06-17

Published Online: 2024-07-15

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Articles in the same Issue

https://doi.org/10.1515/dmpt-2024-0040

Keywords for this article

adverse reactions; SNP; COX-1; NSAIDs-induced gastropathy; PTGS1; ulcers