Nonsteroidal anti-inflammatory drugs: a modern understanding of the mechanisms of damage to the digestive tract, the shortcomings of pathogenetic drugs and prospects for biological therapy of NSAID-induced esophagogastroenterocolonopathy
Keywords:nonsteroidal anti-inflammatory drugs, ulcerogenicity, esophagogastroenterocolonopathy, cryopreserved placental extract
AbstractBackground. Nonsteroidal anti-inflammatory drugs (NSAIDs) are used daily by more than 30 million people, and their arsenal includes more than 80 drugs and about 1,000 dosage forms based on them. They are widely used in many areas of medicine and are one of the most clinically significant groups of drugs. However, the use of NSAIDs can often cause side effects, the most common of which are damage to the gastrointestinal tract. Objective: to characterize the current understanding of the mechanisms of damage to the digestive tract by nonsteroidal anti-inflammatory drugs, to assess the shortcomings of existing pathogenetic drugs and prospects for biological therapy of NSAID-induced esophagogastroenterocolonopathy with cryopreserved human placental extract. Materials and methods. The analysis was performed of the works published in 2010–2020, which covered information on the epidemiology, pathogenesis, diagnosis and treatment of lesions of the esophagus and gastrointestinal tract induced by nonsteroidal anti-inflammatory drugs, as well as the biological properties of cryopreserved human placental extract as biological therapy. Results. Treatment of NSAID-induced esophagogastroenterocolonopathy is usually aimed at acid-suppressive therapy (proton pump inhibitors, H2-histamine blockers, etc.), the use of gastrocytoprotectors (de-nol, sucralfate, etc.) and drugs that restore the content of prostaglandins in the mucous membrane (misoprostol, rebamipide, etc.). However, all these groups of drugs do not sufficiently satisfy clinicians, as they are aimed primarily at treating NSAID gastropathy and have their own side effects. A new promising area for improving the safety of NSAIDs today is the use of biological therapies, the sources of which are microorganisms, organs and tissues of plant or animal origin, cells or fluids (including blood and plasma) of human or animal origin and biotechnological cell structures. Conclusions. The use of nonsteroidal anti-inflammatory drugs is significantly limited by their side effects, the most common of which are disorders of the gastrointestinal tract. Cryopreserved human placental extract is a promising biological therapy for ulcerogenic lesions of the gastrointestinal tract induced by nonsteroidal anti-inflammatory drugs.
Bielsa-Fernández MV, Tamayo-de la Cuesta JL, et al. The Mexican consensus on the diagnosis, treatment, and prevention of NSAID-induced gastropathy and enteropathy. Rev Gastroenterol Mex. 2020 Apr-Jun;85(2):190-206. doi:10.1016/j.rgmx.2019.11.003.
Hladkykh FV, Stepaniuk NH. New approaches to reduce ulcerogenity of nonsteroidal anti-infl ammatory drugs: achievements, unsolved issues and ways to optimize. Zaporozhye Medical Journal. 2014;2(83):82-86. (in Ukrainian).
Amelin AV, Afanasiev VV, Starikov PV, et al. Minutes of the Expert Board of the Northwestern Federal District of the Russian Federation on rational approach to management of pain and inflammation in neurology. Meditsinskiy sovet. 2015;(7):51-52. doi:10.21518/2079-701X-2015-7-51-53. (in Russian).
Hladkykh FV. Multimodal analgesia: polypharmacy in pain relief or rational use of non-steroidal anti-inflammatory drugs to prevent pain chronicity. Path of Science. 2020;6(7):4008-4018. doi:10.22178/pos.60-5. (in Russian).
Lesnaya OA, Rusanova EI, Prokofieva EB, Freire da Silva T. Rational use of NSAIDs according to clinical guidelines and data from recent studies. Difficult patient. 2019;17(10):31-34. doi:10.24411/2074-1995-2019-10072. (in Russian).
Popov OS. Farmakologichne doslidzhennja kombinovanogo nesteroi'dnogo protyzapal'nogo preparatu Dyklokor. Diss. kand. med. nauk [Pharmacological study of the combined non-steroidal anti-inflammatory drug Diclocor. PhD in med. sci. diss.]. Kyiv; 2017. 22 р. (in Ukrainian).
Kursov SV, Nikonov VV. Cyclooxygenase: physilogical effects, inhibitors action and perspectives of paracetamol usage. Medicina neotložnyh sostoânij. 2016;5(76):27-35. doi:10.22141/2224-0522.214.171.1246.76430. (in Russian).
Lazebnik LB, Belova GV. Systemtizing classification of multifocal lesions of the mucosa of the digestive tract by non-steroidal anti-inflammatory and antitrombotic drugs (Moscow classification). Eksperimental'naia i klinicheskaia gastroenterologiia. 2018;(151):19-27. (in Russian).
Barinov E, Sulaieva O, Lyakch Y, Guryanov V, Kondratenko P, Radenko Y. Platelet aggregation measurement for assessment of hemostasis failure mechanisms in patients with gastroduodenal ulcer bleeding. Clin Exp Gastroenterol. 2013 Aug 5;6:139-48. doi:10.2147/CEG.S45685.
Jarosz M, Szkaradek N, Marona H, Nowak G, Młyniec K, Librowski T. Evaluation of anti-inflammatory and ulcerogenic potential of zinc-ibuprofen and zinc-naproxen complexes in rats. Inflammopharmacology. 2017 Dec;25(6):653-663. doi:10.1007/s10787-017-0361-0.
Lim YJ, Lee JS, Ku YS, Hahm KB. Rescue strategies against non-steroidal anti-inflammatory drug-induced gastroduodenal damage. J Gastroenterol Hepatol. 2009 Jul;24(7):1169-78. doi:10.1111/j.1440-1746.2009.05929.x.
Musumba C, Pritchard DM, Pirmohamed M. Review article: cellular and molecular mechanisms of NSAID-induced peptic ulcers. Aliment Pharmacol Ther. 2009 Sep 15;30(6):517-31. doi:10.1111/j.1365-2036.2009.04086.x.
Balabantseva AP, Kliaritskaia IL, Tsapyak TA, Grigorenko EI. Modern approaches to primary prevention of NSAID-gastropathy and enteropathy. Crimean Journal of Internal Disease. 2015;(26):31-38. (in Russian).
Podpletniaia EA, Mamchur VI. Mechanisms of gastroduodenotoxicity of non-steroidal anti-inflammatory drugs. Journal of the National Academy of Medical Sciences of Ukraine. 2005;(1):47-62. (in Russian).
Uspenskii IuP, Baryshnikova NV, Orlov Oiu, Alexandrova IuA. NSAID-associated pathology of the gastrointestinal tract: choice of the drug, tactics of patient management. Spravochnik poliklinicheskogo vracha. 2014;(8):42-47. (in Russian).
Lanas Á, Carrera-Lasfuentes P, Arguedas Y, et al. Risk of upper and lower gastrointestinal bleeding in patients taking nonsteroidal anti-inflammatory drugs, antiplatelet agents, or anticoagulants. Clin Gastroenterol Hepatol. 2015 May;13(5):906-12.e2. doi:10.1016/j.cgh.2014.11.007.
Sulaieva ON, Wallace JL. New strategy for gastrointestinal protection based on gaseous mediators application. Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2016;26(3):17-23. (in Russian).
Evseev MA. Anti-inflammatory drug-induced injury to the intestinal tube: clinical value, pathogenesis, possibilities of prevention. Nevrologiya, Neiropsikhiatriya, Psikhosomatika. 2013;(1):79-87. (in Russian).
Zayachkivska O, Bula N, Khyrivska D, Gavrilyuk E, Wallace JL. Exposure to non-steroid anti-inflammatory drugs (NSAIDs) and suppressing hydrogen sulfide synthesis leads to altered structure and impaired function of the oesophagus and oesophagogastric junction. Inflammopharmacology. 2015 Jun;23(2-3):91-99. doi:10.1007/s10787-015-0230-7.
Zayachkivska ОS, Bula NS, Pavlovskiy YaI, et al. Effect of hydrogen sulfide-releasing aspirin on esophageal and gastric mucosa compromised by stress injury. Ukr Biochem J. 2017;89(Suppl):93-101. doi:10.15407/ubj89.si01.093.
Karateev AE, Nasonov EL, Radenska-Lopovok SG. Efficacy of colloid bismuth subcitrate (De-nol) in gastropathies induced by nonsteroid anti-inflammatory drugs: an open controlled 4-week trial. Terapevticheskii arkhiv. 2005;77(2):46-49. (in Russian).
Fomenko IS. Influence of nonsteroidal anti-inflammatory drugs on indicators of NO and H2S systems in the mucous membrane of the colon. Bulletin of Taras Shevchenko National University of Kyiv. Series: Problems of Physiological Functions Regulation. 2015;18(1):45-47. (in Ukrainian).
Guo CG, Leung WK. Potential Strategies in the Prevention of Nonsteroidal Anti-inflammatory Drugs-Associated Adverse Effects in the Lower Gastrointestinal Tract. Gut Liver. 2020 Mar 15;14(2):179-189. doi:10.5009/gnl19201.
Dydykina IS, Kovalenko PS. Main aspects of prevention and treatment of NSAIDs gastropathy in the light of new ideology of the modern medicine. Therapy. 2019;(27):182-192. doi:10.18565/therapy.2019.1.182-192. (in Russian).
Lazebnik LB, Golovanova EV, Alekseenko SA, et al. Recommendations for the prevention and treatment of esophago-gastro-entero-colopathy induced by nonsteroidal antiinfl ammatory drugs NSAID. Eksperimental'naia i klinicheskaia gastroenterologiia. 2018;151(3):4-18. (in Russian).
Tomash OV, Rudenko NN, Yurenko EA. Antisecretory therapy in the clinical practice: from routine patterns to the evidence-based standards. Ukrainian therapeutical journal. 2011;(2):103-114. (in Russian).
Dikareva EA. The influence of antisecretory therapy adherence on the risk of the development of gastropathy induced by the administration of nonsteroidal anti-inflammatory agents. Vestnik Vitebskogo gosudarstvennogo medicinskogo universiteta. 2019;18(4):60-66. doi:10.22263/2312-4156.2019.4.60. (in Russian).
Marlicz W, Loniewski I, Grimes DS, Quigley EM. Nonsteroidal anti-inflammatory drugs, proton pump inhibitors, and gastrointestinal injury: contrasting interactions in the stomach and small intestine. Mayo Clin Proc. 2014 Dec;89(12):1699-709. doi:10.1016/j.mayocp.2014.07.015.
Fornai M, Colucci R, Antonioli L, et al. Effects of esomeprazole on healing of nonsteroidal anti-inflammatory drug (NSAID)-induced gastric ulcers in the presence of a continued NSAID treatment: Characterization of molecular mechanisms. Pharmacol Res. 2011 Jan;63(1):59-67. doi:10.1016/j.phrs.2010.10.013.
Scheiman JM, Hindley CE. Strategies to optimize treatment with NSAIDs in patients at risk for gastrointestinal and cardiovascular adverse events. Clin Ther. 2010 Apr;32(4):667-77. doi:10.1016/j.clinthera.2010.04.009.
Blackler RW, De Palma G, Manko A, et al. Deciphering the pathogenesis of NSAID enteropathy using proton pump inhibitors and a hydrogen sulfide-releasing NSAID. Am J Physiol Gastrointest Liver Physiol. 2015 Jun 15;308(12):G994-1003. doi:10.1152/ajpgi.00066.2015.
Hladkykh FV. Preventive and therapeutic strategies of pharmaco-correction gastropathy induced by nonsteroidal anti-inflammatory drugs. Reviews on Clinical Pharmacology and Drug Therapy. 2017;15(4):14-23. doi:10.17816/RCF15414-23. (in Russian).
Andersen JT, Mastrogiannis D, Andersen NL, et al. Diclofenac/misoprostol during early pregnancy and the risk of miscarriage: a Danish nationwide cohort study. Arch Gynecol Obstet. 2016 Aug;294(2):245-50. doi:10.1007/s00404-015-3966-9.
Efimov AL, Sigua BV, Filaretova LP. Acute ulcers and erosions of the gastrointestinal tract induced by non-steroidal anti-inflammatory drugs: etiology, pathogenesis, therapeutic tactics. Bulletin of the Russian Military Medical Academy. 2017;(57):198-204. (in Russian).
Satoh H, Takeuchi K. Management of NSAID/aspirin-induced small intestinal damage by GI-sparing NSAIDs, anti-ulcer drugs and food constituents. Curr Med Chem. 2012;19(1):82-9. doi:10.2174/092986712803413980.
Motta JP, Flannigan KL, Agbor TA, et al. Hydrogen sulfide protects from colitis and restores intestinal microbiota biofilm and mucus production. Inflamm Bowel Dis. 2015 May;21(5):1006-17. doi:10.1097/MIB.0000000000000345.
Magierowski M, Magierowska K, Kwiecien S, Brzozowski T. Gaseous mediators nitric oxide and hydrogen sulfide in the mechanism of gastrointestinal integrity, protection and ulcer healing. Molecules. 2015 May 19;20(5):9099-123. doi:10.3390/molecules20059099.
Zanellato I, Bonarrigo I, Ravera M, Gabano E, Gust R, Osella D. The hexacarbonyldicobalt derivative of aspirin acts as a CO-releasing NSAID on malignant mesothelioma cells. Metallomics. 2013 Dec;5(12):1604-13. doi:10.1039/c3mt00117b.
Wallace JL, Caliendo G, Santagada V, Cirino G. Markedly reduced toxicity of a hydrogen sulphide-releasing derivative of naproxen (ATB-346). Br J Pharmacol. 2010 Mar;159(6):1236-46. doi:10.1111/j.1476-5381.2009.00611.x.
Zanardo RC, Brancaleone V, Distrutti E, Fiorucci S, Cirino G, Wallace JL. Hydrogen sulfide is an endogenous modulator of leukocyte-mediated inflammation. FASEB J. 2006 Oct;20(12):2118-20. doi:10.1096/fj.06-6270fje.
Gemici B, Elsheikh W, Feitosa KB, Costa SK, Muscara MN, Wallace JL. H2S-releasing drugs: anti-inflammatory, cytoprotective and chemopreventative potential. Nitric Oxide. 2015 Apr 30;46:25-31. doi:10.1016/j.niox.2014.11.010.
Dillon CT, Hambley TW, Kennedy BJ, et al. Gastrointestinal toxicity, antiinflammatory activity, and superoxide dismutase activity of copper and zinc complexes of the antiinflammatory drug indomethacin. Chem Res Toxicol. 2003 Jan;16(1):28-37. doi:10.1021/tx020078o.
Hladkykh FV. Characteristic of mechanisms of antiulcerogenic action of agents of vanilloid receptors (TRPV1) on the model of gastropathy induced by acetylsalicylic acid. Farmatsiya i farmakologiya. 2017;5(3):283-301. doi:10.19163/2307-9266-2017-5-3-283-301. (in Russian).
Mózsik G. Capsaicin as new orally applicable gastroprotective and therapeutic drug alone or in combination with nonsteroidal anti-inflammatory drugs in healthy human subjects and in patients. Prog Drug Res. 2014;68:209-58. doi:10.1007/978-3-0348-0828-6_9.
Singh DP, Borse SP, Nivsarkar M. Co-administration of quercetin with pantoprazole sodium prevents NSAID-induced severe gastroenteropathic damage efficiently: Evidence from a preclinical study in rats. Exp Toxicol Pathol. 2017 Jan;69(1):17-26. doi:10.1016/j.etp.2016.10.004.
Zupanets IA, Shebeko SK, Popov OS, Shalamay AS. Diclocor is superior to diclofenac sodium and quercetin in normalizing biochemical parameters in rats with collagen-induced osteoarthritis. Inflammopharmacology. 2016 Feb;24(1):53-57. doi:10.1007/s10787-015-0258-8.
Bulgakov SA. Hexapeptide Dalargin in clinical gastroenterology: 30 years of experience using the drug. Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2016;26(3):103-112. (in Russian).
Ul'ianina LR, Il'in DA, Karimova D.R. Experimental evaluation of gastroprotective activity of L-methionine and lithium L-methioninate on the model of indometacin gastric ulcer. In: Proceeding of the 88th All-Russian Scientific and Practical Conference of Students and Young Scientists dedicated to the 200th anniversary of the Kazan State Medical University. 2014, March 26-27; Kazan, Russian federation. Kazan; 2014. 175 p. (in Russian).
Xia X, Chan KF, Wong GTY, et al. Mesenchymal stem cells promote healing of nonsteroidal anti-inflammatory drug-related peptic ulcer through paracrine actions in pigs. Sci Transl Med. 2019 Oct 30;11(516):eaat7455. doi:10.1126/scitranslmed.aat7455.
Askarov MB, Shumakov VI, Onishchenko NA. Multipotent mesenchymal stromal cells of the autologous bone marrow accelerate healing indolent gastric ulcers. Grekov's Bulletin of Surgery. 2009;168(2):22-26. (in Russian).
Askarov MB, Cypin AB, Trubicina IE, Ivanov IM, Onishchenko NA. Reparative processes in lengthily unclosing gastric ulcers at using of bioregulatory spleen tissue peptides. Vestnik Transplantologii i Iskusstvennykh Organov. 2008;(3):34-38. (in Russian).
Lorents SE, Zharikov AYu, Mazko ON, et al. Influence of the peptide complex from pork kidneys tissues on indicators of free radical oxidation and the expression of COX-1,2 in experimental gastropathy. Eksperimental'naia i klinicheskaia gastroenterologiia. 2018;(154):81-85. (in Russian).
Gulevsky AK, Abakumova YeS, Moiseyeva NN, Dolgikh OL. Influence of cattle cord blood fraction below 5 kd on biochemical parameters of blood at experimental chronic stomach ulcer in rats. Ukrainian Biochemical Journal. 2008;80(2):120-127. (in Russian).
Gromova ОА, Torshin IYu, Dibrova ЕА, Karimova IM, Gilels AV, Kustova EV. World-wide experience of the use of placental extracts: results of clinical and experimental studies. Review. Plasticheskaia khirurgiia i kosmetologiia. 2011;(3):525-536. (in Russian).
Takagi K, Okabe S, Saziki R. A new method for the production of chronic gastric ulcer in rats and the effect of several drugs on its healing. Jpn J Pharmacol. 1969 Sep;19(3):418-26. doi:10.1254/jjp.19.418.
Blazhko EV, Bobyreva LE, Geraskina LR, et al., authors; Gol'tsev AN, Iurchenko TN, editors. Platsenta: kriokonservirovanie, klinicheskoe primenenie [Placenta: cryopreservation, clinical use]. Kharkiv; 2013. 268 p. (in Russian).
Gulida MO, Miroshnichenko EV, Berezka MI, Garyachiy EV. Application of placenta extract in complex treatment of patients with rheumatoid arthritis. Experimental and Clinical Medicine. 2014;(62):168-171. (in Russian).
Kapustyanska AA. Application of preparation Cryocell - the cryo-extract of the placenta in the complex treatment of gouty arthritis aggravitations in patients with metabolic syndrome. Actual Problems of the Modern Medicine: Bulletin of Ukrainian Medical Stomatological Academy. 2010;10(2):54–58. (in Ukrainian).
Nasadyuk SM. Biochemical characteristics and approaches to the use of placental extracts in medical practice. Z turbotoju pro zhinku. 2013;(43):54-56. (in Ukrainian).
Shepitko KV. Application of cryopreserved placenta preparations in the small intestine pathologies in rats for their further use in exigent conditions. Bulletin of problems in biology and medicine. 2019;(154):56-61. doi:10.29254/2077-4214-2019-4-2-154-56-61. (in Ukrainian).
Shevchenko NO, Somova KV, Volina VV, Prokopiuk VYu, Prokopiuk OS. Dynamics of activity and duration of functioning of cryopreserved cryoextract, placental cells and fragments in the organism of experimental animals. Morphologia. 2016;10(2):93-98. doi:10.26641/1997-9665.2016.2.93-98. (in Ukrainian).
Copyright (c) 2020 GASTROENTEROLOGY
This work is licensed under a Creative Commons Attribution 4.0 International License.
Our edition uses the copyright terms of Creative Commons for open access journals.
Authors, who are published in this journal, agree with the following terms:
- The authors retain rights for authorship of their article and grant to the edition the right of first publication of the article on a Creative Commons Attribution 4.0 International License, which allows others to freely distribute the published article, with the obligatory reference to the authors of original works and original publication in this journal.
- Directing the article for the publication to the editorial board (publisher), the author agrees with transmitting of rights for the protection and using the article, including parts of the article, which are protected by the copyrights, such as the author’s photo, pictures, charts, tables, etc., including the reproduction in the media and the Internet; for distributing; for the translation of the manuscript in all languages; for export and import of the publications copies of the writers’ article to spread, bringing to the general information.
- The rights mentioned above authors transfer to the edition (publisher) for the unlimited period of validity and on the territory of all countries of the world.
- The authors guarantee that they have exclusive rights for using of the article, which they have sent to the edition (publisher). The edition (the publisher) is not responsible for the violation of given guarantees by the authors to the third parties.
- The authors have the right to conclude separate supplement agreements that relate to non-exclusive distribution of their article in the form in which it had been published in the journal (for example, to upload the work to the online storage of the journal or publish it as part of a monograph), provided that the reference to the first publication of the work in this journal is included.
- The policy of the journal permits and encourages the publication of the article in the Internet (in institutional repository or on a personal website) by the authors, because it contributes to productive scientific discussion and a positive effect on efficiency and dynamics of the citation of the article.
- The rights to the article are deemed transferred by the authors to the edition (the publisher) since the moment of the publication of the article in the printed or electronic version of journal.