Evaluation of anti-inflammatory, immunomodulatory effects and celiac-like side effect of olmesartan medoxomil as a vitamin D receptor agonist and angiotensin II receptor blocker

Prodrug Olmesartan Medoxomil (OM) is an angiotensin II receptor blocker (ARB) and a vitamin D Receptor (VDR) agonist. Reducing the inflammation and improving the immune system OM prevents organ damage. Angiotensin II receptor blockers (ARBs) can raise serum and tissue levels of the membrane-bound form of monocarboxypeptidase angiotensin converting enzyme 2 (ACE2). Increased ACE2 activity causes the balance in the RAAS to shift towards the positive ACE2-Ang-(1-7). Therefore It can be useful with anti-inflammatory, anti-fibrotic and anti-oxidative stress signals in the treatment of immune system diseases. OM is also known to have adverse effects, such as celiac-like enteropathy which was accepted by the FDA. The mechanism of OM's intestinal injury is thought to be the excessive consumption of the enzymes POX1 and carboxymethylenebutenolidase, which are also responsible for the the digestion of gliadin during the hydrolysis of the drug. Cell-mediated immune response and genetic predisposition are the other factors. Our histopathological findings of olmesartan-induced celiac-like enteropathy in rat intestines were increased mononuclear cell infiltration and villous atrophy. In this study these various action mechanisms of OM and its possible immun system booster effects were discussed. The findings of our rat intestines after exposure to OM-Suspension supported and correlated clinical findings of OM. In conclusion, by making extensive evaluations, OM can be a promising immunomodulator agent in immune system diseases.

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[1] Akhtar S, Benter IF, Danjuma MI, Doi SAR, Hasan SS, Habib AM. Pharmacotherapy in COVID-19 patients: a review of ACE2-raising drugs and their clinical safety. J Drug Target. 2020; 28(7-8): 683-699. [CrossRef]
[2] Sacristán D, Marquesz M, Zamorano-León JJ, Luque M, Armengol J, del Castillo J. Modifications by Olmesartan medoxomil treatment of the platelet protein profile of moderate hypertensive patients. Proteomics - Clin Appl. 2008; 2(9): 1300-1312. [CrossRef]
[3 ] Mangin M, Sinha R, Fincher K. Inflammation and vitamin D: the infection connection. Inflamm Res. 2014; 63 (10): 803-819. [CrossRef]
[4] Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP. 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest. 2002; 110(2): 229-238. [CrossRef]
[5] Suzuki Y, Ruiz-Ortega M, Lorenzo O, Ruperez M, Esteban V, Egido J. Inflammation and angiotensin II. Int J Biochem Cell Biol. 2003; 35(6): 881-900. [CrossRef]
[6] Ferder M, Inserra F, Manucha W, Ferder L. The world pandemic of vitamin D deficiency could possibly be explained by cellular inflammatory response activity induced by the renin-angiotensin system. Am J Physiol - Cell Physiol. 2013; 304(11): 1027-1039. [CrossRef]
[7] Talbot G H, Small bowel histopathologic findings suggestive of celiac disease in an asymptomatic patient receiving olmesartan. Mayo Clin Proc. 2012; 87(12): 1231–1232. [CrossRef]
[8] Fummi C. Severe enteropathy induced by olmesartan: a case report. Fundam Clin Pharmacol. 2014; (28): 91-114. [CrossRef]
[9] Papista C, Gerakopoulos V, Kourelis A, Sounidaki M, Kontana A, Berthelot L. Gluten induces coeliac-like disease in sensitised mice involving IgA, CD71 and transglutaminase 2 interactions that are prevented by probiotics. Lab Investig. 2012; 92(4): 625–635. [CrossRef]
[10] Kaswala D, Veeraraghavan G, Kelly C, Leffler D. Celiac Disease: Diagnostic Standards and Dilemmas. Diseases. 2015; 3(2): 86-101. [CrossRef]
[11] Oberhuber G. Histopathology of celiac disease. Biomed Pharmacother. 2000; 54(7): 368-372. [CrossRef]
[12] Niewinski MM. Advances in Celiac Disease and Gluten-Free Diet. J Am Diet Assoc. 2008; 108 (4): 661-672. [CrossRef]
[13] Garrote JA, Gómez-González E, Bernardo D, Arranz E, Chirdo F. Celiac disease pathogenesis: the proinflammatory
cytokine network. J Pediatr Gastroenterol Nutr. 2008; 47(Suppl 1): S27–32. [CrossRef]
[14] Kagnoff MF. Celiac disease: Pathogenesis of a model immunogenetic disease. J Clin Invest. 2007; 117(1): 41-49 [CrossRef]
[15] Gorain B, Choudhury H, Kundu A, Sarkar L, Karmakar S, Jaisankar P, et al. Nanoemulsion strategy for olmesartan medoxomil improves oral absorption and extended antihypertensive activity in hypertensive rats. Colloids Surf B Biointerfaces. 2014; 115: 286–294. [CrossRef]
[16] Mulllertz A, Ogbonna A, Ren S, Rades T. New perspectives on lipid and surfactant based drug delivery systems for oral delivery of poorly soluble drugs. J Pharm Pharmacol. 2010; 62: 1622–1636. [CrossRef]
[17] Fatouros DG, Bergenstahl B, Mullertz A. Morphological observations on a lipid-based drug delivery system during in vitro digestion. Eur J Pharm Sci. 2007; 31(2): 85-94 [CrossRef]
[18] Marshall TG, Lee RE, Marshall FE. Common angiotensin receptor blockers may directly modulate the immune system via VDR, PPAR and CCR2b. Theor Biol Med Model. 2006; 3: 1. [CrossRef]
[19] Jones G, Prosser DE, Kaufmann M. 25-Hydroxyvitamin D-24-hydroxylase (CYP24A1): Its important role in the degradation of vitamin D. Arch Biochem Biophys. 2012; 523(1): 9-18. [CrossRef]
[20] Kongsbak M, Levring TB, Geisler C, von Essen MR. The vitamin D receptor and T cell function. Front Immunol. 2013; 4(18): 1-10. [CrossRef]
[21] Arao T, Okada Y, Mori H, Nishida K, Tanaka Y. Antihypertensive and metabolic effects of high-dose olmesartan and telmisartan in type 2 diabetes patients with hypertension. Endocr J. 2013; 60(5): 563-570. [CrossRef]
[22] Fliser D, Buchholz K, Haller H. Antiinflammatory effects of angiotensin II subtype 1 receptor blockade in hypertensive patients with microinflammation. Circulation. 2004; 110(9): 1103-1107. [CrossRef]
[23] Platten M, Youssef S, Eun MH, Ho PP, Han MH, Lanz T V. Blocking angiotensin-converting enzyme induces potent regulatory T cells and modulates TH1- and TH17-mediated autoimmunity. Proc Natl Acad Sci U S A. 2009; 106(35): 14948-14953. [CrossRef]
[24] Izu Y, Mizoguchi F, Kawamata A, Hayata T, Nakamoto T, Nakashima K, et al. Angiotensin II type 2 receptor blockade increases bone mass. J Biol Chem. 2009; 284(8): 4857-4864. [CrossRef]
[25] Shimizu H, Nakagami H, Osako MK, Hanayama R, Kunugiza Y, Kizawa T, et al. Angiotensin II accelerates osteoporosis by activating osteoclasts. FASEB J. 2008; 22(7): 2465-2475. [CrossRef]