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

Year 2022, Volume: 26 Issue: 1, 63 - 74, 28.06.2025

Yelda Komesli , Ercüment Karasulu

Abstract

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.

Keywords

ARB , vitamin-D , VDR-agonist , ACE2 , Ang-(1-7) , PON1 , celiac-like-enteropathy , immunotherapeutic

References

• [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]
• [26] Li YC, Kong J, Wei M, Chen Z-F, Liu SQ, Cao L-P. 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest. 2002; 110(2): 229-238.[CrossRef]
• [27] Belum GR, Belum VR, Chaitanya Arudra SK, Reddy BSN. The Jarisch-Herxheimer reaction: Revisited. Travel Med Infect Dis. 2013; 11(4): 231-237.[CrossRef]
• [28] Hurley JC. Antibiotic-Induced Release of Endotoxin A Therapeutic Paradox. Drug Saf. 1995; 12 (3): 183-195.[CrossRef]
• [29] Sonawane A, Santos JC, Mishra BB, Jena P, Progida C, Sorensen OE. Cathelicidin is involved in the intracellular killing of mycobacteria in macrophages. Cell Microbiol. 2011; 13(10): 1601-1617.[CrossRef]
• [30] Nickel D, Busch M, Mayer D, Hagemann B, Knoll V, Stenger S. Hypoxia Triggers the Expression of Human β Defensin 2 and Antimicrobial Activity against Mycobacterium tuberculosis in Human Macrophages . J Immunol. 2012; 188(8): 4001-4007.[CrossRef]
• [31] Hajishengallis G, Lambris JD. Microbial manipulation of receptor crosstalk in innate immunity. Nat Rev Immunol. 2011; 11(3): 187-200.[CrossRef]
• [32] Takizawa S, Dan T, Uesugi T, Nagata E, Takagi S, Van Ypersele De Strihou C, et al. A sartan derivative with a very low angiotensin II receptor affinity ameliorates ischemic cerebral damage. J Cereb Blood Flow Metab. 2009; 29(10): 1665–1672.[CrossRef]
• [33] Ferrario C. Effect of angiotensin receptor blockade on endothelial function: Focus on olmesartan medoxomil. Vasc Health Risk Manag. 2009; 5(1): 301-314.[CrossRef]
• [34] Schwocho LR, Masonson HN. Pharmacokinetics of CS-866, a new angiotensin II receptor blocker, in healthy subjects. J Clin Pharmacol. 2001; 41(5): 515-527.[CrossRef]
• [35] Proal AD, Albert PJ, Marshall TG, Blaney GP, Lindseth IA. Immunostimulation in the treatment for chronic fatigue syndrome/myalgic encephalomyelitis. Immunol Res. 2013; 56(2-3): 398-412.[CrossRef]
• [36] Waterhouse JC, Perez TH, Albert PJ. Reversing bacteria-induced vitamin D receptor dysfunction is key to autoimmune disease. In: Annals of the New York Academy of Sciences. 2009; 1173: 757-765.[CrossRef]
• [37] Lemire J. 1,25-Dihydroxyvitamin D3– a hormone with immunomodulatory properties1,25-Dihydroxyvitamin D3– ein Hormon mit immunmodulierenden Eigenschaften. Z Rheumatol. 2000; 59(Suppl 1): 24-27.[CrossRef]
• [38] Zhang Y, Leung DYM, Richers BN, Liu Y, Remigio LK, Riches DW, et al. Vitamin D Inhibits Monocyte/Macrophage Proinflammatory Cytokine Production by Targeting MAPK Phosphatase-1. J Immunol. 2012; 188(5): 2127-2135.[CrossRef]
• [39] Arnson Y, Amital H, Shoenfeld Y. Vitamin D and autoimmunity: New aetiological and therapeutic considerations. Ann Rheum Dis. 2007; 66(9): 1137-1142.[CrossRef]
• [40] Marietta EV, Cartee A, Rishi A, Murray JA. Drug-induced enteropathy. Dig Dis. 2015; 33(2): 215-220.[CrossRef]
• [41] Malfertheiner P, Ripellino C, Cataldo N. Severe intestinal malabsorption associated with ACE inhibitor or angiotensin receptor blocker treatment. An observational cohort study in Germany and Italy. Pharmacoepidemiol Drug Saf. 2018; 27(6): 581-586.[CrossRef]
• [42] Mızuno M, Sada T, Kato M, Koıke H. Renoprotective Effects of Blockade of Angiotensin II AT1 Receptors in an Animal Model of Type 2 Diabetes. Hypertens Res. 2002; 25(2): 271-278.[CrossRef]
• [43] Reagan-Shaw S, Nihal M, Ahmad N. Dose translation from animal to human studies revisited. FASEB J. 2008; 22(3): 659-661.[CrossRef]
• [44] Zanelli M. Sprue-like enteropathy associated with angiotensin ii receptor blockers other than olmesartan. Aliment Pharmacol Ther. 2017; 46(4): 471-473.[CrossRef]
• [45] Marsh MN. Gluten, major histocompatibility complex, and the small intestine. Gastroenterology. 2016; 102(1): 330-354.[CrossRef]
• [46] Husby S, Koletzko S, Korponay-Szabó IR, Mearin ML, Phillips A, Shamir R, et al. European society for pediatric gastroenterology, hepatology, and nutrition guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr. 2012; 54(1): 136–160.[CrossRef]
• [47] Esteve M, Temiño R, Carrasco A, Batista L, Del Val A, Blé M, et al. Potential coeliac disease markers and autoimmunity in olmesartan induced enteropathy: A population-based study. Dig Liver Dis. 2016; 48(2): 154-161.[CrossRef]
• [48] Kourlaba G, Gialama F, Tsioufis K, Maniadakis N. A literature review to evaluate the clinical and economic value of olmesartan for the treatment of hypertensive patients. Int J Cardiol. 2016; 221(15): 60-74.[CrossRef]
• [49] Marthey L, Cadiot G, Seksik P, Pouderoux P, Lacroute J, Skinazi F, et al. Olmesartan-associated enteropathy: Results of a national survey. Aliment Pharmacol Ther. 2014; 40(9): 1103-1109.[CrossRef]
• [50] Mendoza P. Enteropathy related to angiotensin II receptor antagonist losartan: Case study. Clin Transl Allergy. 2016; 6(Suppl 3): 92-101.[CrossRef]
• [51] Hoegh-Petersen M, Thomsen AR, Christensen JP, Holst PJ. Mucosal immunization with recombinant adenoviral vectors expressing murine gammaherpesvirus-68 genes M2 and M3 can reduce latent viral load. Vaccine. 2009; 27(48): 6723-6730.[CrossRef]
• [52] Dreifuss SE, Tomizawa Y, Farber NJ, Davison JM, Sohnen AE. Spruelike Enteropathy Associated with Olmesartan: An Unusual Case of Severe Diarrhea. Case Rep Gastrointest Med. 2013; 618071: 1-3.[CrossRef]
• [53] Cyrany J, Vasatko T, Machac J, Nova M, Szanyi J, Kopacova M. Letter: Telmisartan-associated enteropathy - Is there any class effect? Aliment Pharmacol Ther. 2014; 40(5): 569-570.[CrossRef]
• [54] Mandavdhare HS, Sharma V, Prasad KK, Kumar A, Rathi M, Rana SS. Telmisartan-induced sprue-like enteropathy: A case report and a review of patients using non-olmesartan angiotensin receptor blockers. Intest Res. 2017; 15(3): 419-421.[CrossRef]
• [55] Maier H, Hehemann K, Vieth M. Celiac disease-like enteropathy due to antihypertensive therapy with the angiotensin-II receptor type 1 inhibitor eprosartan. Cesk Patol. 2015; 51(2): 87-88.[CrossRef]
• [56] Khan AS, Peter S, Wilcox CM. Olmesartan-induced enteropathy resembling celiac disease. Endoscopy. 2014; 46: E97-E98.[CrossRef]
• [57] Carneiro L, Moreira A, Pereira A, Andrade C, Soares J, Silva A. Olmesartan-Induced Sprue Like Enteropathy. GE Port J Gastroenterol. 2016; 23(2): 101-105.[CrossRef]
• [58] Lagana SM, Braunstein ED, Arguelles-Grande C, Bhagat G, Green PHR, Lebwohl B. Sprue-Like histology in patients with abdominal pain taking olmesartan compared with other angiotensin receptor blockers. J Clin Pathol. 2015; 68(1): 29-32.[CrossRef]
• [59] Yadav AA, Yadav DS, Karekar PS, Pore Y V, Gajare P. Enhanced solubility and dissolution rate of Olmesartan medoxomil using crystallo-co-agglomeration technique. Pelagia Res Libr. 2012; 3(2): 160-169.[CrossRef]
• [60] Pallav K, Leffler DA, Tariq S, Kabbani T, Hansen J, Peer A, et al. Noncoeliac enteropathy: The differential diagnosis of villous atrophy in contemporary clinical practice. Aliment Pharmacol Ther. 2012; 35(3): 380-390.[CrossRef]
• [61] Seth A, Gupta V, Jain P. Olmesartan: An overlooked cause for non-celiac sprue like enteropathy. Asian J Pharm Pharmacol. 2018; 4(1): 83-86.[CrossRef]
• [62] Marietta E V, Nadeau AM, Cartee AK, Singh I, Rishi A, Choung RS, et al. Immunopathogenesis of olmesartan-associated enteropathy. Aliment Pharmacol Ther. 2015; 42(11-12): 1303-1314.[CrossRef]
• [63] Bhat N, Anupama NK, Yelsangikar A, Vizhi K. Olmesartan-related sprue-like enteropathy. Indian J Gastroenterol. 2014; 33(6): 564–567.[CrossRef]
• [64] Martins C, Teixeira C, Ribeiro S, Trabulo D, Cardoso C, Mangualde J, et al. Seronegative Intestinal Villous Atrophy: A Diagnostic Challenge. Case Rep Gastrointest Med. 2016; 6392028: 1-4.[CrossRef]
• [65] Burbure N, Lebwohl B, Arguelles-Grande C, Green PHR, Bhagat G, Lagana S. Olmesartan-associated sprue-like enteropathy: A systematic review with emphasis on histopathology. Hum Pathol. 2016; 50: 127–134.[CrossRef]
• [66] Scialom S, Malamut G, Meresse B, Guegan N, Brousse N, Verkarre V, et al. Gastrointestinal disorder associated with olmesartan mimics autoimmune enteropathy. PLoS One. 2015; 10(6): e0125024.[CrossRef]
• [67] Kulai T, Arnason T, MacIntosh D, Igoe J. Duodenal Villous Atrophy in a TTG-Negative Patient Taking Olmesartan: A Case Report and Review of the Literature. Can J Gastroenterol Hepatol. 2016; 6091571.[CrossRef]
• [68] Negro A, Rossi GM, Santi R, Iori V, De Marco L. A Case of Severe Sprue-like Enteropathy Associated with Losartan. J Clin Gastroenterol. 2015; 49(9): 794.[CrossRef]
• [69] Hickson J, Ackler S, Klaubert D, Bouska J, Ellis P, Foster K, Oleksijew A, Rodriguez L, Schlessinger S, Wang B, Frost D, et al. Noninvasive molecular imaging of apoptosis in vivo using a modified firefly luciferase substrate, Z-DEVD-aminoluciferin. Cell Death Differ. 2010; 17(6): 1003-1010.[CrossRef]
• [70] Tran TH, Li H. Olmesartan and drug-induced enteropathy. P T a peer-reviewed J Formul Manag a peer-reviewed J Formul Manag. 2014; 39(1): 47–50.[CrossRef]
• [71] Basson M, Mezzarobba M, Weill A, Ricordeau P, Allemand H, Alla F, et al. Severe intestinal malabsorption associated with olmesartan: A French nationwide observational cohort study. Gut. 2015; 65(10): 1664-1669.[CrossRef]
• [72] Hehemann K, Vieth M, Maier H. Celiac disease-like enteropathy due to antihypertensive therapy with the angiotensin-II receptor type 1 inhibitor eprosartan. Cesk Patol. 2015; 51(2): 87-88.[CrossRef]
• [73] Herman ML, Rubio-Tapia A, Wu TT, Murray JA. A case of severe sprue-like enteropathy associated with valsartan. ACG Case Reports J. 2015; 2(2): 92–94.[CrossRef]
• [74] Mondet L. Angiotensin II receptor blockers-induced enteropathy: Not just olmesartan! A case report with candesartan. Fundam Clin Pharmacol. 2016, 30(Suppl. 1): 47-87.[CrossRef]
• [75] Précourt LP, Marcil V, Ntimbane T, Taha R, Lavoie JC, Delvin E, et al. Antioxidative properties of paraoxonase 2 in intestinal epithelial cells. Am J Physiol - Gastrointest Liver Physiol. 2012; 303: G623–G634.[CrossRef]
• [76] Laeis P, Puchler K, Kirch W. The pharmacokinetic and metabolic profile of olmesartan medoxomil limits the risk of clinically relevant drug interaction. J Hypertens Suppl. 2001; 19(1): S21-32.[CrossRef]
• [77] Ma SF, Anraku M, Iwao Y, Yamasaki K, Kragh-Hansen U, Yamaotsu N, et al. Hydrolysis of angiotensin II receptor blocker prodrug olmesartan medoxomil by human serum albumin and identification of its catalytic active sites. Drug Metab Dispos. 2005; 33(12): 1911-1919.[CrossRef]
• [78] Nishimuta H, Houston JB, Galetin A. Hepatic, intestinal, renal, and plasma hydrolysis of prodrugs in human, cynomolgus monkey, dog, and rat: Implications for in vitro-in vivo extrapolation of clearance of prodrugs. Drug Metab Dispos. 2014; 42(9): 1522-1531.[CrossRef]
• [79] Ishizuka T, Yoshigae Y, Murayama N, Izumi T. Different hydrolases involved in bioactivation of prodrug-type angiotensin receptor blockers: Carboxymethylenebutenolidase and carboxylesterase 1. Drug Metab Dispos. 2013; 41(11): 1888-1895.[CrossRef]
• [80] Ishizuka T, Fujimori I, Nishida A, Sakurai H, Yoshigae Y, Nakahara K, et al. Paraoxonase 1 as a major bioactivating hydrolase for olmesartan medoxomil in human blood circulation: Molecular identification and contribution to plasma metabolism. Drug Metab Dispos. 2012; 40(2):374-380.[CrossRef]
• [81] Furlong CE, Marsillach J, Jarvik GP, Costa LG. Paraoxonases-1, -2 and -3: What are their Functions? Chem Biol Interact. 2016; 259(PtB): 51-62.[CrossRef]
• [82] Ishizuka T, Fujimori I, Kato M, Noji-Sakikawa C, Saito M, Yoshigae Y, et al. Human carboxymethylenebutenolidase as a bioactivating hydrolase of olmesartan medoxomil in liver and intestine. J Biol Chem. 2010; 285 (16): 11892-11902.[CrossRef]
• [83] Ishizuka T, Rozehnal V, Fischer T, Kato A, Endo S, Yoshigae Y, et al. Interindividual variability of carboxymethylenebutenolidase homolog, a novel olmesartan medoxomil hydrolase, in the human liver and intestines. Drug Metab Dispos. 2013; 41(5): 1156-1162.[CrossRef]
• [84] Ferretti G, Bacchetti T, Saturni L, Manzella N, Candelaresi C, Benedetti A, et al. Lipid Peroxidation and Paraoxonase-1 Activity in Celiac Disease. J Lipids. 2012; 587479.[CrossRef]
• [85] Hausch F, Shan L, Santiago NA, Gray GM, Khosla C. Intestinal digestive resistance of immunodominant gliadin peptides. Am J Physiol - Gastrointest Liver Physiol. 2002; 283(4): G996-G1003.[CrossRef]
• [86] Woolard MD, Frelinger JA. Outsmarting the host: Bacteria modulating the immune response. Immunol Res. 2008; 41(3): 188-202.[CrossRef]
• [87] Dermine JF, Desjardins M. Survival of intracellular pathogens within macrophages. Protoplasma. 1999; 210: 11–24.[CrossRef]
• [88] Smith GR. Angiotensin and systems thinking: Wrapping your mind around the big picture. Ochsner J. 2013; 13(1): 11-25.[CrossRef]
• [89] Reynolds HR, Adhikari S, Pulgarin C, Troxel AB, Iturrate E, Johnson SB, et al. Renin–Angiotensin–Aldosterone System Inhibitors and Risk of Covid-19. N Engl J Med. 2020; 382(25): 2441-2448.[CrossRef]
• [90] Yang G, Tan Z, Zhou L, Yang M, Peng L, Liu J, et al. Effects Of ARBs And ACEIs On Virus Infection, Inflammatory Status And Clinical Outcomes In COVID-19 Patients With Hypertension: A Single Center Retrospective Study. Hypertens. 2020; 76(1): 51-58.[CrossRef]
• [91] Li J, Wang X, Chen J, Zhang H, Deng A. Association of Renin-Angiotensin System Inhibitors with Severity or Risk of Death in Patients with Hypertension Hospitalized for Coronavirus Disease 2019 (COVID-19) Infection in Wuhan, China. JAMA Cardiol. 2020; 5(7): 825-830.[CrossRef]
• [92] Abajo FJ, Rodríguez-Martín S, Lerma V, Mejía-Abril G, Aguilar M, García-Luque A, et al. Use of renin–angiotensin–aldosterone system inhibitors and risk of COVID-19 requiring admission to hospital: a case-population study. Lancet. 2020; 395(10238): 1705-1714.[CrossRef]
• [93] Tedeschi S, Giannella M, Bartoletti M, ... Clinical impact of renin-angiotensin system inhibitors on in-hospital mortality of patients with hypertension hospitalized for COVID-19. Clin Infect Dis. 2020; 71(15):899-901.[CrossRef]
• [94] Oussalah A, Gleye S, Clerc Urmes I, Laugel E, Callet J, Barbé F, et al. Long-term ACE Inhibitor/ARB Use Is Associated With Severe Renal Dysfunction and Acute Kidney Injury in Patients With Severe COVID-19: Results From a Referral Center Cohort in the Northeast of France. Clin Infect Dis. 2020; 71(9): 2447-2456.[CrossRef]
• [95] Arumugam S, Sreedhar R, Thandavarayan RA, Karuppagounder V, Krishnamurthy P, Suzuki K, et al. Angiotensin receptor blockers: Focus on cardiac and renal injury. Trends Cardiovasc Med. 2016; 26(3): 221-228.[CrossRef]
• [96] Silva-Filho JL, Souza MC, Henriques M das G, Morrot A, Savino W, Nunes MP, et al. AT1 receptor-mediated angiotensin II activation and chemotaxis of T lymphocytes. Mol Immunol. 2011; 48(15-16): 1835-1843.[CrossRef]
• [97] Sukumaran V, Veeraveedu PT, Gurusamy N, Lakshmanan AP, Yamaguchi K, Ma M, et al. Olmesartan attenuates the development of heart failure after experimental autoimmune myocarditis in rats through the modulation of ANG 1-7 mas receptor. Mol Cell Endocrinol. 2011; 351(2): 208-219.[CrossRef]
• [98] Arumugam S, Thandavarayan RA, Palaniyandi SS, Giridharan V V., Arozal W, Sari FR, et al. Candesartan cilexetil protects from cardiac myosin induced cardiotoxicity via reduction of endoplasmic reticulum stress and apoptosis in rats: Involvement of ACE2-Ang (1-7)-mas axis. Toxicology. 2012; 291(1-3): 139-145.[CrossRef]
• [99] Ntountaniotis D, Mali G, Grdadolnik SG, Halabalaki M, Maria H, Skaltsounis A-L, et al. Thermal, dynamic and structural properties of drug AT1 antagonist olmesartan in lipid bilayers. Biochim Biophys Acta. 2011; 1808(12): 2995–3006.[CrossRef]
• [100] Agata J, Ura N, Yoshida H, Shinshi Y, Sasaki H, Hyakkoku M, et al. Olmesartan is an angiotensin II receptor blocker with an inhibitory effect on angiotensin-converting enzyme. Hypertens Res. 2006; 29 (11): 865–874.[CrossRef]
• [101] Igase M, Strawn WB, Gallagher PE, Geary RL, Ferrario CM. Angiotensin II at1 receptors regulate ACE2 and angiotensin-(1-7) expression in the aorta of spontaneously hypertensive rats. Am J Physiol - Hear Circ Physiol. 2005; 289(3): H1013-1019.[CrossRef]
• [102] Magalhães GS, Gregório JF, Ramos KE, Cançado-Ribeiro ATP, Baroni IF, Barcelos LS, et al. Treatment with inhaled formulation of angiotensin-(1-7) reverses inflammation and pulmonary remodeling in a model of chronic asthma. Immunobiology. 2020; 225(3): 151957.[CrossRef]
• [103] Imai Y, Kuba K, Rao S, Huan Y, Guo F, Guan B, et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature. 2005; 436: 112–116.[CrossRef]
• [104] Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med. 2005; 11(8): 875-879.[CrossRef]
• [105] Penna G, Amuchastegui S, Laverny G, Adorini L. Vitamin D receptor agonists in the treatment of autoimmune diseases: Selective targeting of myeloid but not plasmacytoid dendritic cells. J Bone Miner Res. 2007; 22(Suppl 2): V69-73.[CrossRef]
• [106] The RECOVERY Collaborative Group, Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report. N Engl J Med. 2021; 384: 693-704.[CrossRef]
• [107] Theoharides TC, Conti P. Dexamethasone for COVID-19? Not so fast. J Biol Regul Homeost Agents. 2020; 34(3): 1241-1243.[CrossRef]
• [108] Ghadhanfar E, Alsalem A, Al-Kandari S, Naser J, Babiker F, Al-Bader M. The role of ACE2, angiotensin-(1-7) and Mas1 receptor axis in glucocorticoid-induced intrauterine growth restriction. Reprod Biol Endocrinol. 2017; 15(1): 97.[CrossRef]
• [109] Komesli Y, Burak Ozkaya A, Ugur Ergur B, Kirilmaz L, Karasulu E. Design and development of a self-microemulsifying drug delivery system of olmesartan medoxomil for enhanced bioavailability. Drug Dev Ind Pharm. 2019; 45(8): 1292-1305.[CrossRef]
• [110] Cecen B, Kozaci LD, Yuksel M, Ustun O, Ergur BU, Havitcioglu H. Biocompatibility and biomechanical characteristics of loofah based scaffolds combined with hydroxyapatite, cellulose, poly-L-lactic acid with chondrocyte-like cells. Mater Sci Eng C. 2016; 69: 437-446.[CrossRef]