{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:47:01Z","timestamp":1787028421565,"version":"build-2736575974"},"reference-count":44,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2019,10,9]],"date-time":"2019-10-09T00:00:00Z","timestamp":1570579200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Indomethacin (IMC)-induced gastrointestinal (GI) injuries are more common in rheumatoid arthritis (RA) patients than in other IMC users, and the overexpression of nitric oxide (NO) via inducible NO synthase (iNOS) is related to the seriousness of IMC-induced GI injuries. However, sufficient strategies to prevent IMC-induced GI injuries have not yet been established. In this study, we designed dispersions of rebamipide (RBM) solid nanocrystals (particle size: 30\u2013190 nm) by a bead mill method (RBM-NDs), and investigated whether the oral administration of RBM-NDs is useful to prevent IMC-induced GI injuries. The RBM nanocrystals were spherical and had a solubility 4.71-fold greater than dispersions of traditional RBM powder (RBM-TDs). In addition, the RBM-NDs were stable for 1 month after preparation. The RBM contents in the stomach, jejunum, and ileum of rats orally administered RBM-NDs were significantly higher than in rats administered RBM-TDs. Moreover, the oral administration of RBM-NDs decreased the NO levels via iNOS and area of the GI lesions in IMC-stimulated RA (adjuvant-induced arthritis rat) rats in comparison with the oral administration of RBM-TDs. Thus, we show that the oral administration of RBM-NDs provides a high drug supply to the GI mucosa, resulting in a therapeutic effect on IMC-induced GI injuries. Solid nanocrystalline RBM preparations may offer effective therapy for RA patients.<\/jats:p>","DOI":"10.3390\/ijms20204990","type":"journal-article","created":{"date-parts":[[2019,10,9]],"date-time":"2019-10-09T11:25:57Z","timestamp":1570620357000},"page":"4990","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Solid Nanocrystals of Rebamipide Promote Recovery from Indomethacin-Induced Gastrointestinal Bleeding"],"prefix":"10.3390","volume":"20","author":[{"given":"Noriaki","family":"Nagai","sequence":"first","affiliation":[{"name":"Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryusuke","family":"Sakamoto","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seiji","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saori","family":"Deguchi","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroko","family":"Otake","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tadatoshi","family":"Tanino","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Tokushima Bunri University, 180 Yamashiro-Cho, Tokushima 770-8514, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,10,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/0002-9343(91)90118-H","article-title":"Non-steroidal anti-inflammatory drug-associated gastropathy: Incidence and risk factor models","volume":"91","author":"Fries","year":"1991","journal-title":"Am. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1093\/oxfordjournals.aje.a117469","article-title":"Nonsteroidal anti-inflammatory drugs and the incidence of hospitalizations for peptic ulcer disease in elderly persons","volume":"141","author":"Smalley","year":"1995","journal-title":"Am. J. Epidemiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1124\/jpet.102.040659","article-title":"Ulcerogenic influence of selective cyclooxygenase-2 inhibitors in the rat stomach with adjuvant-induced arthritis","volume":"303","author":"Kato","year":"2002","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1159\/000374106","article-title":"NSAID-induced small intestinal damage-roles of various pathogenic factors","volume":"91","author":"Takeuchi","year":"2015","journal-title":"Digestion"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.tox.2008.10.005","article-title":"Involvement of interleukin 18 in indomethacin-induced lesions of the gastric mucosa in adjuvant-induced arthritis rat","volume":"255","author":"Nagai","year":"2009","journal-title":"Toxicology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1580","DOI":"10.1248\/bpb.b15-00375","article-title":"Excessive Interleukin 18 Relate the Aggravation of Indomethacin-Induced Intestinal Ulcerogenic Lesions in Adjuvant-Induced Arthritis Rat","volume":"38","author":"Nagai","year":"2015","journal-title":"Biol. Pharm. Bull."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1016\/S0016-5085(89)80061-7","article-title":"Toward an epidemiology of gastropathy associated with non-steroidal antiinflammatory drug use","volume":"96","author":"Fries","year":"1989","journal-title":"Gastroenterology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.1016\/j.lfs.2007.08.036","article-title":"Increased susceptibility of small intestine to NSAID-provoked ulceration in rats with adjuvant-induced arthritis: Involvement of enhanced expression of TLR4","volume":"81","author":"Kato","year":"2007","journal-title":"Life Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1089\/jop.2011.0147","article-title":"Rebamipide increases mucin-like substance contents and periodic acid Schiff reagent-positive cells density in normal rabbits","volume":"28","author":"Urashima","year":"2012","journal-title":"J. Ocul. Pharmacol. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1586\/egh.10.25","article-title":"Rebamipide: A gastrointestinal protective drug with pleiotropic activities","volume":"4","author":"Naito","year":"2010","journal-title":"Expert Rev. Gastroenterol. Hepatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1136\/bjophthalmol-2012-302868","article-title":"Rebamipide increases barrier function and attenuates TNFalpha-induced barrier disruption and cytokine expression in human corneal epithelial cells","volume":"97","author":"Tanaka","year":"2013","journal-title":"Br. J. Ophthalmol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1500","DOI":"10.1007\/s10620-008-0507-4","article-title":"Rebamipide, a cytoprotective drug, increases gastric mucus secretion in human: Evaluations with endoscopic gastrin test","volume":"54","author":"Iijima","year":"2009","journal-title":"Dig. Dis. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Nanke, Y., Kobashigawa, T., Yago, T., Kawamoto, M., Yamanaka, H., and Kotake, S. (2016). Rebamipide, an Amino Acid Analog of 2(1H)-Quinolinone, Inhibits the Formation of Human Osteoclasts. Biomed. Res. Int., 6824719.","DOI":"10.1155\/2016\/6824719"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1776","DOI":"10.1007\/s10620-006-9367-y","article-title":"Preventive effects of Rebamipide on nsaid-induced gastric mucosal injury and reduction of gastric mucosal blood flow in healthy volunteers","volume":"52","author":"Kim","year":"2007","journal-title":"Dig. Dis. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/S0891-5849(00)00471-8","article-title":"Opc-compounds prevent oxidant-induced carbonylation and depolymerization of the f-actin cytoskeleton and intestinal barrier hyperpermeability","volume":"30","author":"Banan","year":"2001","journal-title":"Free Radic. Biol. Med."},{"key":"ref_16","first-page":"363","article-title":"Free radical scavenging activity of the novel anti-ulcer agent rebsamipide studied by electron spin resonance","volume":"43","author":"Yoshikawa","year":"1993","journal-title":"Arzneimittelforschung"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1023\/A:1018861818023","article-title":"Rebamipide attenuates indomethacin-induced gastric mucosal lesion formation by inhibiting activation of leukocytes in rats","volume":"42","author":"Murakami","year":"1997","journal-title":"Dig. Dis. Sci."},{"key":"ref_18","first-page":"5S","article-title":"Rebamipide: Overview of its mechanisms of action and efficacy in mucosal protection and ulcer healing","volume":"43","author":"Arakawa","year":"1998","journal-title":"Dig. Dis. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1991","DOI":"10.1007\/s10620-013-2606-0","article-title":"Rebamipide helps defend against nonsteroidal anti-inflammatory drugs induced gastroenteropathy: A systematic review and meta-analysis","volume":"58","author":"Zhang","year":"2013","journal-title":"Dig. Dis Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"8393","DOI":"10.1016\/j.biomaterials.2013.06.032","article-title":"Suppression of NSAID-induced small intestinal inflammation by orally administered redox nanoparticles","volume":"34","author":"Sha","year":"2013","journal-title":"Biomaterials"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.colsurfb.2012.04.002","article-title":"Enhanced transdermal permeability of estradiol using combination of PLGA nanoparticles system and iontophoresis","volume":"97","author":"Tomoda","year":"2012","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.colsurfb.2011.11.016","article-title":"Enhanced transdermal delivery of indomethacin using combination of PLGA nanoparticles and iontophoresis in vivo","volume":"92","author":"Tomoda","year":"2012","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1016\/j.colsurfb.2011.08.004","article-title":"Enhanced transdermal delivery of indomethacin-loaded PLGA nanoparticles by iontophoresis","volume":"88","author":"Tomoda","year":"2011","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1023\/A:1015841715384","article-title":"Controlled delivery systems for proteins based on poly(lactic\/glycolic acid) microspheres","volume":"8","author":"Cohen","year":"1991","journal-title":"Pharm. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1918","DOI":"10.1248\/bpb.b15-00567","article-title":"Pharmacokinetics and Antiinflammatory Effect of a Novel Gel System Containing Ketoprofen Solid Nanoparticles","volume":"38","author":"Nagai","year":"2015","journal-title":"Biol. Pharm. Bull."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"29329","DOI":"10.3390\/ijms161226166","article-title":"Intravenous Administration of Cilostazol Nanoparticles Ameliorates Acute Ischemic Stroke in a Cerebral Ischemia\/Reperfusion-Induced Injury Model","volume":"16","author":"Nagai","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Nagai, N., Deguchi, S., Otake, H., Hiramatsu, N., and Yamamoto, N. (2017). Therapeutic Effect of Cilostazol Ophthalmic Nanodispersions on Retinal Dysfunction in Streptozotocin-Induced Diabetic Rats. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18091971"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"177","DOI":"10.5650\/jos.ess13082","article-title":"Improved corneal toxicity and permeability of tranilast by the preparation of ophthalmic formulations containing its nanoparticles","volume":"63","author":"Nagai","year":"2014","journal-title":"J. Oleo Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1248\/bpb.b13-00917","article-title":"Effect of solid nanoparticle of indomethacin on therapy for rheumatoid arthritis in adjuvant-induced arthritis rat","volume":"37","author":"Nagai","year":"2014","journal-title":"Biol. Pharm. Bull."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.2147\/IJN.S196681","article-title":"Energy-dependent endocytosis is responsible for drug transcorneal penetration following the instillation of ophthalmic formulations containing indomethacin nanoparticles","volume":"14","author":"Nagai","year":"2019","journal-title":"Int. J. Nanomed."},{"key":"ref_31","first-page":"454","article-title":"An oral formulation of cilostazol nanoparticles enhances intestinal drug absorption in rats","volume":"15","author":"Yoshioka","year":"2018","journal-title":"Exp. Ther. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.tox.2014.02.012","article-title":"A nanoparticle formulation reduces the corneal toxicity of indomethacin eye drops and enhances its corneal permeability","volume":"319","author":"Nagai","year":"2014","journal-title":"Toxicology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1038\/nature01661","article-title":"Evolving concepts of rheumatoid arthritis","volume":"423","author":"Firestein","year":"2003","journal-title":"Nature"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.cyto.2014.12.026","article-title":"Serum and synovial fluid levels of tumor necrosis factor-like ligand 1A and decoy receptor 3 in rheumatoid arthritis","volume":"72","author":"Xiu","year":"2015","journal-title":"Cytokine"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"52","DOI":"10.2174\/2212703802999151230113431","article-title":"Plant-based anti-inflammatory agents: Progress from Africa and China","volume":"2","author":"Asenso","year":"2015","journal-title":"Clin. Anti-Inflamm. Anti-Allerg Drugs"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1016\/0163-7258(83)90062-1","article-title":"Models of arthritis and the search for anti-arthritic drugs","volume":"21","author":"Billingham","year":"1983","journal-title":"Pharmacol. Ther."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1007\/PL00000227","article-title":"FK506 is superior to methotrexate in therapeutic effects on advanced stage of rat adjuvant-induced arthritis","volume":"50","author":"Sakuma","year":"2001","journal-title":"Inflamm. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1254\/jjp.89.1","article-title":"Alteration of gastric ulcerogenic and healing responses in rats with adjuvant-induced arthritis","volume":"89","author":"Kato","year":"2002","journal-title":"Jpn. J. Pharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"S84","DOI":"10.1007\/s10620-005-2811-6","article-title":"Rebamipide reduces indomethacin-induced gastric injury in mice via down-regulation of ICAM-1 expression","volume":"50","author":"Hiratsuka","year":"2005","journal-title":"Dig. Dis. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.1007\/BF01308601","article-title":"Stimulation of prostaglandin biosynthesis mediates gastroprotective effect of Rebamipide in rats","volume":"38","author":"Kleine","year":"1993","journal-title":"Dig. Dis. Sci."},{"key":"ref_41","first-page":"1462","article-title":"Effect of Rebamipide on mucus secretion by endogenous prostaglandin-independent mechanism in rat gastric mucosa","volume":"42","author":"Ishihara","year":"1992","journal-title":"Arzneimittelforschung"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1159\/000341508","article-title":"Terminal-restriction fragment length polymorphism (T-RFLP) analysis for changes in the gut microbiota Profiles of indomethacin- and rebamipide-treated mice","volume":"86","author":"Imaeda","year":"2012","journal-title":"Digestion"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1046\/j.1440-1746.2001.02592.x","article-title":"Protective effect of Rebamipide on indomethacin-induced intestinal damage in rats","volume":"16","author":"Mizoguchi","year":"2001","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Ishii, M., Fukuoka, Y., Deguchi, S., Otake, H., Tanino, T., and Nagai, N. (2019). Energy-Dependent Endocytosis is Involved in the Absorption of Indomethacin Nanoparticles in the Small Intestine. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20030476"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/20\/4990\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:28:42Z","timestamp":1760189322000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/20\/4990"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,9]]},"references-count":44,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2019,10]]}},"alternative-id":["ijms20204990"],"URL":"https:\/\/doi.org\/10.3390\/ijms20204990","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,10,9]]}}}