{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T06:49:12Z","timestamp":1789886952510,"version":"4.0.1"},"reference-count":52,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2015,2,1]],"date-time":"2015-02-01T00:00:00Z","timestamp":1422748800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Pharmacological Reports"],"published-print":{"date-parts":[[2015,2]]},"DOI":"10.1016\/j.pharep.2014.08.009","type":"journal-article","created":{"date-parts":[[2014,8,23]],"date-time":"2014-08-23T00:40:58Z","timestamp":1408754458000},"page":"102-114","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":38,"title":["Myelosuppressive and hepatotoxic potential of leflunomide and methotrexate combination in a rat model of rheumatoid arthritis"],"prefix":"10.1007","volume":"67","author":[{"given":"Shymaa E.","family":"Bilasy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soha S.","family":"Essawy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed F.","family":"Mandour","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eman A.I.","family":"Ali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sawsan A.","family":"Zaitone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","reference":[{"key":"10.1016\/j.pharep.2014.08.009_bib0005","doi-asserted-by":"crossref","first-page":"R42","DOI":"10.1186\/ar3278","article-title":"Comparative efficacy of a secretory phospholipase A2 inhibitor with conventional anti-inflammatory agents in a rat model of antigen-induced arthritis","volume":"13","author":"Coulthard","year":"2011","journal-title":"Arthritis Res Ther"},{"key":"10.1016\/j.pharep.2014.08.009_bib0010","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1038\/nri2094","article-title":"Cytokines in the pathogenesis of rheumatoid arthritis","volume":"7","author":"McInnes","year":"2007","journal-title":"Nat Rev Immunol"},{"key":"10.1016\/j.pharep.2014.08.009_bib0015","doi-asserted-by":"crossref","first-page":"e16378","DOI":"10.1371\/journal.pone.0016378","article-title":"Prostaglandin E2 synthesizing enzymes in rheumatoid arthritis B cells and the effects of B cell depleting therapy on enzyme expression","volume":"6","author":"Gheorghe","year":"2007","journal-title":"PLoS ONE"},{"key":"10.1016\/j.pharep.2014.08.009_bib0020","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.semarthrit.2007.02.001","article-title":"Response-driven combination therapy with conventional disease-modifying antirheumatic drugs can achieve high response rates in early rheumatoid arthritis with minimal glucocorticoid and non-steroidal anti-inflammatory drug use","volume":"37","author":"Proudman","year":"2007","journal-title":"Semin Arthritis Rheum"},{"key":"10.1016\/j.pharep.2014.08.009_bib0025","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.clim.2004.09.001","article-title":"The anti-inflammatory action of methotrexate is not mediated by lymphocyte apoptosis, but by the suppression of activation and adhesion molecules","volume":"114","author":"Johnston","year":"2005","journal-title":"Clin Immunol"},{"key":"10.1016\/j.pharep.2014.08.009_bib0030","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1172\/JCI2676","article-title":"Immunosuppressive properties of methotrexate: apoptosis and clonal deletion of activated peripheral T cells","volume":"102","author":"Genestier","year":"1998","journal-title":"J Clin Invest"},{"key":"10.1016\/j.pharep.2014.08.009_bib0035","doi-asserted-by":"crossref","first-page":"987508","DOI":"10.1100\/2012\/987508","article-title":"Beneficial effects of montelukast against methotrexate-induced liver toxicity: a biochemical and histological study","volume":"2012","author":"Kose","year":"2012","journal-title":"Sci World J"},{"key":"10.1016\/j.pharep.2014.08.009_bib0040","doi-asserted-by":"crossref","first-page":"422","DOI":"10.4103\/0378-6323.53157","article-title":"Leflunomide","volume":"75","author":"Mehta","year":"2009","journal-title":"Ind J Dermatol Venereol Leprol"},{"key":"10.1016\/j.pharep.2014.08.009_bib0045","first-page":"1228","article-title":"Leflunomide, a new disease-modifying drug for treating active rheumatoid arthritis in methotrexate-controlled phase II clinical trial","volume":"116","author":"Bao","year":"2003","journal-title":"Chin Med J"},{"key":"10.1016\/j.pharep.2014.08.009_bib0050","doi-asserted-by":"crossref","first-page":"R163","DOI":"10.1186\/ar3911","article-title":"Polymorphisms in cytochrome P450 2C19 enzyme and cessation of leflunomide in patients with rheumatoid arthritis","volume":"14","author":"Wiese","year":"2012","journal-title":"Arthritis Res Ther"},{"key":"10.1016\/j.pharep.2014.08.009_bib0055","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1007\/s00011-004-1294-9","article-title":"Comparison of anti-arthritic properties of leflunomide with methotrexate and FK506: effect on T cell activation-induced inflammatory cytokine production in vitro and rat adjuvant-induced arthritis","volume":"53","author":"Magari","year":"2004","journal-title":"Inflamm Res"},{"key":"10.1016\/j.pharep.2014.08.009_bib0060","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.1002\/art.11015","article-title":"The efficacy and safety of leflunomide in patients with active rheumatoid arthritis: a five-year follow up study","volume":"48","author":"Kalden","year":"2003","journal-title":"Arthritis Rheum"},{"key":"10.1016\/j.pharep.2014.08.009_bib0065","doi-asserted-by":"crossref","first-page":"R232","DOI":"10.1186\/ar4075","article-title":"Leflunomide increases the risk of silent liver fibrosis in patients with rheumatoid arthritis receiving methotrexate","volume":"14","author":"Lee","year":"2012","journal-title":"Arthritis Res Ther"},{"key":"10.1016\/j.pharep.2014.08.009_bib0070","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1097\/BOR.0b013e328344f2e4","article-title":"Methotrexate versus leflunomide in rheumatoid arthritis: what is new in 2011?","volume":"23","author":"Singer","year":"2011","journal-title":"Curr Opin Rheumatol"},{"key":"10.1016\/j.pharep.2014.08.009_bib0075","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1016\/0024-3205(66)90088-9","article-title":"Action of anti-inflammatory agents upon blood and histopathological changes","volume":"5","author":"Piliero","year":"1966","journal-title":"Life Sci"},{"key":"10.1016\/j.pharep.2014.08.009_bib0080","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1007\/s00011-011-0431-5","article-title":"Suppressive effect of an orally active MEK1\/2 inhibitor in two different animal models for rheumatoid arthritis: a comparison with leflunomide","volume":"61","author":"Yamaguchi","year":"2012","journal-title":"Inflamm Res"},{"key":"10.1016\/j.pharep.2014.08.009_bib0085","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1002\/art.1780390514","article-title":"Cellular adhesion molecules in rat adjuvant arthritis","volume":"39","author":"Halloran","year":"1996","journal-title":"Arthritis Rheum"},{"key":"10.1016\/j.pharep.2014.08.009_bib0090","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.1172\/JCI0215582","article-title":"Osteoclasts are essential for TNF-alpha-mediated joint destruction","volume":"110","author":"Redlich","year":"2002","journal-title":"J Clin Invest"},{"key":"10.1016\/j.pharep.2014.08.009_bib0095","series-title":"The laboratory rat","first-page":"627","article-title":"Anesthesia and analgesia","author":"Vogler","year":"2006"},{"key":"10.1016\/j.pharep.2014.08.009_bib0100","doi-asserted-by":"crossref","first-page":"R114","DOI":"10.1186\/ar1039","article-title":"Susceptibility to collagen-induced arthritis is modulated by TGF beta responsiveness of T cells","volume":"6","author":"Schramm","year":"2004","journal-title":"Arthritis Res Ther"},{"key":"10.1016\/j.pharep.2014.08.009_bib0105","series-title":"Deci and Lewis","first-page":"47","article-title":"Preparation and staining methods for blood and bone marrow films In: practical hematology","author":"Lewis","year":"2001"},{"key":"10.1016\/j.pharep.2014.08.009_bib0110","first-page":"2026","article-title":"Evaluation of the early effect of local irradiation on normal rodent bone marrow metabolism using FDG: preclinical PET studies","volume":"41","author":"Higashi","year":"2000","journal-title":"J Nucl Med"},{"key":"10.1016\/j.pharep.2014.08.009_bib0115","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1093\/toxsci\/kfh049","article-title":"Extended histopathology in immunetoxicity testing: interlaboratory validation studies","volume":"78","author":"Germolec","year":"2004","journal-title":"Toxicol Sci"},{"key":"10.1016\/j.pharep.2014.08.009_bib0120","doi-asserted-by":"crossref","first-page":"1563","DOI":"10.1016\/S0024-3205(02)02448-7","article-title":"The collagenolytic effects of the traditional Chinese medicine preparation, Han-Dan-Gan-Le, contribute to reversal of chemical-induced liver fibrosis in rats","volume":"72","author":"Li","year":"2003","journal-title":"Life Sci"},{"key":"10.1016\/j.pharep.2014.08.009_bib0125","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1177\/0148607188012004325","article-title":"Effect of a glutamine-supplemented enteral diet on methotrexate-induced enterocolitis","volume":"12","author":"Fox","year":"1988","journal-title":"J Parenter Enteral Nutr"},{"key":"10.1016\/j.pharep.2014.08.009_bib0130","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1053\/gast.1996.v111.pm8690198","article-title":"The effects of lactobacillus strains and oat fiber on methotrexate-induced enterocolitis in rats","volume":"111","author":"Mao","year":"1996","journal-title":"Gastroenterology"},{"key":"10.1016\/j.pharep.2014.08.009_bib0135","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1093\/jnci\/58.4.1011","article-title":"Hepatotoxicity in Wistar rats following chronic methotrexate administration: a model of human reaction","volume":"58","author":"Custer","year":"1977","journal-title":"J Natl Cancer Inst"},{"key":"10.1016\/j.pharep.2014.08.009_bib0140","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1002\/art.1780310614","article-title":"Interleukin-6 in synovial fluid and serum of patients with rheumatoid arthritis and other inflammatory arthritides","volume":"31","author":"Houssiau","year":"1988","journal-title":"Arthritis Rheum"},{"key":"10.1016\/j.pharep.2014.08.009_bib0145","doi-asserted-by":"crossref","first-page":"2672","DOI":"10.1172\/JCI118717","article-title":"Selective inhibition of cyclooxygenase (COX)-2 reverses inflammation and expression of COX-2 and interleukin 6 in rat adjuvant arthritis","volume":"97","author":"Anderson","year":"1996","journal-title":"J Clin Invest"},{"key":"10.1016\/j.pharep.2014.08.009_bib0150","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1081\/IPH-120026442","article-title":"Swertia chirayita mediated modulation of interleukin-1\u03b2, interleukin-6, interleukin-10, interferon-\u03b3, and tumor necrosis factor-\u03b1 in arthritic mice","volume":"25","author":"Kumar","year":"2003","journal-title":"Immunopharmacol Immunotoxicol"},{"key":"10.1016\/j.pharep.2014.08.009_bib0155","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1111\/j.1432-1033.1994.tb20033.x","article-title":"Interleukin-1-induced prostaglandin E2 biosynthesis in human synovial cells involves the activation of cytosolic phospholipase A2 and cyclooxygenase- 2","volume":"226","author":"Angel","year":"1994","journal-title":"Eur J Biochem"},{"key":"10.1016\/j.pharep.2014.08.009_bib0160","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.1172\/JCI117060","article-title":"Cyclooxygenase-1 and -2 expression in rheumatoid synovial tissues","volume":"93","author":"Crofford","year":"1994","journal-title":"J Clin Invest"},{"key":"10.1016\/j.pharep.2014.08.009_bib0165","doi-asserted-by":"crossref","first-page":"2060","DOI":"10.4049\/jimmunol.152.4.2060","article-title":"Production of interleukin-1 receptor antagonist, inflammatory chemotactic proteins, and prostaglandin E by rheumatoid and osteoarthritic synoviocytes-regulation by IFN-gamma and IL-4","volume":"152","author":"Seitz","year":"1994","journal-title":"J Immunol"},{"key":"10.1016\/j.pharep.2014.08.009_bib0170","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1002\/art.1780370409","article-title":"Induction of cyclooxygenase II in human synovial microvessel endothelial cells by interleukin-1: inhibition by glucocorticoids","volume":"7","author":"Szczepanski","year":"1994","journal-title":"Arthritis Rheum"},{"key":"10.1016\/j.pharep.2014.08.009_bib0175","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/j.cyto.2005.06.002","article-title":"Effects of the active metabolite of leflunomide, A77 1726, on cytokine release and the MAPK signaling pathway in human rheumatoid arthritis synoviocytes","volume":"31","author":"Vergne-Salle","year":"2005","journal-title":"Cytokine"},{"key":"10.1016\/j.pharep.2014.08.009_bib0180","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1038\/nrrheum.2010.5","article-title":"Methotrexate-how does it really work?","volume":"6","author":"Chan","year":"2010","journal-title":"Nat Rev Rheumatol"},{"key":"10.1016\/j.pharep.2014.08.009_bib0185","doi-asserted-by":"crossref","first-page":"3831","DOI":"10.1002\/art.20637","article-title":"Effects of disease-modifying antirheumatic drugs and anti-inflammatory cytokines on human osteoclastogenesis through interaction with receptor activator of nuclear factor kappa B, osteoprotegerin, and receptor activator of nuclear factor kappa B ligand","volume":"50","author":"Lee","year":"2004","journal-title":"Arthritis Rheum"},{"key":"10.1016\/j.pharep.2014.08.009_bib0190","first-page":"787","article-title":"Methotrexate suppresses inflammatory agonist induced interleukin 6 synthesis in osteoblasts","volume":"32","author":"Yoshida","year":"2005","journal-title":"J Rheumatol"},{"key":"10.1016\/j.pharep.2014.08.009_bib0195","first-page":"142","article-title":"Rosuvastatin promotes angiogenesis and reverses isoproterenol-induced acute myocardial infarction in rats: role of iNOS and VEGF","volume":"69","author":"Zaitone","year":"2012","journal-title":"Eur J Pharmacol"},{"key":"10.1016\/j.pharep.2014.08.009_bib0200","doi-asserted-by":"crossref","first-page":"S99","DOI":"10.1186\/ar582","article-title":"VEGF and imaging of vessels in rheumatoid arthritis","volume":"4","author":"Taylor","year":"2002","journal-title":"Arthritis Res"},{"key":"10.1016\/j.pharep.2014.08.009_bib0205","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/S1297-319X(03)00088-5","article-title":"Recent data on the role for angiogenesis in rheumatoid arthritis","volume":"70","author":"Clavel","year":"2003","journal-title":"Joint Bone Spine"},{"key":"10.1016\/j.pharep.2014.08.009_bib0210","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1093\/rheumatology\/keh524","article-title":"Serum vascular markers and vascular imaging in assessment of rheumatoid arthritis disease activity and response to therapy","volume":"44","author":"Taylor","year":"2005","journal-title":"Rheumatology"},{"key":"10.1016\/j.pharep.2014.08.009_bib0215","doi-asserted-by":"crossref","first-page":"5922","DOI":"10.4049\/jimmunol.164.11.5922","article-title":"Vascular endothelial growth factor expression and regulation of murine collagen-induced arthritis","volume":"164","author":"Lu","year":"2000","journal-title":"J Immunol"},{"key":"10.1016\/j.pharep.2014.08.009_bib0220","first-page":"240","article-title":"Effect of direct angiogenesis inhibition in rheumatoid arthritis using a soluble vascular endothelial growth factor receptor 1 chimeric protein","volume":"29","author":"Sekimoto","year":"2002","journal-title":"J Rheumatol"},{"key":"10.1016\/j.pharep.2014.08.009_bib0225","doi-asserted-by":"crossref","first-page":"115","DOI":"10.2174\/1874312901105010115","article-title":"Synovial tissue response to treatment in rheumatoid arthritis","volume":"5","author":"Vieira-Sousa","year":"2011","journal-title":"Open Rheumatol J"},{"key":"10.1016\/j.pharep.2014.08.009_bib0230","doi-asserted-by":"crossref","first-page":"R94","DOI":"10.1186\/ar1968","article-title":"Inhibition of protein geranylgeranylation induces apoptosis in synovial fibroblasts","volume":"8","author":"Connor","year":"2006","journal-title":"Arthritis Res Ther"},{"key":"10.1016\/j.pharep.2014.08.009_bib0235","first-page":"1604","article-title":"Differential effect of high-dose methotrexate on erythropoiesis and granulocytopoiesis in humans","volume":"42","author":"Dormer","year":"1982","journal-title":"Cancer Res"},{"key":"10.1016\/j.pharep.2014.08.009_bib0240","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1136\/ard.62.4.297","article-title":"Anti-inflammatory effects of leflunomide on cultured synovial macrophages from patients with rheumatoid arthritis","volume":"62","author":"Cutolo","year":"2003","journal-title":"Ann Rheum Dis"},{"key":"10.1016\/j.pharep.2014.08.009_bib0245","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1007\/BF02238974","article-title":"Clinical characteristics related to methotrexate-induced pancytopenia","volume":"16","author":"Ohosone","year":"1997","journal-title":"Clin Rheumatol"},{"key":"10.1016\/j.pharep.2014.08.009_bib0250","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1093\/ajhp\/57.3.225","article-title":"New drugs for the treatment of rheumatoid arthritis","volume":"57","author":"Schuna","year":"2000","journal-title":"Am J Health Syst Pharm"},{"key":"10.1016\/j.pharep.2014.08.009_bib0255","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1002\/pds.1236","article-title":"The incidence of pancytopenia in patients taking leflunomide alone or with methotrexate","volume":"16","author":"McEwen","year":"2007","journal-title":"Pharmacoepidemiol Drug Saf"},{"key":"10.1016\/j.pharep.2014.08.009_bib0260","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1016\/S0022-3565(25)24292-6","article-title":"The immunosuppressant leflunomide inhibits lymphocyte progression through cell cycle by a novel mechanism","volume":"272","author":"Cherwinski","year":"1995","journal-title":"J Pharmacol Exp Ther"}],"container-title":["Pharmacological Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1734114014002709?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1734114014002709?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T20:35:41Z","timestamp":1752611741000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1016\/j.pharep.2014.08.009"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,2]]},"references-count":52,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2015,2]]}},"alternative-id":["S1734114014002709"],"URL":"https:\/\/doi.org\/10.1016\/j.pharep.2014.08.009","relation":{},"ISSN":["1734-1140"],"issn-type":[{"value":"1734-1140","type":"print"}],"subject":[],"published":{"date-parts":[[2015,2]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Myelosuppressive and hepatotoxic potential of leflunomide and methotrexate combination in a rat model of rheumatoid arthritis","name":"articletitle","label":"Article Title"},{"value":"Pharmacological Reports","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.pharep.2014.08.009","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"Copyright \u00a9 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.","name":"copyright","label":"Copyright"}]}}