{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T17:48:43Z","timestamp":1793296123941,"version":"4.5.0"},"reference-count":40,"publisher":"Bentham Science Publishers Ltd.","issue":"9","content-domain":{"domain":["eurekaselect.com"],"crossmark-restriction":true},"short-container-title":["CDM"],"published-print":{"date-parts":[[2019,10,4]]},"abstract":"<jats:sec>\n<jats:title>Background:<\/jats:title>\n<jats:p>A folic-acid antagonist, methotrexate, is one of the most commonly prescribed drugs with\nits expanding use in clinical practice. The drug requires regular monitoring given its wide range of adverse effects\nincluding bone marrow suppression, hepatic or renal dysfunction, gastrointestinal distress, mucocutaneous damage,\nand neurotoxicity. The toxicity usually occurs rapidly and leads to severe neutropenia, sepsis, and advanced renal\nfailure that are difficult to manage.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Methods:<\/jats:title>\n<jats:p>This review is an update for the clinicians to understand the pharmacology, clinical features, laboratory\nevaluation, and treatment of patients with methotrexate overdose. High-quality literature of the past six decades was\ncollected and reviewed in this article. Several landmark articles were reviewed using PubMed, EMBASE Ovid, and\nthe Cochrane Library, that have important implications in current clinical practice.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Results:<\/jats:title>\n<jats:p>Methotrexate overdose has complex toxicokinetic and produces myriad clinical features mimicking conditions\nof lesser severity. Organ dysfunction related to bone marrow, kidney or central nervous system is lifethreatening.\nThe management should focus on high-quality supportive care, antidotal therapy (folinic acid and carboxypeptidase-\nG2) and plasma alkalization.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Conclusion:<\/jats:title>\n<jats:p>In accordance with the dictum \u201cprevention is better than cure\u201d, the author emphasizes on the role of\npatient education, regular clinical observation, and laboratory monitoring for prompt recognition and diagnosis of\nmethotrexate overdosing at the earliest stage.<\/jats:p>\n<\/jats:sec>","DOI":"10.2174\/1389200220666190806140844","type":"journal-article","created":{"date-parts":[[2019,8,6]],"date-time":"2019-08-06T10:45:49Z","timestamp":1565088349000},"page":"714-719","update-policy":"https:\/\/doi.org\/10.2174\/bsp_crossmark_policy","source":"Crossref","is-referenced-by-count":53,"title":["Methotrexate overdose in clinical practice"],"prefix":"10.2174","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4476-3478","authenticated-orcid":true,"given":"Ashok Kumar","family":"Pannu","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"965","reference":[{"key":"ref=1","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.rdc.2017.09.003","volume":"44","author":"Wood P.R.","year":"2018","unstructured":"Wood P.R.; Caplan L.; Drug-induced gastrointestinal and hepatic disease associated with biologics and nonbiologic disease-modifying antirheumatic drugs. Rheum Dis Clin North Am 2018,44(1),29-43","journal-title":"Rheum Dis Clin North Am"},{"key":"ref=2","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1038\/nrrheum.2010.5","volume":"6","author":"Chan E.S.","year":"2010","unstructured":"Chan E.S.; Cronstein B.N.; Methotrexate-how does it really work? Nat Rev Rheumatol 2010,6(3),175-178","journal-title":"Nat Rev Rheumatol"},{"key":"ref=3","author":"Nelson L.S.","year":"2019","unstructured":"Nelson L.S.; Howland M.A.; Lewin N.A.; Smith S.W.; Goldfrank L.R.; Hoffman R.S.;  Goldfrank\u2019s Toxicological Emergencies 2019","journal-title":"Goldfrank\u2019s Toxicological Emergencies"},{"key":"ref=4","first-page":"1177","author":"Wellstein A.","year":"2018","unstructured":"Wellstein A.; Giaccone G.; Michael B.;  Atkins, MB; Sausville, EA Cytotoxic Drugs Goodman  Brunton, LL; Hilal-Dandan, R 2018,1177-1180","journal-title":"Atkins, MB; Sausville, EA Cytotoxic Drugs Goodman & Gilman\u2019s The Pharmacological Basis of Therapeutics; Brunton, LL; Hilal-Dandan, R"},{"key":"ref=5","first-page":"319","author":"Gugelmann H.","year":"2018","unstructured":"Gugelmann H.;  Methotrexate Poisoning  Olson, KR; Anderson, IB; Benowitz, NL; Blanc, PD; Clark, RF; Kearney, TE; Kim-Katz, SY 2018,319-321","journal-title":"Methotrexate Poisoning & Drug Overdose; Olson, KR; Anderson, IB; Benowitz, NL; Blanc, PD; Clark, RF; Kearney, TE; Kim-Katz, SY"},{"key":"ref=6","first-page":"957","author":"Chu E.","year":"2018","unstructured":"Chu E.;  Basic  2018,957","journal-title":"Basic"},{"key":"ref=7","first-page":"264","author":"Ceacareanu A.C.","year":"2015","unstructured":"Ceacareanu A.C.; Wintrob Z.A.P.;  Casebook in Clinical Pharmacokinetics and Drug Dosing 2015,264-267","journal-title":"Casebook in Clinical Pharmacokinetics and Drug Dosing"},{"key":"ref=8","doi-asserted-by":"publisher","first-page":"2157","DOI":"10.1136\/annrheumdis-2015-208736","volume":"75","author":"Municio C.","year":"2016","unstructured":"Municio C.; Soler Palacios B.; Estrada-Capetillo L.; Benguria A.; Dopazo A.; Garc\u00eda-Lorenzo E.; Fern\u00e1ndez-Arroyo S.; Joven J.; Miranda-Car\u00fas M.E.; Gonz\u00e1lez-\u00c1lvaro I.; Puig-Kr\u00f6ger A.; Methotrexate selectively targets human proinflammatory macrophages through a thymidylate synthase\/p53 axis. Ann Rheum Dis 2016,75(12),2157-2165","journal-title":"Ann Rheum Dis"},{"key":"ref=9","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1111\/j.1365-2125.2005.02513.x","volume":"62","author":"Joerger M.","year":"2006","unstructured":"Joerger M.; Huitema A.D.; van den Bongard H.J.; Baas P.; Schornagel J.H.; Schellens J.H.; Beijnen J.H.; Determinants of the elimination of methotrexate and 7-hydroxy-methotrexate following high-dose infusional therapy to cancer patients. Br J Clin Pharmacol 2006,62(1),71-80","journal-title":"Br J Clin Pharmacol"},{"key":"ref=10","doi-asserted-by":"publisher","first-page":"825","DOI":"10.1007\/s00467-002-0946-7","volume":"17","author":"Saland J.M.","year":"2002","unstructured":"Saland J.M.; Leavey P.J.; Bash R.O.; Hansch E.; Arbus G.S.; Quigley R.; Effective removal of methotrexate by high-flux hemodialysis. Pediatr Nephrol 2002,17(10),825-829","journal-title":"Pediatr Nephrol"},{"key":"ref=11","first-page":"180","author":"Kolesar J.","year":"2016","unstructured":"Kolesar J.; Vermeulen L.;  Top 300 Pharmacy Drug Cards-2016\/2017 2016,180","journal-title":"Top 300 Pharmacy Drug Cards-2016\/2017"},{"key":"ref=12","doi-asserted-by":"publisher","first-page":"833","DOI":"10.7326\/0003-4819-121-11-199412010-00002","volume":"121","author":"Morgan S.L.","year":"1994","unstructured":"Morgan S.L.; Baggott J.E.; Vaughn W.H.; Austin J.S.; Veitch T.A.; Lee J.Y.; Koopman W.J.; Krumdieck C.L.; Alarc\u00f3n G.S.; Supplementation with folic acid during methotrexate therapy for rheumatoid arthritis. A double-blind, placebo-controlled trial. Ann Intern Med 1994,121(11),833-841","journal-title":"Ann Intern Med"},{"key":"ref=13","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1186\/s13075-015-0668-4","volume":"17","author":"Dhir V.","year":"2015","unstructured":"Dhir V.; Sandhu A.; Kaur J.; Pinto B.; Kumar P.; Kaur P.; Gupta N.; Sood A.; Sharma A.; Sharma S.; Comparison of two different folic acid doses with methotrexate-a randomized controlled trial (FOLVARI Study). Arthritis Res Ther 2015,17,156","journal-title":"Arthritis Res Ther"},{"key":"ref=14","doi-asserted-by":"publisher","first-page":"995","DOI":"10.1016\/j.hoc.2017.08.005","volume":"31","author":"Young J.S.","year":"2017","unstructured":"Young J.S.; Simmons J.W.; Chemotherapeutic medications and their emergent complications. Hematol Oncol Clin North Am 2017,31(6),995-1010","journal-title":"Hematol Oncol Clin North Am"},{"key":"ref=15","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1016\/j.emc.2013.09.002","volume":"32","author":"Livshits Z.","year":"2014","unstructured":"Livshits Z.; Rao R.B.; Smith S.W.; An approach to chemotherapy-associated toxicity. Emerg Med Clin North Am 2014,32(1),167-203","journal-title":"Emerg Med Clin North Am"},{"key":"ref=16","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1016\/j.emc.2009.01.005","volume":"27","author":"Adelberg D.E.","year":"2009","unstructured":"Adelberg D.E.; Bishop M.R.; Emergencies related to cancer chemotherapy and hematopoietic stem cell transplantation. Emerg Med Clin North Am 2009,27(2),311-331","journal-title":"Emerg Med Clin North Am"},{"key":"ref=17","doi-asserted-by":"publisher","first-page":"v111","DOI":"10.1093\/annonc\/mdw325","volume":"27","author":"Klastersky J.","year":"2016","unstructured":"Klastersky J.; de Naurois J.; Rolston K.; Rapoport B.; Maschmeyer G.; Aapro M.; Herrstedt J.; Management of febrile neutropaenia. Ann Oncol 2016,27(Suppl. 5),v111-v118","journal-title":"Ann Oncol"},{"key":"ref=18","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1016\/j.cld.2013.07.010","volume":"17","author":"Thatishetty A.V.","year":"2013","unstructured":"Thatishetty A.V.; Agresti N.; O\u2019Brien C.B.; Chemotherapy-induced hepatotoxicity. Clin Liver Dis 2013,17(4),671-686","journal-title":"Clin Liver Dis"},{"key":"ref=19","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1016\/j.emc.2013.09.005","volume":"32","author":"Lopez A.M.","year":"2014","unstructured":"Lopez A.M.; Hendrickson R.G.; Toxin-induced hepatic injury. Emerg Med Clin North Am 2014,32(1),103-125","journal-title":"Emerg Med Clin North Am"},{"key":"ref=20","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1007\/978-3-319-56449-4","author":"Dye L.R.","year":"2017","unstructured":"Dye L.R.; Murphy C.; Calello D.P.; Levine M.; Skolnik A.;  Case Studies in Medical Toxicology 2017,173-179","journal-title":"Case Studies in Medical Toxicology"},{"key":"ref=21","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1016\/j.rdc.2018.06.005","volume":"44","author":"Woodell T.","year":"2018","unstructured":"Woodell T.; Avasare R.S.; Nephrotoxicity of select rheumatologic drugs. Rheum Dis Clin North Am 2018,44(4),605-617","journal-title":"Rheum Dis Clin North Am"},{"key":"ref=22","first-page":"1887","volume":"24","author":"Sandoval C.","year":"2003","unstructured":"Sandoval C.; Kutscher M.; Jayabose S.; Tenner M.; Neurotoxicity of intrathecal methotrexate: MR imaging findings. AJNR Am J Neuroradiol 2003,24(9),1887-1890","journal-title":"AJNR Am J Neuroradiol"},{"key":"ref=23","doi-asserted-by":"publisher","first-page":"803","DOI":"10.1002\/art.38322","volume":"66","author":"Conway R.","year":"2014","unstructured":"Conway R.; Low C.; Coughlan R.J.; O\u2019Donnell M.J.; Carey J.J.; Methotrexate and lung disease in rheumatoid arthritis: A meta-analysis of randomized controlled trials. Arthritis Rheumatol 2014,66(4),803-812","journal-title":"Arthritis Rheumatol"},{"key":"ref=24","doi-asserted-by":"publisher","first-page":"h1269","DOI":"10.1136\/bmj.h1269","volume":"350","author":"Conway R.","year":"2015","unstructured":"Conway R.; Low C.; Coughlan R.J.; O\u2019Donnell M.J.; Carey J.J.; Methotrexate use and risk of lung disease in psoriasis, psoriatic arthritis, and inflammatory bowel disease: Systematic literature review and meta-analysis of randomised controlled trials. BMJ 2015,350,h1269","journal-title":"BMJ"},{"key":"ref=25","doi-asserted-by":"publisher","first-page":"630","DOI":"10.1056\/NEJM197709222971203","volume":"297","author":"Stoller R.G.","year":"1977","unstructured":"Stoller R.G.; Hande K.R.; Jacobs S.A.; Rosenberg S.A.; Chabner B.A.; Use of plasma pharmacokinetics to predict and prevent methotrexate toxicity. N Engl J Med 1977,297(12),630-634","journal-title":"N Engl J Med"},{"key":"ref=26","doi-asserted-by":"publisher","first-page":"161","DOI":"10.4065\/71.2.161","volume":"71","author":"O\u2019Marcaigh A.S.","year":"1996","unstructured":"O\u2019Marcaigh A.S.; Johnson C.M.; Smithson W.A.; Patterson M.C.; Widemann B.C.; Adamson P.C.; McManus M.J.; Successful treatment of intrathecal methotrexate overdose by using ventriculolumbar perfusion and intrathecal instillation of carboxypeptidase G2. Mayo Clin Proc 1996,71(2),161-165","journal-title":"Mayo Clin Proc"},{"key":"ref=27","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1080\/15563650.2016.1271126","volume":"55","author":"Chan B.S.","year":"2017","unstructured":"Chan B.S.; Dawson A.H.; Buckley N.A.; What can clinicians learn from therapeutic studies about the treatment of acute oral methotrexate poisoning? Clin Toxicol (Phila) 2017,55(2),88-96","journal-title":"Clin Toxicol (Phila)"},{"key":"ref=28","first-page":"1169","volume":"66","author":"Gadgil S.D.","year":"1982","unstructured":"Gadgil S.D.; Damle S.R.; Advani S.H.; Vaidya A.B.; Effect of activated charcoal on the pharmacokinetics of high-dose methotrexate. Cancer Treat Rep 1982,66(5),1169-1171","journal-title":"Cancer Treat Rep"},{"key":"ref=29","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1007\/BF03160968","volume":"4","author":"Smith S.W.","year":"2008","unstructured":"Smith S.W.; Nelson L.S.; Case files of the New York City Poison Control Center: Antidotal strategies for the management of methotrexate toxicity. J Med Toxicol 2008,4(2),132-140","journal-title":"J Med Toxicol"},{"key":"ref=30","doi-asserted-by":"publisher","first-page":"1589","DOI":"10.1200\/JCO.1999.17.5.1589","volume":"17","author":"Flombaum C.D.","year":"1999","unstructured":"Flombaum C.D.; Meyers P.A.; High-dose leucovorin as sole therapy for methotrexate toxicity. J Clin Oncol 1999,17(5),1589-1594","journal-title":"J Clin Oncol"},{"key":"ref=31","first-page":"806","author":"Gahart B.L.","year":"2019","unstructured":"Gahart B.L.; Nazareno A.R.; Ortega M.G.;  Gahart\u2019s 2019 Intravenous medications 2019,806-807","journal-title":"Gahart\u2019s 2019 Intravenous medications"},{"key":"ref=32","doi-asserted-by":"publisher","first-page":"302","DOI":"10.1097\/00043426-199608000-00014","volume":"18","author":"Jardine L.F.","year":"1996","unstructured":"Jardine L.F.; Ingram L.C.; Bleyer W.A.; Intrathecal leucovorin after intrathecal methotrexate overdose. J Pediatr Hematol Oncol 1996,18(3),302-304","journal-title":"J Pediatr Hematol Oncol"},{"key":"ref=33","doi-asserted-by":"publisher","first-page":"500","DOI":"10.1179\/1973947815Y.0000000048","volume":"28","author":"Florit-Sureda M.","year":"2016","unstructured":"Florit-Sureda M.; Conde-Est\u00e9vez D.; Vidal J.; Montagut C.; Hypersensitivity reaction caused by folinic acid administration: A case report and literature review. J Chemother 2016,28(6),500-505","journal-title":"J Chemother"},{"key":"ref=34","doi-asserted-by":"publisher","first-page":"1471","DOI":"10.1634\/theoncologist.2015-0164","volume":"21","author":"Howard S.C.","year":"2016","unstructured":"Howard S.C.; McCormick J.; Pui C.H.; Buddington R.K.; Harvey R.D.; Preventing and managing toxicities of high-dose methotrexate. Oncologist 2016,21(12),1471-1482","journal-title":"Oncologist"},{"key":"ref=35","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1002\/cpt1978233351","volume":"23","author":"Gibson T.P.","year":"1978","unstructured":"Gibson T.P.; Reich S.D.; Krumlovsky F.A.; Ivanovich P.; Gonczy C.; Hemoperfusion for methotrexate removal. Clin Pharmacol Ther 1978,23(3),351-355","journal-title":"Clin Pharmacol Ther"},{"key":"ref=36","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1097\/00000441-200609000-00013","volume":"332","author":"Diskin C.J.","year":"2006","unstructured":"Diskin C.J.; Stokes T.J.; Dansby L.M.; Radcliff L.; Carter T.B.; Removal of methotrexate by peritoneal dialysis and hemodialysis in a single patient with end-stage renal disease. Am J Med Sci 2006,332(3),156-158","journal-title":"Am J Med Sci"},{"key":"ref=37","first-page":"788","volume":"84","author":"B\u00e9n\u00e9zet S.","year":"1997","unstructured":"B\u00e9n\u00e9zet S.; Chatelut E.; Bagheri H.; Rigal-Huguet F.; Nguyen L.; Pourrat J.; Robert A.; Montastruc J.L.; Canal P.; Inefficacy of exchange-transfusion in case of a methotrexate poisoning. Bull Cancer 1997,84(8),788-790","journal-title":"Bull Cancer"},{"key":"ref=38","doi-asserted-by":"publisher","first-page":"825","DOI":"10.1016\/S0022-3476(81)80859-1","volume":"98","author":"Addiego J.E.","year":"1981","unstructured":"Addiego J.E.; Ridgway D.; Bleyer W.A.; The acute management of intrathecal methotrexate overdose: Pharmacologic rationale and guidelines. J Pediatr 1981,98(5),825-828","journal-title":"J Pediatr"},{"key":"ref=39","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1016\/j.neuro.2003.10.004","volume":"25","author":"Finkelstein Y.","year":"2004","unstructured":"Finkelstein Y.; Zevin S.; Heyd J.; Bentur Y.; Zigelman Y.; Hersch M.; Emergency treatment of life-threatening intrathecal methotrexate overdose. Neurotoxicology 2004,25(3),407-410","journal-title":"Neurotoxicology"},{"key":"ref=40","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1111\/bcp.12720","volume":"81","author":"Chen H.Y.","year":"2016","unstructured":"Chen H.Y.; Albertson T.E.; Olson K.R.; Treatment of drug-induced seizures. Br J Clin Pharmacol 2016,81(3),412-419","journal-title":"Br J Clin Pharmacol"}],"container-title":["Current Drug Metabolism"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/eurekaselect.com\/article\/download\/174121","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,11,28]],"date-time":"2019-11-28T08:19:37Z","timestamp":1574929177000},"score":1,"resource":{"primary":{"URL":"http:\/\/www.eurekaselect.com\/174121\/article"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,4]]},"references-count":40,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2019,10,4]]}},"alternative-id":["LiveAll1"],"URL":"https:\/\/doi.org\/10.2174\/1389200220666190806140844","relation":{},"ISSN":["1389-2002"],"issn-type":[{"value":"1389-2002","type":"print"}],"subject":[],"published":{"date-parts":[[2019,10,4]]},"assertion":[{"value":"Peer Reviewed","order":0,"name":"review_status","label":"Review Status","group":{"name":"peer_review_details","label":"Peer Review Details"}},{"value":"Single blind","order":1,"name":"review_process","label":"Review Process","group":{"name":"peer_review_details","label":"Peer Review Details"}},{"value":"Checked with iThenticate","order":0,"name":"screening_status","label":"Screening Status","group":{"name":"plagiarism_screening","label":"Plagiarism Screening"}},{"value":"2019-05-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-07-09","order":1,"name":"revised","label":"Revised","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-07-25","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-10-04","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}