{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T14:24:04Z","timestamp":1788445444743,"version":"build-2803163510"},"reference-count":53,"publisher":"Georg Thieme Verlag KG","issue":"07","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Drug Res (Stuttg)"],"published-print":{"date-parts":[[2023,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Loads of new therapeutic regimes have been turned up to manage Myelodysplastic\n                    syndrome (MDS) and acute myeloid leukemia (AML), particularly in elderly\n                    patients who are unfit for intensive chemotherapy. Despite accumulating\n                    research, the best MDS and AML management approach is indeterminate.\n                    Myelodysplastic syndrome implies a group of various hematopoietic stem cell\n                    disorders that may progress to acute myeloid leukemia. These disorders are more\n                    frequent in older adults. To the high rate of morbidity and abundant toxicities\n                    related to the therapeutic approaches, also, the treatment would be challenging.\n                    The clinical effectiveness of valproic acid, a histone deacetylase inhibitor, in\n                    MDS and AML patients is unknown, even though it has demonstrated positive\n                    activities to promote differentiation and apoptosis in cancer cells. We\n                    investigated the clinical research on the effects of valproic acid in\n                    conjunction with various drugs, including low-dose cytarabine, all-trans\n                    retinoic acid, DNA-hypomethylating agents, hydrazine, and theophylline. We\n                    conclude that VPA is a safe and effective treatment option for MDS and AML\n                    patients, particularly when used in conjunction with all-trans retinoic acid,\n                    DNA-hypomethylating drugs, and hydralazine. However, more randomized clinical\n                    studies are required to identify an ideal regimen.<\/jats:p>","DOI":"10.1055\/a-2088-3718","type":"journal-article","created":{"date-parts":[[2023,5,23]],"date-time":"2023-05-23T23:09:41Z","timestamp":1684883381000},"page":"378-387","source":"Crossref","is-referenced-by-count":4,"title":["Efficacy and Safety of Valproic Acid in Myelodysplastic Syndrome and\n                    Acute Myeloid Leukemia; a Narrative Review"],"prefix":"10.1055","volume":"73","author":[{"given":"Navid","family":"Omidkhoda","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, School of Pharmacy, Mashhad University\n                    of Medical Sciences, Mashhad, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sina","family":"Mahdiani","sequence":"additional","affiliation":[{"name":"Department of Pharmacodynamics and Toxicology, School of Pharmacy,\n                    Mashhad University of Medical Sciences, Mashhad, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Samadi","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, School of Pharmacy, Mashhad University\n                    of Medical Sciences, Mashhad, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hossein","family":"Rahimi","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Ghaem Hospital, Mashhad University of\n                    Medical Sciences, Mashhad, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7517-8634","authenticated-orcid":false,"given":"Amir Hooshang","family":"Mohammadpour","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, School of Pharmacy, Mashhad University\n                    of Medical Sciences, Mashhad, Iran"},{"name":"Pharmaceutical Research Center, Pharmaceutical Technology Institute,\n                    Mashhad University of Medical Sciences, Mashhad, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"194","published-online":{"date-parts":[[2023,5,23]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"1358","DOI":"10.1056\/NEJMra1904794","article-title":"Myelodysplastic Syndromes","volume":"383","author":"M Cazzola","year":"2020","journal-title":"N Engl J Med"},{"key":"ref2","first-page":"2322","article-title":"The importance of diagnostic cytogenetics on outcome in AML: analysis of\n                        1,612 patients entered into the MRC AML 10 trial","volume":"92","author":"D Grimwade","year":"1998","journal-title":"Blood, The Journal of the American Society of\n                    Hematology"},{"key":"ref3","doi-asserted-by":"crossref","first-page":"4422","DOI":"10.1182\/blood-2010-03-276485","article-title":"Intensive chemotherapy does not benefit most older patients (age 70 years or\n                        older) with acute myeloid leukemia","volume":"116","author":"H Kantarjian","year":"2010","journal-title":"Blood"},{"key":"ref4","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1053\/j.seminhematol.2007.11.007","article-title":"DNA methyltransferase and histone deacetylase inhibitors in the treatment of\n                        myelodysplastic syndromes","volume":"45","author":"E A Griffiths","year":"2008","journal-title":"Semin Hematol"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"2042","DOI":"10.1056\/NEJMra023075","article-title":"Gene silencing in cancer in association with promoter\n                    hypermethylation","volume":"349","author":"J G Herman","year":"2003","journal-title":"New England Journal of Medicine"},{"key":"ref6","doi-asserted-by":"crossref","first-page":"6969","DOI":"10.1093\/emboj\/20.24.6969","article-title":"Valproic acid defines a novel class of HDAC inhibitors inducing\n                        differentiation of transformed cells","volume":"20","author":"M G\u00f6ttlicher","year":"2001","journal-title":"The EMBO journal"},{"key":"ref7","doi-asserted-by":"crossref","first-page":"1266","DOI":"10.1182\/blood-2003-12-4333","article-title":"Treatment of myelodysplastic syndromes with valproic acid alone or in\n                        combination with all-trans retinoic acid","volume":"104","author":"A Kuendgen","year":"2004","journal-title":"Blood"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1200\/JCO.19.01053","article-title":"Valproate and Retinoic Acid in Combination With Decitabine in Elderly Nonfit\n                        Patients With Acute Myeloid Leukemia: Results of a Multicenter, Randomized,\n                        2 x 2, Phase II Trial","volume":"38","author":"M Lubbert","year":"2020","journal-title":"Journal of Clinical Oncology"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"2943","DOI":"10.1182\/blood-2013-03-492884","article-title":"Diagnosis and treatment of primary myelodysplastic syndromes in adults:\n                        recommendations from the European LeukemiaNet","volume":"122","author":"L Malcovati","year":"2013","journal-title":"Blood"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1038\/leu.2013.305","article-title":"Extended survival and reduced risk of AML progression in erythroid-responsive\n                        lenalidomide-treated patients with lower-risk del(5q) MDS","volume":"28","author":"A F List","year":"2014","journal-title":"Leukemia"},{"key":"ref11","doi-asserted-by":"crossref","first-page":"1794","DOI":"10.1002\/cncr.21792","article-title":"Decitabine improves patient outcomes in myelodysplastic syndromes: results of\n                        a phase III randomized study","volume":"106","author":"H Kantarjian","year":"2006","journal-title":"Cancer"},{"key":"ref12","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/S1470-2045(09)70003-8","article-title":"Efficacy of azacitidine compared with that of conventional care regimens in\n                        the treatment of higher-risk myelodysplastic syndromes: a randomised,\n                        open-label, phase III study","volume":"10","author":"P Fenaux","year":"2009","journal-title":"Lancet Oncol"},{"key":"ref13","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.1002\/ajh.25950","article-title":"Myelodysplastic syndromes: 2021 update on diagnosis, risk stratification and\n                        management","volume":"95","author":"G Garcia-Manero","year":"2020","journal-title":"Am J Hematol"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"2662","DOI":"10.1200\/JCO.2012.46.8652","article-title":"Role of reduced-intensity conditioning allogeneic hematopoietic stem-cell\n                        transplantation in older patients with de novo myelodysplastic syndromes: an\n                        international collaborative decision analysis","volume":"31","author":"J Koreth","year":"2013","journal-title":"Journal of clinical oncology"},{"key":"ref15","doi-asserted-by":"crossref","first-page":"5420","DOI":"10.1002\/cncr.25500","article-title":"Maintenance therapy with low-dose azacitidine after allogeneic hematopoietic\n                        stem cell transplantation for recurrent acute myelogenous leukemia or\n                        myelodysplastic syndrome: a dose and schedule finding study","volume":"116","author":"M De Lima","year":"2010","journal-title":"Cancer"},{"key":"ref16","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/s41408-021-00425-3","article-title":"Acute myeloid leukemia: current progress and future directions","volume":"11","author":"H Kantarjian","year":"2021","journal-title":"Blood cancer journal"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.2174\/138945009789735138","article-title":"The role of sodium channels in the mechanism of action of antidepressants and\n                        mood stabilizers","volume":"10","author":"M Bourin","year":"2009","journal-title":"Current drug targets"},{"key":"ref18","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1038\/nature01411","article-title":"Controlling the double helix","volume":"421","author":"G Felsenfeld","year":"2003","journal-title":"Nature"},{"key":"ref19","doi-asserted-by":"crossref","first-page":"5310","DOI":"10.1038\/sj.onc.1210599","article-title":"HATs and HDACs: from structure, function and regulation to novel strategies\n                        for therapy and prevention","volume":"26","author":"X J Yang","year":"2007","journal-title":"Oncogene"},{"key":"ref20","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1038\/ng1531","article-title":"Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a\n                        common hallmark of human cancer","volume":"37","author":"M F Fraga","year":"2005","journal-title":"Nat Genet"},{"key":"ref21","first-page":"769","article-title":"Expression profile of class I histone deacetylases in human cancer\n                        tissues","volume":"18","author":"M Nakagawa","year":"2007","journal-title":"Oncol Rep"},{"key":"ref22","doi-asserted-by":"crossref","first-page":"3003","DOI":"10.1073\/pnas.95.6.3003","article-title":"A class of hybrid polar inducers of transformed cell differentiation inhibits\n                        histone deacetylases","volume":"95","author":"V M Richon","year":"1998","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref23","doi-asserted-by":"crossref","first-page":"5541","DOI":"10.1038\/sj.onc.1210620","article-title":"Histone deacetylase inhibitors: molecular mechanisms of action","volume":"26","author":"W S Xu","year":"2007","journal-title":"Oncogene"},{"key":"ref24","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.2174\/0929867023369763","article-title":"Valproate and valproate-analogues: potent tools to fight against\n                    cancer","volume":"9","author":"R A Blaheta","year":"2002","journal-title":"Current Medicinal Chemistry"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1002\/cncr.21552","article-title":"The histone deacetylase (HDAC) inhibitor valproic acid as monotherapy or in\n                        combination moth all-trans retinoic acid in patients with acute myeloid\n                        leukemia","volume":"106","author":"A Kuendgen","year":"2006","journal-title":"Cancer"},{"key":"ref26","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1038\/35901","article-title":"Fusion proteins of the retinoic acid receptor-\u03b1 recruit histone\n                        deacetylase in promyelocytic leukaemia","volume":"391","author":"F Grignani","year":"1998","journal-title":"Nature"},{"key":"ref27","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1038\/35895","article-title":"Role of the histone deacetylase complex in acute promyelocytic\n                    leukaemia","volume":"391","author":"R J Lin","year":"1998","journal-title":"Nature"},{"key":"ref28","first-page":"2","article-title":"Histone deacetylase-targeted treatment restores retinoic acid signaling and\n                        differentiation in acute myeloid leukemia","volume":"61","author":"F F Ferrara","year":"2001","journal-title":"Cancer research"},{"key":"ref29","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1007\/s00277-005-0026-8","article-title":"Results of a phase 2 study of valproic acid alone or in combination with\n                        all-trans retinoic acid in 75 patients with myelodysplastic syndrome and\n                        relapsed or refractory acute myeloid leukemia","volume":"84","author":"A Kuendgen","year":"2005","journal-title":"Ann Hematol"},{"key":"ref30","doi-asserted-by":"crossref","first-page":"2717","DOI":"10.1002\/cncr.21589","article-title":"Clinical trial of valproic acid and all-trans retinoic acid in patients with\n                        poor-risk acute myeloid leukemia","volume":"104","author":"G Bug","year":"2005","journal-title":"Cancer"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1002\/cncr.21132","article-title":"Increase in platelet count in older, poor-risk patients with acute myeloid\n                        leukemia or myelodysplastic syndrome treated with valproic acid and\n                        all-trans retinoic acid","volume":"104","author":"C Pilatrino","year":"2005","journal-title":"Cancer"},{"key":"ref32","doi-asserted-by":"crossref","first-page":"8903","DOI":"10.1158\/0008-5472.CAN-05-2726","article-title":"Sequential valproic acid\/all-trans retinoic acid treatment reprograms\n                        differentiation in refractory and high-risk acute myeloid leukemia","volume":"66","author":"G Cimino","year":"2006","journal-title":"Cancer Res"},{"key":"ref33","first-page":"20","article-title":"Demethylating agents in myeloid malignancies","author":"G Garcia-Manero","year":"2008","journal-title":"Current opinion in oncology"},{"key":"ref34","doi-asserted-by":"crossref","first-page":"3271","DOI":"10.1182\/blood-2006-03-009142","article-title":"Phase 1\/2 study of the combination of 5-aza-2'-deoxycytidine\n                        with valproic acid in patients with leukemia","volume":"108","author":"G Garcia-Manero","year":"2006","journal-title":"Blood"},{"key":"ref35","doi-asserted-by":"crossref","first-page":"3884","DOI":"10.1200\/JCO.2006.09.4169","article-title":"Phase I study of decitabine alone or in combination with valproic acid in\n                        acute myeloid leukemia","volume":"25","author":"W Blum","year":"2007","journal-title":"J Clin Oncol"},{"key":"ref36","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1002\/cncr.29085","article-title":"Results of phase 2 randomized study of low-dose decitabine with or without\n                        valproic acid in patients with myelodysplastic syndrome and acute\n                        myelogenous leukemia","volume":"121","author":"J P Issa","year":"2015","journal-title":"Cancer"},{"key":"ref37","doi-asserted-by":"crossref","first-page":"5002","DOI":"10.1158\/1078-0432.CCR-09-0494","article-title":"Valproic acid at therapeutic plasma levels may increase 5-azacytidine\n                        efficacy in higher risk myelodysplastic syndromes","volume":"15","author":"M T Voso","year":"2009","journal-title":"Clin Cancer Res"},{"key":"ref38","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1007\/s13148-011-0031-9","article-title":"Treatment of poor-risk myelodysplastic syndromes and acute myeloid leukemia\n                        with a combination of 5-azacytidine and valproic acid","volume":"2","author":"A Kuendgen","year":"2011","journal-title":"Clin Epigenetics"},{"key":"ref39","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1111\/bjh.18193","article-title":"A randomised phase II study of azacitidine (AZA) alone or with Lenalidomide\n                        (LEN), Valproic acid (VPA) or Idarubicin (IDA) in higher-Risk MDS or low\n                        blast AML: GFM's \u201cpick a winner\u201d trial, with the\n                        impact of somatic mutations","volume":"198","author":"L Ad\u00e8s","year":"2022","journal-title":"British Journal of Haematology"},{"key":"ref40","volume-title":"Future directions for the use of hypomethylating agents. in Seminars in\n                    hematology","author":"G Garcia-Manero","year":"2005"},{"key":"ref41","first-page":"2478","article-title":"Randomized phase II study of fludarabine+ cytosine\n                        arabinoside+ idarubicin\u00b1all-trans retinoic\n                        acid\u00b1granulocyte colony-stimulating factor in poor prognosis newly\n                        diagnosed acute myeloid leukemia and myelodysplastic syndrome","volume":"93","author":"E H Estey","year":"1999","journal-title":"Blood, The Journal of the American Society of\n                    Hematology"},{"key":"ref43","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1126\/science.1065173","article-title":"Methyltransferase recruitment and DNA hypermethylation of target promoters by\n                        an oncogenic transcription factor","volume":"295","author":"L Di Croce","year":"2002","journal-title":"Science"},{"key":"ref44","doi-asserted-by":"crossref","first-page":"2302","DOI":"10.1182\/blood-2007-03-078576","article-title":"Safety and clinical activity of the combination of 5-azacytidine, valproic\n                        acid, and all-trans retinoic acid in acute myeloid leukemia and\n                        myelodysplastic syndrome","volume":"110","author":"A O Soriano","year":"2007","journal-title":"Blood"},{"key":"ref45","doi-asserted-by":"crossref","first-page":"34","DOI":"10.18632\/oncotarget.106","article-title":"Phase 2 clinical trial of 5-azacitidine, valproic acid, and all-trans\n                        retinoic acid in patients with high-risk acute myeloid leukemia or\n                        myelodysplastic syndrome","volume":"1","author":"E Raffoux","year":"2010","journal-title":"Oncotarget"},{"key":"ref46","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1016\/j.leukres.2011.02.021","article-title":"Hematologic improvement and response in elderly AML\/RAEB patients\n                        treated with valproic acid and low-dose Ara-C","volume":"35","author":"M T Corsetti","year":"2011","journal-title":"Leuk Res"},{"key":"ref47","doi-asserted-by":"crossref","first-page":"01","DOI":"10.1186\/1868-7083-5-13","article-title":"The combination of valproic acid, all-trans retinoic acid and low-dose\n                        cytarabine as disease-stabilizing treatment in acute myeloid\n                    leukemia","volume":"5","author":"H Fredly","year":"2013","journal-title":"Clinical Epigenetics"},{"key":"ref48","first-page":"4027","article-title":"Valproic acid in combination with all-trans retinoic acid and intensive\n                        therapy for acute myeloid leukemia in older patients","volume":"123","author":"M Tassara","year":"2014","journal-title":"Blood, The Journal of the American Society of\n                    Hematology"},{"key":"ref49","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1016\/j.leukres.2008.10.005","article-title":"A subset of patients with high-risk acute myelogenous leukemia shows improved\n                        peripheral blood cell counts when treated with the combination of valproic\n                        acid, theophylline and all-trans retinoic acid","volume":"33","author":"A Ryningen","year":"2009","journal-title":"Leuk Res"},{"key":"ref50","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1111\/j.1365-2141.2008.07449.x","article-title":"Elevated FOSB-expression; a potential marker of valproate sensitivity in\n                        AML","volume":"144","author":"F L Khanim","year":"2009","journal-title":"British Journal of Haematology"},{"key":"ref51","doi-asserted-by":"crossref","first-page":"1825","DOI":"10.1007\/s00277-017-3103-x","article-title":"Encouraging results with the compassionate use of\n                        hydralazine\/valproate (TRANSKRIP\u2122) as epigenetic treatment\n                        for myelodysplastic syndrome (MDS)","volume":"96","author":"M Candelaria","year":"2017","journal-title":"Annals of hematology"},{"key":"ref52","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1007\/s00277-010-1090-2","article-title":"Hydralazine and magnesium valproate as epigenetic treatment for\n                        myelodysplastic syndrome. Preliminary results of a phase-II trial","volume":"90","author":"M Candelaria","year":"2011","journal-title":"Ann Hematol"},{"key":"ref53","doi-asserted-by":"crossref","first-page":"809014","DOI":"10.3389\/fonc.2022.809014","article-title":"Epigenetics-Associated Risk Reduction of Hematologic Neoplasms in a\n                        Nationwide Cohort Study: The Chemopreventive and Therapeutic Efficacy of\n                        Hydralazine","volume":"12","author":"B H Yang","year":"2022","journal-title":"Front Oncol"},{"key":"ref54","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.3324\/haematol.11262","article-title":"Leukemia, Valproic acid combined with 13-cis retinoic acid and\n                        1,25-dihydroxyvitamin D3 in the treatment of patients with myelodysplastic\n                        syndromes.","volume":"92","author":"T Siitonen","year":"2007","journal-title":"Haematologica"}],"container-title":["Drug Research"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.thieme-connect.de\/products\/ejournals\/pdf\/10.1055\/a-2088-3718.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,1]],"date-time":"2023-09-01T23:21:51Z","timestamp":1693610511000},"score":1,"resource":{"primary":{"URL":"http:\/\/www.thieme-connect.de\/DOI\/DOI?10.1055\/a-2088-3718"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,23]]},"references-count":53,"journal-issue":{"issue":"07","published-online":{"date-parts":[[2023,9,1]]},"published-print":{"date-parts":[[2023,9]]}},"URL":"https:\/\/doi.org\/10.1055\/a-2088-3718","archive":["Portico","CLOCKSS"],"relation":{},"ISSN":["2194-9379","2194-9387"],"issn-type":[{"value":"2194-9379","type":"print"},{"value":"2194-9387","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,23]]}}}