{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T23:17:52Z","timestamp":1792192672731,"version":"4.4.0"},"reference-count":40,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2014,4,15]],"date-time":"2014-04-15T00:00:00Z","timestamp":1397520000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Drugs R D"],"published-print":{"date-parts":[[2014,6]]},"DOI":"10.1007\/s40268-014-0042-z","type":"journal-article","created":{"date-parts":[[2014,4,14]],"date-time":"2014-04-14T07:31:50Z","timestamp":1397460710000},"page":"85-94","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":55,"title":["Valproate-Induced Liver Injury: Modulation by the Omega-3 Fatty Acid DHA Proposes a Novel Anticonvulsant Regimen"],"prefix":"10.1007","volume":"14","author":[{"given":"Marwa A.","family":"Abdel-Dayem","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed A.","family":"Elmarakby","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Azza A.","family":"Abdel-Aziz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chelsey","family":"Pye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shehta A.","family":"Said","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdalla M.","family":"El-Mowafy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2014,4,15]]},"reference":[{"key":"42_CR1","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1016\/j.phymed.2010.08.004","volume":"17","author":"AM El-Mowafy","year":"2010","unstructured":"El-Mowafy AM, Al-Gayyar MM, El-Mesery ME, Salem HA, Darweish MM. Novel chemotherapeutic and renal protective effects for the green-tea (EGCG): role of oxidative stress and inflammatory-cytokine signaling. Phytomedicine. 2010;17:1067\u201375.","journal-title":"Phytomedicine"},{"issue":"12","key":"42_CR2","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1007\/s11745-004-1342-z","volume":"39","author":"PC Calder","year":"2004","unstructured":"Calder PC. n-3 Fatty acids, inflammation, and immunity relevance to postsurgical and critically ill patients. Lipids. 2004;39(12):1147\u201361.","journal-title":"Lipids"},{"issue":"5","key":"42_CR3","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1093\/carcin\/bgg015","volume":"24","author":"AM El-Mowafy","year":"2003","unstructured":"El-Mowafy AM, Alkhalaf M. Resveratrol activates adenylyl-cyclase in human breast-cancer cells: a novel, estrogen receptor-independent cytostatic mechanism. Carcinogenesis. 2003;24(5):869\u201373.","journal-title":"Carcinogenesis"},{"issue":"7\u20138","key":"42_CR4","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1177\/106002809302700702","volume":"27","author":"TR Einarson","year":"1993","unstructured":"Einarson TR. Drug-related hospital admissions. Ann Pharmacother. 1993;27(7\u20138):832\u201340.","journal-title":"Ann Pharmacother"},{"issue":"2","key":"42_CR5","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1111\/j.1527-3458.2003.tb00249.x","volume":"9","author":"CU Johannessen","year":"2003","unstructured":"Johannessen CU, Johannessen SI. Valproate: past, present, and future. CNS Drug Rev. 2003;9(2):199\u2013216.","journal-title":"CNS Drug Rev."},{"key":"42_CR6","doi-asserted-by":"crossref","unstructured":"Bedry R, Parrot F. Severe valproate poisoning. R\u00e9animation. 2004;13:324\u2013333.","DOI":"10.1016\/j.reaurg.2004.03.014"},{"key":"42_CR7","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1002\/hep.1840020513","volume":"2","author":"RI Zimmerman","year":"1982","unstructured":"Zimmerman RI, Ishak KG. Valproate-induced hepatic injury. Analyses of 23 fatal cases. Hepatology. 1982;2:591\u20137.","journal-title":"Hepatology"},{"issue":"5","key":"42_CR8","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1093\/clinchem\/34.5.890","volume":"34","author":"D Cotarlu","year":"1988","unstructured":"Cotarlu D, Zaldman JL. Valproic acid and the liver. Clin Chem. 1988;34(5):890\u20137.","journal-title":"Clin Chem."},{"key":"42_CR9","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1055\/s-2007-973560","volume":"29","author":"WD Graf","year":"1998","unstructured":"Graf WD, Oleinik OE, Glauser T. Altered antioxidant enzyme activities in children with a serious adverse experience related to valproic acid therapy. Neuropediatrics. 1998;29:195\u2013201.","journal-title":"Neuropediatrics"},{"issue":"2","key":"42_CR10","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1093\/toxsci\/kfi184","volume":"86","author":"V Tong","year":"2005","unstructured":"Tong V, Thomas KH, Frank S. Valproic acid. Time course of lipid peroxidation biomarkers, liver toxicity, and valproic acid metabolite levels in rats. Toxicol Sci. 2005;86(2):427\u201335.","journal-title":"Toxicol Sci"},{"issue":"7","key":"42_CR11","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1081\/CLT-100102388","volume":"38","author":"HA Spiller","year":"2000","unstructured":"Spiller HA, Krenzelok EP, Klein-Schwartz W, Winter ML, Webe JA, Sollee DR, et al. Multicenter case series of valproic acid ingestion: serum concentrations and toxicity. J Toxicol Clin Toxicol. 2000;38(7):755\u201360.","journal-title":"J Toxicol Clin Toxicol"},{"issue":"5","key":"42_CR12","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1021\/tx00047a006","volume":"8","author":"W Tang","year":"1995","unstructured":"Tang W, Borel AG, Fujimiya T, Abbott FS. Fluorinated analogues as mechanistic probes in valproic acid hepatotoxicity: Hepatic microvesicular steatosis and glutathione status. Chem Res Toxicol. 1995;8(5):671\u201382.","journal-title":"Chem Res Toxicol"},{"issue":"2","key":"42_CR13","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1006\/phrs.1997.0134","volume":"35","author":"M Raza","year":"1997","unstructured":"Raza M, Al-Bekairi AM, Ageel AM, Qureshi S. Biochemical basis of sodium valproate hepatotoxicity and renal tubular disorder. Pharmacol Res. 1997;35(2):153\u20137.","journal-title":"Pharmacol Res"},{"issue":"4","key":"42_CR14","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1002\/j.1552-4604.1984.tb01823.x","volume":"24","author":"KN Buchi","year":"1984","unstructured":"Buchi KN, Gray PD, Rollins DE, Tolman KG. Protection against sodium valproate injury in isolated hepatocytes by alpha-tocopherol and N,N\u2019-diphenyl-p-phenylenediamine. J Clin Pharmacol. 1984;24(4):148\u201354.","journal-title":"J Clin Pharmacol."},{"issue":"2","key":"42_CR15","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1080\/15563650902752376","volume":"47","author":"PE Lheureux","year":"2009","unstructured":"Lheureux PE, Hantson P. Carnitine in the treatment of valproic acid-induced toxicity. Clin Toxicol (Phila). 2009;47(2):101\u201311.","journal-title":"Clin Toxicol (Phila)"},{"key":"42_CR16","first-page":"67","volume":"56","author":"AP Simopoulos","year":"2003","unstructured":"Simopoulos AP. Essential fatty acids in health and chronic diseases. Forum Nutr. 2003;56:67\u201370.","journal-title":"Forum Nutr"},{"issue":"1","key":"42_CR17","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/1747-1028-4-6","volume":"4","author":"ME El-Mesery","year":"2009","unstructured":"El-Mesery ME, Al-Gayyar MM, Salem HA, Darweish MM, El-Mowafy AM. Chemopreventive and renal protective effects for docosahexaenoic acid (DHA): implications of CRP and lipid peroxides. Cell Div. 2009;4(1):6.","journal-title":"Cell Div"},{"key":"42_CR18","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1016\/j.yebeh.2010.01.001","volume":"17","author":"AY Taha","year":"2010","unstructured":"Taha AY, Jeffrey MA, Taha NMY, Bala S, Burnham WM. Acute administration of docosahexaenoic acid increases resistance to pentylenetetrazole-induced seizures in rats. Epilepsy Behav. 2010;17:336\u201343.","journal-title":"Epilepsy Behav"},{"issue":"1","key":"42_CR19","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1080\/07315724.2010.10719817","volume":"29","author":"M Rondanelli","year":"2010","unstructured":"Rondanelli M, Giacosa A, Opizzi A, Pelucchi C, La Vecchia C, Montorfano G, Negroni M, Berra B, Politi P, Rizzo AM. Effect of omega-3 fatty acids supplementation on depressive symptoms and on health-related quality of life in the treatment of elderly women with depression: a double-blind, placebo-controlled, randomized clinical trial. J Am Coll Nutr. 2010;29(1):55\u201364.","journal-title":"J Am Coll Nutr."},{"issue":"3","key":"42_CR20","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1016\/j.jhep.2008.10.031","volume":"50","author":"H Ishii","year":"2009","unstructured":"Ishii H, Horie Y, Ohshima S, Anezaki Y, Kinoshita N, Dohmen T, et al. Eicosapentaenoic acid ameliorates steatohepatitis and hepatocellular carcinoma in hepatocyte-specific Pten-deficient mice. J Hepatol. 2009;50(3):562\u201371.","journal-title":"J Hepatol"},{"key":"42_CR21","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1053\/jhep.2001.23505","volume":"33","author":"DM Bissell","year":"2001","unstructured":"Bissell DM, Gores GJ, Laskin DL, Hoofnagle JH. Drug-induced liver injury: mechanisms and test systems. Hepatology. 2001;33:1009\u201313.","journal-title":"Hepatology"},{"key":"42_CR22","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1055\/s-2001-12929","volume":"21","author":"D Pessayre","year":"2001","unstructured":"Pessayre D, Berson A, Fromenty B. Mitochondria in steatohepatitis. Semin Liver Dis. 2001;21:57\u201369.","journal-title":"Semin Liver Dis"},{"issue":"5","key":"42_CR23","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1111\/j.1600-0404.2008.01009.x","volume":"118","author":"E Bj\u00f6rnsson","year":"2008","unstructured":"Bj\u00f6rnsson E. Hepatotoxicity associated with antiepileptic drugs. Acta Neurol Scand. 2008;118(5):281\u201390.","journal-title":"Acta Neurol Scand"},{"key":"42_CR24","doi-asserted-by":"crossref","unstructured":"Szalowska E, van der Burg B, Man HY, Hendriksen PJ, Peijnenburg AA. Model steatogenic compounds (amiodarone, valproic acid, and tetracycline) alter lipid metabolism by different mechanisms in mouse liver slices. PLoS One. 2014;9(1):e86795. doi: 10.1371\/journal.pone.0086795 .","DOI":"10.1371\/journal.pone.0086795"},{"key":"42_CR25","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1079\/BJN2000220","volume":"85","author":"S Higgins","year":"2001","unstructured":"Higgins S, Carroll YL, McCarthy SN. Susceptibility of LDL to oxidative modification in healthy volunteers supplemented with low doses of n-3 polyunsaturated fatty acids. Br J Nutr. 2001;85:23\u201331.","journal-title":"Br J Nutr"},{"issue":"2","key":"42_CR26","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/j.jhep.2008.04.023","volume":"49","author":"BJ Song","year":"2008","unstructured":"Song BJ, Moon KH, Olsson NU, Salem N Jr. Prevention of alcoholic fatty liver and mitochondrial dysfunction in the rat by long-chain polyunsaturated fatty acids. J Hepatol. 2008;49(2):262\u201373.","journal-title":"J Hepatol"},{"issue":"2","key":"42_CR27","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1016\/j.atherosclerosis.2009.07.049","volume":"208","author":"C Calzada","year":"2009","unstructured":"Calzada C, Colas R, Guillot N, Guichardant M, Laville M, V\u00e9ricel E, et al. Subgram daily supplementation with docosahexaenoic acid protects low-density lipoproteins from oxidation in healthy men. Atherosclerosis. 2009;208(2):467\u201372.","journal-title":"Atherosclerosis"},{"key":"42_CR28","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1002\/hep.21626","volume":"45","author":"C Schmocker","year":"2007","unstructured":"Schmocker C, Weylandt KH, Kahlke L, Wang J, Lobeck H, Tiegs G. Omega-3 fatty acids alleviate chemically induced acute hepatitis by suppression of cytokines. Hepatology. 2007;45:864\u20139.","journal-title":"Hepatology"},{"issue":"4","key":"42_CR29","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1016\/j.jmb.2010.02.016","volume":"397","author":"JY Kim","year":"2010","unstructured":"Kim JY, Song EH, Lee HJ, Oh YK, Choi KH, Yu DY, Park SI, Seong JK, Kim WH. HBx-induced hepatic steatosis and apoptosis are regulated by TNFR1- and NF-kappaB-dependent pathways. J Mol Biol. 2010;397(4):917\u201331.","journal-title":"J Mol Biol"},{"issue":"4","key":"42_CR30","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1111\/j.1582-4934.2004.tb00469.x","volume":"8","author":"WX Ding","year":"2004","unstructured":"Ding WX, Yin XM. Dissection of the multiple mechanisms of TNF-alpha-induced apoptosis in liver injury. Cell Mol Med. 2004;8(4):445\u201354.","journal-title":"Cell Mol Med"},{"issue":"5","key":"42_CR31","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1016\/S0028-3908(02)00014-X","volume":"42","author":"TE Cullingford","year":"2002","unstructured":"Cullingford TE, Dolphin CT, Sato H. The peroxisome proliferator-activated receptor alpha-selective activator ciprofibrate upregulates expression of genes encoding fatty acid oxidation and ketogenesis enzymes in rat brain. Neuropharmacology. 2002;42(5):724\u201330.","journal-title":"Neuropharmacology"},{"issue":"2","key":"42_CR32","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/S0014-5793(97)00805-3","volume":"412","author":"K Beier","year":"1997","unstructured":"Beier K, V\u00f6lkl A, Fahimi HD. TNF-alpha downregulates the peroxisome proliferator activated receptor-alpha and the mRNAs encoding peroxisomal proteins in rat liver. FEBS Lett. 1997;412(2):385\u20137.","journal-title":"FEBS Lett"},{"issue":"22","key":"42_CR33","doi-asserted-by":"crossref","first-page":"12559","DOI":"10.1073\/pnas.93.22.12559","volume":"93","author":"M Vreugdenhil","year":"1996","unstructured":"Vreugdenhil M, Bruehl C, Voskuyl RA, Kang JX, Leaf A, Wadman WJ. Polyunsaturated fatty acids modulate sodium and calcium currents in CA1 neurons. Proc Natl Acad Sci USA. 1996;93(22):12559\u201363.","journal-title":"Proc Natl Acad Sci USA"},{"issue":"2","key":"42_CR34","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1097\/MCO.0b013e32802b7030","volume":"10","author":"NG Bazan","year":"2007","unstructured":"Bazan NG. Omega-3 fatty acids, pro-inflammatory signaling and neuroprotection. Curr Opin Clin Nutr Metab Care. 2007;10(2):136\u201341.","journal-title":"Curr Opin Clin Nutr Metab Care"},{"issue":"5","key":"42_CR35","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1211\/jpp.58.5.0010","volume":"58","author":"V Hirunpanich","year":"2006","unstructured":"Hirunpanich V, Sato H. Docosahexaenoic acid (DHA) inhibits saquinavir metabolism in-vitro and enhances its bioavailability in rats. J Pharm Pharmacol. 2006;58(5):651\u20138.","journal-title":"J Pharm Pharmacol"},{"issue":"2","key":"42_CR36","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1124\/dmd.105.007088","volume":"34","author":"V Hirunpanich","year":"2006","unstructured":"Hirunpanich V, Katagi J, Sethabouppha B, Sato H. Demonstration of docosahexaenoic acid as a bioavailability enhancer for CYP3A substrates: in vitro and in vivo evidence using cyclosporin in rats. Drug Metab Dispos. 2006;34(2):305\u201310.","journal-title":"Drug Metab Dispos"},{"issue":"11","key":"42_CR37","doi-asserted-by":"crossref","first-page":"2639","DOI":"10.1007\/s11095-008-9681-5","volume":"25","author":"LC Phua","year":"2008","unstructured":"Phua LC, New LS, Goh CW, Neo AH, Browne ER, Chan EC. Investigation of the drug\u2013drug interaction between alpha-lipoic acid and valproate via mitochondrial beta-oxidation. Pharm Res. 2008;25(11):2639\u201349.","journal-title":"Pharm Res"},{"issue":"4","key":"42_CR38","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1038\/sj.clpt.6100324","volume":"83","author":"JY Chung","year":"2008","unstructured":"Chung JY, Cho JY, Yu KS, Kim JR, Lim KS, Sohn DR, et al. Pharmacokinetic and pharmacodynamic interaction of lorazepam and valproic acid in relation to UGT2B7 genetic polymorphism in healthy subjects. Clin Pharmacol Ther. 2008;83(4):595\u2013600.","journal-title":"Clin Pharmacol Ther"},{"issue":"1","key":"42_CR39","first-page":"50","volume":"5","author":"M Meganathan","year":"2011","unstructured":"Meganathan M, Madhana MG, Sasikala P, Mohan J, Gowdhaman N, Balamurugan K, et al. Evaluation of antioxidant effect of Omega 3-fatty acid against paracetamol-induced liver injury in albino rats. Global J Pharmacol. 2011;5(1):50\u20133.","journal-title":"Global J Pharmacol"},{"issue":"2\u20133","key":"42_CR40","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.phymed.2008.12.018","volume":"16","author":"H Wagner","year":"2009","unstructured":"Wagner H, Ulrich-Merzenich G. Synergy research: approaching a new generation of phytopharmaceuticals. Phytomedicine. 2009;16(2\u20133):97\u2013110.","journal-title":"Phytomedicine"}],"container-title":["Drugs in R&D"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/article\/10.1007\/s40268-014-0042-z\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s40268-014-0042-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s40268-014-0042-z","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,8,17]],"date-time":"2020-08-17T19:22:46Z","timestamp":1597692166000},"score":1,"resource":{"primary":{"URL":"http:\/\/link.springer.com\/10.1007\/s40268-014-0042-z"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,4,15]]},"references-count":40,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2014,6]]}},"alternative-id":["42"],"URL":"https:\/\/doi.org\/10.1007\/s40268-014-0042-z","relation":{},"ISSN":["1174-5886","1179-6901"],"issn-type":[{"value":"1174-5886","type":"print"},{"value":"1179-6901","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,4,15]]}}}