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References
Henry, T.R., The history of valproate in clinical neuro-science. Psychopharmacol Bull2003;37 Suppl 2:5–16.
Gerstner, T., et al., Valproic acid-induced pancreatitis: 16 new cases and a review of the literature.J Gastroenterol 2007; 42(1):39–48.
Doyon, S., Anticonvulsants. 8th ed. Goldfrank’s Toxicologic Emergencies, ed. N. Flomenbaum, Howland, MA, Goldfrank, LR, Lewin, NA, Hoffman, RS, & Nelson, LS.2006, New York: McGraw-Hill. 731–745.
Brubacher, J.R., P. Dahghani, and D. McKnight, Delayed toxicity following ingestion of enteric-coated divalproex sodium (Epival).J Emerg Med 1999; 17(3):463–467.
Routy, J.P., Valproic acid: a potential role in treating latent HIV infection.Lancet 2005;366(9485):523–524.
Schwartz, C., et al., Valproic acid induces non-apoptotic cell death mechanisms in multiple myeloma cell lines.Int J Oncol 2007;30(3):573–582.
Valentini, A., et al., Valproic Acid Induces Apoptosis, p(16INK4A) Upregulation and Sensitization to Chemotherapy in Human Melanoma Cells.Cancer Biol Ther 2007;6(2).
Sztajnkrycer, M.D., Valproic acid toxicity: overview and management.J Toxicol Clin Toxicol 2002;40(6):789–801.
Litovitz, T.L., et al., 1990 annual report of the American Association of Poison Control Centers National Data Collection System.Am J Emerg Med 19919(5):461–509.
Litovitz, T.L., et al., 1995 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System.Am J Emerg Med 1996;14(5):487–537.
Litovitz, T.L., et al., 2000 Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System.Am J Emerg Med 2001; 19(5):337–395.
Hariton, C., et al., Distribution of sodium valproate and GABA metabolism in CNS of the rat.Biopharm Drug Dispos 1984;5(4):409–414.
Johannessen, C.U., Mechanisms of action of valproate: a commentatory.Neurochem Int 2000;37(2-3):103–110.
Gean, P.W., et al., Valproic acid suppresses the synaptic response mediated by the NMDA receptors in rat amygdalar slices.Brain Res Bull 1994;33(3):333–336.
Griffith, W.H. and L. Taylor, Sodium valproate decreases synaptic potentiation and epileptiform activity in hippocampus.Brain Res 1988474(1):155–164.
Zeise, M.L., S. Kasparow, and W. Zieglgansberger, Valproate suppresses N-methyl-D-aspartate-evoked, transient depolarizations in the rat neocortex in vitro.Brain Res 1991;544(2):345–348.
McLean, M.J. and R.L. Macdonald, Sodium valproate, but not ethosuximide, produces use- and voltage-dependent limitation of high frequency repetitive firing of action potentials of mouse central neurons in cell culture. J Pharmacol ExpTher 1986; 237(3):1001–1011.
Albus, H. and R. Williamson, Electrophysiologic analysis of the actions of valproate on pyramidal neurons in the rat hippocampal slice.Epilepsia 1998; 39(2):124–139.
Lheureux, P.E., et al., Science review: carnitine in the treatment of valproic acid-induced toxicity — what is the evidence?Crit Care 2005;9(5):431–440.
Klotz, U., Bioavailability of a slow-release preparation of valproic acid under steady-state conditions.Int J Clin Pharmacol Ther Toxicol 1982;20(1):24–26.
Klotz, U. and K.H. Antonin, Pharmacokinetics and bioavailability of sodium valproate.Clin Pharmacol Ther 1977;21(6):736–743.
al-Shareef, A., et al., The effect of repeated-dose activated charcoal on the pharmacokinetics of sodium valproate in healthy volunteers.Br J Clin Pharmacol 1997;43(1):109–111.
Graudins, A. and C.K. Aaron, Delayed peak serum valproic acid in massive divalproex overdose—treatment with charcoal hemoperfusion.J Toxicol Clin Toxicol 1996;34(3):335–341.
Tank, J.E. and B.F. Palmer, Simultaneous “in series” hemodialysis and hemoperfusion in the management of valproic acid overdose.Am J Kidney Dis 1993;22(2):341–344.
Franssen, E.J., et al., Valproic acid toxicokinetics: serial hemodialysis and hemoperfusion.Ther Drug Monit 1999;21(3):289–292.
Kane, S.L., et al., High-flux hemodialysis without hemoperfusion is effective in acute valproic acid overdose.Ann Pharmacother 2000;34(10):1146–1151.
Brewster, D. and N.C. Muir, Valproate plasma protein binding in the uremic condition.Clin Pharmacol Ther 1980;27(1):76–82.
Andersen, G.O. and S. Ritland, Life threatening intoxication with sodium valproate.J Toxicol Clin Toxicol 1995;33(3):279–284.
Nau, H. and W. Loscher, Valproic acid and metabolites: pharmacological and toxicological studies.Epilepsia 1984;25 Suppl 1:S14-S22.
Stahl, J., Studies of the blood ammonia in liver disease. Its diagnostic, prognostic, and therapeutic significance.Ann Intern Med 1963;58:1–24.
Sugimoto, T., et al., Valproate metabolites in high-dose valproate plus phenytoin therapy.Epilepsia 1996; 37(12):1200–1203.
De Vivo, D.C., et al., L-carnitine supplementation in childhood epilepsy: current perspectives.Epilepsia 1998;39(11):1216–1225.
Duarte, J., et al., Valproate-induced coma: case report and literature review.Ann Pharmacother 1993;27(5):582–583.
Eyer, F., et al., Acute valproate poisoning: pharmacokinetics, alteration in fatty acid metabolism, and changes during therapy.J Clin Psychopharmacol 2005; 25(4):376–380.
Gerstner, T., et al., Valproic acid induced encephalopathy— 19 new cases in Germany from 1994 to 2003—a side effect associated to VPA-therapy not only in young children.Seizure 2006;15(6):443–448.
Ishikura, H., et al., Valproic acid overdose and L-carnitine therapy.J Anal Toxicol 1996;20(1):55–58.
Koenig, S.A., et al., Valproic acid-induced hepatopathy: nine new fatalities in Germany from 1994 to 2003.Epilepsia 2006;47(12):2027–2031.
LoVecchio, F., J. Shriki, and R. Samaddar, L-carnitine was safely administered in the setting of valproate toxicity.Am J Emerg Med 2005;23(3):321–322.
Moreiras Plaza, M., et al., On the toxicity of valproic-acid.Clin Nephrol 1999 51(3):187–189.
Murakami K., et al., Effect of L-carnitine supplementation on acute valproate intoxication.Epilepsia 1996;37(7):687–689.
Ohtani, Y., F. Endo, and I. Matsuda, Carnitine deficiency and hyperammonemia associated with valproic acid therapy.J Pediatr 1982;101(5):782–785.
Rawat, S., W.J. Borkowski, Jr., and H.M. Swick, Valproic acid and secondary hyperammonemia.Neurology 1981;31(9):1173–1174.
Scheffner, D., Fatal liver failure in children on valproate.Lancet 1986;2(8505):511.
Scheffner, D. and S. Konig, Valproate hepatotoxicity.Lancet 1987;1(8529):389–390.
Stadler, D.D., et al., Effect of long-term valproic acid administration on the efficiency of carnitine reabsorption in humans.Metabolism 1999;48(1):74–79.
van der Merwe, A.C., et al., Sodium valproate poisoning. A case report.S Afr Med J 1985;67(18):735–736.
Verrotti, A., et al., Carnitine deficiency and hyperammonemia in children receiving valproic acid with and without other anticonvulsant drugs.Int J Clin Lab Res 1999;29(1):36–40.
Warter, J.M., et al., The renal origin of sodium valproateinduced hyperammonemia in fasting humans.Neurology 198333(9):1136–1140.
Hathcock, J.N. and A. Shao, Risk assessment for carnitine. Regul ToxicolPharmacol 2006;46(1):23–28.
Steiber, A., J. Kerner, and C.L. Hoppel, Carnitine: a nutritional, biosynthetic, and functional perspective.Mol Aspects Med;2004;25(5–6):455–473.
Scaglia, F., Carnitine Deficiency, in Emedicine, C.J. Renner, Editor. 2006; WebMD.
Sahajwalla, C.G., et al., Multiple-dose pharmacokinetics and bioequivalence of L-carnitine 330-mg tablet versus 1-g chewable tablet versus enteral solution in healthy adult male volunteers.J Pharm Sci 1995;84(5):627–633.
Raskind, J.Y. and G.M. El-Chaar, The role of carnitine supplementation during valproic acid therapy.Ann Pharmacother 2000;34(5):630–638.
Carter, A.L., T.O. Abney, and D.F. Lapp, Biosynthesis and metabolism of carnitine.J Child Neurol 1995;10 Suppl 2:S3-S7.
Rebouche, C.J., Renal handling of carnitine in experimental vitamin C deficiency. Metabolism,1995;44(12):1639–1643.
Okamura, N., et al., Involvement of recognition and interaction of carnitine transporter in the decrease of L-carnitine concentration induced by pivalic acid and valproic acid.Pharm Res 2006;23(8):1729–1735.
Roe, C.R., et al., Carnitine homeostasis in the organic acidurias.Prog Clin Biol Res 1990;321:383–402.
Dupuis, R.E., S.N. Lichtman, and G.M. Pollack, Acute valproic acid overdose. Clinical course and pharmacokinetic disposition of valproic acid and metabolites.Drug Saf 1990;5(1):65–71.
Rajantie, J., M. Kajosaari, and V. Ylitalo, Fatal pancytopenia during high-dose valproate monotherapy.Eur J Pediatr 1992;151(8):619.
Coulter, D.L., Carnitine deficiency: a possible mechanism for valproate hepatotoxicity.Lancet;1984, 1(8378):689.
Kuhara, T., et al., Markedly increased omega-oxidation of valproate in fulminant hepatic failure.Epilepsia 1990;31(2):214–217.
Kesterson, J.W., G.R. Granneman, and J.M. Machinist, The hepatotoxicity of valproic acid and its metabolites in rats. I. Toxicologic, biochemical and histopathologic studies.Hepatology 1984;4(6):1143–1152.
Rettie, A.E., et al., Cytochrome P-450—catalyzed formation of delta 4-VPA, a toxic metabolite of valproic acid.Science 1987;235(4791):890–893.
Brusilow, S.W., Hyperammonemic encephalopathy.Medicine (Baltimore)2002; 81(3):240–249.
Sherlock, S., Fulminant hepatic failure.Adv Intern Med 1993;38:245–267.
Cotariu, D. and J.L. Zaidman, Valproic acid and the liver.Clin Chem 1988;34(5):890–897.
Thakur, V., et al., Fatal cerebral edema from late-onset ornithine transcarbamylase deficiency in a juvenile male patient receiving valproic acid.Pediatr Crit Care Med 2006;7(3):273–276.
Hjelm, M., et al., Evidence of inherited urea cycle defect in a case of fatal valproate toxicity.Br Med J (Clin Res Ed) 1986;292(6512):23–24.
Hjelm, M., et al., Valproate-induced inhibition of urea synthesis and hyperammonaemia in healthy subjects.Lancet 1986;2(8511):859.
Pellock, J.M., et al., Acute pancreatitis coincident with valproate use: a critical review.Epilepsia 2002;43(11):1421–1424.
Asconape, J.J., et al., Valproate-associated pancreatitis.Epilepsia 1993:34(1):177–183.
Pippenger CE, M.X., Rothner AD, Cruse RP, Erenberg G, and Solano R., Free radical scavenging enzyme activity profiles in risk assessment of idiosyncratic drug reactions. Idiosyncratic reactions to valproate: clinical risk patterns and mechanisms of toxicity, ed. L.R.a.P. JK.1991; New York: Raven Press Ltd. 75–88.
Underwood, T.W. and C.B. Frye, Drug-induced pancreatitis.Clin Pharm 1993 12(6):440–448.
Teich, M., et al., Factor XIII deficiency associated with valproate treatment.Epilepsia 2004;45(2):187–189.
Gerstner, T., et al., Valproate-associated coagulopathies are frequent and variable in children.Epilepsia 2006;47(7):1136–1143.
Gidal, B., et al., Valproate-mediated disturbances of hemostasis: relationship to dose and plasma concentration.Neurology 1994;44(8):1418–1422.
Sleiman, C., et al., Fatal pulmonary hemorrhage during high-dose valproate monotherapy.Chest 2000;117(2):613.
Winter, S.L., et al., Perioperative blood loss: the effect of valproate. PediatrNeurol 1996;15(1):19–22.
Bryant, A.E., 3rd and F.E. Dreifuss, Valproic acid hepatic fatalities. III. U.S. experience since 1986.Neurology 1996;46(2):465–469.
Dreifuss, F.E., et al., Valproic acid hepatic fatalities. II. US experience since 1984.Neurology 1989;39(2 Pt 1):201–207.
Werlin, S.L. and D.L. Fish, The spectrum of valproic acid-associated pancreatitis.Pediatrics 2006;118(4):1660–1663.
Spiller, H.A., et al., Multicenter case series of valproic acid ingestion: serum concentrations and toxicity.J Toxicol Clin Toxicol 2000;38(7):755–760.
Beauchamp, J., Oslon, K., Valproic Acid Overdose: A Retrospective Study Comparing Serum Drug Levels And The Incidence Of Adverse Outcomes.J Toxicol Clin Toxicol 1999;37:637–638.
Chyka, P.A. and D. Seger, Position statement: single-dose activated charcoal. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists.J Toxicol Clin Toxicol 1997;35(7):721–741.
Bell, E.A., et al., Treatment of valproic acid-associated hepatic failure with orthotopic liver transplantation.Ann Pharmacother 1992;26(1):18–21.
Steiman, G.S., R.W. Woerpel, and E.S. Sherard, Jr., Treatment of accidental sodium valproate overdose with an opiate antagonist.Ann Neurol 1979;6(3):274.
Mortensen, P.B., et al., Acute valproate intoxication: bio-chemical investigations and hemodialysis treatment.Int J Clin Pharmacol Ther Toxicol 1983;21(2):64–68.
Coulter, D.L., Carnitine and anticonvulsant drugs. L-carnitine in the pharmacotherapy of epilepsy1994;9–15.
Laub, M.C., I. Paetzke-Brunner, and G. Jaeger, Serum carnitine during valproic acid therapy.Epilepsia 1986;27(5):559–562.
Rebouche, C.J. and C.A. Chenard, Metabolic fate of dietary carnitine in human adults: identification and quantification of urinary and fecal metabolites.J Nutr 1991;121(4):539–546.
Harper, P., C.E. Elwin, and G. Cederblad, Pharmacokinetics of bolus intravenous and oral doses of L-carnitine in healthy subjects.Eur J Clin Pharmacol 1988;35(1):69–75.
Kielstein, J.T., et al., Efficiency of high-flux hemodialysis in the treatment of valproic acid intoxication.J Toxicol Clin Toxicol 2003;41(6):873–876.
Singh, S.M., et al., Extracorporeal management of valproic acid overdose: a large regional experience.J Nephrol 2004;17(1):43–49.
Hicks, L.K. and P.A. McFarlane, Valproic acid overdose and haemodialysis.Nephrol Dial Transplant,2001;16(7):1483–1486.
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Katiyar, A., Aaron, C. Case files of the Children’s Hospital of Michigan Regional Poison Control Center: The use of carnitine for the management of acute valproic acid toxicity. J. Med. Toxicol. 3, 129–138 (2007). https://doi.org/10.1007/BF03160923
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DOI: https://doi.org/10.1007/BF03160923