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American Journal of Medical Sciences and Medicine. 2020, 8(1), 1-5
DOI: 10.12691/ajmsm-8-1-1
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Dichloroacetate is Cardiotonic and Suggested for Treating Metabolic Acidosis: Alleviating Lactate Effects and Beta-ketothiolase Deficiency (An Original Article)

Amr El-Dardear1, Elsayed Abdelkreem2, Hussam Baghdadi3, Naif Aljuhani4, Osama Alhadramy5, Mohammed Hassan2, Faten M. Omran6, Hytham Mahmoud Abdel-Latif6, Wafaa A. Abdellah6, Azza Mahmoud Ahmed Abouelella6, Mohamed Abdel-haleem7, Momen El-shazley8, 9, Manal Mohamed Helmy Nabo10 and Salah Mohamed El Sayed3, 11,

1Department of Pediatrics, Taibah Faculty of Medicine, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia

2Department of Pediatrics, Faculty of Medicine, Sohag University, Sohag, Egypt

3Department of Clinical Biochemistry and Molecular Medicine, Taibah Faculty of Medicine, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia

4Department of Pharmacology and Toxicology, Faculty of Pharmacy, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia

5Division of Cardiology, Department of Medicine, Taibah College of Medicine, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia

6Department of Medical Pharmacology, Sohag Faculty of Medicine, Sohag University, Egypt

7Department of Ear, Nose and Throat, Taibah Faculty of Medicine, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia

8Department of Medicine, Taibah College of Medicine, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia

9Department of Occupational Diseases and Toxigenomics, Sohag Faculty of Medicine, Sohag University, Egypt

10Division of Pediatric Cardiology, Sohag Teaching Hospital, Sohag, Egypt

111Department of Medical Biochemistry, Sohag Faculty of Medicine, Sohag University, Egypt

Pub. Date: January 22, 2020

Cite this paper:
Amr El-Dardear, Elsayed Abdelkreem, Hussam Baghdadi, Naif Aljuhani, Osama Alhadramy, Mohammed Hassan, Faten M. Omran, Hytham Mahmoud Abdel-Latif, Wafaa A. Abdellah, Azza Mahmoud Ahmed Abouelella, Mohamed Abdel-haleem, Momen El-shazley, Manal Mohamed Helmy Nabo and Salah Mohamed El Sayed. Dichloroacetate is Cardiotonic and Suggested for Treating Metabolic Acidosis: Alleviating Lactate Effects and Beta-ketothiolase Deficiency (An Original Article). American Journal of Medical Sciences and Medicine. 2020; 8(1):1-5. doi: 10.12691/ajmsm-8-1-1


Dichloroacetate (DCA) is an acetate analog that was reported to improve the hemodynamic functions and mechanical efficiency in patients with congestive heart failure. DCA is also known for decades as an activator of pyruvate dehydrogenase (stimulates oxidation of pyruvate to acetyl CoA). This prevents lactate accumulation (stimulating conversion of lactate to form pyruvate then acetyl CoA). Currently, DCA is an effective and safe drug for treating lactic acidosis, a clinical condition due to the accumulation of hydrogen (H+) ions from lactic acid, characterized by blood lactate levels > 5 mM and arterial pH < 7.25. Interestingly, DCA was reported to cause a significant decrease in serum lactate that was accompanied by an increase in arterial blood pH. Moreover, DCA decreases blood lactate levels under various conditions in both man and laboratory animals via diverting pyruvate metabolism (source of lactate) towards oxidation through activating the target enzyme pyruvate dehydrogenase. High serum lactate (due to anerobic metabolism or as a side effect of insulin/glucose therapy) may occur during treatment of beta ketothiolase deficiency (BKTD). In some BKTD patients, serum lactate may increase contributing to the refractory metabolic acidosis. DCA minimized ketone bodies formation (benefits BKTD patients) but not elimination that can be achieved by insulin/glucose treatment. Current insulin/glucose treatment (for BKTD) causes increased glycolysis (i.e. increased lactate production and metabolic acidosis). On biochemical, pharmacological and medical bases, we suggest that can be normalized upon combining insulin/glucose treatment with DCA. In phenformin-induced lactic acidosis, DCA therapy increased arterial pH and bicarbonate, increased intracellular liver pH and cardiac index causing a fall in blood lactate. In hepatectomy-induced lactic acidosis, animals treated with DCA exhibited stabilization of cardiac index, decreased blood lactate, and decreased mortality. That was better in outcome than sodium bicarbonate treatment. We suggest that DCA may exert pharmacological antagonism with ketone bodies effects e.g. acidosis. DCA may be a promising evidence-based adjuvant therapy for acute refractory metabolic acidosis conditions as BKTD and lactic acidosis.

Dichloroacetate beta-ketothiolase deficiency lactate lactic acidosis ketone bodies acidosis isoleucine

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[1]  Bersin RM, Stacpoole PW. Dichloroacetate as metabolic therapy for myocardial ischemia and failure. Am Heart J. 1997 Nov; 134(5 Pt 1): 841-55.
[2]  Stacpoole PW, Wright EC, Baumgartner TG, Bersin RM, Buchalter S, Curry SH, Duncan CA, Harman EM, Henderson GN, Jenkinson S, et al. A controlled clinical trial of dichloroacetate for treatment of lactic acidosis in adults. The Dichloroacetate-Lactic Acidosis Study Group. N Engl J Med. 1992 Nov 26; 327(22): 1564-9.
[3]  Barak C, Reed MK, Maniscalco SP, Sherry AD, Malloy CR, Jessen ME. Effects of dichloroacetate on mechanical recovery and oxidation of physiologic substrates after ischemia and reperfusion in the isolated heart. J Cardiovasc Pharmacol. 1998 Mar; 31(3): 336-44.
[4]  Arnon S, Litmanovits I, Regev R, Elpeleg O, Dolfin T. Dichloroacetate treatment for severe refractory metabolic acidosis during neonatal sepsis. Pediatr Infect Dis J. 2001 Feb; 20(2): 218-9.
[5]  Fukao T, Sasai H, Aoyama Y, Otsuka H, Ago Y, Matsumoto H, Abdelkreem E. Recent advances in understanding beta-ketothiolase (mitochondrial acetoacetyl-CoA thiolase, T2) deficiency. J Hum Genet. 2019 Feb; 64(2): 99-111.
[6]  Vakili R, Hashemian S. A Novel Mutation of Beta-ketothiolase Deficiency: The First Report from Iran and Review of Literature. Iran J Child Neurol. 2018 Summer; 12(3): 113-121.
[7]  Reddy N, Calloni SF, Vernon HJ, Boltshauser E, Huisman TAGM, Soares BP. Neuroimaging Findings of Organic Acidemias and Aminoacidopathies. Radiographics. 2018 May-Jun; 38(3): 912-931.
[8]  Shiasi Arani K, Soltani B. First Report of 3-Oxothiolase Deficiency in Iran, Int J Endocrinol Metab. 2014; 12(2):e10960.
[9]  Fukao T. Beta-ketothiolase deficiency. Orphanet encyclopedia, September 2001. › data › patho › uk-T2.
[10]  Graf H, Leach W, Arieff A I. Effects of dichloroacetate in the treatment of hypoxic lactic acidosis in dogs. J Clin Invest. 1985 Sep; 76(3): 919-923.
[11]  Blackshear PJ, Fang LS, Axelrod L. Treatment of severe lactic acidosis with dichloroacetate. Diabetes Care. 1982 Jul-Aug; 5(4): 391-4.
[12]  McAllister A, Allison SP, Randle PJ. Effects of dichloroacetate on the metabolism of glucose, pyruvate, acetate, 3-hydroxybutyrate and palmitate in rat diaphragm and heart muscle in vitro and on extraction of glucose, lactate, pyruvate and free fatty acids by dog heart in vivo. Biochem J. 1973 Aug; 134(4): 1067-81.
[13]  Li Q, Liu X, Yin Y, Zheng JT, Jiang CF, Wang J, Shen H, Li CY, Wang M, Liu LZ, Jiang BH. Insulin regulates glucose consumption and lactate production through reactive oxygen species and pyruvate kinase M2. Oxid Med Cell Longev. 2014; 2014: 504953.
[14]  Backshear PJ, Holloway PA, Alberti KG. Metabolic interactions of dichloroacetate and insulin in experimental diabetic ketoacidosis. Biochem J. 1975 Feb; 146(2): 447-56.
[15]  Shangraw RE, Lohan-Mannion D, Hayes A, Moriarty RM, Fu R, Robinson ST. Dichloroacetate stabilizes the intraoperative acid-base balance during liver transplantation. Liver Transpl. 2008 Jul; 14(7): 989-98.
[16]  Preiser JC, Moulart D, Vincent JL. Dichloroacetate administration in the treatment of endotoxin shock. Circ Shock. 1990 Mar; 30(3): 221-8.
[17]  Gin-Shaw SL, Barsan WG, Eymer V, Hedges J. Effects of dichloroacetate following canine asphyxial arrest. Ann Emerg Med. 1988 May; 17(5): 473-7.
[18]  Schneider SH, Komanicky PM, Goodman MN, Ruderman NB. Dichloroacetate: effects on exercise endurance in untrained rats. Metabolism. 1981 Jun; 30(6): 590-5.
[19]  Park R, Arieff AI.Treatment of lactic acidosis with dichloroacetate in dogs. J Clin Invest. 1982 Oct; 70(4): 853-62.
[20]  Strum SB, Adalsteinsson O, Black RR, Segal D, Peress NL, Waldenfels J. Case report: Sodium dichloroacetate (DCA) inhibition of the "Warburg Effect" in a human cancer patient: complete response in non-Hodgkin's lymphoma after disease progression with rituximab-CHOP. J Bioenerg Biomembr. 2013 Jun; 45(3): 307-15.
[21]  Yang, Y, Jiang SH, Shuang Liu, Han XY,Wang Y, Wang LL, and Bin Yu. Two Infants With Beta-Ketothiolase Deficiency Identified by Newborn Screening in China. Front Genet. 2019; 10: 451.
[22]  Köse MD, Canda E, Kağnıcı M, İşgüder R, Ünalp A, Uçar SK, Bahr L, Britschgi C, Sass JO, Çoker M. Two Siblings with Beta-Ketothiolase Deficiency: One Genetic Defect Two Different Pictures. J Pediatr Res 2016; 3(2): 113-116.
[23]  Nielsen J, Ytrebø LM, Borud O. Lactate and pyruvate concentrations in capillary blood from newborns. Acta Paediatr. 1994 Sep; 83(9): 920-2.
[24]  Otsuka H, Sasai H, Abdelkreem E, Kawamoto N, Kawamoto M, Kamiya T, Tanimoto Y, Kikuchi A, Kure S, Numakura C, Hayasaka K, Fukao T. Effectiveness of Medium-Chain Triglyceride Oil Therapy in Two Japanese Citrin-Deficient Siblings: Evaluation Using Oral Glucose Tolerance Tests. Tohoku J Exp Med. 2016 Dec; 240(4): 323-328.
[25]  Blackshear PJ, Holloway PA, Alberti KG. The metabolic effects of sodium dichloroacetate in the starved rat. Biochem J. 1974 Aug; 142(2): 279-86.
[26]  Ward RA, Wathen RL, Harding GB, Thompson LC. Comparative metabolic effects of acetate and dichloroacetate infusion in the anesthetized dog. Metabolism. 1985 Jul; 34(7): 680-7.
[27]  Ribes G, Valette G, Loubatieres-Mariani MM. Metabolic effects of sodium dichloroacetate in normal and diabetic dogs. Diabetes. 1979 Sep; 28(9): 852-7.
[28]  James MO, Jahn SC, Zhong G, Smeltz MG, Hu Z, Stacpoole PW. Therapeutic applications of dichloroacetate and the role of glutathione transferase zeta-1. Pharmacol Ther. 2017 Feb; 170: 166-180.
[29]  Bull RJ, Sanchez IM, Nelson MA, Larson JL, Lansing AJ. Liver tumor induction in B6C3F1 mice by dichloroacetate and trichloroacetate. Toxicology. 1990 Sep; 63(3): 341-59.
[30]  Flavin DF. Non-Hodgkin's Lymphoma Reversal with Dichloroacetate. J Oncol. 2010; 2010. pii: 414726.