Dichloroacetic acid

Last updated
Dichloroacetic acid
Dichloroacetic-acid-2D-skeletal.png
Dichloroacetic-acid-3D-vdW.png
Names
Preferred IUPAC name
Dichloroacetic acid
Other names
Dichloroethanoic acid, bichloroacetic acid, DCA, BCA, dichloracetic acid, bichloracetic acid
Identifiers
3D model (JSmol)
1098596
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.001.098 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 201-207-0
2477
KEGG
MeSH Dichloroacetate
PubChem CID
RTECS number
  • AG6125000
UNII
UN number 1764
  • InChI=1S/C2H2Cl2O2/c3-1(4)2(5)6/h1H,(H,5,6) Yes check.svgY
    Key: JXTHNDFMNIQAHM-UHFFFAOYSA-N Yes check.svgY
  • InChI=1/C2H2Cl2O2/c3-1(4)2(5)6/h1H,(H,5,6)
    Key: JXTHNDFMNIQAHM-UHFFFAOYAK
  • ClC(Cl)C(O)=O
Properties
C2H2Cl2O2
Molar mass 128.94 g·mol−1
AppearanceColorless liquid
Density 1.5634 g/cm3 (20 °C)
Melting point 9 to 11 °C (48 to 52 °F; 282 to 284 K)
Boiling point 194 °C (381 °F; 467 K)
miscible
Solubility miscible with ethanol, diethyl ether [1]
Acidity (pKa)1.35 [1]
-58.2·10−6 cm3/mol
Thermochemistry
−496.3 kJ·mol−1 [1]
Hazards
GHS labelling:
GHS-pictogram-acid.svg GHS-pictogram-pollu.svg
Warning
H314, H400
P260, P264, P273, P280, P301+P330+P331, P303+P361+P353, P304+P340, P305+P351+P338, P310, P321, P363, P391, P405, P501
NFPA 704 (fire diamond)
NFPA 704.svgHealth 3: Short exposure could cause serious temporary or residual injury. E.g. chlorine gasFlammability 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g. canola oilInstability 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g. liquid nitrogenSpecial hazards (white): no code
3
1
0
Safety data sheet (SDS) MSDS (jtbaker)
Related compounds
Chloroacetic acid
Trichloroacetic acid
Related compounds
 Acetic acid
Difluoroacetic acid
Dibromoacetic acid
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

Dichloroacetic acid (DCA), sometimes called bichloroacetic acid (BCA), is the organic compound with formula CHCl2CO2H. It is an analogue of acetic acid, in which 2 of the 3 hydrogen atoms of the methyl group have been replaced by chlorine atoms. Like the other chloroacetic acids, it has various practical applications. The salts and esters of dichloroacetic acid are called dichloroacetates.

Contents

Reactions

The chemistry of dichloroacetic acid is typical for halogenated organic acids. It is an alkylating agent. It forms esters.

It is a member of the chloroacetic acids family. As such it is more acidic than acetic acid. It fully dissociates into dichloroacetate when dissolved in water, consistent with it pKa of 1.35, [1] pure dichloroacetic acid is classed as a strong organic acid; it is very corrosive and extremely destructive to tissues of the mucous membranes and upper respiratory tract via inhalation. [2]

Natural occurrence

DCA has been shown to occur in nature in at least one seaweed, Asparagopsis taxiformis [3] and also in the mushroom Russula nigricans . [4] It is a trace product of the chlorination of drinking water and is produced by the metabolism of various chlorine-containing drugs or chemicals. [5] DCA is typically prepared by the reduction of trichloroacetic acid (TCA). DCA is prepared from chloral hydrate also by the reaction with calcium carbonate and sodium cyanide in water followed by acidifying with hydrochloric acid. It can also be made by passing acetylene through solutions of hypochlorous acid.[ citation needed ]

As a laboratory reagent, both DCA and TCA are used as precipitants to prompt macromolecules such as proteins to precipitate out of solution.[ citation needed ]

Therapeutic uses

Salts of DCA have been studied as potential drugs because they inhibit the enzyme pyruvate dehydrogenase kinase. [6] Although preliminary studies found that DCA can slow the growth of certain tumors in animal studies and in vitro studies, as of 2012 insufficient evidence supported the use of DCA for cancer treatment. [7]

Lactic acidosis

A randomized controlled trial in children with congenital lactic acidosis found that while DCA was well tolerated, it was ineffective in improving clinical outcomes. [8] A separate trial of DCA in children with MELAS (a syndrome of inadequate mitochondrial function, leading to lactic acidosis) was halted early, as all 15 of the children receiving DCA experienced significant nerve toxicity without any evidence of benefit from the medication. [9] A randomized controlled trial of DCA in adults with lactic acidosis found that while DCA lowered blood lactate levels, it had no clinical benefit and did not improve hemodynamics or survival. [10]

Thus, while early case reports and pre-clinical data suggested that DCA might be effective for lactic acidosis, subsequent controlled trials have found no clinical benefit of DCA in this setting. In addition, clinical trial subjects were incapable of continuing on DCA as a study medication owing to progressive toxicities.

Cancer

In 2007 reports emerged in the press and via the Internet that Evangelos Michelakis and coworkers at the University of Alberta had found that dichloroacetic acid, or rather its sodium salt sodium dichloroacetate, reduced tumors in rats and killed cancer cells in vitro . A story in New Scientist sparked "unprecedented interest among readers", as it spoke of "a cheap and simple drug" that was "known to be relatively safe" and could kill most cancers. [11] An accompanying editorial pointed out that no drug company would be interested in getting the compound approved as a cancer treatment because it is unpatentable. [12] The magazine later published an article emphasizing the dangers involved, such as damage to nerves. [13] The US Food and Drug Administration began enforcing a law that prohibits the sale of substances with the suggestion that they are cancer treatments unless they have been approved by the FDA. [14]

The American Cancer Society in 2012 stated that "available evidence does not support the use of DCA for cancer treatment at this time." [7] Physicians warned of potential problems if people attempt to try DCA outside a controlled clinical trial. [15] One problem with attempting this is obtaining the chemical. One fraudster was sentenced to 33 months in prison for selling a white powder containing starch, but no DCA, to people with cancer. [16]

The only monitored in vivo dosage of five human patients with glioblastoma with DCA was not designed to test its efficacy against their cancer. This study was rather to see whether it could be given at a specific dosage safely without causing side effects (e.g. neuropathy). All five patients were receiving other treatments during the study. [17] [18] Observations in vitro and of tumours extracted from those five patients suggest that DCA might act against cancer cells by depolarising abnormal mitochondria found in glioblastoma cancer cells – allowing the mitochondria to induce apoptosis (cell death) of the malignant cells. [17] In vitro work with DCA on neuroblastomas (which have fewer recognised mitochondrial abnormalities) showed activity against malignant, undifferentiated cells. [19] A 2016 case report discusses and reviews the potential application of DCA in central nervous system malignancies. [20] A 2018 study found that DCA could trigger a metabolic switch from glycolysis (the Warburg effect) to mitochondrial OXPHOS and increase reactive oxygen stress affecting tumor cells. These effects were not observed in non-tumor cells. [21]

Neuropathy

Neuropathy has been a problem in some clinical trials with DCA causing them to be effectively halted, [9] but a 2008 BJC review found that it has not occurred in other DCA trials. [22] The mechanism of DCA induced neuropathy is not well understood. [23] On the one hand in vitro work with nerves has suggested a mechanism for the neuropathic effect of DCA; with DCA showing a dose and exposure dependent demyelination of nerves (stripping of the nerve 'sheath'), which demyelination was partially reversible over time, following washout of DCA. [24] On the other hand, the 2008 review in BJC [22] states "This neurotoxicity resembled the pattern of length-dependent, axonal, sensorimotor polyneuropathy without demyelination." with regard to the 2006 study by Kaufman et al. [9]

Heart failure

DCA has been investigated as a treatment for post-ischemic recovery. [25] There is also evidence that DCA improves metabolism by NADH production stimulation, but may lead to a depletion of NADH in normoxia. [26]

See also

Related Research Articles

<span class="mw-page-title-main">Lipoic acid</span> Chemical compound

Lipoic acid (LA), also known as α-lipoic acid, alpha-lipoic acid (ALA) and thioctic acid, is an organosulfur compound derived from caprylic acid (octanoic acid). ALA is made in animals normally, and is essential for aerobic metabolism. It is also manufactured and is available as a dietary supplement in some countries where it is marketed as an antioxidant, and is available as a pharmaceutical drug in other countries. Lipoate is the conjugate base of lipoic acid, and the most prevalent form of LA under physiological conditions. Only the (R)-(+)-enantiomer (RLA) exists in nature and is essential for aerobic metabolism because RLA is an essential cofactor of many enzyme complexes.

Pyruvic acid (IUPAC name: 2-oxopropanoic acid, also called acetoic acid) (CH3COCOOH) is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate base, CH3COCOO−, is an intermediate in several metabolic pathways throughout the cell.

<span class="mw-page-title-main">Mitochondrial disease</span> Spontaneously occurring or inherited disorder that involves mitochondrial dysfunction

Mitochondrial disease is a group of disorders caused by mitochondrial dysfunction. Mitochondria are the organelles that generate energy for the cell and are found in every cell of the human body except red blood cells. They convert the energy of food molecules into the ATP that powers most cell functions.

<span class="mw-page-title-main">Disulfiram</span> Chemical compound

Disulfiram is a medication used to support the treatment of chronic alcoholism by producing an acute sensitivity to ethanol. Disulfiram works by inhibiting the enzyme aldehyde dehydrogenase, causing many of the effects of a hangover to be felt immediately following alcohol consumption. Disulfiram plus alcohol, even small amounts, produces flushing, throbbing in the head and neck, a throbbing headache, respiratory difficulty, nausea, copious vomiting, sweating, thirst, chest pain, palpitation, dyspnea, hyperventilation, fast heart rate, low blood pressure, fainting, marked uneasiness, weakness, vertigo, blurred vision, and confusion. In severe reactions there may be respiratory depression, cardiovascular collapse, abnormal heart rhythms, heart attack, acute congestive heart failure, unconsciousness, convulsions, and death.

<span class="mw-page-title-main">Lactic acidosis</span> Metabolic medical condition

Lactic acidosis is a medical condition characterized by a build-up of lactate in the body, with formation of an excessively low pH in the bloodstream. It is a form of metabolic acidosis, in which excessive acid accumulates due to a problem with the body's oxidative metabolism.

<span class="mw-page-title-main">Tumor hypoxia</span> Situation where tumor cells have been deprived of oxygen

Tumor hypoxia is the situation where tumor cells have been deprived of oxygen. As a tumor grows, it rapidly outgrows its blood supply, leaving portions of the tumor with regions where the oxygen concentration is significantly lower than in healthy tissues. Hypoxic microenvironements in solid tumors are a result of available oxygen being consumed within 70 to 150 μm of tumour vasculature by rapidly proliferating tumor cells thus limiting the amount of oxygen available to diffuse further into the tumor tissue. In order to support continuous growth and proliferation in challenging hypoxic environments, cancer cells are found to alter their metabolism. Furthermore, hypoxia is known to change cell behavior and is associated with extracellular matrix remodeling and increased migratory and metastatic behavior.

<span class="mw-page-title-main">Leigh syndrome</span> Mitochondrial metabolism disease characterized by progressive loss of mental and movement abilities

Leigh syndrome is an inherited neurometabolic disorder that affects the central nervous system. It is named after Archibald Denis Leigh, a British neuropsychiatrist who first described the condition in 1951. Normal levels of thiamine, thiamine monophosphate, and thiamine diphosphate are commonly found, but there is a reduced or absent level of thiamine triphosphate. This is thought to be caused by a blockage in the enzyme thiamine-diphosphate kinase, and therefore treatment in some patients would be to take thiamine triphosphate daily. While the majority of patients typically exhibit symptoms between the ages of 3 and 12 months, instances of adult onset have also been documented.

<span class="mw-page-title-main">Cori cycle</span> Series of interconnected biochemical reactions

The Cori cycle, named after its discoverers, Carl Ferdinand Cori and Gerty Cori, is a metabolic pathway in which lactate, produced by anaerobic glycolysis in muscles, is transported to the liver and converted to glucose, which then returns to the muscles and is cyclically metabolized back to lactate.

In oncology, the Warburg effect is the observation that most cancer cells release energy predominantly not through the 'usual' citric acid cycle and oxidative phosphorylation in the mitochondria as observed in normal cells, but through a less efficient process of 'aerobic glycolysis' consisting of a high level of glucose uptake and glycolysis followed by lactic acid fermentation taking place in the cytosol, not the mitochondria, even in the presence of abundant oxygen. This observation was first published by Otto Heinrich Warburg, who was awarded the 1931 Nobel Prize in Physiology for his "discovery of the nature and mode of action of the respiratory enzyme". The precise mechanism and therapeutic implications of the Warburg effect, however, remain unclear.

<span class="mw-page-title-main">Pyruvate dehydrogenase lipoamide kinase isozyme 1</span> Protein-coding gene in the species Homo sapiens

Pyruvate dehydrogenase lipoamide kinase isozyme 1, mitochondrial is an enzyme that in humans is encoded by the PDK1 gene. It codes for an isozyme of pyruvate dehydrogenase kinase (PDK).

<span class="mw-page-title-main">Mitochondrial myopathy</span> Medical condition

Mitochondrial myopathies are types of myopathies associated with mitochondrial disease. Adenosine triphosphate (ATP), the chemical used to provide energy for the cell, cannot be produced sufficiently by oxidative phosphorylation when the mitochondrion is either damaged or missing necessary enzymes or transport proteins. With ATP production deficient in mitochondria, there is an over-reliance on anaerobic glycolysis which leads to lactic acidosis either at rest or exercise-induced.

<span class="mw-page-title-main">MELAS syndrome</span> Medical condition

Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is one of the family of mitochondrial diseases, which also include MIDD, MERRF syndrome, and Leber's hereditary optic neuropathy. It was first characterized under this name in 1984. A feature of these diseases is that they are caused by defects in the mitochondrial genome which is inherited purely from the female parent. The most common MELAS mutation is mitochondrial mutation, mtDNA, referred to as m.3243A>G.

Pyruvate dehydrogenase deficiency is a rare neurodegenerative disorder associated with abnormal mitochondrial metabolism. PDCD is a genetic disease resulting from mutations in one of the components of the pyruvate dehydrogenase complex (PDC). The PDC is a multi-enzyme complex that plays a vital role as a key regulatory step in the central pathways of energy metabolism in the mitochondria. The disorder shows heterogeneous characteristics in both clinical presentation and biochemical abnormality.

<span class="mw-page-title-main">Dihydrolipoyl transacetylase</span>

Dihydrolipoyl transacetylase is an enzyme component of the multienzyme pyruvate dehydrogenase complex. The pyruvate dehydrogenase complex is responsible for the pyruvate decarboxylation step that links glycolysis to the citric acid cycle. This involves the transformation of pyruvate from glycolysis into acetyl-CoA which is then used in the citric acid cycle to carry out cellular respiration.

Pyruvate carboxylase deficiency is an inherited disorder that causes lactic acid to accumulate in the blood. High levels of these substances can damage the body's organs and tissues, particularly in the nervous system. Pyruvate carboxylase deficiency is a rare condition, with an estimated incidence of 1 in 250,000 births worldwide. Type A of the disease appears to be much more common in some Algonkian Indian tribes in eastern Canada, while the type B disease is more present in European populations.

<span class="mw-page-title-main">Pyruvate dehydrogenase</span> Class of enzymes

Pyruvate dehydrogenase is an enzyme that catalyzes the reaction of pyruvate and a lipoamide to give the acetylated dihydrolipoamide and carbon dioxide. The conversion requires the coenzyme thiamine pyrophosphate.

<span class="mw-page-title-main">Pyruvate dehydrogenase kinase</span> Class of enzymes

Pyruvate dehydrogenase kinase is a kinase enzyme which acts to inactivate the enzyme pyruvate dehydrogenase by phosphorylating it using ATP.

<span class="mw-page-title-main">Lactate dehydrogenase</span> Class of enzymes

Lactate dehydrogenase (LDH or LD) is an enzyme found in nearly all living cells. LDH catalyzes the conversion of pyruvate to lactate and back, as it converts NAD+ to NADH and back. A dehydrogenase is an enzyme that transfers a hydride from one molecule to another.

<span class="mw-page-title-main">PDK2</span> Protein-coding gene in the species Homo sapiens

Pyruvate dehydrogenase kinase isoform 2 (PDK2) also known as pyruvate dehydrogenase lipoamide kinase isozyme 2, mitochondrial is an enzyme that in humans is encoded by the PDK2 gene. PDK2 is an isozyme of pyruvate dehydrogenase kinase.

<span class="mw-page-title-main">Mitochondrial pyruvate carrier 2</span> Protein-coding gene in the species Homo sapiens

Mitochondrial pyruvate carrier 2 (MPC2) also known as brain protein 44 (BRP44) is a protein that in humans is encoded by the MPC2 gene. It is a member of the Mitochondrial Pyruvate Carrier (MPC) protein family. This protein is involved in transport of pyruvate across the inner membrane of mitochondria in preparation for the pyruvate dehydrogenase reaction.

References

  1. 1 2 3 4 Haynes, William M., ed. (2011). CRC Handbook of Chemistry and Physics (92nd ed.). Boca Raton, FL: CRC Press. ISBN   1-4398-5511-0.
  2. ↑ "Dichloroacetic Acid". Hazard.com. 1998-04-21. Retrieved 2015-04-17.
  3. ↑ Archived April 16, 2015, at the Wayback Machine
  4. ↑ Lajin, B.; Braeuer, S.; Borovička, J.; Goessler, W. (2021). "Is the water disinfection by-product dichloroacetic acid biosynthesized in the edible mushroom Russula nigricans?". Chemosphere. 281: 130819. Bibcode:2021Chmsp.281m0819L. doi: 10.1016/j.chemosphere.2021.130819 . PMID   33991903.
  5. ↑ Stacpoole, Peter W.; Henderson, George N.; Yan, Zimeng; James, Margaret O. (1998). "Clinical Pharmacology and Toxicology of Dichloroacetate". Environmental Health Perspectives. 106 (Suppl 4): 989–94. doi:10.1093/jnci/djx071. JSTOR   3434142. PMC   1533324 . PMID   9703483.
  6. ↑ Stacpoole, Peter W. (2017). "Therapeutic Targeting of the Pyruvate Dehydrogenase Complex/Pyruvate Dehydrogenase Kinase (PDC/PDK) Axis in Cancer". JNCI: Journal of the National Cancer Institute. 109 (11). doi: 10.1093/jnci/djx071 . PMID   29059435.
  7. 1 2 "Dichloracetate (DCA)". American Cancer Society. Retrieved 1 December 2012.
  8. ↑ Stacpoole, P. W.; Kerr, D. S.; Barnes, C; Bunch, S. T.; Carney, P. R.; Fennell, E. M.; Felitsyn, N. M.; Gilmore, R. L.; Greer, M; Henderson, G. N.; Hutson, A. D.; Neiberger, R. E.; O'Brien, R. G.; Perkins, L. A.; Quisling, R. G.; Shroads, A. L.; Shuster, J. J.; Silverstein, J. H.; Theriaque, D. W.; Valenstein, E (2006). "Controlled Clinical Trial of Dichloroacetate for Treatment of Congenital Lactic Acidosis in Children". Pediatrics. 117 (5): 1519–31. doi:10.1542/peds.2005-1226. PMID   16651305. S2CID   38328451.
  9. 1 2 3 Kaufmann, P.; Engelstad, K.; Wei, Y.; Jhung, S.; Sano, M. C.; Shungu, D. C.; Millar, W. S.; Hong, X.; Gooch, C. L.; Mao, X.; Pascual, J. M.; Hirano, M.; Stacpoole, P. W.; Dimauro, S.; De Vivo, D. C. (2006). "Dichloroacetate causes toxic neuropathy in MELAS: A randomized, controlled clinical trial". Neurology. 66 (3): 324–30. doi:10.1212/01.wnl.0000196641.05913.27. PMID   16476929. S2CID   19623200.
  10. ↑ Stacpoole, Peter W.; Wright, Elizabeth C.; Baumgartner, Thomas G.; Bersin, Robert M.; Buchalter, Scott; Curry, Stephen H.; Duncan, Charles A.; Harman, Eloise M.; Henderson, George N.; Jenkinson, Steven; Lachin, John M.; Lorenz, Anthea; Schneider, Stephen H.; Siegel, John H.; Summer, Warren R.; Thompson, Douglas; Wolfe, Christopher L.; Zorovich, Barbara (1992). "A Controlled Clinical Trial of Dichloroacetate for Treatment of Lactic Acidosis in Adults". New England Journal of Medicine. 327 (22): 1564–9. doi: 10.1056/NEJM199211263272204 . PMID   1435883.
  11. ↑ Andy Coghlan (Jan 17, 2007). "Cheap, 'safe' drug kills most cancers". New Scientist. Archived from the original on June 12, 2019. The original article did not have quotation marks around the word "safe".
  12. ↑ "No patent? No cancer drug development". New Scientist. Jan 17, 2007.
  13. ↑ Linda Geddes (Mar 31, 2019). "Cancer therapy: When all else fails". New Scientist.
  14. ↑ "'Cancer drug' site shut down". New Scientist. Jul 25, 2007.
  15. ↑ Andrea Sands (March 18, 2007). "Patients tout database for drug treatment". Edmonton Journal. p. A13. "If it starts going badly, who is following you before it gets out of control? By the time you realize your liver is failing, you're in big trouble", said Laura Shanner, Associate Professor of Health Ethics at the University of Alberta.
  16. ↑ "Canadian Man Sentenced to 33 Months in Prison for Selling Counterfeit Cancer Drugs Using the Internet". US Department of Justice. 25 August 2010. Retrieved January 5, 2018.
  17. 1 2 Michelakis, E. D.; Sutendra, G.; Dromparis, P.; Webster, L.; Haromy, A.; Niven, E.; Maguire, C.; Gammer, T. L.; MacKey, J. R.; Fulton, D.; Abdulkarim, B.; McMurtry, M. S.; Petruk, K. C. (2010). "Metabolic Modulation of Glioblastoma with Dichloroacetate". Science Translational Medicine. 2 (31): 31ra34. doi:10.1126/scitranslmed.3000677. PMID   20463368. S2CID   616711.
  18. ↑ Archived February 18, 2011, at the Wayback Machine
  19. ↑ Vella, Serena; Conti, Matteo; Tasso, Roberta; Cancedda, Ranieri; Pagano, Aldo (2012). "Dichloroacetate inhibits neuroblastoma growth by specifically acting against malignant undifferentiated cells". International Journal of Cancer. 130 (7): 1484–93. doi:10.1002/ijc.26173. PMID   21557214. S2CID   19111145.
  20. ↑ Lemmo, W; Tan, G (2016). "Prolonged Survival After Dichloroacetate Treatment of Non-Small-Cell Lung Carcinoma-Related Leptomeningeal Carcinomatosis". Journal of Medical Cases. 7 (4): 136–142. doi: 10.14740/jmc2456w .
  21. ↑ Zhou, Li; Liu, Lianlian; Chai, Wei; Zhao, Ting; Jin, Xin; Guo, Xinxin; Han, Liying; Yuan, Chunli (February 2019). "Dichloroacetic acid upregulates apoptosis of ovarian cancer cells by regulating mitochondrial function". OncoTargets and Therapy. 12: 1729–1739. doi: 10.2147/ott.s194329 . PMC   6419601 . PMID   30881027.
  22. 1 2 Michelakis, E D; Webster, L; MacKey, J R (2008). "Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer". British Journal of Cancer. 99 (7): 989–94. doi:10.1038/sj.bjc.6604554. PMC   2567082 . PMID   18766181.
  23. ↑ Archived April 6, 2015, at the Wayback Machine
  24. ↑ Felitsyn, Natalia; Stacpoole, Peter W.; Notterpek, Lucia (2007). "Dichloroacetate causes reversible demyelination in vitro: Potential mechanism for its neuropathic effect". Journal of Neurochemistry. 100 (2): 429–36. doi: 10.1111/j.1471-4159.2006.04248.x . PMID   17241159.
  25. ↑ McVeigh JJ, Lopaschuk GD (Oct 1990). "Dichloroacetate stimulation of glucose oxidation improves recovery of ischemic rat hearts". Am J Physiol. 259 (4 Pt 2): H1079-85. doi:10.1152/ajpheart.1990.259.4.H1079. PMID   2221115.
  26. ↑ Jaimes, R 3rd (Jul 2015). "Functional response of the isolated, perfused normoxic heart to pyruvate dehydrogenase activation by dichloroacetate and pyruvate". Pflügers Arch. 468 (1): 131–42. doi:10.1007/s00424-015-1717-1. PMC   4701640 . PMID   26142699.{{cite journal}}: CS1 maint: numeric names: authors list (link)
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