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Dichloroacetate
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'''Dichloroacetate''' or '''dichloroacetic acid''' or '''DCA''' is an analogue of acetic acid. Salts of DCA such as [[#Sodium_dichloroacetate|sodium dichloroacetate]] may be used as drugs because they inhibit [[pyruvate dehydrogenase kinase]] and boost or restore the function of mitochondria (cellular power plants).<ref name="pubchem">{{Cite web | url = https://dcaguide.org/dca-information/what-is-dca/ | title = What is DCA ? | last = |website=DCA Guide|language=en|access-date=2021-05-27 | date = | first = | authorlink = |archive-url=|archive-date=|url-status=live}}</ref> ==Sodium dichloroacetate== Sodium dichloroacetate is most popular and most researched form of DCA and was investigated in pilot trials as a possible treatment for [[ME/CFS]]. The first open-label pilot trial examined 22 patients (14 women, 8 men, mean age 43.3) suffering from long-lasting ME/CFS. The study found that 10 patients responded well, their score on the Fatigue severity scale decreased at least by 40%.<ref name="Comhaire2018a">{{Cite web | url = https://pubmed.ncbi.nlm.nih.gov/29602463/ | title = Treating Patients Suffering From Myalgic Encephalopathy/Chronic Fatigue Syndrome (ME/CFS) With Sodium Dichloroacetate: An Open-Label, Proof-Of-Principle Pilot Trial | last = Comhaire | first = F | authorlink = Frank Comhaire | date = May 2018 | website = Medical hypotheses |language=en|pmid=29602463|archive-url=|archive-date=|url-status=|access-date=2020-05-21}}</ref> Soon after the trial, members from of a ME/CFS community forum also shared their experiences with the substance, some of them positive.<ref name="PR58184">{{Cite web | url = https://forums.phoenixrising.me/threads/treating-patients-suffering-from-me-cfs-with-sodium-dichloroacetate-pilot-trial.58184/ | title = DISCUSSION: Treating patients suffering from ME/CFS with sodium dichloroacetate (pilot trial) | website = Phoenix Rising ME/CFS Forums|language=en-US|access-date=2021-05-29}}</ref> ===Molecular formulas=== *{{Chem2|C2H2Cl2O2}} [[File:DCA molecule.jpg|alt=Molecule of DCA (Sodium dichloroacetate)|left|thumb]] ==Uses== DCA, salts of dichloracetic acid, have been discovered in the 1960s. Since then the compound has been intensively researched. In 1983 it has been confirmed to be a potential remedy in treating congenital children mitochondrial disorders.<ref name="Stacpoole1983">{{Cite journal | last = Stacpoole | first = Peter W. | last2 = Harman | first2 = Eloise M. | last3 = Curry | first3 = Stephen H. | last4 = Baumgartner | first4 = Thomas G. | last5 = Misbin | first5 = Robert I. | date = 1983-08-18 | title = Treatment of Lactic Acidosis with Dichloroacetate | url =http://www.nejm.org/doi/abs/10.1056/NEJM198308183090702|journal=New England Journal of Medicine|language=en|volume=309|issue=7 | pages = 390–396|doi=10.1056/NEJM198308183090702|issn=0028-4793}}</ref> Up till now, dozens of studies have proven that DCA can be useful in managing illnesses such as elevated serum cholesterol and triglycerides, [[diabetes]], [[amyotrophic lateral sclerosis]], pulmonary arterial hypertension, [[chronic fatigue syndrome]], [[endometriosis]] and some forms of cancer.<ref name="Comhaire2018a" /><ref name="Moore1979">{{Cite journal | last = Moore | first = George W. | authorlink = | last2 = Swift | first2 = Larry L. | authorlink2 = | last3 = Rabinowitz | first3 = David | authorlink3 = | last4 = Crofford | first4 = Oscar B. | authorlink4 = | last5 = Oates | first5 = John A. | author-link5 = | last6 = Stacpoole | first6 = Peter W. | author-link6 = | date = Jul 1979 | title = Reduction of serum cholesterol in two patients with homozygous familial hypercholesterolemia by dichloroacetate | url =https://linkinghub.elsevier.com/retrieve/pii/0021915079901801|journal=Atherosclerosis|language=en|volume=33|issue=3 | pages = 285–293|doi=10.1016/0021-9150(79)90180-1|pmc=|pmid=|access-date=|quote=|via=}}</ref><ref name="Stacpoole1978">{{Cite journal | last = Stacpoole | first = Peter W. | last2 = Moore | first2 = George W. | last3 = Kornhauser | first3 = David M. | date = 1978-03-09 | title = Metabolic Effects of Dichloroacetate in Patients with Diabetes Mellitus and Hyperlipoproteinemia | url = http://www.nejm.org/doi/abs/10.1056/NEJM197803092981002|journal=New England Journal of Medicine|language=en|volume=298|issue=10 | pages = 526–530|doi=10.1056/NEJM197803092981002|issn=0028-4793}}</ref><ref name="Miquel2012">{{Cite journal | last = Miquel | first = Ernesto | last2 = Cassina | first2 = Adriana | last3 = Martínez-Palma | first3 = Laura | last4 = Bolatto | first4 = Carmen | last5 = Trías | first5 = Emiliano | last6 = Gandelman | first6 = Mandi | last7 = Radi | first7 = Rafael | last8 = Barbeito | first8 = Luis | last9 = Cassina | first9 = Patricia | date = 2012-04-03 |editor-last = Ferreira|editor-first = Sergio T. | title = Modulation of Astrocytic Mitochondrial Function by Dichloroacetate Improves Survival and Motor Performance in Inherited Amyotrophic Lateral Sclerosis |url =https://dx.plos.org/10.1371/journal.pone.0034776|journal=PLoS ONE|language=en|volume=7|issue=4| pages = e34776|doi=10.1371/journal.pone.0034776|issn=1932-6203|pmc=PMC3318006|pmid=22509356}}</ref><ref name="Michelakis2017">{{Cite journal | last = Michelakis | first = Evangelos D. | last2 = Gurtu | first2 = Vikram | last3 = Webster | first3 = Linda | last4 = Barnes | first4 = Gareth | last5 = Watson | first5 = Geoffrey | last6 = Howard | first6 = Luke | last7 = Cupitt | first7 = John | last8 = Paterson | first8 = Ian | last9 = Thompson | first9 = Richard B. | date = 2017-10-25 | title = Inhibition of pyruvate dehydrogenase kinase improves pulmonary arterial hypertension in genetically susceptible patients |url =https://stm.sciencemag.org/lookup/doi/10.1126/scitranslmed.aao4583|journal=Science Translational Medicine|language=en|volume=9|issue=413| pages = eaao4583|doi=10.1126/scitranslmed.aao4583|issn=1946-6234}}</ref><ref name="Leow2021">{{Cite journal | last = Leow|first = H. W. | authorlink = | last2 = Koscielniak | first2 = M. | authorlink2 = | last3 = Williams | first3 = L. | authorlink3 = | last4 = Saunders | first4 = P. T. K. | authorlink4 = | last5 = Daniels | first5 = J. | author-link5 = | last6 = Doust | first6 = A.M. | author-link6 = | last7 = Jones | first7 = M-C | last8 = Ferguson | first8 = G.D. | last9 = Bagger | first9 = Y. | date = Dec 2021 | title = Dichloroacetate as a possible treatment for endometriosis-associated pain: a single-arm open-label exploratory clinical trial (EPiC) | url = https://pilotfeasibilitystudies.biomedcentral.com/articles/10.1186/s40814-021-00797-0|journal=Pilot and Feasibility Studies|language=en|volume=7|issue=1 | pages = 67|doi=10.1186/s40814-021-00797-0|issn=2055-5784|pmc=PMC7953373|pmid=33712086|access-date=|quote=|via=}}</ref><ref name="Michelakis2010">{{Cite journal | last = Michelakis | first = E.D. | last2 = Sutendra | first2 = G. | last3 = Dromparis | first3 = P. | last4 = Webster | first4 = L. | last5 = Haromy | first5 = A. | last6 = Niven | first6 = E. | last7 = Maguire | first7 = C. | last8 = Gammer | first8 = T.L. | last9 = Mackey | first9 = J.R. | date = 2010-05-12 | title = Metabolic Modulation of Glioblastoma with Dichloroacetate | url =https://stm.sciencemag.org/lookup/doi/10.1126/scitranslmed.3000677|journal=Science Translational Medicine|language=en|volume=2|issue=31 | pages = 31ra34–31ra34 |doi=10.1126/scitranslmed.3000677|issn=1946-6234}}</ref> In 1989, Canada approved DCA for applying to the skin for treating warts and for "cauterization and removal of a wide variety of skin and tissue lesions", though this was cancelled post-market.<ref name="drugbank">{{Cite web | url = https://go.drugbank.com/drugs/DB08809 | title = Dichloroacetic acid|website=DrugBank|access-date=2021-05-29}}</ref> ==Endometriosis== Recently, dichloroacetate has been described as a potential breakthrough treatment for [[endometriosis]]. It has been shown to reduce pain from endometriosis and also reduce the size of lesions associated with endometriosis.<ref name="Horne2019">{{Cite journal | title = Repurposing dichloroacetate for the treatment of women with endometriosis| date = 2019-12-17 | url = https://pnas.org/doi/full/10.1073/pnas.1916144116|journal=Proceedings of the National Academy of Sciences|volume=116|issue=51|pages=25389–25391|last=Horne | first = Andrew W. | last2 = Ahmad | first2 = S. Furquan | last3 = Carter | first3 = Roderick|last4=Simitsidellis | first4 = Ioannis | last5 = Greaves | first5 =Erin|last6=Hogg | first6 = Chloe|last7=Morton | first7 = Nicholas M. | last8=Saunders | first8 = Philippa T. K.|language=en|doi=10.1073/pnas.1916144116|pmc=PMC6925989|pmid=31792175|issn=0027-8424}}</ref><ref name="Devlin2023News">{{Cite news| title = Researchers optimistic about potential new treatment for endometriosis | first = Hannah | last = Devlin | date = Mar 8, 2023 | url = https://www.theguardian.com/society/2023/mar/08/endometriosis-new-treatment-non-hormonal-drug-dichloroacetate| publisher = The Guardian | access-date=2023-03-09}}</ref> Currently sodium dichloroacetate is approved in [[Canada]] as an orphan-drug, the only way of treating children with inborn mitochondrial-errors. It is also used off-label in alternative cancer clinics in North America, South America and Europe.<ref name="arcadia">{{Cite web | url = https://www.arcadia-praxisklinik.de/en/cancer-therapies/ | title = Cancer Therapies|website=Arcadia Praxisklinik|language=en-US|access-date=2021-05-29}}</ref> ==Theory== Sodium dichloroacetate is a molecule that can enter our cells. The living cells of most organisms have specialized structures that make chemical energy in our body, the mitochondria. Once DCA enters the mitochondria, it inhibits the enzyme [[pyruvate dehydrogenase kinase]]. After this enzyme is halted, it stops blocking the pyruvate dehydrogenase enzyme. As a result this increases the energy output in our cells.<ref>{{Cite web | url = https://dcaguide.org/dca-information/how-dca-works/ | title = How DCA works ? | website = DCA Guide|language=en-US|access-date=2021-05-29}}</ref> It is thought that many sufferers of ME/CFS have mitochondrial dysfunction resulting from epigenetic, immunologic and inflammatory factors. Restoring the function of impaired mitochondria could potentially alleviate the symptoms of this disease.<ref name="Comhaire2018a" /> ==Evidence== Open-label pilot trial done in Belgium with 22 patients suffering from ME/CFS had favorable results. The [[Fatigue Severity Scale]] score decreased at least by 40% in 10 out of 22 patients.<ref name="Comhaire2018a" /> Anecdotal evidence from the members of Phoenix Rising forum, the results range from none, to positive or dramatic improvement.<ref name="PR58184" /> ===Formula used in the trials=== DCA and its most popular form sodium dichloroacetate were used in the ME/CFS pilot trials. Both powder and capsules were found to be acceptable. The DCA purity used in the pilot trial for ME/CFS treatment was 99.9%. The full nutraceutical formula was never revealed, however, based on the available literature it looked something like this: * DCA 400 mg * [[thiamine|Vitamin B1]] (thiamine) 100 mg * Alpha-lipoic acid 100 mg * Oxidoreductase [[ubiquinone]] (Q10) 50 mg The formula was taken for 30 days straight. However, if symptom relief is not achieved after a month, DCA could be taken 5 days straight with a 2 day break at the end of the week. Researchers stated these cycles should be repeated every week for symptom control. ==Risks and safety== Dichloroacetic acid is a strong acid and sodium dichloroacetate is the form closest to getting FDA-approved registration for other uses, and has the most extensively studied safety data.<ref>{{Cite web | url = https://grantome.com/grant/NIH/R01-FD005407-02 | title = Phase 3 Trial of DCA in PDC Deficiency IND 028,625 (02/04/2015) | last = | first = | authorlink = | date = | website = grantome.com|archive-url=|archive-date=|url-status=|access-date=May 29, 2012}}</ref> Nevertheless, additional trials are needed to draw further conclusions. A side effect reported by Comhaire (2018) was [[tremor]]s.<ref name="Comhaire2018a" /> ==Costs and availability== DCA and its most popular form '''sodium dichloroacetate''' are available in naturopath clinics, as an off-label drug in Canada or on the internet. It is a non-patentable generic drug that can be freely transported all around the world. Daily dose of DCA with the additional supplements in the nutraceutical formula cost about $1-2 daily. Dichloroacetate is approved in [[Canada]] as an orphan-drug, and used off-label in alternative cancer clinics in North America, South America and Europe.<ref name="arcadia" /> ==Notable studies and publications== *2018, Treating patients suffering from myalgic encephalopathy/chronic fatigue syndrome (ME/CFS) with sodium dichloroacetate: An open-label, proof-of-principle pilot trial<ref name="Comhaire2018a" /> - [[pubmed:29602463|(Full text)]] * 2018, Why do some ME/CFS patients benefit from treatment with sodium dichloroacetate, but others do not?<ref name="Comhaire2018b">{{Cite journal | last = Comhaire | first = Frank | date = 2018-11-01 | title = Why do some ME/CFS patients benefit from treatment with sodium dichloroacetate, but others do not? | url = http://www.sciencedirect.com/science/article/pii/S0306987718307734|journal=Medical Hypotheses|language=en|volume=120 | pages = 65–67|doi=10.1016/j.mehy.2018.08.014|issn=0306-9877}}</ref> - [https://www.sciencedirect.com/science/article/pii/S0306987718307734 (Full text)] ==News and articles == * 2023, [https://www.theguardian.com/society/2023/mar/08/endometriosis-new-treatment-non-hormonal-drug-dichloroacetate Researchers optimistic about potential new treatment for endometriosis] - The Guardian ==See also== *[[Mitochondrion]] ==Learn more== *[https://pubchem.ncbi.nlm.nih.gov/compound/Dichloroacetic-acid PubChem] *[https://www.drugbank.ca/drugs/DB08809 Drugbank.ca] *[https://dcaguide.org/dca-information/ Phoenix Rising DCA thread (2018)] *[https://dcaguide.org/dca-information/ DCAGuide.org] ==References== {{Reflist}} [[Category:Potential treatments]]
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