Stem cells in urine easy to isolate and have potential for numerous therapies

Could harvesting stem cells for therapy one day be as simple as asking patients for a urine sample? Researchers at Wake Forest Baptist Medical Center’s Institute for Regenerative Medicine and colleagues have identified stem cells in urine that can be directed to become multiple cell types.

“These cells can be obtained through a simple, non-invasive low-cost approach that avoids surgical procedures,” said Yuanyuan Zhang, M.D., Ph.D., assistant professor of regenerative medicine and senior researcher on the project. Reporting online in the journal Stem Cells, the team successfully directed stem cells from urine to become bladder-type cells, such as  and urothelial, the cells that line the bladder. But the urine-derived cells could also form bone,, fat, , nerve, and, which line blood vessels. The multipotency of the cells suggests their use in a variety of therapies. “These stem cells represent virtually a limitless supply of autologous cells for treating not only urology-related conditions such as  and erectile dysfunction, but could be used in other fields as well,” said Zhang. “They could also potentially be used to engineer replacement bladders, urine tubes and other urologic organs.” Being able to use a patient’s own stem cells for therapy is considered advantageous because they do not induce immune responses or rejection. However, because tissue-specific cells are a very small subpopulation of cells, they can be difficult to isolate from organs and tissues.

Zhang’s team first identified the cells, which are a small subset of the many cells found in urine, in 2006. The current research builds on earlier studies by confirming the multipotency of the cells. In addition, the research found that unlike iPS cells or , the urine derived-stem cells do not form tumors when implanted in the body, indicating they may be safe for use in patients. The research involved obtaining urine samples from 17 healthy individuals ranging in age from five to 75 years. Isolating the cells from urine involves minimal processing, according to the authors. Next, they evaluated the cells’ ability to become multiple cell types. Importantly, the cells differentiated into the three tissue layers (endoderm, ectoderm and mesoderm) that are a hallmark of true stem cells and also differentiated into the specific cell types mentioned earlier.

Next, the researchers placed cells that had been differentiated into smooth muscle and urothelial cells onto scaffolds made of pig intestine. When implanted in mice for one month, the cells formed multi-layer, tissue-like structures. The urine-derived stem cells have markers of mesenchymal cells, which are adult stem cells from connective tissue such as bone marrow. They also have markers for pericytes, a subset of mesenchymal cells found in small blood vessels. Where do the cells come from? Researchers suspect that the cells originate from the upper urinary tract, including the kidney. Female study participants who had received kidney transplants from male donors were found to have the y chromosome in their urine-derived stem cells, suggesting the kidney as the source of the cells. “Identifying the origins of the cells will lead to a better understanding of the biology of this multipotent population of mesenchymal cells within the urinary tract system,” said Zhang.

Cancer Cured For Good

It works 100% of the time to eradicate cancer completely, and cancer does not recur even years later. That is how researchers describe the most convincing cancer cure ever announced.

The weekly injection of just 100 billionths of a gram of a harmless glyco-protein (a naturally-produced molecule with a sugar component and a protein component) activates the human immune system and cures cancer for good, according to human studies among breast cancer and colon cancer patients, producing complete remissions lasting 4 and 7 years respectively. This glyco-protein cure is totally without side effect but currently goes unused by cancer doctors.

Normal Gc protein (also called Vitamin-D binding protein) , an abundant glyco-protein found in human blood serum, becomes the molecular switch to activate macrophages when it is converted to its active form, called Gc macrophage activating factor (Gc-MAF). Gc protein is normally activated by conversion to Gc-MAF with the help of the B and T cells (bone marrow-made and thymus gland-made white blood cells). But, as researchers explain it themselves, cancer cells secrete an enzyme known as alpha-Nacetylgalactosaminidase (also called Nagalase) that completely blocks conversion of Gc protein to Gc-MAF, preventing tumor-cell killing by the macrophages. This is the way cancer cells escape detection and destruction, by disengaging the human immune system.

This also leaves cancer patients prone to infections and many then succumb to pneumonia or other infections. The once-weekly injection of minute amounts of Gc-MAF, just 100 nanograms (billionths of a gram), activates macrophages and allows the immune system to pursue cancer cells with vigor, sufficient to produce total long-term cures in humans.

Nobuto Yamamoto, director of the Division of Cancer Immunology and Molecular Biology, Socrates Institute for Therapeutic Immunology, Philadelphia, Pennsylvania, says this is “probably the most potent macrophage activating factor ever discovered.”

Once a sufficient number of activated macrophages are produced, another Gc-MAF injection is not needed for a week because macrophages have a half-life of about six days. After 16-22 weekly doses of Gc-MAF the amount of Nagalase enzyme fell to levels found in healthy people, which serves as evidence tumors have been completely eliminated. The treatment was fool-proof – – – it worked in 100% of 16 breast cancer patients and there were no recurrent tumors over a period of 4 years, says a report in the January 15 issue of the International Journal of Cancer. [International Journal2008 January15; 122(2):461-7]

In another startling follow-up report by Dr. Yamamoto and colleagues, published in the upcoming July issue of Cancer Immunology Immunotherapy, Gc-MAF therapy totally abolished tumors in 8 colon cancer patients who had already undergone surgery but still exhibited circulating cancer cells (metastases). After 32-50 weekly injections, ”allsaid researchers, an effect that lasted 7 colorectal cancer patients exhibited healthy control levels of the serum Nagalase activity, indicating eradication of metastatic tumor cells,” years with no indication of cancer recurrence either by enzyme activity or CT scans, said researchers. [Cancer Immunology, Immunotherapy Volume 57, Number 7 / July 2008]

Published in an early online edition of this journal, this confirming report has received no attention by the new media so far, despite its striking importance.

Gc-MAF treatment for cancer has been agonizingly slow to develop. Dr. Yamamoto first described this immuno-therapy in 1993. [The Journal of Immunology, 1993 151 (5); 2794-2802]

In a similar animal experiment published in 2003, researchers in Germany, Japan and the United States collaborated to successfully demonstrate that after they had injected macrophage activating factor (Gc-MAF) into tumor-bearing mice, it totally eradicated tumors. [Neoplasia 2003 January; 5(1): 32–40]

In 1997 Dr. Yamamoto injected GcMAF protein into tumor-bearing mice, with the same startling results. A single enzyme injection doubled the survival of these mice and just four enzyme injections increased survival by 6-fold. [Cancer Research 1997 Jun 1; 57(11):2187-92]

In 1996 Dr. Yamamoto reported that all 52 cancer patients he had studied carried elevated blood plasma levels of the immune inactivating alpha-Nacetylgalactosaminidase enzyme (Nagalase), whereas healthy humans had very low levels of this enzyme. [Cancer Research 1996 Jun 15; 56(12):2827-31]

In the early 1990s, Dr. Yamamoto first described how the human immune system is disengaged by enzymes secreted from cancer cells, even filing a patent on the proposed therapy. [US Patent 5326749, July 1994; Cancer Research 1996 June 15; 56: 2827-31]

Activated Gc protein has been used in humans at much higher doses without side effect. This Gc macrophage activating factor (Gc-MAF) has been shown to be effective against a variety of cancers including breast, prostate, stomach, liver, lung, uterus, ovary, brain, skin, head/neck cancer, and leukemia.

Although GcMAF is also called Vitamin-D binding protein, the activation of macrophages does not require Vitamin D. It cannot be said the Gc-MAF cancer cure has gone unheralded. Reuters News covered this developing story in January. But the news story still did not receive top billing nor did it fully elucidate the importance of the discovery, actually made years ago, that the human body is capable of abolishing cancer once its immune system is properly activated.

GcMAF is a naturally made molecule and is not patentable, though its manufacturing process is patent protected. There is no evidence of any current effort to commercialize this therapy or put it into practice. Should such an effective treatment for cancer come into common practice, the income stream from health-insurance plans for every oncology office and cancer center in the world Would likely be reduced to the point of financial insolvency and hundreds of thousands of jobs would be eliminated.

The National Cancer Institute estimates cancer care in the U.S. costs ~$72 billion annually (2004). Furthermore, about $55 billion of cancer drugs are used annually, none which have not significantly improved survival rates throughout the history of their use.

If a typical cancer patient had to undergo 30 GcMAF injections at a cost of $150 per injection, that would cost ~$4500, not counting doctor’s office visits and follow-up testing. For comparison, gene-targeted cancer drugs range from $13,000 to $100,000 in cost per year and produce only marginal improvements in survival (weeks to months). [Targeted Oncology 2007 April, 2 (2); 113-19]

Up to this point, the National Cancer Institute is totally silent on this discovery and there is no evidence the cancer care industry plans to quickly mobilize to use this otherwise harmless treatment.

Dichloroacetate cancer treatment

It is our immune system that prevents and cures cancer.
Part of the immune system involves damaged cells such as malignancies recognising they have mutated, and the mitochondria within then initiate cell suicide. But cancer cells make themselves ‘immortal” by turning off the mitochondria. The Michelakis team from the University of Alberta reports that DCA (sodium dichloroacetate) turns the mitochondria of cancer cells back on, allowing them to commit cellular suicide, or apoptosis. To quote from the report: “The decrease in [Ca2+]i occurs within 5 min and is sustained after 48 hr of DCA exposure. The mitochondria are so sensitive to DCA that just 5 minutes of exposure reactivates them for 48 hours.”    DCA re-activates this part of the immune system very efficiently, and it then attacks cancer. A non-cancerous cell will initiate apoptosis when it detects damage within itself that it cannot repair. But a cancer cell resists the suicide process. That is why chemotherapy and radiation treatments do not work well and result in terrible side effects: the healthy cells die much easier. DCA has been used as a medication for over 30 years, mostly in the treatment of inherited mitochondrial disorders and lactic acidosis ( NCT01083524), and its safety record is well known.


DCA -Chemical formula.


Dichloroacetate is Cl2HC2NaO2, the sodium salt of dichloroacetic acid. Dichloroacetic acid is acetic acid with 2 chlorines. The molecular formula is Cl2H2C2O2. Replace a hydrogen with a sodium atom and you get sodium dichloroacetate, abbreviated to DCA.  DCA is a small molecule, which enables it to get inside cancer cells.

Our DCA has been tested with a Nuclear magnetic resonance spectroscopy (NMR) assay and the pulse position modulation (ppm) peaks are: Hydrogen (DCA 1H) 6.0, Carbon: C0 172 and CH 69, which exactly matches the peaks for Sodium Dichloroacetate. (Our DCA is identical to that used by and NMR spectroscopy failed to find impurities: Our DCA is exceptionally pure. Tests commissioned by two users of our DCA showed the same results.


A Reversible Metabolic-Electrical Remodeling in Cancer Contributes to Resistance to Apoptosis and Reveals Several Potential Therapeutic T argetsIn cancer, mitochondrial glucose oxidation is inhibited and energy production relies on the cytoplasmic glycolysis. This “inactivity” of the mitochondria likely induces a state of apoptosis resistance. Activation of PDH by DCA increases glucose oxidation by promoting the influx of acetyl-CoA into the mitochondria and the Krebs cycle, thus increasing NADH delivery to complex I of the electron transport chain, increasing the production of superoxide, which in the presence of MnSOD is dismutated to the more stable H2O2. Sustained increase in ROS generation can damage the redox-sensitive complex I, inhibiting H+ efflux and decreasing mitochondrial membrane potential (mmp). Opening of the mmp-sensitive mitochondrial transition pore (MTP) allows the efflux of cytochrome c and apoptosis inducing factor (AIF). Both cytochrome c and H2O2 open the redox-sensitive K+ channel Kv1.5 in the plasma membrane and hyperpolarize the cell (increased Em), inhibiting a voltage-dependent Ca 2+entry. The decreased [Ca2+]i suppresses a tonic activation of NFAT, resulting in its removal from the nucleus, thus increasing Kv1.5 expression. The increased efflux of K+ from the cell decreases the tonic inhibition of [K+]i on caspases, further enhancing apoptosis. DCA’s selectivity is based on its ability to target the unique metabolic profile that characterizes most cancers, and its effectiveness is explained by its dual mechanism of apoptosis induction, both by depolarizing mitochondria (proximal pathway) and activating/upregulating Kv1.5 (distal pathway).

Human Studies Involving DCA Use

DCA has been used as a medication for over 30 years, mostly in the treatment of inherited mitochondrial disorders and lactic acidosis ( NCT01083524), and its safety record is well known. DCA has only been used for cancer in the last five years: See “DCA cancer results”  on the left. (Some agencies, like the EPA, call Dichloroacetic Acid DCA. Do not confuse that with the Dichloroacetate we use)

Evaluation of Long-term Treatment of Children
With Congenital Lactic Acidosis With Dichloroacetate

Peter W. Stacpoole, PhD, MD, Lesa R. Gilbert, RN, Richard E. Neiberger, MD, PhD, Paul R. Carney, MD, Edward Valenstein, MD, Douglas W. Theriaque, MSc and Jonathan J. Shuster, PhD Departments of Medicine Biochemistry, Molecular Biology Pediatrics, Neurology, Biomedical Engineering, Epidemiology and Health Policy Research  General Clinical Research Center, University of Florida, Gainesville, Florida

13px; color: #333333;” align=”left”>OBJECTIVE. The purpose of this research was to report results on long-term administration of dichloroacetate in 36 children with congenital lactic acidosis who participated previously in a controlled trial of this drug.
PATIENTS AND MET HODS. We conducted a randomized control trial, followed by an open-label study. Data were analyzed for each patient from the time they began treatment through May 2005.
RESULTS.Subject exposure to dichloroacetate totaled 110.42 years. Median height and weight increased over time, but the standardized values declined slightly and remained below the first percentile. There were no significant changes in biochemical metabolic indices, except for a 2% rise in total protein and a 22% increase in 24-hour urinary oxalate. Both the basal and carbohydrate meal-induced rises in lactate were blunted by dichloroacetate. The median cerebrospinal fluid lactate also decreased over time. Conduction velocity decreased and distal latency increased in peroneal nerves. Mean 3-year survival for all of the subjects was 79%.
CONCLUSIONS. Oral dichloroacetate is generally well tolerated in young children with congenital lactic acidosis. Although continued dichloroacetate exposure is associated with evidence of peripheral neuropathy, it cannot be determined whether this is attributable mainly to the drug or to progression of underlying disease.

Dichloroacetate as metabolic therapy for
myocardial ischemia and failure.

Clinical Investigations

American Heart Journal. 134(5 (Part 1)):841-855, November 1997. Bersin, Robert M. MD; Stacpoole, Peter W. PhD, MD
This article critically reviews the pharmacologic effects of the investigational drug dichloroacetate (DCA), which activates the mitochondrial pyruvate dehydrogenase enzyme complex in cardiac tissue and thus preferentially facilitates aerobic oxidation of carbohydrate over fatty acids. The pharmacologic effects of DCA are compared with other interventions, such as glucose plus insulin, inhibitors of long chain fatty acid oxidation and adenosine, that are also thought to exert their therapeutic effects by altering myocardial energy metabolism. Short-term clinical and laboratory experiments demonstrate that intravenous DCA rapidly stimulates pyruvate dehydrogenase enzyme complex activity and, therefore, aerobic glucose oxidation in myocardial cells. Typically these effects are associated with suppression of myocardial long chain fatty acid metabolism and increased left ventricular stroke work and cardiac output without changes in coronary blood flow or myocardial oxygen consumption. Although long-term studies are lacking, short-term parenteral administration of DCA appears to be safe and capable of significantly improving myocardial function in conditions of limited oxygen availability by increasing the efficient conversion of myocardial substrate fuels into energy.

Dichloroacetate Enhances Performance and Reduces Blood Lactate during Maximal Cycle Exercise in Chronic Obstructive Pulmonary Disease


Lori D. Calvert, Rhea Shelley, Sally J. Singh, Paul L. Greenhaff, John Bankart, Mike D. Morgan and Michael C. Steiner. American Journal of Respiratory and Critical Care Medicine Vol 177. pp. 1090-1094, (2008) © 2008 American Thoracic Society doi: 10.1164/rccm.200707-1032OC

Conclusions: We have shown that a pharmacologic intervention known to activate muscle PDC can reduce blood lactate and ammonia accumulation during exercise and improve maximal exercise performance in subjects with COPD. Skeletal muscle PDC activation may be a target for pharmacologic intervention in the management of exercise intolerance in COPD.

Effects of dichloroacetate on exercise performance in healthy volunteers

Bernhard Ludvik1, Gert Mayer1, Sibylle Stifter1, Dinah Putz1, Ursula Barnas1 and Helmut Graf1

(1) Klinik für Innere Medizin III, Department of Nephrology, University of Vienna, Währinger Gürtel 18-22, A-1090 Vienna, Austria
(2) III. Medizinische Abt., KA Rudolfstiftung, Juchgasse 25, A-1030 Vienna, Austria

Received: 14 April 1992 Revised: 10 November 1992 Accepted: 19 November 1992

Abstract Dichloroacetate (DCA), a stimulator of the pyruvate dehydrogenase complex, decreases lactate levels and peripheral resistance and increases cardiac output. This study was performed to examine the effects of DCA on exercise performance in humans. Eight healthy male volunteers (age 20–28 years) were tested by bicycle spiro-ergometry using a microprocessor-controlled gas analysis system after infusion of DCA (50 mg/kg body weight) or saline. Prior infusion of DCA significantly reduced the increase of lactate levels during exercise when compared with infusion of saline (1.40±0.21 vs 2.10±0.09 mmol·l–1 at 50% of the expected maximal working capacity, P<0.05; 8.53±0.45 vs 9.92±0.59 mmol·l–1 at maximal working capacity, P<0.05). Oxygen uptake increased significantly after DCA when compared with saline from 7.5±0.4 vs 7.4±0.5 to 27.2±1.5 vs 23.7±1.7 (P<0.05) at anaerobic threshold and to 35.6±1.7 vs 30.5±1.0 ml · kg–1 min–1 (P<0.05) at maximal exercise capacity. Following DCA infusion the workload at which the anaerobic threshold was reached was significantly higher (160±7 vs 120±5 W, P<0.05) and the maximal working capacity was significantly increased (230±9 vs 209±8 W, P<0.05). In summary, DCA reduced the increase of lactate levels during exercise and increased oxygen uptake at the anaerobic threshold and at maximal working capacity, which was significantly increased. These results warrant further studies on a potential therapeutic application of DCA in patients with reduced exercise capacity.

New England Journal of Medicine, Volume 298:526-530 March 9, 1978 Number 10

Metabolic effects of dichloroacetate in patients with diabetes mellitus and hyperlipoproteinemia

PW Stagpoole, GW Moore, and DM Kornhauser


Dichloroacetate is known to reduce plasma glucose and triglycerides in diabetic and starved animals and to lower plasma lactate under various experimental conditions. To investigate its metabolic effects in man, we administered oral doses (3 to 4 g) of dichloroacetate as the sodium salt to patients with diabetes mellitus or hyperlipoproteinemia or both for six to seven days. Dichloroacetate significantly reduced fasting hyperglycemia an average of 24 per cent (P less than 0.01) from base line and produced marked, concomitant falls in plasma lactate (73 per cent; P less than 0.05 to less than 0.01) and alanine (82 per cent; P less than 0.01 to less than 0.001). In addition, it significantly decreased plasma cholesterol (22 per cent; P less than 0.01 to less than 0.001) and triglyceride (61 per cent; P less than 0.01) levels while increasing (71 per cent; P less than 0.01) plasma ketone-body concentrations. Plasma insulin, free fatty acid and glycerol levels were not affected. Serum uric acid rose, whereas excretion and renal clearance fell. Some patients experienced mild sedation, but no other laboratory or clinical evidence of adverse effects was noted during or immediately after the treatment phase.

Clinical Investigation
Sodium dichloroacetate treatment of children
with mitochondrial encephalomyopathies

JiÞ’ Zeman1,2, Hana Houäékov‡1, Zlata Dudkov‡1, Leona Stratilov‡1, Hana Hans’kov‡1,
V. Konr‡dov‡1, Stanislav Kmoch2, Josef Houätžk3 1Department of Pediatrics, 2Institute of Inherited Metabolic Diseases, 1st Medical Faculty, Charles University, Prague, Czech Republic 3Institute of Physiology, Academy of Sciences of Czech Republic, Prague, Czech Republic

This is copied from the discussion portion of the paper: The recommended therapeutical range of DCA dosage in children is 100- 150 mg DCA/kg/day should be well tolerated. Nevertheless, DCA therapy can be problematic in some cases. It has been reported that after DCA treatment (100 mg/kg) for 20 weeks, a girl with mitochondrial encephalomyopathy developed distal polyneuropathy. This was reversible and disappeared after termination of DCA treatment [38]. According to our experience, however, efficient decreases of blood lactate levels can be achieved by lower DCA dosages.

Eur J Pediatr. 1995 Nov;154(11):928-32. Related Articles, Links

Therapy of complex I deficiency: peripheral neuropathy during dichloroacetate therapy.

Kurlemann G, Paetzke I, Moller H, Masur H, Schuierer G, Weglage J, Koch HG.

Children’s Hospital, Albert-Schweitzer-Strasse, Munster, Germany.

A therapeutic trial with polyvitamins and dichloroacetate (DCA) in combination with thiamine in a 13-year-old girl with complex I deficiency is reported. The polyvitamin therapy included thiamine, riboflavin, ascorbate, coenzyme Q 10 and carnitine. This therapeutic regine was used over a period of 17 months without any effect. Although DCA lowered the lactate concentration in blood and CNS–measured by magnetic resonance spectroscopy–no clinical benefit was achieved. After 20 weeks of DCA therapy a distal polyneuropathy with areflexia developed although 100 mg thiamine daily as comedication was given from the beginning of DCA therapy. Nerve conduction velocity of the peroneal nerve was not detectable, sensible evoked potentials of the tibialis posterious nerve were normal. This side-effect resolved completely within 6 months after omission of DCA. Our observation suggests a direct toxic effect of DCA only on the peripheral nervous system in our patient since several cerebral MRI and magnetic resonance spectroscopy studies showed no abnormalities. CONCLUSION. DCA lowers the lactate concentration in children with complex I deficiency of the respiratory chain in a dose of 100 mg/kg body weight without clinical benefit. Reversible peripheral polyneuropathy may develop under DCA therapy despite thiamine medication.


April 1999, Vol. 8, No. 4, Pages 373-382 (doi:10.1517/13543784.8.4.373)

Dichloroacetate and cerebral ischaemia therapeutics

Paul J Marangos ?, Zofia E Dziewanowska ?
Cypros Pharmaceutical Corporation, 2714 Loker Avenue West, Carlsbad, CA 92008, USA.

Brain ischaemia is a major medical problem which totally lacks meaningful therapeutic options. A drug that reduces morbidity and mortality associated with head injury and stroke would constitute a major medical breakthrough. Although many mechanistic approaches have been evaluated clinically for both stroke and head injury, none have yet to be proven successful. Dichloroacetate (DCA, Ceresine™) is a small molecule that activates pyruvate dehydrogenase (PDH) and crosses the blood-brain barrier. PDH activation reduces neurotoxic lactic acidosis which always accompanies brain ischaemia. DCA shows substantial efficacy in a variety of models of stroke, pre-stroke, head or spinal cord injury. Agents that lower cerebral lactic acidosis have not yet been clinically evaluated in head injury and stroke, although DCA has been shown clinically to reduce ambient lactate concentrations in patients with such conditions. DCA has also been shown to be well-tolerated in these patients, and unlike many halogenated molecules, is not mutagenic. Since elevated brain lactate is correlated with poor outcome in both preclinical and clinical studies, an agent such as DCA may prove to reduce the brain injury associated with these disorders. Potential clinical applications of DCA include stroke, head injury, spinal cord injury, and chronic disorders such as congenital lactic acidosis (CLA) and mitochondrial lactic acidosis and stroke-like syndrome (MELAS

J Neurochem. 2007 Jan ;100 (2):429-36 17241159
Dichloroacetate causes reversible demyelination in vitro: potential mechanism for its neuropathic effect. 

Natalia Felitsyn*,†*Neuroscience†Medicine (Division of Endocrinology and Metabolism),
Peter W. Stacpoole†,‡†Medicine (Division of Endocrinology and Metabolism)‡Biochemistry and Molecular Biology, College of Medicine, McKnight Brain Institute, University of Florida, Gainesville, Florida, USA and Lucia Notterpek**Neuroscience Departments of *Neuroscience, †Medicine (Division of Endocrinology and Metabolism), and ‡Biochemistry and Molecular Biology, College of Medicine, McKnight Brain Institute, University of Florida, Gainesville, Florida, USA

Dichloroacetate (DCA) is an investigational drug for genetic mitochondrial diseases whose use has been mitigated by reversible peripheral neuropathy. We investigated the mechanism of DCA neurotoxicity using cultured rat Schwann cells (SCs) and dorsal root ganglia (DRG) neurons. Myelinating SC-DRG neuron co-cultures, isolated SCs and DRG neurons were exposed to 1-20 mm DCA for up to 12 days. In myelinating co-cultures, DCA caused a dose- and exposure-dependent decrease of myelination, as determined by immunolabeling and immunoblotting for myelin basic protein (MBP), protein zero (P0), myelin-associated glycoprotein (MAG) and peripheral myelin protein 22 (PMP22). Partial recovery of myelination occurred following a 10-day washout of DCA. DCA did not affect the steady-state levels of intermediate filament proteins, but promoted the formation of anti-neurofilament antibody reactive whirls. In isolated SC cultures, DCA decreased the expression of P0 and PMP22, while it increased the levels of p75(NTR) (neurotrophin receptor), as compared with non-DCA-treated samples. DCA had modest adverse effects on neuronal and glial cell vitality, as determined by the release of lactate dehydrogenase. These results demonstrate that DCA induces a reversible inhibition of myelin-related proteins that may account, at least in part, for its clinical peripheral neuropathic effects.

Link to full text of article

J Clin Pharmacol. 2006 Dec ;46 (12):1449-59 17101744
Human Kinetics of Orally and Intravenously Administered Low-Dose 1,2-13C-Dichloroacetate.

Minghong Jia , Bonnie Coats , Monisha Chadha , Barbara Frentzen , Javier Perez-Rodriguez , Paul A Chadik , Richard A Yost , George N Henderson , Peter W Stacpoole

Dichloroacetate (DCA) is a putative environmental hazard, owing to its ubiquitous presence in the biosphere and its association with animal and human toxicity. We sought to determine the kinetics of environmentally relevant concentrations of 1,2-(13)C-DCA administered to healthy adults.Subjects received an oral or intravenous dose of 2.5 mug/kg of 1,2-(13)C-DCA. Plasma and urine concentrations of 1,2-(13)C-DCA were measured by a modified gas chromatography-tandem mass spectrometry method. 1,2-(13)C-DCA kinetics was determined by modeling using WinNonlin 4.1 software. Plasma concentrations of 1,2-(13)C-DCA peaked 10 minutes and 30 minutes after intravenous or oral administration, respectively. Plasma kinetic parameters varied as a function of dose and duration. Very little unchanged 1,2-(13)C-DCA was excreted in urine. Trace amounts of DCA alter its own kinetics after short-term exposure. These findings have important implications for interpreting the impact of this xenobiotic on human health.

NEUROLOGY 2006;66:324-330

© 2006 American Academy of Neurology

Dichloroacetate causes toxic neuropathy in MELAS 
For extended source material. click here.

A randomized, controlled clinical trial

P. Kaufmann, MD, MSc, K. Engelstad, BS, Y. Wei, PhD, S. Jhung, MPH, M. C. Sano, PhD, D. C. Shungu, PhD, W. S. Millar, MS, MD, X. Hong, MD, C. L. Gooch, MD, X. Mao, MS, J. M. Pascual, MD, PhD, M. Hirano, MD, P. W. Stacpoole, MD, PhD, S. DiMauro, MD and D. C. De Vivo, MD

From the Departments of Neurology (P.K., K.E., S.J., X.H., C.L.G., J.M.P., M.H., S.D., D.C.D.), Pediatrics (K.E., S.J., J.M.P., D.C.D.), Biostatistics (Y.W.), and Radiology (W.S.M.), Columbia University, New York; Department of Psychiatry (M.C.S.), Mount Sinai School of Medicine, New York; Department of Radiology (D.C.S., X.M.), Weill Medical College of Cornell University, New York, NY; and Departments of Pediatrics, Medicine, Biochemistry, and Molecular Biology (P.W.S.), University of Florida, Gainesville.

Address correspondence and reprint requests to Dr. Petra Kaufmann, The Neurological Institute, Columbia University, 710 W 168th Street, New York, NY 10032; e-mail:

Objective: To evaluate the efficacy of dichloroacetate (DCA) in the treatment of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS).

Background: High levels of ventricular lactate, the brain spectroscopic signature of MELAS, correlate with more severe neurologic impairment. The authors hypothesized that chronic cerebral lactic acidosis exacerbates neuronal injury in MELAS and therefore, investigated DCA, a potent lactate-lowering agent, as potential treatment for MELAS.

Methods: The authors conducted a double-blind, placebo-controlled, randomized, 3-year cross-over trial of DCA (25 mg/kg/day) in 30 patients (aged 10 to 60 years) with MELAS and the A3243G mutation. Primary outcome measure was a Global Assessment of Treatment Efficacy (GATE) score based on a health-related event inventory, and on neurologic, neuropsychological, and daily living functioning. Biologic outcome measures included venous, CSF, and 1H MRSI-estimated brain lactate. Blood tests and nerve conduction studies were performed to monitor safety.

Results: During the initial 24-month treatment period, 15 of 15 patients randomized to DCA were taken off study medication, compared to 4 of 15 patients randomized to placebo. Study medication was discontinued in 17 of 19 patients because of onset or worsening of peripheral neuropathy. The clinical trial was terminated early because of peripheral nerve toxicity. The mean GATE score was not significantly different between treatment arms.

Conclusion: DCA at 25 mg/kg/day is associated with peripheral nerve toxicity resulting in a high rate of medication discontinuation and early study termination. Under these experimental conditions, the authors were unable to detect any beneficial effect. The findings show that DCA-associated neuropathy overshadows the assessment of any potential benefit in MELAS.

For extended source material. click here.

A controlled clinical trial of dichloroacetate for treatment of lactic acidosis in adults. The Dichloroacetate-Lactic Acidosis Study Group

PW Stacpoole, EC Wright, TG Baumgartner, RM Bersin, S Buchalter, SH Curry, CA Duncan, EM Harman, GN Henderson, S Jenkinson, and et al.


BACKGROUND. Mortality is very high in lactic acidosis, and there is no satisfactory treatment other than treatment of the underlying cause. Uncontrolled studies have suggested that dichloroacetate, which stimulates the oxidation of lactate to acetyl-coenzyme A and carbon dioxide, might reduce morbidity and improve survival among patients with this condition. METHODS. We conducted a placebo-controlled, randomized trial of intravenous sodium dichloroacetate therapy in 252 patients with lactic acidosis; 126 were assigned to receive dichloroacetate and 126 to receive placebo. The entry criteria included an arterial-blood lactate concentration of > or = 5.0 mmol per liter and either an arterial-blood pH of < or = 7.35 or a base deficit of > or = 6 mmol per liter. The mean (+/- SD) arterial-blood lactate concentrations before treatment were 11.6 +/- 7.0 mmol per liter in the dichloroacetate-treated patients and 10.4 +/- 5.5 mmol per liter in the placebo group, and the mean initial arterial-blood pH values were 7.24 +/- 0.12 and 7.24 +/- 0.13, respectively. Eighty-six percent of the patients required mechanical ventilation, and 74 percent required pressor agents, inotropic drugs, or both because of hypotension. RESULTS. The arterial-blood lactate concentration decreased 20 percent or more in 83 (66 percent) of the 126 patients who received dichloroacetate and 45 (36 percent) of the 126 patients who received placebo (P = 0.001). The arterial-blood pH also increased more in the dichloroacetate-treated patients (P = 0.005). The absolute magnitude of the differences was small, however, and they were not associated with improvement in hemodynamics or survival. Only 12 percent of the dichloroacetate-treated patients and 17 percent of the placebo patients survived to be discharged from the hospital. CONCLUSIONS. Dichloroacetate treatment of patients with severe lactic acidosis results in statistically significant but clinically unimportant changes in arterial-blood lactate concentrations and pH and fails to alter either hemodynamics or survival

PEDIATRICS Vol. 117 No. 5 May 2006, pp. 1519-1531 (doi:10.1542/peds.2005-1226)

Controlled Clinical Trial of Dichloroacetate for Treatment of Congenital Lactic Acidosis in Children

Peter W. Stacpoole, MD, PhDa,b,c, Douglas S. Kerr, MD, PhDd, Carie Barnes, RNa, S. Terri Bunch, MDe, Paul R. Carney, MDe, Eileen M. Fennell, PhDf, Natalia M. Felitsyn, PhDa, Robin L. Gilmore, MDg, Melvin Greer, MDg, George N. Henderson, PhDa,c, Alan D. Hutson, PhDc,h, Richard E. Neiberger, MD, PhDe, Ralph G. O’Brien, PhDc,h, Leigh Ann Perkins, RNa, Ronald G. Quisling, MDi, Albert L. Shroads, MSa, Jonathan J. Shuster, PhDc,h, Janet H. Silverstein, MDe, Douglas W. Theriaque, MSc and Edward Valenstein, MDg a Division of Endocrinology and Metabolism, Department of Medicine, University of Florida, Gainesville, Florida

b Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida
c General Clinical Research Center, University of Florida, Gainesville, Florida
d Rainbow Babies and Children’s Hospital, Case Western Reserve University, Cleveland, Ohio
e Department of Pediatrics, University of Florida, Gainesville, Florida
f College of Public Health and Health Professions, the Department of Clinical Health Psychology, University of Florida, Gainesville, Florida
g Department of Neurology, University of Florida, Gainesville, Florida
h Department of Statistics, University of Florida, Gainesville, Florida
i Department of Radiology, University of Florida, Gainesville, Florida

OBJECTIVE. Open-label studies indicate that oral dichloroacetate (DCA) may be effective in treating patients with congenital lactic acidosis. We tested this hypothesis by conducting the first double-blind, randomized, control trial of DCA in this disease.

METHODS. Forty-three patients who ranged in age from 0.9 to 19 years were enrolled. All patients had persistent or intermittent hyperlactatemia, and most had severe psychomotor delay. Eleven patients had pyruvate dehydrogenase deficiency, 25 patients had 1 or more defects in enzymes of the respiratory chain, and 7 patients had a mutation in mitochondrial DNA. Patients were preconditioned on placebo for 6 months and then were randomly assigned to receive an additional 6 months of placebo or DCA, at a dose of 12.5 mg/kg every 12 hours. The primary outcome results were (1) a Global Assessment of Treatment Efficacy, which incorporated tests of neuromuscular and behavioral function and quality of life; (2) linear growth; (3) blood lactate concentration in the fasted state and after a carbohydrate meal; (4) frequency and severity of intercurrent illnesses and hospitalizations; and (5) safety, including tests of liver and peripheral nerve function.

OUTCOME. There were no significant differences in Global Assessment of Treatment Efficacy scores, linear growth, or the frequency or severity of intercurrent illnesses. DCA significantly decreased the rise in blood lactate caused by carbohydrate feeding. Chronic DCA administration was associated with a fall in plasma clearance of the drug and with a rise in the urinary excretion of the tyrosine catabolite maleylacetone and the heme precursor -aminolevulinate.

CONCLUSIONS. In this highly heterogeneous population of children with congenital lactic acidosis,oral DCA for 6 months was well tolerated and blunted the postprandial increase in circulating lactate. However, it did not improve neurologic or other measures of clinical outcome.