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Research Notes: Dichloroacetate (DCA)Related articles: Lactic acidosis, Muscle biopsy results From Medscape Pediatrics, Treatment of Mitochondrial Cytopathies Dichloroacetate (DCA) is an investigational drug that stimulates the activity of the pyruvate dehydrogenase multienzyme (PDH) complex. PDH catalyzes the irreversible oxidation of pyruvate, the product of glycolysis, to acetyl coenzyme A and carbon dioxide. Reducing equivalents in the form of NADH, which enter complex I of the ETC, are also generated. Acetyl coenzyme A then is condensed with oxaloacetate to form citrate, the first step in the citric acid cycle. Regulation of the enzyme complex is mediated by phosphorylation of one of its subunits, whereby in the phosphorylated state the PDH complex is rendered inactive. DCA stimulates PDH complex activity by inhibiting the PDH complex kinases that are responsible for phosphorylation, thereby maintaining the PDH complex in its unphosphorylated, hence active, state. The result is improved oxidation of lactate and consequent increased supply of acetyl coenzyme A and NADH. This NADH is then utilized by complex I, but if there is a defect at or distal to complex I, it is not known if lowering lactate concentrations or improving the flux through PDH can improve energy production. One property of DCA is that it may inhibit its own metabolism. The major side effect of DCA is a reversible peripheral neuropathy that may have some relation to thiamine deficiency.[12]
A number of reports support the effectiveness of DCA in treating congenital and acquired lactic acidosis. DCA has been associated with a lowering of serum lactate in addition to clinical improvement. Stacpoole et al report on 53 patients with congenital lactic acidosis who were treated over a 1- to 5-year period with oral DCA.[13,14] Decreased serum lactate was demonstrated in 27 whereas decreased serum and cerebrospinal fluid (CSF) lactate was observed in 11 patients. Some clinical improvement (vital signs, muscle tone, exercise endurance, cognition, stabilization of neurologic decline) was observed for 15% of the 39 patients whose subsequent clinical course was known. For patients who respond to DCA, there should be a 20% decrease of serum lactate within 6 hours of the first dose. For patients who do not respond within 24 hours of oral or intravenous dosing, any response is not likely and therefore treatment is probably unnecessary.[13,14]
In a controlled clinical trial involving adult patients with varied etiologies of severe lactic acidosis, intravenous DCA was shown to significantly reduce (P = 0.001) serum lactate concentrations when compared with placebo. The changes in serum lactate concentrations were not associated with clinical improvement or survival.[15]
More recently, DCA has been evaluated in the setting of mitochondrial encephalomyopathies. Most reports are anecdotal and present conflicting clinical outcomes. Two siblings with MELAS having clinical deterioration were treated with a combination of DCA (50 mg per kg) and multiple other medications, including vitamin B1. The plasma lactate diminished within 2 days in both patients. The frequency and severity of myoclonic seizures (patient 1) were decreased within 1 month. The drug was maintained in this patient for 25 months without apparent side effects. No additional strokelike episodes, headaches, or abdominal pain were observed in the second patient for the 22 months of observation.[16] A patient with MELAS was shown to improve after treatment with oral DCA on two separate occasions with regards to reduction in serum and CSF lactate levels. Additionally, this patient showed reduction of neurologic decline and cessation of auditory and visual hallucinations in conjunction with the normalization of the biochemical parameters.[17] Improvement of magnetic resonance imaging (MRI) abnormalities occurred in two patients with Leigh syndrome following treatment with DCA (30 or 50 mg per kg per day). The improvement was mild and transitory (2-1/2 months) in one patient (PDH complex deficiency) and more significant and sustained over the follow-up period of 9 months in the second patient (complex I deficiency). Both demonstrated reduction of serum and/or CSF lactate associated with initiation and continuation of therapy.[18]
Other than a lowering of serum lactate, Tulinius et al[19] did not find any significant difference clinically following treatment with DCA in a 6-month-old boy with myopathy and cardiomyopathy.
DCA (50 mg per kg per day following a load of 50 mg per kg every 12 hours for three doses) was used to treat a 1-year-old girl with Leigh's syndrome. She demonstrated gradual improvement in her clinical symptoms (respiratory status, physical activity, and muscle strength) and biochemical profile (lactate diminished in blood and CSF). Despite this, 2 months after the start of therapy, MRI revealed continued cerebral atrophy. At the same time 1H magnetic resonance spectroscopy was indicative of reduced neuronal function. The investigators conclude that DCA may lead to some improvement of neurologic symptoms via reduction of serum lactate without truly affecting the underlying disease process.[20]
In a double-blind, placebo-controlled study of DCA in 11 patients with mitochondrial disease, DeStefano et al evaluated several measures of oxidative metabolism following 1 week of treatment. A significant decrease (P <0.05) in serum lactate, pyruvate, and alanine occurred both at rest and after exercise. In addition, proton magnetic spectroscopy showed a decrease of brain lactate/creatine ratio by 42% (P <0.05) in addition to other changes indicative of improvements of oxidative metabolism (NAA/creatine ratio increased by 8%, P <0.05). Evaluation of the gastrocnemius muscle by phosphorous magnetic spectroscopy showed no significant change following treatment with DCA. No significant clinical improvement was noted following treatment despite the biochemical improvements, but may be due to the short treatment time of one week.[21]
In association with the administration of intravenous DCA at a dose of 50 mg per kg per day for 13 days followed by 25 mg per kg per day for 6 days, arterial lactate decreased as did seizure activity in a patient with MELAS. Serial proton magnetic resonance spectroscopy revealed improvement in terms of the magnitude of the lactate peak and NAA/Cr ratio in the region compatible with this patient's symptoms.[22]
Three children with mitochondrial encephalomyopathy were administered DCA at a dose of 30 mg per kg per day. These children demonstrated radiologic and clinical improvements following this oral treatment regimen. MRS findings revealed a marked reduction of lactic acid peaks in two of the patients. Both serum and CSF lactate levels diminished. Serial MRI scans demonstrated gradual decrease of white matter lesions in two patients, and the pontine and medullary lesions in the third. Developmental progress was observed following treatment in the two patients with Leigh's syndrome. These patients received oral DCA for 21 or more months without any significant side effects.[23]
In summary, DCA will lower serum lactate and improve other biochemical markers such as CSF lactate or serum alanine in some patients. For patients with a DCA-responsive PDH deficiency, the use of DCA can be helpful. It is not clear for those with electron transport defects whether or not lowering lactate is helpful. By increasing the flux of pyruvate through PDH, the kinetics of the reaction pyruvate + NADH = lactate + NAD+ lowers the lactate, but also increases the ratio of NADH/NAD+. The NADH produced cannot be utilized by the (impaired) ETC. Furthermore, the putative role of the increased concentration of NAD+, produced by the conversion of pyruvate to lactate, is to allow glycolysis to proceed and generate ATP under anaerobic conditions. A reduced amount of available NAD+ results in reduced production of anerobically generated ATP.
Unfortunately, despite lowering of serum and/or CSF levels of lactate, DCA treatment does not universally lead to overall clinical improvement.
Pediatrics. 2006 May. 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 delta-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. Neurology. 2006 Feb 14. 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. Brain Dev. 2004 Oct. The long-term effects of the sodium salt of dichloroacetic acid (DCA) were evaluated in four patients with mitochondrial encephalomyelopathy with lactic acidosis and stroke-like episodes (MELAS) carrying A3243G mutation. Oral administration of DCA in MELAS patients was followed for an average of 5 years 4 months. Serum levels of lactate and pyruvate were maintained at around 10 and 0.6 mg/dl, respectively. Serum levels of DCA were 40-136 microg/ml. Symptoms responding to treatment included persistent headache, abdominal pain, muscle weakness, and stroke-like episodes. In contrast, no improvements in mental status, deafness, short stature, or neuroelectrophysiological findings were observed. Adverse effects included mild liver dysfunction in all patients, hypocalcemia in three and peripheral neuropathy in one. None of these adverse events was severe enough to require discontinuation of treatment. To determine suitable indications for DCA therapy, analysis of many more patients who have undergone DCA administration is required. Mol Genet Metab. 2004 Sep-Oct. Clinical features are reported for 37 patients with various mitochondrial disorders, treated with sodium dichloroacetate (DCA) for 3 weeks to 7 years (mean 3.25 years) at 11-50 mg/kg/day (34.6+/-13.1) in an open-label format. DCA pharmacokinetics showed half-times approximately 86 min for the first intravenous dose of 50 mg/kg, 3.2 h for a subsequent intravenous dose 4-6 h later, and 11 h after continued oral dosing of 12.5-25 mg/kg twice daily. Basal blood and CSF lactate (mean values at entry 29.6 and 46.8 mg/dL, respectively) decreased at 3 months (to 18.1 and 34.2, respectively) and 12 months (to 17.7 and 33.1, respectively). There was some attenuation of the blood lactate response to oral fructose but not glucose, although the baseline lactate was lower with DCA. A standardized neurologic inventory showed stabilization or improvement over one year. The subjective impression of overall disease course was worsening in 21.6%, improvement in 48.6%, and no discernable effect in 29.7%. Among 8 patients who had 17 stroke-like events in 0.25-5 years prior to study entry, there were a total of 2 events over 3-6 years of treatment. In two cases institution of DCA resulted in dramatic relief of severe headaches which had been refractory to narcotics. Given variability of symptoms and limited understanding of natural history of mitochondrial disease, it is difficult to determine the efficacy of DCA in this open-label study, but there did appear to be some cases in which there were at least temporary benefits. J Lab Clin Med. 2004 Jun. Energy-metabolism disturbances during sepsis are characterized by enhanced glycolytic fluxes and reduced mitochondrial respiration. However, it is not known whether these abnormalities are the result of a specific mitochondrial alteration, decreased pyruvate dehydrogenase (PDH) complex activity, depletion of ubiquinone (CoQ(10); electron donor for the mitochondrial complex III), or all 3. In this study we sought to specify metabolism disturbances in a murine model of sepsis, using either a PDH-activator infusion (dichloroacetate, DCA) or CoQ(10) supplementation. After anesthesia, Sprague-Dawley rats received intravenous saline solution (control; n = 5), DCA (n = 5; 20 mg/100 g), or CoQ(10) (n = 5; 1 mg/100 g), before the induction of sepsis. Increased plasma lactate levels and increased muscle glucose content were observed after 4 hours in the control group. In the DCA group, a decrease in the muscle content of lactate (P <.05) and an increase in muscle glucose content (P <.05) were observed at 4 hours, but no lactatemia variation was noted. In the CoQ(10) group, only increased plasma lactate levels were observed. Increased muscle glycolysis fluxes were observed after 4 hours in the control group, but to a slighter degree in both the DCA and CoQ(10) groups. Only DCA restored a normal temperature sensitivity in the hyperthermia range, but we noted no differences in survival time. In conclusion, only DCA infusion restores normal glycolysis function. Rinsho Shinkeigaku. 2003 Apr. We report beneficial and adverse effects of sodium dichloroacetate (DCA) in three adult Japanese patients with mitochondrial disease: a 21-year-old male with involuntary movements, optic atrophy, hearing loss, and convulsions (patient 1), a 28-year-old man with mental deterioration, hemianopia, hearing disturbance, and convulsions (patient 2), and a 50-year-old woman with hearing disturbance, generalized muscle atrophy, and insulin dependent diabetes mellitus (patient 3). A3243G mutation was found in patient 2 and patient 3. Oral administration of DCA improved consciousness level and gait disturbances in patient 1, and ameliorated headaches, easy fatiguability, and muscle cramps in patient 2 and patient 3. DCA normalized high levels of lactate and pyruvate in blood and cerebrospinal fluids in all three patients. In patient 3, daily insulin needs decreased from 38 to 24 units, and urine C peptide increased from an undetectable level to 16 micrograms/day. In patient 1, DCA 23 mg/kg/day had been beneficial without adverse effects and he became free of convulsions for more than 32 months. However, despite of normal lactate and pyruvate, unsteady gait and lethargy developed after 50 mg/kg/day treatment for two months and one month in patient 2 and patient 3, respectively. In both patients, deep tendon reflexes disappeared and Romberg sign became positive. Nerve conduction studies confirmed sensory-dominant polyneuropathy and electroencephalogram showed diffuse slow basic activities. Cessation of DCA resulted in recovery of gait and consciousness, but sensory nerve action potentials did not recover in one month. Long term treatment of 50 mg/kg/day DCA may affect adversely the peripheral and central nervous systems in adult patients. Although effective plasma DCA concentration was previously reported as 25-160 micrograms/ml in patients under 18 years old, plasma DCA concentration of 10.2 micrograms/ml was sufficient in patient 1. We recommend lower dose of DCA in adult patients than in child patients. No To Hattatsu. 2003 Jan. We present the effects and adverse effects of dichloroacetate (DCA) in a girl with mitochondrial disorder. Oral administration of DCA 50 mg/kg per day, reduced the elevated levels of lactate to below the normal range. Treatment with DCA ameliorated electroencephalogram abnormalities, but caused the adverse effects with hepatomegaly and decreased activity, which were improved by reduction or withdrawal of DCA. The decreased activity may be an adverse effect on the central nervous system. The dosage of DCA should be adjusted for each patient. Muscle Nerve. 2001 Jul. Serial measurements of nerve conduction velocities and amplitudes were performed in 27 patients with congenital lactic acidemia over 1 year of sodium dichloroacetate (DCA) administration. Patients were treated with oral thiamine (100 mg) and DCA (initial dose of 50 mg/kg) daily. Nerve conduction velocity and response amplitude were measured in the median, radial, tibial, and sural nerves at 0, 3, 6, and 12 months, and plasma DCA pharmacokinetics were measured at 3 and 12 months. Baseline electrophysiologic parameters in this population were generally below normal but as a group were within 2 standard deviations of normal means. Although symptoms of neuropathy were reported by only three patients or their families, nerve conduction declined in 12 patients with normal baseline studies, and worsening of nerve conduction occurred in the two who had abnormalities at baseline. Peripheral neuropathy appears to be a common side effect during chronic DCA treatment, even with coadministration of oral thiamine. Nerve conduction should be monitored during DCA treatment. Neurology. 1998 Feb. We present the clinical and laboratory effects of dichloroacetate (DCA) in three children with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) who had not responded to other medications. Administration of DCA lowered the elevated levels of lactate and pyruvate in the serum and CSF. DCA ameliorated abdominal pain, headache, and strokelike episodes, and improved cognitive function and fatigability in the three patients during the study period. Some transient liver dysfunction, hypocalcemia, and peripheral neuropathy were observed. The use of DCA in MELAS merits further study. J Mol Cell Cardiol. 1996 May. The regulation of fatty acid oxidation in isolated myocytes was examined by manipulating mitochondrial acetyl-CoA levels produced by carbohydrate and fatty acid oxidation. L-carnitine had no effect on the oxidation of [U-14C]glucose, but stimulated oxidation of [1-14C]palmitate in a concentration-dependent manner. L-carnitine (5 mM) increased palmitate oxidation by 37%. The phosphodiesterase inhibitor, enoximone (250 microM), also increased palmitate oxidation by 51%. Addition of L-carnitine to enoximone resulted in a two-fold increase of palmitate oxidation. Whereas, dichloroacetate (DCA, 1 mM), which stimulates PDH activity, decreased palmitate oxidation by 25%. Furthermore, the addition of DCA to myocytes preincubated with either L-carnitine or enoximone, had no effect on the carnitine-induced stimulation of palmitate, and reduced that of enoximone by 50%. Varied concentrations of DCA decreased the oxidation of palmitate and octanoate; but increased glucose oxidation in myocytes. The rate of efflux of acetylcarnitine was highest when pyruvate was present in the medium compared to efflux rates in presence of palmitate or palmitate plus glucose. Although the addition of L-carnitine plus enoximone resulted in a two-fold increase in palmitate oxidation, acetylcarnitine efflux was minimal under these conditions. Acetylcarnitine efflux was highest when pyruvate was present in the medium. These rates were dramatically decreased when myocytes were preincubated with enoximone, despite the stimulation of palmitate oxidation by this compound. These data suggest that: (1) fatty acid oxidation is influenced by acetyl-CoA produced from pyruvate metabolism; (2) L-carnitine may be specific for mitochondrial acetyl-CoA derived from pyruvate oxidation; and (3) it is probable that acetyl-CoA from beta-oxidation of fatty acids is directly channeled into the citric acid cycle. Neuropediatrics. 1991 Aug. We report a patient with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes who experienced visual and auditory hallucinations. His blood and cerebrospinal fluid lactate levels were remarkably elevated. Sodium dichloroacetate was administered orally at doses of 12.5 to 100 mg/kg/day. On normalization of the lactate levels, the hallucinations disappeared. Brain Dev. 1989. Sodium dichloroacetate (DCA) was administered orally at doses of 12.5 to 50 mg/kg body weight twice or three times per day to a patient with mitochondrial encephalomyopathy associated with congenital lactic acidemia. During therapy, the rates of decarboxylation of (1-14C) pyruvate and (3-14C) pyruvate, which represent the activity of the pyruvate dehydrogenase (PDH) complex and the function of the TCA cycle, respectively, were markedly increased in the platelets and increases in the lactate levels in the blood and urine during exercise were markedly reduced. These results suggest that oral administration of DCA causes significant increases in the activities of the PDH complex and TCA cycle not only in the platelets but also in various tissues of humans, which is important as a pathway for production of energy, resulting in decreases in the lactate and pyruvate levels in the blood and cerebrospinal fluid. From the EPA toxicological review of DCA: For over 25 years, DCA has been used clinically as an investigational drug to treat several metabolic disorders (congenital lactic acidosis, familial hypercholesterolemia, and diabetes). At the present time the most active pharmaceutical use of DCA is its application in the treatment of congenital lactic acidosis; applications in the treatment of diabetes and hypercholesteremia do not appear to have continued. Congenital lactic acidosis includes a group of inborn metabolic disorders that result in increased blood lactate concentrations. In most cases the metabolic defect is located in the pyruvate dehydrogenase complex, but it can also involve enzymes in the citric acid cycle, enzymes in the respiratory chain, pyruvate carboxylase or phosphoenolpyruvate kinase (Stacpoole et al., 1998b). Each of these enzymes is involved either in bridging the end products of glycolysis to the citric acid cycle or in mitochondrial oxidative metabolism. Affected children exhibit accumulation of lactate and hydrogen ions in blood, urine or cerebrospinal fluid, failure to thrive, and neuromuscular degeneration. Approximately 250 new cases are identified per year and there is about a 20% annual mortality rate for the affected population (Stacpoole et al., 1998b). Some cases of congenital lactic acidosis do not respond to DCA treatment.
Effects of DCA treatment have been limited to transient central neuropathy (sedation), peripheral neuropathy (tingling in fingers and toes and nerve conduction changes), and metabolic changes such as decreases in fasting glucose, plasma lactate and cholesterol, and alanine. For example, Stacpoole et al. (1978) studied diabetic or hyperlipoproteinemic patients, ranging in age from 42 to 71 years. They each received a daily oral dose of 3 to 4 g DCA (43 to 57 mg/kgday, assuming a 70-kg body weight) for 6 or 7 days. Seven female patients were studied over the subsequent 7 days, while four patients (three female, one male) were studied in more detail over a 15-day period after treatment. Some patients experienced mild sedation, but no other laboratory or clinical evidence of adverse effects were noted either during or immediately after the treatment phase.
Dichloroacetate treatment significantly reduced fasting blood glucose levels an average of 24% and produced marked, concomitant decreases in plasma lactate (73%) and alanine (82%) (Stacpoole et al., 1978). Plasma cholesterol levels significantly decreased (22%) and triglyceride levels decreased by 71%. Plasma insulin, free fatty acid, and glycerol levels were not altered. The treatment also depressed uric acid excretion, resulting in elevated serum uric acid levels. Maximum effects were generally noted at the end of the 6- to 7-day treatment period and returned to pretreatment levels during the post-treatment observation period. Plasma cholesterol levels were not altered by treatment in one patient, and the depression of cholesterol levels in the others returned to the pretreatment levels during the recovery period.
The effects of DCA on intermediary metabolites appear to be the result of its activation of pyruvate dehydrogenase, a key enzyme controlling the flow of three carbon metabolites into the citric acid cycle. Pyruvate dehydrogenase exists in active and inactive forms, and is deactivated by phosphorylation through the action of pyruvate dehydrogenase kinase. It is activated through the removal of the phosphate via pyruvate dehydrogenase phosphatase. DCA is an inhibitor of the kinase, thus maintaining the enzyme in its active form (Stacpoole et al., 1998a).
Moore et al. (1979) evaluated clinical effects in two individuals treated with dichloroacetate for radically elevated serum cholesterol. An 8-year-old boy with severe familial hypercholesteremia was given 50 mg/kg-day DCA orally. Total serum cholesterol levels decreased from >1,000 to 849 mg/dL within 7 days. Continued treatment for 5 weeks resulted in a further decrease to 727 mg/dL. No adverse clinical or laboratory signs were detected in this individual.
In a case study of a 21-year-old man reported by Moore et al. (1979), dichloroacetate treatment (50 mg/kg-day) decreased total serum cholesterol levels from 578 to 372 mg/dL in 1 week. At this point, the patient was switched to therapy with nicotinic acid and cholestyramine, but treatment was ineffective and cholesterol levels rose to more than 500 mg/dL. Therapy was reinstated and serum cholesterol levels decreased to 363 mg/dL after 2 weeks and to 325 mg/dL after 10 weeks. After 16 weeks of treatment, the patient complained of tingling in his fingers and toes. Physical examination revealed slight decreases in the strength of facial and finger muscles, diminished to absent deep tendon reflexes, and decreased strength in all muscle groups of the lower extremities (distal muscle groups being most severely affected). Electromyographic studies revealed denervation changes in foot and distal leg muscles. Mild slowing of conduction velocity was noted in both posterior tibial nerves, and no measurable response was obtained in the peroneal or sural nerves. Treatment was immediately discontinued. Eight weeks after treatment stopped, the patient stated that the tingling sensation had subsided. The strength of his facial muscles was normal, and strength in his legs and feet was slightly improved. Six months after treatment was stopped, the patient exhibited normal motor strength, increased deep tendon reflexes and marked improvement in electromyographic and nerve conduction examinations. Serum cholesterol returned to its former high level following the cessation of treatment.
Stacpoole et al. (1998a, b) reviewed observations in humans that have accrued from nearly 25 years of experimental DCA clinical use, primarily in the treatment of congenital lactic acidosis. Therapeutic doses of DCA are usually in the range of 25-50 mg/kg-day (either oral or intravenous). In several cases, treatments at 25 mg/kg-day have occurred for as long as 5 years. Evidence of clinically-significant DCA toxicity in humans is primarily limited to the central and peripheral nervous system. Approximately 50% of patients receiving 25-50 mg/kg-day experience sedative effects. This effect is observed following oral, intravenous, or repeated dosing regimens. There have been three reported cases of peripheral neuropathy following DCA treatment, but all were completely reversible within 6 months of cessation of treatment. In one case, following the reversal of neurological symptoms, reinstitution of DCA at 10 to 25 mg/kg day was maintained for 2 years without further evidence of neuropathy. Two children that were treated for congenital lactic acidosis with 25-75 mg/kg-day DCA orally for several months had a two-fold increase in serum transaminases, suggesting preclinical hepatic toxicity. This increase was also reversible after the treatment ended. One child received oral doses of #25 mg/kg-day for five years before death from pneumonia.
Nerve conduction velocities and amplitudes were studied for one year in 27 patients with congenital lactic acidemia who received sodium dichloroacetate treatment (Spruijt et al., 2001). The patients (16 male, 11 female) whose age ranged from 9 months to 37.4 years (mean 9.8 ± 9.4 years), were started on 50 mg/kg-day DCA and were coadministered 100 mg/day thiamine. Lactate and plasma DCA concentrations were measured at 3, 6, and 12 months, and pharmacokinetics of DCA was measured at 3 and 12 months (data were not reported for these time intervals). All but two of the patients had normal baseline nerve conduction tests prior to DCA administration. Twelve of the patients (9 male, 3 female) who had prior normal baseline electrophysiology showed evidence of neuropathy (decreased nerve conduction velocity and response amplitude) by the end of treatment. Three patients showed neuropathy early, within 3 months of treatment. Neuropathy increased during treatment in the two patients who exhibited neuropathy prior to the start of therapy. Patients with neuropathy were notably older than those with normal electrophysiology; while age was significantly correlated with the deterioration in conduction of some nerves at certain time periods, there was an insufficient number of individuals in the study to provide statistical power for testing age and the deterioration of most nerves.
Data on DCA in humans are scarce, and the fact that available studies in humans have predominantly focused on individuals who were being treated for a disease complicates the assessment of DCA-mediated toxicity. Many of these individuals were extremely ill and the fact that they were being dosed with other medications in addition to DCA presents the possibility that any adverse effects of DCA treatment might not be observed by a clinician. For example, effects might have been masked or developed over a longer period than the treatment period used. To date, there have been no reports of DCA-induced neoplasia in any tissue or gonadal toxicity in humans.
(02/21/07) New Scientist: Cheap, 'safe' drug kills most cancers It sounds almost too good to be true: a cheap and simple drug that kills almost all cancers by switching off their "immortality". The drug, dichloroacetate (DCA), has already been used for years to treat rare metabolic disorders and so is known to be relatively safe. It also has no patent, meaning it could be manufactured for a fraction of the cost of newly developed drugs. Evangelos Michelakis of the University of Alberta in Edmonton, Canada, and his colleagues tested DCA on human cells cultured outside the body and found that it killed lung, breast and brain cancer cells, but not healthy cells. Tumours in rats deliberately infected with human cancer also shrank drastically when they were fed DCA-laced water for several weeks. DCA attacks a unique feature of cancer cells: the fact that they make their energy throughout the main body of the cell, rather than in distinct organelles called mitochondria. This process, called glycolysis, is inefficient and uses up vast amounts of sugar. Until now it had been assumed that cancer cells used glycolysis because their mitochondria were irreparably damaged. However, Michelakis’s experiments prove this is not the case, because DCA reawakened the mitochondria in cancer cells. The cells then withered and died (Cancer Cell, DOI: 10.1016/j.ccr.2006.10.020). Michelakis suggests that the switch to glycolysis as an energy source occurs when cells in the middle of an abnormal but benign lump don’t get enough oxygen for their mitochondria to work properly (see diagram). In order to survive, they switch off their mitochondria and start producing energy through glycolysis. Crucially, though, mitochondria do another job in cells: they activate apoptosis, the process by which abnormal cells self-destruct. When cells switch mitochondria off, they become "immortal", outliving other cells in the tumour and so becoming dominant. Once reawakened by DCA, mitochondria reactivate apoptosis and order the abnormal cells to die. "The results are intriguing because they point to a critical role that mitochondria play: they impart a unique trait to cancer cells that can be exploited for cancer therapy," says Dario Altieri, director of the University of Massachusetts Cancer Center in Worcester. The phenomenon might also explain how secondary cancers form. Glycolysis generates lactic acid, which can break down the collagen matrix holding cells together. This means abnormal cells can be released and float to other parts of the body, where they seed new tumours. DCA can cause pain, numbness and gait disturbances in some patients, but this may be a price worth paying if it turns out to be effective against all cancers. The next step is to run clinical trials of DCA in people with cancer. These may have to be funded by charities, universities and governments: pharmaceutical companies are unlikely to pay because they can’t make money on unpatented medicines. The pay-off is that if DCA does work, it will be easy to manufacture and dirt cheap. Paul Clarke, a cancer cell biologist at the University of Dundee in the UK, says the findings challenge the current assumption that mutations, not metabolism, spark off cancers. "The question is: which comes first?" he says. Other resources: |