Dichloroacetate is Cardiotonic and Suggested for Treating Metabolic Acidosis: Alleviating Lactate Effects and Beta-ketothiolase Deficiency (An Original Article)

Dichloroacetate (DCA) is an acetate analog that was reported to improve the hemodynamic functions and mechanical efficiency in patients with congestive heart failure. DCA is also known for decades as an activator of pyruvate dehydrogenase (stimulates oxidation of pyruvate to acetyl CoA). This prevents lactate accumulation (stimulating conversion of lactate to form pyruvate then acetyl CoA). Currently, DCA is an effective and safe drug for treating lactic acidosis, a clinical condition due to the accumulation of hydrogen (H+) ions from lactic acid, characterized by blood lactate levels u003e 5 mM and arterial pH u003c 7.25. Interestingly, DCA was reported to cause a significant decrease in serum lactate that was accompanied by an increase in arterial blood pH. Moreover, DCA decreases blood lactate levels under various conditions in both man and laboratory animals via diverting pyruvate metabolism (source of lactate) towards oxidation through activating the target enzyme pyruvate dehydrogenase. High serum lactate (due to anerobic metabolism or as a side effect of insulin/glucose therapy) may occur during treatment of beta ketothiolase deficiency (BKTD). In some BKTD patients, serum lactate may increase contributing to the refractory metabolic acidosis. DCA minimized ketone bodies formation (benefits BKTD patients) but not elimination that can be achieved by insulin/glucose treatment. Current insulin/glucose treatment (for BKTD) causes increased glycolysis (i.e. increased lactate production and metabolic acidosis). On biochemical, pharmacological and medical bases, we suggest that can be normalized upon combining insulin/glucose treatment with DCA. In phenformin-induced lactic acidosis, DCA therapy increased arterial pH and bicarbonate, increased intracellular liver pH and cardiac index causing a fall in blood lactate. In hepatectomy-induced lactic acidosis, animals treated with DCA exhibited stabilization of cardiac index, decreased blood lactate, and decreased mortality. That was better in outcome than sodium bicarbonate treatment. We suggest that DCA may exert pharmacological antagonism with ketone bodies effects e.g. acidosis. DCA may be a promising evidence-based adjuvant therapy for acute refractory metabolic acidosis conditions as BKTD and lactic acidosis.