Sodium dichloroacetate 250mg/5ml oral solution

Pyruvate dehydrogenase complex deficiency (PDCD) is a heterogenous mitochondrial inborn error in carbohydrate oxidation manifesting as congenital lactic acidosis. PDCD presents diagnostic and therapeutic challenges. While no curative treatment exists for PDCD, certain therapeutic modalities may improve prognosis and ameliorate symptom severity. This article examines the effectiveness of treatments for PDCD and presents a case series of three patients with PDCD. A scoping literature review was conducted for treatments of PDCD. Patient data for case reports was extracted retrospectively from electronic medical records from a large tertiary hospital. We reviewed and summarized findings from seven preclinical studies and ten human studies, which showed that dichloroacetate and the ketogenic diet were the most frequently studied treatments. Therapeutic approaches observed select positive outcomes such as reduced lactate levels, improved neuropathological manifestations, and increased longevity. However, most interventions have yet to be rigorously investigated. Early diagnosis of PDCD is integral, as treatment methods may offer improved clinical and biochemical outcomes. Clinical trials of existing and novel treatments are necessary to improve management and further understand the prognostic potential of this metabolic disorder.

Abstract licence: CC BY

Rarely has a chemical elicited as much controversy as dichloroacetate (DCA). DCA was initially considered a dangerous toxic industrial waste product, then a potential treatment for lactic acidosis. However, the main controversies started in 2008 when DCA was found to have anti-cancer effects on experimental animals. These publications showed contradictory results in vivo and in vitro such that a thorough consideration of this compound’s in cancer is merited. Despite 50 years of experimentation, DCA’s future in therapeutics is uncertain. Without adequate clinical trials and health authorities’ approval, DCA has been introduced in off-label cancer treatments in alternative medicine clinics in Canada, Germany, and other European countries. The lack of well-planned clinical trials and its use by people without medical training has discouraged consideration by the scientific community. There are few thorough clinical studies of DCA, and many publications are individual case reports. Case reports of DCA’s benefits against cancer have been increasing recently. Furthermore, it has been shown that DCA synergizes with conventional treatments and other repurposable drugs. Beyond the classic DCA target, pyruvate dehydrogenase kinase, new target molecules have also been recently discovered. These findings have renewed interest in DCA. This paper explores whether existing evidence justifies further research on DCA for cancer treatment and it explores the role DCA may play in it.

Abstract licence: CC BY 4.0

Summary. It is known that the arsenal of chemotherapeutic agents for the treatment of malignant brain tumors is quite limited, which causes the high relevance of research aimed at finding new effective antitumor regimens, including the use of energy metabolism modifiers. Aim: To investigate the anti-glioma activity of sodium dichloroacetate (DCA) and metformin (MTF) used in combination in vitro and in vivo. Materials and Methods: Cell survival, cell cycle, apoptosis, mitochondrial membrane potential (Δψm), ATP level, the glucose consumption rate, and lactate production rate were determined in vitro in cultured glioma C6 cells. The antitumor action of agents in vivo was evaluated routinely by the prolongation of the life span of rats with transplanted intracerebral glioma C6 and was confirmed by histological examination of tumor tissue. Results: The half maximal inhibitory concentration (IC50) for DCA and MTF used separately was 79.2 ± 2.1 mM and 78.4 ± 4.0 mM, respectively, whereas IC50 for DCA used in combination with 7.8 mM MTF was 3.3 fold lower (24.0 ± 1.2 mM, p < 0.05). The 1-day incubation of cells with DCA at a concentration close to IC50 (25 mM), in combination with MTF at a concentration by order lower than IC50 (7.8 mM), in contrast to their separate use, resulted in a decrease in the number of viable cells by 40% (p < 0.05); redistribution of the cells by the cell cycle phases toward decreased proportion of cells in the S-phase by 46% (p < 0.05) and an increased percentage of cells in the G0/G1 phase by 24% (p < 0.05) compared to similar indices in the control. High proapoptotic activity of DCA in combination with MTF was supported by a significantly higher percentage of apoptotic cells in vitro than in the control (18.9 ± 4.4% vs 5.7 ± 1.3%, p < 0.05) and a high number of tumor cells with signs of apoptosis revealed during the histological examination of tumor pathomorphosis. The combined effect of DCA and MTF resulted in almost 4-fold decrease of the glucose consumption rate by glioma C6 cells (0.23 ± 0.05 μmol/106 cells/h vs 0.91 ± 0.12 μmol/106 cells/h, p < 0.05) compared to the corresponding parameters in the control, and 2-fold increased rate of lactate production (1.06 ± 0.03 μmol/106 cells/h vs 0.53 ± 0.03 μmol/106 cells/h, p < 0.05). At the same time, both Δψm and the level of intracellular ATP in the glioma C6 cells treated with DCA and MTF, both separately and in combination, did not differ significantly from those indices in the control. In in vivo studies, the average life span of rats with intracranial transplanted glioma C6, treated with DCA in combination with MTF in a total dose of 1.1 and 2.6 g/kg body weight, respectively, was 50% higher (p < 0.001) than in the control group. In contrast, in the case of single-use (at a dose of 2.6 g/kg), MTF increased the life span of tumor-bearing animals just by 19% (p < 0.01), whereas DCA alone (at a dose of 1.1 g/kg) did not significantly change the survival time of rats. Conclusions: The obtained data indicate synergism of anti-glioma action of DCA and MTF in a case of their combined use both in vitro and in vivo and may be considered a starting point for the development of effective treatment regimens for malignant brain tumors based on the combined use of DCA and MTF.

Abstract licence: CC BY-NC 4.0