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.
Summary Background Recurrent malignant brain tumors (RMBTs) carry a poor prognosis. Dichloroacetate (DCA) activates mitochondrial oxidative metabolism and has shown activity against several human cancers. Design We conducted an open-label study of oral DCA in 15 adults with recurrent WHO grade III – IV gliomas or metastases from a primary cancer outside the central nervous system. The primary objective was detection of a dose limiting toxicity for RMBTs at 4 weeks of treatment, defined as any grade 4 or 5 toxicity, or grade 3 toxicity directly attributable to DCA, based on the National Cancer Institute’s Common Toxicity Criteria for Adverse Events, version 4.0. Secondary objectives involved safety, tolerability and hypothesis-generating data on disease status. Dosing was based on haplotype variation in glutathione transferase zeta 1/maleylacetoacetate isomerase (GSTZ1/MAAI), which participates in DCA and tyrosine catabolism. Results Eight patients completed at least 1 four week cycle. During this time, no dose-limiting toxicities occurred. No patient withdrew because of lack of tolerance to DCA, although 2 subjects experienced grade 0–1 distal parasthesias that led to elective withdrawal and/or dose-adjustment. All subjects completing at least 1 four week cycle remained clinically stable during this time and remained on DCA for an average of 75.5 days (range 26–312). Conclusions Chronic, oral DCA is feasible and well-tolerated in patients with recurrent malignant gliomas and other tumors metastatic to the brain using the dose range established for metabolic diseases. The importance of genetic-based dosing is confirmed and should be incorporated into future trials of chronic DCA administration.
Dichloroacetate (DCA), a chemical relevant to environmental science and allopathic medicine, is dehalogenated by the bifunctional enzyme glutathione transferase zeta (GSTz1) maleylacetoacetate isomerase (MAAI), the penultimate enzyme in the phenylalanine/tyrosine catabolic pathway. The authors postulated that polymorphisms in GSTz1/MAAI modify the toxicokinetics of DCA. GSTz1/MAAI haplotype significantly affected the kinetics and biotransformation of 1,2-13C-DCA when it was administered at either environmentally (μg/kg/d) or clinically (mg/kg/d) relevant doses. GSTz1/MAAI haplotype also influenced the urinary accumulation of potentially toxic tyrosine metabolites. Atomic modeling revealed that GSTz1/MAAI variants associated with the slowest rates of DCA metabolism induced structural changes in the enzyme homodimer, predicting protein instability or abnormal protein-protein interactions. Knowledge of the GSTz1/MAAI haplotype can be used prospectively to identify individuals at potential risk of DCA’s adverse side effects from environmental or clinical exposure or who may exhibit aberrant amino acid metabolism in response to dietary protein.
We followed 8 patients (4 males) with biochemically and/or molecular genetically proven deficiencies of the E1α subunit of the pyruvate dehydrogenase complex (PDC; 3 patients) or respiratory chain complexes I (1 patient), IV (3 patients) or I+IV (1 patient) who received oral dichloroacetate (DCA; 12.5 mg/kg/12 hours) for 9.7 to 16.5 years. All subjects originally participated in randomized controlled trials of DCA and were continued on an open-label chronic safety study. Patients (1 adult) ranged in age from 3.5 to 40.2 years at the start of DCA administration and are currently aged 16.9 to 49.9 years (mean ± SD: 23.5 ± 10.9 years). Subjects were either normal or below normal body weight for age and gender. The 3 PDC deficient patients did not consume high fat (ketogenic) diets. DCA maintained normal blood lactate concentrations, even in PDC deficient children on essentially unrestricted diets. Hematological, electrolyte, renal and hepatic status remained stable. Nerve conduction either did not change or decreased modestly and led to reduction or temporary discontinuation of DCA in 3 patients, although symptomatic worsening of peripheral neuropathy did not occur. We conclude that chronic DCA administration is generally well-tolerated in patients with congenital causes of lactic acidosis and is effective in maintaining normal blood lactate levels, even in PDC-deficient children not consuming strict ketogenic diets.
Dichloroacetate (DCA) is an investigational drug for certain metabolic diseases. It is biotransformed principally by the -1 family isoform of glutathione transferase (GSTz1), also known as maleylacetoacetate isomerase (MAAI), which catalyzes the penultimate step in tyrosine catabolism. DCA causes a reversible peripheral neuropathy in several species, including humans. However, recent clinical trials indicate that adults are considerably more susceptible to this adverse effect than children. We evaluated the kinetics and biotransformation of DCA and its effects on tyrosine metabolism in nine patients treated for 6 months with 25 mg/kg/day and in rats treated for 5 days with 50 mg/kg/day. We also measured the activity and expression of hepatic GSTz1/MAAI. Chronic administration of DCA causes a striking age-dependent decrease in its plasma clearance and an increase in its plasma half-life in patients and rats. Urinary excretion of unchanged DCA in rats increases with age, whereas oxalate, an end product of DCA metabolism, shows the opposite trend. Low concentrations of monochloroacetate (MCA), which is known to be neurotoxic, increase as a function of age in the urine of dosed rats. MCA was detectable in plasma only of older animals. Hepatic GSTz1/MAAI-specific activity was inhibited equally by DCA treatment among all age groups, whereas plasma and urinary levels of maleylacetone, a natural substrate for this enzyme, increased with age. We conclude that age is an important variable in the in vivo metabolism and elimination of DCA and that it may account, in part, for the neurotoxicity of this compound in humans and other species.
We present the first population pharmacokinetic analysis of quinine in patients with Plasmodium falciparum malaria. Ghanaian children (n ؍ 120; aged 12 months to 10 years) with severe malaria received an intramuscular loading dose of quinine dihydrochloride (20 mg/kg of body weight). A two-compartment model with first-order absorption and elimination gave post hoc estimates for pharmacokinetic parameters that were consistent with those derived from non-population pharmacokinetic studies (clearance [CL] ؍ 0.05 liter/h/kg of body weight; volume of distribution in the central compartment [V 1 ] ؍ 0.65 liter/kg; volume of distribution at steady state ؍ 1.41 liter/kg; half-life at  phase ؍ 19.9 h). There were no covariates (including age, gender, acidemia, anemia, coma, parasitemia, or anticonvulsant use) that explained interpatient variability in weightnormalized CL and V 1 . Intramuscular quinine was associated with minor, local toxicity in some patients (13 of 108; 12%), and 11 patients (10%) experienced one or more episodes of postadmission hypoglycemia. A loading dose of intramuscular quinine results in predictable population pharmacokinetic profiles in children with severe malaria and may be preferred to the intravenous route of administration in some circumstances.Although quinine is one of the oldest drugs in the pharmacopoeia, the optimum usage of quinine in children with severe malaria is still debated (12, 29). The choice of route and dose of quinine for children with severe malaria will vary depending on circumstances and particularly on the capability of administering intravenous infusions reliably. Quinine is the drug of choice for the management of severe malaria in most areas of the world, and it is frequently deployed in conditions where intravenous infusions cannot be rapidly established or reliably monitored.Recent pharmacokinetic studies using African children have revived the intramuscular route as an alternative, cheaper, practicable, and potentially safer route for quinine administration (15, 25,27). However, classical pharmacokinetic studies are not always applicable to populations at highest risk of death from Plasmodium falciparum infection. One of the most important risk factors that identify these children is the complication of lactic acidosis (plasma or whole blood lactate concentration of Ն5 mmol/liter) (11). Dichloroacetate (DCA) is a potential treatment for malaria-associated lactic acidosis (7).We recently conducted a randomized, double-blind, placebo-controlled investigation to test the hypothesis that treatment with the lactate-lowering drug DCA, given with quinine, significantly improved morbidity and mortality in Ghanaian children with lactic acidosis due to severe P. falciparum malaria infection. This report describes the population pharmacokinetics of a loading dose of intramuscular quinine dihydrochloride (20 mg/kg of body weight) in 120 patients. The size of this study also allows assessment of covariables that may be important in influencing quinine kinetics. The ...
The use of dichloroacetate (DCA) for treating patients with mitochondrial diseases is limited by the induction of peripheral neuropathy. The mechanisms of DCA-induced neuropathy are not known. Oral DCA treatment (50–500 mg/kg/day for up to 16 weeks) induced tactile allodynia in both juvenile and adult rats; concurrent thermal hypoalgesia developed at higher doses. Both juvenile and adult rats treated with DCA developed nerve conduction slowing that was more pronounced in adult rats. No overt axonal or glial cell abnormalities were identified in peripheral nerves or spinal cord of any DCA-treated rats but morphometric analysis identified a reduction of mean axonal caliber of peripheral nerve myelinated fibers. DCA treatment also caused accumulation of oxidative stress markers in the nerves. These data indicate that behavioral, functional and structural indices of peripheral neuropathy may be induced in both juvenile and adult rats treated with DCA at doses similar to those in clinical use. DCA-induced peripheral neuropathy primarily afflicts axons and involves both metabolic and structural disorders. The DCA-treated rat may provide insight into the pathogenesis of peripheral neuropathy and facilitate development of adjuvant therapeutics to prevent this disorder that currently restricts the clinical use of DCA.
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