Phase 1 trial of dichloroacetate (DCA) in adults with recurrent malignant brain tumors.

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.

Development of optimized AAV3 serotype vectors: mechanism of high-efficiency transduction of human liver cancer cells.

Our recent studies have revealed that among the 10 different commonly used adeno-associated virus (AAV) serotypes, AAV3 vectors transduce human liver cancer cells extremely efficiently because these cells express high levels of human hepatocyte growth factor receptor (hHGFR), and AAV3 utilizes hHGFR as a cellular co-receptor for viral entry. In this report, we provide further evidence that both extracellular as well as intracellular kinase domains of hHGFR are involved in AAV3 vector entry and AAV3-mediated transgene expression. We also document that AAV3 vectors are targeted for degradation by the host cell proteasome machinery, and that site-directed mutagenesis of surface-exposed tyrosine (Y) to phenylalanine (F) residues on AAV3 capsids significantly improves the transduction efficiency of Y701F, Y705F and Y731F mutant AAV3 vectors. The transduction efficiency of the Y705+731F double-mutant vector is significantly higher than each of the single mutants in liver cancer cells in vitro. In immunodeficient mouse xenograft models, direct intratumoral injection of AAV3 vectors also led to high-efficiency transduction of human liver tumor cells in vivo. We also document here that the optimized tyrosine-mutant AAV3 vectors lead to increased transduction efficiency following both intratumoral and tail-vein injections in vivo. The optimized tyrosine-mutant AAV3 serotype vectors containing proapoptotic genes should prove useful for the potential gene therapy of human liver cancers.

In vivo regulation of human mononuclear leukocyte 3-hydroxy-3-methylglutaryl coenzyme A reductase. Studies in normal subjects.

In vivo regulation of microsomal HMG CoA reductase activity was investigated in freshly isolated mononuclear leukocytes from 26 healthy adult males. Reductase activity exhibited a diurnal rhythm and decreased during fasting. Enzyme activity was also modulated in vivo by alterations in dietary and plasma cholesterol, suggesting the existence of an operative cholesterol feedback regulatory system. A single, high cholesterol meal decreased reductase activity within 2 h. In addition, rapid depletion of circulating cholesterol levels by plasmapheresis led to an approximately twofold elevation in enzyme activity within 90 min of treatment. Finally, reductase activity was inhibited by dichloroacetate, a compound known to lower plasma cholesterol in man and inhibit the human leukocyte enzyme in vitro. The regulatory mechanisms controlling HMG CoA reductase activity in the human mononuclear leukocyte in vivo thus are similar to those that modulate the mammalian liver enzyme in vivo. Assessment of mononuclear leukocyte reductase activity may provide insight into the in vivo regulation of human cholesterol metabolism.

Regulation of rat liver hydroxymethylglutaryl coenzyme A reductase by a new class of noncompetitive inhibitors. Effects of dichloroacetate and related carboxylic acids on enzyme activity.

Dichloroacetate (DCA) markedly reduces circulating cholesterol levels in animals and in patients with combined hyperlipoproteinemia or homozygous familial hypercholesterolemia (FH). To investigate the mechanism of its cholesterol-lowering action, we studied the effects of DCA and its hepatic metabolites, glyoxylate and oxalate, on the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase) obtained from livers of healthy, reverse light-cycled rats. Oral administration of DCA for 4 d decreased HMG CoA reductase activity 46% at a dose of 50 mg/kg per d, and 82% at a dose of 100 mg/kg per d. A 24% decrease in reductase activity was observed as early as 1 h after a single dose of 50 mg/kg DCA. The inhibitory effect of the drug was due to a fall in both expressed enzyme activity and the total number of reductase molecules present. DCA also decreased reductase activity when added to suspensions of isolated hepatocytes. With chronic administration, DCA inhibited 3H2O incorporation into cholesterol by 38% and into triglycerides by 52%. When liver microsomes were incubated with DCA, the pattern of inhibition of reductase activity was noncompetitive for both HMG CoA (inhibition constant [Ki] 11.8 mM) and NADPH (Ki 11.6 mM). Inhibition by glyoxylate was also noncompetitive for both HMG CoA (Ki 1.2 mM) and NADPH (Ki 2.7 mM). Oxalate inhibited enzyme activity only at nonsaturating concentrations of NADPH (Ki 5.6 mM). Monochloroacetate, glycollate, and ethylene glycol, all of which can form glyoxylate, also inhibited reductase activity. Using solubilized and 60-fold purified HMG CoA reductase, we found that the inhibitory effect of glyoxylate was reversible. Furthermore, the inhibition by glyoxylate was an effect exerted on the reductase itself, rather than on its regulatory enzymes, reductase kinase and reductase phosphatase. We conclude that the cholesterol-lowering effect of DCA is mediated, at least in part, by inhibition of endogenous cholesterol synthesis. The probable mechanisms are by inhibition of expressed reductase activity by DCA per se and by conversion of DCA to an active metabolite, glyoxylate, which noncompetitively inhibits HMG CoA reductase. These studies thus identify a new class of pharmacological agents that may prove useful in regulating cholesterol synthesis and circulating cholesterol levels in man.

Defects in the E2 lipoyl transacetylase and the X-lipoyl containing component of the pyruvate dehydrogenase complex in patients with lactic acidemia.

Three patients with chronic lacticacidemia and deficiency of the pyruvate dehydrogenase complex demonstrated in cultured skin fibroblasts showed abnormalities on Western blotting with anti-pyruvate dehydrogenase complex antiserum which were not located in the E1 (alpha and beta) component of the complex. One of these patients had an enzymatically demonstrable deficiency in the E2 dihydrolipoyl transacetylase segment of the complex and very low observable E2 protein component on Western blotting of fibroblast proteins. The other two patients had abnormalities observable in the X component but no observable reduction in either E1, E2, or E3 enzymatic activities. One patient appeared to have a missing X component while the other had two distinct bands where X should be on Western blotting of fibroblast proteins. All three patients appeared to have severe clinical sequelae resulting from these defects. This is the first time that defects in either the E2 or the X component of the pyruvate dehydrogenase complex have been observed in the human population.

In vivo regulation of human mononuclear leukocyte 3-hydroxy-3-methylglutaryl coenzyme A reductase. Decreased enzyme catalytic efficiency in familial hypercholesterolemia.

3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase) controls the rate of cholesterol biosynthesis and is itself modulated through feedback suppression by internalized low density lipoprotein (LDL) cholesterol. We measured HMG CoA reductase protein concentration and microsomal enzyme activity in freshly isolated mononuclear leukocytes from normal individuals and patients with heterozygous or homozygous familial hypercholesterolemia (FH). Reductase protein concentration was similar in normal and heterozygous subjects, but was over twofold elevated in patients with homozygous FH. Reductase protein concentration was inversely related to LDL receptor status. Total activity and catalytic efficiency of reductase, however, were decreased in heterozygous and homozygous FH patients. The decrease in catalytic efficiency was not due to enzyme phosphorylation or thiol-disulfide formation. Reduction of plasma cholesterol concentration over 2 h by plasmapheresis increased reductase activity, the degree of which was directly proportional to the LDL-receptor status of the subjects. Decreased HMG CoA reductase activity and catalytic efficiency in mononuclear leukocytes and perhaps other cells in FH may represent a fundamental abnormality in the regulation of this enzyme independent of that induced by the LDL-receptor defect and may provide new insight into the control of cholesterol metabolism in FH.

Elevated cholesterol and bile acid synthesis in an adult patient with homozygous familial hypercholesterolemia. Reduction by a high glucose diet.

Elevated levels of cholesterol synthesis are reported for several young children with homozygous familial hypercholesterolemia (HFH) and are considered to contribute directly to their hypercholesterolemia. In contrast, increased cholesterol production has not previously been found in adult patients with HFH. Using the fecal steroid balance technique, we studied rates of cholesterol and bile acid synthesis in a 24-yr-old man who had severe hypercholesterolemia typical of HFH and who lacked skin fibroblast low density lipoprotein (LDL) receptor activity. On an average diet (45% carbohydrate, 40% fat, 15% protein) mean +/- SEM cholesterol (24.8 +/- 1.4 mg/kg per d) and bile acid (11.1 +/- 1.6 mg/kg per d) excretion were approximately threefold higher than normal. When an isocaloric high carbohydrate, low fat diet (90.5% glucose oligosaccharides, 1.3% safflower oil, 8.2% crystalline amino acids was substituted, mean cholesterol (13.0 +/- 0.5 mg/kg per d) and bile acid (8.6 +/- 0.4 mg/kg per d) fell markedly. The decline in fecal steroid excretion was accompanied by modest reductions in plasma total and LDL cholesterol concentrations and by a softening of cutaneous xanthomata. Although the patient phenotypically and biochemically resembled the HFH state, his family pedigree was not noteable for hypercholesterolemia. While the patient's father had premature cardiovascular disease, his mother had no evidence of heart disease, had normal plasma total and LDL cholesterol levels, and had normal fibroblast LDL receptor activity. Likewise, the plasma cholesterol levels of three other members of the patient's family were normal. Despite the unusual genotypic background of this individual, however, the fecal balance data shows that elevated cholesterol and bile acid synthesis may occur in adult, as well as juvenile, patients with HFH and may be responsive to dietary control.

Metabolic complications of severe malaria.

Metabolic complications of malaria are increasingly recognized as contributing to severe and fatal malaria. Disorders of carbohydrate metabolism, including hypoglycaemia and lactic acidosis, are amongst the most important markers of disease severity both in adults and children infected with Plasmodium falciparum. Amino acid and lipid metabolism are also altered by malaria. In adults, hypoglycaemia is associated with increased glucose turnover and quinine-induced hyperinsulinaemia, which causes increased peripheral uptake of glucose. Hypoglycaemia in children results from a combination of decreased production and/or increased peripheral uptake of glucose, due to increased anaerobic glycolysis. Patients with severe malaria should be monitored frequently for hypoglycaemia and treated rapidly with intravenous glucose if hypoglycaemia is detected. The most common aetiology of hyperlactataemia in severe malaria is probably increased anaerobic glucose metabolism, caused by generalized microvascular sequestration of parasitized erythrocytes that reduces blood flow to tissues. Several potential treatments for hyperlactataemia have been investigated, but their effect on mortality from severe malaria has not been determined.

Fibric acid derivatives: effects on the synthesis of isoprenoid lipids in cultured human lymphocytes.

Fibric acid derivatives have been demonstrated to reduce circulating lipoprotein and triacylglycerol concentrations and to inhibit hydroxymethylglutaryl CoA reductase, a key regulatory enzyme of cholesterol biosynthesis. This study describes the effect of four fibric acid derivatives on the biosynthesis of isoprenoid products from acetate and mevalonate in Molt-4 cells, a human leukemic T-lymphocyte cell line. The isoprenoids analyzed were cholesterol as well as dolichol and ubiquinone, alternative products of the branched isoprenoid biosynthetic pathway. None of the fibric acid derivatives showed significant effects on the synthesis of cholesterol from acetate or mevalonate and there was little change in the flux of these metabolites into either dolichol and ubiquinone compared to cells grown in drug-free medium. Therefore, in contrast to the reported inhibitory effects of fibric acids on hepatic sterol synthesis in rats and humans and on hydroxymethylglutaryl CoA reductase activity in human nonmalignant lymphocytes, our results show that these drugs do not significantly affect any of the post-reductase enzymes in the branched metabolic pathways leading from acetate to dolichol, ubiquinone and cholesterol in short term culturing of human malignant lymphocytes.

Regulation of human leukocyte microsomal hydroxymethylglutaryl-CoA reductase activity by a phosphorylation and dephosphorylation mechanism.

The activity of microsomal 3-hydroxy-3-methylglutaryl coenzyme A reductase (EC 1.1.1.34), obtained from cultured human IM-9 lymphoid cells or freshly isolated human peripheral blood leukocytes, is modulated by a phosphorylation/dephosphorylation mechanism. Addition of MgATP + ADP to IM-9 cell microsomal reductase leads to a time-dependent loss of enzyme activity. Inactivated reductase is reactivated by rat liver reductase phosphatase. Kinase-dependent IM-9 cell microsomal reductase, prepared by heating IM-9 microsomes for 15 min at 50 degrees C, is inactivated in the presence of MgATP and ADP only after addition of cytosolic reductase kinase from either IM-9 cells, freshly isolated leukocytes or rat liver. Inactivation is time-dependent and dependent on the cytosolic protein concentration. Inactivated reductase is reactivated by rat liver reductase phosphatase. For cultured IM-9 cells and freshly isolated leukocytes incubated with culture medium for 2 h, the ratios of active (unphosphorylated) to total (phosphorylated + unphosphorylated) reductase activity are 0.22 and 0.43, respectively. Thus, in addition to its regulation by changes in the amount of total enzyme protein, human leukocyte reductase activity is also modulated by a phosphorylation/dephosphorylation mechanism.

Ascorbic acid regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and cholesterol synthesis in guinea pig liver.

Guinea pigs fed a normal diet show the expected diurnal variation in 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. Vitamin C deficiency, however, suppresses the diurnal peak activity of reductase, due to a decrease in active (unphosphorylated) enzyme. Inhibition of reductase is paralleled by both a fall in hepatic cholesterol synthesis and a rise in serum cholesterol. Incubation of normal guinea pig hepatic microsomes with physiologic and supraphysiologic concentrations of sodium ascorbate also leads to a concentration-dependent inhibition of reductase activity. Thus, dietary extremes of vitamin C may exert similar effects on reductase activity and cholesterolgenesis. Moreover, the changes in enzyme activity induced by ascorbic acid appear to be due in part to a direct effect of the vitamin on the microsomally bound enzyme.

Morphologic abnormalities of erythrocytes from patients with homozygous familial hypercholesterolemia.

Erythrocytes from patients with various disorders of lipoprotein metabolism have been found to have abnormal morphology. We report morphologic abnormalities of erythrocytes from two patients with homozygous familial hypercholesterolemia (HFH), in which knisocytes, stomatocytes and crenated cells were observed. The membrane lipid and phospholipid fatty acid composition of HFH erythrocytes was not significantly different from controls. HFH erythrocytes incubated in HFH patient plasma and a lipoprotein-rich fraction of HFH plasma appeared morphologically similar to erythrocytes from HFH patients. These studies support the concept that serum lipids exert an important role in the regulation of erythrocyte morphology in the normal state, as well as in patients with disorders of lipoprotein metabolism.

Biological effects of omega-3 fatty acids in diabetes mellitus.

Fish oils exert important biological effects on several pathways predisposing to atherosclerosis. Epidemiological studies provided the initial evidence that omega-3 fatty acids may be the principal factor in fish oils responsible for these effects and have led to several short-term clinical trials in which fish-oil concentrates have been administered to various populations at risk for coronary heart disease, including patients with diabetes mellitus. omega-3 Fatty acids reduce serum lipids and lipoproteins, impair platelet aggregation, increase cell membrane fluidity, and lower blood pressure in humans. In this review, we highlight these and other potentially antiatherogenic properties of marine lipids in diabetic subjects.

Dichloroacetate.

Dichloroacetate (DCA) represents a potentially novel class of oral antidiabetic agents that reduce blood glucose and lipids without stimulating insulin secretion. DCA reduces blood glucose by inhibiting hepatic glucose synthesis and stimulating glucose clearance and use by peripheral tissues. A major site of action of the drug is pyruvate dehydrogenase (PDH), the rate-limiting enzyme of aerobic glucose oxidation. Stimulation of PDH by DCA increases peripheral oxidation of alanine and lactate, thereby interrupting the Cori and alanine cycles and reducing the availability of three-carbon precursors for gluconeogenesis. In experimental models of ketosis, DCA reduces ketonemia and ketonuria while significantly lowering blood glucose. DCA inhibits hepatic triglyceride and cholesterol biosynthesis. Short-term studies in patients with non-insulin-dependent diabetes have demonstrated a capacity of the drug to markedly reduce circulating a very-low-density lipoprotein cholesterol and triglyceride concentrations. In genetic models of insulin-dependent diabetes, oral administration of DCA significantly reduces insulin requirements and blood levels of glucose and triglycerides. Several derivatives of DCA have been synthesized and found to have biological activity in animals. Further work is required to determine whether DCA and its analogues may be safe and effective agents for chronic treatment of the carbohydrate and lipid abnormalities of human diabetes.

Haplotype variations in glutathione transferase zeta 1 influence the kinetics and dynamics of chronic dichloroacetate in children.

Dichloroacetate (DCA) is biotransformed by glutathione transferase zeta 1 (GSTZ1), a bifunctional enzyme that, as maleylacetoacetate isomerase (MAAI), catalyzes the penultimate step in tyrosine catabolism. DCA inhibits GSTZ1/MAAI, leading to delayed plasma drug clearance and to accumulation of potentially toxic tyrosine intermediates. Haplotype variability in GSTZ1 influences short-term DCA kinetics in healthy adults, but the impact of genotype in children treated chronically with DCA is unknown. Drug kinetics was studied in 17 children and adolescents with congenital mitochondrial diseases administered 1,2-(13) C-DCA. Plasma drug half-life and trough levels varied 3-6-fold, depending on GSTZ1/MAAI haplotype and correlated directly with urinary maleylacetone, a substrate for MAAI. However, chronic DCA exposure did not lead to progressive accumulation of plasma drug concentration; instead, kinetics parameters plateaued, consistent with the hypothesis that equipoise is established between the inhibitory effect of DCA on GSTZ1/MAAI and new enzyme synthesis. GSTZ1/MAAI haplotype variability affects DCA kinetics and biotransformation. However, these differences appear to be stable in most individuals and are not associated with DCA plasma accumulation or drug-associated toxicity in young children.

Recombinant adeno-associated virus vector-based gene transfer for defects in oxidative metabolism.

Defects in oxidative metabolism may be caused by mutations either in nuclear genes or in mitochondrial DNA (mtDNA). We tested the hypothesis that recombinant adeno-associated virus (rAAV) could be used to complement mtDNA mutations. AAV vector constructs were designed to express the reporter gene encoding green fluorescent protein (GFP), fused to a targeting presequence that directed GFP to be translocated into mitochondria. These vectors mediated expression of mitochondrial-localized GFP, as indicated by fluorescence microscopy and electron microscopy, in respiring human embryonic kidney 293 cells and nonrespiring mtDNA-deficient (rho 0) cells. However, when sequences encoding hydrophobic segments of proteins normally encoded by mtDNA were inserted between the presequence and GFP, mitochondrial import failed to occur. In similar experiments, a fusion was created between pyruvate dehydrogenase (PDH) E1 alpha subunit, a nuclear-encoded mitochondrial gene with its own targeting presequence, and GFP. With this construct, expression of GFP was observed in mitochondria in vitro and in vivo. We conclude that the hydrophobicity of mtDNA-encoded proteins limits their ability to be transported from the cytoplasm. However, rAAV-based gene therapy may hold promise for gene therapy of PDH deficiency, the most common biochemically proven cause of congenital lactic acidosis.

QUICKI does not accurately reflect changes in insulin sensitivity with exercise training.

A novel index of insulin sensitivity, the quick insulin sensitivity check index, termed QUICKI (1/[log (insulin) + log (glucose)]), was recently developed. We examined whether QUICKI accurately reflects changes in insulin sensitivity after exercise training, a perturbation known to improve insulin sensitivity. Sedentary, nondiabetic adults underwent a frequently sampled iv glucose tolerance test before and after 6 months of training. Insulin sensitivity was estimated from the glucose tolerance test using Bergman's minimal model (insulin sensitivity-minimal model), and QUICKI was calculated from basal insulin and glucose. Exercise increased (P = 0.003) insulin sensitivity-minimal model but did not change (P = 0.12) QUICKI. Before and after training, the rank-correlation between QUICKI and insulin sensitivity-minimal model was significant (r = 0.79, P = 0.0005; r = 0.56, P = 0.03, respectively). However, the rank-correlation between fasting insulin alone with insulin sensitivity-minimal model was as good (before training r = -0.77, P = 0.0009; after training r = -0.55, P = 0.03) as that between QUICKI and insulin sensitivity-minimal model. Fasting glucose was not related to insulin sensitivity-minimal model at either time. When difference scores (i.e. after pretraining values) were examined, neither QUICKI nor fasting insulin correlated with insulin sensitivity-minimal model (QUICKI vs. insulin sensitivity-minimal model r = 0.24, P = 0.39; fasting insulin vs. insulin sensitivity-minimal model r = -0.40, P = 0.14). We conclude that fasting insulin is equivalent to fasting insulin plus glucose (i.e. QUICKI) at estimating basal insulin sensitivity in nondiabetic adults. However, QUICKI does not accurately reflect exercise-induced changes in insulin sensitivity within individual subjects.

Dichloroacetate therapy attenuates the blood lactate response to submaximal exercise in patients with defects in mitochondrial energy metabolism.

We determined acute and chronic effects of dichloroacetate (DCA) on maximal (MAX) and submaximal (SUB) exercise responses in patients with abnormal mitochondrial energetics. Subjects (n = 9) completed a MAX treadmill bout 1 h after ingesting 25 mg/kg DCA or placebo (PL). A 15-min SUB bout was completed the next day while receiving the same treatment. After a 1-d washout, MAX and SUB were repeated while receiving the alternate treatment (acute). Gas exchange and heart rate were measured throughout all tests. Blood lactate (Bla) was measured 0, 3, and 10 min after MAX, and 5, 10, and 15 min during SUB. MAX and SUB were repeated after 3 months of daily DCA or PL. After a 2-wk washout, a final MAX and SUB were completed after 3 months of alternate treatment (chronic). Average Bla during SUB was lower (P < 0.05) during both acute (1.99 +/- 1.10 vs. 2.49 +/- 1.52 mmol/liter) and chronic (1.71 +/- 1.37 vs. 2.39 +/- 1.32 mmol/liter) DCA vs. PL despite similar exercise intensities between conditions ( approximately 75 and 70% maximal exercise capacity during acute and chronic treatment). Thus, although DCA does not alter MAX responses, acute and chronic DCA attenuate the Bla response to moderate exercise in patients with abnormal mitochondrial energetics.

Glucose and lactate kinetics in children with severe malaria.

Children with severe malaria often present with lactic acidosis and hypoglycemia. Although both complications independently predict mortality, mechanisms underlying their development are poorly understood. To study these metabolic derangements we sequentially allocated 21 children with falciparum malaria and capillary lactate concentrations of 5 mmol/L or more to receive either quinine or artesunate as antimalarial therapy, and dichloroacetate or saline placebo for lactic acidosis. We then administered a primed infusion (90 min) of L-[3-13C1]sodium lactate and D-[6,6-D2]glucose to determine the kinetics of these substrates. The mean (SD) glucose disposal rate in all patients was 56 (16) micromol/kg x min, and the geometric mean (range) lactate disposal rate was 100 (66-177) micromol/kg x min. Glucose and lactate disposal rates were positively correlated (r = 0.62; P = 0.005). Artesunate was associated with faster parasite clearance, lower insulin/glucose ratios, and higher glucose disposal rates than quinine. Lactate disposal was positively correlated with plasma lactate concentrations (r = 0.66; P = 0.002) and time to recovery from coma (r = 0.82; P < 0.001; n = 15). Basal lactate disposal rates increased with dichloroacetate treatment. Elevated glucose turnover in severe malaria mainly results from enhanced anaerobic glycolysis. Quinine differs from artesunate in its effects on glucose kinetics. Increased lactate production is the most important determinant of lactic acidosis.

Plasma concentrations and metabolic effects of intravenous sodium dichloroacetate.

Eleven healthy subjects received five doses of intravenous sodium dichloroacetate (DCA) at 2-hr intervals. Determinations of DCA in plasma and of lactate and glucose in blood were made at various times until 24 hr after starting the first infusion. Twenty-four-hour urinary oxalate excretion was also measured. DCA levels rose and fell during and after each dose, with higher levels induced by higher doses. Lactate levels fell as the result of DCA treatment, with greater falls after higher doses, and returned to normal after 24 hr at the two lower dose levels but not at the level of 50 mg/kg. Lactate levels did not change parallel to changes in DCA levels. Only the doses of 50 mg/kg prevented postprandial rises in lactate levels. Blood glucose levels were not altered. The mean DCA t1/2 after the initial doses was 63.3 min (range 15.0 to 112.2 min), while that after the final doses was 374.0 min (range 37.8 to 1386.0 min). The AUC and the DCA-induced increase in urinary oxalate excretion were linearly related to dose. Mean DCA apparent volume of distribution was 0.30 l/kg (range 0.09 to 0.60 l/kg).