The Experts below are selected from a list of 5142 Experts worldwide ranked by ideXlab platform

Peter W. Stacpoole - One of the best experts on this subject based on the ideXlab platform.

  • Personalized Dosing of Dichloroacetate Using GSTZ1 Clinical Genotyping Assay.
    Genetic testing and molecular biomarkers, 2018
    Co-Authors: Taimour Y. Langaee, Richard E Wagner, Lloyd P. Horne, Lee Ann Lawson, Cecilia Becker, Mohamed H. Shahin, Petr Starostik, Peter W. Stacpoole
    Abstract:

    Aims: Dichloroacetate (DCA) represents the first targeted therapy for pyruvate dehydrogenase complex deficiency; it is metabolized by glutathione transferase zeta1 (GSTZ1). Variation in the GSTZ1 h...

  • Peripheral neuropathy in rats exposed to Dichloroacetate.
    Journal of neuropathology and experimental neurology, 2009
    Co-Authors: Nigel A. Calcutt, Veronica L. Lopez, Arjel D. Bautista, Leah M. Mizisin, Brenda R. Torres, Albert L. Shroads, Andrew P. Mizisin, Peter W. Stacpoole
    Abstract:

    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 per 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 rat, but morphometric analysis identified a reduction of mean axonal caliber of peripheral nerve myelinated fibers. Dichloroacetate 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. Dichloroacetate-induced peripheral neuropathy primarily afflicts axons and involves both metabolic and structural disorders. The DCA-treated rat may provide insight into the pathogenesis of this peripheral neuropathy and facilitate development of adjuvant therapeutics to prevent this disorder that currently restricts the clinical use of DCA.

  • Evaluation of Long-term Treatment of Children With Congenital Lactic Acidosis With Dichloroacetate
    Pediatrics, 2008
    Co-Authors: Peter W. Stacpoole, Lesa R. Gilbert, Richard E. Neiberger, Paul R. Carney, Edward Valenstein, Douglas W. Theriaque, Jonathan J. Shuster
    Abstract:

    Dichloroacetate has been administered for several years to children and adults with genetic mitochondrial diseases. The primary rationale for its use is its ability to stimulate the activity of the pyruvate dehydrogenase complex, thereby facilitating aerobic glucose and lactate oxidation and energetics.1 Most published information on the safety and efficacy of Dichloroacetate in this patient population is derived from open-label studies in 1 or a few individuals. Recently, a randomized, controlled trial evaluated oral Dichloroacetate at a dose of 12.5 mg/kg twice daily for the chronic treatment of older adolescents and adults (mean age at entry: 30 years) with the common A3243G mutation in mitochondrial DNA that gives rise to the syndrome of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes.2 This study was terminated prematurely because of an undue incidence of worsening or new onset of peripheral neuropathy associated with Dichloroacetate administration compared with placebo administration. Another recently completed randomized, controlled trial investigated the same Dichloroacetate dose in 43 young children (mean age at entry: 5.6 years) with congenital lactic acidosis (CLA) because of defects in pyruvate dehydrogenase or in ≥1 complex of the respiratory chain or a mitochondrial DNA mutation.3 In contrast to the findings in older subjects with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes, this study demonstrated good tolerability of Dichloroacetate, and there were no significant differences in the severity or frequency of adverse events between the drug and placebo groups after 6 months of treatment. Here we report our experience with long-term administration of Dichloroacetate in the 36 children on the trial who received Dichloroacetate, from their starting times on the drug. Some of these patients have received treatment continuously for ~10 years.

  • pharmacokinetics metabolism and toxicology of Dichloroacetate
    Drug Metabolism Reviews, 1998
    Co-Authors: Peter W. Stacpoole, George N. Henderson, Zimeng Yan, Rachel Cornett, Margaret O. James
    Abstract:

    (1998). Pharmacokinetics, Metabolism, and Toxicology of Dichloroacetate. Drug Metabolism Reviews: Vol. 30, No. 3, pp. 499-539.

  • Clinical pharmacology and toxicology of Dichloroacetate.
    Environmental Health Perspectives, 1998
    Co-Authors: Peter W. Stacpoole, George N. Henderson, Zimeng Yan, Margaret O. James
    Abstract:

    Dichloroacetate (DCA) is a xenobiotic of interest to both environmental toxicologists and clinicians. The chemical is a product of water chlorination and of the metabolism of various drugs and indu...

George N. Henderson - One of the best experts on this subject based on the ideXlab platform.

  • pharmacokinetics metabolism and toxicology of Dichloroacetate
    Drug Metabolism Reviews, 1998
    Co-Authors: Peter W. Stacpoole, George N. Henderson, Zimeng Yan, Rachel Cornett, Margaret O. James
    Abstract:

    (1998). Pharmacokinetics, Metabolism, and Toxicology of Dichloroacetate. Drug Metabolism Reviews: Vol. 30, No. 3, pp. 499-539.

  • Clinical pharmacology and toxicology of Dichloroacetate.
    Environmental Health Perspectives, 1998
    Co-Authors: Peter W. Stacpoole, George N. Henderson, Zimeng Yan, Margaret O. James
    Abstract:

    Dichloroacetate (DCA) is a xenobiotic of interest to both environmental toxicologists and clinicians. The chemical is a product of water chlorination and of the metabolism of various drugs and indu...

  • Kinetics and Metabolism of Chloral Hydrate in Children: Identification of Dichloroacetate as a Metabolite☆
    Biochemical and biophysical research communications, 1997
    Co-Authors: George N. Henderson, Zimeng Yan, Margaret O. James, Natalia Davydova, Peter W. Stacpoole
    Abstract:

    Chloral hydrate was introduced into therapeutics more than 100 years ago, and since then a number of kinetic and metabolic studies have been conducted on this drug. Trichloroethanol, its glucuronide and trichloroacetic acid have been identified as the metabolites of chloral hydrate. We now report the identification of Dichloroacetate as a major product of chloral hydrate metabolism in children, in addition to trichloroethanol and trichloroacetic acid. Furthermore, pretreatment of children with chloral hydrate appears to retard the plasma clearance of Dichloroacetate.

  • Pharmacokinetics of Dichloroacetate in Adult Patients with Lactic Acidosis
    Journal of clinical pharmacology, 1997
    Co-Authors: George N. Henderson, Stephen H. Curry, Hartmut Derendorf, Elizabeth C. Wright, Peter W. Stacpoole
    Abstract:

    The pharmacokinetic properties of the lactate-lowering drug Dichloroacetate were investigated in 111 adult patients with lactic acidosis who were randomized to receive Dichloroacetate as part of a placebo-controlled clinical trial. The clinical symptoms and etiology of lactic acidosis varied markedly among patients. Dichloroacetate, at a dose of 50 mg per kilogram of body weight, was administered in a 30-minute intravenous infusion into a peripheral vein. A second dose, identical to the first, was administered 2 hours after beginning the first infusion. Plasma levels of Dichloroacetate were determined from blood samples collected periodically up to 288 hours after administration and the data were subjected to pharmacokinetic modeling. The pharmacokinetic properties of Dichloroacetate in these acutely ill patients were complex and differed markedly from those in healthy volunteers, whose data fitted a one-compartment pharmacokinetic model. In contrast, the data from patients fitted one-, two-, or three-compartment pharmacokinetic models or even none of these, depending on the individual. Drug clearance in plasma tended to decrease as the number of compartments required to fit the data increased or as the number of drug treatments increased.

  • Improved hemodynamic function and mechanical efficiency in congestive heart failure with sodium Dichloroacetate.
    Journal of the American College of Cardiology, 1994
    Co-Authors: Robert M. Bersin, Christopher L. Wolfe, Michael Kwasman, Deborah Lau, Cindy Klinski, Kevin Tanaka, Payman Khorrami, George N. Henderson, Teresa De Marco, Kanu Chatterjee
    Abstract:

    Abstract Objectives . The purpose of this study was to determine whether sodium Dichloroacetate improves hemodynmic performance and mechanical efficiency in congestive heart failure. Background . Congestive heart failure is associated with impaired hemodynamic performance and reduced mechanical efficiency. Dichloroacetate stimulates pyruvate dehydrogenase activity by inhibition of pyruvate dehydrogenase kinase, which results in inhibition of free fatty acid metabolism and stimulation of high respiratory quotient glucose and lactate consumption by the heart. Facilitation of glucose and lactate consumption with Dichloroacetate should improve mechanical efficiency of the failing ventricle. Methods . Ten patients with New York Heart Association functional class III to IV congestive heart failure were studied. Dichloroacetate (50 mg/kg body weight) was administered intravenously for 30 min, with measurements of hemodynamic variables, coronary sinus blood flow and blood gas, glucose and lactate levels for 2 h. The same patients were also given dobutamine (5 to 12.5 mg/kg per min) for comparison. Results . Therapeutic levels of Dichloroacetate were achieved (100 to 160 μg/liter of plasma). Myocardial consumption of lactate was stimulated from 29% to 37.4%. Forward stroke volumes increased (+5.3 ml/beat, p 2 per beat, p 2 per min, p Dobutamine administration resulted in the opposite trend with respect to myocardial lactate extraction (from 34% to 15.3%, p 2 per min, p Conclusions . Dichloroacetate administration stimulates myocardial lactate consumption and improves left ventricular mechanical efficiency. Forward stroke volume and left ventricular minute work increase significantly, with a simultaneous reduction in myocardial oxygen consumption. Dobutamine administration results in similar hemodynamic improvements but with no change in left ventricular mechanical efficiency and with opposite effects on lactate metabolism. The opposing metabolic actions, yet similar hemodynamic responses, of Dichloroacetate and dobutamine suggest that these agents may be complementary in the treatment of congestive heart failure.

Margaret O. James - One of the best experts on this subject based on the ideXlab platform.

Lawrence L Spriet - One of the best experts on this subject based on the ideXlab platform.

Junichi Yoshitake - One of the best experts on this subject based on the ideXlab platform.

  • The effects of Dichloroacetate on liver damage and circulating fuels in rats exposed to carbon tetrachloride
    Journal of gastroenterology and hepatology, 1994
    Co-Authors: Kazuo Irita, Hironao Okabe, Akitoshi Koga, Masae Yamakawa, Junichi Yoshitake, Shosuke Takahashi
    Abstract:

    It has been known that carbon tetrachloride-induced liver damage in starved rats is ameliorated simply by restoration of feeding. An analogue of Dichloroacetate has been reported to ameliorate carbon tetrachloride-induced liver damage, and Dichloroacetate has been shown to have a variety of effects on fuel metabolism. We investigated simultaneously the effects of Dichloroacetate on liver damage and on circulating fuels in rats exposed to carbon tetrachloride. The effects of carbon tetrachloride varied with the rat's condition. In starved rats, the liver damage was more severe, and serum ketone body concentration decreased. In non-starved rats, the liver damage was not as severe and the serum ketone body concentration increased. The administration of Dichloroacetate ameliorated liver damage both in starved and in non-starved rats given carbon tetrachloride: the administration of Dichloroacetate protected from the liver damage particularly in starved rats. There were associated changes in the concentractions of circulating fuels. When the pyruvate-lowering effect of Dichloroacetate was diminished in carbon tetrachloride-injected, starved rats, the alanine aminotransferase-lowering effect of Dichloroacetate was also diminished. We propose that Dichloroacetate's effect on fuel metabolism may produce a hepato-protective effect.

  • The Limiting Effect of Dichloroacetate on Endotoxin-Induced Liver Damage in Starved Rats
    The Journal of surgical research, 1994
    Co-Authors: Kazuo Irita, Hironao Okabe, Akitoshi Koga, Masae Yamakawa, Junichi Yoshitake
    Abstract:

    Abstract Dichloroacetate has been shown to have therapeutic effects on sepsis and endotoxin shock and to reduce liver damage in rats intoxicated with ethanol or carbon tetrachloride. In this study, the effect of Dichloroacetate on endotoxin hepatitis was investigated. Endotoxin hepatitis was induced by an intraperitoneal coadministration of 50 μg/kg lipopolysaccharide from Escherichia coli, and 200 mg/kg D-galactosamine in starved, male Wistar rats. This treatment induced the following changes within 24 hr: an increase in the serum aminotransferase activity, histological alterations of the liver including focal necrosis of liver cells and inflammatory infiltrates, an increase in blood pyruvate and alanine concentrations, and inhibition of starvation ketosis. The intraperitoneal administration of 250 mg/kg Dichloroacetate 30 min after the administration of the toxins partially counteracted all of these changes. The administration of Dichloroacetate might be useful in coping with hepatic damage as well as lacticemia and cardiovascular depression induced by endotoxins.