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DCA AND Neuropathy

Margaret O James, Stephan C Jahn, Guo Zhong, Marci G Smeltz, Zhiwei Hu, Peter W Stacpoole
Dichloroacetate (DCA) has several therapeutic applications based on its pharmacological property of inhibiting pyruvate dehydrogenase kinase. DCA has been used to treat inherited mitochondrial disorders that result in lactic acidosis, as well as pulmonary hypertension and several different solid tumors, the latter through its ability to reverse the Warburg effect in cancer cells and restore aerobic glycolysis. The main clinically limiting toxicity is reversible peripheral neuropathy. Although administration of high doses to rodents can result in liver cancer, there is no evidence that DCA is a human carcinogen...
February 2017: Pharmacology & Therapeutics
Gonzalo Perez-Siles, Carolyn Ly, Adrienne Grant, Alexander P Drew, Eppie M Yiu, Monique M Ryan, David T Chuang, Shih-Chia Tso, Garth A Nicholson, Marina L Kennerson
Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy. An X-linked form of CMT (CMTX6) is caused by a missense mutation (R158H) in the pyruvate dehydrogenase kinase isoenzyme 3 (PDK3) gene. PDK3 is one of 4 isoenzymes that negatively regulate the activity of the pyruvate dehydrogenase complex (PDC) by reversible phosphorylation of its first catalytic component pyruvate dehydrogenase (designated as E1). Mitochondrial PDC catalyses the oxidative decarboxylation of pyruvate to acetyl CoA and links glycolysis to the energy-producing Krebs cycle...
October 2016: Neurobiology of Disease
Alexis Valauri-Orton, Frizzi Bschorer, Karen K Bernd
Dichloroacetate (DCA) is a water purification byproduct that is known to be hepatotoxic and hepatocarcinogenic and to induce peripheral neuropathy and damage macrophages. This study characterizes the effects of the haloacetate on lung cells by exposing rat alveolar type II (L2) cells to 0-24 mM DCA for 6-24 hours. Increasing DCA concentration and the combination of increasing DCA concentration plus longer exposures decrease measures of cellular health. Length of exposure has no effect on oxidative stress biomarkers, glutathione, SOD, or CAT...
2015: BioMed Research International
Quincy Siu-Chung Chu, Randeep Sangha, Jennifer Spratlin, Larissa J Vos, John R Mackey, Alexander J B McEwan, Peter Venner, Evangelos D Michelakis
Purpose Preclinical evidence suggests dichloroacetate (DCA) can reverse the Warburg effect and inhibit growth in cancer models. This phase 1 study was undertaken to assess the safety, recommended phase 2 dose (RP2D), and pharmacokinetic (PK) profile of oral DCA in patients with advanced solid tumors. Patients and Methods Twenty-four patients with advanced solid malignancies were enrolled using a standard 3 + 3 protocol at a starting dose of 6.25 mg/kg twice daily (BID). Treatment on 28 days cycles was continued until progression, toxicity, or consent withdrawal...
June 2015: Investigational New Drugs
Akbar Khan, Denis Marier, Eric Marsden, Douglas Andrews, Isaac Eliaz
Oral dichloroacetate sodium (DCA) is currently under investigation as a single agent and as an adjuvant for treatment of various cancers. One of the factors limiting its clinical use in a continuous oral regimen is a dose-related, reversible neurotoxicity, including peripheral neuropathy and encephalopathy. The intravenous (IV) route has a number of potential advantages, including (1) pulsed dosing to achieve higher concentrations than feasible with oral use, (2) a longer washout period to reduce the potential for neurotoxicity, and (3) a bypassing of the digestive system, which is particularly significant for advanced-stage cancer patients...
October 2014: Alternative Therapies in Health and Medicine
Monica Abdelmalak, Alicia Lew, Ryan Ramezani, Albert L Shroads, Bonnie S Coats, Taimour Langaee, Meena N Shankar, Richard E Neiberger, S H Subramony, Peter W Stacpoole
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 h) 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...
June 2013: Molecular Genetics and Metabolism
Yasutoshi Koga, Nataliya Povalko, Koujyu Katayama, Noriko Kakimoto, Toyojiro Matsuishi, Etsuo Naito, Masashi Tanaka
Leigh syndrome (LS) is a progressive untreatable degenerating mitochondrial disorder caused by either mitochondrial or nuclear DNA mutations. A patient was a second child of unconsanguineous parents. On the third day of birth, he was transferred to neonatal intensive care units because of severe lactic acidosis. Since he was showing continuous lactic acidosis, the oral supplementation of dichloroacetate (DCA) was introduced on 31st day of birth at initial dose of 50 mg/kg, followed by maintenance dose of 25 mg/kg/every 12 h...
February 2012: Brain & Development
N Nasr, M Czosnyka, F Arevalo, H Hanaire, B Guidolin, V Larrue
HYPOTHESIS: The mechanisms underlying impairment of dynamic cerebral autoregulation in diabetes are not well known. Cardiovascular autonomic neuropathy (CAN) could contribute to dynamic cerebral autoregulation impairment. In this study, we assessed the association between CAN and impairment of dynamic cerebral autoregulation in patients with type 1 diabetes. METHODS: We evaluated dynamic cerebral autoregulation (DCA) in patients with type 1 diabetes and no history of cerebrovascular disease...
February 24, 2011: Autonomic Neuroscience: Basic & Clinical
E D Michelakis, G Sutendra, P Dromparis, L Webster, A Haromy, E Niven, C Maguire, T-L Gammer, J R Mackey, D Fulton, B Abdulkarim, M S McMurtry, K C Petruk
Solid tumors, including the aggressive primary brain cancer glioblastoma multiforme, develop resistance to cell death, in part as a result of a switch from mitochondrial oxidative phosphorylation to cytoplasmic glycolysis. This metabolic remodeling is accompanied by mitochondrial hyperpolarization. We tested whether the small-molecule and orphan drug dichloroacetate (DCA) can reverse this cancer-specific metabolic and mitochondrial remodeling in glioblastoma. Freshly isolated glioblastomas from 49 patients showed mitochondrial hyperpolarization, which was rapidly reversed by DCA...
May 12, 2010: Science Translational Medicine
Randy L Jensen, Peter R Jensen, Annabelle F Shrieve, Lisa Hazard, Dennis C Shrieve
Linear accelerator single-fraction radiosurgery (SRS) for skull base lesions is usually delivered with dynamic conformal arcs (DCAs), but intensity-modulated radiosurgery (IMRS) is another option when SRS dose is limited by proximity of the optic nerve and chiasm. We review the long-term outcome of patients treated with IMRS for parasellar lesions. Fourteen patients with parasellar lesions were treated with IMRS when standard DCA radiosurgery was limited by optic nerve tolerance. Prospective patient data included endocrine function, visual acuity and field testing, nonoptic nerve cranial neuropathy, and overall survival...
June 2010: Journal of Neuro-oncology
Douglas S Kerr
While many treatments for mitochondrial electron transport (respiratory) chain disorders have been suggested, relatively few have undergone controlled clinical trials. This review focuses on the recent history of clinical trials of dichloroacetate (DCA), arginine, coenzyme Q(10), idebenone, and exercise in both primary (congenital) disorders and secondary (degenerative) disorders. Despite prior clinical impressions that DCA had a positive effect on mitochondrial disorders, two trials of diverse subjects failed to demonstrate a clinically significant benefit, and a trial of DCA in MELAS found a major negative effect of neuropathy...
March 2010: Molecular Genetics and Metabolism
Nigel A Calcutt, Veronica L Lopez, Arjel D Bautista, Leah M Mizisin, Brenda R Torres, Albert L Shroads, Andrew P Mizisin, Peter W Stacpoole
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...
September 2009: Journal of Neuropathology and Experimental Neurology
Natalia Felitsyn, Colin McLeod, Albert L Shroads, Peter W Stacpoole, Lucia Notterpek
Delta-aminolevulinic acid (delta-ALA) is a heme precursor implicated in neurological complications associated with porphyria and tyrosinemia type I. Delta-ALA is also elevated in the urine of animals and patients treated with the investigational drug dichloroacetate (DCA). We postulated that delta-ALA may be responsible, in part, for the peripheral neuropathy observed in subjects receiving DCA. To test this hypothesis, myelinating cocultures of Schwann cells and sensory neurons were exposed to delta-ALA (0...
September 2008: Journal of Neurochemistry
Albert L Shroads, Xu Guo, Vaishali Dixit, Hui-Ping Liu, Margaret O James, Peter W Stacpoole
Dichloroacetate (DCA) is an investigational drug for certain metabolic diseases. It is biotransformed principally by the zeta-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...
March 2008: Journal of Pharmacology and Experimental Therapeutics
Natalia Felitsyn, Peter W Stacpoole, Lucia Notterpek
Dichloroacetate (DCA) is an investigational drug for genetic mitochondrial diseases whose use has been mitigated by reversible peripheral neuropathy. We investigated the mechanism of DCA neurotoxicity using cultured rat Schwann cells (SCs) and dorsal root ganglia (DRG) neurons. Myelinating SC-DRG neuron co-cultures, isolated SCs and DRG neurons were exposed to 1-20 mm DCA for up to 12 days. In myelinating co-cultures, DCA caused a dose- and exposure-dependent decrease of myelination, as determined by immunolabeling and immunoblotting for myelin basic protein (MBP), protein zero (P0), myelin-associated glycoprotein (MAG) and peripheral myelin protein 22 (PMP22)...
January 2007: Journal of Neurochemistry
P Kaufmann, K Engelstad, Y Wei, S Jhung, M C Sano, D C Shungu, W S Millar, X Hong, C L Gooch, X Mao, J M Pascual, M Hirano, P W Stacpoole, S DiMauro, D C De Vivo
OBJECTIVE: To evaluate the efficacy of dichloroacetate (DCA) in the treatment of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). BACKGROUND: High levels of ventricular lactate, the brain spectroscopic signature of MELAS, correlate with more severe neurologic impairment. The authors hypothesized that chronic cerebral lactic acidosis exacerbates neuronal injury in MELAS and therefore, investigated DCA, a potent lactate-lowering agent, as potential treatment for MELAS...
February 14, 2006: Neurology
Masato Mori, Takanori Yamagata, Tamako Goto, Shigeko Saito, Mariko Y Momoi
The long-term effects of the sodium salt of dichloroacetic acid (DCA) were evaluated in four patients with mitochondrial encephalomyelopathy with lactic acidosis and stroke-like episodes (MELAS) carrying A3243G mutation. Oral administration of DCA in MELAS patients was followed for an average of 5 years 4 months. Serum levels of lactate and pyruvate were maintained at around 10 and 0.6 mg/dl, respectively. Serum levels of DCA were 40-136 microg/ml. Symptoms responding to treatment included persistent headache, abdominal pain, muscle weakness, and stroke-like episodes...
October 2004: Brain & Development
Michael G Walsh, Janice Zgibor, Knut Borch-Johnsen, Trevor J Orchard et al.
OBJECTIVE: To describe the global geographic variation of micro- and macrovascular complications in childhood-onset type 1 diabetes assessed by both reported and measured disease and risk factors and relate any such variation to diabetes control and health care activities. RESEARCH DESIGN AND METHODS: The DiaComp study is a multinational (17 countries) cross-sectional study of complications in type 1 diabetes and is comprised of two levels (level 1 includes survey only and level 2 includes survey plus examination)...
July 2004: Diabetes Care
K E Hall, J Liu, A A Sima, J W Wiley
There is a growing body of evidence that sensory neuropathy in diabetes is associated with abnormal calcium signaling in dorsal root ganglion (DRG) neurons. Enhanced influx of calcium via multiple high-threshold calcium currents is present in sensory neurons of several models of diabetes mellitus, including the spontaneously diabetic BioBred/Worchester (BB/W) rat and the chemical streptozotocin (STZ)-induced rat. We believe that abnormal calcium signaling in diabetes has pathologic significance as elevation of calcium influx and cytosolic calcium release has been implicated in other neurodegenerative conditions characterized by neuronal dysfunction and death...
August 2001: Journal of Neurophysiology
L Spruijt, R K Naviaux, K A McGowan, W L Nyhan, G Sheean, R H Haas, B A Barshop
Serial measurements of nerve conduction velocities and amplitudes were performed in 27 patients with congenital lactic acidemia over 1 year of sodium dichloroacetate (DCA) administration. Patients were treated with oral thiamine (100 mg) and DCA (initial dose of 50 mg/kg) daily. Nerve conduction velocity and response amplitude were measured in the median, radial, tibial, and sural nerves at 0, 3, 6, and 12 months, and plasma DCA pharmacokinetics were measured at 3 and 12 months. Baseline electrophysiologic parameters in this population were generally below normal but as a group were within 2 standard deviations of normal means...
July 2001: Muscle & Nerve
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