5/2/2016 Alpha ‐ Lipoic Acid and Its Clinical Applications Objectives Burton M. Berkson, MD, MS, PhD • Describe the structure and metabolic function of Alpha ‐ Lipoic Acid. Relevant financial relationships in the past twelve months by presenter or • Present some of the history of Alpha ‐ Lipoic Acid as an investigational spouse/partner: drug and as a nutraceutical. Employment: Integrative Medical Center of New Mexico • Describe the role of Alpha ‐ Lipoic Acid in mitochondrial function. Grant/Research Support: N/A Consultant: Livon Labs Supplements • Characterize the role of Alpha ‐ Lipoic Acid in liver disease. Speakers Bureau: Livon Labs • Portray the role of Alpha ‐ Lipoic Acid in cancer therapy. Stock Shareholder: N/A Other: Bio ‐ tech Products Consultant • Describe the role of Alpha ‐ Lipoic Acid in auto ‐ immune disease. Status of FDA devices used for the material being presented N/A Status of off ‐ label use of devices, drugs or other materials that constitute the subject of this presentation N/A ACTION AC ONS OF OF ALA ALA Alpha-lipoic acid, (ALA), Thioctic Acid EUK EUKARYOTIC IC RE RESP SPIRATIO ION Glycolysis: Gly anaerobic • GLYCOLYSIS (cytoplasm) Occurs in the cytoplasm pyruvate dehyrogenase (ALA) Glucose is converted to pyruvate. No oxygen is required. KREBS CYCLE (mitochrondrion) Cancer cells typically just go this far and convert pyruvate to lactate even in the presence of O2. 1
5/2/2016 Alpha lipoic acid is fundamental, Kr Krebs Cy Cycle cle for the conversion of food to energy. It is my understanding that ALA is the rate ‐ limiting agent for the production of Glycolysis Occurs in the energy from food in aerobic cells anaerobic mitochondrion In the presence • ALA of oxygen aerobic Pyruvate Dehydrogenase Complex Korotchkina LG, Sidhu S, Patel MS. Lipoic acid inhibits mammalian pyruvate dehydrogenase kinase. Free Radic Res. 2004 Oct;38(10):1083 ‐ 92. FATS CARBS PROTEINS Pyruvate Dehyrogenase Kinase (PDK) inhibits the enzyme complex (PDH) that converts Pyruvate into Acetyl CoA GLYCEROL PYRUVATE PDH ALPHA ‐ LIPOIC ACID Alpha Lipoic Acid decreases the rate of action of Pyruvate Dehyrogenase Kinase ACETYL CO A Sutendra G, Kinnaird A, Michelakis ED Pyruvate dehydrogenase Nuclear pyruv Nu pyruvate de dehydrogenase co comple lex is is im important kinase inhibits Pyruvate for the fo the ge generation of of ac acetyl etyl ‐ CoA CoA an and his histone ac acetyla etylatio ion. n. Dehydrogenase Cell. 2014 Jul 3;158(1):84 ‐ 97. More available Pyruvate Dehyrogenase Alpha Lipoic Acid is important for the results in increased acetylation of histones in the cell nucleus. Pyruvate being directed into the Alpha Lipoic Acid helps repair DNA Krebs Cycle over the conversion of Pyruvate to Lactate 2
5/2/2016 Since Since a yo young ung per person on Wha What if if a mito tocho chondr ndrio ion re receives to too much much ALA ALA? produce duces eno enormous amo amounts of of ALA, ALA, Lipoi Lipoic acid acid LD5 LD50 Studies Studies by by Dr Drs Vigil igil and and Co Couch uch. what happ wha happen ens when when yo you feed eed a Thanksgi ksgivin ving dinner dinner to a 2 year to year old old child child; Couch RC, Vigil M. et al. A dose escalation toxicity study of DL ‐ 6 ‐ 8 thioctic acid (lipoic acid) in Rhesus monkeys. 1997. Poster display. or an or an 80 80 year year old old man man? Annual Meeting Society of Toxicology. LOE B Healthy prima Health primate mito tocho chondr ndrio ion (hepa epatocyt ocyte) e) • Following these studies I was asked to observe the necropsies and perform the electron microscopy work on the damaged tissues at NMSU. • I observed extensive necrotic lesions in the liver, kidneys, heart, and the large muscles of the extremities. Primate hepato Pr tocy cyte te mi mito tochondr ndria follo llowing a LD50 LD50 IV lip IV lipoic aci cid do dose of of ab about out 90m 90mg/kg Mitochondria from animals who had received excessively high doses of ALA became extremely edematous, and demonstrated a disruption of all the crucial structures. These mitochondria did not exhibit the regular double membrane wall structure, but showed a coalescence of these structures with a deliquescence of membranes thus exhibiting a complete disruption of normal ultrastructure. 3
5/2/2016 LIVE LIVER MI MITOCHO CHONDRIA IA SUFFERED ERED SE SEVERE ST STRU RUCTU CTUAL DAM DAMAGE GE BY BY EXTREMEL EMELY HIG HIGH DO DOSES OF OF INT INTRAVENOUS ALPH ALPHA LIPO LIPOIC AC ACID Gl Global Ad Advance nces in in Hea Health th an and Me Medic dicine ne January,201 2014, 4, vo volume 3 number 1 num • In reality, much lower doses of IV lipoic acid may cause Michael Vigil MD Adjunct Associate Research Professor, Department of Biochemistry NMSU serious bouts of hypoglycemia and the doctor and nurse must at all times watch carefully for possible problems. Burton M. Berkson MD MS PhD Former Assistant Professor, Rutgers University Former Associate Professor, Chicago State University Founder, The Integrative Medical Center of New Mexico Adjunct Professor, NMSU Adjunct Professor Oklahoma State Univ. College of Medicine bberkson@nmsu.edu (corresponding author) Ana Patricia Garcia DVM MS PhD Associate Research Professor and Veterinary Pathologist Yerkes Assistant Professor, Department of Pathology and Laboratory Medicine Emory University School of Medicine If the mitochondrion is supplied with excessive amounts of ALA, it accelerates aerobic respiration and the process runs ahead With appropriate ALA levels, the mitochondrion of the other necessary constituents. functions normally. The mitochondrion heats up, free radicals accumulate, and its If the mitochondrion does not obtain sufficient ALA, it membranous components break down. suffers, Severe damage to the mitochondrion is first seen by gross and the organism dies. swelling and then severe damage to the cristae and matrix material. It is interesting to note that therapeutic doses of intravenous ALA helps a liver regenerate but extremely high doses of the same agent causes liver necrosis. Does ALA help regenerate livers? Of course, excessive and unreasonable amounts of any 1 st large scale clinical trial with IV alpha ‐ lipoic acid at substance given intravenously can be lethal, including water NIH. and salt. (Bartter, Berkson, et. al. 1977 ‐ 1980) B 4
5/2/2016 We reported in 3 publications that we treated 79 people waiting for liver transplant surgery (acute hepatic necrosis) and 75 regenerated their livers with just the administration of intravenous Alpha ‐ lipoic acid. I was appointed by the FDA principal investigator for alpha lipoic acid as a prescription drug in 1983. That lasted 23 years. Bartter FC, Barry Rumack, and Berkson B 1978 As visiting scientists at the Max Planck Institute in Heidelberg B Our first paper. Should have been titled ALA reverses Acute Hepatic Necrosis CIRR CIRRHOTIC LIVER LIVER If If IV IV ALA ALA re revers rses acut acute liv liver er diseas disease, will will it it re reverse chronic liv chr liver er disea disease, fo for exa example hepa hepatitis C? C? 5
5/2/2016 GE GERM RMAN AN JO JOURNAL OF OF INT INTERNAL ME MEDI DICINE CINE AR ARTICLE Conclusion of my 1999 paper. I offered a more conservative Berkson BM. A conservative triple antioxidant approach to the treatment of approach to the treatment of hepatitis C. Combination of alpha lipoic acid (thioctic acid), silymarin, and hepatitis C, selenium.Med Klin (Munich). 1999 Oct 15;94 Suppl 3:84 ‐ 9. that is exceedingly less expensive. One year of the triple anti-oxidant therapy described I took 3 cirrhotic hepatitis C patients in the process of liver transplant in this paper costs less than evaluation at University Hospital and administered ALA, silymarin and $ 3,000, as compared to more selenium (inhibition of replication). than The 3 recovered normal liver function within 6 months. $ 500,000 a year for liver transplant surgery. B B Are there other diseases that ALA might help? Lipoic Acid prevents ischemia- reperfusion injury Smith AR, Shenvi SV, Widlansky M, et al. Curr Med Chem. 2004 May;11(9):1135-46.) Panigrahi M, Sadguna Y, Shivakumar BR, Kolluri SV, Roy Lipoic acid is a potential therapy for chronic diseases S, Packer L, Ravindranath V. Brain Res . 1996;717(1- 2):184-188. - associated with oxidative stress. Alpha-Lipoic acid protects against Most chronic diseases are associated with OS. ischemia reperfusion injury following cerebral ischemia. B B What about ALA and diabetes? Jacob S, Henriksen E, Schiemann A. et al. Enhancement of glucose disposal in patients with type 2 diabetes Suh JH, Shigeno ET, Morrow JD, et al. Faseb J. 2001;15(3):700-706. by alpha-lipoic acid. Arzneimittel-Forschung 1995, 45(8):872-874. Oxidative stress in the aging rat heart is reversed Henriksen et al. published the first human study to by supplementation with alpha-lipoic acid. show that ALA increases insulin stimulated glucose movement into the cell, and out of the blood stream, in diabetes. B B 6
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