THE AVENGERCoenzyme Q10: Ubiquinone BY DR. ABDULRAB SHAIKH
History 1957 - Coenzyme Q10 was first isolated from beef heart mitochondria by Dr. Frederick Crane 1958 - The precise chemical structure of Coenzyme Q10 was determined by professor Karl Folkers and collaborators at Merck, Inc. 1961 - Coenzyme Q10 was considered as a potential treatment for cancer. 1964 – Coenzyme Q10 demonstrated its usefulness for the treatment of congestive heart failure. 1970 – Coenzyme Q10 demonstrated its effectiveness as an anti-oxidant.
Biosynthesis of Coenzyme Q1. Synthesis of the benzoquinone structure from either tyrosine or phenylalanine2. Synthesis of the isoprene side chain from acetyl- coenzyme A via the mevalonate pathway.3. Condensation by the HMG-CoA reductase
Coenzyme Q10: Ubiquinone lipophilic, water-insoluble substances benzoquinone “head” and terpinoid “tail” various coenzymes Q relate to the number of isoprenoid units (5-carbon structure) in the tail Can be one to 12 isoprenoid units 10 isoprenoid units are the prevalent form in humans Solid-waxlike substance present in most tissues § The highest concentrations is found in the heart, the liver, the kidneys, and the pancreas. § The lowest concentration is found in the lungs.
Oxidation States of Coenzyme Q10: Ubiquinone Exists in three oxidation states.
Functions of Coenzyme Q10: Mitochondrial ATP Synthesis transfer electrons from complex I or complex II complexIII. initially is reduced to the semi-ubiquinone radical and thenubiquinone by transfering electrons one at a time to complexIII At the same time, transfers the protons outside the innermitochondrial membrane, generates a proton gradient acrossthe membrane. The energy released when the protons flow back into themitochondrial interior is used to form ATP.Plays an integral role in supplying energy to chemical reactions in the body
Functions of Coenzyme Q10: Antioxidant neutralize free-radical an effective lipid-soluble antioxidant continuously go through an oxidation-reduction state hold electrons loosely in its reduced form regenerate α-tocopherol from the α-tocopheroxyl radical. interact with dihydrolipoic acid. Dihydrolipoic acid reduces ubiquinone to ubiquinol inhibit lipid peroxidation occurs when cell membranes and low-density lipoproteins (LDL) are oxidized ex vivoMay prevent signs of skin aging
Functions of Coenzyme Q10: Lysosomal Function transport protons across lysosomal membranes help to maintain the optimal pH for cellular recycling
Disease Treatment of Coenzyme Q10: Ubiquinone Reliable and relatively consistent scientific data showing a substantial health benefit for Angina and Hypertension – Singh et. al. – double-blind, placebo-controlled study 59 men already on hypertension medications had 120mg Coenzyme Q10 daily for 8 week Blood pressure reduced by about 9% as compared to placebo – Burke et. al – double-blind, placebo-controlled study 83 people with isolated systolic hypertension had 60mg Coenzyme Q10 daily for 12 week Blood pressure reduced Contradictory, insufficient, or preliminary studies suggesting a health benefit or minimal health benefit for Cardiomyopathy, Cerebellar ataxia (familial), Congestive heart failure, Diabetes, Gingivitis (periodontal disease), Halitosis (if gum disease), Migraine headaches, Parkinsons disease, Renal (kidney) failure – Baggio et al. – open marketing study 2500 Class II or III patients had 100mg Coenzyme Q10 for 3 months with Signs of heart failure were reduced: 77% in edema, 54% in dyspnea, 82% in jugular venous pressure. – Khatta et al. – double-blind, placebo-controlled study 85 CHF patients had Coenzyme Q10 treatment Failed to find any evidence of benefit the patients with coenzyme Q treatment. For an herb, supported by traditional use but minimal or no scientific evidence. For a supplement, little scientific support and/or minimal health benefit for Alzheimer’s disease, Athletic performance, Breast cancer, Chronic obstructive pulmonary disease (COPD), HIV support, Infertility (male), Insulin resistance syndrome (Syndrome X), Lung cancer, Muscular dystrophy, Prostate cancer
Efficacy Data A lot of studies in the literature (70+) – Laboratory/Animal/Preclinical studies Laboratory – Coenzyme’ structures and function in cell respiration Animal – pretreatment – Human/Clinical studies Disease treatment For Heart disease: – Some large trials (up to 360 patients) – Some long term (up to 30 months) – Double-blind placebo-controlled trial, or meta-analysis Others: – Small trials (usually less than 100 people) – Short term (up to 12 week) – Most are double-blind randomized placebo-controlled trial – Few are non-double blind, or non-randomized
Coenzyme Q10: Ubiquinone By definition not a vitamin Produced endogenously in all tissues (~0.5g/day regenerated, with a body pool of ~2g) Naturally present in small amounts in a wide varied of foods Rich sources can be found in organ meats such as heart, liver and kidney, as well as beef, soy oil, sardines, mackerel and peanuts 1 pound of sardines = 30 mg 2 pounds of beef = 30 mg 2.5 pounds of peanuts = 30 mg 50 times more antioxidant power than Vitamin E Found to sustain vitamin E’s antioxidant effects
Coenzyme Q10: UbiquinoneEndogenous synthesis decreases after age 20Believed to fall off rapidly in middle age, accelerating theaging processExercise increases catabolism of and need for CoQ10Disease or other stress impairs intake and absorption ofthe substrate
Drug Action of Coenzyme Q10: UbiquinoneAbsorption Absorbed in the small intestines directly into the lymphatic system, followed by absorption into the blood stream Absorption tends to be poor (lipophilicity) ~60% or more of oral dosage forms are excreted in the feces Can be highly variable, depending upon dosage form and on food intake at time of CoQ ingestion Absorption is lower if taken on an empty stomach and higher if taken with foods, especially those with a high lipid content
Drug Action of Coenzyme Q10: UbiquinoneDistribution/Metabolism In the blood, CoQ10 is partitioned into various lipoproteins: VLDL, LDL and HDL, with peak blood levels occurring in 5 to 10 hours It is found in all cells of the body and is distributed to the various tissues of the body (important to know that is able to enter the brain) Takes roughly 3 weeks of daily dosing to reach the maximum serum concentrationsExcretion Of what is absorbed elimination occurs through the bodies bile Low plasma clearance Elimination half-life of 34 hours
Dosage Forms of Coenzyme Q10: Ubiquinone Capsules (10 mg, 30 mg, 75 mg, 100 mg, 150 mg) Chewable Tablets (100 mg, 200 mg) Liquid softgel (30 mg/5 ml) Tablets (25 mg, 50 mg, 60 mg, 200 mg) Wafers (60 mg, 200 mg) Vcaps (bio-grown CoQ10; 22mg) Can also be found in a number of skin products on the market
Recommended Dosage Amounts for Coenzyme Q: Ubiquinone No known toxic dose For Hypertension: 30 mg, 2 times a day For Angina: 50 mg, 3 times a day For Congestive Heart Failure Mild: 30 mg a day Severe: 30 mg, 3 times a day For Cardiomyopathy: 50 mg, 2 times a day As an Antioxidant: 30 mg to 60 mg a day Mitral Valve Prolapse in Children: 2 mg/kg/day
Dietary Supplement Health and Education Act of 1994 The term "dietary supplement“ under Section 201 (21 U.S.C. 321)(1) means a product (other than tobacco) intended to supplement the diet that bears or contains one or more of the following dietary ingredients: (A) a vitamin; (B) a mineral; (C) an herb or other botanical; (D) an amino acid; (E) a dietary substance for use by man to supplement the diet by increasing the total dietary intake; or (F) a concentrate, metabolite, constituent, extract, or combination of any ingredient described in clause (A), (B), (C), (D), or (E);(2) means a product that (A)(i) is intended for ingestion in a form described in section 411(c)(1)(B)(i); or (ii) complies with section 411(c)(1)(B)(ii); (B) is not represented for use as a conventional food or as a sole item of a meal or the diet; and (C) is labeled as a dietary supplement; and
FDA: Laws and regulations No determined state regulations on this product Violations of the Dietary Supplement Health and Education Act of 1994 (amendment to the Federal Food, Drug, and Cosmetic Act) occur when claims are made that a supplement are intended for the use in the diagnosis, cure, mitigation, treatment or prevention of disease Why is this important? Because the above statement is the FDA’s definition of a drug And a new drug may not be legally marketed in the United States without an approved New Drug Application (NDA)T.J. Clark Liquid Co-Q10 Advanced Formula:“[A] very beneficial supplement for individuals who suffer from disorders of the cardiovascular system....““Revive failing hearts... Lower blood pressure”
References Anne Keogh, Steve Fenton, Christina Leslie, et. al. Randomised Double-Blind, Placebo-Controlled Trial of Coenzyme Q10 Therapy in Class II and III Systolic Heart Failure. Heart Lung & Circulation. 2003;12:135-41. Baggio E, Gandini R, Plancher A, et. al. Italian multicentre study on the safety and efficacy of Coenzyme Q10 as adjunctive therapy in heart failure. The Coenzyme Q10 Drug Survellance Investigators. Clin. Invest. 1993;71:S145-9. Burke BE, Neuenschwander R, Olson RD. Randomized, double-blind, placebo-controlled trial of coenzyme Q10 in isolated systolic hypertension. South Med Journal. 2001;94:1112-7. Flint Beal, Clifford Shults. Effects of Coenzyme Q10 in Huntington’s disease and early Parkinson’s disease. BioFactors 18. 2003;18:153-161. Franklin Rosenfield, Deborah Hilton, Salvatore Pepe, et. al. Systematic review of effect of coenzyme Q10 in physical exercise, hypertension and heart failure. BioFactors. 2003;18:91-100. Kenneth Jones, Kerry Hughs, Laurie Mischley, et. al. Coenzyme Q-10 and Cardiovascular Health. Alternative therapies. 2004;10(1):22-30. Langsjoen PH, Langsjoen PH, Folkers K. A six year clinical study of therapy of cardiomyopathy with coenzyme Q10. Int J Tissue React(Swtizerland), 1990;12(3):169-71. Singh R, Niaz MA, Rastogi SS, et. al. Effect of hydrosoluble coenzyme Q10 on blood pressures and insulin resistance in hypertensive patients with coronary artery disease. J Human Hypertens. 1999:13:203-8. Ely, JTA and Krone, CA. A Brief Update on Ubiquinone (Coenzyme Q10). Journal of Orthomolecular Medicine 2000; 15(2):63-68. Retrived from the web on May 8, 2005 at http://faculty.washington.edu/~ely/JOM5.html Langsjoen, PH. Introduction to Coenzyme Q10. Retrieved from the web on May 8, 2005 at http://faculty.washington.edu/~ely/coenzq10.html#FAQ Facts and Comparisons: The review of Natural Products. Aug 1997 Physicians Desk Reference. 2005. Retrieved from the web on May 6, 2005 at http://www.pdrhealth.com/drug_info/nmdrugprofiles/nutsupdrugs/coe_0084.shtml Micromedix. 2005. OSU subscription National Cancer Institute (NCI) and National Center for Complementary and Alternative Medicine (NCAM). Retrieved from the web on May 8, 2005 at http://cis.nci.nih.gov/fact/9_16.htm Dietary Supplement Health and Education Act of 1994, Public Law 103-417, 103rd Congress. Retrieved from the web on May 8, 2005 at http://www.fda.gov/opacom/laws/dshea.html Federal Food, Drug and Cosmetic Act, Title 21, Chapter 9. Retrieved from the web on May 8, 2005 at http://www.access.gpo.gov/uscode/title21/chapter9_.html Walgreens.com Drugstore.com