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Ubiquinone

Scientific Name(s): Coenzyme Q-10 , Ubidecarenone , Mitoquinone

Common Name(s): Adelir , coenzyme Q10 , heartcin , inokiton , neuquinone , taidecanone , udekinon , ubiquinone . Idebenone is an analog of ubiquinone.

Uses

Ubiquinone may have applications in cardiovascular disease, especially congestive heart failure (CHF), although there is a lack of consensus. Studies in neurological disorders are less promising. Limited clinical trials have been conducted to support its widespread use for other conditions.

Dosing

Cardiovascular and neurologic trials predominantly use ubiquinone dosages of 300 mg/day or idebenone dosages of 5 mg/kg/day. Higher dosages of ubiquinone (up to 3,000 mg/day) have been used. Pharmacokinetic studies suggest split dosing is superior to single daily dosing.

Contraindications

Absolute contraindications have not been identified.

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

Findings are conflicting. Case reports show ubiquinone decreases the anticoagulant effect of warfarin; however, a randomized clinical trial found no effect on the international normalized ratio (INR).

Adverse Reactions

Adverse effects are rare and include diarrhea, GI discomfort, headache, loss of appetite, and nausea. Allergic reactions have been reported.

Toxicology

An observed intake safety level of 1,200 mg/day is based on clinical data; however, dosages exceeding this amount have been used with no apparent adverse effect. No accumulation in plasma or tissue following cessation of coenzyme Q10 consumption has been noted.

Ubiquinones are a class of lipid-soluble benzoquinones that are involved in mitochondrial electron transport. They are found in the majority of aerobic organisms, from bacteria to mammals, hence the name ubiquinone (“ubiquitous quinone”).

History

The first ubiquinone was isolated in 1957. Since that time, ubiquinones have been studied extensively in Japan, Russia, and Europe, with research in the United States beginning more recently. Popular press accounts claim that roughly 12 million Japanese people use ubiquinones as the medication of choice for management of cardiovascular diseases, supplied via more than 250 commercially available preparations. Ubiquinone is touted as an effective treatment for CHF, cardiac arrhythmias, hypertension, and in reducing hypoxic injury to the myocardium. Other claims include increases in exercise tolerance, stimulation of the immune system, and counteraction of the aging process. Ubiquinone has not been approved for therapeutic use in the United States; however, it is available as a food supplement. 1

Chemistry

Ubiquinones participate in oxidation-reduction reactions in the mitochondrial respiratory chain. They also have properties of hydrogen carriers, providing a coupling of proton translocation to respiration by means of a chemiosmotic mechanism. Ubiquinol (the reduced form of ubiquinone), present in all cellular membranes, is a recognized antioxidant that can reduce oxidized tocopherol and ascorbate after free radicals have been removed. Other membrane-related functions have been identified for coenzyme Q10, including the activation of the sodium/hydrogen ion antiporter, apoptosis control, and nicotinamide adenine dinucleotide/nicotinamide/adenine dinucleotide hydrogen ratio control. Reviews of the actions of coenzymes have been published. 1 , 2

Laboratory monitoring of coenzyme Q10 is possible using high-performance liquid chromatography with ultraviolet, coulometric assay or electrochemical detection. 3

Uses and Pharmacology

Cardiovascular disease

The American College of Cardiology does not support the use of coenzyme Q10 in cardiovascular disease because a mortality benefit has not been established, 4 while the Agency for Healthcare Research and Quality finds no convincing evidence to either support or refute coenzyme Q10's place in therapy. 5

Animal data

The widespread use of coenzyme Q10 as a supplement and the availability of numerous trial data suggesting the relative nontoxicity of the compound makes data derived from animal experiments less important.

Clinical data
Cardiac surgery/Cardiac arrest

The use of coenzyme Q10 in improving mitochondrial function has been evaluated in cardiac surgery. A review was published of 8 studies, in which improvements in contractility of the myocardial tissue were demonstrated in association with increases in serum coenzyme Q10. 6 , 7 Doses of coenzyme Q10 300 mg daily for 2 weeks prior to surgery were evaluated versus placebo. 6 A randomized, placebo-controlled trial evaluated coenzyme Q10 450 mg in divided doses in conjunction with hypothermia after cardiac arrest. Increased survival was shown for the coenzyme Q10 group. 8

Congestive heart failure

Several meta-analyses and systematic reviews of clinical trials in CHF have been published, with results generally being more consistent for CHF than with other disease states. 4 , 7 , 9 , 10 , 11 , 12 , 13 , 14 The inclusion of 2 trials in which coenzyme Q10 failed to show an effect greater than placebo in these analyses, results in only a trend in favor of ubiquinone in improving cardiac function (an increase in resting ejection fraction of 1.9% [95% confidence interval [CI], −0.13% to 3.9%]). 4 , 7 , 9 , 12 In a meta-analysis that included trials with a crossover or parallel-arm design, a 3.7% absolute difference in resting ejection fraction was found for coenzyme Q10 (95% CI, 1.59 to 5.77). 7 , 11

The studies, however, either do not evaluate or are underpowered to evaluate mortality outcomes. 7 , 11 , 15 Because differing ubiquinone preparations were used in the studies, both the bioavailability of the compound 7 , 16 and the adequacy of dosing to reach sufficient plasma coenzyme Q10 levels for effect have been questioned. 13 , 14

Hypertension

Systematic reviews and meta-analyses have been conducted evaluating coenzyme Q10 in hypertension versus placebo. Trials comparing coenzyme Q10 with conventional therapy are lacking. 7 , 12 , 17 Decreases in systolic pressure were found in some patients. However, confounding variables, small trial size, and variable study designs make extrapolation of the data difficult. 7 , 12

Friedreich ataxia (hypertrophic cardiomyopathy)

Most studies used an open-label design. 7 , 18 Idebenone, an analog of coenzyme Q10, was commonly employed in these trials at dosages of 5 mg/kg/day to a maximum of 300 mg/day 19 and used for periods of 6 months to 5 years. 19 , 20 , 21 , 22 , 23 Increases in heart and skeletal muscle bioenergetics are reported for all the studies, as well as decreases in ventricular hypertrophy (left ventricular mass index). 19 , 20 , 21 , 22 , 23 Results for fractional shortening and ejection fraction are mixed, with 1 study reporting a deterioration 23 and another citing improvement in cardiac function. 22

Reversal of statin-induced myopathy

Statins (HMG-CoA reductase inhibitors) deplete circulating coenzyme Q10 levels by interfering with its biosynthesis. 7 , 10 , 24 Most studies indicate a correlation between the decrease in serum coenzyme Q10 and decreases of total and low-density lipoprotein cholesterol levels. This effect may be particularly important in elderly patients, in whom coenzyme Q10 levels are already compromised, and is also associated with higher dosages (lower dosages do not seem to affect intramuscular levels of coenzyme Q10). 24 , 25 The use of ezetimibe alone or in combination with a statin does not offer protection against depletion of coenzyme Q10. 10 , 24 No correlation has been established for decreased serum coenzyme Q10 and cardiovascular events. 7 , 24 Supplemental coenzyme Q10 increased circulating levels of the compound. However, results from randomized clinical trials are inconsistent in showing an effect on statin-associated myopathy. 3 , 16 , 24 , 26

Neurological disorders

The case for coenzyme Q10 as a treatment option in neurological (mitochondrial-related) disease is not as strong. 27 The role of coenzyme Q10 in Parkinson, Alzheimer, and Huntington diseases; amyotrophic lateral sclerosis; and Friedreich ataxia is postulated but not established. 2 , 28 , 29

Studies in Friedreich and non-Friedreich ataxia have largely shown a continued worsening of disease, as measured by the International Cooperative Ataxia Group rating scale, irrespective of idebenone use (5 mg/kg/day). 19 , 20 , 23 , 30 , 31

A link between mitochondrial dysfunction and Parkinson disease has been established, but the relationship with coenzyme Q10 has not. 32 A multicenter clinical trial found a decrease in worsening of symptoms in patients with early Parkinson disease receiving coenzyme Q10 1,200 mg/day, but not at lower dosages. 33 Effects were not apparent at 1 month, but were evident at 8 months. Changes in daily living factors were more pronounced than clinical disease progression changes. 32 , 34 Increases in plasma coenzyme Q10 were recorded. 33 A larger trial using higher dosages (coenzyme Q10 600 mg chewable wafers 4 times a day) found a mean change in total rating score high enough to warrant a phase 3 trial 35 ; however, the trial was not designed to evaluate efficacy. 34 , 35 A multicenter trial of patients receiving anti-Parkinson medication found no difference in symptoms over placebo. 36

The role of mitochondrial stress in Alzheimer disease led to more studies of coenzyme Q10. 31 Multicenter clinical trials using idebenone dosages of up to 360 mg 3 times a day found no effect on the rate of decline over placebo. Analyses using various rating scales showed some differences that were not considered clinically important, mirroring other older trials. 37 Similarly, no slowing of decline was noted in Huntington disease. 3

Other effects

Coenzyme Q10 has been evaluated in migraine versus placebo in small trials. Decreases in attack frequency, days with headache, and days with nausea were found for a daily dose of 300 mg. 38 The coadministration of ubiquinone with tamoxifen mitigated the hyperlipidemia associated with tamoxifen, and tumor marker levels indicated an antiangiogenesis effect. 39 An Agency for Healthcare Research and Quality review of clinical trials reported no evidence to support the use of ubiquinone in the prevention or treatment of cancer. 40

Deficiencies of coenzyme Q10 have been described, predominantly affecting children, in a spectrum of diseases including infantile-onset, multisystem diseases, as well as adult-onset cerebellar ataxia and pure myopathies. 28 , 29 Lymphocyte and platelet coenzyme Q10 levels were lower in Down syndrome, 41 while lowered serum levels are associated with phenylketonuria and mevalonic aciduria. 42

In infants with Prader-Willi syndrome, coenzyme Q10 had no effect on lean mass versus growth hormone. 43

Dosage

Several dosage forms exist, including compressed and chewable tablets, powder-filled and gel-filled capsules, liquid syrups, and newer solubilized formulations. The reduced form of coenzyme Q10, ubiquinol, is also commercially available. 44

Pharmacokinetic studies suggest split dosing is superior to single daily dosing; for tissue uptake and crossing the blood-brain barrier, plasma coenzyme Q10 levels should be higher than normal. 44

Cardiovascular and neurologic trials predominately use ubiquinone dosages of 300 mg/day 4 , 7 , 9 , 10 , 11 , 12 , 13 , 14 or idebenone dosages of 5 mg/kg/day. 19 , 20 , 21 , 22 , 23

High-dose ubiquinone (1,200 mg/day) was used in patients with early Parkinson disease, 33 while dosages of 2,700 to 3,000 mg/day were used in amyotrophic lateral sclerosis trials. 45 , 46 An open-label study that included children evaluated tolerability of high-dose idebenone. Daily dosages of 60 mg/kg given in 3 divided doses were used for 1 month. 47

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

In a placebo-controlled, double-blind, crossover study in patients on long-term warfarin, coenzyme Q10 did not affect the anticoagulant response (INR) of warfarin. 48 However, case reports exist of increased anticoagulant effect of warfarin. 49

Adverse Reactions

No serious adverse events have been associated with the use of ubiquinone. Allergic reactions, including tongue swelling, were reported in a clinical trial. 35 One open-label clinical trial involving severely affected patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes syndrome reported 2 deaths. 50 On autopsy, fibrotic changes in the myocardium were observed, but a causal relationship with coenzyme Q10 was not established. 51

Clinical trials evaluating high-dose idebenone found only mild GI effects, headache, and fatigue. 47 Similarly, clinical trials report mild GI effects (dyspepsia, loose stool, nausea, vomiting) for ubiquinone. 45 , 46 , 47 , 51 Urine discoloration has also been noted, with no abnormalities in urine laboratory indices. 47

Toxicology

A review of animal experiments and clinical trials has estimated an acceptable daily intake for coenzyme Q10 to be 12 mg/kg (ie, 720 mg/day for a 60 kg person) based on a no-observed-adverse-effect level in rats of 1,200 mg/kg/day. An observed safety level based on clinical data is given as 1,200 mg/day. No accumulation in plasma or tissue following cessation of coenzyme Q10 consumption was noted and endogenous biosynthesis was not affected. 51

Bibliography

1. Crane FL. Discovery of ubiquinone (coenzyme Q) and an overview of function. Mitochondrion . 2007;7(suppl):S2-S7.
2. Crane FL. The evolution of coenzyme Q. BioFactors . 2008;32(1-4):5-11.
3. Steele PE, Tang PH, DeGrauw AJ, Miles MV. Clinical laboratory monitoring of coenzyme Q10 use in neurologic and muscular diseases. Am J Clin Pathol . 2004;121(suppl):S113-S120.
4. Vogel JH, Bolling SF, Costello RB, et al; American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. Integrating complementary medicine into cardiovascular medicine. A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents (Writing Committee to Develop an Expert Consensus Document on Complementary and Integrative Medicine). J Am Coll Cardiol . 2005;46(1):184-221.
5. Shekelle P, Morton S, Hardy M. Effect of Supplemental Antioxidants Vitamin C, Vitamin E, and Coenzyme Q10 for the Prevention and Treatment of Cardiovascular Disease . Evidence Report/Technology Assessment No. 83 (Prepared by Southern California-RAND Evidence-based Practice Center, under Contract No 290-97-0001). AHRQ Publication No. 03-E043. Rockville, MD: Agency for Healthcare Research and Quality; 2003. http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=hserta&part=A123449 . Accessed March 3, 2010.
6. Rosenfeldt F, Marasco S, Lyon W, et al. Coenzyme Q10 therapy before cardiac surgery improves mitochondrial function and in vitro contractility of myocardial tissue. J Thorac Cardiovasc Surg . 2005;129(1):25-32.
7. Pepe S, Marasco SF, Haas SJ, Sheeran FL, Krum H, Rosenfeldt FL. Coenzyme Q10 in cardiovascular disease. Mitochondrion . 2007;7(suppl):S154-S167.
8. Damian MS, Ellenberg D, Gildemeister R, et al. Coenzyme Q10 combined with mild hypothermia after cardiac arrest: a preliminary study. Circulation . 2004;110(19):3011-3016.
9. Soja AM, Mortensen SA. Treatment of congestive heart failure with coenzyme Q10 illuminated by meta-analyses of clinical trials. Mol Aspects Med . 1997;18(suppl):S159-S168.
10. Littarru GP, Tiano L. Clinical aspects of coenzyme Q10: an update. Curr Opin Clin Nutr Metab Care . 2005;8(6):641-646.
11. Sander S, Coleman CI, Patel AA, Kluger J, White CM. The impact of coenzyme Q10 on systolic function in patients with chronic heart failure. J Card Fail . 2006;12(6):464-472.
12. Bonakdar RA, Guarneri E. Coenzyme Q10. Am Fam Physician . 2005;72(6):1065-1070.
13. Sinatra ST. Metabolic cardiology: an integrative strategy in the treatment of congestive heart failure. Altern Ther Health Med . 2009;15(3):44-52.
14. Singh U, Devaraj S, Jialal I. Coenzyme Q10 supplementation and heart failure. Nutr Rev . 2007;65(6, pt 1):286-293.
15. Adarsh K, Kaur H, Mohan V. Coenzyme Q10 (Coenzyme Q10) in isolated diastolic heart failure in hypertrophic cardiomyopathy (HCM). Biofactors . 2008;32(1-4):145-149.
16. Young JM, Florkowski CM, Molyneux SL, et al. Effect of coenzyme Q(10) supplementation on simvastatin-induced myalgia. Am J Cardiol . 2007;100(9):1400-1403.
17. Burke BE, Neuenschwander R, Olson RD. Randomized, double-blind, placebo-controlled trial of coenzyme Q10 in isolated systolic hypertension. South Med J . 2001;94(11):1112-1117.
18. Cooper JM, Schapira AH. Friedreich's ataxia: coenzyme Q10 and vitamin E therapy. Mitochondrion . 2007;7(suppl 1):S127-S135.
19. Buyse G, Mertens L, Di Salvo G, et al. Idebenone treatment in Friedreich's ataxia: neurological, cardiac, and biochemical monitoring. Neurology . 2003;60(10):1679-1681.
20. Mariotti C, Solari A, Torta D, Marano L, Fiorentini C, Di Donato S. Idebenone treatment in Friedreich patients: one-year-long randomized placebo-controlled trial. Neurology . 2003;60(10):1676-1679.
21. Hausse AO, Aggoun Y, Bonnet D, et al. Idebenone and reduced cardiac hypertrophy in Friedreich's ataxia. Heart . 2002;87(4):346-349.
22. Hart PE, Lodi R, Rajagopalan B, et al. Antioxidant treatment of patients with Friedreich ataxia: four-year follow-up. Arch Neurol . 2005;62(4):621-626.
23. Ribaï P, Pousset F, Tanguy ML, et al. Neurological, cardiological, and oculomotor progression in 104 patients with Friedreich ataxia during long-term follow-up. Arch Neurol . 2007;64(4):558-564.
24. Marcoff L, Thompson PD. The role of coenzyme Q10 in statin-associated myopathy: a systematic review. J Am Coll Cardiol . 2007;49(23):2231-2237.
25. Laaksonen R, Jokelainen K, Sahi T, Tikkanen MJ. Decreases in serum ubiquinone concentrations do not result in reduced levels in muscle tissue during short-term simvastatin treatment in humans. Clin Pharmacol Ther . 1995;57(1):62-66.
26. Caso G, Kelly P, McNurlan MA, Lawson WE. Effect of coenzyme q10 on myopathic symptoms in patients treated with statins. Am J Cardiol . 2007;99(10):1409-1412.
27. Marriage B, Clandinin MT, Glerum DM. Nutritional cofactor treatment in mitochondrial disorders. J Am Diet Assoc . 2003;103(8):1029-1038.
28. Quinzii CM, Hirano M, DiMauro S. CoQ10 deficiency diseases in adults. Mitochondrion . 2007;7(suppl 1):S122-S126.
29. Quinzii CM, López LC, Naini A, DiMauro S, Hirano M. Human CoQ10 deficiencies. Biofactors . 2008;32(1-4):113-118.
30. Lamperti C, Naini A, Hirano M, et al. Cerebellar ataxia and coenzyme Q10 deficiency. Neurology . 2003;60(7):1206-1208.
31. Schapira AH. Mitochondrial disease. Lancet . 2006;368(9529):70-82.
32. Schapira AH, Olanow CW. Neuroprotection in Parkinson disease: mysteries, myths, and misconceptions. JAMA . 2004;291(3):358-364.
33. Shults CW, Oakes D, Kieburtz K, et al; Parkinson Study Group. Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline. Arch Neurol . 2002;59(10):1541-1550.
34. LeWitt PA. Clinical trials of neuroprotection for Parkinson's disease. Neurology . 2004;63(7 suppl 2):S23-S31.
35. NINDS NET-PD Investigators. A randomized clinical trial of coenzyme Q10 and GPI-1485 in early Parkinson disease. Neurology . 2007;68(1):20-28.
36. Storch A, Jost WH, Vieregge P, et al; German Coenzyme Q(10) Study Group. Randomized, double-blind, placebo-controlled trial on symptomatic effects of coenzyme Q(10) in Parkinson disease. Arch Neurol . 2007;64(7):938-944.
37. Thal LJ, Grundman M, Berg J, et al. Idebenone treatment fails to slow cognitive decline in Alzheimer's disease. Neurology . 2003;61(11):1498-1502.
38. Sándor PS, Di Clemente L, Coppola G, et al. Efficacy of coenzyme Q10 in migraine prophylaxis: a randomized controlled trial. Neurology . 2005;64(4):713-715.
39. Sachdanandam P. Antiangiogenic and hypolipidemic activity of coenzyme Q10 supplementation to breast cancer patients undergoing tamoxifen therapy. Biofactors . 2008;32(1-4):151-159.
40. Coulter I, Hardy M, Shekelle P, et al. Effect of the Supplemental Use of Antioxidants Vitamin C, Vitamin E, and Coenzyme Q10 for the Prevention and Treatment of Cancer . Evidence Report/Technology Assessment Number 75 (Prepared by Southern California Evidence-based Practice Center under Contract No. 290-97-0001). AHRQ Publication No. 03-E047. Rockville, MD: Agency for Healthcare Research and Quality; 2003. http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=hserta&part=A113485 . Accessed March 3, 2010.
41. Tiano L, Padella L, Carnevali P, et al. Coenzyme Q10 and oxidative imbalance in Down syndrome: biochemical and clinical aspects. Biofactors . 2008;32(1-4):161-167.
42. Hargreaves IP. Coenzyme Q10 in phenylketonuria and mevalonic aciduria. Mitochondrion . 2007;7(suppl 1):S175-S180.
43. Eiholzer U, L'allemand D, Schlumpf M, Rousson V, Gasser T, Fusch C. Growth hormone and body composition in children younger than 2 years with Prader-Willi syndrome. J Pediatr . 2004;144(6):753-758.
44. Bhagavan HN, Chopra RK. Potential role of ubiquinone (coenzyme Q10) in pediatric cardiomyopathy. Clin Nutr . 2005;24(3):331-338.
45. Ferrante KL, Shefner J, Zhang H, et al. Tolerance of high-dose (3,000 mg/day) coenzyme Q10 in ALS. Neurology . 2005;65(11):1834-1836.
46. Levy G, Kaufmann P, Buchsbaum R, et al. A two-stage design for a phase II clinical trial of coenzyme Q10 in ALS. Neurology . 2006;66(5):660-663.
47. Di Prospero NA, Sumner CJ, Penzak SR, Ravina B, Fischbeck KH, Taylor JP. Safety, tolerability, and pharmacokinetics of high-dose idebenone in patients with Friedreich ataxia. Arch Neurol . 2007;64(6):803-808.
48. Engelsen J, Nielsen JD, Winther K. Effect of coenzyme Q10 and Ginkgo biloba on warfarin dosage in stable, long-term warfarin treated outpatients. A randomised, double blind, placebo-crossover trial. Thromb Haemost . 2002;87(6):1075-1076.
49. Spigset O. Reduced effect of warfarin caused by ubidecarenone. Lancet . 1994;344(8933):1372-1373.
50. Remes AM, Liimatta EV, Winqvist S, et al. Ubiquinone and nicotinamide treatment of patients with the 3243A→G mtDNA mutation. Neurology . 2002;59(8):1275-1277.
51. Hidaka T, Fujii K, Funahashi I, Fukutomi N, Hosoe K. Safety assessment of coenzyme Q10 (CoQ10). Biofactors . 2008;32(1-4):199-208.

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