Int. J. Mol. Sci. 2015, 16, 18185-18223; doi:10.3390/ijms160818185 OPEN ACCESS International Journal of Molecular Sciences ISSN 1422-0067 Exploiting the Pleiotropic Antioxidant Effects of Established Drugs in Cardiovascular Disease Sebastian Steven 1,2,†, Thomas Münzel 1,† and Andreas Daiber 1,†,*
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Vol. 19 No. 5 Sept/Oct 2014 CoQ10 Quality Quotient By Sandy Almendarez, Editor in Chief Not to be dramatic, but without CoQ10, life would not exist. The body uses coenzyme Q10 (CoQ10) to create the essential energy chemical compound adenosine triphosphate (ATP), which fuels cellular metabolic activity. In the cell, CoQ10's main role is in the mitochondria, where it helps convert fuel (food) into energy for the body to use. CoQ10 is in every cell, but is used most in organs that demand the highest amount of energy, such as the heart, brain and the immune system.1 Without CoQ10, there would be no ATP, and without ATP, there would be no cellular activity, and thus, no life. The energetic compound not only creates reactions, but also does its fair share of action. It has the ability to gain or lose two electrons; this is called redox chemistry. When it has the two extra elections, it's known as the reduced form or ubiquinol; when it loses the two electrons, the oxidized form is known as ubiquinone. Just these two small electrons make a big difference when it comes to human bioavailability. Ubiquinol is absorbable in the intestine and is easier for the body to transport in the blood than ubiquinone. The body converts ubiquinone to ubiquinol to be used by the body; this conversion process that may be difficult for some individuals, such as aging adults and those with chronic disease such as heart disease and metabolic syndrome.2 Others may have a compromised activity of CoQ10 reductase, the enzyme that moves CoQ10 in the body. Ubiquitous Health Benefits
With CoQ10's ubiquity in the body, it affects many functions, but those that require the most energy seem to benefit the most from CoQ10 supplementation. For instance, the heart is a major focus for CoQ10 research. A 2014 meta-analysis found CoQ10 supplementation improved ejection fraction, a measurement of how well the heart is pumping blood.3 Another meta-analysis from 2009 found higher blood levels of CoQ10 (greater than 3.5 micrograms/ml) enhanced both the magnitude and rate of clinical improvement in studies on patients with congestive heart failure, ischemic heart disease, hypertensive heart disease and diastolic dysfunction.4 A 2008 study reported plasma CoQ10 concentration is an independent predictor of mortality in patients with chronic heart failure (CHF); patients with lower levels were less likely to survive,5 while another 2013 study noted 100 mg of CoQ10 improved survival of chronic heart failure in patients receiving current pharmacologic therapy.6 Ubiquinol dramatically improved plasma CoQ10 levels in patients with severe heart failure, and led to clinical improvement and improvement in measurement of left ventricular function.7 CoQ10 has shown to help people with specific heart concerns, such as cholesterol and blood pressure. Supplementing with 150 mg/d of ubiquinol reduced LDL cholesterol in healthy men,8 and 12
Vol. 19 No. 5 Sept/Oct 2014 weeks of 60 mg/d of CoQ10 reduced blood pressure in men and women with systolic hypertension by an average of 17.8 mm Hg.9 And those with heart troubles who are improving their health with exercise also benefit from supplementation. Oral CoQ10 CoQ10 for Statin Users
improved functional capacity, endothelial function and left ventricle contractility in patients with congestive heart failure CoQ10 supplementation is without any side effects; but the researchers noted combining recommended for patients who CoQ10 with exercise resulted in higher plasma CoQ10 levels use statins to reduce cholesterol. and more pronounced effects on all heart health parameters.10 Statins inhibit the enzyme HMG CoA reductase, which reduces CoQ10 also plays a strong role in brain health, according to the production of cholesterol in research from the last decade. Ubiquinone (from Tishcon) and the liver, but also share the ubiquinol (from Kaneka) offered neuroprotection against an same biological pathway as animal model of Parkinson's disease in a 2008 study.11 The CoQ10, thus reducing the researchers found ubiquinol produced larger increases in nutrient in the body. plasma concentrations of CoQ10. A 2004 study from Columbia The nutrient further helps the head by reducing migraine University noted brief exposure to the statin atorvastatin caused frequency and disability in adolescents,12 and increasing a decrease in blood CoQ10 plasma levels of CoQ10 reduced tinnitus (ringing in the ears) in concentration, and this inhibition patients with a low plasma CoQ10 concentration.13 of CoQ10 synthesis could The immune system presents itself throughout the body as explain the adverse effects of does CoQ10, solidifying their relationship. A 2009 study noted statins, including exercise CoQ10 was helpful in vertigo and Meniere-like syndrome intolerance, muscle pain and muscle deterioration.19 (disorders of the inner ear) by improving the immune system.14 However, researchers have Considering all the energy associated with CoQ10, noted statin-induced CoQ10 supplementing with the nutrient for sports nutrition is intuitive. A 2010 review reported studies have confirmed CoQ10's effect in deficiency is completely preventable by supplemental reducing fatigue and exercise-related damage, and improving CoQ10 with no adverse impact physical performance.15 CoQ10 provided energy during sports on the cholesterol lowering or performance, at least for mice. It improved swimming anti-inflammatory properties of endurance and had an anti-fatigue effect in a 2010 study.16 the statin drugs.20 German researchers reported topical application of CoQ10 rapidly improved skin's mitochondrial function in vivo, creating an anti-aging effect on the skin,17 and a 1-percent CoQ10 cream used for five months reduced wrinkles, as observed by a dermatologist in a Japanese study.18 The Absorption Issue
Co10's numerous health effects make it seem like a wonder ingredient, but there's a catch: it's not easily absorbed. CoQ10 is a large lipid molecule; its fat-loving nature renders it practically insoluble in water, making its absorption poor, variable and dependent on a consumer's diet (it's better digested with fats).
Vol. 19 No. 5 Sept/Oct 2014 "The plain CoQ10 powder form is absorbed less than 1 percent," said Robin Koon, executive vice-president, Best Formulations, "So, solid dosage forms (tablets, capsules and powders) do not deliver much. For example, 100 mg of a CoQ10 powder will deliver to the bloodstream about 1 mg. Not very good." However, research has shown a lipid microsphere formulation in a softgel was superior to conventional formulations in dogs.21 Beyond using basic softgel formulations, CoQ10 supplement brands are on a quest to increase absorption in the body with a goal of more efficacious products with lower dosages and reduced costs. Technical advancements at several ingredient suppliers have addressed this problem by producing CoQ10 ingredients that are better absorbed. Alice Chin, quality control director, GWI, noted a successful approach is using an emulsion system to facilitate absorption from the gastrointestinal (GI) tract and improve bioavailability. Emulsification is achieved when a lipophilic compound is surrounded by particles that are both fat and water soluble; this creates a bond where one wouldn't have naturally been. In a liposome, one layer of lipophilic compounds are on the inside bonding to the fat-soluble compound, such as CoQ10, and the outer layer is hydrophilic, bonding with water in the GI tract. "Emulsions of soybean oil (lipid microspheres) could be stabilized very effectively by lecithin and are utilized in the preparation of soft gelatin capsules," Chin said. Indeed, a study from 2007 found solubilized formulations of CoQ10 (both ubiquinone and ubiquinol) had superior bioavailability as evidenced by their enhanced plasma CoQ10 responses compared to unsolubilized formulations.22 Another approach is to reduce the particle size of CoQ10, thus increasing its surface area. "Crystals are formed when CoQ10 is produced commercially," explained Steve Holtby, president and CEO, Soft Gel Technologies Inc. "CoQ10 crystals dissolve when they are mixed with certain solvents, or if they are heated, and will recrystallize upon cooling to room temperature. This recrystallization frequently creates larger crystals than the finely milled starting material, which are even more difficult for the body to assimilate. The size of CoQ10 crystals and degree of solubility of a CoQ10 mixture will likely affect the bioavailability of CoQ10." Holbty said Soft Gel Technologies' CoQsol-CF® (crystal free) achieves complete solubility by combining CoQ10 with d-limonene and natural tocopherols (vitamin E). "This unique formula dissolves the crystals that are formed when CoQ10 is produced commercially, and prevents the solution from recrystallizing," he said. A 2009 double-blind, randomized crossover study sponsored by Soft Gel Technologies noted the bioavailability of a single, 100-mg dose of reduced CoQH-CF was greater than a CoQ10 hard-shell capsule in individuals older than 60 years.23 Subjects who received CoQH-CF experienced a 430-percent increase in CoQ10 plasma concentrations compared to those who took the CoQ10 hard-shell formula. An unpublished human study conducted by KGK Synergize found 100 mg of CoQsol-CF led to higher plasma CoQ10 levels compared to 100 mg of powdered CoQ10 in two-piece, hard shell capsules. The study authors noted the CoQsol-CF-supplemented group also showed increased antioxidant
Vol. 19 No. 5 Sept/Oct 2014 status and anti-atherosclerotic potential based changes in the levels of selected markers, including serum levels of glutathione, C-reactive protein (CRP) and total antioxidants. Another unpublished human pilot study conducted by SIBR Research reported 60 mg of CoQsol-CF increased Raw material price of CoQ10
plasma levels of CoQ10 with peak plasma levels after six hours of consumption, showing that 7.95 percent of the Beyond the cost difference between CoQ10 from the product was absorbed. And another ubiquinol and ubiquinone, Alice Chin, unpublished animal study conducted by KGK found quality control director, GWI, said the CoQsol-CF concentrated in the blood serum, heart and raw material price of CoQ10 has shifted in the past decade. She said about 10 years ago, CoQ10 was new in the Dan Lifton, president, proprietary branded ingredients supplement market and the raw material division, Maypro Industries, noted the variance between price was around USD $2,000/kg, but it different consumers' ability to absorb CoQo10 is still sold quickly because manufacturing significant, even when it's delivered in a solubilized, was limited. "This of course, led to a enhanced bioavailability form. In addition, "In order to higher cost at the consumer level, and maintain peak CoQ10 levels in the blood, it must be taken lower levels of CoQ10 in the two times/d, while most consumers only take it once a formulation, often on the label as a day," he said. Maypro addressed this issue with its glamour ingredient," she said. Microactive® CoQ10, which Lifton said provides a 24-hour sustained release, enabling consumers to take it In 2005 to 2006, the Chinese company Xi'an Haotian successfully developed CoQ10 from tobacco leaves, which In a five-subject, 180 mg/d single-dose study, MicroActive significantly decreased the global raw Co-Q10 complex showed a higher uptake compared with materials price to around USD crystalline CoQ10 in health subjects.24 However, the $1000/kg, according to Chin. absorption of MicroActive Co-Q10 did not reach statistical "The real breakthrough lies with significance compared to an advanced solubilized softgel fermentation technology," Chin said. formulation because of high variance in the absorption of "When CoQ10 was able to be the solubilized form (some of the subjects showed a high fermented, costs decreased even more, absorption, whereas others did not absorb CoQ10 from and in 2008, it went down to $300/kg to the solubilized form). In general, MicroActive CoQ10 $400/kg. The price has remained stable, showed a trend toward better and more uniform because the fermentation process has bioavailability compared with the solubilized form. made this product mature. Currently, consumers can purchase high-quality Finished Product Forms: Ubiquinone v. Ubiquinol
CoQ10 products for a much more reasonable price at $10-20 a bottle." Another solution to increasing absorption of CoQ10 is to offer it in the reduced ubiquinol form, so the body doesn't need to convert it. "Ubiquinol is a reduced form, bioactive, stable and absorbed by the body more efficiently than ubiquinone," Chin said. "When taken directly, it works more quickly and can be delivered in lower concentrations." The two extra electrons attached to ubiquinol also make it a potent antioxidant, a trait ubiquinone doesn't share. Soft Gel Technologies' CoQH-CF™ utilizes soft gels created with Kaneka QH™ (from Kaneka) that provide a stabilized and protected form of ubiquinol, according to Holtby. "CoQH-CF specifically
Vol. 19 No. 5 Sept/Oct 2014 addresses the needs of the 40-plus age group, and those suffering from various diseases and symptoms of lifestyle related conditions such as fatigue, stress and lack of stamina or energy. Ubiquinol from the supplement is readily available to enter the energy production process." CoQH-CF soft gels contain a liquid inner fill of Kaneka QH, alpha lipoic acid, d-limonene, and capric and caprylic However, Koon said both ubiquinone and ubiquinol are absorbed by the body. "To me, the difference really rests in the price, since both forms are CoQ10 and are absorbed similarly. Note that patented ubiquinol form is four times more expensive as ubiquinone is. The reduced form is primarily marketed and sold for product differentiation reasons." Product differentiation is a good thing, especially in a crowded market, and product formulation—including whether a company chooses to use ubiquinol or ubiquinone—can help a CoQ10 product stand out. "If they are utilizing a soft gel, brands need to consider what other ingredients are appropriate for that delivery system," Lifton said. "For functional food and beverages, brands have to seek water-soluble or water-dispersible CoQ10 ingredients that are also stable. Since the market for CoQ10 finished products is highly saturated, brands need to find novel forms of CoQ10 and create innovative, synergistic formulas around this versatile ingredient, trying to creative meaningful differentiation." A stand-out CoQ10 ingredient could use ubiquinol or ubiquinone, but a brand needs to be sure to create a stable product that offers enough of a bioavailable ingredient to impart the many health benefits of CoQ10. References:
1. Miles L, et al. "Ubiquinol: a potential biomarker for tissue energy requirements and oxidative stress." Clin Chim Acta. 2005 Oct;360(1-2):87-96. 2. Miles MV et al. "Coenzyme Q10 changes are associated with metabolic syndrome." Clin Chim Acta. 2004 Jun;344(1-2):173-9. 3. Madmani ME et al. "Coenzyme Q10 for heart failure." Cochrane Database Syst Rev. 2014 Jun 2;6:CD008684. DOI: 10.1002/14651858.CD008684.pub2. 4. Langsjoen P, Langsjoen A. "Overview of the use of CoQ10 in cardiovascular disease." BioFactors. 1999;9:273-284 5. Molyneux S et al. "Coenzyme Q10: An Independent Predictor of Mortality in Chronic Heart Failure." Journal American College of Cardiology. 10.2008; 52: 1435-1441 6. Mortensen S et al. "The effect of coenzyme Q10 on morbidity and mortality in chronic heart failure. Results from the Q-SYMBIO study." European Journal of Heart Failure (2013) 15 (S1), S20 7. Langsjoen P, Langsjoen A. "Supplemental ubiquinol in patients with advanced congestive heart failure." BioFactors 2008; 119-128
Vol. 19 No. 5 Sept/Oct 2014 8. Schmelzer C et al. "Ubiquinol-induced gene expression signatures are translated into altered parameters of erythropoiesis and reduced low density lipoprotein cholesterol levels in humans." IUBMB Life. 2011 Jan;63(1):42-8. DOI: 10.1002/iub.413. 9. Burke B, Neuenschwander R, Olson RD. "Randomized, double-blind, placebo-controlled trial of coenzyme Q10 in isolated systolic hypertension." South Med J. 2001 Nov;94(11):1112-7. 10. Belardinelli R et al. "Coenzyme Q10 and exercise training in chronic heart failure." European Heart Journal. 2006; 27:2675-2681 11. Cleren C, et al. "Therapeutic effects of coenzyme Q10 (CoQ10) and reduced CoQ10 in the MPTP model of Parkinsonism." J Neurochem. 2008 Mar;104(6):1613-21. 12. Hershey AD, et al. "Coenzyme Q10 deficiency and response to supplementation in pediatric and adolescent migraine." Headache. 2007 Jan;47(1):73-80. 13. Khan M, et al. "A pilot clinical trial of the effects of coenzyme Q10 on chronic tinnitus aurium." Otolaryngol Head Neck Surg. 2007 Jan;136(1):72-7 14. Kumar A et al. "Role of coenzyme q10 (CoQ10) in cardiac disease, hypertension, and Meniere-like syndrome." Pharmacology & Therapeutics 2009; 259-268 15. Littarru GP, Tiano L . "Clinical aspects of coenzyme Q10: an update." Nutrition. 2010 Mar;26(3):250-4. 16. Fu X, Ji R, Dam J. "Antifatigue effect of coenzyme Q10 in mice." J Med Food. 2010 Feb;13(1):211-5. 17. Prahl S et al. "Aging skin is functionally anaerobic: importance of coenzyme Q10 for anti aging skin care." Biofactors. 2008;32(1-4):245-55. 18. Inui M et al. "Mechanisms of inhibitory effects of CoQ10 on UVB-induced wrinkle formation in vitro and in vivo." Biofactors. 2008;32(1-4):237-43. 19. Rundek T et al. "Atorvastatin decreases the coenzyme Q10 level in the blood of patients at risk for cardiovascular disease and stroke." Arch Neurol. 2004 Jun;61(6):889-92. 20. Langsjoen P, Langsjoen A. "The clinical use of HMG CoA-reductase inhibitors and the associated depletion of coenzyme Q10." A review of animal and human publications. BioFactors. 2003; 18: 101–111 21. Ozawa Y et al. "Intestinal absorption enhancement of coenzyme Q10 with a lipid microsphere." Arzneimittelforschung. 1986 Apr;36(4):689-90. 22. Bhagavan HN, Chopra RK. "Plasma coenzyme Q10 response to oral ingestion of coenzyme Q10 formulations." Mitochondrion. 2007 Jun;7 Suppl:S78-88. 23. Evans M et al. "A randomized, double-blind trial on the bioavailability of two CoQ10 formulations." Journal of Functional Foods, Volume 1, Issue 2, April 2009, Page 240
Vol. 19 No. 5 Sept/Oct 2014 24. Madhavi D, Kagan D. "A Study on the Bioavailability of a Sustained-release Coenzyme Q10-β- Cyclodext." Integrative Medicine Vol. 9, No. 1 Feb/Mar 2010
Embargoed until February 17, 2016 at 2:00 p.m. EST Media Contacts: Rebecca Porterfield Sandwich Generation Take Note: Your Parents May Not Be Getting Care They Need Worse, They Could Also Be Taking Risky Medicines Lebanon, N.H. (February 17, 2016) – Members of the "sandwich" generation can attest to how much time their aging parents spend inside the health care system, because they often accompany them on their succession of visits to the doctor's office, lab, or hospital. Yet despite the fact that on average Medicare recipients spend more than half a month a year (17.1 days) in contact with the health care system, all those visits don't always add up to good care. Depending on where they live, these patients too often don't receive medical care that reflects the best evidence available and, despite progress, many still receive potentially harmful medications, according to a new report from the Dartmouth Atlas Project. The report, "Our Parents, Ourselves: Health Care for an Aging Population," is a review of how adults ages 65 and older, a population predicted to surge from 43.1 million in 2012 to 83.7 million by 2050, receive health care in the U.S., based on 2012 Medicare data. It is also a roadmap for caregivers and patients, especially those with multiple ongoing health problems or dementia. "Our bodies change as we age, and our priorities change, too, as the number of years ahead are fewer than the years behind us," said Julie P.W. Bynum, MD, MPH, associate professor of The Dartmouth Institute for Health Policy & Clinical Practice and the report's lead author. "The information in this report is a good starting point for patients and their caregivers to begin a conversation with their doctor about certain aspects of their care." "The findings from this report will generate meaningful conversation about the care for our aging population and identify areas of action for consumers, advocates, health systems, and policy makers," said Terry Fulmer, PhD, RN, FAAN, president of The John A. Hartford Foundation, which funded the report. "This action is especially needed for older adults with multiple, ongoing health problems or dementia who face complex challenges when navigating the health care system and advocating for the best care possible." The report highlights several items that individuals caring for aging parents should be mindful of: