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The Importance of CRYSTAL-FREE Coenzyme Q10

My article titled Coenzyme Q10: A Miracle Nutrient was published in the April 2020 issue of Integrative Medicine: A Clinician's Journal (IMCJ). In addition so summarizing the many health benefits of coenzyme Q10, I also discuss the ubiquinone vs ubiquinol controversy and I explain the importance of crystal-free CoQ10.

In the past several years, there have been some important breakthroughs in understanding coenzyme Q10’s biological effects and how to achieve maximum therapeutic benefits from CoQ10 supplementation.

The purpose of this article is to provide a brief overview of the history of CoQ10 and the role it plays in the prevention and treatment of cardiovascular disease. After this brief introduction, I will mention newer areas of therapeutic potential and then end by addressing the following two very important CoQ10 topics: a) the issue of crystallization and absorption and, b) the difference between ubiquinone and ubiquinol, and which form is best.

History: In 1957, University of Wisconsin biochemist Fred Crane isolated a yellowish substance from beef hearts. He sent samples to a colleague, biochemist Dr. Karl Folkers who worked at the pharmaceutical company Merck, Sharpe and Dohme. in 1958, Dr. Folkers successfully determined the chemical structure of CoQ10 and conducted some preliminary studies, which led him to believe that CoQ10 had enormous potential as a cardiovascular drug. At the time, Merck executives were not interested in developing a new cardiovascular drug. Consequently, the patent rights to CoQ10 were sold to a company in Japan.

It took Japanese scientists about ten years to develop industrial fermentation technology that resulted in the production of commercial quantities of CoQ10. This enabled the initiation of the first clinical trials in which CoQ10 was used to treat patients with heart failure in Japan. In 1976, CoQ10 was approved in Japan as a drug to treat cardiovascular disease, and it remained one of the top-selling cardiovascular drugs in Japan for over twenty years.

In the 1970s, Dr. Folkers and his colleague, Dr. Gian-Paolo Littarru of Italy published data they had collected with tissue biopsies from 200 patients, which revealed that patients with heart disease and patients undergoing heart surgery had blood and tissue Coenzyme Q10 levels significantly below normal levels.[1]

In 1978, British biochemist Peter Mitchell was awarded the Nobel Prize in Chemistry for discovering the key role coenzyme Q10 plays in the electron transport chain in mitochondrial membranes, which results in the generation of cellular energy in the form of ATP.[2] Folkers’ early work along with Mitchell’s Nobel prize dramatically increased scientific interest in CoQ10 around the world.

Biosynthesis of CoQ10: The biosynthesis of CoQ10 from the amino acid tyrosine is a multistage process requiring at least eight vitamins and several trace elements. Considering the widespread consumption of nutrient-deficient fast foods and highly processed foods and the fact that nutritional content of our commercial food supply has been steadily declining since the end of World War II, due to the use of toxic chemicals, artificial fertilizers and other destructive farming practices, it is easy to see why many people have nutritional deficiencies that hinder the body’s ability to synthesize coenzyme Q10.

Drug-Induced Nutrient Depletions: I am the author of The Drug-Induced Nutrient Depletion Handbook.[3] In this handbook, I present peer-reviewed scientific studies which document that 11 different classes of drugs deplete coenzyme Q10. The classes of drugs that deplete CoQ10 are oral contraceptives, hormone replacement therapy (HRT), tricyclic antidepressants, adrenergic stimulants, thiazide diuretics, antipsychotics, statins, most chemotherapy drugs, beta-blockers and oral hypoglycemics: both sulfonylureas and biguanides.

Thus, it is easy to see why many people are coenzyme Q10 deficient due to poor nutrient intake from poor diets and the fact that many people may be taking one or more drugs that deplete coenzyme Q10.

The Drug-Induced Nutrient Depletion Handbook is out-of-print. However, I have created a Quick Reference Guide to Drug-Induced Nutrient Depletions. As part of my commitment to help people improve their health, I am offering this Quick Reference Guide FREE to everyone. Use the link below to get your free copy of the Quick Reference Guide to Drug-Induced Nutrient Depletions and feel free to distribute this offer to your patients, family and friends.

naturalpharmacist.net/dind     Let’s Make Good Health Go Viral…!!!

Coenzyme Q10 exists in two forms: Ubiquinone is the oxidized form, which has a molecular weight of 864. Ubiquinol, which is the reduced form, has two more hydrogen molecules in its structure, giving it a molecular weight of 866. Ubiquinone and ubiquinol are a redox pair (oxidation-reduction) that can be rapidly converted from one form to the other in cells, lymph or blood depending on the demand for their various functions.

CoQ10’s Antioxidant Functions: The reduced form of CoQ10, ubiquinol, is a powerful lipid-soluble antioxidant that provides critical antioxidant protection in the lymph and blood throughout the body.[4] Ubiquinol is the only known fat-soluble antioxidant that human cells can synthesize.[5] In its reduced form, ubiquinol coenzyme Q10 plays a major role in preventing oxidation in both the lipids that make up much of the structure of cellular membranes in cells throughout the body and also in lipoprotein lipids present in circulation.[6] Coenzyme Q10 can also recycle or regenerate other antioxidants such as vitamin E[7] and vitamin C.[8]

Cellular Energy Production: The oxidized form of CoQ10, ubiquinone, is required for energy production in the mitochondria of all cells except the red blood cells. Specifically, CoQ10 is required in several steps of the electron transport chain in mitochondrial inner membranes, which is where cellular energy, known as ATP, is produced. This is the work that earned Peter Mitchell his 1978 Nobel Prize.

Bi-directional Conversion of Ubiquinone to Ubiquinol: When ubiquinone is taken orally, it is converted to ubiquinol during absorption and remains in its reduced form in the lymph and in blood. CoQ10 is not needed to produce energy when it is circulating in the lymph or blood. This conversion takes place so that reduced ubiquinol form of CoQ10 can provide antioxidant protection as it is being circulated throughout the body.

For decades, physicians have prescribed statin drugs in the belief that elevated LDL-cholesterol is a major risk factor for cardiovascular disease. This is unfortunate because LDL-cholesterol is not a “bad” molecule. However, when LDL-cholesterol becomes oxidized, it becomes a “damaged” molecule that is capable of causing vascular endothelial injury which contributes to atherosclerosis and cardiovascular disease.[9]

A 1997 study by cardiologist Svend Aage Mortensen made the following important statement. Dr. Mortensen announced that CoQ10 is an antioxidant that is “packaged into the LDL & VLDL fractions of cholesterol.” This means that LDL cholesterol is the “carrier” that transports coenzyme Q10 around the body. It also means that when CoQ10 is being transported on the LDL cholesterol molecule, its antioxidant properties enable it to protect LDL cholesterol against oxidative damage. This explains why CoQ10 helps prevent the formation of oxidized LDL cholesterol, which is one important way that CoQ10 reduces cardiovascular disease risks.[10]

CoQ10 Studies: In this section I will present some selected studies that show coenzyme Q10’s therapeutic benefits in various medical conditions.
CoQ10 & Cardiovascular Disease: Over the past 40 years, the results of many clinical trials confirm that coenzyme Q10 supplementation is useful in the prevention and treatment of many aspects of cardiovascular disease such as congestive heart failure, hypertension, ischemic heart disease, cardiac arrhythmias.[11]

The 2014 Q-Symbio Study[12]: Chronic heart failure patients (average age: 63 years) administered 3 x 100 mg of ubiquinone coenzyme Q10 or matching placebo daily for two years along with patient’s conventional heart failure medicine.

RESULT: significantly improved symptoms and survival in the coenzyme Q10 group.Sub-group analysis of just the European study participants showed significantly improved ejection fraction in the coenzyme Q10 treatment group.[13]

The 2013 KiSel-10 Study: Community living senior citizens (average age: 78 years) administered 2 x 100 mg of ubiquinone CoQ10 in combination with 200 mcg of selenium or matching placebo daily for four years.

RESULT: significantly reduced risk of death from heart disease and improved heart function in the active treatment group.[14]

Langsjoen Hypertension Study: Cardiologist Peter Langsjoen selected 109 patients with essential hypertension. Patients added high-dose CoQ10 (average dose 225 mg/day) to their existing antihypertensive drugs.

RESULT: New York Heart Association (NYHA) functional class improved from a mean of 2.40 to 1.36, and 51% of patients came completely off from 1 to 3 blood pressure meds within average of 4.4 months after starting high-dose CoQ10.[15]

CoQ10 & Cancer: Studies reveal that cancer patients have low levels of coenzyme Q10.[16] Thomas Seyfried, MD has written an important book titled Cancer as a Metabolic Disease: On the Origin, Management and Prevention of Cancer.[17] Seyfried explains that cancer is a metabolic disease that initiates with damage to mitochondrial DNA, which hinders the ability of cells to produce adequate energy. This causes the metabolic shift from oxygen to glucose for energy production, which is the hallmark of cancer cell metabolism. Coenzyme Q10 in its reduced form--ubiquinol plays a critically important role in mitochondria by protecting mitochondrial membranes and mitochondrial DNA (mtDNA) from free radical damage.[18]

Breast Cancer: In a small study, 32 advanced breast cancer patients with lymph metastasis were treated with 390 mg of CoQ10 daily. Either partial or complete tumor regression was documented in 6 of the 32 women.[19]

Prostate Cancer: In men with prostate cancer, treatment with high-dose CoQ10 resulted in substantial reductions in PSA and tumor size. An important finding was that the men did not begin to show any signs of response until about 90 days into the trial.[20]

Reducing Chemotherapy Side Effects: clinical trials have also reported that coenzyme Q10 substantially protects against and/or reduces side effects in patients undergoing various forms of chemotherapy.[21]

Neurological Conditions: Reduced levels of coenzyme Q10 are associated with several neurological diseases and its ability to reduce oxidative stress suggests that CoQ10 may be able to slow the progression and in some cases, possibly provide some therapeutic benefit. Conditions in which CoQ10 may play a role include Parkinson’s disease[22], Huntington’s disease[23] and Alzheimer’s disease.[24]

Life Extension: Coenzyme Q10’s ability to protect mitochondria against excessive free radical damage makes it a candidate for consideration as a life extension nutrient. Although studies in animal models have had mixed results, a study conducted by Emile Bliznakov, MD has fascinating implications.
Dr. Bliznakov started his experiment with 100 “old” female white mice 16 to 18 months of age, which is equivalent to humans in their 60s to 70s. Being elderly, these mice were already beginning to show some signs of decreased immunity and aging bodily functions.[25] Fifty mice regularly received CoQ10; the other 50 old mice served as controls. All mice were maintained on optimally nutritious diets.

• At 36 weeks into the study, 100% of the control mice were dead while 40% of the CoQ10-treated mice were still alive, active and not showing the normal signs of physical deterioration commonly associated with advanced age.
• At week 56, 10% of the CoQ10-treated mice were still alive and thriving. This is 2X longer than these mice would normally be expected to survive beyond the beginning of the experiment.
• At the 80th week 4 mice were still alive; at the 82nd week, the last mouse died. In human terms, this is a life span of roughly 130 years of age! (the last control mouse died at week 36).

I spoke with Dr. Bliznakov personally, and he explained the following remarkable visual differences between the two groups of mice at 30 weeks, when some of the control mice were still alive. The fur on the controls was dull, coarse, matted and on some mice, clumps of hair had fallen out, leaving bald patchy spots. All the remaining control mice were very listless and spent most of their time lying around and not socializing. On the other hand, the fur in the coats of the CoQ10-treated mice remained smooth and soft, and they maintained a much greater level of activity and socialization.

Ubiquinone vs Ubiquinol: CoQ10 is poorly absorbed because of its lipophilic nature and its large molecular weight. In 2006, Kaneka Corporation in Japan began marketing the ubiquinol (reduced) form of CoQ10 with claims that it was better absorbed than ubiquinone and hence, more effective. This has been a very successful marketing strategy for Kaneka, but actually, the claims are not scientifically accurate.

Ubiquinol CoQ10 products are substantially more expensive than ubiquinone CoQ10 products. However, when ubiquinol is ingested, it is oxidized by gastric acid to ubiquinone before it is absorbed.[26] Hence, people pay more for ubiquinol, but really do not get added benefit(s). Research has shown that it is not necessary to take ubiquinol in order to significantly increase ubiquinol levels in plasma and in plasma lipoproteins.Taking a ubiquinone supplement will do the same.[27]

Dosing Advice: The following advice pertains to all CoQ10 products, regardless of the type of CoQ10 being taken. Coenzyme Q10 is a fat-soluble nutrient and humans do not absorb fat-soluble nutrients very efficiently. CoQ10 supplements should be taken at a meal that contains some fat. This enhances the absorption of the CoQ10.

The following data was gathered from multiple human clinical trials. On average, participants’ pre-test CoQ10 blood levels were 1.09 ug/ml. After ingestion of a single 100 mg dose of CoQ10, blood levels increased to 2.33 ug/ml. However, when people ingested 200 mg of CoQ10 in a single dose, the blood level only increased to 2.35 ug/ml—almost no different than the blood level following a 100 mg dose. However, when individuals took 100 mg of CoQ10 in divided doses, twice daily, blood levels rose to 3.47 ug/ml.

Because coenzyme Q10 is a large molecular weight, fat-soluble compound, its absorption is slow and limited. This explains why better blood levels are achieved with divided doses rather than taking a large single dose of coenzyme Q10.[28]

The Crystallization Problem: CoQ10’s melting point is 10oC higher than human body temperature, which equates to about 118oF. Consequently, at temperatures below 118oF, single molecules of CoQ10 dissolved in water or oil begin to clump into crystals. We cannot absorb CoQ10 crystals; we can only absorb single molecules. Upon microscopic examination, many CoQ10 softgel capsules contain crystals, which partially explains why many CoQ10 products have low absorbability. Even CoQ10 products that are dissolved in oil recrystallize in the body, which prevents absorption.

Absorption Studies: Until recently, there was a lack of standardization in most CoQ10 absorption studies, which made it difficult to make product comparisons. However, a recently published, head-to-head study that compared the absorption of variously formulated ubiquinone products with a well-formulated ubiquinol product, revealed conclusively that a well-formulated ubiquinone product is about 200% better absorbed than ubiquinol products.[29] However, this is not the end of the story.

The Oil Matrix: William Judy, Ph.D. has been a highly respected coenzyme Q10 scientist for over 40 years. In the past several years, he has focused on CoQ10 absorption issues and conducting CoQ10 absorption studies. Dr. Judy’s absorption studies have led him to realize that the form of coenzyme Q10 in a product (ubiquinone or ubiquinol) is less important than the oil matrix that the CoQ10 is dissolved in. Most coenzyme Q10 products are not simply CoQ10, they contain other ingredients such as various oils or a substance like piperine, which is a compound derived from black pepper. These substances may enhance the absorption of coenzyme Q10.

Formulation is More Important Than Form: Dr. Judy’s research has revealed that the following two important factors determine the absorption (and effectiveness) of coenzyme Q10. One is the composition of the oil matrix in which the CoQ10 is dissolved and the second factor is the heating and cooling process used prior to filling the coenzyme Q10/oil mixture into the soft-gel capsules. These are the factors that differentiate between a crystal free CoQ10 product vs a product with CoQ10 crystals.

Crystal Free CoQ10: Numerous companies that produce coenzyme Q10 products are engaged in research to develop their own patented delivery system that keeps their CoQ10 in solution, both in the capsule and after it has been ingested. These are called Crystal Free coenzyme Q10 products.

Pharma Nord is a Denmark-based company that that has been committed to producing quality coenzyme Q10 products for over 30 years. During the 1990s they funded numerous absorption and bioavailability studies on their Bio-QuinoneTM Active CoQ10 GOLD product. These studies confirmed that their patented oil mixture provided a crystal free product that is well absorbed.[30],[31],[32]

Industry Acceptance: Pharma Nord’s willingness to fund studies that document the superior absorbability of their Bio-Quinone CoQ10 resulted in their products being selected to be used in a majority of the large clinical trials conducted around the world. To date, 78 human studies have been conducted using Bio-Quinone Active CoQ10 GOLD, and 26 of these studies are randomized, double-blind, placebo-controlled studies with 30 or more participants.

CoQ10 & Immunity: The global COVID-19/coronavirus pandemic has made people much more conscious about taking steps to boost their immune system. Coenzyme Q10 supports and/or enhances immune function in the following ways: stimulates production of red blood cells and hemoglobin[33], improves ratio between T4/T8 lymphocytes[34], increases production of natural killer cells[35] and stimulates the production of antibodies.[36]Thus, coenzyme Q10 should be considered along nutrients like vitamin C and vitamin D, as important natural therapies to enhance immune function.

Bio-Quinone’s Superior Absorbability: One of the world’s leading coenzyme Q10 scientists, Dr. Guillermo Lopez-Lluch of Spain, conducted a bioavailability study with seven of the leading coenzyme Q10 formulations on the market. In this double-blind, crossover study, individuals were given a single 100 mg dose of CoQ10 and plasma CoQ10 levels were measured 48 hours after ingestion. Pharma Nord’s Bio-Quinone was found to be from 3 to 10 times better absorbed than the other 6 brands tested.[37] This explains why Pharma Nord’s Bio-Quinone has been the CoQ10 product selected to be used in the majority of large coenzyme Q10 clinical trials around the world over the past thirty years.

The slide/image below shows how Pharma Nord’s patented process keeps their coenzyme Q10 in solution, which results in a product that is largely crystal free. Coenzyme Q10 is an incredibly important nutrient, but in order to be effective, it must be well absorbed and bioavailable. That’s why I use and recommend Pharma Nord’s Bio-Quinone Active CoQ10 GOLD.

To Order: Practitioners, if you would like to get product information or order Pharma Nord’s Bio-Quinone at wholesale prices for yourself or for your patients, send a request to:   practitioner@pharmanord.com



REFERENCES:

[1] Folkers K, Littarru GP, Ho L, Runge TM, Havanonda S, & Cooley D. (1970). Evidence for a deficiency of coenzyme Q10 in human heart disease. International Journal of Vitamin Research 40(3):380-90.
[2] https://www.nobelprize.org/prizes/chemistry/1978/s...
[3] Pelton R. The Drug-Induced Nutrient Depletion Handbook (2nd Edition). Hudson, OH, Lexi-Comp, 2001.
[4] De Barcelos IP and Haas RH. CoQ10 and Aging. Biology (Basel). 2019 Jun;8(2):28.
[5] Ernster L and Forsmakr-Andree P. Ubiquinol: An Endogenous Antioxidant in Aerobic Organisms. Clin Investig. 1973;71(8 Suppl):S60-65.
[6] Littarru GP and Tiano L. Coenzyme Q10: Recent Developments. Molecular Biotechnology. 2007;37:31-37.
[7] Kagan VE, et al. Role of Coenzyme Q and Superoxide in Vitamin E recycling. Subcell Biochem. 1998;30:491-507.
[8] Albano CB, et al Distribution of Coenzyem Q Homologues in Brain. Neurochem Res. May 2002;27(5):359-68.
[9] Gao S and Liu J. Association between circulating oxidized low-density lipoprotein and atherosclerotic cardiovascular disease. Chronic Dis Transl Med. 2017 Jun 25;3(2):89-94.
[10] Mortensen SA. Dose-related decrease of serum coenzyme Q10 during treatment with HMG-CoA reductase inhibitors. Mol Aspects Med. 1997;18 Suppl:S137-44.
[11] Sharma A, et al. Coenzyme Q10 and Heart Failure: A State-of-the-Art Review. Circ Heart Fail;9(4):e002639.
[12] Mortensen SA, et al. The effect of coenzyme Q10 on morbidity and mortality in chronic heart failure: results from Q-SYMBIO: a randomized double-blind trial. JACC. Heart Failure. 2014, 2(6): 641-649.
[13] Mortensen SA, et al. Effect of Coenzyme Q10 in Europeans with chronic heart failure: A sub-group analysis of the Q-Symbio randomized double-blind study. Cardiology Journal. 2019, 26(2): 147-156.
[14] Slehagen U, et al. Cardiovascular mortality and N-terminal-proBNP reduced after combined selenium and coenzyme Q10 supplementation: a 5-year prospective randomized double-blind, placebo-controlled trial among elderly Swedish citizens. International Journal of Cardiology, 2013, 167(5): 1860-1866.
[15] Langsjoen P, et al. Treatment of Essential Hypertension With Coenzyme Q10. Mol Aspects Med. 1994;15 Suppl: S265-72.
[16] Folkers K, et al. Activities of vitamin Q10 in animal models and a serious deficiency in patients with cancer. Biochem Biophys Res Commun 234:296-299, 1997.
[17] Seyfried T. Cancer as a Metabolic Disease: On the Origin, Management and Prevention of Cancer. Hoboken, NJ. John Wyley & Sons, Inc. 2012.
[18] Ernster L and Dallner G. Biochemical, physiological and medical aspects of ubiquinone function. Biochim Biophys Acta. May 24, 1995;1271(1):195-204.
[19] Lockwood K, et al. Partial and complete regression of breast cancer in patients in relation to dosage of coenzyme Q10. Biochem Biophys Res Commun. 1994 Mar 30;199(3):1504-8.
[20] Judy WV, Willis RA, Folkers K. Regression of prostate cancer and plasma specific antigens (PSA) in patients on treatment with CoQ10. Boston: 1st Conf. of the Intl. Coenzyme Q10 Assn. 1998. 143.
[21] Judy WV , Hall JH , Dugan W , Toth PD , Folkers K. Coenzyme Q10 reduction of Adriamycin cardiotoxicity. In: Folkers K , Yamamura Y , eds. Biomedical and Clinical Aspects of Coenzyme Q. Vol 4. Amsterdam, the Netherlands: Elsevier/North-Holland Biomedical Press; 1984:231-241.
[22] Mischley LK, et al. Coenzyme Q10 deficiency in patients with Parkinson's disease. J Neurol Sci 318(1-2), 72-5 (2012).
[23] Naia L, et al. Mitochondrial and metabolic-based protective strategies in Huntington's disease: the case of creatine and coenzyme Q. Rev Neurosci 23(1), 13-28 (2012)
[24] Wadsworth TL, et al. Evaluation of coenzyme Q as an antioxidant strategy for Alzheimer's disease. J Alzheimers Dis 14(2), 225-34 (2008)
[25] Bleznakov E. (1986)The Miracle Nutrient: Coenzyme Q10. New York. Bantam Books.
[26] Judy WV. Coenzyme Q10: The Substance That Powers Life, An Insider’s Guide. 2018. ISBN: 978-87-7776-186-7. Figure 20 on page 60.
[27] Mohr D, et al. Dietary supplementation with coenzyme Q10 results in increased levels of ubiquinol-10 within circulating lipoproteins and increased resistance of human low-density lipoprotein to the initiation of lipid peroxidation. Biochim Biophys Acta. 1992, 1126(3):247-54.
[28] Bhagavan HN and Chopra RK. Coenzyme Q10: Absorption, Tissue Uptake, Metabolism and Pharmacokinetics. Free Radic Res. May 2006;40(5):445-53.
[29] López-Lluch, G. Bioavailability of coenzyme Q10 supplements depends on carrier lipids and solubilization. Nutrition. Jan 2019;57:133-140.
[30] Folkers K. A one year bioavailability study of coenzyme Q10 with 3 months withdrawal period. Molecular Aspects of Medicine. 1994;15:Suppls281-s285.
[31] Weber C and Bysted AH. Intestinal absorption of Coenzyme Q10 administered in a meal or as capsules to healthy subjects. Nutrition Research. 1997;17(6):941-945.
[32] Weber C, et al. Antioxidative effect of dietary coenzyme Q10 in human blood plasma. International Journal for Vitamin and Nutrition Research. 1994;64(4):311-315.
[33] Diaz-Castro J, et al. Beneficial Effect of Ubiquinol on Hematological and
Inflammatory Signaling during Exercise. Nutrients. Feb. 6, 2020;12(2). doi:10.3390/nu12020424
[34] Folkers K, et al. Coenzyme Q10 increases T4/T8 ratios of lymphocytes in ordinary subjects and relevance to patients having the AIDS related comples. Biochem Biophys Res Commun. 1991 Apr 30;176(2):786-91.
[35] Favaglia G, et al. Effect of micronutrient status on natural killer cell immune function in healthy free-living subjects aged ≥90 y. Am J Clin Nutr. Feb 2000;71(2):590-598.
[36] Barbieri B, et al. Coenzyme Q10 Administration Increases Antibody Titer in Hepatitis B Vaccinated Volunteers--A Single Blind Placebo-Controlled and Randomized Clinical Study. Biofactors. 1999;9(2-4):351-7.
[37] Lopez-Lluch G, et al. Bioavailability of Coenzyme Q10 Supplements Depends on Carrier Lipids and Solubilization. Nutrition. Jan. 2019;57:133-140.

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