February 2003

© Whole Foods magazine
 

Coenzyme Q-10: An interview with Emile G. Bliznakov, M.D.

Part 2: Don’t take cholesterol-lowering drugs
unless you also take coenzyme Q-10.

by

Richard A. Passwater, Ph.D.
 

                Emile G. Bliznakov, M.D. is a leading expert on the immune system, aging and coenzyme Q-10 (CoQ-10). He has published more than 100 research studies. Dr. Bliznakov’s research has led to important findings about the role of CoQ-10 as a modulating agent of the immune system, with potentiating far-reaching applications in clinical medicine. His clinical and laboratory research over more than 30 years with CoQ-10 has increased our understanding of CoQ-10 and bioenergetics, the immune system and the aging process. His research on CoQ-10 safety and with drugs that interfere with CoQ-10 production are becoming of paramount importance.               

                In the first part of this discussion, we chatted with Dr. Bliznakov about CoQ-10 and its role in the immune system and how a deficiency of CoQ-10 can increase our susceptibility to many diseases including neurodegenerative diseases, cancer, and other diseases of aging.

 

Passwater: Before we proceed further on more specific matters, please tell us about the availability of scientific literature on the subjects we have been discussing. Some critics assert that the literature is scarce.

Bliznakov: Well, that would be a myopic view. An old English proverb, appropriate for this case, pronounces that “the eye does not see what the mind does not know! The literature accumulated about CoQ clinical research, accumulated during the past 30 years, is enormous.

                Since 1960, the biochemistry, physiology, and clinical effectiveness of CoQ-10 have been discussed at 16 specialized international CoQ-10 symposia and the published proceedings total almost 5,000 pages. The most recent symposium took place in London this past November. In addition, hundreds and hundreds of scientific articles have been published in various medical journals all around the world. Furthermore, during the past few years, five more technical books on CoQ-10 were published.

                The greatest amount of CoQ-10 clinical research is conducted in the area of cardiovascular diseases. We have already discussed why this is so. More specifically, the results of 58 clinical trials in patients with various forms of cardiovascular diseases were critically evaluated by the renowned cardiologist Dr. Peter Langsjoen and his colleagues (BioFactors 9:273; 1999). From the 58 clinical studies involving 5,727 patients, three studies reported negative results (1.7%), experienced by 110 participants (1.9%). A more general review was compiled by another cardiologist and author, Dr. Stephen Sinatra of Manchester, CT (Heart Disease 2:16; 2002). This study was based on 39 placebo-controlled CoQ-10 clinical trials since 1972 as part of more than 100 general trials in cardiac patients. Of the 39 placebo-controlled trials, 36 (92.3%) showed a beneficial CoQ-10 effect. Earlier, Dr. Sinatra strongly declared, “If there is just one thing you do to help maintain your heart’s health, make sure you’re taking CoQ-10 daily.”

                And I should add for the benefit of all those seeking general—rather than clinical—information on CoQ-10, they should read your interview with the discoverer of CoQ-10, Dr. Fred Crane [Whole Foods 25 (9&10) 2002]. Anyone interested in the history of CoQ discovery and in the mystery of how humans produce energy should read that thought-provoking superb interview. In 1958, Dr. Karl Folkers and his associates determined the chemical structure of CoQ-10 and in 1978, Dr. Peter Mitchell in England was awarded the Nobel Prize in Chemistry for his elucidation of some of the complex biochemical characteristics.

Passwater: Thank you for the CoQ-10 overview and your kind words. Dr. Bliznakov, you wrote three major reviews and have been the lead crusader with regard to a perplexing problem—that the cholesterol-lowering drugs called “statins” inhibit CoQ-10 production in the body and thus are a bioenergy, heart, and health risk. [Adv. Therapy 15:218; 1998, Biomed. Pharmacol. 56:56; 2002 and J. Am. Nutr. Assoc. 5:32; 2002] Please tell our readers about this problem.

Bliznakov: Many colleagues call me—some as a compliment, and others as an accusation—an “anti-statin crusader.” For that reason, I lost many friends from the pharmaceutical industry. I am not a crusader against statin drugs—just against their indiscriminate use without providing CoQ-10 as a supplement to make up for the fact that the statins reduce CoQ-10 production, and probably transport, in the body.

                Despite these cautionary suggestions, in 2001, two pharmaceutical companies filed a petition with the U.S. Food and Drug Administration (FDA) to market their statins (Mevacor and Pravachol) as over-the-counter (OTC) products, without prescriptions. Fortunately, the FDA rejected this unsound request at that time.

                Furthermore, recently Health News (8:3; 2002), sponsored by the Massachusetts Medical Society, published an editorial entitled shockingly, “A Statin in Every Medicine Cabinet.” Another article, authored by the editor of the American Journal of Cardiology, advocates unjustifiably, the elimination of statins titration (starting treatment with a low dose) and the elimination of the existing requirement for liver function testing, during treatment with statin drugs. This is an unfortunate example of encouraging the indiscriminate drug use, without physicians’ guidance and control—a practice resembling the regretful well-known “direct-to-consumer” advertising campaigns, perfected since 1977. In my opinion, drug advertising and public relation officials are slowly replacing uninfluenced physicians as medical treatment decision-makers.

                It is interesting that some general publications are more critical of the suggestions for indiscriminate use of statins than the medical professionals. For example, U. S. News & World Report published an article in the “Health and Medicine” section entitled “Heartfelt Hurt—Why Statins are Making Some Patients Sore.” The magazine reports, that according to new data, up to 5% of people placed on statins complain of muscle weakness and pain, with various degrees of severity (pp58-59 October 7, 2002).

Passwater: Were you the first to bring to light this problem of statins lowering CoQ-10 production in the body?

Bliznakov: No, I wasn’t the first to report this; Dr. Karl Folkers did that in 1990, and it was later confirmed by other studies. It was not considered important then. At that time, statins had just appeared, and there were very few users. Nobody paid attention.

                Later, I unearthed an important aspect of this story within two statin patents. Two U.S. patents were granted to Merck in 1990 describing a method for counteracting the statin-associated myopathy and potential nerve damage caused by statins. The method described was the addition of CoQ-10 to compensate for the reduced production of CoQ-10 caused by the statins. Thus, the manufacturer itself implicated the serious side effects of statins and the protective role played by CoQ-10 in preventing these statin side effects. The manufacturer has not disseminated these data for 12 years, which incriminates them seriously.

Passwater: Just how do statins reduce CoQ-10 production in the body?

Bliznakov: The long answer to this important question is that CoQ-10 is supplied partly by food and partly by synthesis in the body from several other nutrients in a complicated 17-step process. CoQ-10 is a relatively simple molecule comprised of a quinone ring with a side chain attached. The side chain in humans has 10 isoprenoid units so it is called CoQ-10. In rodents, that side chain has nine isoprenoid units and is called CoQ-9. (Figure 1)

                For decades, the major cause of mortality in the industrialized western countries has been cardiovascular diseases. Studies have established a close relationship between high cholesterol level, atherosclerosis and cardiovascular diseases. Today, many scientists are questioning the validity of this statement. Therefore, reducing the level of cholesterol is expected to decrease the incidence of cardiovascular diseases and prolong life. Cholesterol-lowering drugs called “statins”—which are hydroxymethylglutaryl coenzyme A (HMG-CoA) inhibitors—are a class of cholesterol-reducing agents. They effectively inhibit the biosynthetic pathway of cholesterol at the level of mevalonate. (Figure  2)

                The statin enthusiasts constantly use the statement that statins are “well tolerated.” But as usual, many events in our lives are relative. The 2001 National Cholesterol Education Program (NCEP) report recommends that, in practice, 36 million Americans should be treated with statins. Even at 1% accepted claims for liver and muscle toxicity symptoms, a simple calculation reveals the disturbing fact that 360,000 patients will be afflicted with liver and muscle side effects. So this grows from a simple medical problem to a major yet unrealized societal dilemma.

                The proverbial other side of the coin is that mevalonate is not only the cholesterol precursor but also the precursor of many other compounds, among them CoQ-10, that are critical for various other cellular functions. Thus, the inhibition of the mevalonate pathway suppresses the cholesterol biosynthesis, but at the same time unintentionally inhibits the biosynthesis of CoQ-10 causing a pronounced CoQ-10 deficiency of about 40%, according to published reports.

Passwater: Do the statins also restrict the transport of CoQ-10 within the body, in addition to its production decrease?

Bliznakov: This very important point has not been studied adequately. My personal opinion is that this effect is probable. Statins reduce the blood level of some lipoproteins—especially low-density lipoproteins (LDL)—as part of their effect. Lipoproteins have the important function to transport cholesterol in the blood. Here again comes the other side of the coin: LDL also transports CoQ-10, vitamin E and other molecules. When we have a shortage of transport vehicles (LDL), we do not know which compounds have priority to be transported to the cells. If LDL is reduced, cholesterol transport may be decreased, but is the transport of CoQ-10, vitamin E and other important compounds decreased to a more or lesser extent? Is that decrease more critical to health than decreased cholesterol? Some scientists support this view strongly.

Passwater: So, long-term use of the statin drugs can have deleterious effects?

Bliznakov: We, along with others, suggested many years ago that it is not necessary to discontinue the clinical use of statins because of expected side effects. But, we advocated, during extended statin therapy, these drugs should be combined with CoQ-10 supplementation in order to support the development of deficient cellular bioenergetic states, as well as to minimize the oxidative stress. This should be mandatory in patients with compromised bioenergy states or immune systems, for example, elderly patients treated with statins. Moreover, the distinct possibility of additive therapeutic CoQ-10 effects discussed earlier when administered concurrently with statins deserves further evaluation.

                The first statin (lovastatin, Mevacor) was introduced in the year 1987. Until August 2001, a total of six statins were available commercially. As of 1999, atorvastatin (distributed as Lipitor by Pfizer Inc.) was ranked number one in sales. It is expected that when the results are tabulated, the sales of Lipitor will be $4.8 billion in 2000, and the sales are projected to be $10 billion in 2010.

                As with many other drugs, statins also have significant side effects, many of them related to the injury of the intracellular bioenergetic process. Among them are some of today’s well-known conditions such as myalgia and myopathy, which may lead to often-fatal rhabdomyolysis and kidney damage. Rhabdomyolysis is a condition in which skeletal muscle cells break down, releasing myoglobin (the oxygen-carrying pigment in muscle) together with enzymes and electrolytes from inside the muscle cells. The risks with rhabdomyolysis include muscle breakdown and kidney failure since myoglobin is toxic to the kidneys. Some of the other suspected or established adverse reactions are peripheral neuropathies, gastrointestinal symptoms, including hepatic injuries, initiation or accelerated progression of cataracts, neoplasia and mental disorders. They could be a direct or indirect result of the CoQ-10 deficiency coincidental with statin treatment. So, in the case of statins, we shot first and then asked questions. This is why, with their extended long-term use, the list of side effects is growing so fast.

Passwater: Dr. David Gaist and co-workers at the University of Southern Denmark in Odense published three papers, the most recent in May, in the journal Neurology (58:1333; 2002). They initially suggested that statins may be related to a rare nerve disorder called polyneuropathy. After additional research, they reported this summer that polyneuropathy was indeed a side effect, although rare.

Bliznakov: Yes, this is correct. Their work just extends the long list of side effects.

Passwater: And more recently, Dr. S. Paul Phillips, a cardiologist at Scripps Mercy Hospital in San Diego, reported in the October 1 issue of the Annals of Internal Medicine that statins caused “rare” muscle tissue abnormalities and weakness that can’t be detected by present standard tests. The important issue is that in the past, muscle damage was assessed by looking for an enzyme called creatine kinase which is released during tissue damage. Recommendations are that when patients taking statins have creatine kinase levels 10 times normal or more, they be taken off the statins. These patients complained of weakness and tiredness, but did not show an elevation in creatine kinase. Muscle biopsies confirmed muscle damage. When the patients were taken off the statins, they slowly regained their strength and biopsies returned toward normal.

Bliznakov: What is disturbing is that there was a significant increase in breast cancer incidence in one of the statin clinical trials designated inappropriately as “CARE.” This finding has been disregarded by many clinicians. Yet, Dr. Matthew Muldoon, quoted in The New York Times on September 5, 2000, said, “… we have studies that show statins don’t cause cancer within a five-year period.” Of course, neither does smoking.

                One of the latest, newly described adverse effects of statins is immunosuppression. This fact could explain the increased cancer incidence after long treatment with statins.

                As more and more people are urged to take statins but are not advised to also take CoQ-10 and other antioxidants, the problem will worsen. The 2001 report of the NCEP recommends that 36 million Americans should be taking drugs in order to lower their cholesterol level, nearly three times the 13 million who qualified under the previous guidelines in 1993. At that time, the San Francisco Chronicle (June 4, 2001), published a sharp critical note entitled, “U.S. Cholesterol Guidelines Have Some Suspecting Bias. Favorable studies said to be pharmaceutical boostering.”

                The long-lasting, trumped-up concept for statins as “well-tolerated” drugs was eroded on August 8, 2001. On that date, the German chemical giant, Bayer AG, announced the voluntary withdrawal from the market of their product cerivastatin (Baycol), a statin distributed also as Lipobay—one of the six statins available. Preliminary data at that time indicated that treatment with Baycol alone or in combination with gemfibrozil (Lopid) resulted in 52 deaths worldwide. On January 8, 2002, the CNN Television network reported that the number of deaths resulting from Baycol treatment exceeded 100.

                Legal actions against the Baycol manufacturer have been reported in Switzerland and the United States of America. An ethical issue in this area of medicine deserves our attention. Package inserts and publicity material for various marketed statins usually ignore the CoQ-10-statin link. Nevertheless, in 1990, two U.S. patents were granted to Merck, a major statin producer and distributor, describing a method for counteracting statin-associated myopathy and potential neural damage by the adjunctive administration of statins with CoQ-10, thus implicating and admitting again the role played by CoQ-10 in the statin side effects. For more than 12 years the producers of statins did not act on this information and failed to reveal the vital statin-CoQ-10 link to the millions of statin users and even to the medical community.

                It seems to me, that in today’s “advanced” modern world, the ancient medical ethical principle attributed to Hippocrates (460-370 BC)—“First do no harm”—has been quietly disregarded for the time being.

Passwater: This problem with the statins, which you have vigorously called attention to, spawned two independent citizen’s petitions to the FDA on May 29, 2002. One, by cardiologist, Dr. Peter Langsjoen, states that all prescribing physicians should be notified that statin drugs produce a depletion in CoQ-10, which in settings of pre-existing CoQ-10 deficiency, such as in congestive heart failure and aging, has the ability to markedly worsen heart function. The Dr. Langsjoen petition states “the potential for statin-induced cardiomyopathy must be seriously considered and must be prevented with the concomitant administration of CoQ-10."

                The second petition was filed by a California physician, Dr. Julian Whitaker. Dr. Whitaker’s petition addresses the fact that, as stated in the Physician’s Desk Reference, 0.5% to 2.3% of patients taking statins experience adverse effects including myopathies (any disease of the muscles). Dr. Whitaker asks the FDA act immediately to require that a medication guide warning of the dangers and explaining the need for CoQ-10 supplementation be included with statin drug prescriptions.

Bliznakov: Even the Merck patents (4,929,437 and 4,933,165) stated this problem in 1990, so it’s nothing new. The issue is that the pharmaceutical companies are closing their eyes to this problem and not doing anything about it. I am becoming upset because this is not only a medical problem; it is mainly an ethical problem. We can envision people now suing the manufacturers even in countries such as Switzerland. That becomes an intolerable situation, begging for action.

Passwater: Do you think these petitions will be effective? Do you think the FDA will require the labeling?

Bliznakov: I think it depends on the future pressure placed by the public and the medical community on the FDA. Some colleagues who are very interested in this subject asked me why the pharmaceutical industry does not now include CoQ-10 in its pharmaceuticals. That would solve the problem. Perhaps the companies are afraid that doing this at this late date and with their prior knowledge may possibly lead to thousands of people suing them. To add CoQ-10 to their product, which is to admit that it is important, raises the question, “Why didn’t you do it 12 years ago when the combination was patented and the problem identified?”

                So now, in my opinion, they continue to do something wrong to protect themselves. I don’t think it is going to work. To keep being stubborn and not admitting something that is now becoming a fact for most scientists, physicians and the public is already a lost case. Time will be the ultimate judge. This is especially true in today’s era of increased conscientiousness about “medical ethics” and “conflict of interest.” Our modest contribution to this new and welcomed evolution is a short publication in The Lancet (356:1522; 2000).

Passwater: You are indeed quite interested in bringing this information to the public.

Bliznakov: I am interested very much because, as I mentioned, I am not saying that statins should not be used. I am saying they should have a restricted use together with CoQ-10 and other antioxidants for two reasons. First, it will reduce the toxic side effects; and second, probably it can increase the beneficial effects resulting from the statin treatments because we know that CoQ-10 has effectiveness in the cardiovascular diseases by itself, as discussed earlier. So combining the two probably will result in an additive or synergistic action. From the beginning until now, my objective was to bring this problem to the attention of our medical community and to the pharmaceutical industry and not to address the public directly.

Passwater: Could there be other drugs that interfere with CoQ-10 production?

Bliznakov: Dr. Ross Pelton and his colleagues published in their very useful book Drug-Induced Nutritional Depletion Hand Book, a list of 49 drugs—among them statins—that interfere with either the production of CoQ-10 or its transport. As another example, Adriamycin is an antibiotic and is also regarded as a major drug in cancer therapy. Its clinical application, however, has been limited by often lethal cardiotoxicity. Ultrastructurally, this cardiomyopathy is characterized by necrosis and degeneration in the mitochondria, resulting in inhibition of their respiratory and thus energy metabolism. Furthermore, Adriamycin is accumulated within macrophages, the critical cells of the immune system, causing loss of cell function. Published results indicate that CoQ-10 administration alleviates this cardiotoxicity—in humans and in animals. I have discussed this in a short review of the literature published in Cardiovascular Research (43:248; 1999).

                In addition to its well-known cardiotoxicity, we established earlier that Adriamycin acts as an overwhelming immunosuppressive agent and that this immunosuppression is associated with a significant reduction of the thymus and spleen weights—a reduction of more than 50% from their normal organ weights. A single administration of this drug suppressed almost completely the hemolytic antibody production in mice—a very sensitive test for immunosuppression and its correction. CoQ-10 treatment partially, but significantly, restored the antibody production.

Passwater: It is amazing that some of the chemotherapeutic drugs work at all as they suppress the immune system, the body’s defense against cancer and cancer spread.

Bliznakov: Cancer chemotherapy is effective in the clinical treatment of various forms of cancer to varying degrees. Yet, this effectiveness is not specific and together with cancer cells, they destroy normal cells including the cells of the immune system -- “the good and bad guys.” For this reason, the therapeutic effect is associated with a profound immunosuppression, as evident by our studies and the studies of others. This immunosuppressive effect is well-recognized by medical professionals: some of these drugs are used for the treatment of autoimmune diseases such as lupus erythematosus or in organ transplantation. Nevertheless, many years ago, a paper was published in Cancer Research entitled “Are the anticancer drugs self-defeating?” This question still has not been answered.

                All the results cited here indicate that CoQ-10 is a critical component, at the mitochondrial level, for the optimal function of the immune system. We have established by using various experimental models including phagocytic rate, circulating antibody levels, neoplasia, aging and viral and parasitic infections) the role of CoQ-10 as an active immunomodulating agent with clinical applicability.

Passwater: Do physicians understand the difference in bioavailability between the different commercially available forms of CoQ-10 supplements such as dry powder versus oil solution?

Bliznakov: The question of CoQ-10 bioavailability after oral supplementation is rarely discussed, particularly among clinicians. The problem is that CoQ-10 is a fat-soluble material and not water-soluble. CoQ-10 is available as crystallized material or as a powder and this is the worst formulation available with the lowest bioavailability.

                All this depends on how much fat is available in the food to dissolve the CoQ-10 and to assist the passage through the intestinal wall to the circulation. According to one study, only 60% to 80% from an oral dose passes from the intestine to the circulation, and according to other studies, only 50% is absorbed. In today’s low-fat diets, even less is bioavailable because, as you know, we avoid eating high-fat food—no fat fish, no butter, no fat meat, less and less chicken, so even less CoQ-10 goes into the circulation because there is not the fat available to dissolve it. On one hand, a low-fat diet is good for your heart and on the other hand it is not so good because it reduces the bioavailability of CoQ-10 coming with the food and this necessitates the use of supplements to increase the CoQ-10 availability.

                A frequent question heard from the medical community is whether CoQ-10 is “the new snake oil.” This question arises because there are reports that CoQ-10 is effective for a variety of conditions, ranging from cardiovascular diseases to neoplasia and from periodontal diseases to neurodegenerative diseases. Well, it sounds like snake oil when you talk about the multiple medical indications. And even I have a problem with this at times. But when you look at the physiological and functional background of this material, it should be remembered that it is not a drug that cures specific diseases, but a major biochemical component of our most important energy production mechanism in each cell. So you can see that if you have a CoQ-10 deficiency in different systems, clinical symptoms will depend on which system is involved. If you have the brain involved you can have some form of neurodegenerative disease, if you have gingivitis, you eventually will have periodontal disease with heart complications. Usually you have cardiovascular diseases because the heart is often the first organ affected by the energy deficiency. The same thing applies to cancer. When you have CoQ-10 deficiency, the immune system activity is reduced and the body cannot fight the tumor invasion. When you look at this from a general bio-physiological point of view, you can see that it fits. Unfortunately, we physicians are narrow specialists and are not trained to do that.

Passwater: Have you investigated the safety of CoQ-10?

Bliznakov: Parallel with our CoQ-10 efficacy studies, we conducted an extensive toxicological evaluation—first as preclinical studies and then as an FDA Phase I study in terminal cancer patients; the latter was conducted at Yale Medical School during 1972-74. Our results, confirmed by other investigators involving thousands of patients, revealed no significant abnormalities that would contraindicate the use of CoQ-10 in humans. The Physicians Desk Reference categorically states, “Adverse reactions—none reported” (1999 PDR, p3286)

                Another observation that is important for the clinical applicability of CoQ-10 is that the enhancement of the activity of the immune system does not result from the hyperplastic alteration of the spleen, liver and other organs directly involved in the immune system responsiveness. If hyperplastic alteration were the case, it would be  an undesirable side effect. Accordingly, the observed desirable enhancement effect most likely results from an increased activity of existing cells, via the improved bioenergetic balance.

Passwater: What are your research interests today?

Bliznakov: For me, your question is somewhat philosophical and far-reaching. I believe strongly that even an entire human life is not enough time to grasp the intricate interplay between the body and the offensive elements. Fashion and other fads that change twice yearly should not have place in medical research; unfortunately they do! Dr. Karl Folkers’ work for more than 30 years was in the field of CoQ-10. The life of a soul flying from blossom to blossom is usually very short and not productive. My plan is to stay with CoQ-10 and to participate in the ever-changing research aspects of this fascinating constituent of our cells.

                At present, I am participating in the preparation of a chapter on the link between CoQ-10 and cancer, part of a book, to be published next year. I also have special interest in the large group of neurodegenerative disorders (Parkinson’s, Huntington’s and other diseases). With the aging of the world population the incidence of neurodegenerative diseases is fast increasing. This problem today, is not only medical, but more important, also societal and ethical, and it should be attacked on all three fronts.

Passwater: Well, we certainly appreciate your past CoQ research, and we eagerly look forward to your future research. It has been a fascinating journey with you, and we thank you for sharing your knowledge with us. WF

 

© 2003 Whole Foods Magazine and Richard A. Passwater, Ph.D.

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