The clinical use of HMG CoA-reductase inhibitors (statins) and the associated
depletion of the essential co-factor coenzyme
a review of
pertinent human and animal data.
Peter H. Langsjoen, M.D.,
HMG CoA-reductase inhibitors or statins are clearly the most effective class of drugs for lowering LDL cholesterol. Those drugs have been associated with a beneficial impact on cardiovascular and mortality. As such, statins have become some of the most widely prescribed drugs in the United States with many millions of patients taking them on a regular basis. According to the most recent NCEP (National Cholesterol Education Program) guidelines, the indications for the use of statins have been broadened such that patients with even low normal LDL cholesterol levels are now being treated in hopes of favorably altering the incidence of stroke and myocardial infarction. Statins are frequently used in the elderly and have gained very broad acceptance in the medical community. Statins have been noted to have significant anti-inflammatory and plaque-stabilizing effects which has added to their broader usage. It is well established that the mevalonate pathway is involved not only in the biosynthesis of cholesterol but also in the biosynthesis of the essential co-factor required for energy production, coenzyme ubiquinone). As such, HMG reductase inhibitors block the cellular production of cholesterol and of coenzyme (Rudney 1981, Goldstein 1990). This nutrient interaction has been reviewed (Bliznakov 1998, Bliznakov 2002). The peer-reviewed scientific evidence supports the following findings: 1. Statins block the endogenous biosynthesis of both cholesterol and by inhibiting the reductase, thus decreasing mevalonate, the precursor of both cholesterol and is essential for mitochondrial ATP production and is a potent lipid soluble antioxidant present in cell membranes and carried in the blood by LDL. CoQl 0 is biosynthesized in the body and available fiom dietary sources. Statin-induced decreases in are more than just hypothetical drug-nutrient interactions. Good evidence exists of significant depletion in humans and animals during statin 4. Scientific evidence the existence of detrimental cardiac consequences from statin- deficiencies in man and animals. Dr. Langsjoen's curriculum vitae is attached. 5. Statin-induced deficiency is dose related and the clinical consequences are notable most in the elderly and in settings of pre-existing congestive heart failure (CHF). 6. Statin-induced deficiency can be completely reversed by supplemental is safe and has no adverse effect on statin cholesterol-lowering or on statin anti-inflammatory effects. 8. We are in the midst of a congestive heart failure epidemic in the United States. Approximately 4.8 millions Americans are diagnosed with congestive heart failure. Half of those patients will die within 5 years. Each year, there are an estimated 400,000 new cases of CHF (Congestive Heart Failure Data Fact Sheet, Although the causes of this epidemic are unknown, statin-induced deficiency has not been excluded as a possible contributing 9. All large-scale statin trials excluded patients with NYHA class and IV heart failure such that the long term safety of statins in patients with heart failure has not been established. Background
is the coenzyme for mitochondrial enzyme complexes involved in oxidative phosphorylation in the production of ATP (Mitchell 1976, Mitchell 1990, Lenaz 199 1). That bioenergetic effect of is believed to be of fundamental importance in its clinical application, particularly as it relates to cells with exceedingly high metabolic demands such as cardiac myocytes. The second fundamental property of involves its antioxidant (free radical scavenging) (Beyer 1990, Villalba 1997). is the only known naturally occurring lipid soluble antioxidant for which the body has enzyme systems capable of regenerating the active reduced ubiquinol form (Ernster 1993). is carried in the blood with low density lipoprotein and serves to diminish the oxidation of LDL cholesterol in settings of oxidative stress (Alleva 1997). to be closely linked to Vitamin E and serves to regenerate the reduced (active) alpha-tocopherol form of Vitamin E (Constantinescu 1994) as well as the reduced form of ascorbate (Rodriguez-Aguilera 1995). Other more recently discovered aspects of function include its involvement in extramitochondrial electron transfer, e. g. plasma membrane oxidoreductase activity (Villalba involvement in cytosolic glycolysis (Lawen and potential activity in both Golgi apparatus and lysosomes (Gille also plays a role in improvement in membrane fluidity (Lenaz 1985). The multiple biochemical functions of have recently been reviewed by Crane (Crane 200 1). is essential for all cellular ATP production and is of particular importance in heart muscle function given that tissue's extreme energy requirements. A deficiency of
blood and the heart muscle has been documented in congestive heart failure (Kitamura 1984, Folkers 1985). An Australian group of cardiovascular surgeons has recently documented impairment in myocardial function secondary to age-related deficiency in patients undergoing coronary artery bypass surgery (CABG). That impairment was completely eliminated with incubation of the atrial myocardium with (Rosenfeldt 1999). Later the researchers performed a trial of preoperative supplemental therapy and found improved outcomes in coronary artery bypass surgery (Pepe 2001). The clinical experience with in cardiovascular disease, including congestive heart failure, ischemic heart disease, hypertensive heart disease and heart surgery has been recently reviewed (Langsj oen 1998, Langsjoen 1999). In the US we are presently in the midst of a congestive heart failure (CHF) epidemic, with a significant increase in the incidence of congestive heart failure over the past decade (see the figure below as reproduced from Center for Health Statistics NIH number of deaths directly from CHF increased from 10,000 in 1968 to 42,000 in 1993. The rate of hospitalizations for heart failure increased more than three times between 1970 and 1994. In the largest health system study of its kind, researchers at the Henry Ford Heart and Vascular Institute in Detroit found that the annual number of heart failure cases more than doubled from 1989-1997. Over that nine-year period, 26,442 cases were identified in the Henry Ford Health System in Detroit. Strikingly, the annual prevalence rose from 9 to 20 cases per 1000 health system patients ( reference). Those results were compiled in the Resource Utilization Among Congestive Heart Failure (REACH) study ( McCullough 2002). Figure 1. Congestive Heart Failure: A New Epidemic. Reproduced from figure 5 at Statins were first given pre1987. Since that time, there has been a slow but steady accumulation of scientific evidence that the coenzyme Q statin medications has clinical relevance and should be considered by all physicians when prescribing this class of medication. Human Trials
From 1990 to date there have been 15 published studies in humans evaluating the effects of Nine were controlled trials and eight of those demonstrated significant depletions secondary to statin therapy. Human observations on the interaction between statins and coenzyme published in 1990 by Folkers et al, who observed that five patients with pre-existing cardiomyopathy exhibited a significant decline in blood coenzyme level and clinical deterioration following lovastatin (Folkers 1990) treatment. That decrease in coenzyme Q blood level and decline in clinical status was reversed through an increase in supplemental In 1993, Watts et studied 20 hyperlipidemic patients treated with a low cholesterol diet and simvastatin and compared them to 20 hyperlipidemic patients treated with diet alone and 20 normal controls (Watts 1993). Patients treated with simvastatin had significantly lower plasma coenzyme levels and a lower coenzyme to cholesterol ratio than either patients on diet alone or normal controls. The depletion of plasma was significantly inversely associated with the dose of simvastatin. It was concluded that simvastatin may lower plasma coenzyme concentration and that the reduction may be proportionally greater than the reduction in cholesterol. The authors felt that the adverse effect of simvastatin on the biosynthesis of coenzyme may be clinically important and requires In 1993, Ghirlanda et studied 30 hypercholesterolemic patients and 10 healthy volunteers in a double-blind controlled trial, comparing placebo with either pravastatin or simvastatin for a three-month treatment period (Ghirlanda 1993). Both of those HMG CoA-reductase inhibitors showed significant reduction in total cholesterol and plasma levels, not only in hypercholesterolemic patients but also in the normal healthy volunteers. In 1994, Bargossi et performed a randomized controlled trial evaluating 34 hypercholesterolemic patients treated with either 20 mg of simvastatin for six months or 20 mg of simvastatin plus 100 mg of supplemental coenzyme (Bargossi 1994). The study demonstrated that simvastatin lowered LDL cholesterol and lowered plasma and platelet coenzyme levels. The depletion of in both plasma and platelets was prevented in the supplemental Coenzyme Q group without affecting cholesterol lowering caused by In 1995, Laaksonen et al. documented a significant decrease in in hypercholesterolemic patients treated with four weeks of simvastatin, with no reduction in skeletal muscle ubiquinone (Laaksonen 1995). In 1996, Laaksonen et evaluated skeletal muscle biopsy specimens in 19 hypercholesterolemic patients treated with simvastatin at 20 mg per day and found no depletion of skeletal muscle ubiquinone concentration as compared to control subjects (Laaksonen 1996). In 1996, De Pinieux et evaluated 80 hypercholesterolemic patients (40 patients treated with statins, 20 patients treated with fibrates, and 20 untreated controls) (De Pinieux 1996). Further, they evaluated 20 non-hyperlipidemic health controlled patients. Serum ubiquinone levels were significantly lower in statin treated patients and were not depleted in treated patients or in untreated controls. Lactate to pyruvate ratios were significantly higher in statin treated patients, indicating mitochondrial dysfunction in patients treated with statins, which was not observed in untreated hypercholesterolemic patients or in healthy controls. In 1997, Palomaki et al. studied 27 hypercholesterolemic men in a double-blind placebo controlled crossover trial with six weeks of lovastatin at 60 mg per day (Palomaki 1997). Lovastatin therapy was associated with a significant decline in serum ubiquinol content as measured per LDL phosphorus, and there was an increased oxidizability of LDL in the lovastatin treated patients. In 1997, Mortensen et studied 45 hypercholesterolemic patients in a randomized double- blind trial with either lovastatin or pravastatin for 18 weeks (Mortensen 1997). A related significant decline in total serum coenzyme found in the pravastatin group from 1.27 +/- 0.34 to 1.02 +/- 0.31 In the lovastatin group, there was a more pronounced decrease in serum level from 1.18 +/- 0.36 to 0.84 +/- 0.17 The authors concluded that although HMG CoA-reductase inhibitors are safe and effective within a limited time horizon, possible adverse consequences fiom coenzyme lowering was an important factor in long-term therapy. In 1998, Palomaki et evaluated 19 men with hypercholesterolemia and coronary artery disease treated with lovastatin with or without ubiquinone supplementation (Palomaki 1 998). The lag time in copper mediated oxidation of LDL increased by observed that the faster depletion of LDL ubiquinol and shortened lag diene formation during lovastatin therapy may partially be restored with ubiquinone supplementation. In 1999, Miyake et studied 97 non-insulin-dependent diabetic patients treated with simvastatin and observed a significant decrease in serum concentrations along with the decrease in serum cholesterol (Miyake 1999). Oral supplementation in diabetic patients receiving simvastatin significantly increased serum coenzyme Q levels without affecting cholesterol levels. Furthermore, the supplemental coenzyme Q significantly decreased cardiothoracic ratios from 51.4 +/- 5.1 to 49.2 +/- 4.7% concluded that serum coenzyme levels in diabetic patients are decreased by statin therapy and may be associated with subclinical diabetic cardiomyopathy, reversible by coenzyme Q supplement In 1999, De Lorgeril et al. studied in a double-blind fashion 32 patients treated with 20 mg of simvastatin compared to 32 patients treated with 200 mg of fenofibrate (De Lorgeril 1999). levels were significantly reduced after treatment with simvastatin but 5
not with fenofibrate. No significant change in left ventricular ejection fraction could be determined after 12 weeks of therapy. They observed a loss of myocardial reserve with a flattening of the ejection fraction response to exercise, which could be explained by the statin-induced diastolic in those patients. Unfortunately, only systolic measurements of ejection fraction were obtained in this study. In 2001, Bleske et al. failed to show a depletion in whole blood in 12 young, healthy cholesterol levels treated with either pravastatin or atorvastatin for four weeks (Bleske 2001). Also in 200 1, Wong et al. documented that the beneficial anti-inflammatory effect of simvastatin on human monocytes was completely reversible with supplemental mevalonate but not with coenzyme indicating that supplemental coenzyme would not interfere with this important statin-mediated anti-inflammatory effect (Wong 200 1). study was a randomized controlled trial by Jula et al., published in JAMA (Jula 2002). Simvastatin at 20 mg per day caused a reduction in serum The clinical consequences of this significant deficiency were not evaluated in this short term trial. In summary, in human trials evaluating coenzyme in statin therapy, there appears to be frequent and significant depletion in blood levels, particularly when statins are taken at higher doses and most notably in the elderly. In one study involving patients with preexisting CHF, the depletion in blood coenzyme levels was associated with a drop in ejection fraction and clinical deterioration. Supplemental coenzyme has been found to prevent the depletion in blood and in one study also to prevent the depletion measured in platelet serum depletion of was associated with an elevation in lactate to pyruvate ratio, suggesting an impairment in mitochondrial bioenergetics, secondary to statin-induced depletion. Furthermore, two trials demonstrated enhanced oxidizability of LDL cholesterol related to the lowering of serum by statins. Supplemental has been shown to content in low density lipoproteins and to decrease significantly LDL cholesterol oxidizability (Alleva 1997). One trial demonstrated no significant 12 young normolipidemic volunteers treated with statins and one trial found no skeletal muscle in statin treated hypercholesterolemic patients. In diabetic patients, the depletion with statin therapy appears to be associated with subclinical cardiomyopathy, with significant improvement in cardiothoracic ratios upon supplementation. From these studies, one can conclude that supplemental coenzyme prevents the statin deficiency state without altering the cholesterol-lowering ability of these drugs and appears to have benefit both in terms of decreasing the oxidizability of low density lipoprotein cholesterol, as well as preventing or reversing observed detrimental clinical changes. Animal Studies
From 1990 through 200 1 there have been 15 published animal studies involving six different animal species (six rat studies, three hampster studies, three dog studies, one rabbit study, one guinea pig study and one study looking at squirrel monkeys, mini pigs and hampsters) evaluating the effect of statins on coenzyme Q blood and/or tissue levels. Nine of these 15 studies looked specifically at the adverse consequences of this statin-induced depletion: decreased ATP production, increased injury after increased mortality in cardiomyopathy, and skeletal muscle injury and dysfunction. Some of the animals use coenzyme shorter chain homologue of coenzyme and in those cases the term coenzyme Q or Some of the first animal data was published in 1990 by Willis et al. and documented statistically significant decreases in coenzyme Q concentration in blood, heart and liver in 45 adult male rats. This blood and tissue deficiency could be completely prevented by supplementing the lovastatin treated animals with coenzyme Q In 1992, Low et al. found similar decreases in ubiquinone in liver and heart in rats treated with lovastatin (mevinolin), confirming observations by Willis et 1993, Fukami et al. studied simvastatin treated rabbits and specifically looked at those animals with elevations in creatinine kinase, lactate dehydrogenase, and skeletal muscle necrosis (Fukami 1993). The simvastatin treated rabbits were noted to have significantly reduced liver and cardiac muscle coenzyme Q content as compared to the control group. Interestingly, skeletal muscle ubiquinone content in this study was not affected. In 1993, Belichard et studied lovastatin in cardiomyopathic hamsters and found a 33% decrease in ubiquinone content in heart muscle as compared to control (Belichard 1993). Cholesterol lowering in cardiomyopathic hamsters with fenofibrate did not lower coenzyme levels. Statins are the only class of lipid-lowering drugs that axe known to block the synthesis of mevalonate. In 1994, Diebold et documented a depletion in Coenzyme content in heart muscle in guinea pigs when treated with lovastatin in older age (2 years of age) animals, and further observed no significant depletion in coenzyme content in heart muscle in the guinea pigs in the younger age group (2 to 4 months of age) (Diebold 1994). The authors evaluated mitochondrial function as measured by the potential to phosphorylate ADP to ATP, and again documented a decrease by up to 45% in cardiac mitochondria in the 2-year-old animals treated with lovastatin, and no significant decrease in phosphorylation in the younger age group animals. This sensitivity for older animals to show clinically relevant heart muscle depletion is of concern in humans as older patients are treated with statin medications and are observed to be more and more susceptible to side effects. In 1994, Loop et al. documented again that lovastatin decreased coenzyme Q content in rat liver that could be completely prevented with supplemental coenzyme In 1995, Satoh et evaluated ischemic reperfusion in dog hearts and documented that simvastatin significantly decreased myocardial coenzyme Q levels and worsened ischemia injury (Satoh 1995). Water soluble pravastatin was also studied in this dog model and did not appear to cause worsening of mitochondrial respiration in the dog heart muscle, nor did the pravastatin reduce myocardial levels. It is believed that the lipid soluble simvastatin may be more detrimental in this model due to better membrane penetration of that fat In 1997, Morand et studied hamsters, squirrel monkeys, and mini pigs, and documented depletion in heart and liver with simvastatin treatment (Morand 1997). They saw no decrease in coenzyme in heart and liver using the experimental cholesterol lowering drug cyclase, which blocks the synthesis of cholesterol below the mevalonate level and thus does not impair the biosynthesis of coenzyme In 1998, Nakahara et al. evaluated simvastatin (a lipophilic inhibitor of HMG reductase) or pravastatin (a hydrophilic inhibitor) (Nakahara 1998). In group I, rabbits were treated with simvastatin at 50 per day for four weeks. There was a 22% to 36% reduction in ubiquinone content in skeletal muscle and the observation of skeletal muscle necrosis and elevated CK levels. Group rabbits were treated with pravastatin at 100 per day for four weeks, which did not cause skeletal muscle injury and reduced coenzyme in skeletal muscle by 18% to 52%. In group treated with high dose pravastatin at 200 per day for three weeks followed by 300 per day for another three weeks, there was a greater reduction in ubiquinone skeletal muscle content from 49% to and evidence of skeletal muscle necrosis and CK elevation. In 1998, Sugiyama observed that pravastatin caused significant decrease in the activity of mitochondrial complex I in diaphragm skeletal muscle in rats age 35-55 weeks (Sugiyama 1998). The authors concluded that careful clinical examination of respiratory muscle function is necessary in patients treated with pravastatin, particularly in the elderly. In 1999, Ichihara et studied the effect of statins on ischemia reperfusion in dogs and observed that pretreatment of the dogs with the lipophilic HMG CoA-reductase inhibitors simvastatin, atorvastatin, fluvastatin, and cerivastatin all worsened recovery of myocardial contraction after ischemia reperfusion, but the water soluble pravastatin had no detrimental effect on myocardial contraction in this model (Ichihara 1999). In 2000, Satoh et further observed a detrimental effect fiom atorvastatin, fluvastatin, and cerivastatin in dog ischemia reperfusion, confirming that lipophilic HMG CoA-reductase inhibitors enhance myocardial stunning in association with ATP reduction after ischemia and reperfusion (Satoh 2000). In 2000, Caliskan et studied rats treated with simvastatin and found significant reductions in plasma cholesterol and ATP concentrations, indicating an impairment in bioenergetics related to depletion (Caliskan 2000). In 2000, Marz et studied hamsters with inherited cardiomyopathy and concluded that lovastatin but not pravastatin at a dose of 10 body weight significantly increased the mortality of cardiomyopathic hamsters, as a result of inhibition of myocardial ubiquinone Finally, the most recent animal study by Pisarenko et in rats treated with simvastatin at 24 for 30 days showed a significant decrease in ATP and creatinine phosphate in myocardium, again indicating that statin-induced depletion has a detrimental impact on energy production in the heart muscle (Pisarenko 2001). animal studies to date uniformly document varying degrees of coenzyme Q depletion in blood and in tissue with statin therapy, and that the coenzyme Q deficiency is associated with adverse effects in cardiomyopathic hamster models, in the ischemia reperfusion
injury in dog models, as well as in liver and cardiac coenzyme Q content in rabbits with skeletal
muscle damage. A decrease in cardiac
content and in ATP production has been documented in 2-year-old (elderly) guinea pigs. Significant depletion was documented in the heart and liver in hamsters, squirrel monkeys, and mini pigs. It is also noteworthy that the lipid soluble statins appear to show more animal toxicity, particularly in the ischemia reperfusion dog models. One can surmise from these animal studies that statins have the potential to produce clinically meaningful coenzyme Q depletion in several animal species and that the depletion is dose related. In all animal studies where supplemental coenzyme Q was given to the animals prior to the institution of statins, the coenzyme Q blood and tissue depletion was completely prevented. Safety and Drug Interactions
is sold in the United States and abroad as an over-the-counter dietary supplement and is widely recognized as completely safe with no reported toxicity in over a thousand published human and animal trials. The most recent animal safety study was published in 1999 by Williams et al. Potential toxicity was assessed in rats administered gavage for 1 year at 100,300,600, and 1200 mg per body weight per day. No adverse changes in mortality, clinical signs, body weight, food consumption, or clinical pathology results occurred. To date, there have been at least 34 placebo controlled trials using in cardiovascular disease involving a total of 2152 patients with no toxicity or drug interactions reported in the group as compared to the placebo group. Most of these controlled trials have been reviewed (Langsjoen 1998, Langsjoen 1999). In addition to these controlled trials there have been many open-label long term trials using in doses up to 600 mg per day with up to eight year follow up, again with a complete lack of toxicity. In heart failure alone there have been at least 39 open trials with supplemental published involving 4498 patients again with remarkable safety with the only reported side-effects being rare cases of mild nausea. Long term safety and tolerability of was documented by Langsjoen in 1990 in a six year study of 126 heart failure patients (Langsjoen 1990). Later, in 1993, Morisco published a double blind controlled trial on 641 heart failure patients treated with either placebo or year (Morisco 1993). The investigators found a significant reduction of hospitalizations for worsening of heart failure in the group and no evidence of side effects. In 1994 Baggio published an open-label multi-center trial on 2664 patients with heart failure, treated with 150 mg per day for three months and reported good tolerability (Baggio 1994). Also in 1994 Langsjoen published long term observations on 424 cardiac patients, treated with 75 to 600 mg per day for up to eight years with no adverse effects or drug interactions. One out of the 424 patients experienced transient nausea. There have been two case reports published claiming potential interaction between coumadin (warfarin), suggesting that has a vitamin K-like effect (Spigset 1994, Landbo 1998). This has not been corroborated by other investigators and was the subject of a prospective trial which was presented at the most recent coenzyme conference of the International Coenzyme Q 1 0 Association in Frankfurt, Germany, 1-3,2000 (Engelsen 2000). Physicians wisely and routinely follow prothrombin times very closely in patients on coumadin, particularly after any change in diet, medication or over-the-counter supplements. In this author's 18 year experience with the use of in many thousands of cardiac patients we have yet to see a single case of interaction at doses up to 600 mg of day (unpublished observations). Discussion and Conclusions
The widely prescribed HMG CoA-reductase inhibitors block the endogenous biosynthesis both of cholesterol and of coenzyme and the decrease in both substances is related to the dose as well as the potency of those drugs. The depletion of the essential co-factor required for energy production, coenzyme Q appears to be well tolerated in younger and healthier patients, particularly in the short term, but the data reveal detrimental cardiac effects in humans with pre- existing cardiac dysfunction and in several animal models, particularly in older animals. is known to be deficient in congestive heart failure (CHF), with the degree of deficiency in blood and cardiac tissue correlating with the severity of the CHF (Kitamura 1984, Folkers 1985). Normal whole blood levels of with deficiency in the range of It is also known that levels steadily fall after the age of Soderberg 1990). The best recent data documenting impairment in myocardial secondary to age-related deficiency in older patients undergoing coronary artery bypass graft surgery is by an Australian group of cardiovascular surgeons who obtained atrial muscle from patients at the time of open heart surgery and evaluated it for a post-ischemic contractile recovery. Older patients had significantly lower myocardial tissue levels of of the atrial myocardium with completely abolished the difference between the contractile recovery of the senescent atrial tissue (greater than the age of 70) as compared to the atrial tissue from patients under the age of 60 (Rosenfeldt 1999). Later those researchers performed a randomized, double-blind, placebo controlled trial of preoperative supplemental and found improved outcomes in coronary artery bypass surgery. The results of that trial were presented at the 2001 American Heart Association Scientific Sessions in Anaheim (Pepe 2001). Certainly, patients undergoing bypass surgery may be more susceptible to statin-induced lowering of coenzyme cardiac tissue levels, and elderly patients who are on statin therapy would greatly benefit from supplemental Thus, all prescribing physicians should be notified that statin drugs produce a depletion in which in settings of pre-existing deficiency, such as in CHF (Folkers 1970, Littarru 1972, Kitamura 1984, Folkers 1985) and ageing (Kalen has the ability to markedly worsen myocardial function. As the potency of statin drugs increases and as the target LDL cholesterol level decreases, the potential for statin-induced cardiomyopathy must be seriously considered and must be prevented with the concomitant administration of all statin medications. In addition, since CoQl 0 is not obtainable fiom daily dietary sources sufficient to bolster flagging levels of statin-induced 10 deficiencies, the aforementioned concomitant administration must be in specific supplement form and within 100-200 mg. A black box warning in the labeling for all statins sold in the Unites States should read as
reductase inhibitors block the endogenous biosynthesis of an essential co- factor, coenzyme required for energy production. A deficiency of coenzyme
Q 10 is associated with impairment of myocardial function, with liver dysfunction and with myopathies (including cardiomyopathy and congestive heart failure). All patients taking HMG reductase inhibitors should therefore be advised to take 100 to 200 mg per day of supplemental coenzyme Peter H. Langsjoen, M.D., F.A.C.C. Cardiovascular Diseases Research in Biomedical Aspects of Coenzyme 1107 Doctors Dr. Tyler, Texas 75701 ,USA Fax (903) 595-4962 References
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Effects of diet and simvastatin on serum lipids, insulin, and antioxidants in hypercholesterolemic men. A randomized conrolled trial. JAMA 2002 Feb 42. Willis RA; Folkers K; Tucker JL; Ye CQ; Xia LJ; Tamagawa H. Lovastatin decreases coenzyme Q levels in rats. Proc Natl Acad U S A, 87: 22, 1990 Nov, 8928-30 43. Low P, Andersson M, Edlund C, Dallner G. Effects of mevinolin treatment on tissue dolichol and ubiquinone levels in the rat. Biochim Biophys Acta 1992 Nov 44. Fukami M, Maeda N, Fukushige J, Kogure Y, Shimada Y, Ogawa T, Tsujita Y. Effects of HMG-CoA reductase inhibitors on skeletal muscles of rabbits. Res Exp Med (Berl) 45. Belichard P, Pruneau D, Zhiri A. Effect of a long-term treatment with lovastatin or fenofibrate on hepatic and cardiac ubiquinone levels in cardiomyopathic hamster. Biochim Biophys Acta 1993 46. Diebold BA, Bhagavan NV, Guillory RJ. 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57. Nobuyoshi M, Saito T, Takahira H, Yamano Y, Kanazawa T. Levels of coenzyme biopsies of left ventricular muscle and influence of administration of coenzyme K, Yamamura Y, (Eds) Biomedical and Clinical Aspects of Coenzyme Q. Elsevier, Amsterdam 58. Folkers K, Littarru GP, Ho L, Runge TM, Havanonda S, D. Evidence for a deficiency of coenzyme in human heart disease. Int Z Vitaminforsch, 59. Littarru G.P., Ho L., Folkers K. Deficiency of Coenzyme in human heart disease. Part I. Internat. J. Vit. Nutr. Res., 60. Littarru G.P., Ho L., Folkers K. Deficiency of Coenzyme in human heart disease. Part Internat. J. Vit. Nutr. Res., 6 1. Kalen A, Appelkvist EL, Dallner G. Age-related changes in the lipid compositions of rat
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62. Soderberg M, Edlund Kristensson K, Dallner G. Lipid composition of different regions of the human brain during aging. J. Week oral gavage chronic toxicity study with ubiquinone in rats with a 4-week recovery. J Agric Food Chem 1999 64. Langsjoen PH, Langsjoen PH, Folkers K. Long-term efficacy and safety of coenzyme therapy for idiopathic dilated cardiomyopathy. Am J Cardiol 1990 Feb 65. Morisco C, Trimarco Condorelli M. Effect of coenzyme therapy in patients with congestive heart failure: a long-term multicenter randomized study. Clin Investig 66. Baggio E, Gandini R, Plancher AC, Passeri M, Carmosino G. Italian multicenter study on the safety and efficacy of coenzyme as adjunctive therapy in heart failure. Surveillance Investigators. 67. Langsjoen H, Langsjoen P, Langsjoen P, Willis R, Folkers. clinical cardiology: a long-term study. Mol Aspects Med 68. Landbo C, Almdal TP. [Interaction between warfarin and coenzyme Laeger 1998 May 25; 69. Spigset 0. Reduced effect of warfarin caused by ubidecarenone. Lancet 1994 Nov 893 3) 1 3 72-3. 70. Engelsen J, Dalsgaard Nielsen J, Winther K. Stable long-term warfarin treatment. Second Coference of the International Coenzyme Association, Frankfurt Germany, CURRICULUM VITAE PETERH. LANGSJOEN, M.D., F.A.C.C. OF BIRTH: May 3, 1954, San Francisco, California Married - Alena M. Langsjoen Children - Jens, Luke, Kent and Lauren 1107 Doctors Drive Tyler, Tx 75701, USA Phone (903) 595-3778, Fax (903) 595-4962 22736 CR 181, Bullard, Texas 75757 Phone (903) 894-7644 (in construction) Temple High School, Temple, Texas, 1969-1 972 The University of Texas at Austin, 1972- 1975; Bachelor of Science in Chemistry with Honors. The University of Texas Health Science Center, San Antonio, Texas, The University of North Dakota, North Dakota, Internal Medicine Residency, 1980-1 983. Scott and White Memorial Hospital, Temple, Texas, Cardiology Fellowship, 1983- 1985. CERTIFICATIONS: Diplomate, American Board of Internal Medicine, 1983. Diplomate, American Board of Internal Medicine, Cardiovascular Disease, MEDICAL LICENSURE: 1980 - present, Texas Alpha Omega Alpha Honor Society American College of Cardiology - Fellow American College of Physicians - Member Texas Club of Cardiologists - Member (President 1997- 1998) Texas Medical Association Member Smith County Medical Society - Member The International Coenzyme ) Founding Member of (1 997 to present) 1983 - 1 98 5 : Involved in the first controlled study of coenzyme Q in cardiomyopathy with Per H. Langsjoen, M.D., F.A.C.C. during cardiology fellowship at Scott and White Hospital, Temple, Texas. 1985-1 990: Associate Professor of Medicine and staff invasive cardiologist at The University of Texas Health Center at Tyler, Tyler, Texas. 1986- 1987: Performed the first exploratory treatment of AIDS patients with Coenzyme at the University of Texas Health Center in Tyler, Texas. 1990-present: Private practice of non-invasive cardiology, Tyler, Texas, specializing in congestive heart failure and other diseases of the heart muscle. Presentations at the 8th and 9th International Symposiums on the Biomedical and Clinical Aspects of Coenzyme Q (held in Rome, Italy, 1990, in Stockholm, Sweden, 1993 and in Ancona, Italy, 1996, respectively), at the First Conference of the International Coenzyme Association (in Boston, USA, 1998) and many other presentations in the US and abroad Numerous TV and radio appearances and interviews 1997 - Became a Founding Member of the Executive Committee of the International Association, based in Ancona, Italy and has served on the Executive and Scientific Committee of this Association since then. Ongoing research into application of coenzyme to the treatment of the broad range of cardiovascular diseases, including long term follow up study in heart failure and later in primary diastolic dysfunction and hypertensive heart disease. 1. Langsjoen P.H. Comment. 2. Langsjoen P.H. and Langsjoen A.M. Overview of the Use of in Cardiovascular 3. Langsjoen P.H., Langsjoen A.M. Review of Coenzyme
in Cardiovascular Disease with Emphasis on Heart Failure and Ischemia 4. Langsjoen P.H., Langsjoen A., Willis A, Folkers, K. The Aging Heart: Reversal of
Diastolic Dysfunction Through the Use of Oral
in the Elderly. Anti-Aging Medical Therapeutics, 1997, eds., Health Quest Publications, pp.113-120. 5 . Langsjoen P.H., Langsjoen A., Willis R., Folkers K. Treatment of Hypertrophic
Cardiomyopathy with Coenzyme
Mol Aspects Med, 6. Langsjoen P.H., Langsjoen P.H., Willis R., Folkers K. Treatment of essential hypertension with coenzyme Mol Aspects Med, 7. Langsjoen H.A., Langsjoen P.H., Langsjoen P.H., Willis R., Folkers K. Usefulness of coenzyme in clinical cardiology, a long-term study. Mol Aspects Med, 1994; 15 8. Langsjoen P.H., Langsjoen P.H., Folkers K. Isolated diastolic dysfunction of the myocardium and its response to treatment. Clin Investig. 9. Folkers K., Langsjoen P.H., Langsjoen P.H. Therapy with coenzyme heart failure who are eligible or ineligible for a transplant. Biochem Biophys Res Commun. 1992 10. Folkers K; Hanioka T; Xia LJ; JT Jr; Langsjoen P. Coenzyme ratios of lymphocytes in ordinary subjects and relevance to patients having the AIDS related complex. Biochem Biophys Res Commun, 199 1 11. Langsjoen P.H., Langsjoen, P.H., Folkers, K. Long term efficacy and safety of coenzyme therapy for idiopathic dilated cardiomyopathy. Am J Cardiol. 1990 Feb 12. Langsjoen P.H., Langsjoen P.H., Folkers K., Richardson P. Treatment of patients with human immunodeficiency virus infection with coenzyme Folkers K., Littarru G.P., and Yamagami, T., (eds} Biomedical and Clinical Aspects Coenzyme Q, 1990; 13. Langsjoen P.H., Langsjoen P.H., Folkers K. A six-year clinical study of therapy of
cardiomyopathy with Coenzyme Q Int J Tissue React 1990; 14. Folkers K; Langsjoen P; Willis R; Richardson P; Xia LJ; Ye CQ; Tamagawa H. Lovastatin decreases coenzyme Q levels in humans. Proc Natl Acad 15. Langsjoen PH, Folkersn K, Lyson K, Muratsu K, Lyson T, Langsjoen P. Pronounced increase of survival of patients with cardiomyopathy when treated with coenzyme conventional therapy. Int J Tissue React 16. Langsjoen P.H., Folkers K., Lyson K., Muratsu K., Lyson T., Langsjoen Peter H. Effective and safe therapy with coenzyme for cardiomyopathy. Wochenschr. 1988 Jul 17. Folkers K., Langsjoen P.H., Langsjoen P.H., Nara Y., Muratsu K., Komorowski J., Richardson P., Smith T.H. (1 988) Biochemical Deficiencies of Coenzyme in HIV-Infection and Exploratory Treatment. Biochem Biophys Res Commun 1988; 18. Langsjoen P.H., Langsjoen P.H., Morishita M., Muratzu K., Lyson K., Folkers K. The long - term value of Coenzyme in patients with cardiomyopathy. Biomedical and Clinical Aspects of Coenzyme Q, Folkers K., Yamamura Y., (eds) Elsevier, Amsterdam, 1986; vol. 5.


Hich 7730 benzoyl peroxide hardener for light weight filler

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