Secondary Prevention and Rehabilitation

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1 Secondary Prevention and Rehabilitation The effect of pravastatin and atorvastatin on coenzyme Q10 Barry E. Bleske, PharmD, a,d Richard A. Willis, PhD, f Mark Anthony, PhD, f Nicole Casselberry, PharmD, a Meeta Datwani, PharmD, a Virginia E. Uhley, PhD, RD, b,d Stephanie G. Secontine, BS, RD, e and Michael J. Shea, MD c,d Ann Arbor and Detroit, Mich, and Austin, Tex Background Coenzyme Q10 (CoQ10) is an antioxidant and plays an important role in the synthesis of adenosine triphosphate. Studies suggest that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors reduce CoQ10 levels; however, no studies have directly compared HMG-CoA reductase inhibitors in a randomized crossover fashion. Methods Twelve healthy volunteers received either 20 mg pravastatin (P) or 10 mg atorvastatin (A) for 4 weeks in a randomized crossover fashion. There was a 4- to 8-week washout period between the 2 phases. CoQ10 levels and a lipid profile were obtained. Results There was no difference in CoQ10 levels from baseline to post drug therapy for either P or A (0.61 ± 0.14 vs 0.62 ± 0.2 µg/ml and 0.65 ± 0.22 vs 0.6 ± 0.12 µg/ml, respectively; P >.05). There was a significant difference in lowdensity lipoprotein (LDL) levels from baseline to post drug therapy for both P and A (97 ± 21 vs 66 ± 19 mg/dl and 102 ± 21 vs 52 ± 14 mg/dl, respectively; P <.01). There was no significant correlation between LDL and CoQ10. Conclusions P and A did not decrease CoQ10 despite a significant decrease in LDL levels. These findings suggest that HMG-CoA reductase inhibitors do not significantly decrease the synthesis of circulating CoQ10 in healthy subjects. Routine supplementation of CoQ10 may not be necessary when HMG-CoA reductase inhibitor therapy is administered. (Am Heart J 2001;142:e2.) Coenzyme Q 10 (CoQ10), or ubiquinone, a lipophilic compound, is naturally found throughout the body including the heart, liver, and skeletal muscle. 1,2 CoQ10 acts in the body as an antioxidant and may have membrane-stabilizing properties. 1,3-5 In addition, CoQ10 is an important factor for cellular mitochondrial respiration. CoQ10 acts in part as a redox link between flavoproteins and the cytochromes, which are needed for oxidative phosphorylation and the synthesis of adenosine triphosphate (ATP). 1,6,7 In other words, CoQ10 is essential for energy production (cellular bioenergetics) From the a College of Pharmacy, the b General Clinical Research Center, the c Division of Cardiology, Department of Medicine, and the d University of Michigan Health Systems, University of Michigan, Ann Arbor, the e Department of Nutrition and Food Science, Wayne State University, Detroit, Mich, and the f Institute of Biomedical Research, University of Texas at Austin, Austin, Tex. Supported in part by a grant from Bristol-Myers Squibb and by General Clinical Research Center grant No. M01-RR N. C. and M. D. were PharmD candidates during the time in which the study was completed. Submitted August 28, 2000; accepted April 16, Reprint requests: Barry E. Bleske, PharmD, University of Michigan, College of Pharmacy, 428 Church St, Ann Arbor, MI bbleske@umich.edu Copyright 2001 by Mosby, Inc /2001/$ /90/ doi: /mhj including in the heart. The cellular effects of CoQl0 may be especially important in patients with cardiac disease, specifically coronary artery disease and congestive heart failure. CoQ10 antioxidant and membrane-stabilizing properties may be important for patients with coronary artery disease and its role in the synthesis of ATP or energy may be important for patients with congestive heart failure. It is now well established that hyperlipidemia needs to be aggressively treated, especially in patients with a history of cardiac disease, including heart failure. Today, one of the most important classes of drugs for treating hyperlipidemia is the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins). However, recent studies have shown that HMG-CoA reductase inhibitors may reduce plasma CoQl0 levels 8-14 by competitively inhibiting the conversion of HMG-CoA to mevalonate, a precursor for CoQ10. These findings may have implications for patients with heart failure because significant decreases in CoQ10 levels may contribute to the signs, symptoms, and pathophysiologic consequence of heart failure, although it should be noted that there are significant limitations in these studies that limit their conclusions. In addition, decreasing CoQl0 and its antioxidant effects may also be important for pa-

2 tients with coronary artery disease. There are data to suggest that not all HMG-CoA reductase inhibitors may equally reduce CoQ10 levels, with perhaps pravastatin having the least effect. 10,13 This finding may have important implications in regard to the drug of choice for treating hyperlipidemia in patients with cardiac disease. Despite this potential decrease in CoQ10 levels, it should be appreciated that HMG-CoA reductase inhibitors have still demonstrated important and substantial clinical benefits, including reducing mortality. 23,24 A clinical question that remains is whether these important clinical benefits may be further optimized by administering HMG-CoA reductase inhibitors that do not affect CoQ10 levels or by dietary supplementation of CoQ10. Theoretically, as discussed above, maintaining CoQl0 levels may be important in patients with cardiovascular disease, especially in patients with congestive heart failure or coronary artery disease. Available data are limited and there are no studies, to the best of our knowledge, that have directly compared 2 HMG-CoA reductase inhibitors in a randomized crossover study. Therefore the purpose of this study was to determine the effect of 2 different HMG-CoA reductase inhibitors, pravastatin and atorvastatin, on CoQ10 levels in a randomized crossover fashion. Pravastatin was decided on the basis of previous studies suggesting that this drug has limited effects in reducing CoQ10 levels and is less lipophilic than atorvastatin. Atorvastatin was chosen on the basis of its lipophilicity and because it is the most potent HMG-CoA reductase that theoretically may have the greatest effect on reducing mevalonate and CoQ10 among the reductase inhibitors. In addition, atorvastatin s long half-life may also contribute to a greater reduction in mevalonate and CoQ10 levels as a result of a longer inhibition of HMG-CoA reductase. Methods A total of 12 healthy subjects completed an open-label randomized crossover trial evaluating the effect of pravastatin and atorvastatin on CoQ10 plasma levels. After approval from the hospital s Institutional Review Board and before study entry, informed consent was obtained from each subject. Inclusion criteria included the following: age >18 years and normolipidemic, defined as low-density lipoprotein (LDL) levels <160 mg/dl, total cholesterol (TC) levels <200 mg/dl, high-density lipoprotein (HDL) levels >35 mg/dl, and triglycerides (TG) <160 mg/dl. Individuals taking scheduled medications concurrently (excluding oral contraceptives), those with significant medical histories, as well as smokers and pregnant females were excluded from the study. In addition, any individual with persistent liver function test (LFT) elevations was not included in the study. Subjects were admitted to the General Clinical Research Center, and after physical examination and baseline laboratory measurements were obtained patients were randomized into one of 2 groups: pravastatin 20 mg daily for a 4-week period (P) or atorvastatin 10 mg daily for a 4-week period (A). After the 4-week treatment period there was a 4- to 8-week washout period to minimize any carryover effects and to ensure that lipid levels were back to baseline values. After the washout period, subjects received the alternate drug for another 4 weeks. Compliance was assessed in accordance with the number of tablets remaining in medication vials after each treatment phase. Laboratory measurements of CoQ10, lipids, and LFTs were taken before and after each treatment including the washout phase; levels before the start of the first phase and at the end of washout were considered to be baseline. Patients also were required to keep a dietary journal. At baseline, an in-person 24-hour dietary recall was conducted and reviewed by a registered dietitian. Subjects were asked not to change their normal dietary habits and eating patterns during the study periods. At the end of the 4-week treatment period, subjects were instructed and given guidelines on how to keep a 4-day food intake record. A registered dietitian collected and verified the data recorded on the dietary records. The 4-day food records were kept on consecutive days: Tuesday, Thursday, Friday, and Saturday 1 week before the end of each treatment period. An additional 4-day food intake record was collected at the baseline visit for the second 4-week treatment period. The 24-hour dietary recall and 4-day food intake records were analyzed for their CoQ10 content according to published food values. 25,26 An average CoQ10 intake was calculated at the beginning and end of each treatment period. CoQ10 assay For the CoQl0 analysis, 5 ml of whole blood was collected from a forearm vein by direct venipuncture into a lavendertop Vacutainer blood-collecting tube (Becton-Dickinson). Whole blood concentrations of CoQ10 were determined by high-pressure liquid chromatography (HPLC) by a modification of the method of Ye et al, 27 in which coenzyme Q7 was substituted for coenzyme Q11 as the internal standard. The limit of detection was 0.1 to 15 µg/ml. The intraday and interday coefficient of variation was <6%. Statistical analysis The data were analyzed by a paired t test within and between groups. In addition, the Pearson correlation was used to determine whether a relationship existed between CoQ10 and lipid parameters (LDL, TC, HDL, TG). A P value <.05 was considered the critical probability level. The reported data are represented as the mean ± SD unless otherwise stated. Results There were a total of 20 patients screened with a total of 12 patients completing the study, 5 male and 7 female. The subjects ranged in age from 21 to 40 years old (mean 26 ± 5 years), and all were within 25% of their ideal body weights. Patients were excluded because of baseline elevation of LFTs (n = l), high TG and low HDL (n = l), high LDL and TC (n = 1), low LDL (n = l), high TC and TG (n = l), and personal reasons (n = 3). All subjects tolerated the medication well and did not report any adverse effects throughout the course of the

3 Table I. CoQ10 and lipid profile before and after pravastatin therapy (median and interquartile range) Variable Baseline After therapy Figure 1 CoQ10 (µg/ml) 0.6 (0.1) 0.55 (0.1) TC (mg/dl) 170 (29) 140 (19)* LDL (mg/dl) 92 (36) 63 (28)* HDL (mg/dl) 51 (14) 57 (16)* TG (mg/dl) 84 (38) 67 (39) *P <.04. Table II. CoQ10 and lipid profile before and after atorvastatin therapy (median and interquartile range) Variable Baseline After therapy CoQ10 (µg/ml) 0.65 (0.2) 0.60 (0.03) TC (mg/dl) 170 (24) 122 (13)* LDL (mg/dl) 104 (18) 51 (16)* HDL (mg/dl) 52 (23) 55 (15) TG (mg/dl) 76 (10) 65 (24) *P <.04. study. In addition, LFTs were monitored and remained within normal limits throughout the study for each subject. According to tablet count, subjects were compliant. One subject missed 3 doses during one treatment course and none of the remaining subjects had more tablets than expected remaining at the end of each treatment phase. The results for CoQ10 and lipid profile from baseline to posttreatment for each treatment phase are shown in Tables I and II. For both groups there were significant decreases in TC and LDL as expected. Pravastatin demonstrated a significant increase in HDL levels, whereas atorvastatin did not. For both treatment phases there was no significant change in CoQ10 concentrations from baseline to posttherapy. In fact, the concentration at baseline was nearly identical to the concentration after therapy. Individual changes in CoQ10 concentrations from baseline to posttreatment are shown in Figure 1. When the ratio of CoQ10 to LDL was evaluated, a significant increase in this ratio was observed for both pravastatin and atorvastatin before and after therapy (0.007 ± vs 0.01 ± and ± vs ± 0.003, respectively, P <.05). There were no statistical differences in the baseline values between the 2 groups. When the mean change in CoQ10 and lipid concentrations was compared between the 2 treatment groups, a significantly greater decrease in TC and LDL concentrations was observed in the atorvastatin group (Table III). No significant difference was seen for CoQ10. The correlation between CoQl0 and lipid variables (TC, LDL, HDL, and TG) was also evaluated. There was Individual change in CoQ10 levels before and after therapy for pravastatin (dashed line) and atorvastatin (solid line). Table III. Mean change in CoQ10 and lipid profile before and after therapy for pravastatin and atorvastatin Variable Pravastatin Atorvastatin P value CoQ10 (µg/ml) 0.01 ± ± TC (mg/dl) 25.3 ± ± LDL (mg/dl) 27.5 ± ± HDL (mg/dl) 4.1 ± ± TG (mg/dl) 8.5 ± ± no significant correlation between CoQ10 and TC, LDL, or TG, demonstrating that as these lipid concentrations are decreased CoQ10 decreases. There was also no correlation between HDL concentrations and CoQ10. Evaluation of the dietary journals demonstrated no statistical difference between baseline and posttreatment values. For the pravastatin phase the mean dietary CoQ10 values for baseline and treatment phases were 3.14 ± 3.0 mg per day and 1.70 ± 1.18 mg per day. For the atorvastatin phase the mean dietary CoQ10 values for baseline and treatment phases were 1.60 ± 1.09 mg per day and 2.44 ± 3.18 mg per day. Discussion The results of this study demonstrated that there was no difference between pravastatin and atorvastatin in decreasing CoQl0 concentrations in healthy subjects. In fact, the data suggest that these drugs had no effect at all in decreasing CoQ10 concentrations after 4 weeks of therapy despite significant decreases in TC and LDL. The finding that neither HMG-CoA reductase inhibitor reduced CoQ10 concentrations was not expected. Data from a variety of studies have shown that HMG-CoA reductase inhibitors including simvastatin, lovastatin, and pravastatin significantly reduce CoQ10 concentrations

4 after treatment These reductions have been shown to occur in study designs similar to this study, specifically in healthy subjects, at the dose of pravastatin used in this study, and over a 4-week time period. 10,13,28 The majority of studies evaluating CoQ10 has been performed in patients with hypercholesterolemia; however, one study evaluated 2 groups of 5 healthy volunteers and demonstrated a reduction in CoQ10 of up to 40% after drug therapy. 10 Another study demonstrated that at both a 10-mg and 20-mg dose of pravastatin that significant reduction in CoQl0 and TC occurred. 13 In regard to a time frame, studies have demonstrated that after shortterm treatment with statin therapy, significant reductions in both CoQ10 and TC occurred. 10,28 These findings suggest that our study design was sufficient to allow an HMG-CoA reductase inhibitor to reduce CoQ10 concentrations. In addition, in support of this study design, there were significant decreases in TC and LDL after 4 weeks of therapy for both drugs in this study. HMG-CoA reductase inhibitors competitively inhibit the enzyme HMG-CoA reductase, which decreases the conversion of HMG-CoA to mevalonate, which is a precursor to cholesterol synthesis. 29 Mevalonate is also thought to be a precursor for the synthesis of several isoprenoid compounds, including CoQ Therefore the reduction in TC and LDL as a result of the drug therapy should have ensured a decrease in CoQ10. In fact, previous studies have shown that CoQ10 and cholesterol levels parallel or are correlated with each other. 8,28,31,32 The reason this study, and apparently only this study, has not shown a significant reduction in CoQ10 is not certain. One explanation may be related to the low mean serum CoQ10 concentrations that were observed. The mean CoQl0 was approximately 0.6 mg/l; in other studies the mean CoQ10 concentrations were usually >1 mg/l. This study was performed mainly with university students, whereas most other studies were performed in patients with cardiac disease or hypercholesterolemia. Our level of CoQl0 is consistent with another study evaluating CoQ10 concentrations in university students. 31 Previous animal and human studies have suggested that CoQl0 is carried by lipoproteins with the LDL fraction carrying about 60% of total serum CoQ It has been suggested that the reduction in plasma CoQ10 seen after statin therapy is due to a decrease in the amount of lipoproteins available for transport. In support of this, studies have shown that the ratio of CoQl0 to lipoprotein does not change after statin therapy. 13,28,32 In the current study the ratio for CoQ10 to lipoprotein significantly increased, which has not been shown previously. The CoQ10 concentrations in this study were sufficiently low that the decrease in lipoprotein probably did not affect CoQ10 concentrations. In other words, there were still a sufficient number of lipoproteins to bind to the available CoQl0 molecules. This supports the previous suggestion that the decrease in CoQl0 after statin therapy is due to a reduction in transport molecules and not in the synthesis of CoQl0. The reason why CoQ10 synthesis may not be affected by HMG-CoA reductase inhibition is not known but may relate to modulation in enzyme activity beyond mevalonate formation or to enzyme affinity. For example, enzyme affinity for mevalonate in the CoQ10 pathway may be greater than for the cholesterol pathway, resulting in no reduction in the synthesis of CoQ10 despite decrease mevalonate formation. 28,35 There are data to suggest that this may occur at least in fibroblast cells. 36 Obviously, further studies are needed to evaluate this concept. Another explanation for our findings may be culture based. We believe this is the first study beyond a case report to evaluate the effect of HMG-CoA reductase inhibitors on CoQ10 in the United States. 37 Perhaps differences in diet that were not captured by the study or environmental factors may contribute to our findings. Assay error may be another explanation; however, this is unlikely because the laboratory performing the assay is experienced and published in regard to performing the CoQ10 assay, the interday and intraday coefficient of variation is low, and the samples were within the detectable concentration range. Alternatively, the baseline CoQ10 plasma concentrations in this study may be sufficiently low that it may not be able to be further depressed; there may be a minimal baseline level that is judiciously maintained by the body that is not easily affected by endogenous or exogenous factors. There are a number of limitations in this study, including a small sample size and the open-label nature of the trial. Whether more subjects would have shown a difference is not known but is unlikely because the change in CoQ10 was small and the SD was not large. The openlabel design of the trial appears not to be a factor because the effect of both pravastatin and atrovastatin on lipid levels were as expected and there were no subjective data evaluated in this study. Nevertheless, unexpected bias still may have entered the study and altered our results. Another concern with the study is the dose used for pravastatin and atorvastatin. There are no definitive data demonstrating what is an equivalent dose conversion between these 2 drugs; we decided on the doses used in part on the basis of safety concerns and what we felt were common starting doses for both drugs. The question does arise as to whether higher doses of pravastatin or atorvastatin would have shown different results. We do not know that answer; however, the observed decrease in LDL by both drugs (>25%) is a good response to the doses used and may often be greater than what is seen at higher doses in many patients clinically. Furthermore, as observed in other studies, this decrease in LDL should have been suf-

5 ficient to reduce CoQ10 concentrations as previously suggested. Despite these conjectures, higher doses that may have greater effect on the HMG-CoA reductase pathway than lower doses may have shown different results than what were observed in this study. Higher dose levels should be evaluated in further studies. The results of this study may have important clinical implications. In the recent light of renewed interest in natural or alternative medicine, administration of supplemental CoQl0 has drawn attention, especially in patients with cardiac disease. Because CoQ10 is an antioxidant and is required for synthesis of ATP, decreased concentrations of CoQ10 may be of importance in patients with coronary artery disease and congestive heart failure. Very limited data have suggested that supplementation of CoQ10 may be of benefit in cardiac patients (although this has not been shown in all studies) ,38 Therefore any therapy, such as HMG-CoA reductase inhibitors, that may further decrease CoQ10 especially in cardiac patients is of concern to health care practitioners. There has even been some suggestion that CoQl0 should be supplemented in patients receiving statin therapy. However, the data from our study suggest that this is not required because the synthesis of CoQ10 appears not to be affected by HMG-CoA reductase inhibitor therapy. Furthermore, there are data from other studies demonstrating that muscle CoQ10 concentrations are also not decreased after drug therapy, again questioning the need for supplemental CoQ10. 28,32 In conclusion, neither pravastatin nor atorvastatin decreased CoQ10 concentrations despite significant decreases in TC and LDL levels in healthy subjects. This is the first study to demonstrate this and suggests that HMG-CoA reductase inhibitors do not decrease the synthesis of circulating CoQ10. This finding may have clinical implications in regard for the need to supplement CoQ10 in patients receiving HMG-CoA reductase inhibitor therapy. References 1. Greenberg S, Frishman WH. Co-enzyme Q10: a new drug for cardiovascular disease. J Clin Pharmacol 1990;30: Mortensen SA, Vadhanavikit S, Muratsu K, et al. Coenzyme Q10: clinical benefits with biochemical correlates suggesting a scientific breakthrough in the management of chronic heart failure. Int J Tissue Reac 1990;12: Stocker R, Bowry VW, Frei B. Ubiquinone-10 protects human low density lipoprotein more efficeintly against lipid peroxidation than does alpha-tocopherol. Proc Natl Acad Sci U S A 1991;88: Mohr D, Bowry VW, Stocker R. 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: Frei B, Kim M, Ames B. Ubiquinol-10 is an effective lipid-soluble antioxidant at physiological concentrations. Proc Natl Acad Sci U S A 1990;87: Rauchova H, Drahota Z, Lenaz G. Function of coenzyme Q in the cell: some biochemical and physiological properties. Physiol Res 1995;44: Battino M, Fato R, Parenti-Castelli G, et al. Coenzyme Q can control the efficiency of oxidative phosphorylation. Int J Tissue Reac 1990;12: Laaksonen R, Ojala JP, Tikkanen MJ, et al. Serum ubiquinone concentrations after short-and long-term treatment with HMG-CoA reductase inhibitors. Eur J Clin Pharmacol 1994;46: Watts GF, Castelluccio C, Rice-Evans C, et al. Plasma coenzyme Q (ubiquinone) concentrations in patients treated with simvastatin. J Clin Pathol 1993;46: Ghirlanda G, Oradei A, Manto A, et al. Evidence of plasma CoQ10- lowering effect by HMG-CoA reductase inhibitors: a double-blind, placebo-controlled study. J Clin Pharmacol 1993;33: Fukami M, Maeda N, Fukushige J, et al. Effects of HMG-CoA reductase inhibitors on skeletal muscles of rabbits. Res Exp Med 1993;263: De Pinieux G, Chariot P, Ammi-Said M, et al. Lipid-lowering drugs and mitochondrial function: effects of HMG-CoA reductase inhibitors on serum ubiquinone and blood lactate/pyruvate ratio. Br J Clin Pharmcol 1996;42: Mortensen SA, Leth A, Agner E, et al. Dose-related decrease of serum coenzyme Q10 during treatment with HMG-CoA reductase inhibitors. Mol Aspect Med 1997;18(Suppl):S Folkers K, Langsjoen P, Willis R, et al. Lovastatin decreases coenzyme Q levels in humans. Proc Nat Acad Sci U S A 1990;87: Langsjoen P, Folkers K, Lyson K, et al. Pronounced increase of survival of patients with cardiomyopathy when treated with coenzyme Q10 and coventional therapy. Int J Tissue Reac 1990;12: Manzoli U, Rossi E, Littarru GP, et al. Coenzyme Q10 in dilated cardiomyopathy. Int J Tissue Reac 1990;12: Sinatra ST. Refractory congestive heart failure successfully managed with high dose coenzyme Q10 administration. Mol Aspects Med 1997;18(Suppl):S Soja AM, Mortensen SA. Treatment of congestive with coenzyme Q10 illuminated by meta-analyses of clinical trials. Mol Aspects Med 1997;18(Suppl):S Langsjoen PH, Langsjoen PH, Folkers K. A six-year clinical study of therapy of cardiomyopathy with coenzyme Q10. Int J Tissue Reac 1990;12: Morisco C, Trimarco B, Condorelli M. Effect of coenzyme QI0 therapy in patients with congestive heart failure: a long-term multicenter randomized study. Clin Invest 1993;71:S Baggio E, Gandini R, Plancher AC, et al. Italian multicenter study on the safety and efficacy of coenzyme Q10 as adjunctive therapy in heart failure: CoQ10 Drug Surveillance Investigators. Mol Aspects Med 1994;15(Suppl):S Morisco C, Nappi A, Argenziano L, et al. Noninvasive evaluation of cardiac hemodynamics during exercise in patients with chronic heart failure: effects of short-term coenzyme Q10 treatment. Mol Aspects Med 1994;15(Suppl):S Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995;333: Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary artery disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:

6 25. Weber C, Bysted A, Holmer G. The coenzyme Q10 content of the average Danish diet. Int J Vit Nutr Res 1996;67: Kamei M, Fujita T, Kanbe T, et al. The distribution and content of ubiquinone in foods. Int J Vit Nutr Res 1986;56: Ye C-Q, Folkers K, Tamagawa H, et al. A modified determination of coenzyme Q10 in human blood and CoQ10 blood levels in diverse patients with allergies. Biofactors 1988;1: Laaksonen R, Jokelainen K, Sahi T, et al. Decrease in serum ubiquinone concentrations do not result in reduced levels in muscle tissue during short-term simvastatin treatment in humans. Clin Pharmacol Ther 1995;57: Grundy S. HMG-CoA reductase inhibitors for treatment of hypercholesterolemia. N Engl J Med 1988;319: Goldstein J, Brown M. Regulation of the mevalonate pathway. Nature 1990;343: Laaksonen R, Riihimaki A, Laitila J, et al. Serum and muscle tissue ubiquinone levels in healthy subjects. J Lab Clin Med 1995;125: Laaksonen R, Jokelainen K, Laakso J, et al. The effect of simvastatin treatment on natural antioxidants in low-density lipoproteins and high energy phosphates and ubiquinone in skeletal muscle. Am J Cardiol 1996;77: Ingold KU, Bowry VW, Stocker R, et al. Autoxidation of lipids and antioxidation by tocopherol and ubiquinol in homogeneous solution and in aqueous dispersions of lipids: unrecognized consequences of lipid particle size exemplified by oxidation human low density lipoprotein. Proc Natl Acad Sci U S A 1993;90: Johansen K, Theorell H, Karlsson J, et al. Coenzyme Q10, alphatocopherol and free cholesterol in HDL and LDL fractions. Ann Med 1991;23: Brown M, Goldstein J. Multivalent feedback regulation of HMG- CoA reductase, a control mechanism coordinating isoprenoid synthesis and cell growth. J Lipid Res 1980;21: Faust J, Goldstein J, Brown M. Synthesis of ubiquinone and cholesterol in human fibroblasts: regulation of a branched pathway. Arch Biochem Biophys 1979;192: Folkers L, Langsjoen P, Willis R, et al. Lovastatin decreases coenzyme Q levels in humans. Proc Natl Acad Sci U S A 1990;87: Meenakshi K, Alexander BS, Krichten CM, et al. The effect of Coenzyme Q10 in patients with congestive heart failure. Ann Intern Med 2000;132: