ubiquinone and Rhabdomyolysis

Statins are the first-line pharmacotherapy for cholesterol reduction. Use of these drugs in large randomized clinical trials has consistently shown significant reductions in major vascular events, including death, myocardial infarction, stroke, and coronary revascularization. The updated guidelines for the treatment of high blood cholesterol from the American College of Cardiology/American Heart Association (ACC/AHA), will lead to an increase in the number of patients taking statins. Hence, the number of cases of statin intolerance may subsequently increase, emphasizing the need to understand and treat this important problem.

Topics: Cholesterol; Creatine Kinase; Drug Interactions; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Liver; Liver-Specific Organic Anion Transporter 1; Myalgia; Myositis; Organic Anion Transporters; Polymorphism, Genetic; Rhabdomyolysis; Risk Factors; Ubiquinone

Statins have demonstrated substantial benefits in supporting cardiovascular health. Older individuals are more likely to experience the well-known muscle-related side effects of statins compared with younger individuals. Elderly females may be especially vulnerable to statin-related muscle disorder. This review will collate and discuss statin-related muscular effects, examine their molecular and genetic basis, and how these apply specifically to elderly women. Developing strategies to reduce the incidence of statin-induced myopathy in older adult women could contribute to a significant reduction in the overall incidence of statin-induced muscle disorder in this vulnerable group of patients. Reducing statin-related muscle disorder would likely improve overall patient compliance, thereby leading to an increase in improved short- and long-term outcomes associated with appropriate use of statins.

Topics: Aged; Aging; Cell Death; Comorbidity; Drug Interactions; Female; Genetic Predisposition to Disease; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Incidence; Muscular Diseases; Myositis; Polyisoprenyl Phosphates; Quality of Life; Rhabdomyolysis; Sesquiterpenes; Sex Factors; Ubiquinone

Statins are effective in the treatment of hypercholesterolemia for primary and secondary prevention of cardiovascular disease. While most side effects of statins are mild and transient, muscular symptoms are relatively common (5 to 10% of patients), but rarely serious (myositis, rhabdomyolysis). In cases of myopathy, the severity of symptoms and the determination of CK (creatine kinase) determine whether discontinuation of statin is necessary. Alternative strategies are also suggested. This article reviews suggestions on the management of these complaints that are a challenge in clinical practice.

Topics: Age Factors; Aged, 80 and over; Algorithms; Anticholesteremic Agents; Azetidines; Biopsy; Cardiovascular Diseases; Creatine Kinase; Ezetimibe; Female; Humans; Life Style; Male; Muscle, Skeletal; Muscular Diseases; Myositis; Pain; Primary Prevention; Randomized Controlled Trials as Topic; Retrospective Studies; Rhabdomyolysis; Secondary Prevention; Sex Factors; Ubiquinone

Genetic predisposition to statin myopathy is a rapidly expanding area of investigation. This review summarizes the latest information on genetic risk factors associated with statin-induced myopathy. Genetic determinants involved in both pharmacokinetics of statins and metabolic muscle diseases are discussed. Data are provided on the prevalence of statin use in the United States; incidence of associated myopathy; terminology relating to statin myopathy and genetic susceptibility; and common myths surrounding this disorder.. Technological advances now make it possible to identify genetic variation in the human genome that reveals disease-causing mutations and single nucleotide polymorphisms associated with disease. More than 30,000 individuals in the United States suffer from severe life-threatening symptoms of statin-induced myopathy that may, in some cases, persist long after the cessation of therapy. Genes of interest include those involved in the pharmacokinetics of the statin response, muscle atrophy, exercise intolerance, pain perception, and mitochondrial energy metabolism.. Genetic analysis for variants and disease-causing mutations relevant to statin myopathy will provide predisposition testing for this and other drug-induced disorders. This testing will become an integral part of personalized medicine that will contribute to the safe and informed use of selected drugs and improved compliance.

Topics: Carnitine O-Palmitoyltransferase; Creatine Kinase; Gene Expression; Genetic Predisposition to Disease; Glycogen Storage Disease Type V; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Muscular Diseases; Pharmacogenetics; Rhabdomyolysis; Risk Factors; Ubiquinone; United States

Statins are first-line drugs for prevention and treatment of hypercholesterolemia and atherosclerotic disease. Despite the fact that statins are generally well tolerated and have a positive impact on human health, their myotoxic properties should keep physicians on alert. Mechanisms of statin-induced myopathy are still not fully understood. Phenotypic characteristics of patients, individual statin properties, and metabolic interaction with other drugs are important factors that may increase risk for statin myopathy. The lowest effective dose of statin should be used during treatment. Early recognition of myopathy and discontinuation of statin is critical in preventing serious sequelae such as rhabdomyolysis with all its complications.

Topics: Aged; Animals; Cholesterol; Cytochrome P-450 Enzyme System; Female; GTP-Binding Proteins; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Muscle, Skeletal; Muscular Diseases; Receptors, LDL; Rhabdomyolysis; Risk Assessment; Ubiquinone

The sequelae of cardiovascular disease contribute significantly to morbidity and mortality in developed nations. As a class, the statins have been shown to measurably reduce the burden of atherosclerotic illness. However, muscle- and, more recently, nerve-related toxicity have emerged as potential complications leading to treatment withdrawal. Generally, the myopathic signs and symptoms of tenderness, myalgias, cramping and elevated serum creatine kinase (CK) activity are fully reversible after drug discontinuation. Growing evidence suggests that latent or previously minimal symptomatic muscle disease may predispose to the development of myopathy. Less information is available regarding the natural history of the sensorimotor neuropathy, but it appears to be less reversible if large fiber function is clinically manifest. Pathophysiologic clues regarding the potential causes of statin myopathy with or without neuropathy are discussed with particular attention paid to the implications of disrupted mevalonate metabolism. For example, secondary defects in isoprenoid biosynthesis are expected to impair the production of a variety of intermediaries such as dolichols, which are crucial for N-linked glycosylation; geranylgeranyl pyrophosphate, which is necessary for coenzyme Q(10) and G-protein synthesis; farnesyl-pyrophosphate, which facilitates the endoproteolytic cleavage and maturation of prelamin A and modifies B-type lamins and G-proteins; and isopentenylpyrophosphate, which is involved in a nucleoside modification of selenocysteinyl-tRNA and thus indirectly related to the synthesis of all selenoproteins (approximately 35). The nature of statin neuromyotoxicity remains unresolved; however, investigating the cellular corollaries of deranged isoprenoid metabolism may uncover clues that lead to a more complete understanding of the elusive pathophysiology.

Topics: Acyl Coenzyme A; Adverse Drug Reaction Reporting Systems; Cholesterol; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mevalonic Acid; Muscular Diseases; Peripheral Nervous System Diseases; Rhabdomyolysis; Terpenes; Ubiquinone

Topics: Cholesterol, LDL; Creatine Kinase; Drug Monitoring; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Muscle, Skeletal; Muscular Diseases; Practice Guidelines as Topic; Rhabdomyolysis; Ubiquinone

Although statins remain the cornerstone of lipid-lowering therapy for reducing the burden of atherosclerotic vascular disease, their administration has been associated with muscle-related adverse effects, including myalgia and rhabdomyolysis. Such adverse events are probably due to reduced antioxidant defenses associated with fewer intermediate metabolites in the cholesterol synthesis pathway. We hypothesize that the concomitant inhibition of xanthine oxidase via coadministration of allopurinol with statins could diminish reactive oxygen species (ROS)-related muscle damage, which would have in turn have positive effects on both the incidence of muscle-related adverse events and cardiovascular outcomes. Accordingly, inhibition of xanthine oxidase has been previously shown to be effective for reducing biomarkers of muscle damage following exercise in professional athletes. Because of the widespread statin utilization and increasing trends in their therapeutic use in atherosclerotic vascular diseases, the proposed strategy could have important clinical implications for reducing statin-induced myalgia and rhabdomyolysis.

Topics: Allopurinol; Animals; Biomarkers; Cardiovascular Diseases; Enzyme Inhibitors; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Myalgia; Reactive Oxygen Species; Rhabdomyolysis; Ubiquinone; Xanthine Oxidase

Rhabdomyolysis is a rare, but serious complication of statin therapy, and represents the most severe end of the spectrum of statin-induced myotoxicity. We report a case where coenzyme Q10 facilitated recovery from statin-induced rhabdomyolysis and acute renal failure, which had initially persisted despite statin cessation and haemodialysis. This observation is biologically plausible due to the recognised importance of coenzyme Q10 in mitochondrial bioenergetics within myocytes, and the fact that statins inhibit farnesyl pyrophosphate production, a biochemical step crucial for coenzyme Q10 synthesis. Coenzyme Q10 is generally well tolerated, and may potentially benefit patients with statin-induced rhabdomyolysis.

Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Recovery of Function; Rhabdomyolysis; Ubiquinone

Topics: Adult; Black or African American; Case-Control Studies; Creatine Kinase; Female; Humans; Male; Rhabdomyolysis; Risk Factors; Ubiquinone; Young Adult

Topics: Acyl-CoA Dehydrogenases; Adolescent; Diet Therapy; Disease Management; Humans; Male; Mitochondrial Myopathies; Mutation, Missense; Rhabdomyolysis; Riboflavin; Secondary Prevention; Ubiquinone; Vitamins

Topics: Atorvastatin; Clinical Trials as Topic; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; Evidence-Based Practice; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Outcome Assessment, Health Care; Practice Guidelines as Topic; Pyrroles; Rhabdomyolysis; Risk Adjustment; Ubiquinone; Vitamins

Statin medications diminish cholesterol biosynthesis and are commonly prescribed to reduce cardiovascular disease. Statins also reduce production of ubiquinol, a vital component of mitochondrial energy production; ubiquinol reduction may contribute to rhabdomyolysis. Human rhabdomyosarcoma cells were treated with either ethanol and dimethyl sulfoxide (DMSO) control, or simvastatin at 5 µM or 10 µM, or simvastatin at 5 µM with ubiquinol at 0.5 µM or 1.0 µM for 24 h or 48 h. PGC-1α RNA levels were determined using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Mitochondrial content was determined using flow cytometry and immunocytochemistry. Metabolism was determined by quantification of extracellular acidification rate and oxygen consumption rate. Treatment of human rhabdomyosarcoma cells with simvastatin significantly reduced oxidative, total metabolism, and cellular ATP content in a time- and dose-dependent manner which was rescued by concurrent treatment with ubiquinol. Treatment with simvastatin significantly reduced mitochondrial content as well as cell viability which were both rescued by simultaneous treatment with ubiquinol. This work demonstrates that the addition of ubiquinol to current statin treatment regimens may protect muscle cells from myopathies.

Topics: Adenosine Triphosphate; Biomarkers; Cell Line, Tumor; Cell Proliferation; Cell Survival; Gene Expression Regulation; Glycolysis; Humans; Mitochondria; Oxidation-Reduction; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Rhabdomyolysis; Simvastatin; Time Factors; Transcription Factors; Ubiquinone

In order to investigate the potential involvement of mitochondrial electron transport chain (ETC) dysfunction in myotoxicity associated with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin) treatment, assessment was made of ETC activity and ubiquinone status in two patients experiencing myopathy following treatment with simvastatin (40 mg/day) and cyclosporin (patient 1) and simvastatin (40 mg/day) and itraconazole (patient 2). Analysis of skeletal muscle biopsies revealed a decreased ubiquinone status (77 and 132; reference range: 140-580 pmol/mg) and cytochrome oxidase (complex IV) activity (0.006 and 0.007 reference range: 0.014-0.034). To assess statin treatment in the absence of possible pharmacological interference from cyclosporin or itraconazole, primary astrocytes were cultured with lovastatin (100 microM). Lovastatin treatment resulted in a decrease in ubiquinone (97.9 +/- 14.9; control: 202.9 +/- 18.4 pmol/mg; p < 0.05), and complex IV activity (0.008 +/- 0.001; control: 0.011 +/- 0.001; p < 0.05) relative to control. These data, coupled with the patient findings, indicate a possible association between statin treatment, decreased ubiquinone status, and loss of complex IV activity.

Topics: Aged; Animals; Astrocytes; Cells, Cultured; Cyclosporine; Drug Interactions; Drug Therapy, Combination; Electron Transport Complex IV; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Itraconazole; Male; Middle Aged; Muscle, Skeletal; Muscular Diseases; Rats; Rhabdomyolysis; Simvastatin; Ubiquinone

Topics: Coenzymes; Disease Susceptibility; Genetic Predisposition to Disease; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Malignant Hyperthermia; Mutation; Rhabdomyolysis; Ryanodine Receptor Calcium Release Channel; Ubiquinone

Topics: Anticholesteremic Agents; Coenzymes; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Liver; Phenols; Plant Extracts; Rhabdomyolysis; Ubiquinone

Administration of simvastatin (80 mg/kg, po. evening dose) and gemfibrozil (600 mg/kg, po twice) for 30 days produced significant decrease in the level of reduced glutathione, superoxide dismutase, catalase and increase in the level of lipid peroxidation and various serum parameters (creatine phosphokinase, lactate dehydrogenase, serum glutamate oxaloacetate transaminase, creatinine, urea and blood urea nitrogen). This suggested involvement of oxidative stress in rhabdomyolysis. Increase in the level of reduced glutathione, superoxide dismutase, catalase and decrease in the level of lipid peroxidation and serum parameters after administration of antioxidant CoQ10 (10 mg/kg.ip) proved the protective effect of CoQ10 in rhabdomyolysis.

Topics: Animals; Antioxidants; Blood Urea Nitrogen; Catalase; Coenzymes; Creatinine; Female; Gemfibrozil; Glutathione; Humans; Hypolipidemic Agents; Lipid Peroxidation; Oxidants; Oxidative Stress; Rats; Rats, Wistar; Renal Insufficiency; Rhabdomyolysis; Simvastatin; Superoxide Dismutase; Ubiquinone

Cerivastatine was administered as a reversible HMG-CoA reductase inhibitor (statine) to treat hypercholesterolemia until its withdrawal from the market following 52 reports of death due to drug-related rhabdomyolysis and acute renal failure. In most cases, cerivastatine was applied in combination with drugs which influenced the liver metabolism of cerivastatine via cytochromeoxidase P 450 isoenzymes. We report a well-documented case of acute rhabdomyolysis following cerivastatine monotherapy. The diagnosis was confirmed additionally by muscle biopsy.Finally,we give an overview of the current knowledge concerning therapy with HMG-CoA reductase inhibitors,1 year after the withdrawal of cerivastatine from the market.

Topics: Acute Disease; Anticholesteremic Agents; Aryl Hydrocarbon Hydroxylases; Biopsy; Coenzymes; Comorbidity; Creatine Kinase; Cytochrome P-450 CYP2C8; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Diagnosis, Differential; Drug Interactions; Electromyography; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Liver Cirrhosis, Alcoholic; Liver Function Tests; Middle Aged; Muscle, Skeletal; Neurologic Examination; Pancreatic Diseases; Pyridines; Rhabdomyolysis; Stomach Neoplasms; Ubiquinone

Topics: Coenzymes; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Rhabdomyolysis; Ubiquinone

Topics: Cardiovascular Diseases; Cholesterol; Coenzymes; Drug Synergism; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pyridines; Rhabdomyolysis; Ubiquinone; United States; United States Food and Drug Administration

Topics: Humans; Lovastatin; Rhabdomyolysis; Ubiquinone