HMG CoA reductase‐inhibitor‐related myopathy and the influence of drug interactions

Huynh, Tyler; Cordato, Dennis; Yang, F.; Choy, Tak-Kee; Johnstone, Karen A.; Bagnall, F.; Hitchens, N.; Dunn, Richard F.

doi:10.1046/j.1445-5994.2002.00264.x

Cited by 24 publications

(8 citation statements)

References 18 publications

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“…In addition, statininduced skeletal myopathy might be due to depletion of the isoprenoid pool by statins (HMG-CoA reductase inhibitors) with subsequent generalized insufficient protein modification inducing myopathy [32] . The histopathological adverse effects induced by statin in rat quadriceps femoris muscle fibers observed in the present work reinforce previous reports [33][34][35] . At the ultrastructure level, the focal areas of degenerated myofibrils showed disruption of Z-lines, dilated SER cisternae, together with numerous, subsarcolemmal and perinuclear, giant mitochondria, sometimes with destructed cristae.…”

Section: Discussionsupporting

confidence: 82%

The Possible Protective Role of Ginger Extract Versus Vitamin E Against Simvastatin-Induced Skeletal Myotoxicity in Adult Male Albino Rats: Histological, Physiological and Biochemical Study

Hamid¹,

Mola²,

Meligy³

et al. 2017

Egyptian Journal of Histology

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Introduction: Statins are group of drugs used to reduce total and low density lipoprotein (LDL)-cholesterol level and to reduce the morbidity and mortality of cardiovascular diseases. Meanwhile, induced skeletal muscle-specific mitochondrial impairment, oxidative stress and myotoxicity are serious side effects . Vitamin E and ginger extract are well known potent antioxidants. Aim: To study the possible protective effect of ginger extract versus vitamin E against simvastatin-induced skeletal muscle histological and the associated biophysiological changes. Materials and Methods: Forty adult male albino rats were randomly divided into four equal groups (10 rats, each).; Group 1: was the control rats. Group 2: received 0.54 mg/kg/day simvastatin orally for 8 weeks. Group 3: received concomitant treatment of simvastatin and 30 mg/kg/day vitamin E orally for 8 weeks. Group 4 received concomitant treatment of simvastatin and 500mg/kg/day ginger extract orally for 8 weeks. After sacrifice, specimens were taken from the belly of the quadriceps femoris muscles of all animal groups and processed for light and electron microscopy. Biochemical tests and statistical analysis were done. Results: Group 2 showed focal areas of muscle fiber loss, mononuclear cellular infiltration and variable staining density. Ultra structurally, myofibrillar degeneration and accumulation of numerous giant infrequently damaged mitochondria were observed. The skeletal muscle fibers of animals from group 3 and group 4, both were markedly improved. Group 4 revealed obviously normal mitochondria. Conclusion: Administration of simvastatin for 8 weeks induced histological, physiological and biochemical skeletal myotoxic effects. These effects were greatly ameliorated by concomitant administration vitamin E or ginger extract. Ginger extract was more effective.

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Section: Discussionsupporting

confidence: 82%

The Possible Protective Role of Ginger Extract Versus Vitamin E Against Simvastatin-Induced Skeletal Myotoxicity in Adult Male Albino Rats: Histological, Physiological and Biochemical Study

Hamid¹,

Mola²,

Meligy³

et al. 2017

Egyptian Journal of Histology

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“…Despite the fact that today statins are the first line of treatment against hypercholesterolemia (competitive HMG-CoA reductase inhibitors), these drugs are often considered insufficient in preventing cardiovascular diseases (Gilad and Lampl, 1999; Huynh et al, 2002). Chronic inhibition of HMG-CoA reductase can lead to decreased levels of numerous non-sterol metabolites that are essential for cell viability (Levy and Kohlhaas, 2006).…”

Section: Isoprenoids Fpps/ggpps and Neurodegeneration—the Current Hypmentioning

confidence: 99%

Human isoprenoid synthase enzymes as therapeutic targets

et al. 2014

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In the human body, the complex biochemical network known as the mevalonate pathway is responsible for the biosynthesis of all isoprenoids, which consists of a vast array of metabolites that are vital for proper cellular functions. Two key isoprenoids, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) are responsible for the post-translational prenylation of small GTP-binding proteins, and serve as the biosynthetic precursors to numerous other biomolecules. The down-stream metabolite of FPP and GGPP is squalene, the precursor to steroids, bile acids, lipoproteins, and vitamin D. In the past, interest in prenyl synthase inhibitors focused mainly on the role of the FPP in lytic bone diseases. More recently pre-clinical and clinical studies have strongly implicated high levels of protein prenylation in a plethora of human diseases, including non-skeletal cancers, the progression of neurodegenerative diseases and cardiovascular diseases. In this review, we focus mainly on the potential therapeutic value of down-regulating the biosynthesis of FPP, GGPP, and squalene. We summarize the most recent drug discovery efforts and the structural data available that support the current on-going studies.

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“…Some of these drugs have the potential to inhibit the metabolism of most statins leading to an increase of statin concentrations. Grapefruit juice contains inhibitors, furanocoumarin derivatives, of statin metabolism . There are case reports of CK increases with or without myalgia after adding ezetimibe to a well‐tolerated statin therapy .…”

Section: Risk Factorsmentioning

confidence: 99%

Mechanisms and assessment of statin‐related muscular adverse effects

Moßhammer

Schaeffeler

Schwab

et al. 2014

Brit J Clinical Pharma

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Statin-associated muscular adverse effects cover a wide range of symptoms, including asymptomatic increase of creatine kinase serum activity and life-threatening rhabdomyolysis. Different underlying pathomechanisms have been proposed. However, a unifying concept of the pathogenesis of statin-related muscular adverse effects has not emerged so far. In this review, we attempt to categorize these mechanisms along three levels. Firstly, among pharmacokinetic factors, it has been shown for some statins that inhibition of cytochrome P450-mediated hepatic biotransformation and hepatic uptake by transporter proteins contribute to an increase of systemic statin concentrations. Secondly, at the myocyte membrane level, cell membrane uptake transporters affect intracellular statin concentrations. Thirdly, at the intracellular level, inhibition of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase results in decreased intracellular concentrations of downstream metabolites (e.g. selenoproteins, ubiquinone, cholesterol) and alteration of gene expression (e.g. ryanodine receptor 3, glycine amidinotransferase). We also review current recommendations for prescribers.

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HMG CoA reductase‐inhibitor‐related myopathy and the influence of drug interactions

Cited by 24 publications

References 18 publications

The Possible Protective Role of Ginger Extract Versus Vitamin E Against Simvastatin-Induced Skeletal Myotoxicity in Adult Male Albino Rats: Histological, Physiological and Biochemical Study

The Possible Protective Role of Ginger Extract Versus Vitamin E Against Simvastatin-Induced Skeletal Myotoxicity in Adult Male Albino Rats: Histological, Physiological and Biochemical Study

Human isoprenoid synthase enzymes as therapeutic targets

Mechanisms and assessment of statin‐related muscular adverse effects

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