Effect of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on high-sensitivity C-reactive protein levels

Cardiovascular disease is the leading cause of death among adults in the United States, in Europe, and in much of Asia. Despite advances in primary prevention of coronary artery disease, including early detection and treatment of dyslipidemia, one half of all myocardial infarctions and strokes occur in patients with normal serum cholesterol levels. Observations like this prompt the search for new risk factors and improved identification of individuals at high risk. One proposed risk factor is an elevated level of C-reactive protein (CRP), a marker of inflammation independent of other risk factors. The CRP assay is desirable in terms of standardization and cost. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are indicated for the treatment of dyslipidemias, but data support their protective role against cardiovascular disease beyond their effects on lipids. Statins directly affect inflammatory markers, and nearly 2 dozen randomized studies have demonstrated statins' effects on CRP. Because information regarding the role of CRP in cardiovascular disease is compelling but sometimes contradictory and because the need to reduce CRP levels is unclear, the American Heart Association and the Centers for Disease Control and Prevention presented a panel statement on the topic. Ongoing trials will assist in determining the need to reduce CRP levels to lower cardiovascular risk. An understanding of these issues is important for improving the prediction of cardiovascular risk and for intervening to reduce this risk.     

Differential effect of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on plasma paraoxonase 1 activity in the rat

Statins (3-hydroxy-3-methylglutarylcoenzyme A reductase inhibitors), apart from lowering plasma cholesterol, modulate other processes involved in atherogenesis. The aim of this study was to investigate the effect of a natural statin, pravastatin, and of the synthetic one, fluvastatin, on plasma paraoxonase 1 (PON1), the antioxidant enzyme contained in plasma high-density lipoproteins. The adult male Wistar rats received either pravastatin (4 or 40 mg/kg/day) or fluvastatin (2 or 20 mg/kg/day) for 3 weeks. Then, plasma PON1 activity, lipid peroxidation products and total antioxidant capacity were assayed. Fluvastatin at a dose of 20 mg/kg/day decreased paraoxonhydrolyzing activity of PON1 by 23.6% and its phenyl acetate-hydrolyzing activity by 17.4%. Lower dose of this drug as well as either dose of pravastatin had no effect on these activities. Fluvastatin at doses of 2 and 20 mg/kg/day decreased gamma-decanolactone-hydrolyzing activity of plasma by 19.1% and 30.9%, respectively. Statins had no effect on either total or HDL-cholesterol but markedly reduced plasma triglycerides. Fluvastatin had a more marked antioxidant activity, as evidenced by significant reduction of plasma concentration of malonyldialdehyde + hydroxydialkenals and lipid hydroperoxides, as well as by elevation of total plasma antioxidant capacity and plasma concentration of reduced sulfhydryl groups. These results suggest that fluvastatin but not pravastatin decreases plasma PON1 activity in normolipidemic rats, however, the former drug is more effective in reducing the level of oxidative stress.     

Effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on mitochondrial respiration in ischemic rat hearts

The aim of the present study was to examine the effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors on mitochondrial respiration in ischemic rat hearts, and to compare the effects between water-soluble pravastatin and lipid-soluble simvastatin. Either vehicle (0.5% carboxymethyl cellulose), pravastatin (2 or 4 mg/kg per day), or simvastatin (1 or 2 mg/kg per day) was orally administered for 3 weeks. Ischemia was induced by ligating the aorta for 60 min in anesthetized open chest rats under artificial respiration. The hearts were removed, mitochondria were isolated, and the respiration was determined by polarography using glutamate and succinate as substrates. When succinate was used as a substrate, the ADP-stimulated respiration (QO₃) and ATP production per unit oxygen (ADP/O ratio) were decreased by ischemia. The decreases in QO₃ and ADP/O ratio in the pravastatin-and simvastatin-treated groups appeared to be more prominent than those in the vehicle-treated group. This was especially true in the simvastatin-treated group. The ADP-limited respiration (QO₄) with succinate in the vehicle-treated heart was slightly increased by ischemia, while that in the pravastatin- or simvastatin-treated hearts was decreased. In conclusion, HMG-CoA reductase inhibitors may result in worsening of myocardial mitochondrial respiration during ischemia.     

Pannorin, a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor produced by Chrysosporium pannorum

Pannorin, a naphthopyrone that inhibits 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol synthesis, was isolated from a culture broth of Chrysosporium pannorum M10539 by solvent extraction, Bio-Gel P-6 column chromatography and reverse phase HPLC (Silica ODS). Spectroscopic analyses of the compound yielded 4,8,10-trihydroxy-5-methyl-2H-naphtho[1,2-b]pyran-2-one as the proposed structure. Pannorin inhibited HMG-CoA reductase and in vitro sterol synthesis 50% at a concentration of 160 microM.     

Thermodynamic and structure guided design of statin based inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase

Clinical studies have demonstrated that statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) inhibitors, are effective at lowering mortality levels associated with cardiovascular disease; however, 2-7% of patients may experience statin-induced myalgia that limits compliance with a treatment regimen. High resolution crystal structures, thermodynamic binding parameters, and biochemical data were used to design statin inhibitors with improved HMGR affinity and therapeutic index relative to statin-induced myalgia. These studies facilitated the identification of imidazole 1 as a potent (IC 50 = 7.9 nM) inhibitor with excellent hepatoselectivity (>1000-fold) and good in vivo efficacy. The binding of 1 to HMGR was found to be enthalpically driven with a Delta H of -17.7 kcal/M. Additionally, a second novel series of bicyclic pyrrole-based inhibitors was identified that induced order in a protein flap of HMGR. Similar ordering was detected in a substrate complex, but has not been reported in previous statin inhibitor complexes with HMGR.     

Studies on the effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on the rodent forestomach

A novel class of hypocholesterolaemic agents, HMG CoA reductase inhibitors, was shown to cause mucosal thickening in the rodent (mouse and rat) forestomach after subacute/subchronic oral administration. These changes were characterized histologically by acanthosis and hyperkeratosis of the squamous epithelium with submucosal oedema and occasionally cellular infiltration. This drug-induced hyperplastic response was both dose and time dependent, did not occur after subcutaneous administration, and was confined entirely to the rodent forestomach (not observed in any other area of the gastro-intestinal tract). The forestomach hyperplastic response correlated with the pharmacological potency of HMG CoA reductase inhibitors of similar structure (observed to varying degrees with all HMG CoA reductase inhibitors examined to date).     

Hypolipidemic effect of NK-104 and other 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in guinea pigs

Hypolipidemic effects of various HMG-CoA reductase inhibitors (statins) were examined in guinea pigs. After 2-week administration of NK-104 ((+)-monocalcium bis((3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3, 5-dihydroxy-6-heptenoate), CAS 147526-32-7), simvastatin (SV), pravastatin (PV), fluvastatin (FV), cerivastatin (CV) and atorvastatin (AV) to guinea pigs at various doses, which did not affect body weight, plasma and liver lipids were measured. Liver endoplasmic reticulum (ER) was isolated and measured for lipid content and activity of ER enzymes (NK-104: 3 mg/kg, SV: 30 mg/kg). Each statin except CV dose-dependently lowered total cholesterol (TC), with NK-104 showing the greatest effect. Only NK-104 and AV, long-acting statins, significantly lowered triglycerides (TG). A significant reduction of the liver cholesterol content was observed for NK-104 and AV. The liver TG content increased with dose for SV or PV, but not for NK-104 or AV. The TG content in ER and activity of diacylglycerol acyltransferase of ER, increased with SV and slightly with NK-104. Activity of microsomal triglyceride transfer protein, which is necessary for both apoB particle formation at rough ER and TG droplet production at smooth ER, increased by SV but not by NK-104. It is suggested that statins with prolonged action lower TG by decreasing cholesterol ester supply necessary for very low density lipoprotein formation and by attenuating an increase in TG production at ER after HMG-CoA reductase inhibition.     

Effect of treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on serum coenzyme Q10 in diabetic patients.

Serum coenzyme Q10 (CoQ10: 2-(3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,22,26,30,34 ,38 -tetracontadecaenyl)-5,6-dimethoxy-3-methyl-1,4-benzoquinone, CAS 303-98-0) and cholesterol levels were measured to assess the effect of cholesterol-lowering therapy in patients with non-insulin-dependent diabetes mellitus (NIDDM). Twenty healthy volunteers, 97 NIDDM patients and 2 patients with familial hypercholesterolemia were studied. None had overt heart failure or any other heart disease. Mean serum CoQ10 concentrations were significantly (p < 0.01) lower in diabetic patients with normal serum cholesterol concentrations, either with or without administration of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (HMG-CoA RIs) including simvastatin (normal: 0.91 +/- 0.26 (mean +/- SD) mumol 1(-1); diabetic with HMG-CoA RI: 0.63 +/- 0.19; diabetic without HMG-CoA RI: 0.66 +/- 0.21). CoQ10 concentrations were higher (1.37 +/- 0.48, p < 0.001) in diabetic patients with hypercholesterolemia. Simvastatin or low density lipoprotein apheresis decreased serum CoQ10 concentrations along with decreasing serum cholesterol. Oral CoQ10 supplementation in diabetic patients receiving HMG-CoA RI significantly (p < 0.001) increased serum CoQ10 from 0.81 +/- 0.24 to 1.47 +/- 0.44 mumol 1(-1), without affecting cholesterol levels. It significantly (p < 0.03) decreased cardiothoracic ratios from 51.4 +/- 5.1 to 49.2 +/- 4.7%. In conclusion, serum CoQ10 levels in NIDDM patients are decreased and may be associated with subclinical diabetic cardiomyopathy reversible by CoQ10 supplementation.     

Effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on mitochondrial respiration in ischaemic dog hearts.

1. Effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, pravastatin and simvastatin, on the myocardial level of coenzyme Q10, and on mitochondrial respiration were examined in dogs. 2. Either vehicle (control), pravastatin (4 mg kg-1 day-1), or simvastatin (2 mg kg-1 day-1) was administered orally for 3 weeks. First, the myocardial tissue level of coenzyme Q10 was determined in the 3 groups. Second, ischaemia was induced by ligating the left anterior descending coronary artery (LAD) in anaesthetized open chest dogs, pretreated with the inhibitors. After 30 min of ischaemia, nonischaemic and ischaemic myocardium were removed from the left circumflex and LAD regions, respectively, and immediately used for isolation of mitochondria. The mitochondrial respiration was determined by polarography, with glutamate and succinate used as substrates. 3. Simvastatin significantly decreased the myocardial level of coenzyme Q10, but pravastatin did not. 4. Ischaemia decreased the mitochondrial respiratory control index (RCI) in both groups. Significant differences in RCI between nonischaemic and ischaemic myocardium were observed in the control and simvastatin-treated groups. 5. Only in the simvastatin-treated group did ischaemia significantly decrease the ADP/O ratio, determined with succinate. 6. The present results indicate that simvastatin but not pravastatin may cause worsening of the myocardial mitochondrial respiration during ischaemia, probably because of reduction of the myocardial coenzyme Q10 level.     

Synthesis, biological profile, and quantitative structure-activity relationship of a series of novel 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors

A series of 9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(alkyltetrazol-5-yl)- 6,8-nonadienoic acid derivatives 1 were synthesized and found to inhibit competitively the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. The analogues having 1N-methyltetrazol-5-yl attached to the C8-position (3a, 4a, R1 = R2 = F) are the most active in suppressing cholesterol biosynthesis in both in vitro and in vivo models: the IC50 for the chiral form of 3a is 19 nM, Ki = 4.3 x 10(-9)M when Km for HMG-CoA is 28 x 10(-6) M;1 the ED50 (oral) value corresponding to the lactone derivative (4a, BMY 22089) is approximately 0.1 mg/kg. Further, BMY 21950 is nearly 2 orders of magnitude more active in parenchymal heptaocytes, from which most of the serum cholesterol originates, than in other cell preparations (such as spleen, testes, ileum, adrenal, and ocular lens epithelial cells; Table III). This apparent tissue specificity may be highly beneficial since the blocking of cholesterol biosynthesis in other vital organs could eventually lead to undesirable side effects. In addition to the chemical synthesis and biological evaluation, a theoretical study aimed at relating the HMG-CoA reductase inhibitory potency to the three-dimensional structure of the inhibitors was undertaken. With a combination of molecular mapping and 3D-QSAR techniques, it was possible to determine a logical candidate for the conformation of the bound inhibitor and to quantitatively relate inhibitory potency to the shape and size of both the binding site and the C8-substituent.     

Direct vascular effects of HR780, a novel 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor

1. We have examined the effects of HR780, a novel 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on porcine endothelial cell (EC) injury induced by xanthine (X)/xanthine oxidase (XO), a source of superoxide anion. Furthermore, the effects of HR780 on platelet-derived growth factor (PDGF)-induced migration and fetal calf serum (FCS)-induced proliferation of rabbit smooth muscle cells (SMC) were investigated. 2. Probucol, at 10 micro mol/L, significantly (P < 0.001) and completely suppressed lactate dehydrogenase leakage induced by X/XO. At 10 micro mol/L, HR780 significantly (P = 0.010) inhibited X/XO-induced EC injury. 3. HR780 dose-dependently inhibited PDGF-induced SMC migration and FCS-induced SMC proliferation. The addition of mevalonate completely abolished the inhibitory effect of HR780 on SMC proliferation. Another HMG-CoA reductase inhibitor, simvastatin (0.1-100 micro mol/L), also inhibited the migration and proliferation responses as potently as HR780. In contrast, pravastatin (0.1-100 micro mol/L) did not show any effects. 4. This in vitro study provides the first evidence that HR780 protects the vascular endothelium from oxidant stress and inhibits the migration and proliferation of SMC.     

Pharmacokinetics and disposition of rosuvastatin,a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor,in rat

1. The pharmacokinetics and disposition of rosuvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, were investigated following single administration of 14 C-rosuvastatin in the Sprague-Dawley rat. 2. Following oral administration of 14 C-rosuvastatin at 1, 5 and 25?mg kg -1, the C max and AUC of the radioactivity in the plasma increased more than the increase in dose ratio. 3. Excretion of radioactivity was 98.0% of the dose in the faeces and 0.4% in the urine up to 168 h after oral administration in the intact rat, and was 55.1% in the bile and 0.5% in the urine up to 48 h post-dosing in the bile duct-cannulated rat. The unchanged compound mainly accounted for the radioactivity in the bile and faeces. 4. In the tissue distribution study, the concentration of the radioactivity in the liver was markedly higher than those in the other tissues, and the radioactivity concentration ratios of the liver to the plasma were between 8 and 25 up to 48 h after oral administration. The liver-specific distribution of rosuvastatin was similarly recognized in whole-body autoradiography. 5. Metabolic profiling studies indicated that rosuvastatin would not be metabolized by CYP enzymes. 6. These results clarified that rosuvastatin selectively distributed in the liver - the target organ - and was excreted in the bile mainly as the unchanged compound.     

Pharmacokinetics and disposition of rosuvastatin,a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor,in rat

1. The pharmacokinetics and disposition of rosuvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, were investigated following single administration of (14)C-rosuvastatin in the Sprague-Dawley rat. 2. Following oral administration of (14)C-rosuvastatin at 1, 5 and 25 mg kg(-1), the C(max) and AUC of the radioactivity in the plasma increased more than the increase in dose ratio. 3. Excretion of radioactivity was 98.0% of the dose in the faeces and 0.4% in the urine up to 168 h after oral administration in the intact rat, and was 55.1% in the bile and 0.5% in the urine up to 48 h post-dosing in the bile duct-cannulated rat. The unchanged compound mainly accounted for the radioactivity in the bile and faeces. 4. In the tissue distribution study, the concentration of the radioactivity in the liver was markedly higher than those in the other tissues, and the radioactivity concentration ratios of the liver to the plasma were between 8 and 25 up to 48 h after oral administration. The liver-specific distribution of rosuvastatin was similarly recognized in whole-body autoradiography. 5. Metabolic profiling studies indicated that rosuvastatin would not be metabolized by CYP enzymes. 6. These results clarified that rosuvastatin selectively distributed in the liver - the target organ - and was excreted in the bile mainly as the unchanged compound.     

Selective inhibition of formyl-methionyl-leucyl-phenylalanine (fMLF)-dependent superoxide generation in neutrophils by pravastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase

It has been shown previously that inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, such as compactin, lovastatin, and pravastatin, block cholesterol synthesis, suppress lymphocyte functions, and beneficially affect atherogenesis. Recently, it was reported that compactin and lovastatin inhibit the respiratory burst of DMSO-differentiated HL-60 cells, an effect reversed by mevalonic acid. The mode of action of these inhibitors in this role is not understood fully. Thus, we studied the mechanism of inhibition of neutrophil superoxide (O2*-) generation by pravastatin and found that pravastatin at 0.5 mM inhibited the receptor-mediated tyrosine kinase (TK)-dependent pathway of O2*- generation and also luminol chemiluminescence but not the protein kinase C (PKC)-dependent or the TK- and PKC-independent pathways of O2*- generation in neutrophils. Pravastatin also inhibited the tumor necrosis factor-alpha- and formyl-methionyl-leucyl-phenylalanine-induced phosphorylation of a tyrosine of a 115-kDa protein. These effects were not reversed by mevalonate. From these results it is concluded that pravastatin inhibited receptor-mediated O2*-generation by decreasing tyrosine phosphorylation but not by inhibiting the formation of an intermediate in the biosynthesis of cholesterol.     

NK-104, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, reduces osteopontin expression by rat aortic smooth muscle cells

1. It has been suggested that osteopontin promotes the development of atherosclerosis, especially under diabetic conditions. 2. In the present study, we found that NK-104, a new potent synthetic inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, reduced osteopontin expression both at protein and mRNA levels in cultured rat aortic smooth muscle cells. 3. The inhibitory effect of NK-104 was almost completely reversed by mevalonate, suggesting that mevalonate or its metabolites play important roles in the regulation of osteopontin expression. 4. Furthermore, oral administration of NK-104 (3 mg kg(-1) day(-1) for 7 days) effectively suppressed abnormally upregulated expression of osteopontin mRNA in the aorta and kidney of streptozotocin-induced diabetic rats. 5. These data support a notion that NK-104 is a suitable drug for the treatment of diabetic patients with hypercholesterolaemia.     

Hypocholesterolemic effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors in the guinea pig: atorvastatin versus simvastatin.

Male Hartley guinea pigs were fed a hypercholesterolemic diet rich in lauric and myristic acids with 0, 10, or 20 mg/kg of simvastatin or atorvastatin for 21 days. Atorvastatin and simvastatin resulted in a lowering of plasma low-density lipoprotein (LDL) cholesterol in a dose-dependent manner by an average of 48 and 61% with 10 and 20 mg/kg, respectively. Both statins were equally effective in lowering plasma LDL cholesterol and apolipoprotein B (apo-B) levels. Atorvastatin and simvastatin treatments yielded LDL particles that differed in composition from the control. Due to the relevance of LDL oxidation and cholesteryl ester transfer in plasma to the progression of atherosclerosis, these parameters were analyzed after statin treatment. Atorvastatin and simvastatin treatment decreased the susceptibility of LDL particles to oxidation by 95% as determined by the formation of thiobarbituric acid reactive substances. An 80% decrease in the transfer of cholesteryl ester between high-density lipoprotein (HDL) and the apo-B-containing lipoproteins was observed after simvastatin and atorvastatin treatment. In addition, statin effects on plasma LDL transport were studied. Simvastatin- and atorvastatin-treated guinea pigs exhibited 125 and 175% faster LDL fractional catabolic rates, respectively, compared with control animals. No change in LDL apo-B flux was induced by either treatment; however, LDL apo-B pool size was reduced after statin treatment. Hepatic microsomal free cholesterol was lower in the atorvastatin and simvastatin groups. However, only atorvastatin treatment resulted in an 80% decrease of acyl-CoA:cholesterol acyltransferase activity (P < 0.001). In summary, atorvastatin and simvastatin had similar LDL cholesterol lowering properties, but these drugs modified LDL transport and hepatic cholesterol metabolism differently.     

Synthesis and biological evaluation of dihydroeptastatin, a novel inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase.

The total synthesis of the novel hydroxylated HMG-CoA reductase inhibitor dihydroeptastatin (7) is described. The key C-3 hydroxyl group is introduced via a Baeyer-Villiger reaction on the methyl ketone 17 which is obtained in three high-yielding steps from the known tricyclic lactone 12. In an isolated enzyme assay dihydroeptastatin had a similar IC50 to mevinolin but in cellular assays using Hep G2 and HES 9 cell lines, dihydroeptastatin was much less potent. No selectivity between the two cell lines was observed.     

Comparing myotoxic effects of squalene synthase inhibitor, T-91485, and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors in human myocytes

TAK-475 is a squalene synthase inhibitor, rapidly metabolized to T-91485 in vivo. We investigated the myotoxicities of T-91485 and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors in a human rhabdomyosarcoma cell line, RD, and in human skeletal myocytes. In differentiated RD cells, T-91485, atorvastatin (ATV) and simvastatin acid (SIM) inhibited cholesterol biosynthesis, with IC(50) values of 36, 2.8 and 3.8 nM, respectively. ATV and SIM decreased the intracellular ATP content, with IC(25) values (concentrations giving a 25% decrease in intracellular ATP content) of 0.61 and 0.44 microM, respectively. Although T-91485 potently inhibited cholesterol synthesis in RD cells, the IC(25) value exceeded 100 microM. In human skeletal myocytes, T-91485, ATV and SIM concentration-dependently inhibited cholesterol biosynthesis, with IC(50) values of 45, 8.6 and 8.4 nM, respectively. ATV and SIM decreased intracellular ATP content, with IC(25) values of 2.1 and 0.72 microM, respectively. Although T-91485 potently inhibited cholesterol synthesis, the IC(25) value exceeded 100 microM. Myotoxicity induced by ATV was prevented by mevalonate or geranylgeranyl-PP, but not by squalene in skeletal cells. Furthermore, T-91485 attenuated the myotoxicity of ATV. These findings suggest that TAK-475 and T-91485 may not only be far from myotoxic, they may also decrease statin-induced myotoxicity in lipid-lowering therapy.