At steady state, the mean volume of distribution for rosuvastatin is about 130 L, and it is tightly bound in a reversible manner to plasma proteins (88%), while other statins are more than 95% protein bound except pravastatin (which is approximately 50% bound).11
rosuvastatin side effects pdf 12
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Metabolism of rosuvastatin and its interactions with cytochrome P450 isoenzymes were evaluated in vitro using human hepatic microsomes. No significant inhibitory effect was noted on CYP1 A2, 2C9, 2C19, 2D6, 2E1, and 3 A4 activity. The most potent inhibition was found against the CYP2C9, but the enzyme activity was reduced by only 10%.19 The metabolism of rosuvastatin via cultured human hepatocytes (3% to 50% over 3 days) produces an N-desmethyl-metabolite and a 5S-lactone product. The N-desmethyl-metabolite is 7-fold less potent than rosuvastatin for inhibition of HMG-CoA reductase activity.10 The slow metabolism and the limited inhibitory effect of rosuvastatin on CYP isoenzymes suggest that it is unlikely to cause any significant pharmacokinetic interactions with other drugs metabolized by hepatic CYP isoenzymes. On the contrary, lovastatin, simvastatin, and atorvastatin are extensively metabolized by CYP3 A4, and inhibitors of this enzymatic system (such as itraconazole) were found to increase serum concentrations of these statins by several-fold, with an increased risk of muscle toxicity.19,20
Recovery of rosuvastatin is primarily via the fecal route of elimination: approximately 70% of absorbed dose is eliminated via bile secretion, and 30% via renal excretion. The circulating plasma half-life of rosuvastatin is about 20 hours.10,16
Itraconazole is a potent inhibitor of CYP3 A4 and P-glycoprotein, and is known to interact with other statins. In two randomized, double-blind, placebo-controlled trials the effect of itraconazole on the pharmacokinetics of rosuvastatin was evaluated in 26 healthy volunteers. In these studies, the coadministration of itraconazole produced only modest increases in plasma concentrations of rosuvastatin, which are unlikely to be of clinical relevance.23
Dosing of rosuvastatin ranging from 1 to 80 mg daily over 6 weeks has resulted in LDL-cholesterol reductions compared with the baseline values from 34% to 65%, and the LDL cholesterol reduction at the probable starting dose range (5 to 10 mg) was 43% to 51%.27
In a direct comparative trial, rosuvastatin or atorvastatin was administered to patients with familial heterozygous hypercholesterolemia. Subjects were randomized to either 20 mg of rosuvastatin or atorvastatin and the dose was doubled at 6-week periods until all patients reached the maximum dose of 80 mg for both drugs at weeks 12 to 18. Decreases in LDL cholesterol concentrations were significantly greater for rosuvastatin compared with atorvastatin at all time points, and 61% of patients taking rosuvastatin reached target goals according to NCEP-ATP II guidelines, compared to 46% of those taking atorvastatin.28
The STELLAR study29 was a 6-week, open-label, randomized, multicenter trial comparing rosuvastatin with atorvastatin, pravastatin, and simvastatin across dose ranges for reduction of LDL cholesterol, changes in other lipid parameters, and achievement of NCEP-ATP III LDL-cholesterol goals.
A substudy of the STELLAR trial assessed non-HDL cholesterol, apolipoprotein (apo) B, and lipid and apolipoprotein ratios that included both atherogenic and antiatherogenic lipid components in 2,268 patients with hypercholesterolemia. All participants were randomized to therapy with rosuvastatin (10, 20, 40, or 80 mg daily), atorvastatin (10, 20, 40, or 80 mg daily), simvastatin (10, 20, 40, or 80 mg daily), or pravastatin (10, 20, or 40 mg daily) for 6 weeks. At the end of follow-up, rosuvastatin reduced non-HDL cholesterol, apo B, and all lipid and apolipoprotein ratios assessed significantly more than milligram-equivalent doses of atorvastatin, and milligram-equivalent or higher doses of simvastatin and pravastatin (all P
A post-hoc subanalysis of the STELLAR trial evaluated the effects of maximal doses of rosuvastatin and atorvastatin on LDL cholesterol and small dense LDL (sLDL) cholesterol levels in 271 hyperlipidemic patients. All participants were randomized to therapy with rosuvastatin 40 mg daily or atorvastatin 80 mg daily for 6 weeks. Rosuvastatin was significantly more effective than atorvastatin in reducing LDL cholesterol, sLDL cholesterol, total cholesterol/HDL cholesterol ratio, and non-HDL cholesterol, even though the magnitude of these differences was modest, and both statins caused similar decreases in triglyceride levels.31
Two studies have evaluated the efficacy of rosuvastatin therapy after a 52-week follow-up. In the first randomized, double-blinded, multicenter study, 412 subjects with elevated LDL cholesterol levels received fixed doses of rosuvastatin (5 or 10 mg daily) or atorvastatin (10 mg daily) for 12 weeks, followed by dose adjustements up to 80 mg if the NCEP-ATP III goals were not met. Both doses of rosuvastatin resulted in greater LDL cholesterol reductions than atorvastatin at 12 weeks (46% and 50%, respectively, versus 39%; P
In a similarly designed trial, 477 patients with hypocholesterolemia received fixed doses of rosuvastatin (5 or 10 mg daily), pravastatin (20 mg), or simvastatin (20 mg) for 12 weeks followed by 40 weeks of liberal-dose titration up to 80 mg for rosuvastatin and simvastatin and 40 mg for pravastatin. After 52 weeks, more rosuvastatin-treated subjects achieved the NCEP-ATP III LDL cholesterol goals (88% and 87.5%, respectively) than recipients of pravastatin (60%) or simvastatin (73%).33
The JUPITER trial36 was a randomized, double-blind, placebo-controlled study designed to compare whether rosuvastatin (20 mg daily) versus placebo would reduce major cardiovascular events in 17,802 apparently healthy patients with low to normal LDL cholesterol levels but elevated C-reactive protein (CRP) levels. Notably, this trial was prematurely interrupted after a median follow-up of 1.9 years based on unequivocal evidence of a reduction in cardiovascular morbidity and mortality in rosuvastatin-treated patients. The rates of first major cardiovascular events (defined as non-fatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, arterial revascularization procedure, or confirmed death from cardiovascular causes) were 0.77 and 1.36 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (P
A retrospective matched cohort study compared the incidence rates of hospitalization associated with rhabdomyolysis, myopathy, renal or hepatic dysfunction, and of inhospital death, among over 48,000 initiators of rosuvastatin and other statins. This study found no difference between rosuvastatin and the other statins in the incidence of hospitalization because of renal or hepatic dysfunction, or death, while the absolute incidence rates of rhabdomyloysis and myopathy were reassuringly low among all statin initiators but remain too small for firm conclusions to be drawn on any difference between the statins. Particularly, incidence rate per 1000 person-years of rhabdomyolysis was 0.1 among subjects taking rosuvastatin and 0.06 among those taking other statins, while incidence rate of myopathy was 0.2 among rosuvastatin-treated subjects and 0 among other statin initiators.42
Recently, the in vitro effects of statins on peripheral blood mononuclear cells and fibroblast-like synoviocytes were analyzed in 25 patients with rheumatoid arthritis and in 20 healthy blood donors. In fibroblast-like cells stimulated with atorvastatin a significant downregulation of proinflammatory cytokine (interleukin-6) and chemokine (interleukin-8) expression was detected, showing a marked in vitro anti-inflammatory activity of atorvastatin in rheumatoid arthritis, including a systemic effect on a pathogenic CD4+ T cell population and a local effect on fibroblast-like synoviocytes.46 Moreover, simvastatin and atorvastatin inhibited the CRP-induced chemokine secretion, intercellular adhesion molecule (ICAM-1) upregulation, and migration in human adherent monocytes, through the inhibition of HMG-CoA reductase-extracellular signal-regulated kinase 1/2 pathway.47
The effect of rosuvastatin on plasma inflammation markers, endogenous nitric oxide synthase inhibitor levels, and reactive oxygen species generated by circulating leukocytes was evaluated in normotensive and in spontaneously hypertensive rats. In the experimental conditions, rosuvastatin lessened pro-inflammatory cytokines, increased interleukin-4 levels, and reduced reactive oxygen species production in circulating monocytes of spontaneously hypertensive rats.48
The effect of rosuvastatin on CRP expression in stimulated human hepatocytes was also investigated. Experimental results showed a direct inhibitory effect of rosuvastatin on interleukin-6-induced expression of CRP in human hepatoma cells and primary human hepatocytes. Statins may reduce C-reactive protein levels by inhibiting its production in the liver rather than by exerting systemic anti-inflammatory effects.49
Main outcome measures: Rate of change in maximum CIMT (assessed with B-mode ultrasound) for 12 carotid sites; changes in maximum CIMT of the common carotid artery, carotid bulb, and internal carotid artery sites and in mean CIMT of the common carotid artery sites. CIMT regression was assessed in the rosuvastatin group only.
Conclusions: In middle-aged adults with an FRS of less than 10% and evidence of subclinical atherosclerosis, rosuvastatin resulted in statistically significant reductions in the rate of progression of maximum CIMT over 2 years vs placebo. Rosuvastatin did not induce disease regression. Larger, longer-term trials are needed to determine the clinical implications of these findings.
BACKGROUND: Statins are a class of prescription medicines that have been used for decades to lower low-density lipoprotein (LDL-C or "bad") cholesterol in the blood. Medicines in the statin class include atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin. 2ff7e9595c
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