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Different Statins (different + statin)
Selected AbstractsLipophilic but not hydrophilic statins selectively induce cell death in gynaecological cancers expressing high levels of HMGCoA reductaseJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 5 2010S. Kato Abstract Recent reports have suggested that statins induce cell death in certain epithelial cancers and that patients taking statins to reduce cholesterol levels possess lower cancer incidence. However, little is known about the mechanisms of action of different statins or the effects of these statins in gynaecological malignancies. The apoptotic potential of two lipophilic statins (lovastatin and simvastatin) and one hydrophilic statin (pravastatin) was assessed in cancer cell lines (ovarian, endometrial and cervical) and primary cultured cancerous and normal tissues. Cell viability was studied by MTS assays and apoptosis was confirmed by Western blotting of PARP and flow cytometry. The expressions of key apoptotic cascade proteins were analysed. Our results demonstrate that both lovastatin and simvastatin, but not pravastatin, selectively induced cell death in dose- and time-dependent manner in ovarian, endometrial and cervical cancers. Little or no toxicity was observed with any statin on normal cells. Lipophilic statins induced activation of caspase-8 and -9; BID cleavage, cytochrome C release and PARP cleavage. Statin-sensitive cancers expressed high levels of HMG-CoA reductase compared with resistant cultures. The effect of lipophilic statins was dependent on inhibition of enzymatic activity of HMG-CoA reductase since mevalonate pre-incubation almost completely abrogated the apoptotic effect. Moreover, the apoptotic effect involved the inhibition of synthesis of geranylgeranyl pyrophosphate rather than farnesyl pyrophosphate. In conclusion, lipophilic but not hydrophilic statins induce cell death through activation of extrinsic and intrinsic apoptotic cascades in cancerous cells from the human female genital tract, which express high levels of HMG-CoA reductase. These results promote further investigation in the use of lipophilic statins as anticancer agents in gynaecological malignancies. [source] Therapeutic effect of statin on aortic stenosis: a review with meta-analysisJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 4 2010H. Ge MD Background:, Aortic stenosis (AS) is a common progressive disease. Statins have been hypothesized to delay its progression via pleiotropic mechanisms. However, results of clinical trials focusing on statin therapy in AS patients have been controversial. Objective:, To analyse and summarize the findings in recent statin trials and to discuss the rationale of statin usage in AS populations. Methods:, A comprehensive database search was conducted by two independent reviewers. Controlled trials that compared progression of AS between statin and non-statin therapy published before 31 December 2008 were included. Data were extracted for meta-analysis, to estimate overall effects, if available. Factors that contributed to heterogeneities among the trials were analysed. Results:, The meta-analysis included nine trials with a total of 2947 patients. Statin therapy displayed an overall statistically significant effect on delaying AS progression. The weighted mean difference (statin vs. control) of annual increase of peak aortic-jet velocity was ,0·12 m/s (95% confidence interval ,0·22 to ,0·03); the increase of mean transaortic pressure gradient was ,1·64 mmHg per year (,3·27 to ,0·01); Heterogeneity-analysis suggested that the baseline risk factors and characteristics of the patients, the use of different statins, and the time point to initiate statin therapy, may be important considerations when interpreting the result of individual studies. Conclusion:, Although the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial reported negative results in delaying AS progression in low-risk patients, the potential benefits of statins in those with multiple risk factors and their value in preventing future coronary events call for further investigation of different categories of AS patients. [source] A systematic review and meta-analysis on the therapeutic equivalence of statinsJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 2 2010T.-C. Weng MSc (Clin Pharm) Summary Background:, Statins are the most commonly prescribed agents for hypercholesterolemia because of their efficacy and tolerability. As the number of patients in need of statin therapy continues to increase, information regarding the relative efficacy and safety of statins is required for decision-making. Objective:, This study will use systematic review to compare the efficacy and safety profiles of different statins at different doses and determine the therapeutically equivalent doses of statins to achieve a specific level of low-density lipoprotein cholesterol (LDL-C) lowering effect. Methods:, Publications of head-to-head randomized controlled trials (RCTs) of statins were retrieved from the Oregon state database (1966,2004), MEDLINE (2005-April of 2006), EMBASE (2005-April of 2006), and the Cochrane Controlled Trials Registry (up to the first quarter of 2006). The publications were evaluated with predetermined criteria by a reviewer before they were included in the review. The mean change in cholesterol level of each statin was calculated and weighted by number of subjects involved in each RCT. Where possible, meta-analysis was performed to generate pooled estimates of the cholesterol lowering effect of statins and the difference between statins. Results:, Seventy-five studies reporting RCTs of head-to-head comparisons on statins were included. Most studies had similar baseline characteristics, except the rosuvastatin related studies. A daily dose of atorvastatin 10 mg, fluvastatin 80 mg, lovastatin 40,80 mg, and simvastatin 20 mg could decrease LDL-C by 30,40%, and fluvastatin 40 mg, lovastatin 10,20 mg, pravastatin 20,40 mg, and simvastatin 10 mg could decrease LDL-C by 20,30%. The only two statins that could reduce LDL-C more than 40% were rosuvastatin and atorvastatin at a daily dose of 20 mg or higher. Meta-analysis indicated a statistically significant but clinically minor difference (<7%) between statins in cholesterol lowering effect. Comparisons of coronary heart disease prevention and safety could not be made because of insufficient data. Conclusions:, At comparable doses, statins are therapeutically equivalent in reducing LDL-C. [source] Equally potent inhibitors of cholesterol synthesis in human hepatocytes have distinguishable effects on different cytochrome P450 enzymesBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 9 2000L.H. Cohen Abstract Six 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (the present cholesterol-lowering drugs known as statins), lovastatin (L), simvastatin (S), pravastatin (P), fluvastatin (F), atorvastatin (A) and cerivastatin (C) are shown to be potent inhibitors of cholesterol synthesis in human hepatocytes, the target tissue for these drugs in man. All six inhibited in the nM range (IC50 values: 0.2,8.0 nM). As daily used cholesterol-lowering drugs they are likely coadministered with other drugs. While several cytochrome P450 (CYP) enzymes are involved in drug metabolism in the liver and thus play an important role in drug,drug interaction it was investigated which of these enzymes are influenced by the active forms of the six statins. These enzyme activities were studied in human liver microsomal preparations, and in simian and human hepatocytes in primary culture. The following CYP reactions were used: nifedipine aromatization (CYP3A4), testosterone 6,-hydroxylation (CYP3A4), tolbutamide methylhydroxylation (CYP2C9), S -mephenytoin 4-hydroxylation (CYP2C19), bufuralol 1,-hydroxylation (CYP2D6), aniline 4-hydroxylation (CYP2E1), coumarin 7-hydroxylation (CYP2A6) and 7-ethoxyresorufin O -dealkylation (CYP1A1/2). In the human liver microsomes the statins (concentrations up to 400 µM) did not influence the CYP1A1/2 activity and hardly the CYP2A6 and CYP2E1 activities. Except P, the other five statins were stronger inhibitors of the CYP2C19 activity with IC50 values around 200 µM and the same holds for the effect of A, C and F on the CYP2D6 activity. L and S were weaker inhibitors of the latter enzyme activity, whereas P did not influence both activities. About the same was observed for the statin effect on CYP2C9 activity, except that F was a strong inhibitor of this activity (IC50 value: 4 µM). Using the assay of testosterone 6,-hydroxylation the CYP3A4 activity was decreased by L, S and F with IC50 values of about 200 µM and a little more by C and A (IC50 around 100 µM). P had hardly an effect on this activity. To a somewhat less extent the same trend was seen when CYP3A4 activity was measured using nifedipine as substrate. The inhibitory effects observed in microsomes were verified in suspension culture of freshly isolated hepatocytes from Cynomolgus monkey (as a readily available model) and of human hepatocytes. In general the same trends were seen as in the human microsomes, except that in some cases the inhibition of the CYP activity was less, possibly by the induction of the particular CYP enzyme by incubation of the cells with a particular statin. F remained a strong inhibitor of CYP2C9 activity in human and monkey hepatocytes. A induced the CYP2C9 in monkey hepatocytes but was an inhibitor of the CYP2C9 in human hepatocytes. A, S, L and C were moderate inhibitors in both cellular systems of CYP3A4. P was not affecting any of the CYP activities in the three systems studied. It is concluded that different CYP enzymes interact with different statins and therefore differences in between these drugs are to be expected when drug,drug interaction is considered. Copyright © 2000 John Wiley & Sons, Ltd. [source] | ||||||||||