匹伐他汀和阿托伐他汀诱发HepG2细胞发生胰岛素抵抗

目的研究匹伐他汀和阿托伐他汀诱发Hep G2细胞发生胰岛素抵抗的作用。方法 Hep G2细胞分别给予胰岛素0.5μmol·L-1,匹伐他汀1,10和100μmol·L-1,阿托伐他汀1,10和100μmol·L-1,以及阿托伐他汀100μmol·L-1+MK886 100μmol·L-1。48,72和96 h后检测细胞残余[125I]胰岛素结合率,[3H]D-葡萄糖摄取率,糖原和三酰甘油(TG)含量;作用48 h时细胞载脂蛋白A5(Apo A5)mRNA、Apo A5蛋白和Akt信号通路。结果与阴性对照组相比,匹伐他汀和阿托伐他汀对残余[125I]胰岛素结合率和糖原含量无明显作用。阿托伐他汀100μmol·L-1增加TG含量(mg·g蛋白:0.71±0.04 vs 1.51±0.05,P<0.05),降低[3H]D-葡萄糖摄取率〔37.2±3.2 vs(26.7±1.9)μmol·g-1·h-1,P<0.05),减少磷酸化Akt表达水平(0.92±0.09 vs 0.32±0.02,P<0.05),升高Apo A5 mRNA(0.30±0.02 vs 0.69±0.06,P<0.05)和蛋白表达水平(0.30±0.04 vs0.91±0.03,P<0.05),与胰岛素0.5μmol·L-1组类似。阿托伐他汀100μmol·L-1上述作用与作用时间呈正相关(r=0.729,P<0.05),而MK886可拮抗这些作用。结论阿托伐他汀100μmol·L-1时间依赖性地增强Apo A5表达,导致细胞糖脂代谢异常,诱发Hep G2细胞胰岛素抵抗。     

阿托伐他汀对ox-LDL诱导的人脐静脉内皮细胞缝隙连接的影响

目的:研究阿托伐他汀对氧化型低密度脂蛋白(ox-LDL)诱导的人脐静脉内皮细胞(HUVECs)连接蛋白(Connexin)43、Connexin40表达的影响。方法:将体外培养的HUVECs分为对照组、ox-LDL组、阳性对照组和阿托伐他汀组,除对照组外,其余组分别先在培养液、加入50μmol/L庚醇的培养液、加入不同剂量(0.01、0.1、1.0、10μmol/L)阿托伐他汀的培养液中处理30min,再分别加入50mg/L的ox-LDL继续培养24h。采用硝酸还原酶法测定各组NO浓度,免疫细胞化学法测定Connexin43蛋白定位表达,蛋白印迹法检测Connexin43、Connexin40蛋白定量表达。结果:与对照组比较,其余各组NO浓度均明显减少、Connexin43和Connexin40蛋白定量表达均明显增加(P均<0.01),其中除阳性对照组和10μmol/L阿托伐他汀组外,剩余各组均有Connexin43蛋白定位表达。与ox-LDL组比较,阳性对照组NO浓度明显增加、Connexin43和Connexin40蛋白定量表达明显减少(P<0.05或P<0.01),阿托伐他汀组随剂量增加NO浓度逐渐增加、Connexin43和Connexin40蛋白定量表达逐渐减少(P<0.05或P<0.01)。与阳性对照组比较,10μmol/L阿托伐他汀组上述指标均无统计学差异(P>0.05)。结论:阿托伐他汀呈剂量依赖性抑制ox-LDL诱导的HUVECs中Connexin43、Connexin40蛋白的增加,保护内皮间缝隙连接,从而发挥他汀类药物调脂外的抗动脉粥样硬化作用。     

大剂量阿托伐他汀预防缺血性脑卒中复发的效果评价

目的探讨大剂量阿托伐他汀预防缺血性脑卒中复发的应用效果。方法选择缺血性脑卒中患者148例随机分为观察组及对照组各74例,常规实施抗血小板聚集、抗凝剂等,对照组加阿托伐他汀1日20mg;观察组应用阿托伐他汀40mg口服、1日1次,时间一年。结果两组临床治疗总有效91.68%VS95.54%无差异(P>0.05);治疗前hs-CRP水平无差异,治疗以后均显著性下降,观察组(6.13±1.23)μg·L-1较对照组(9.87±2.05)μg·L-1下降明显(P<0.05),一年后观察组复发(1.02±0.11)低于对照组的(2.21±0.24)次。观察组12.16%出现药物不良反应与对照组的8.11%比较无统计学差异(P>0.05)。结论他汀类药物可有效预防缺血性脑血管病,且大剂量阿托伐他汀更加有效,不良反应发生率并未显著增加,安全有效,具有一定的临床意义。     

阿托伐他汀对自发性高血压大鼠肠系膜动脉内皮功能障碍的改善作用研究

目的:研究阿托伐他汀对自发性高血压大鼠(SHRs)肠系膜动脉内皮功能障碍的改善作用。方法:取京都种维斯特大鼠(WKYs)为对照组(生理盐水),另取SHRs分为模型组(生理盐水)和阿托伐他汀组(10mg.kg-1.d-1),每组8只,灌胃给予相应药物,连续8周,处死后采用敏感的肌张力描记技术测定各组大鼠离体肠系膜动脉环对KCl、苯肾上腺素(PE)、乙酰胆碱(Ach)引起的收缩/舒张反应的张力变化,以及抗坏血酸(100μmol.L-1)和一氧化氮合酶(NOS)拮抗药N-硝基-L-精氨酸甲酯(L-NAME)(100μmol.L-1)对Ach舒张反应的影响。结果:与对照组比较,模型组大鼠动脉环对KCl和PE引起的最大收缩反应明显增强(P<0.01),对Ach的最大舒张反应明显减弱(P<0.01);而阿托伐他汀组可对抗模型组的上述作用。L-NAME可抑制对照组Ach的舒张反应,但不能影响模型组,阿托伐他汀治疗后恢复了L-NAME对Ach舒张反应的抑制作用。抗坏血酸可促进模型组Ach的舒张反应,但不能影响对照组,阿托伐他汀作用后抗坏血酸的作用消失。结论:阿托伐他汀可以通过提高抗氧化能力和/或增加NO的利用度来改善自发性高血压大鼠肠系膜动脉的内皮功能障碍。     

他汀类药物促骨形成作用

他汀类药物为 HMG Co- A抑制剂 ,用于降低血浆胆固醇的浓度 ,减低心脏病发生的危险。采用荧光标记法测定骨形态发生蛋白 - 2 ( BMP- 2 )基因表达发现 ,辛伐他汀 ( simvastatin)、美伐他汀 ( mevastatin)和氟伐他汀 ( fluvastatin)均可促进 BMP- 2基因的表达 ,最大有效剂量为 5μmol·L- 1 。浓度低于 1 μmol· L- 1 时则无效。通过 RNA的 Northern印迹分析发现 ,暴露于他汀类药物下的鼠 ( 2 T3)或人 ( MG- 63)BMP- 2 m RNA的表达明显增加 ,这种作用是特异性的。用夹心酶联免疫吸附实验测定 BMP- 2结果显示 ,辛伐他汀与 NG- 63…     

肾上腺髓质素前体肽来源的肽段对cAMP的影响——在细胞内信号转导途径的“分子内调控”现象

目的探讨肾上腺髓质素前体肽来源的肽段对cAMP的影响。方法ADM、PAMP和ADT孵育离体大鼠主动脉2h后,以放射免疫标记技术,按试剂盒说明书进行操作检测血管组织中cAMP的含量。结果①10-8及10-7mol.L-1的ADM孵育血管后,血管cAMP浓度分别较对照组增加,与对照组相比差异具有显著性(P<0.01)。10-9mol.L-1孵育组与对照组相比差异无显著性(P>0.05)。PAMP(10-8mol.L-1)和ADT(10-8mol.L-1)单独孵育血管,其血管cAMP浓度分别与对照组相比差异有显著性(P<0.01)。②ADM10-8mol.L-1与PAMP10-8mol.L-1或ADT10-8mol.L-1共同孵育血管,其cAMP浓度与相同浓度的ADM10-8mol.L-1单独孵育组相比差异无显著性(P>0.05)。但与PAMP10-8mol.L-1或ADT10-8mol.L-1单独孵育组相比,差异有显著性(P<0.01)。相同摩尔浓度的ADM、PAMP和ADT共同孵育血管,其cAMP浓度与ADM10-8mol.L-1组相比差异无显著性(P>0.05),但低于PAMP10-8mol.L-1或ADT10-8mol.L-1单独孵育组(P<0.01)。结论同一肾上腺髓质素前体肽来源的不同肽段ADM与PAMP或/和ADT在血管cAMP生成中发挥相互拮抗作用。     

靶向内皮细胞α7受体的新化合物对鸡胚绒毛尿囊膜血管生成的影响

目的 :研究靶向内皮细胞α7受体的新化合物对鸡胚绒毛尿囊膜 (CAM)血管新生的影响。方法 :应用鸡胚绒毛尿囊膜模型 ,通过计数血管的分支点数 ,观察 16种靶向内皮细胞α7受体的新化合物对于在体血管新生的影响。结果与结论 :化合物 13、14在 1～ 10 0 μmol·L-1浓度范围内 ,既没有促进血管新生的作用 ,也没有抑制血管新生的作用 ,与生理盐水组相比无显著差异 ,而在浓度为 10 0 0 μmol·L-1时 ,对CAM的血管新生有促进作用。化合物 5在浓度为 10 0和 10 0 0 μmol·L-1有抑制血管新生的作用 ,而在浓度为 1和 10 μmol·L-1时 ,则对血管新生没有影响     

氟伐他汀对体外人眼Tenon''''s囊成纤维细胞增殖的抑制作用

目的观察氟伐他汀对体外培养的人Tenon’s囊成纤维细胞增殖的影响,探讨该药作为眼部抗增殖药物的可行性。方法体外培养人Tenon’s囊成纤维细胞,分别给予含1.0×10-9,1.0×10-8,1.0×10-7,1.0×10-6,5.0×10-6,1.0×10-5,2.0×10-5mol.L-1氟伐他汀的10%新生牛血清的DMEM培养基培养24,48,72 h后,应用MTT比色法检测不同作用时间及不同浓度药物对细胞增殖的抑制作用。结果培养细胞的吸光度值随着氟伐他汀浓度的增加及作用时间的延长而降低。作用24 h后,氟伐他汀浓度≥5.0×10-6mol.L-1的各实验组的吸光度值与空白对照组比较均差异有极显著性(均P<0.01);作用48 h后,氟伐他汀浓度≥1.0×10-6mol.L-1的各实验组细胞的吸光度值与对照组比较,均差异有显著性(均P<0.05);作用72 h后,氟伐他汀浓度≥1.0×10-7mol.L-1的各实验组细胞的吸光度值均小于对照组,且均差异有显著性(均P<0.05)。结论氟伐他汀能抑制体外培养的人眼Tenon’s囊成纤维细胞的增殖,且该作用呈剂量和时间依赖性。氟伐他汀有望成为治疗成纤维细胞增殖性眼病的新型药物。     

瑞舒伐他汀对猪骨髓间充质干细胞增殖、凋亡及分泌功能的影响

目的观察不同浓度的瑞舒伐他汀在体外水平对猪骨髓间充质干细胞(BMSCs)增殖、凋亡及细胞分泌功能的影响。方法分离培养猪BMSCs,取第3代细胞随机分为对照组和不同浓度瑞舒伐他汀(0.001、0.01、0.1、1.0μmol/L)干预组。MTT比色法检测各组细胞增殖情况,膜联蛋白V-异硫氰酸荧光素/碘化丙啶(Annexin V-FITC/PI)流式细胞术检测各组抗凋亡情况,ELISA法测定细胞上清液中血管内皮生长因子(VEGF)和碱性成纤维生长因子(bFGF)含量。结果与对照组相比,瑞舒伐他汀在一定浓度范围内(0.001～0.1μmol/L)可促进BMSCs增殖,抑制其凋亡,在0.01～1.0μmol/L内增加BMSCs VEGF和bFGF的分泌(P<0.05);当瑞舒伐他汀浓度升高至1.0μmol/L时则未见促增殖和抑制凋亡的作用(P>0.05)。结论瑞舒伐他汀在一定浓度范围内可促进猪BMSCs增殖,抑制其凋亡,并对VEGF和bFGF的分泌有促进作用。     

血管紧张素-Ⅱ对血管内皮细胞内皮素-1 mRNA表达水平的影响及阿托伐他汀的保护作用

目的观察血管紧张素(Ang)-Ⅱ对血管内皮细胞内皮素(ET)-1 mRNA表达水平的影响及阿托伐他汀的保护作用。方法将培养的血管内皮细胞随机分为4组:空白对照组(仅给予细胞培养液)、单纯Ang-Ⅱ组(细胞培养液中加入Ang-Ⅱ,使其终浓度为10-7mol/L)、Ang-Ⅱ+小剂量阿托伐他汀组(在单纯Ang-Ⅱ组的基础上加入阿托伐他汀,使阿托伐他汀的终浓度为0.1μmol/L)、Ang-Ⅱ+大剂量阿托伐他汀组(在单纯Ang-Ⅱ组的基础上加入阿托伐他汀,使阿托伐他汀的终浓度为1μmol/L)。以反转录-聚合酶链反应(RT-PCR)方法检测血管内皮细胞的ET-1mRNA表达水平。结果①与空白对照组相比,单纯Ang-Ⅱ组血管内皮细胞的ET-1 mRNA表达水平显著增高(P<0.01);②与单纯Ang-Ⅱ组相比,两个Ang-Ⅱ+阿托伐他汀组大鼠的心肌ET-1 mRNA表达水平显著降低(P<0.01);③Ang-Ⅱ+高浓度阿托伐他汀组的ET-1 mRNA表达水平显著低于Ang-Ⅱ+低浓度阿托伐他汀组(P<0.05)。结论Ang-Ⅱ可使血管内皮细胞ET-1 mRNA表达水平显著增高,阿托伐他汀可逆转这一作用,且其作用呈剂量依赖性。     

基于层次分析法合理选择他汀类药物

目的基于最高的性价比选择他汀类药物。方法在调脂强度达标的范围内,基于层次分析法构建评价指标体系,确定减低LDL-C强度和价格为评价指标,设计问卷调查表确定个体化的评价指标权重,使用matlab软件进行矩阵计算,根据结果选择最适合患者长期治疗的性价比最高的他汀类药物。结果根据患者调脂目标及经济能力合理选择他汀,如更关注药物的调脂强度,则依次选择阿托伐他汀40mg,瑞舒伐他汀10mg,阿托伐他汀20mg,辛伐他汀20mg,阿托伐他汀10mg,辛伐他汀40mg,氟伐他汀80mg,普伐他汀80mg及普伐他汀40mg。如更加关注价格,依次选择辛伐他汀20mg,阿托伐他汀10mg,氟伐他汀80mg,辛伐他汀40mg,瑞舒伐他汀10mg,阿托伐他汀20mg,普伐他汀40mg,阿托伐他汀40mg及普伐他汀80mg。如药物的调脂强度和价格同等重要,则依次选择辛伐他汀20mg,阿托伐他汀10mg,氟伐他汀80mg,辛伐他汀40mg,瑞舒伐他汀10mg,阿托伐他汀20mg,阿托伐他汀40mg,普伐他汀40mg及普伐他汀80mg。结论在调脂强度达标的范围内,可以通过层次分析法获得最适合患者的性价比最高的他汀类药物。     

他汀类药物对TNFa诱导成骨细胞生长抑制的保护作用

目的比较4种他汀类药物对TNF-诱导的小鼠成骨细胞(MC3T32-E1)生长抑制的影响。方法小鼠成骨细胞MC3T3-E1用DMEM+10%胎牛血清培养,细胞活性用MTT法测定。结果 TNFα(1~100 ng.mL 1)呈浓度和时间依赖抑制MC3T3-E1细胞生长;低浓度的辛伐他汀(10 10~10 7mol.L 1)、氟伐他汀(10 10~10 6mol.L 1)和阿托伐他汀(10 8~10 6mol.L 1)处理MC3T3-E1细胞72 h后能明显促进成骨细胞生长,而低浓度的罗舒伐他汀(10 10~10 7mol.L 1)无作用,在高浓度(10 6~10 5mol.L 1)时抑制MC3T3-E1的生长;用辛伐他汀、氟伐他汀和阿托伐他汀与TNF-α(10 ng.mL 1)共同培养MC3T3-E1细胞72 h,呈浓度依赖逆转TNF-α诱导的MC3T3-E1生长抑制,而罗舒伐他汀在低浓度时显示较强的逆转作用,在高浓度(10 6mol.L 1)时无作用或促进TNFα诱导的MC3T3-E1生长抑制。结论辛伐他汀、氟伐他汀和阿托伐他汀(10 10~10 7mol.L 1)能促进MC3T3-E1细胞生长,逆转TNFα诱导的MC3T3-E1生长抑制;而罗舒伐他汀高浓度(10 6~10 5mol.L 1)时抑制MC3T3-E1的生长,在低浓度时能明显逆转TNF-α诱导的成骨细胞生长抑制。     

Which statin, what dose?

Five prescribable statins are licensed in the UK: atorvastatin (Lipitor); fluvastatin (Lescol); pravastatin (Lipostat or generic); rosuvastatin (Crestor); simvastatin (Zocor or generic or branded generic e.g. Simvador). Here we discuss the relative merits of different statins in addressing cardiovascular risk.     

Eltrombopag in patients with chronic liver disease

Objective: To compare change in low-density lipoprotein cholesterol (LDL-C) levels and National Cholesterol Education Program (NCEP) Adult Treatment Panel III LDL-C goal attainment in diabetic patients treated with rosuvastatin versus other statins in a large, managed care health plan. Research Design and Methods: This retrospective cohort analysis used medical and pharmacy claims linked to laboratory results from a commercial/MedicareAdvantage health plan. Study participants were ≥ 18 years of age, had a diagnosis of diabetes, were newly treated with statins from 8/1/03 to 2/28/05, and were considered at high risk for cardiovascular events as defined by NCEP guidelines. Subjects were continuously enrolled for 12 months pre-index and ≥ 30 days post-index, with variable follow-up until therapy discontinuation or end of health plan eligibility. Main Outcome Measures: Change in LDL-C from baseline, and attainment of NCEP LDL-C goal among patients not at goal before starting therapy. Results: A total of 3337 adult patients with diabetes were identified with new use of statin therapy during the identification period. A total of 9% (n = 301) started on rosuvastatin, 49.4% (n = 1,649) on atorvastatin, 20.7% (n = 690) on simvastatin, 7.0% (n = 234) on pravastatin, 11.7% (n = 391) on lovastatin and 2.2% (n = 72) on fluvastatin. After controlling for covariates, rosuvastatin patients experienced a significantly greater decrease in LDL-C from baseline (38.7%) than patients taking atorvastatin (34.2%) (p = 0.05), simvastatin (31.5%), pravastatin (24.2%), fluvastatin (26.3%) or lovastatin (24.9%) (p < 0.0001). Rosuvastatin users were significantly more likely to attain LDL-C goal than those taking the other statins (odds ratio: 0.44, 0.28, 0.14, 0.14, 0.19, respectively; p < 0.001). Predicted percent attaining goal was significantly greater for those taking rosuvastatin (87.3%) than for those taking atorvastatin (76.9%), simvastatin (68.7%), pravastatin (55.0%), lovastatin (55.3%) or fluvastatin (61.3%) (p < 0.001). Conclusion: For diabetic patients, rosuvastatin is more effective at reducing LDL-C levels and attaining NCEP ATP III LDL-C goal than other statins in real-world clinical practice.     

Rosuvastatin: new preparation. Opt for statins with evidence of efficacy on clinical outcome

(1) Simvastatin and pravastatin are the two reference statins for type IIA and type IIB hypercholesterolaemia because they have the best-documented protective effect against cardiovascular events. Simvastatin and pravastatin are also the reference statins for familial heterozygous hypercholesterolaemia, though there is no evidence that they prevent cardiovascular events in this group. Statins are not very effective in familial homozygous hypercholesterolaemia. (2) Rosuvastatin is the sixth statin to arrive on the French market. The fifth, cerivastatin, was withdrawn from the market in 2001 because of serious adverse effects. (3) Rosuvastatin has not been assessed in terms of morbidity or mortality. The results of comparative trials in type IIA and type IIB hypercholesterolaemia suggest that rosuvastatin is slightly more active than simvastatin, pravastatin and atorvastatin on some lipid parameters after a few weeks of treatment. (4) Rosuvastatin has not been compared with simvastatin or pravastatin in familial heterozygous hypercholesterolaemia. One trial showed it to be slightly more effective than atorvastatin on cholesterol levels. According to one trial, rosuvastatin does not appear to be more effective than atorvastatin in homozygous forms. (5) In clinical trials the adverse effects of rosuvastatin were similar to those of other statins, with the exception of renal adverse effects. We don't know whether rosuvastatin is more or less likely than other statins to cause rhabdomyolysis. (6) Clinical trials reported some cases of proteinuria and renal failure suggesting there is a need for more thorough assessment in long-term trials. (7) In practice, statins with the best-documented benefits (simvastatin and pravastatin) should be used first for cardiovascular prevention in patients with hypercholesterolaemia.     

Comparison of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) as inhibitors of cytochrome P450 2C8

Statins are involved in different types of drug interactions. Our objective was to study the effect of statins on cytochrome P450 (CYP) 2C8-mediated paclitaxel 6 alpha-hydroxylation by incubating paclitaxel and statins (0--100 microM) with pooled human liver microsomes. Simvastatin, lovastatin, atorvastatin and fluvastatin were the most potent inhibitors of CYP2C8 activity with K(i) (IC(50)) values of 7.1 (9.6) muM, 8.4 (15) microM, 16 (38) microM and 19 (37) microM, respectively. Cerivastatin, simvastatin acid and lovastatin acid were less potent inhibitors with K(i) (IC(50)) values ranging from 32 to 55 (30--67) microM. Rosuvastatin and pravastatin showed no appreciable effect on CYP2C8 activity even at 100 microM. In conclusion, all the statins tested, except rosuvastatin and pravastatin, had a significant inhibitory effect on the activity of CYP2C8 in vitro. Because many of the statins accumulate in the liver and because also their metabolites may inhibit CYP2C8 activity, in vivo studies are needed to investigate a possible interaction of simvastatin, lovastatin, atorvastatin and fluvastatin with CYP2C8 substrate drugs.     

Effect of rosuvastatin compared with other statins on lipid levels and National Cholesterol Education Program goal attainment for low-density lipoprotein cholesterol in a usual care setting

STUDY OBJECTIVE: To compare, in a usual care setting, the effects of rosuvastatin and other 3-hydroxy-3-methylglutaryl coenzyme A inhibitors (statins) on lipid levels and on goal attainment of low-density lipoprotein cholesterol (LDL) levels from the National Cholesterol Education Program (NCEP) third report of the Adult Treatment Panel (ATP III). DESIGN: Retrospective, longitudinal, cohort study. DATA SOURCE: Managed care medical and pharmacy claims and laboratory database. PATIENTS: A total of 8251 patients starting treatment with rosuvastatin, atorvastatin, simvastatin, pravastatin, lovastatin, or fluvastatin from August 1, 2003-September 30, 2004, excluding those who received dyslipidemic therapy in the previous 12 months. MEASUREMENTS AND MAIN RESULTS: Patients with at least one pretreatment and posttreatment lipid level were followed until their initial statin was changed or they reached the end of benefit eligibility or the study period. Percent changes in lipid levels were calculated, and adjusted changes in LDL and goal attainment were evaluated by regression techniques. Absolute and percent reductions in LDL, triglyceride, and total cholesterol levels were significantly greater with rosuvastatin than with other statins (all p<0.05 except for triglyceride reduction vs atorvastatin). After adjustment for age, sex, and baseline LDL, percent LDL reductions still were significantly greater with rosuvastatin than with other statins (p<0.05). Changes in high-density lipoprotein cholesterol were not significant. Goal attainment was higher with rosuvastatin than with other statins after adjustment for age, sex, baseline LDL, risk status, dose, and duration of therapy (p<0.05). Dose-stratified analysis showed that LDL goal attainment was significantly higher with rosuvastatin 10 mg than with atorvastatin 10 or 20 mg. CONCLUSION: Rosuvastatin was more effective than other statins in reducing LDL, triglyceride (except vs atorvastatin), and total cholesterol levels. Significantly more patients taking rosuvastatin than patients taking other statins attained their LDL goals.     

Interaction potential between clarithromycin and individual statins—A systematic review

The high prevalence of statin and clarithromycin utilization creates potential for overlapping use. The objectives of this MiniReview were to investigate the evidence base for drug‐drug interactions between clarithromycin and currently marketed statins and to present management strategies for these drug combinations. We conducted a systematic literature review following PRISMA guidelines with English language studies retrieved from PubMed and EMBASE (from inception through March 2019). We included 29 articles (16 case reports, 5 observational, 5 clinical pharmacokinetic and 3 in vitro studies). Based on mechanistic/clinical studies involving clarithromycin or the related macrolide erythromycin (both strong inhibitors of CYP3A4 and of hepatic statin uptake transporters OATP1B1 and OATP1B3), clarithromycin is expected to substantially increase systemic exposure to simvastatin and lovastatin (>5‐fold increase in area under the plasma concentration‐time curve (AUC)), moderately increase AUCs of atorvastatin and pitavastatin (2‐ to 4‐fold AUC increase) and slightly increase pravastatin exposure (≈2‐fold AUC increase) while having little effect on fluvastatin or rosuvastatin. The 16 cases of statin‐clarithromycin adverse drug reactions (rhabdomyolysis (n = 14) or less severe clinical myopathy) involved a CYP3A4‐metabolized statin (simvastatin, lovastatin or atorvastatin). In line, a cohort study found concurrent use of clarithromycin and CYP3A4‐metabolized statins to be associated with a doubled risk of hospitalization with rhabdomyolysis or other statin‐related adverse events as compared with azithromycin‐statin co‐administration. If clarithromycin is necessary, we recommend (a) avoiding co‐administration with simvastatin, lovastatin or atorvastatin; (b) withholding or dose‐reducing pitavastatin; (c) continuing pravastatin therapy with caution, limiting pravastatin dose to 40 mg daily; and (d) continuing fluvastatin or rosuvastatin with caution.     

Consideraciones específicas en la prescripción e intercambio terapéutico de estatinas

ObjectiveThe pharmaceutical industry currently offers six different statins in Spain and there is one more soon to be available. Choosing the most appropriate drug and dose is determined by the therapeutic target (reduction in LDL-C levels). Statin doses that decrease LDL-C at the same percentage are considered equivalent. Evaluating the pharmacokinetic characteristics of each statin can be useful when setting selection criteria, helping to determine which statin may be more appropriate for a patient based on their individual characteristics and on the other co-administered drugs.MethodsWe reviewed the pharmacokinetics properties of each statin and its possible involvement in drug interactions.ResultsCYP3A4 was responsible for the metabolism of lovastatin, simvastatin and atorvastatin; fluvastatin depends on CYP2C9; P-glycoprotein is responsible for decreased atorvastatin, pravastatin, simvastatin and lovastatin concentrations. The OATPA1B1 transporter involved in all statins’ access to the hepatocyte, except for fluvastatin, is essential for rosuvastatin and pravastatin. These circumstances cause those drugs inhibiting or inducing isoenzymes or transporters’ activity not to have the same effect on the different statins.ConclusionThe pharmacokinetics is important when choosing the best statin and could be a limitation in the use of interchange therapeutic programmes when other drugs are present.     

Comparison of the efficacies of five different statins on inhibition of human saphenous vein smooth muscle cell proliferation and invasion

Statins (HMG-CoA reductase inhibitors) exhibit beneficial effects on the vasculature independently of their cholesterol-lowering properties. These pleiotropic effects underlie the ability of statins to reduce intimal hyperplasia in saphenous vein (SV) bypass grafts by attenuating smooth muscle cell (SMC) invasion and proliferation. Although all statins can effectively lower cholesterol, the pleiotropic effects of individual statins may well differ. We therefore compared the concentration-dependent effects of 4 lipophilic statins (simvastatin, atorvastatin, fluvastatin, and lovastatin) and 1 hydrophilic statin (pravastatin) on the proliferation and invasion of SMC cultured from SV of 9 different patients undergoing coronary artery bypass grafting (CABG). The lipophilic statins inhibited SV-SMC proliferation over a 4-day period with an order of potency of fluvastatin > atorvastatin > simvastatin > lovastatin (IC50 range = 0.07 to 1.77 microM). Similarly, these statins also inhibited SV-SMC invasion through an artificial basement membrane barrier (fluvastatin > atorvastatin > simvastatin > lovastatin; IC50 range = 0.92 to 26.9 microM). In contrast, the hydrophilic pravastatin had no significant effect on SV-SMC proliferation at concentrations up to 10 microM, nor did it attenuate SV-SMC invasion (up to 30 microM). Our data provide strong evidence that individual statins possess differential pleiotropic effects on SV-SMC function. This may be of clinical relevance in the selection of individual statins for the treatment of CABG patients.