Pharmacodynamic interaction between the new selective cholesterol absorption inhibitor ezetimibe and simvastatin

AIMS: The primary aims of these two single-centre, randomized, evaluator-blind, placebo/positive-controlled, parallel-group studies were to evaluate the potential for pharmacodynamic and pharmacokinetic interaction between ezetimibe 0.25, 1, or 10 mg and simvastatin 10 mg (Study 1), and a pharmacodynamic interaction between ezetimibe 10 mg and simvastatin 20 mg (Study 2). Evaluation of the tolerance of the coadministration of ezetimibe and simvastatin was a secondary objective. METHODS: Eighty-two healthy men with low-density lipoprotein cholesterol (LDL-C) >or=130 mg dl-1 received study drug once daily in the morning for 14 days. In Study 1 (n=58), five groups of 11-12 subjects received simvastatin 10 mg alone, or with ezetimibe 0.25, 1, or 10 mg or placebo. In Study 2 (n=24), three groups of eight subjects received simvastatin 20 mg alone, ezetimibe 10 mg alone, or the combination. Blood samples were collected to measure serum lipids in both studies. Steady-state pharmacokinetics of simvastatin and its beta-hydroxy metabolite were evaluated in Study 1 only. RESULTS: In both studies, reported side-effects were generally mild, nonspecific, and similar among treatment groups. In Study 1, there were no indications of pharmacokinetic interactions between simvastatin and ezetimibe. All active treatments caused statistically significant (P<0.01) decreases in LDL-C concentration vs placebo from baseline to day 14. The coadministration of ezetimibe and simvastatin caused a dose-dependent reduction in LDL-C and total cholesterol, with no apparent effect on high-density lipoprotein cholesterol (HDL-C) or triglycerides. The coadministration of ezetimibe 10 mg and simvastatin 10 mg or 20 mg caused a statistically (P<0.01) greater percentage reduction (mean -17%, 95% CI -27.7, -6.2, and -18%, -28.4, -7.4, respectively) in LDL-C than simvastatin alone. CONCLUSIONS: The coadministration of ezetimibe at doses up to 10 mg with simvastatin 10 or 20 mg daily was well tolerated and caused a significant additive reduction in LDL-C compared with simvastatin alone. Additional clinical studies to assess the efficacy and safety of coadministration of ezetimibe and simvastatin are warranted.     

Effects of simvastatin,an HMG-CoA reductase inhibitor,in patients with hypertriglyceridemia

BACKGROUND: Patients with elevated levels of serum triglycerides (TG) often have other associated lipid abnormalities (e.g., low levels of high-density lipoprotein cholesterol [HDL-C]) and are at increased risk of developing coronary heart disease. Although the therapeutic benefits of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) in hypercholesterolemic patients have been well established, less is known about the effects of statins in patient populations with hypertriglyceridemia. HYPOTHESIS: The purpose of this study was to evaluate the lipoprotein-altering efficacy of simvastatin in hypertriglyceridemic patients. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled study. In all, 195 patients with fasting serum triglyceride levels between 300 and 900 mg/dl received once daily doses of placebo or simvastatin 20, 40, or 80 mg for 6 weeks. RESULTS: Compared with placebo, simvastatin treatment across all doses resulted in significant reductions (p < 0.05 - < 0.001) in serum levels of triglycerides (-20 to -31% decrease) and TG-rich lipoprotein particles. Significant (p < 0.001) reductions were also seen in low-density lipoprotein cholesterol (-25 to -35%) and non-HDL-C (-26 to -40%). Levels of HDL-C were increased (7-11%) in the simvastatin groups compared with placebo (p < 0.05 - < 0.001). CONCLUSION: The results of this study demonstrate the beneficial effects of simvastatin in patients with hypertriglyceridemia.     

血脂康与辛伐他汀治疗原发性高脂血症的对比研究

目的比较中药血脂康、辛伐他汀(舒降之)治疗原发性高脂血症的调脂作用和安全性。方法80例原发性高脂血症患者随机分为血脂康组和舒降之组,各服药8周为1个疗程,治疗期间患者保持治疗前的饮食习惯,不用其他干扰血脂代谢的药物。8周后观察两组调脂效果和不良反应。结果血脂康组:TC降低25.15%,TG降低21.22%,DL-C降低38.08%,TC-HDL-C/HDL-C降低44.03%。舒降之组:TC降低26.02%,TG降低22.62%,LDL-C降低38.50%,TC-HDL-C/HDL-C降低44.22%,两组各项指标治疗后的组内相比,均有统计学意义(P<0.001),两组间各项指标治疗后对应比较均无统计学意义(P>0.05),两组间不良反应轻微,不影响继续治疗,不良反应总发生率血脂康组较低(P<0.05)。结论血脂康和辛伐他汀均有强大的降低TC、TG、LDL-C和TC-HDL-C/HDL-C的作用,均为治疗原发性高脂血症有效和安全的药物,血脂康不良反应更低,提示中药血脂康具有更好的耐受性。     

辛伐他汀对老年冠心病患者血脂及血液流变学的影响

目的研究辛伐他汀对老年冠心病患者血脂及血液流变学的影响。方法观察55例老年冠心病患者服用辛伐他汀治疗前后血脂及血液流变学变化。结果冠心病患者服用辛伐他汀血脂下降、血液流变学指标有明显改善,治疗前后比较有显著性差异(p<0.05)。结论辛伐他汀能降低冠心病血脂水平,改善异常的血液流变学指标。     

辛伐他汀治疗老年高脂血症的疗效和安全性

目的观察辛伐他汀治疗老年高脂血症，特别是高胆固醇血症的疗效和安全性。方法选取58名老年高脂血症患者应用辛伐他汀20mg／d治疗，每3个月检查血脂、血尿常规、肝肾功能、肌酸激酶等生化指标1次．随访至少24个月，观察其调脂疗效和不良反应。结果辛伐他汀能使总胆固醇（TC）平均下降26．30％，低密度脂蛋白胆固醇（LDL—C）平均下降28．63％，甘油三酯（TG）平均下降16．38％，高密度脂蛋白胆固醇（HDL—C）平均上升8．16％；在随访期间，未发现有明显的不良反应出现。结论辛伐他汀有明显降低TC、LDL—C的作用，对TG也有一定降低作用，HDL—C则有一定升高作用；该药长期应用具有良好的安全性。     

辛伐他汀诱导K562细胞凋亡及对细胞内活性氧和Ca2+动态变化的影响

目的研究辛伐他汀诱导人红白血病细胞株K562细胞凋亡及细胞内活性氧与Ca2+水平的变化,以探讨凋亡机制.方法20 μmol·L-1辛伐他汀处理K562细胞,24 h 后光镜观察细胞形态;流式细胞术检测细胞凋亡率、活性氧和细胞内游离Ca2+水平.结果20 μmol·L-1辛伐他汀作用K562细胞 48 h 后出现核固缩、核碎裂和凋亡小体等形态学改变;AnnexinV-FITC/PI检测细胞早期凋亡率,处理组凋亡率高于对照组,随药物作用时间延长逐渐增大,具有时间依赖性.荧光染料2',7'-二氯荧光乙酰乙酸(2',7'-dichloro fluorescein diacetate, DCFH-DA)检测K562细胞内活性氧,不同时间处理组与对照组比较活性氧均升高,峰值时间为 24 h,与对照组比较发生显著改变.荧光染料Fluo-3AM检测K562细胞内游离Ca2+浓度,不同时间细胞内游离Ca2+浓度均升高,峰值时间为 12 h,与对照组比较发生显著变化.结论辛伐他汀诱导K562细胞凋亡的可能机制是通过提高细胞内活性氧及游离Ca2+水平,从而导致细胞凋亡.     

辛伐他汀对大鼠心肌梗死后心室重塑影响的实验研究

目的探讨辛伐他汀对大鼠心肌梗死后心脏功能和心室重塑的影响。方法结扎大鼠冠状动脉前降支建立心肌梗死模型,24 h后存活大鼠随机分成心肌梗死组(M I组)、辛伐他汀20 mg组(20 mg.kg-1.d-1)和40 mg组(40 mg.kg-1.d-1),另单设假手术组(Sham组)。8 wk后测定血液动力学指标,血清血脂水平,心室重量指数,苦味酸天狼猩红染色后观察心脏形态学改变,测定心肌胶原容积分数。结果各组血脂水平无统计学差异;MI组心室重量指数增加,心脏收缩及舒张功能受损,梗死边缘区胶原沉积明显,胶原比例改变。两个辛伐他汀(simvastatin,Sim)组均能减轻心室重量指数,改善心脏功能,减少梗死边缘区胶原沉积。结论辛伐他汀能抑制心肌梗死后心室重塑,其机制可能与抑制心肌梗死后心肌肥大和心肌间质纤维化相关,而与其降脂作用关系不大。     

辛伐他汀与厄贝沙坦单用或联用治疗早期糖尿病肾病的疗效观察

目的比较他汀类药物辛伐他汀、厄贝沙坦联用或单用治疗早期糖尿病肾病(EDN)的疗效。方法99例早期糖尿病肾病(EDN)患者,均伴有不同程度的高脂血症,随机分三组,辛伐他汀组32人给予辛伐他汀20mg/日,厄贝沙坦组33人给予厄贝沙坦应用75mg/日,联合治疗组34人给予辛伐他汀20mg/日同时联合厄贝沙坦应用75mg/日,疗程均为24周,所有病人均予降血糖治疗,比较治疗前后血脂及24h尿微量白蛋白(uMA)及血压的变化。结果治疗24周后,三组血浆总胆固醇(TC)、甘油三酯(TG)和低密度脂蛋白胆固醇(LDL-C)、24h微量白蛋白(24huMA)均降低,但联合用药组降低(76.4±35.3)mg.24h-1比单用辛伐他汀或厄贝沙坦组降低[(35.7±19.3),(52.8±24.1)mg.24h-1]明显(P<0.05),三组血脂和血压均有所改善,联合用药组改善明显。结论联合使用辛伐他汀和厄贝沙坦治疗EDN效果优于单用辛伐他汀或厄贝沙坦。     

辛伐他汀对不稳定型心绞痛患者的C反应蛋白、白细胞介素-6和纤维蛋白原水平的影响

目的观察辛伐他汀对不稳定型心绞痛(UAP)患者血清C反应蛋白(CRP)、白细胞介素-6(IL-6)、纤维蛋白原(FIB)等的影响.方法选择UAP患者60例,随机分为辛伐他汀组和对照组,每组30例.对照组常规给药,辛伐他汀组在此基础上加服辛伐他汀20 mg,每晚1次,疗程8周.结果治疗后辛伐他汀组血清中CRP、IL-6、FIB浓度明显降低,和对照组相比P＜0.05,有显著性差异,并且与降脂作用无关.结论辛伐他汀除降脂作用外,具有抗炎、抗血栓形成作用.     

辛伐他汀对大鼠急性心肌梗死后心肌白细胞介素-6表达的影响

目的:观察辛伐他汀对大鼠急性心肌梗死(AMI)后心肌组织白细胞介素- 6 (IL -6)基因及其蛋白表达的影响。方法:Wistar大鼠随机分 3组:辛伐他汀治疗组(MI- S组)、梗死对照组(MI C组)和假手术组 (Sham组 )。前2组大鼠结扎左冠状动脉前降支(LAD)制成AMI模型,MI S组给辛伐他汀 40mg/kg灌胃治疗,余 2组给予生理盐水灌胃。4周后,RT- PCR法和免疫组织化学法分别检测左心室梗死及非梗死区IL- 6mRNA和蛋白的表达,Westernblot法测定左心室非梗死区心肌IL- 6蛋白表达。结果:大鼠AMI后 4周,MI C和MI S组左心室梗死及非梗死区心肌IL- 6mRNA及蛋白表达均较Sham组明显升高(P<0. 05),MI S组IL- 6mRNA及蛋白表达均较MI C组低 (P<0. 05)。3组血脂差异无统计学意义。结论:辛伐他汀可减少AMI大鼠左心室心肌IL 6mRNA及蛋白表达,此改变不依赖其降脂作用。