辛伐他汀的合成

辛伐他汀是国外最畅销的新药，该药合成采用洛伐他汀为起始原料，用2，4－二甲基吡啶替代文献中1，4－Hyrrolidinoloyridine作为催化剂，并对各步反应筛选了最佳的反应条件和投料比，经水解、上叔丁基二甲基氯硅烷保护、酰化、脱甲硅化得到辛伐他汀，总收率39．8％。     

由辛伐铵盐合成辛伐他汀药物的研究

研究了从辛伐铵盐到辛伐他汀的合成工艺,并阐述了其反应机理,即在甲苯存在的条件下,反应借助乙酸酐的水解消耗水和氨,从而使反应向成环的方向进行。实验结果表明,合成的样品中含辛伐他汀98.8%,洛伐他汀0.21%,其他单杂均小于0.1%,总杂0.43%。且优化的辛伐他汀的合成工艺适合工业化大生产的需求。     

辛伐他汀对肺间质纤维化患者预后影响的研究

目的探讨辛伐他汀对肺纤维化患者预后的影响。方法将120例肺纤维化患者随机均分为治疗组和对照组,对照组用泼尼松治疗,治疗组用泼尼松加辛伐他汀治疗,比较治疗前后的症状改善、肺活量、动脉氧分压、二氧化碳分压及影像学变化。结果治疗组总有效率79.17%,对照组总有效率68.33%,治疗组优于对照组(P<0.05)。2组患者的VC都提高(P<0.05),组间比较提高的幅度无显著性差异(P>0.05);2组的PO2都提高(P<0.05),组间比较治疗组提高幅度大于对照组(P>0.05);2组的PCO2都升高(P<0.05),但组间比较降低的幅度无显著性差异(P>0.05)。2组影像学改变无统计学差异(P>0.05)。     

辛伐他汀合成进展

介绍了降血脂新药辛伐他汀的各种合成方法，并评价了其优缺点。     

辛伐他汀治疗高血脂症的疗效观察

目的观察辛伐他汀的降血脂作用。方法高脂血症患者118例,用辛伐他汀20mg每晚1次,连服4周和8周后各复查血脂1次,进行疗效分析。结果4周后,血清胆固醇(TC)、三酰甘油(TG)、低密度脂蛋白胆固醇(LDL-C)等水平均有下降,其中以TC降低最为明显。结论辛伐他汀降血脂疗效确切。     

辛伐他汀临床治疗高脂血症效果观察

目的了解辛伐他汀用于临床治疗高脂血症的效果。方法选择高脂血症患者25例,服用辛伐他汀10～20mg,每日1次,晚间顿服,疗程8周。观察用药前后血浆总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白固醇(LDL—C)的水平变化。结果对TC的有效率达91.5%,对TG、HDL-C和LDL-C的有效率分别为76.2%、72.2%和82.5%;治疗前后血脂水平变化有统计学意义。结论辛伐他汀可作为治疗高血脂的一种有效、安全的理想药物。     

辛伐他汀调脂作用临床观察

目的观察辛伐他汀对高脂血症患者降脂治疗有效性和安全性。方法对60例高脂血症患者予晚间服辛伐他汀,剂量20mg,共8周,观察用药前后血浆总胆固醇、甘油三酯、高密度脂蛋白胆固醇、低密度脂蛋白胆固醇、谷丙转氨酶水平变化。结果治疗4周和8周后TG、TC、LDL-C均较前明显下降(P<0.01),HDL-C明显提高(P>0.05),治疗前后ALT无明显变化,整个治疗过程的严重不良反应有:2例出现轻微的ATL升高,占6.7%,停药后1周复查恢复正常。治疗前后尿素氮、肌酐及CPK无显著变化。不良反应轻,未出现肝功能、肾功能改变或加重的情况,能持续用药。结论辛伐他汀对高脂血症患者降脂治疗是有效和安全的。     

辛伐他汀的抗纤维化研究进展

辛伐他汀(Simvastatin)是胆固醇调节药物,通过抑制3-羟基-3-甲基戊二酰辅酶A(HMG-CoA)还原酶作用于甲羟戊酸途径,被证明可以通过减少致命的冠状动脉事件来提高临床试验的存活率。随着国内外对此研究的不断深入和完善,发现辛伐他汀除了降脂作用外,还具有抗纤维化、控制炎症、降低氧化应激、抗血栓、抗肿瘤等作用。本文就辛伐他汀在抗纤维化方面的机制进行综述。     

辛伐他汀片处方工艺探究

目的：以不同处方及工艺考察辛伐他汀片的稳定性。方法：根据原辅料相容性试验结果,采用正交设计实验,以休止角、溶出度及有关物质综合评分筛选出最合理处方及制备工艺。结果：本法可解决辛伐他汀易氧化及质量不稳定的问题,结论：辛伐他汀片处方合理,工艺可行,符合片剂的质量要求。     

辛伐他汀的合成工艺改进

本文对辛伐他汀合成路线进行了改进,以洛伐他汀为起始原料合成辛伐他汀。在羟基保护工序以二氯甲烷替代DMF为溶剂与叔丁基二甲基氯硅烷反应进行羟基保护,在甲基化工序以溴甲烷替代碘甲烷进行甲基化反应,甲基化产物经脱保护、脱丁胺、成铵盐、环化得到辛伐他汀。改进后的工艺不产生难处理的含DMF废水,对环境友好且成本更低廉。     

高效液相色谱法测定辛伐他汀中的抗氧化剂叔丁基羟基茴香醚

建立了测定辛伐他汀中抗氧化剂叔丁基羟基茴香醚(BHA)含量的高效液相色谱方法.采用C18色谱柱(Supelcosil C18, 4.6 mm i.d.×33 mm,3 μm);流动相A为乙腈,流动相B为0.1 %磷酸水溶液;洗脱梯度为0～3 min 65 % B,3～3.5 min 65 %～45 % B,3.5～8.5 min 45 %～10 % B,8.5～9.5 min 10 % B,9.5～10 min 10 %～65 % B,10～11.9 min 65 % B,12 min stop.检测波长为292 nm,流速为3.0 mL·min-1,柱温为35 ℃.结果BHA与辛伐他汀及各杂质分离良好,BHA在0.1～0.9 μg·mL-1范围内峰面积与浓度呈良好的线性关系(r=0.9998),最低检出量为0.4 ng,回收率为99.3 %,相对标准偏差为1.0 %.该方法简便、快速、准确,可用于辛伐他汀中微量BHA的含量测定.     

Simvastatin Downregulates Cofilin and Stathmin to Inhibit Skeletal Muscle Cells Migration

Statins are the most effective therapeutic agents for reducing cholesterol synthesis. Given their widespread use, many adverse effects from statins have been reported; of these, musculoskeletal complications occurred in 15% of patients after receiving statins for 6 months, and simvastatin was the most commonly administered statin among these cases. This study investigated the negative effects of simvastatin on skeletal muscle cells. We performed RNA sequencing analysis to determine gene expression in simvastatin-treated cells. Cell proliferation and migration were examined through cell cycle analysis and the transwell filter migration assay, respectively. Cytoskeleton rearrangement was examined through F-actin and tubulin staining. Western blot analysis was performed to determine the expression of cell cycle-regulated and cytoskeleton-related proteins. Transfection of small interfering RNAs (siRNAs) was performed to validate the role of cofilin and stathmin in the simvastatin-mediated inhibition of cell migration. The results revealed that simvastatin inhibited the proliferation and migration of skeletal muscle cells and affected the rearrangement of F-actin and tubulin. Simvastatin reduced the expression of cofilin and stathmin. The knockdown of both cofilin and stathmin by specific siRNA synergistically impaired cell migration. In conclusion, our results indicated that simvastatin inhibited skeletal muscle cell migration by reducing the expressions of cofilin and stathmin.     

洛伐他汀提取工艺研究

通过实验研究确定了从洛伐他汀发酵液中提取洛伐他汀的最佳工艺条件。实验表明乙醇作为溶剂时,其最佳工艺条件:浸提温度45℃,物料比5∶1(乙醇/mL∶菌丝/g),浸提时间4h,闭环温度80℃,闭环时间5h。本工艺简便、收率高,适用于工业化生产。     

复方烟酸辛伐他汀缓释片的制备及体外释放度研究

目的：制备复方烟酸辛伐他汀缓释片并考查其体外释放度。方法：采用亲水凝胶骨架材料（HPMC）制备复方烟酸辛伐他汀缓释片;采用紫外分光光度法,以去离子纯化水900mL为溶剂,篮法测定本品释放度,并与参比制剂进行比较。结果：释放曲线经相似因子（f2）判断,与参比制剂相似。结论：本品处方工艺稳定,重现性好,体外累积释放度符合要求。     

A Case Study of Single‐Pill Combination Therapy: The Ezetimibe/Simvastatin Combination for Treatment of Hyperlipidemia

In recent years, combination therapy has received growing popularity as a powerful therapeutic tactic for the treatment of diseases. The justifications and benefits of combination therapy are far‐reaching, including but not limited to addressing unmet medical needs such as cancer, malaria, and HIV/AIDS, improved clinical efficacy and safety with reduced dosage of a single medication, understanding the underlying science of the disease, alleviating pharmaco‐economic impacts, and better drug life‐cycle management. Using the ezetimibe/simvastatin combination therapy as a case study, a comprehensive overview of the successful discovery and development of the single‐pill combination, Vytorin, is presented in this review. A cursory introduction to combination therapy and the rationale for the ezetimibe/simvastatin combination for the treatment of hyperlipidemia provides an instructive entry point. The discovery and mode of action of simvastatin and ezetimibe monotherapies set the scene for a detailed discussion on the discovery and development of Vytorin, with emphasis on bioequivalency studies, clinical efficacy and safety profile studies, and the economic consequences of the single‐pill combination therapy. Large‐scale outcome clinical trials are also discussed to demonstrate the long‐term effects of Vytorin.     

Bone-Targeting Nanoparticles of a Dendritic (Aspartic acid)3-Functionalized PEG-PLGA Biopolymer Encapsulating Simvastatin for the Treatment of Osteoporosis in Rat Models

Simvastatin (SIM) is a lipid-lowering drug that also promotes bone formation, but its high liver specificity may cause muscle damage, and the low solubility of lipophilic drugs limits the systemic administration of SIM, especially in osteoporosis (OP) studies. In this study, we utilized the bone-targeting moiety of dendritic oligopeptides consisting of three aspartic acid moieties (_dAsp₃) and amphiphilic polymers (poly(ethylene glycol)-block-poly(lactic-co-glycolic acid); PEG-PLGA) to create _dAsp₃-PEG-PLGA (APP) nanoparticles (NPs), which can carry SIM to treat OP. An in vivo imaging system showed that gold nanocluster (GNC)-PLGA/APP NPs had a significantly higher accumulation rate in representative bone tissues. In vivo experiments comparing low-dose SIM treatment (0.25 mg/kg per time, 2 times per week) showed that bone-targeting SIM/APP NPs could increase the bone formation effect compared with non-bone-targeting SIM/PP NPs in a local bone loss of hindlimb suspension (disuse) model, but did not demonstrate good bone formation in a postmenopausal (ovariectomized) model of systemic bone loss. The APP NPs could effectively target high mineral levels in bone tissue and were expected to reduce side effects in other organs affected by SIM. However, in vivo OP model testing showed that the same lower dose could not be used to treat different types of OP.     

Co-Administration of Simvastatin Does Not Potentiate the Benefit of Gene Therapy in the mdx Mouse Model for Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is the most common and cureless muscle pediatric genetic disease, which is caused by the lack or the drastically reduced expression of dystrophin. Experimental therapeutic approaches for DMD have been mainly focused in recent years on attempts to restore the expression of dystrophin. While significant progress was achieved, the therapeutic benefit of treated patients is still unsatisfactory. Efficiency in gene therapy for DMD is hampered not only by incompletely resolved technical issues, but likely also due to the progressive nature of DMD. It is indeed suspected that some of the secondary pathologies, which are evolving over time in DMD patients, are not fully corrected by the restoration of dystrophin expression. We recently identified perturbations of the mevalonate pathway and of cholesterol metabolism in DMD patients. Taking advantage of the mdx model for DMD, we then demonstrated that some of these perturbations are improved by treatment with the cholesterol-lowering drug, simvastatin. In the present investigation, we tested whether the combination of the restoration of dystrophin expression with simvastatin treatment could have an additive beneficial effect in the mdx model. We confirmed the positive effects of microdystrophin, and of simvastatin, when administrated separately, but detected no additive effect by their combination. Thus, the present study does not support an additive beneficial effect by combining dystrophin restoration with a metabolic normalization by simvastatin.     

Effects of Simvastatin on Lipid Metabolism in Wild-Type Mice and Mice with Muscle PGC-1α Overexpression

Previous studies suggest that statins may disturb skeletal muscle lipid metabolism potentially causing lipotoxicity with insulin resistance. We investigated this possibility in wild-type mice (WT) and mice with skeletal muscle PGC-1α overexpression (PGC-1α OE mice). In WT mice, simvastatin had only minor effects on skeletal muscle lipid metabolism but reduced glucose uptake, indicating impaired insulin sensitivity. Muscle PGC-1α overexpression caused lipid droplet accumulation in skeletal muscle with increased expression of the fatty acid transporter CD36, fatty acid binding protein 4, perilipin 5 and CPT1b but without significant impairment of muscle glucose uptake. Simvastatin further increased the lipid droplet accumulation in PGC-1α OE mice and stimulated muscle glucose uptake. In conclusion, the impaired muscle glucose uptake in WT mice treated with simvastatin cannot be explained by lipotoxicity. PGC-1α OE mice are protected from lipotoxicity of fatty acids and triglycerides by increased the expression of FABP4, formation of lipid droplets and increased expression of CPT1b.