应用HMG-CoA还原酶抑制剂筛选虾青素高产突变株

研究了HMG-CoA还原酶抑制剂辛伐他汀对法夫酵母生长及其虾青素合成的影响,实验结果表明,当辛伐他汀浓度在4·78×10-6mol/L时对酵母细胞的生长的抑制表现不明显,但对虾青素合成具有显著的抑制作用。以此浓度作为筛选浓度,经亚硝基胍(NTG)诱变后,通过辛伐他汀平板初筛与摇瓶复筛,获得较高虾青素产率的突变株。实验结果表明,菌体生物量、类胡萝卜总量和虾青素产量都有明显的提高,其中NPX-3_05突变株类胡萝卜总量与虾青素产量分别达到3·823、2·755mg/L,比出发菌株依次提高了163%、143%(1·453mg/L、1·134mg/L)。菌株NPX-3_05经连续发酵5次的稳定性实验表明其性状稳定。目标产物经HPLC定性分析,确定为反式虾青素。因此,以辛伐他汀等HMG-CoA还原酶抑制剂作为选择压力,对虾青素高产突变株的筛选上具有较好的“筛分”能力。     

LC-MS/MS法测定人血浆中辛伐他汀浓度

为了建立高效液相色谱-质谱联用法测定人血浆中辛伐他汀浓度的方法,选用Ultimate XB-C₁₈柱（2.1 m×100 mm,3 μm）,以V（甲醇）：V（乙腈）∶V（2.5 mmol/L乙酸铵）=45∶50∶5的溶液为流动相,样品用沉淀蛋白法处理后进样,流速为0.3 mL/min。选用Finnigan TSQ Quantum Access液质联用（LC-MS/MS）分析仪的选择反应监测（SRM）扫描方式进行监测,选择电喷雾离子源ESI,正离子方式。辛伐他汀的线性范围为0.1～20 μg/L,定量下线为0.1 μg/L。准确度与精密度结果显示,方法日间、日内相对标准偏差（RSD）小于15%,方法提取回收率为71.96%～78.44%。稳定性试验中,血浆中辛伐他汀在各种储存条件下均较稳定。试验表明,该方法快速、灵敏,专属性强、重现性好,可用于人血浆中辛伐他汀浓度的测定和药代动力学研究。     

Design and in vitro evaluation of polymeric formulae of simvastatin for local bone induction

Simvastatin (SVS), a cholesterol-lowering drug, has been shown to stimulate bone formation. This study deals with the design and in vitro evaluation of local delivery systems for simvastatin. They are intended to treat bony defects resulting from periodontitis or to induce osteogenesis around the titanium implants. Granules and gels were formulated using bioerodible/biocompatible polymers, namely hydroxypropylmethyl cellulose (H), sodium carboxymethyl cellulose (C), and chitosan (Ch). The in vitro release profiles and kinetics were evaluated and the swelling and/or erosion was monitored. Differential scanning calorimetry (DSC) and infrared (IR) were used to detect any SVS/polymer interactions that may affect drug release. The results revealed variable extents of controlled drug release from the designed formulae depending on the polymer nature. About 50% cumulative SVS was released from both H granules and gel formulae within 24 h and ∼66% and ∼88% from C granules and gel, respectively. Ch formulae exhibited ∼50% release from granules and ∼30% from gel.     

Oral solid compritol 888 ATO nanosuspension of simvastatin: optimization and biodistribution studies

The purpose of the present investigation was to develop solid lipid nanoparticles (SLNs) of simvastatin in order to enhance its oral bioavailability by minimizing its first-pass metabolism. To achieve our goal, SLNs were prepared by solvent injection technique and optimized by 2³ full factorial experimental design using Design Expert software. The SLN formulations were optimized for amount of compritol, concentration of poloxamer, and volume of acetone in order to achieve desired responses of particle size, entrapment efficiency (EE), and cumulative drug release (CDR). Response surface plots were constructed to study the influence of each variable on each response and the interactions between any two variables were also analyzed. Formulation F₁₀ with particle size of 271.18?nm, % EE of 68.16% and % CDR of 76.23%, and highest desirability value of 0.645 was selected as optimized formulation. The optimized formulation was evaluated for biodistribution and pharmacokinetics by technetium-99m (Tc-99m) radiolabeling technique in mice. The relative bioavailability of simvastatin from optimized SLNs was found to be 220%, substantiating the protective action of SLNs against liver metabolism. However, though the drug initially bypassed the liver metabolism, simvastatin continuously entered in liver to exert its therapeutic action that was evidenced by biodistribution study.     

Preparation,characterization, stability and in vitro-in vivo evaluation of pellet-layered Simvastatin nanosuspensions

The objective of the present study was to develop stable pellets-layered Simvastatin (SIM) nanosuspensions with improved dissolution and bioavailability. The nanosuspensions were prepared with 7% HPMC, antioxidant 0.03% butylated hydroxyanisole and 0.2% citric acid (m/v) by low temperature grinding. After that, SDS with SIM was in a ratio of 1:5 (m/m), was evenly dispersed in the nanosuspensions. Then, they were layered on the surface of sugar pellets. The mean particle size of the SIM nanosuspensions was 0.74 µm, and 80.6% of the particles was below 1 µm in size. The pellets could re-disperse into nanoparticle status in the dissolution medium. In 900?mL pH 7.0 phosphate solutions, the dissolution of the layered pellets was better than that of commercial tablets. Also, nearly 100% of the drug dissolved from the pellets within 5?min under sink conditions. During the stability studies, SIM pellets exhibited good physical and chemical stability. The relative bioavailability of SIM and Simvastatin β-hydroxy acid (SIMA) for nanosuspensions layered pellets compared with commercial tablets was 117% and 173%, respectively. The bioavailability of SIMA was improved significantly (p < 0.05), confirming the improvement of bioavailability. Thus, the present study demonstrates that the pellet-layered SIM nanosuspensions improved both the dissolution and bioavailability of SIM.     

辛伐他汀和罗格列酮对糖尿病患者动脉粥样硬化的影响

目的研究辛伐他汀和罗格列酮对2型糖尿病患者动脉粥样硬化的作用。方法 78例2型糖尿病伴颈动脉粥样斑块患者随机分为辛伐他汀组、罗格列酮组和联合组,分别口服辛伐他汀20mg/次、罗格列酮4mg/次及辛伐他汀20mg+罗格列酮4mg/次,每日1次,疗程3个月。在基线水平和疗程结束时经颈动脉超声检测CIMT,同时检测患者脂肪因子和炎症因子水平。观察治疗前后颈动脉内膜中层厚度及斑块变化。结果各组用药治疗3月后血脂、脂肪因子和炎性因子降低,CIMT厚度减低、斑块面积缩小,但斑块数量无减少,且联合用药比单一用药效果更显著。结论 2型糖尿病患者联合使用辛伐他汀和罗格列酮可改善胰岛素抵抗、改善脂类代谢、抑制大血管炎症反应、稳定和缩小动脉粥样斑块。     

<Emphasis Type="SmallCaps">l</Emphasis>-Carnitine/Simvastatin Reduces Lipoprotein (a) Levels Compared with Simvastatin Monotherapy: A Randomized Double-Blind Placebo-Controlled Study

Lipoprotein (a) [Lp(a)] is an independent risk factor for cardiovascular disease. There are currently limited therapeutic options to lower Lp(a) levels. l ‐Carnitine has been reported to reduce Lp(a) levels. The aim of this study was to compare the effect of l ‐carnitine/simvastatin co‐administration with that of simvastatin monotherapy on Lp(a) levels in subjects with mixed hyperlipidemia and elevated Lp(a) concentration. Subjects with levels of low‐density lipoprotein cholesterol (LDL‐C) >160 mg/dL, triacylglycerol (TAG) >150 mg/dL and Lp(a) >20 mg/dL were included in this study. Subjects were randomly allocated to receive l ‐carnitine 2 g/day plus simvastatin 20 mg/day (N = 29) or placebo plus simvastatin 20 mg/day (N = 29) for a total of 12 weeks. Lp(a) was significantly reduced in the l ‐carnitine/simvastatin group [?19.4%, from 52 (20–171) to 42 (15–102) mg/dL; p = 0.01], but not in the placebo/simvastatin group [?6.7%, from 56 (26–108) to 52 (27–93) mg/dL, p = NS versus baseline and p = 0.016 for the comparison between groups]. Similar significant reductions in total cholesterol, LDL‐C, apolipoprotein (apo) B and TAG were observed in both groups. Co‐administration of l ‐carnitine with simvastatin was associated with a significant, albeit modest, reduction in Lp(a) compared with simvastatin monotherapy in subjects with mixed hyperlipidemia and elevated baseline Lp(a) levels.     

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。     

天然维生素E对辛伐他汀体内代谢的影响

目的 阐明天然维生素E 对降脂药辛伐他汀代谢的影响。 方法 12 名男性健康志愿者, 随机分两组, 采用两阶段双周期交叉设计。一组口服天然维生素E 600 mg d, 另一组空白对照。连续14 d, 在第15 天两组均同时口服辛伐他汀40 mg 。在0 、0.25 、0.5 、0.75、1 、1.5、2、2.5、3 、4 、6 、8 、12 、24 h 采5 mL 外周静脉血, 洗脱4 周交叉进行下阶段试验。采血后0.5 h 内进行离心和分离血浆, 运用HPLC-MS-MS 分别测定血浆中辛伐他汀总药物浓度、辛伐他汀酸药物浓度, 分析比较不同处理组间药代动力学参数的差异。 结果 天然维生素E 服用组辛伐他汀、辛伐他汀酸血浆药物浓度显著降低。天然维生素E 服用组与空白对照组之间辛伐他汀曲线下面积AUC_(0~24h) 和峰浓度Cmax 之间的差异有统计学意义(P <0.05) 。天然维生素E 服用组与空白对照组辛伐他汀酸曲线下面积AUC_(0~24h) 和峰浓度C_max 之间的差异也有统计学意义(P <0.05) 。 结论 天然维生素E明显加快了辛伐他汀的清除速度, 辛伐他汀与天然维生素E 同时服用有可能产生药物相互作用,降低其降脂效果, 导致不良反应。     

Design and In Vitro Evaluation of Polymeric Formulae of Simvastatin for Local Bone Induction

ABSTRACT

Simvastatin (SVS), a cholesterol-lowering drug, has been shown to stimulate bone formation. This study deals with the design and in vitro evaluation of local delivery systems for simvastatin. They are intended to treat bony defects resulting from periodontitis or to induce osteogenesis around the titanium implants. Granules and gels were formulated using bioerodible/biocompatible polymers, namely hydroxypropylmethyl cellulose (H), sodium carboxymethyl cellulose (C), and chitosan (Ch). The in vitro release profiles and kinetics were evaluated and the swelling and/or erosion was monitored. Differential scanning calorimetry (DSC) and infrared (IR) were used to detect any SVS/polymer interactions that may affect drug release. The results revealed variable extents of controlled drug release from the designed formulae depending on the polymer nature. About 50% cumulative SVS was released from both H granules and gel formulae within 24 h and ～66% and ～88% from C granules and gel, respectively. Ch formulae exhibited ～50% release from granules and ～30% from gel.