Lomitapide for the treatment of hypercholesterolemia

Introduction: Homozygous familial hypercholesterolemia (HoFH) is a serious rare inherited condition that leads to extremely elevated levels of low density lipoprotein cholesterol (LDL-C), and predisposes affected individuals to high risk of atherosclerotic vascular disease. Traditional therapies are largely ineffective in managing the hypercholesterolemia in these patients; diet and regular LDL-apheresis are the mainstays of management. Lomitapide is an inhibitor of microsomal triglyceride transfer protein (MTP) that blocks the assembly of metabolic precursors of LDL particles. Lomitapide has been approved for use in the HoFH population.

Areas covered: This article explores the basic properties of lomitapide, including its pharmacodynamic, pharmacokinetic and metabolic profiles. It also reports the current market status of lomitapide and its close competitors. Trials of lomitapide are also briefly reviewed as well as the safety and tolerability of the drug.

Expert opinion: Lomitapide has been recently approved for use in HoFH, a population that has been traditionally very difficult to effectively manage. While lomitapide has some safety concerns, including gastrointestinal symptoms and potential hepatotoxicity, and has yet to prove long term efficacy on hard cardiovascular endpoints, it does represent an attractive treatment option for a small group of patients who, until now, had very limited available effective therapies.     

同种种苗异地栽培丹参质量比较研究

目的 对同种丹参种苗在不同地区栽培的丹参质量进行分析评价.方法 根据2015年版药典方法,采用高效液相色谱法(HPLC),对同种种苗异地栽培丹参的根、须根及地上部分茎、叶、花、花托6个部位的丹酚酸B、丹参酮类(丹参酮ⅡA、隐丹参酮、丹参酮I)进行含量测定.结果 同种种苗的含山栽培丹参中两类成分含量均略高于太和栽培丹参,丹参酮类在不同部位分布的含量为根>须根>花托>茎>叶>花,丹酚酸B则为根>须根>花>茎>花托>叶,丹参不同部位含量有较大差异,其中根和须根的含量均高于药典标准.结论 异地栽培的丹参脂溶性成分差异有统计学意义,含山产栽培丹参优于太和产;异地栽培的丹参水溶性成分丹参含量无差异;该实验为指导优质产区种苗的扩大种植提供参考依据.     

4种丹参酮类化合物对U266细胞增殖的抑制作用及机制

目的 研究丹参酮ⅡA(TAⅡA)、丹参酮Ⅰ(TAⅠ)、隐丹参酮(CTA)及二氢丹参酮Ⅰ(DIA Ⅰ)对U266细胞的增殖抑制作用及其可能的机制.方法 采用CCK法检测4种丹参酮类化合物对U266细胞的增殖抑制率,用Annexin-V-FITC/PI检测细胞的凋亡,用PI法检测细胞周期;收集多发性骨髓瘤患者的骨髓标本,分离培养间充质干细胞(MSCs),用流式细胞仪检测4种丹参酮类化合物对MSCs分泌白介素6(IL-6)的影响.结果 4种丹参酮类化合物对U266细胞的增殖均有抑制作用;DIA Ⅰ较其余3种化合物的作用更强,引起细胞早期凋亡较多,细胞周期被阻滞在S期;DIAⅠ能明显抑制IL-6的分泌,其余3种化合物对IL-6的分泌作用无统计学意义.结论 DIA Ⅰ能明显抑制多发性骨髓细胞株U266的增殖,其抑制作用可能是通过抑制MSCs分泌IL-6而实现的.     

Insight into the pharmacokinetic behavior of tanshinone IIA in the treatment of Crohn’s disease: comparative data for tanshinone IIA and its two glucuronidated metabolites in normal and recurrent colitis models after oral administration

1.?Previous reports implied that tanshinone IIA (TSA) may offer potential benefits for Crohn’s disease (CD). However, the detailed pharmacokinetic behavior of TSA in the treatment of colitis remain unclear. Herein, a recurrent trinitrobenzene sulfonic acid (TNBS)-colitis mouse model was used to investigate whether TSA possesses favorable pharmacokinetic and colonic distribution profiles to serve as a candidate drug.

2.?Although the systemic TSA exposures were low (AUC_0–t approximately 330?ng*h/ml) in both the normal and colitis models after oral administration TSA 20?mg/kg, high levels of TSA were found in the gastrointestinal tract (GI). Such a GI exposure of TSA in colitis mice is adequate to exert anti-inflammatory effects as observed in various in vitro studies.

3.?Interestingly, colonic TSA exposure in the colitis mouse model was much lower than that in the normal mice, which may be explained by a significant upregulation of colonic UDP-glucuronosyltransferase (Ugt)1a9 expression and a higher plasma concentration of TSA glucuronides in the model mice at 0.5, 1 and 2?h after TSA administration.

4.?Together, these results reveal high accumulation at the site of inflammation and minimal systemic concentration of TSA, which are favorable pharmacokinetic behaviors to meet the requirements for CD treatment.     

Effects of tanshinone VI on phosphorylation of ERK and Akt in isolated cardiomyocytes and cardiac fibroblasts

Effects of tanshinone VI, a diterpene from Tan-Shen, on humoral factor-induced phosphorylation of ERK and Akt during hypertrophy of cardiomyocytes and fibrosis of cardiac fibroblasts isolated from neonatal rats were examined. Treatment of cultured cardiomyocytes with 10 nM insulin-like growth factor-1 (IGF-1) or 10 nM endothelin-1 resulted in an increase in leucine incorporation into acid-insoluble fraction. Treatment of cultured cardiac fibroblasts with 10 nM IGF-1 or 10 nM angiotensin II increased incorporation of proline. IGF-1 increased phosphorylated extracellular signal-regulated kinase (pERK) and protein kinase B (pAkt) of cardiomyocytes, whereas endothelin-1 increased pERK, but not pAkt. Treatment of cardiac fibroblasts with 10 nM IGF-1 or 10 nM angiotensin II also increased pERK, whereas pAkt was increased by treatment with IGF-1 alone. When the cardiomyocytes were incubated in the presence of 10 μM tanshinone VI, IGF-1- and endothelin-1-induced increases in pERK, but not pAkt, were partially attenuated. Treatment of cardiac fibroblasts with 10 μM tanshinone VI also attenuated IGF-1-induced increases in pERK and pAkt. Tanshinone VI also partially attenuated angiotensin II-induced increase in proline incorporation into cardiac fibroblasts. PD98059, an inhibitor for phosphorylation of extracellular signal-regulated kinase (ERK), but not wortmannin, that for protein kinase B phosphorylation, attenuated an increase in leucine incorporation into cardiomyocytes in the presence of either IGF-1 or endothelin-1. These results suggest that tanshinone VI is a possible agent that can attenuate the humoral factor-induced hypertrophy of cardiomyocytes and fibrosis of cardiac fibroblasts via an attenuation of ERK phosphorylation in these cells.     

艾拉光动力疗法联合丹参酮胶囊治疗中度痤疮的疗效观察

目的 探讨5-氨基酮戊酸凝胶(商品名:艾拉)-光动力疗法(ALA-PDT)联合丹参酮胶囊治疗中度痤疮的有效性与安全性.方法 选择2015年6月至2017年1月期间惠州市皮肤病防治研究所皮肤科收治的中度痤疮患者133例,并随机分为3组,对照A组41例给予丹参酮胶囊治疗,对照B组46例给予5-氨基酮戊酸光动力疗法(ALA-PDT)治疗,观察组46例给予5-氨基酮戊酸光动力疗法(ALA-PDT)联合丹参酮胶囊治疗.比较3组的临床效果.结果 治疗4周后,观察组总有效率为 84.78％,显著高于对照A组的36.59％及对照B组的56.52％(x2=21.389 4、8.859 3,P＜0.05),对照B组总有效率56,52％明显高于对照A组的36.59％(x2=3.457 9,P＜0.05).结论 艾拉光动力疗法联合丹参酮胶囊治疗中度痤疮具有较好的疗效,损伤小,恢复时间短,安全性高,为基层医院提供了一种安全、有效、理想的治疗方法,值得临床推广.     

葛根素注射液联合丹参酮ⅡA磺酸钠治疗慢性充血性心力衰竭患者的疗效及对血浆血浆肾素活性和醛固酮的影响

目的:探讨葛根素注射液联合丹参酮ⅡA磺酸钠治疗慢性充血性心力衰竭(CHF)患者的疗效及对血浆肾素活性(PRA)和醛固酮(ALD)的影响。方法:选取2015年2月至2017年9月六安市中医院收治的CHF患者90例作为研究对象,按照随机数字表法分为对照组和观察组,每组45例。对照组患者接受西医联合丹参酮ⅡA磺酸钠治疗,观察组患者在对照组基础上加入葛根素注射液治疗,均持续30 d。比较2组治疗后近期疗效、心功能及血浆PRA、醛固酮水平的差异。结果:治疗后,观察组患者治疗有效率高于对照组患者;心功能指标心排出量(CO)、左室射血分数(LVEF)高于对照组患者,左室舒张末期内径(LVEDD)、左室收缩末期内径(LVESD)低于对照组患者;血浆PRA、醛固酮低于对照组患者,差异均有统计学意义(P 0. 05)。结论:在西医以及丹参酮ⅡA磺酸钠治疗同时加入葛根素注射液联合治疗CHF患者,可进一步提升患者的近期疗效,改善心功能和机体神经内分泌状态。     

丹参酮类化合物诱导白血病干细胞凋亡的体外研究

目的 探讨丹参酮类化合物对白血病干细胞(LSCs)的促凋亡作用.方法 将二氢丹参酮Ⅰ、丹参酮Ⅰ、隐丹参酮与丹参酮ⅡA等4种丹参酮类化合物分别作用于白血病NB4细胞,以CD34+、CD38-、CD123+为标记确定NB4细胞中的LSCs,采用Annexin V/PI双标记法检测LSCs的凋亡率.结果 在20 μmol·L-二氢丹参酮Ⅰ和丹参酮Ⅰ条件下作用24h后,可显著诱导LSCs凋亡,而隐丹参酮和丹参酮ⅡA不能诱导LSCs凋亡.结论 丹参酮类化合物诱导NB4中LSCs的凋亡能力与其结构有关,与课题组前期报道的其对NB4细胞的增殖抑制作用基本一致.     

HPLC测定心元胶囊中大黄素与丹参Ⅱ_A的含量

目的 :用 HPL C法测定心元胶囊中大黄素与丹参酮 A 的含量。方法 :样品的甲醇提取物经酸水解用乙醚提取后 ,以 ODS柱分析 ,大黄素的测定 ,流动相为甲醇 -水 -磷酸 (80∶ 2 0∶ 0 .0 5 ) ,检测波长为 2 86 nm;丹参酮 A的测定 ,流动相为甲醇 -水 (80∶ 2 0 ) ,检测波长为 2 6 8nm。结果 :大黄素的线性范围为 0 .0 2 13～ 0 .2 13μg(r=0 .9999) ,样品加样回收率为 99.85 % ,RSD为 1.95 % (n=6 ) ;丹参酮 A 的线性范围为 0 .0 12～ 0 .0 5 9μg(r=0 .9993) ,样品加样回收率为 97.3% ,RSD为 1.3% (n=6 )。结论 :该法可供该制剂含量测定