A safety evaluation of evolocumab

Introduction: Evolocumab is an injectable, fully human monoclonal antibody and a member of the newest class of low density lipoprotein cholesterol (LDL-C) lowering agents called proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. The PCSK9 inhibitors are the most significant advance in lipid therapy since the introduction of the first statin 30 years ago.

Areas covered: The PCSK9 monoclonal antibodies have demonstrated a consistently high LDL-C lowering efficacy with and without statins and/or other lipid lowering therapies (LLT). LDL-C levels achieved with these agents are lower than has ever been possible before. This review will focus on the overall safety of evolocumab including cognitive impairment, very low LDL-C levels, new onset diabetes and glucose abnormalities, effect on vitamin E and steroid hormones, liver and muscle abnormalities, and immunogenicity and injection site reactions. The phase II and III clinical trials had relatively low patient-years of exposure, but the open label extension studies and the recently published outcomes trial, FOURIER, will be the focus of this paper. The safety profile of evolocumab to date is remarkable and extremely encouraging as will be demonstrated.

Expert opinion: The PCSK9 inhibitors will be responsible for a new era in lipid therapy that will expand our knowledge of lipid levels and cardiovascular disease (CVD) prevention with an efficacy and safety profile not previously available in clinical practice.     

不同剂量米力农对新生儿肺动脉高压的疗效及肝肾功能的影响

目的 探讨不同剂量米力农对新生儿肺动脉高压（PPHN）的疗效及肝肾功能的影响。方法 将2013年5月—2017年6月收治的96例肺动脉高压新生儿均分为A、B、C 3组,在常规治疗的基础上应用米力农注射液治疗,3组维持剂量分别为0.25、0.50、0.75 μg/(kg·min)。比较3组的血气指标、疗效和肝肾功能指标。结果 3组治疗后的肺动脉血氧饱和度（SpO₂）、氧分压（PaO₂）高于治疗前且二氧化碳分压（PaCO₂）、肺动脉收缩压（PASP）低于治疗前,同组治疗前后比较差异有统计学意义（P<0.05）;且C组的改善幅度大于A、B组,差异有统计学意义（P<0.05）;A组的改善幅度小于B组,差异有统计学意义（P<0.05）。经治疗,C组的总有效率高于A、B两组,差异有统计学意义（P<0.05）;A组总有效率低于B组,差异有统计学意义（P<0.05）。3组治疗后的丙氨酸氨基转移酶（ALT）、天门冬氨酸氨基转移酶（AST）、尿素氮（BUN）和血肌酐（Scr）与治疗前差异无统计学意义,且治疗前后组间差异无统计学意义。结论 在常规治疗的基础上应用米力农治疗PPHN可明显改善血气指标,疗效显著,无肝肾功能损伤及其他不良反应,最佳维持剂量为0.75 μg/(kg·min)。但有必要扩大样本量以对合适的剂量做进一步系统研究。     

头孢丙烯干混悬剂溶出度方法学验证

]目的：建立头孢丙烯干混悬剂溶出度的测定方法。方法：以十八烷基硅烷键合硅胶为填充剂[Luna C18（2） 100A,4.6 mm×150 mm,5 μm];以磷酸二氢铵溶液（取磷酸二氢铵20.7 g,加水1 800 mL使溶解,用磷酸调节pH值至4.4）-乙腈（90∶10）为流动相;检测波长为280 nm,柱温为25 ℃,采用HPLC法测定头孢丙烯含量;以纯化水为溶出介质,桨法25 r·min-1,测定头孢丙烯的溶出,并对溶出测定方法学进行验证。结果：头孢丙烯干混悬剂溶出方法专属性、线性关系、精密度、回收率等良好。结论：本方法能准确的测定头孢丙烯干混悬剂的溶出度。     

HPLC同时测定复方鸡骨草胶囊中绿原酸、芍药苷和栀子苷的含量

目的：建立高效液相色谱法（HPLC）测定复方鸡骨草胶囊中绿原酸、芍药苷、栀子苷的含量.方法：采用Agilent TC-C18色谱柱（4.6 mm×150 mm,5μm）;流动相为乙腈-0.1％磷酸溶液,梯度洗脱;检测波长为0～21 min：327 nm,21 ～ 27min：238 nm,27～40min：230 nm.结果：绿原酸线性范围为0.036 1～0.902 5μg,平均加样回收率为97.74％,RSD为1.40％（n=6）,栀子苷线性范围为0.148 2～5.929 6μg,平均加样回收率为97.68％,RSD为1.14％（n=6）,芍药苷线性范围为0.098 9～3.954 8μg,平均加样回收率为97.70％,RSD为0.99％（n=6）.结论：该方法简便可行,结果可靠,可有效控制复方鸡骨草胶囊的质量.     

连续性血液净化治疗心力衰竭Ⅳ级合并肾衰竭患者56例疗效观察

目的 观察和分析连续性血液净化在治疗重症心力衰竭合并肾衰竭中的作用和疗效.方法 应用连续性血液净化技术治疗2010年1月至2013年12月间我院收治的56例药物治疗效果不佳的重症心力衰竭合并肾衰竭的患者,并于治疗前后对患者心率、心脏指数、左室射血分数、心输出量、血肌酐（SCr）、尿素氮（BUN）、Na＋、K＋、Cl进行统计、分析和比较,观察患者心功能、血生化指标改善情况.结果 与治疗前相比,患者治疗后[心率（79.7±9.0）次/min、心脏指数（3.35±0.91）L/（min·m2）、左室射血分数（53.55±10.32）％、心输出量（4.47±0.35） L/min、SCr （392.00±86.32）μmol/L、BUN（11.2±4.5）mmol/L、K＋（4.4±0.5）mmol/L]均优于治疗前[心率（128.2±14.2）次/min,心脏指数（1.96±0.57） L/（min·m2）、左室射血分数（39.25±8.55）％、心输出量（3.08±0.54） L/min、SCr（903.00±106.10） μmol/L、BUN（20.5±9.4）mmol/L、K＋ （5.60±0.97） mmol/L差异具有统计学意义（P＜0.05）;而Na＋、Cl变化不大,无统计学差异（P＞0.05）.结论 连续性血液净化疗效确切,安全性高,是治疗重症心力衰竭合并肾衰竭的有效手段.     

Pharmacokinetics of dolutegravir in HIV-seronegative subjects with severe renal impairment

Purpose

Dolutegravir (DTG), an unboosted HIV integrase inhibitor (INI), is metabolized by UGT1A1 and to a minor extent by CYP3A. Renal elimination of unchanged DTG is very low (< 1 %). As renal impairment may affect pharmacokinetics (PK), even for drugs primarily metabolized or secreted in bile, this study investigated the effect of renal impairment on the PK of DTG.

Methods

This was an open-label, single-dose study of oral DTG 50 mg administered to subjects with severe renal impairment (creatinine clearance [CLcr] <30 mL/min; not on dialysis) and to healthy controls (CLcr >90 mL/min) matched for gender, age and body mass index (8 subjects per group). Serial PK samples were collected up to 72 h post-dose for determination of DTG and DTG-glucuronide (DTG-Gluc) concentrations in plasma. DTG unbound fraction in plasma was determined at 3 and 24 h. PK parameters were determined by non-compartmental methods and compared between groups by analysis of covariance.

Results

DTG was well tolerated with a low incidence of Grade 1 adverse events. DTG PK parameters showed significant overlap between groups. DTG mean exposure was lower in subjects with severe renal impairment compared to healthy, matched subjects: AUC(0-∞) and Cmax were 40 % and 23 % lower, while mean DTG-Gluc was increased. Renal impairment did not affect DTG fraction unbound in plasma.

Conclusions

The modest reductions in mean PK exposures for DTG and increases for DTG-Gluc in the severe renal impairment group are not considered clinically significant. DTG does not require dose adjustment in patients with renal impairment.     

HPLC法测定复方丹参微丸中丹酚酸B的含量

目的：用高效液相色谱法测定复方丹参微丸中丹酚酸B的含量。方法以乙腈-甲醇-甲酸-水（10∶30∶1∶59）为流动相,色谱柱 Diamon-silTM C18（5μm,4.6＆#215;250mm）,波长286nm、柱温40℃、流速1.0mL＆#183; min -1为色谱条件,对复方丹参微丸中丹酚酸 B含量进行分析。结果丹酚酸B在59.5～1487.5 ng范围内成良好的线性关系（ r＝0.99995）。结论本法简便、准确、重现性好。     

止痛顺气胶囊的薄层色谱鉴别简

目的建立止痛顺气胶囊的薄层色谱鉴别方法。方法采用薄层色谱法对处方中的黄柏、陈皮、肉桂进行定性鉴别。结果薄层色谱法可鉴别出处方中的黄柏、陈皮、肉桂。结论该方法专属性强、重现性好,可用于止痛顺气胶囊的质量控制。     

瑞舒伐他汀钙片溶出度研究

目的建立瑞舒伐他汀钙片溶出度研究方法。方法HPLC法,色谱柱：AgilentExtendC18（4．6×250mm,5μm）;流动相：以乙腈为流动相A,以0．02％三氟乙酸溶液为流动相B,0～13min,A：37％,13—27min,A：37％--90％;检测波长：242nm;流速：1．0mL·min-1;发生降解行为的溶出度样品经碱中和前处理后以瑞舒伐他汀钙与瑞舒伐他汀非对映异构体峰面积之和计算累积溶出量（％）。结果瑞舒伐他汀钙在pH1．0盐酸溶液不稳定,降解生成瑞舒伐他汀非对映异构体,瑞舒伐他汀-5S-内酯和瑞舒伐他汀-5R-内酯,后两者经碱中和处理后重新生成瑞舒伐他汀及瑞舒伐他汀非对映异构体,且瑞舒伐他汀钙片在pH1．0盐酸溶液中溶出速率最慢。结论瑞舒伐他汀钙在pH1．0盐酸溶液中溶出曲线可作为处方筛选的依据。