FDA Breakthrough Therapy Designation: Evaluating the Quality of the Evidence behind the Drug Approvals

The United States Food and Drug Administration (FDA) has created approval pathways and designations to accelerate access to medications indicated for serious or life‐threatening conditions with limited treatment options. Implemented in 2012, the most recent of these is the breakthrough therapy designation (BTD). The purpose of this article was to review the evidence surrounding approval of medications with nononcology indications approved with the BTD designation from 2012 to 2016. Fifteen medications were identified for eight conditions, ranging from conditions that are relatively common, such as chronic hepatitis C infection, to those that are extremely rare, such as lysosomal acid lipase deficiency. The quality of evidence behind these approvals was highly heterogeneous. Much remains unknown about the safety and efficacy of many agents approved through the BTD. Health care professionals should be aware of these limitations to better educate patients and other providers appropriately.     

Species differences in bile acids II. Bile acid metabolism

One of the mechanisms of drug‐induced liver injury (DILI) involves alterations in bile acid (BA) homeostasis and elimination, which encompass several metabolic pathways including hydroxylation, amidation, sulfation, glucuronidation and glutathione conjugation. Species differences in BA metabolism may play a major role in the failure of currently used in vitro and in vivo models to predict reliably the DILI during the early stages of drug discovery and development. We developed an in vitro cofactor‐fortified liver S9 fraction model to compare the metabolic profiles of the four major BAs (cholic acid, chenodeoxycholic acid, lithocholic acid and ursodeoxycholic acid) between humans and several animal species. High‐ and low‐resolution liquid chromatography–tandem mass spectrometry and nuclear magnetic resonance imaging were used for the qualitative and quantitative analysis of BAs and their metabolites. Major species differences were found in the metabolism of BAs. Sulfation into 3‐O‐sulfates was a major pathway in human and chimpanzee (4.8%–52%) and it was a minor pathway in all other species (0.02%–14%). Amidation was primarily with glycine (62%–95%) in minipig and rabbit and it was primarily with taurine (43%–81%) in human, chimpanzee, dog, hamster, rat and mice. Hydroxylation was highest (13%–80%) in rat and mice followed by hamster, while it was lowest (1.6%–22%) in human, chimpanzee and minipig. C6‐β hydroxylation was predominant (65%–95%) in rat and mice, while it was at C6‐α position in minipig (36%–97%). Glucuronidation was highest in dog (10%–56%), while it was a minor pathway in all other species (<12%). The relative contribution of the various pathways involved in BA metabolism in vitro were in agreement with the observed plasma and urinary BA profiles in vivo and were able to predict and quantify the species differences in BA metabolism. In general, overall, BA metabolism in chimpanzee is most similar to human, while BA metabolism in rats and mice is most dissimilar from human.     

Penta-block copolymer microspheres: Impact of polymer characteristics and process parameters on protein release

Here, we aimed to develop protein loaded microspheres (MSs) using penta-block PLGA-based copolymers to obtain sustained and complete protein release. We varied MS morphology and studied the control of protein release. Lysozyme was used as a model protein and MSs were prepared using the solid-in-oil-in-water emulsion solvent extraction method. We synthesized and studied various penta-block PLGA-based copolymers. Copolymer characteristics (LA/GA ratio and molecular weight of PLGA blocks) influenced MS morphology. MS porosity was influenced by process parameters (such as solvent type, polymer concentration, emulsifying speed), whereas the aqueous volume for extraction and stabilizer did not have a significant effect. MSs of the same size, but different morphologies, exhibited different protein release behavior, with porous structures being essential for the continuous and complete release of encapsulated protein. These findings suggest strategies to engineer the morphology of MSs produced from PLGA-based multi-block copolymers to achieve appropriate release rates for a protein delivery system.     

Effect of residual doxycycline concentrations on resistance selection and transfer in porcine commensal Escherichia coli

Pig feed may contain various levels of antimicrobial residues due to cross-contamination. A previous study showed that a 3% carry-over level of doxycycline (DOX) in the feed results in porcine faecal concentrations of approximately 4?mg/L.The aim of this study was to determine the effect of residual DOX concentrations (1 and 4?mg/L) in vitro on selection of DOX–resistant porcine commensal Escherichia coli and transfer of their resistance plasmids.Three different DOX–resistant porcine commensal E. coli strains and their plasmids were characterised. These strains were each brought in competition with a susceptible strain in a medium containing 0, 1 and 4?mg/L DOX. Resistant bacteria, susceptible bacteria and transconjugants were enumerated after 24?h and 48?h.The tet(A)–carrying plasmids showed genetic backbones that are also present among human E. coli isolates. Ratios of resistant to susceptible bacteria were significantly higher at 1 and 4?mg/L DOX compared with the blank control, but there was no significant difference between 1 and 4?mg/L. Plasmid transfer frequencies were affected by 1 or 4?mg/L DOX in the medium for only one of the resistance plasmids.In conclusion, DOX concentrations of 1 and 4?mg/L can select for resistant E. coli in vitro. Further research is needed to determine the effect of these concentrations in the complex environment of the porcine intestinal microbiota.     

品管圈在提高病区药房服务满意度中的应用

目的：探讨改善住院药房-静脉药物配置中心复合型病区药房服务质量的方法,提高临床科室的满意度,提升药学服务水平。方法：按照品管圈活动的基本步骤和方法,调查分析临床各科室对病区药房不满意的原因,然后拟定对策并结合五常法（又称5S法：常组织、常整顿、常清洁、常规范、常自律）加以标准化,最后对效果进行评价和分析。结果：临床各科室对病区药房的满意度从活动前的67.08%提升至活动后的87.18%。结论：品管圈活动和5S法联合应用,能够更好地发现和解决药房工作中的各种问题,形成长效管理机制,对保障药品质量、提高工作效率、提升药学服务水平有重要的作用。     

一种难溶性原料药细菌内毒素检查方法的建立

摘 要 目的：建立原料药HSSYO 001 3S细菌内毒素检查方法。方法: 以二甲亚砜（DMSO）溶解HSSYO 001 3S,用适量细菌内毒素检查用水（BET水）稀释后,离心取上清液,按中国药典2015年版四部通则11431检查凝胶法,对HSSYO 001 3S进行细菌内毒素检查的方法学研究。结果:HSSYO 001 3S加助溶剂并以BET水稀释至1 mg·m^-1 ,经离心后取上清液稀释4倍及以上时对鲎试剂凝集反应无干扰作用。结论:HSSYO 001 3S可采用细菌内毒素检查法控制其质量。     

双波长HPLC同时测定小儿咳喘灵颗粒中8种有效成分的含量

目的 采用HPLC同时测定小儿咳喘灵颗粒中盐酸麻黄碱、盐酸伪麻黄碱、（R,S）告依春、绿原酸、苦杏仁苷、甘草苷、木犀草苷、甘草酸的含量。方法 采用双波长HPLC,以Agilent ZORBAX SB-C₁₈色谱柱（4.6 mm×250 mm,5 μm）进行分离;流动相：0.1%磷酸水溶液-乙腈梯度洗脱;流速1 mL·min^-1;柱温30℃;检测波长210 nm（盐酸麻黄碱、盐酸伪麻黄碱、苦杏仁苷、甘草苷、木犀草苷）,245nm[（R,S）告依春、绿原酸、甘草酸]。结果 8种成分的峰面积与质量浓度的线性关系良好,加样回收率96.23%~100.7%。结论 该方法简便、快速、准确,可用于小儿咳喘灵颗粒的质量控制。     

参芎葡萄糖注射液对新生儿缺氧缺血性脑病的临床疗效及作用机制

目的探讨参芎葡萄糖注射液对新生儿缺氧缺血性脑病(HIE)的临床疗效及其血清神经因子、S100B蛋白及脂联素(APN)表达水平变化。方法选取2015年1月-2017年4月鄂州市中心医院入住的67例HIE患儿,随机分为对照组30例和观察组37例。两组均给予支持和对症综合治疗,观察组在上述治疗的基础上另给予参芎葡萄糖注射液静注,疗程均为14d,疗程结束后评价两组临床疗效,采用ELISA法检测血清脂联素(APN)、S100B蛋白、髓磷脂碱性蛋白(MBP)、神经元特异性烯醇化酶(NSE)、神经营养因子(NTF)及神经生长因子(NGF)表达水平。结果治疗14d后,观察组与对照组临床总有效率分别为73.33%和83.78%,两组总有效率比较差异有统计学意义(P<0.05);观察组血清MBP、NSE、NTF、NGF、APN及S100B水平改善程度均优于对照组(P<0.05)。参芎葡萄糖注射液可以使HIE患儿的意识障碍恢复时间、原始反射恢复时间和肌张力恢复时间明显缩短(P<0.05)。随着治疗时间的增加,观察组HIE患儿NBNA评分也明显增高(P<0.05)。结论参芎葡萄糖注射液治疗HIE具有较好的临床疗效,可明显改善HIE症状、体征,改善血清神经、APN、S100B表达水平。     

On the use of denaturing gradient gel electrophoresis approach for bacterial identification in endodontic infections

Bacteria in infected root canals of teeth evincing chronic apical periodontitis lesions were identified by a polymerase chain reaction–denaturing gradient gel electrophoresis (PCR-DGGE) approach. DNA was extracted from root canal samples, and part of the 16S rRNA gene of all bacteria was amplified by PCR and separated by DGGE, generating banding patterns representative of the community structure. Twenty visible bands were cut out of the gel, re-amplified, and sequenced to provide identification. Sequencing analysis revealed the presence of both cultivable and as-yet-uncultivated species in the samples analyzed, including representatives of the genera Fusobacterium, Bacteroides, Dialister, Synergistes, Prevotella, Eubacterium and Peptostreptococcus. Unambiguous identification was not always possible and the method’s limitations are discussed. In general, the findings showed that PCR-DGGE can be useful for the identification of both cultivable and as-yet-uncultivated bacteria in endodontic infections.