特殊制剂一致性评价的开发策略

2016 年 3 月 5 日,国务院办公厅《开展仿制药质量和疗效一致性评价的意见》正式对外公布,提出了全面提高仿制药质量,开 展仿制药质量一致性评价,确保中国仿制药质量不低于美国、欧盟、日本的标准。文章介绍了美国和日本的一致性评价背景,根据中国国情, 结合政策法规,阐述如何科学性、合理性地开展仿制药一致性评价,重点介绍低剂量和微丸压片特殊口服固体制剂一致性评价的开发策略。     

仿制药一致性评价中有关物质研究的思考

有关物质是药品的关键质量属性之一,也是仿制药一致性评价的重要内容,其涉及药品的安全性及其质量的可控性。文章梳理了 仿制药有关物质的来源及研究重点,评估仿制药有关物质的文献分析方法,总结归纳仿制药与被仿制药实际样品的杂质谱分析比较及其 意义,探讨杂质限度的确定原则与方法。     

氯雷他定固体自乳化制剂的体外溶出及体内药动学研究

目的:研究氯雷他定固体自乳化制剂的体外溶出行为及其在比格犬体内的药物动力学。方法:采用HPLC方法测定氯雷他定固体自乳化制剂与市售片剂的体外溶出曲线;采用LC-MS/MS测定市售片剂和氯雷他定固体自乳化制剂在比格犬体内的血药浓度,考察氯雷他定固体自乳化制剂的相对生物利用度。结果:以0.1 mol·L-1盐酸溶液为溶出介质的体外溶出结果表明,氯雷他定固体自乳化胶囊与市售片剂30 min时均可以溶出80%以上;比格犬体内药物动力学研究结果表明,固体自乳化制剂比市售片剂最高血药浓度显著性增加(P0.05),Cmax=1.79μg·L-1,而市售片剂Cmax=0.67μg·L-1;AUC(0~t)提高了149%(P0.05)。结论:固体自乳化制剂可以显著提高氯雷他定的体内吸收。     

右美托咪定对过敏性鼻炎大鼠模型血流动力学和炎症因子的影响

为了考察右美托咪定对过敏性鼻炎大鼠模型血流动力学和炎症因子的影响,本研究将40只Wistar大鼠随机分为对照组、模型组、枸地氯雷他定组和右美托咪定组,每组10只。建立过敏性鼻炎大鼠模型后,分别用枸地氯雷他定和右美托咪定治疗大鼠14 d。检测用药前后大鼠的血流动力学指标变化,采用酶联免疫吸附测定法检测各组大鼠血清中的Ig E含量。采用q RT-PCR和Western blotting检测大鼠鼻粘膜组织中IL-1β、IL-5和TNF-α的表达,采用苏木素伊红(HE)染色评价大鼠的病理变化。研究显示,经相应药物治疗后,枸地氯雷他定组和右美托咪定组大鼠的行为评分均显著低于建模后,且两组间未见显著差异。在用药5 min后,右美托咪定组大鼠的SBP、DBP、HR和MAP水平均比用药前显著降低。而对照组、模型组和枸地氯雷他定组未见明显变化。HE染色病理评分显示,枸地氯雷他定组和右美托咪定组大鼠的病理评分均显著低于模型组。经相应的药物治疗后,枸地氯雷他定组和右美托咪定组大鼠鼻黏膜组织中的IL-1β、IL-5和TNF-αmRNA和蛋白相对表达量均显著低于模型组。本研究证实,右美托咪定除了具有较好的镇静作用外,在治疗过敏性鼻炎方面同样疗效显著,可有效减少过敏性鼻炎大鼠的症状和疾病进展,其治疗机制与抑制炎症因子Ig E、IL-1β、IL-5和TNF-α的合成和分泌有关。     

地氯雷他定联合地塞米松鼓室内注射对分泌性中耳炎患者咽鼓管功能的影响

目的:观察地氯雷他定联合地塞米松鼓室内注射治疗分泌性中耳炎的效果及对咽鼓管功能的影响。方法:选择我院2013年6月-2014年6月收治的分泌性中耳炎患者116例,随机分为两组,对照组采用地塞米松鼓室内注射治疗,观察组在此基础上加服地氯雷他定。观察并比较两组临床疗效及咽鼓管功能的恢复情况。结果:治疗后,两组咽鼓管功能不良率较治疗前明显降低(P0.05),观察组咽鼓管功能恢复率高于对照组,观察组治疗前后气骨导差差值明显大于对照组(P0.05),观察组在治疗后1周及1月的总有效率均高于对照组(P0.05)。结论:地氯雷他定联合地塞米松鼓室内注射可减少渗出和中耳积液潴留,有效改善分泌性中耳炎患者的咽鼓管功能,促进听力恢复。     

我国仿制药人体生物等效性临床试验研究室建设的现状与发展路径

我国开展仿制药一致性评价最主要的困难之一是临床试验资源不足,解决办法是考虑将生物等效性临床试验资格认定调整为备案 管理。因此,对备案的医疗机构建设生物等效性试验研究室是一个潜在的挑战。文章分析了国内当前具备生物等效性 / I期临床资质的 机构、分布、承担项目能力及生物等效性临床试验机构、药物分析实验室和合同研究组织之间的关系等,对仿制药生物等效性临床试验 研究室的建设内容和规模展开讨论,供业内及监管部门参考。     

灭荨汤和隔盐灸联合枸地氯雷他定片提高慢性荨麻疹的治疗效果

本研究旨在考察一种中医学结合疗法在治疗慢性荨麻疹中的效果。将300例慢性荨麻疹患者随机分为试验组和对照组,每组150例。对照组患者应用西药枸地氯雷他定片治疗,试验组应用中医学结合疗法(枸地氯雷他定片+中药灭荨汤+隔盐灸)。两组患者经治疗后,试验组的总有效率(93.3%)显著高于对照组(76.7%)(p0.05);试验组治疗后的单项症状积分均显著低于对照组(p0.05);试验组治疗后的DLQI评分均显著低于对照组(p0.05)。试验组治疗后的IL-4和总Ig E水平均显著低于对照组(p0.05),而IFN-γ水平显著高于对照组(p0.05);且试验组的复发率(7.7%)显著低于对照组(31.1%)(p0.05)。本研究结果表明,与单用西药枸地氯雷他定片相比,枸地氯雷他定片联合中药灭荨汤和隔盐灸可显著提高慢性荨麻疹的治疗效果,并且可增强患者的免疫功能,提高生活质量,降低复发率。     

药物经济学在仿制药一致性评价中的运用

药物经济学评价作为新兴学科,在目前如火如荼的仿制药一致性评价中得到广泛关注。文章在简介药物经济学评价基本方法的基础 上,对制药企业在仿制药一致性评价过程中的经济学问题及对策进行了探讨。     

地氯雷他定片与匹多莫德片联合治疗慢性荨麻疹的临床疗效 及对血清IL-2 及IL-4水平的影响

目的:观察地氯雷他定片联合匹多莫德片治疗慢性荨麻疹的临床疗效,及治疗前后患者血清IL-2及IL-4水平的变化。方法:将2014年6月-2015年7月我院收治的112例慢性荨麻疹患者随机分成两组各56例,其中治疗组给予口服地氯雷他定片与匹多莫德片治疗,对照组单独口服地氯雷他定片治疗;治疗4周后对比两组临床疗效,并测定两组患者治疗前后血清IL-2及IL-4水平。结果:治疗4周后,治疗组治疗总有效率为92.86%,明显高于对照组82.14%,差异具有统计学意义(P0.05);两组患者治疗后血清IL-2水平升高,IL-4水平降低,且治疗组改变相比对照组更显著,差异均有统计学意义(P0.05)。结论:地氯雷他定片联合匹多莫德片治疗慢性荨麻疹疗效显著,其机制可能与提高血清IL-2水平及降低IL-4水平有关。     

氯雷他定联合甲基强的松冲击治疗小儿过敏性紫癜的临床疗效

目的:观察氯雷他定联合甲基强的松冲击疗法治疗小儿过敏性紫癜的疗效,及其对患儿血清免疫学指标的影响。方法:将180例过敏性紫癜患儿随机分为对照组和观察组,每组各90例。所有患者均接受包括氯雷他定的基础治疗,观察组在此基础上加用甲基强的松冲击治疗。观察并比较两组的临床疗效、临床症状消失时间及治疗前后血清免疫学指标的变化情况。结果:观察组患儿治愈率和总有效率显著高于对照组,差异具有统计学意义(P0.05);观察组临床症状消失时间显著短于对照组,差异具有统计学意义(P0.05);治疗后,观察组患儿血清Ig A、C3、TNF-α及IL-10水平显著低于对照组,差异具有统计学意义(P0.05)。结论:氯雷他定联合甲基强的松龙能有效抑制炎症反应,调节免疫平衡,在小儿过敏性紫癜治疗中具有积极意义。     

A Unique Protease Cleavage Site Predicted in the Spike Protein of the Novel Pneumonia Coronavirus (2019-nCoV) Potentially Related to Viral Transmissibility

正Dear Editor,In December 2019, a novel human coronavirus caused an epidemic of severe pneumonia(Coronavirus Disease 2019,COVID-19) in Wuhan, Hubei, China(Wu et al. 2020; Zhu et al. 2020). So far, this virus has spread to all areas of China and even to other countries. The epidemic has caused 67,102 confirmed infections with 1526 fatal cases     

Curcuminoids as inhibitors of thioredoxin reductase: A receptor based pharmacophore study with distance mapping of the active site

Curcumin is the yellow pigment of turmeric that interacts irreversibly forming an adduct with thioredoxin reductase (TrxR), an enzyme responsible for redox control of cell and defence against oxidative stress. Docking at both the active sites of TrxR was performed to compare the potency of three naturally occurring curcuminoids, namely curcumin, demethoxy curcumin and bis-demethoxy curcumin. Results show that active sites of TrxR occur at the junction of E and F chains. Volume and area of both cavities is predicted. It has been concluded by distance mapping of the most active conformations that Se atom of catalytic residue SeCYS498, is at a distance of 3.56 from C13 of demethoxy curcumin at the E chain active site, whereas C13 carbon atom forms adduct with Se atom of SeCys 498. We report that at least one methoxy group in curcuminoids is necessary for interation with catalytic residues of thioredoxin. Pharmacophore of both active sites of the TrxR receptor for curcumin and demethoxy curcumin molecules has been drawn and proposed for design and synthesis of most probable potent antiproliferative synthetic drugs.     

Comparative morphology of the carpel in the Liliaceae: Hewardieae, Petrosavieae, and Tricyrteae

The young pistils in the melanthioid tribes, Hewardieae, Petrosavieae and Tricyrteae, are uniformly tricarpellate and syncarpous. They lack raphide idioblasts. All are multiovulate, with bitegmic ovules. The Petrosavieae are marked by the presence of septal glands and incomplete syncarpy. Tepals and stamens adhere to the ovary in the Hewardieae and the Petrosavieae but not in the Tricyrteae. Two vascular bundles occur in the stamens of the Hewartlieae and Tricyrtis latifolia. Ventral bundles in the upper part of the ovary of the Hewardieae are continuous with compound septal bundles and placental bundles in the lower part. Putative ventral bundles occur in the alternate position in the Tricyrteae and putative placental bundles in the opposite. position in the Petrosavieae. The dichtomously branched stigma in each carpel of the Tricyrteae is supplied by a bifurcated dorsal bundle.     

Enterovirus 71 3C proteolytically processes the histone H3 N-terminal tail during infection

Highlights
1. The N-terminal tail of histone H3 is specifically cleaved during EV71 infection.
2. Viral protease 3C is identified as a protease responsible for proteolytically processing the N-terminal H3 tail.
3. Our finding reveals a new epigenetic regulatory mechanism for Enterovirus 71 in virus-host interactions.     

Detection of EBV and HHV6 in the Brain Tissue of Patients with Rasmussen’s Encephalitis

Rasmussen’s encephalitis (RE) is a rare pediatric neurological disorder, and the exact etiology is not clear. Viral infection may be involved in the pathogenesis of RE, but conflicting results have reported. In this study, we evaluated the expression of both Epstein-Barr virus (EBV) and human herpes virus (HHV) 6 antigens in brain sections from 30 patients with RE and 16 control individuals by immunohistochemistry. In the RE group, EBV and HHV6 antigens were detected in 56.7% (17/30) and 50% (15/30) of individuals, respectively. In contrast, no detectable EBV and HHV6 antigen expression was found in brain tissues of the control group. The co-expression of EBV and HHV6 was detected in 20.0% (6/30) of individuals. In particular, a 4-year-old boy had a typical clinical course, including a medical history of viral encephalitis, intractable epilepsy, and hemispheric atrophy. The co-expression of EBV and HHV6 was detected in neurons and astrocytes in the brain tissue, accompanied by a high frequency of CD8⁺ T cells. Our results suggest that EBV and HHV6 infection and the activation of CD8⁺ T cells are involved in the pathogenesis of RE.     

Perinatal Vertical Transmission of Chikungunya Virus in Ruili,a Town on the Border between China and Myanmar

正Dear Editor,Chikungunya virus (CHIKV), an arbovirus in the family of Togaviridae, genus Alphavirus, is transmitted by the A.aegyptii or A. albopictus mosquito, and causes disease in humans characterized by fever, rash, and arthralgia (Silva and Dermody 2017; Suhrbier 2019). It was first reported in 1953 in Tanzania, and caused only a few outbreaks and sporadic cases in Africa and Asia in last century. However, in the epidemic in 2004, CHIKV acquired mutations that conferred enhanced transmission by the A. albopictus mosquito(Schuffenecker et al. 2006). Since then, it has successively caused outbreaks in Africa, the Indian Ocean, South East Asia, the South America, and Europe (Zeller et al. 2016).     

Development of a Novel Reverse Transcription Loop-Mediated Isothermal Amplification Method for Rapid Detection of SARS-CoV-2

In conclusion, the novel visual RT-LAMP assay is a simple, rapid, and sensitive approach for detection of SARS-CoV-2, and it is ready for application in primary care and community hospitals or health care centers, and even patients' own houses in response to the current SARS-CoV-2 epidemic because the assay does not require sophisticated equipment and skilled personnel. Furthermore, it is also ready to be used in fields for screening samples from wild animals and environments to facilitate the identification of potential intermediate hosts that mediate the cross-species transmission of SARS-CoV-2 from bats to humans.