吡拉西坦改善慢性精神分裂症患者认知功能的临床研究

目的 探讨吡拉西坦改善慢性精神分裂症患者认知功能的效果。方法 对68例慢性精神分裂症患者随机分为试验组和治疗组。治疗前进行阳性和阴性症状量表(PANSS)、简明精神状态量表(MMSE)、中国修订韦氏成人智力量表、韦氏记忆量表(WMS)及威斯康星卡片分类测验等评定,然后经利培酮(2.7±0.8)mg/d治疗8周。研究组与利培酮治疗同步使用吡拉西坦1200mg/d治疗,治疗组仅用利培酮治疗。治疗后第8周末再次进行上述评定,将结果与正常人组成的对照组进行比较。结果 治疗前研究组和治疗组的MMSE、WMS及WAIS-RC均低于对照组,差异有非常显著性(P<0.05),提示患者组的认知功能呈广泛性损害;研究组治疗后认知功能评定MMSE、MCST、WMS、WAIS-RC分数与治疗前比较有显著性差异(P<0.05);而治疗组治疗后认知功能测定MCST、WMS、WAIS-RC分数与治疗前比较无差异性(P>0.05)。结论 吡拉西坦对神经细胞有激活、保护和修复作用,能有效改善患者的认知功能,疗效确切。     

Design, synthesis, and evaluation of orally active 4-(2,4-difluoro-5-(methoxycarbamoyl)phenylamino)pyrrolo[2,1-f][1,2,4]triazines as dual vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1 inhibitors

A series of substituted 4-(2,4-difluoro-5-(methoxycarbamoyl)phenylamino)pyrrolo[2,1-f][1,2,4]triazines was identified as potent and selective inhibitors of the tyrosine kinase activity of the growth factor receptors VEGFR-2 (Flk-1, KDR) and FGFR-1. The enzyme kinetics associated with the VEGFR-2 inhibition of compound 50 (K(i) = 52 +/- 3 nM) confirmed that the pyrrolo[2,1-f][1,2,4]triazine analogues are competitive with ATP. Several analogues demonstrated low-nanomolar inhibition of VEGF- and FGF-dependent human umbilical vein endothelial cell (HUVEC) proliferation. Replacement of the C6-ester substituent of the pyrrolo[2,1-f][1,2,4]triazine core with heterocyclic bioisosteres, such as substituted 1,3,5-oxadiazoles, afforded compounds with excellent oral bioavailability in mice (i.e., 50 F(po) = 79%). Significant antitumor efficacy was observed with compounds 44, 49, and 50 against established L2987 human lung carcinoma xenografts implanted in athymic mice. A full account of the synthesis, structure-activity relationships, pharmacology, and pharmacokinetic properties of analogues within the series is presented.     

肿瘤乏氧分子靶向治疗

乏氧是多数实体瘤的固有特征之一,可增加肿瘤细胞对放化疗的耐受性、促使肿瘤血管生成,是重要的不良预后因素.靶向杀伤肿瘤内的乏氧细胞成为肿瘤治疗的热点.生物还原性药物可通过特定的还原反应激活为细胞毒性代谢产物进而杀伤乏氧肿瘤细胞,而小分子靶点抑制剂则选择性地作用于乏氧途径中的关键环节,二者为肿瘤的乏氧靶向治疗开辟了新的途径.     

The association between Internet addiction and both impulsivity and effortful control and its variation with age

Although the association of Internet addiction (IA) with self-regulation has been widely observed in previous studies, its variance with age remains poorly understood. Using dual models of self-regulation, we aimed to test the effects of effortful control and impulsivity on IA and to explore the effect of the interaction between age stage and self-regulation on IA. In this study, 4313 students nested in 100 classes were surveyed using the Internet Addiction Test (IAT), the Dual-Modes of Self-Control Scale (DMSC-S) and a demographic questionnaire. Hierarchical generalized linear models (HGLMs) were then used to test our assumptions. The results indicated that the IA prevalence rate among the surveyed adolescents was 10.9%, and IA was found to be negatively related to the effortful control trait and positively related to the impulsivity trait. Compared with primary school students, middle school students were more likely to be Internet addicts; however, the prevalence of IA among college students was comparable to that among middle school students. A slopes-as-outcome model showed that the association between IA and effort control was stronger among junior high school students than among students in other grade levels, but no grade differences were found in the slopes for impulsivity. We integrate our results with the findings of previous studies and discuss possible theoretical implications.     

Intracellular localisation of proteins to specific cellular areas by nanocapsule mediated delivery

Nanocapsules are promising carriers with great potential for intracellular protein transport. Although many studies have intended to improve cell uptake efficacy, there is an increasing interest in understanding of subcellular distribution of cargoes inside cells, which is essential for purposeful delivery of biomolecules into specific sites within cells. Herein, we interrogate the intracellular localisation of exogenous proteins, including fluorescein isothiocyanate (FITC)-labelled bovine serum albumin (BSA) and green fluorescent protein (GFP), mediated by specially designed nanocapsules. The results show that the designed nanocapsules can deliver the two types of fluorescent proteins into different cellular destinations (cytosol, nucleus or the whole cell), depending on the composition of nanocapsules. Meanwhile, several impact factors that influence the distribution of proteins in cells have also been investigated, and the results suggest that the localisation of capsule-mediated proteins in cells is strongly affected by the surface properties of nanocapsules, the types of stabilisers and proteins, and environmental temperatures. The rational control of intracellular localised delivery of exogenous proteins as we demonstrated in this study might open new avenues to obtain desired magnitude of drug effects for modulating cell activity.     

年龄、季节、性别、种族与呼伦贝尔地区居民25-(OH)D表达水平的相关性

目的 探讨年龄、季节、性别、种族与呼伦贝尔地区居民25-羟基维生素D[25-(OH)D]表达水平的相关性.方法 回顾性分析2017年1月至2019年8月于本院就诊的27534例呼伦贝尔地区居民的临床资料,检测25-(OH)D水平,并根据年龄、季节、性别、种族分为不同群组,比较不同群组间25-(OH)D水平.结果 未成年组25-(OH)D水平及维生素D充足占比明显高于其他群组,冬季组低于其他季节组,男性组高于女性组,汉族组低于少数民族组,差异均有统计学意义(P<0.05).结论 呼伦贝尔地区人群维生素D不足与缺乏现象较严重,其中成人、老年人、汉族、女性、春冬季应更注意检查维生素D情况,并及时补充维生素D.     

Discovery of brivanib alaninate ((S)-((R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-yl)2-aminopropanoate), a novel prodrug of dual vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1 kinase inhibitor (BMS-540215)

A series of amino acid ester prodrugs of the dual VEGFR-2/FGFR-1 kinase inhibitor 1 (BMS-540215) was prepared in an effort to improve the aqueous solubility and oral bioavailability of the parent compound. These prodrugs were evaluated for their ability to liberate parent drug 1 in in vitro and in vivo systems. The l-alanine prodrug 8 (also known as brivanib alaninate/BMS-582664) was selected as a development candidate and is presently in phase II clinical trials.