对“药物警戒”的认知和探讨(一)

在震惊全球的“反应停事件”水落石出之后,世界各国于20世纪70年代中期先后开展了药物不良反应监测工作。20世纪80年代初,世界上少数几个国家将临床药理学和流行病学相互渗透形成了一门新的学科药物流行病学,将上市后的药物不良反应监测工作纳入其中。然而,在上市前的临床试验中还会涉及到安全性问题和许多非预期的药物不良事件,甚至暴露出不少有关伦理学的问题;其次,在药物不良反应监测中会进一步察觉到其监测的范围不应仅限于临床治疗药物,而应扩大到所有应用于广大公众的传统药(包括中草药和其他民族药物)、营养品、血液制品、生物制品(包括疫苗)和医疗器械(材)等。因此,有人于20世纪末提出了“药物警戒”这个新术语。它把监测的范围扩大到所有与预防和治疗有关的物质, 并将医疗器械也纳入其中,从而将被动的监测转变为主动的警戒,以防患于未然。笔者通过学习世界卫生组织发布的《The Importance of Pharmacovigilance Safety Monitoring of medical Products》所获得的肤浅认识结合我国国情试作探讨。     

对"药物警戒"的认知和探讨(续完)

在震惊全球的“反应停事件”水落石出之后,世界各国于20世纪70年代中期先后开展了药物不良反应监测工作。20世纪80年代初,世界上少数几个国家将临床药理学和流行病学相互渗透形成了一门新的学科药物流行病学,将上市后的药物不良反应监测工作纳入其中。然而,在上市前的临床试验中还会涉及到安全性问题和许多非预期的药物不良事件,甚至暴露出不少有关伦理学的问题;其次,在药物不良反应监测中会进一步察觉到其监测的范围不应仅限于临床治疗药物,而应扩大到所有应用于广大公众的传统药(包括中草药和其他民族药物)、营养品、血液制品、生物制品(包括疫苗)和医疗器械(材)等。因此,有人于20世纪末提出了“药物警戒”这个新术语。它把监测的范围扩大到所有与预防和治疗有关的物质,并将医疗器械也纳入其中,从而将被动的监测转变为主动的警戒,以防患于未然。笔者通过学习世界卫生组织发布的《The Importance of Pharmacovigilance Safety Monitoring of Medical Products》所获得的肤浅认识结合我国国情试作探讨。     

对"药物警戒"的认识和探讨(续二)

在震惊全球的"反应停事件"水落石出之后,世界各国于20世纪70年代中期先后开展了药物不良反应监测工作.20世纪80年代初,世界上少数几个国家将临床药理学和流行病学相互渗透形成了一门新的学科药物流行病学,将上市后的药物不良反应监测工作纳入其中.然而,在上市前的临床试验中还会涉及到安全性问题和许多非预期的药物不良事件,甚至暴露出不少有关伦理学的问题;其次,在药物不良反应监测中会进一步察觉到其监测的范围不应仅限于临床治疗药物,而应扩大到所有应用于广大公众的传统药(包括中草药和其他民族药物)、营养品、血液制品、生物制品(包括疫苗)和医疗器械(材)等.因此,有人于20世纪末提出了"药物警戒"这个新术语.它把监测的范围扩大到所有与预防和治疗有关的物质,并将医疗器械也纳入其中,从而将被动的监测转变为主动的警戒,以防患于未然.笔者通过学习世界卫生组织发布的<TheImportance ofPharmacovigilance Safety Monitoring ofMedical Products>所获得的肤浅认识结合我国国情试作探讨.     

药物流行病学与药物警戒

药物流行病学学科的形成，起源于药物警戒的开展。经过不断地发展，现在的药物流行病学早已不仅仅是药物警戒，而药物警戒仍是药物流行病学研究的一个重要方面。本文就药物流行病学的专业特征和面临的任务，特别是药物流行病学与药物警戒之间的关系，作如下交流。     

药物警戒方法概述

药物警戒是有关药物不良反应及任何其他药物相关问题的检出、评估、理解和防范的科学与活动。这一定义包含了药物流行病学的研究方法在药物警戒中的应用。本文简述目前主要应用于药物警戒的研究方法。     

药物警戒及其信号问题

论述药物警戒及其信号产生与检验的一些方法，阐明相关的药物流行病学方法的特点，介绍近年国际上药物警戒概念、范围的变化。     

药物警戒的概念与起源

本文叙述了药物警戒的起源和演变的过程,综述不同时期,不同侧面对药物警戒概念和内涵的定义,试剖析其利弊,以期助益于读者理解药物警戒基本概念.     

药物警戒研究方法简述

本文概述目前开展药物警戒常用的研究方法,并分析不同方法的优势和缺欠,期望对开展相关工作起到一定的参考作用.     

药物基因组学基础的药物警戒研究进展

摘要：主要从药物基因组学角度回顾了常见药物的不良反应,特别是严重不良反应,如药物过敏反应,药物心脏、肾脏、肝脏毒性与相关基因的的研究进展,探讨了药物遗传/基因组学技术在药物警戒中的应用现状,并对未来药物遗传/基因组学技术的发展方向及对药物警戒工作的意义作以预测和展望。     

Identification of 5-(3-(methylsulfonyl)phenyl)-3-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine as novel orally bioavailable and metabolically stable antimalarial compound for further exploration

Malaria continues to be a significant public health problem threatened by the emergence and spread of resistance to artemisinin-based combination therapies and marked half a million deaths in 2016. A new imidazopyridine chemotype has been envisaged through scaffold-hopping approach combined with docking studies for putative-binding interactions with Plasmodium falciparum phosphatidylinositol-4-kinase (PfPI4K) target. The docking results steered to the synthesis of compound 1 [5-(3-(methylsulfonyl)phenyl)-3-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine] followed by the in vitro screening for antiplasmodial activity and ADME-PK studies. Combined with potent antimalarial activity of compound 1 (Pf3D7 IC₅₀ = 29 nM) with meager in vitro intrinsic clearance, moderate plasma-protein binding, and acceptable permeability, compound 1 displayed sustained exposure and high oral bioavailability in mice and can thus have the potential as next generation PI4K inhibitor for in vivo studies.     

3D-QSAR CoMFA study on imidazolinergic I(2) ligands: a significant model through a combined exploration of structural diversity and methodology

Displaying an unprecedented structural diversity, 119 I(2) ligands, and their pK(i) values, were collected and submitted to a comparative molecular fields analysis (CoMFA) study. They were discerned into three structural subsets (A, B, C), to explore the I(2) 3D-QSARs from finite structural systems (A, B, C) to more complex ones (AB, AC, BC, ABC). In addition, various key steps of the CoMFA methology were explored. The applied method used two pharmacophore templates and seven molecular field combinations (electrostatic, lipophilic, steric), as well as eight alignment methods (two point-by-point and six similarity-based variations). That way, 644 CoMFA models were obtained and further selected according to their predictive ability through two filters. The first filter was mainly based on the q(2), which internally evaluates the predictive ability from the training set. For the second filter, the predictive ability was externally evaluated through the prediction of test sets. Finally, one model was extracted from the whole data as the best. Indeed, it combines three features of upmost importance for the further design of ligands endowed with high I(2) affinity: structural diversity (n = 73), robustness (N = 9, r(2) = 0.96, s = 0. 28, F = 148), and a great fully assessed predictive ability (q(2) = 0.50, r(2)(test set) = 0.81, n(test set) = 46). On the basis of structural data and CoMFA isocontours, some elements of the I(2) tridimensional pharmacophore are also suggested.     

The effects of hemicholinium-3 (Hc-3) during tetanic (TP) and posttetanic potentiation (PTP) on sympathetic ganglion

An electrophysiological analysis has been made of the synaptic plasticity in the eighth sympathetic ganglion of the toad. The mean amplitude of Compound Action Potential (CAP) recorded extracellularly was taken as a measure of the synaptic transmission. Repetitive stimulation of the preganglionic axonal fibers at 50 Hz for 40 seconds in the presence of Hc-3 led to facilitatory and depressant actions on ganglionic synaptic transmission. Hc-3 in the presence of elevated extracellular Ca2+ concentration (5.4 mM) increased Tetanic Potentiation (TP) and Posttetanic Potentiation (PTP) on eighth sympathetic ganglion. Hc-3 plus 3,4-diaminopyridine (3,4-DAP) increased synaptic transmission, TP, and PTP from postganglionic CAP responses to supramaximal preganglionic stimulation.     

Preliminary exploration on anti-inflammatory mechanism of Corilagin (beta-1-O-galloyl-3,6-(R)-hexahydroxydiphenoyl-D-glucose) in vitro

Corilagin (beta-1-O-galloyl-3,6-(R)-hexahydroxydiphenoyl-D-glucose) is a novel member of the tannin family which has been discovered from many medicinal plants and has been confirmed in many pharmacological activities. However, the purified Corilagin that was used in experiment is rare, and the anti-inflammatory mechanism of Corilagin has not been investigated clearly. This study is to explore the inner anti-inflammatory mechanism of Corilagin. Inflammatory cellular model was established by lipopolysaccharide (LPS) interfering on RAW264.7 cell line. Levels of TNF-alpha, IL-1beta, IL-6, NO and IL-10 in supernatant, mRNA expression of TNF-alpha, COX-2, iNOS and HO-1, protein expression of COX-2 and HO-1, translocation of NF-kappaB were assayed by ELISA or Griess method, real-time quantitative PCR, western blot and immunocytochemistry method, respectively. As a result, Corilagin could significantly reduce production of pro-inflammatory cytokines and mediators TNF-alpha, IL-1beta, IL-6, NO (iNOS) and COX-2 on both protein and gene level by blocking NF-kappaB nuclear translocation. Meanwhile Corilagin could notably promote release of anti-inflammatory factor HO-1 on both protein and gene level, but suppress the release of IL-10. In conclusion, the anti-inflammatory effects of Corilagin are attributed to the suppression of pro-inflammatory cytokines and mediators by blocking NF-kappaB activation. Corilagin also can promote HO-1 production to induce regression of inflammation but can inhibit IL-10 production like Dexamethasone. Corilagin possesses a potential anti-inflammatory effect by not only abating inflammatory impairment but also promoting regression of inflammation and has a good prospect to be used in many inflammation-related diseases.     

Synthesis and antiproliferative activity of novel 3-(indazol-3-yl)-quinazolin-4(3H)-one and 3-(indazol-3-yl)-benzotriazin-4(3H)-one derivatives.

Several new 3-(indazol-3-yl)-quinazolin-4(3H)-one and 3-(indazol-3-yl)-benzotriazin-4(3H)-one derivatives 5 and 6 were synthesized and tested for their in vitro antiproliferative activity against Raji, K562, and K562-R cell lines. The pharmacological screening showed that some 2, 6, or 7-substituted quinazolinones 5 posses a significant antiproliferative activity, with a percentage growth inhibition ranging from 44.8% to 100% at 50 microM, which was higher than that showed by the unsubstituted derivative 5a previously synthesized. For the most active compounds 5d, 5f, and 5g the IC50 were recorded.     

Chromonyl-(3)-methanol- and bischromonyl-(3)-methane derivatives. 46. Studies on 4-pyrones

Chromonyl-(3)-methanol- and Bischromonyl-(3)-methane-derivatives Chromonyl-(3)-methanol- and bischromonyl-(3)-methane-derivatives ( 1, 3 ) were prepared from o-hydroxy-ω-formylacetophenone ( 2 ) and aldehydes. Hydrolysis of 3 leads to the bissalicyloyl-propane-derivatives ( 5 ), which react with dimethylformamide-dimethylacetal to 3 .