Quantitative and comparative study of haematoporphyrin-derived photosensitizers on a murine tumour model

Eight commercially available HPD-photosensitizers intended for photodynamic therapy were tested in a murine tumour model with regard to their therapeutic efficacy. The regrowth delay of the fibrosarcoma SSK-2 on the mouse C3H, Neuherberg-line, was determined 3, 24, 48 and 72 h after injection of the drugs (dose: 9 mg kg^–1 body weight). The corresponding pharmacodynamics, as measured by regrowth delay, were approximated by an exponential function and the characterizing coefficients derived. These coefficients served to quantify the photodynamic properties of the drugs.The pharmacodynamics of five substances were compared with those obtained fluorometrically. The latter showed shorter decay constants than the therapy-correlated substances which indicates different metabolic behaviour of the therapeutic and diagnostically useful fluorescent components of haematoporphyrin-derived photosensitizers.     

刺五加混悬剂小鼠体内药动学研究

目的 考察刺五加混悬剂小鼠体内药动学特征。方法 分别采用药理效应法中的效量法与药效法,选择吞噬指数为检测指标,研究刺五加在小鼠体内药动学规律。结果 效量法:K_(el)=0.2d~(-1) K_a=2.5d~(-1),AUC(S_o)=10.4g·kg~(-1)·d,VRT=19.3d~2。药效法:K_(el(ef))=0.1d~(-1),K_(a(ef))=2.9d~(-1),AUC(S_o)_((ef))=62.7(％)·d,VRT_((ef))=43.2d~2。药效法所得数据大于效量法,说明药效的出现有滞后性。结论 用药理效应法研究刺五加有效成分的体内药动学规律是可行的,并且首次得到了有关药动学数据。     

分子对接在中药药效物质筛选及作用机制研究中的应用进展

摘 要分子对接技术属于计算机辅助药物设计(computer aided drug design, CADD)的一种主要方法,近年来,在筛选中药药效物质、寻找药物作用于疾病的靶点以及探索中药的作用机制被广泛运用并取得了一定进展。本文通过文献综述,介绍了分子对接的原理、分子对接机制以及部分常用的软件,并着重总结了分子对接技术在中药药效物质筛选及作用机制研究中的应用,此外对分子对接存在的问题进行讨论与展望,以期为中药临床研究及新药研发提供更多的理论依据。     

升黄克痛软膏对小鼠的药效学实验研究

目的:探讨升黄克痛软膏体内抗病毒作用。方法:用HSV感染小鼠,经阴道给药,观察升黄克痛软膏对疱疹病毒感染的小鼠的抑制作用,评价药物抗病毒作用。结果:本品对感染了HSV病毒的小鼠有明显的抑制作用,与对照组相比,有显著性差异(P<0.05)。结论:升黄克痛软膏对感染了HSV病毒的小鼠作用显著,疗效确切。     

Immuno-pharmacodynamics for evaluating mechanism of action and developing immunotherapy combinations

Immunotherapy has become a major modality of cancer treatment, with multiple new classes of immunotherapeutics recently entering the clinic and obtaining market approval from regulatory agencies. While the promise of these therapies is great, so is the number of possible combinations not only with each other but also with small molecule therapeutics. Furthermore, the observation of unusual dose-response relationships suggests a critical dependency of drug effectiveness on the dosage regimen (dose and schedule). Clinical pharmacodynamic (PD) biomarkers will be useful endpoints for confirming drug mechanism of action, evaluating combination therapies for synergy or antagonism, and identifying optimal dosage regimens. In contrast to conventional PD in which drug action occurs entirely within a single target cell (ie, is self-contained within the malignant cell), immunotherapy involves a complex mechanism of action with sequential steps that propagate through multiple cell types, both normal and malignant. Its intercellular pharmacology begins with molecular target engagement either on an immune effector cell or a malignant cell, followed by stimulatory biochemical and biological signals in immune effector cells, and then finally ends with activation of cell death mechanisms in malignant cells lying within a certain distance from the activated effector cells (immune cell–tumor cell proximity). Evaluating such “trans-cellular pharmacology,” in which different steps of drug action are distributed across multiple cell types, requires novel microscopy and image analysis tools capable of quantifying PD-biomarker responses, mapping the responses onto the cellular geography of the tumor using phenotypic biomarkers to identify specific cell types, and finally analyzing the spatial relationships between biomarkers in the context of each cell’s biological role. We have termed this form of nearest neighbor image analysis of drug action “proximity PD microscopy,” to indicate the importance of the location of the PD-biomarker response within the cellular landscape of a tumor specimen. We discuss herein the major modes of immunotherapy, and lay out a blueprint for using PD assessment to optimize dosage regimens of single agents and guide development of combination immunotherapy regimens, using PD1/PD-L1 immune checkpoint inhibition as a case study.     

从药动学/药效学角度优化头孢哌酮/舒巴坦的临床给药方案

头孢哌酮/舒巴坦是目前临床广泛使用的一种β-内酰胺类合剂。该药抗菌谱广,主要用于治疗呼吸道感染、腹腔感染等多种感染。该药临床已使用多年,对于耐药菌的治疗地位也越来越受到广泛关注。故综述其药动学/药效学特点,总结文献报道的给药方案优化策略,以供临床使用中借鉴和参考。     

化瘀消脂止痛膏主要药效学研究

目的：探讨化瘀消脂止痛膏降血脂及改善血液流变学的作用。方法：以日本大耳白家兔为高脂模型,以总胆固醇（TC）、三酰甘油（TG）、高密度脂蛋白-胆固醇（HDL-C）和低密度脂蛋白-胆固醇（LDL-C）为指标,研究化瘀消脂止痛膏降脂作用;以Wistar大鼠为血瘀证模型,测定血液流变学相关指标,研究化瘀消脂止痛膏对血液流变学的影响。结果：化瘀消脂止痛膏能显著地降低高脂动物的胆固醇和低密度脂蛋白-胆固醇,也可降低血清三酰甘油含量,并能明显降低血瘀证动物的全血黏度、血浆黏度和血纤维蛋白原含量,降低血小板黏附率。结论：化瘀消脂止痛膏能降血脂,改善血液流变学。     

童乐口服液的药效学研究

目的探讨童乐口服液对正常小鼠腹腔巨噬细胞吞噬功能的影响及其解热、抗炎作用。方法正常小鼠腹腔巨噬细胞吞噬实验(吞噬百分率和吞噬指数),大鼠角叉菜胶足爪肿胀法,干酵母致大鼠发热实验。结果童乐口服液提高正常小鼠腹腔巨噬细胞吞噬功能,抑制角叉菜胶诱导的大鼠足肿胀,高剂量组对于酵母所致大鼠发热有解热作用。结论童乐口服液能提高机体非特异性免疫功能,并具有一定的解热、抗炎作用。     

Neuromuscular paralysis as a pharmacodynamic probe to assess organ function during liver transplantation

Potential for assessing liver function during liver transplantation surgery by monitoring muscle paralysis from nondepolarizing neuromuscular blockers that are hepatically cleared is critically assessed. Rocuronium is strongly favored as a promising pharmacodynamic probe for predicting allograft liver function because it is predominantly eliminated via the liver and its putative metabolites are not active. Prolongation of recovery from rocuronium paralysis is closely correlated with allograft liver function postoperatively. Vecuronium, pancuronium, and perhaps pipecuronium may also prove to be useful probes, but the two former blockers have active metabolites. Further prospective studies are necessary with more precise measurement of neuromuscular function to confirm the predictive value of this method. Alterations in neuromuscular blocker plasma concentrations that are correlated with changes in liver function and either the dose required or the intensity or duration of paralysis needs to be demonstrated for this technique to be clinically useful.