Ultrastructural organization of proteoglycans and fibrillar matrix of the tectorial membrane

The molecular and supramolecular structure of the tectorial membrane (TM) was studied by transmission electron microscopy (TEM). Collagen (type A) fibrils in the TM were found associated with proteoglycans (PGs) and type B fibrils. Most PGs were orthogonally oriented and attached D-periodically to collagen fibrils. Computer averaged projections of PG particles and linear aggregates of PGs in crystalline arrays, stained with Cuprolinic blue, showed an elongated, electron-dense structure 50–65 nm in length and 10 nm in width. Image analysis of type B fibrils showed that they are constructed of globular domains arranged with a periodicity of 12–14 nm. Each globular domain contains two thin ‘arms', extended in opposite directions, which contact the ‘arms' of adjacent fibrils. Numerous type B fibrils were found between collagen fibrils. They are attached to adjacent collagen fibrils by the ‘arms' of their globular domains. An association of type B fibrils and PGs with collagen seems to result in the local ordered arrangement of the TM matrix. A hypothetical model of the TM matrix supramolecular structure is presented.     

吡啶-2,6(1H,3H)二酮生物碱对ADP、AA、Collagen诱导的兔血小板聚集的影响

目的观察吡啶－２，６（１Ｈ，３Ｈ）二酮生物碱（ＳＨ１）对ＡＤＰ、ＡＡ、Ｃｏｌｌａｇｅｎ诱导的兔血小板聚集的影响。方法用比浊法测定了ＳＨ１体外对兔血小板聚集的影响。结果ＳＨ１对３种诱导剂的最大抑制率分别为６２．１６％、４５．２５％、５３．６７％。大剂量组明显加快ＡＤＰ诱导的兔血小板聚集后的解聚速度。ＳＨ１显著延长Ｃｏｌａｇｅｎ的诱导起聚时间。结论ＳＨ１０．８～４．０ｍｍｏｌＬ－１范围内明显抑制ＡＡ、ＡＤＰ、Ｃｏｌａ－ｇｅｎ诱导的兔血小板聚集。其抑制作用有明显的量效关系。其机制待进一步研究。     

丹红合剂对家兔血小板聚集的影响

目的 观察丹红合剂对家兔血小板聚集的影响.方法 采用随机数字表法将40只大耳白家兔随机分为5组,每组8只,分别为空白对照组(予等容量的0.5％羧甲基纤维素纳),丹红合剂5、2.5、1.25 g/kg组,阿司匹林0.025 g/kg组.各组均按1ml/kg容积灌胃,1次/d,连续给药8d.于末次给药1h后心脏取血,用二磷酸腺苷(ADP)、胶原、花生四烯酸(AA)3种诱导剂进行血小板聚集实验.结果 丹红合剂5、2.5、1.25 g/kg组对ADP诱导的家兔血小板聚集率的抑制率分别为9.4％、5.1％、0.6％,对胶原诱导的家兔血小板聚集抑制率分别为34.5％、11.1％、5.6％;对花生四烯酸(AA)诱导的家兔血小板聚集抑制率分别为21.4％、11.6％、2.3％.结论 丹红合剂具有抑制血小板聚集作用.     

益母草水提物对异丙肾上腺素致大鼠心肌重构的影响

目的:从心肌组织胶原表达的角度观察益母草水提物对实验性大鼠心肌重构的影响。方法:SD大鼠皮下注射异丙肾上腺素建立心肌重构模型,随机分为正常对照组、模型组、依那普利组及益母草水提物低、高剂量组,药物干预15 w。检测大鼠心脏血流动力学指标、心输出量、心脏质量系数、左室质量系数、心肌羟脯氨酸含量、心肌组织Ⅰ、Ⅲ型胶原含量。结果:与模型组比较,益母草水提物高剂量能改善模型大鼠LVSP、+dp/dtmax和CO(P<0.05),益母草低剂量能改善-dp/dtmax、心脏质量系数和左室质量系数、心肌组织羟脯氨酸含量及Ⅰ、Ⅲ型胶原含量、Ⅰ/Ⅲ型胶原比(P<0.05)。结论:高剂量益母草水提物能改善ISO致大鼠心肌重构模型心脏收缩功能;低剂量益母草水提物能改善ISO致大鼠心肌重构模型舒张功能,下调胶原表达,改善心肌胶原构成比,减轻心肌重构程度。     

降钙素对白介素-1β诱导的大鼠软骨细胞炎性反应的作用

目的：探讨降钙素对白介素-1β(IL-1β)诱导的大鼠骨关节炎(OA)中基质金属蛋白酶-13(MMP-13)、Ⅱ型胶原、p38及P-p38表达的影响。方法分离SD大鼠关节软骨,消化、培养。采用甲苯胺蓝染色鉴定软骨细胞。将第2代软骨细胞分为空白对照组、IL-1β诱导组和IL-1β+降钙素治疗组,空白对照组和IL-1β诱导组分别给予完全培养基、含10 ng/ml IL-1β的完全培养基,IL-1β+降钙素治疗组先加入含10 ng/ml IL-1β的完全培养基15 min,再加入50 ng/ml降钙素,均培养24 h。用透射电镜观察细胞的超微结构,蛋白免疫印迹检测MMP-13、Ⅱ型胶原、p38、P-p38表达。实时荧光定量PCR检测MMP-13、Ⅱ型胶原 mRNA的表达。结果3组软骨细胞p38蛋白及mRNA表达水平比较差异无统计学意义(P>0．05)。 IL-1β诱导组和IL-1β+降钙素治疗组P-p38、MMP-13蛋白及mRNA表达水平均高于空白对照组,但IL-1β+降钙素治疗组低于IL-1β诱导组( P<0．05);IL-1β诱导组和IL-1β+降钙素治疗组Ⅱ型胶原蛋白及mRNA表达水平低于空白对照组(P<0．05),IL-1β+降钙素治疗组高于IL-1β诱导组,但差异无统计学意义(P>0．05)。结论 IL-1β可以体外诱导大鼠软骨细胞形成OA病变。降钙素对IL-1β诱导的大鼠OA模型中软骨细胞损伤具有一定的改善作用,其机制之一可能是通过抑制p38信号通路的激活降低MMP-13的表达,减少Ⅱ型胶原的降解,从而延缓OA进程。     

山药配方颗粒溶化性差的原因分析与解决策略

山药配方颗粒由山药饮片经水煎煮提取、分离、浓缩、干燥、制粒而成,具有调剂简单、使用方便、免煎易服等优势。然而,因山药富含淀粉与黏液质类成分,其提取物粉末与配方颗粒溶化性差,在5 min内难以完全溶化或分散,不溶物即使在水中静置24 h也难以完全溶散,影响了配方颗粒的质量评价与患者的服药心理。因此,通过研究山药提取物及其配方颗粒的溶化过程与机制,发现山药特殊的化学组成、高温提取过程中淀粉的变性及其与蛋白质等物质的复合、喷雾干燥过程中“衣膜”的收缩形成等因素综合叠加,最终形成“衣膜”包覆淀粉粒的特殊微观结构,是山药配方颗粒溶化性差的根本原因。基于课题组前期对粉体结构-性质-功能的研究,笔者提出采用粉体改性工艺改善山药配方颗粒溶化性的技术策略,并通过实验证明改性处理后的山药配方颗粒能在2 min内实现全部溶散,解决了该技术难题,可为其他类似品种的溶化性改善提供借鉴,推动中药配方颗粒产业的高质量发展。     

An Investigation of Oral Exposure Variability and Formulation Strategy: A Case Study of PI3Kδ Inhibitor and Physiologically Based Pharmacokinetic Modeling in Beagle Dogs

It is well acknowledged that drugs with poor aqueous solubility are often associated with poor oral absorption. Fortunately, drugs with a basic pKa can take advantage of solubilization in the stomach under the acidic environment to improve exposure. Consequently, high in vivo variability is often observed when stomach pH is altered. When issue encountered, enabling formulations are often used to solve the problem. However, each enabling formulation has its limitations and the situation can be further complicated by other absorption distribution metabolism elimination parameters. Therefore, formulation strategies need to consider various scenarios in order to be effective. Compound 1 is a potent phosphoinositide 3-kinase delta inhibitor with poor intrinsic solubility and 2 basic pKas. It was dosed as a suspension in dogs and found to have mediocre oral bioavailability with high variability. It was hypothesized that this variability was caused by their stomach pH variability. Pharmacokinetic modeling suggested that the issue could be improved with particle size reduction. Meanwhile, it was found that although the Madin-Darby canine kidney permeability was reasonable, Madin-Darby canine kidney transfected with human MDR1 gene (MDCK-MDR1) suggested that Compound 1 is an efflux transporter substrate. Findings were integrated into the design for in vivo studies in dogs. Data obtained from those studies allowed us to quickly narrow down the formulation approaches.     

新药开发中药物的盐型选择

成盐是改善弱酸性及弱碱性药物的溶解度和提高药物生物利用度的重要手段.因此,为药物筛选合适的反离子是药品研发过程的关键步骤.本文探讨了筛选反离子时需考虑的因素和成盐对药物的溶解度和溶出速率的影响.     

板蓝根脂溶性提取物固体分散体的溶解特性研究

分别以PVP K30、PEG6000、泊洛沙姆188为载体制备板蓝根脂溶性提取物的固体分散体，并以靛玉红为指标，采用HPLC法测定含量以考察制得固体分散体的溶解特性。结果显示，3种固体分散体均能显著增加板蓝根脂溶性成分在水中的溶解度，但随时间延长，溶解度下降，以PVP K30为载体的制品下降趋势最缓。     

消旋棉酚晶态结构的研究

目的:研究消旋棉酚晶形结构。方法:采用红外光谱(IR)、差示扫描量热法(DSC)、测定溶解度和粉末X射线衍射法(XRD)来研究消旋棉酚晶态结构。结果:消旋棉酚[(±)G]、左旋棉酚[(-)G]和右旋棉酚[(+)G]的红外谱图基本相同;DSC图谱及热特征数据不一致;在消旋棉酚的饱和溶液中加入光学活性棉酚,光学活性棉酚可以继续溶解,并且有旋光产生;(±)G与(-)G及(+)G的XRD图完全不同。结论:消旋棉酚晶体属于外消旋化合物。