肿瘤光化学诊治新药癌光啉（PsD—007）的研究

一种新的卟啉类肿瘤光化学诊治剂癌光啉(PsD-007)从血卟啉光敏剂PsD-001经柱层析分离而得到。它对NADPH在D_2O中光氧化作用的敏化效应高于HpD。其对体外培养人癌细胞系的光灭活作用和对三种动物移植瘤的光化疗效果均略优于光敏素Ⅱ。     

酞菁化合物作为新型肿瘤光化学诊治剂的研究进展

八十年代问世的肿瘤光化学诊治剂已引起越来越多的肿瘤学家和药物化学家的广泛注意,目前临床应用的药物如美国的血卟啉衍生物(HpD)、光敏素Ⅱ(PhotofrinⅡ)和我国的YHpD、癌光啉(PsD-007)等均为复杂的混合卟啉制剂,由于其组成不定和有效成分不明限制了对它们作用机理的深入研究和进一步发展成为商品,因此,研究提供具有结构明确、性质稳定、肿瘤选择性摄入率高和光敏化效应强的新型肿瘤光化学诊治剂已成为当前药物化学研究的一个迫切课题。酞菁(Phthalocyanines,PCs)又称酞花菁或四苯骈四氮杂卟啉(tetrabenztetraaza-porphyrin),包括其金属络合物(metal phthalocyanines,M-PCs)。Braun等于1907     

肿瘤光化学诊治剂癌光啉(代号PsD-007)静脉注射液的配制

随着肿瘤光化学诊治研究的深入发展和临床应用的不断扩大,配制符合药典要求的光化学诊治剂注射液已日益成为医院药房制剂工作的新课题。目前国内外使用的肿瘤光化学诊治剂如血卟啉衍生物(HpD)、光敏素Ⅱ(photofrinⅡ)、癌光啉及光卟啉等均属羧基卟啉类化合物,它们共同的特性是对光和热不稳定。系两性有机分子。癌光啉是我国独立研制的一种新的卟啉类肿瘤光化学诊治剂,实验证明其对恶性组织的选择性摄入     

六味地黄汤的化学研究(Ⅱ)

本文通过对组成六味地黄汤的各单味药、各种不同配伍及全方水煎剂的pH值、水溶性浸出物、醇溶性浸出物的测定,对六味地黄汤的组方原理从化学方面进行了初步探讨,运用薄层层析、薄层扫描观察全方、三补及各单味药之间化学成份的变化;用紫外分光光度法测定六味地黄汤及丹皮煎剂中丹皮酚的含量,认为丹皮酚不一定是六味地黄汤中发挥疗效的主要成分。     

当归地上与地下部分挥发油的比较研究

目的　研究当归 Angelica sinensis地上部分挥发油成分的组成。方法　分别提取当归地上部分与药用根部的挥发油 ,以气相色谱 -质谱联用技术测定其成分。结果　从当归地上部分挥发油中鉴定了 35种成分 ,占挥发油成分的 4 6 .2 7% ;药用根部挥发油中鉴定了 39种成分 ,占挥发油组成的 6 0 .0 9%。结论　当归地上部分挥发油与根的挥发油化学组成上有明显不同 ,对传统中药当归的综合开发利用具有一定的意义     

提高暗疮搽剂稳定性的配制方法

我们医院制剂室配制的暗疮搽剂是临床应用非常广泛的一种外用混悬型液体制剂,疗效显著。但由于其所含药物成分比较多,特别是其中有些成分的化学稳定性差,且由于这种制剂属于热力学不稳定的粗分散体系,假若配方中处方组成不合理,配制方法不恰当,必然会降低稳定性而影响疗效。经过我们多次的实验,不断总结经验,摸索岀一种较完善的、能有效提高暗疮搽剂稳定性的配制方法。     

血卟啉单甲醚（PsD—044）在家兔体内的药物动力学

用荧光分光光度法测定血卟啉单甲醚(PsD-044)的血药浓度激发光波长为395nm;发射光波长为613nm。PsD-044血浆浓度为10和20μg/ml时,测定回收率分别为98.31±1.17％(cv=1.19％)和97.76±6.35％(cv=6.80％)。PsD-044在家兔体内的药物动力学按三房室拟合。其主要药物动力学参数分别为:π=16.60h~(-1);α=0.546h~(-1);β=0.0303h~(-1);t_(1/2π)=0.0427h;t_(1/2α)=1.31h;t_(1/2β)=28.08h;V_c=0.0704L/kg;V_(area)=16.19L/kg;V_(ss)=6.26L/kg;Cl=0.487L/kg·h。     

苯丙醇胺的药理和安全性

苯丙醇胺(去甲麻黄碱,简称 PPA)是对映体 d-和1-去甲麻黄碱(NOR)的外消旋混合物,属内源性拟交感神经胺的化学类似物。PPA被作为非处方的鼻粘膜血管收缩剂、感冒药和食欲抑制剂的组成成分。     

一测多评法应用于化学药及中药的化学药成分质量控制研究进展

一测多评法（QAMS法）是通过采用一种对照品同时测定多种成分含量的定性定量分析方法,具有高选择性、经济、准确等特点,目前在化学药物、中药及其制剂的含量测定中已得到推广应用。简述了QAMS法建立流程,综述了近年来QAMS法在化学药物定量分析、中药的化学药物成分、中药违法添加化学药物及药物杂质的定性定量分析中的研究进展,并对其应用前景进行了展望。     

高效液相色谱法在体液成分分析中的应用

高效液相色谱法(HPLC)自1967年问世以来,发展和普及十分迅速,每年有关HPLC文献呈指数函数增长,1983年化学文摘就选登了2501篇文章。近年,HPLC的高灵敏度检测器不断发展,高性能填充剂相继出现、衍生化试剂种类逐渐扩大,为遇热不稳定和微量体液成分的分析创造了有利条件。如血浆、尿等都是由分子量大的多种成分组成的,而这些成分又与身体功能有密切关系。以体液为对象的临床化学检查对诊断和治疗效果的判定都起着重要作用。本文就HPLC在体液成分分析的自动化及其应用加以概述。     

HPLC法测定卡莫氟片的含量及溶出度

目的：采用高效液相色谱法测定卡莫氟片的含量和溶出度。方法：以十八烷基硅烷键合硅胶为填充剂,以甲醇-0．25％醋酸溶液为流动相,检测波长为258nm。结果：卡莫氟在0．00768～0．06912g·L^-1浓度范围内线性关系良好,平均回收率为100．06％,RSD=0．82％（n=9）。结论：方法简便、快速、结果准确。     

HPLC法测定复方莪术油栓的含量

目的:建立复方莪术油栓中硝酸益康唑和牻牛儿酮的含量测定方法.方法:采用高效液相色谱法.结果:硝酸益康唑在0.02058～0.205 8 mg·mL-1范围内,牻牛儿酮峰在0.00799～0.079 92 mg·mL-1范围内,线性关系良好;平均回收率分别为97.9%和98.7%,RSD分别为1.5%与1.2%(n＝9).结论:所建方法简便、准确,适用于复方莪术油栓中硝酸益康唑和牻牛儿酮的含量测定.     

T0070907 inhibits repair of radiation-induced DNA damage by targeting RAD51

T0070907 (T007), a PPARγ inhibitor, can reduce α and β tubulin proteins in some cancer cell lines. Thus, T007 has been suggested as an antimicrotubule drug. We previously reported that T007 increased radiosensitivity by inducing mitotic catastrophe in cervical cancer cells. In this study, we investigated the underlying mechanisms of the T007-mediated increase in radiosensitivity. T007 pre-treatment attenuated RAD51 protein levels and ionising radiation (IR)-induced nuclear foci formation, resulting in more frequent centrosome amplification and multipolar mitotic spindle formation in cervical cancer cells. Furthermore, T007 pre-treatment delayed the clearance of IR-induced γ-H2AX and increased radiosensitivity in cervical cancer cells. In contrast, none of these changes were observed in normal cells. Our data demonstrate for the first time that T007 impairs the repair of IR-induced DNA double-strand breaks by inhibiting RAD51, a key protein in homologous recombination repair, increases IR-induced mitotic catastrophe, and leads to increased death of IR-treated cells. These findings support T007 as a potential RAD51 inhibitor to increase tumour response to radiation therapy.     

Removal of cysteinylation from an unpaired sulfhydryl in the variable region of a recombinant monoclonal IgG1 antibody improves homogeneity, stability, and biological activity

The antibody MAB007 was recently shown to be cysteinylated on an unpaired cysteine residue in the CDR3 variable region. Cysteinylation at this position was not complete and resulted in heterogeneous lots of MAB007 with respect to this posttranslational modification. In this report, a mild redox step was used that effectively removed cysteinylation while keeping native inter and intra-molecular disulfide bonds intact. Biophysical methods were employed to determine what consequences cysteinylation of the variable region had by directly comparing cysteinylated and de-cysteinylated MAB007 antibodies. No differences were detected in secondary structure; however, several pieces of evidence indicated that cysteinylation may result in tertiary or quaternary structural perturbations. These included differences in the cation-exchange chromatography and fluorescence-emission spectra of the cysteinylated and de-cysteinylated antibodies as well as differences in the solvent accessibility of the unpaired cysteine residue determined by labeling experiments. Such structural changes induced by cysteinylation were shown to increase the rate of MAB007 aggregation and to decrease the melting temperature of the Fab region by as much as 6 degrees C. The bioactivity of MAB007 was also shown to be adversely affected by cysteinylation and a direct correlation was made between the percent cysteinylation and biological activity.     

癌光啉在兔体内的药代动力学及生物利用度

目的研究癌光啉在兔体内的药代动力学及生物利用度特点,为药物进一步研究提供依据。方法兔腹腔注射或静脉注射10 mg.kg-1癌光啉,于给药后的10 min、30 min、1h、2 h、4 h、8 h、24 h、48 h、72 h耳缘静脉采血,以全波长酶标仪荧光法测定兔血浆中癌光啉浓度,用3P97处理血药浓度-时间数据,分析房室模型,得到最佳房室模型和药代动力学参数。结果家兔腹腔注射癌光啉10 mg.kg-1的时量曲线符合一室开放模型,静脉注射时的时量曲线符合三室模型,但其消除快于ip。主要药代动力学参数:ip给药组,T12Ke=11.6 h,Cmax=2.312 mg.L-1,AUC=43.177 mg.L-1.h,CL=0.232 L.kg-1.h-1,V/F(c)=3.888 L.kg-1;iv给药组,Vc=0.75 L.kg-1,T12α=2.824 h,T 12β=40.632 h,AUC=65.161 mg.L-1.h,CL(s)=0.153 L.kg-1.h-1。腹腔给药后绝对生物利用度是66.2%。结论癌光啉在兔体内吸收快、起效快、消除快,无蓄积现象,给药方式不同,药代动力学特点不同。     

HPLC法同时测定糖浆剂中三种B族维生素及山梨酸的含量

目的建立高效液相色谱法同时测定多维生素糖浆中盐酸硫胺(VitB1)、核黄素-5′-磷酸钠(VitB2)、盐酸吡多辛(VitB6)及防腐剂山梨酸的含量。方法采用高效液相色谱法,使用Allthna C18柱(4.6×250mm,5μm),流动相A为8mmol·L-1己烷磺酸钠溶液(1000mL溶液加入三乙胺0.25mL和乙酸9.2mL);流动相B为甲醇;梯度洗脱;流速为1.0mL·min-1;检测波长为280nm。结果 VitB1、VitB2、VitB6、山梨酸的浓度分别在0.02～0.4mg·L-1、0.02～0.4mg·mL-1、0.007～0.1mg·.mL-1、0.03～0.6mg·mL-1范围内与峰面积线性关系良好;平均回收率分别为99.2%、101.9%、101.5%、101.5%。结论本实验所建立的高效液相色谱分析方法快速、灵敏,色谱峰分离度良好,结果准确可靠,可作为多维生素糖浆的质量控制项目之一。     

A novel tylophorine analog NK-007 ameliorates colitis through inhibition of innate immune response

In this study, we synthesized (±)-tylophorine malate (NK-007), an analog of tylophorine (DCB3503), and analyzed its anti-inflammatory effect in vivo using a dextran sulfate sodium (DSS)-induced colitis model and an acetic acid-induced colitis model. As indicated by disease activity index (DAI) and degree of macroscopic colonic damage, NK-007 can significantly suppress colitis. To delineate the underlying mechanism, we have explored the influence of NK-007 on the production of TNF-α by murine primary bone marrow-derived dendritic cells (BMDCs) as well as monocyte/macrophage cell line Raw 264.7 triggered by lipopolysaccharide (LPS). For both types of innate immune cells, NK-007 showed a potent TNF-α inhibitory effect, and has in addition reduced the expression of IL-12 in BMDCs. Moreover, Raw cells treated with NK-007 also showed decreased phosphorylation of NF-κB, which may explain the protective immune-regulatory effect of NK-007 for experimental colitis.     

Dual inhibition of topoisomerase I and tubulin polymerization by BPR0Y007, a novel cytotoxic agent

Through the screening of DNA topoisomerase I (Top I) inhibitors, a new cytotoxic agent, BPR0Y007 [2,5-bis(4-hydroxy-3-methoxybenzylidene)cyclopentanone], was identified. BPR0Y007 was less potent than camptothecin (CPT) in the inhibition of Top I in vitro. Also, in vitro data showed that BPR0Y007 induces DNA cleavage in the presence of Top I at micromolar concentrations, with a cleavage specificity similar to that of CPT. High concentrations of BPR0Y007 did not produce detectable DNA unwinding, suggesting that BPR0Y007 is not a DNA intercalator. However, BPR0Y007 displaced Hoechst 33342 dye, suggesting that BPR0Y007 binds to DNA at the Hoechst 33342 binding site. Furthermore, BPR0Y007 generated protein-linked DNA breaks in a cell-based study. Cell cycle analysis demonstrated that the cell cycle effect of BPR0Y007 differs from that of CPT. Cells accumulated in the S-phase when treated with high concentrations of CPT, whereas cells accumulated gradually in the G(2)/M phase when treated with increasing concentrations of BPR0Y007. Further studies showed that BPR0Y007 inhibits tubulin polymerization in vivo and in vitro, and induces apoptosis in a concentration-dependent manner. No cross-resistance with BPR0Y007 was observed in CPT-, VP-16-, or vincristine-resistant cell lines. The IC(50) of BPR0Y007 for various human cancer cell lines ranged from 1 to 8 microM. Taken together, these results suggest that BPR0Y007 acts on both Top I and tubulin. Given its unique biochemical mechanisms of action, BPR0Y007 warrants exploration as an antitumor compound.     

A novel bis-benzylidenecyclopentanone derivative, BPR0Y007, inducing a rapid caspase activation involving upregulation of Fas (CD95/APO-1) and wild-type p53 in human oral epidermoid carcinoma cells

BPR0Y007, a bis-benzylidenecyclopentanone derivative (2,5-bis- (4-hydroxy-3-methoxybenzylidene) cyclopentanone), was identified in our laboratory as a novel antineoplastic agent with a broad spectrum of antitumor activity against many human cancer cells. A previous study showed that BPR0Y007 inhibited DNA topoisomerase I (Top 1) activity and prevented tubulin polymerization. Notably, no cross-resistance with BPR0Y007 was observed in camptothecin-, VP-16- or vincristine-resistant cell lines. In this study, we further investigated the cellular and molecular events underlying the antitumoral function of this compound in human oral epidermoid carcinoma KB cells, focusing on the early cytotoxic effect. Treatment of KB cells with BPR0Y007-induced G(2)/M phase arrest followed by sub-G(1) phase accumulation. Annexin-V-propidium iodide (PI) binding assay and DNA fragmentation assay further indicated that BPR0Y007-induced cell death proceeded through an apoptotic pathway as opposed to via necrosis. This compound produced a time-dependent activation of caspases-3 and -8, however, another caspase-3 initiator, caspase-9, was only marginally activated at later time point. We further demonstrated that the activation of the caspases cascade and nuclear fragmentation was not associated with inactivated Bcl-2 and perturbed mitochondrial membrane potential by BPR0Y007. The finding that BPR0Y007-induced apoptosis through a membrane-mediated mechanism was supported by up-regulated expression of Fas (CD95/APO-1), but not Fas-L. Furthermore, up-regulation of p53 and its affected gene, MDM2, in KB cells was found after BPR0Y007 exposure. Overall, our results demonstrated that the BPR0Y007 could induce an early cytotoxic apoptosis through a caspase-8-dependent but mitochondrial-caspase-9 independent pathway, and involving upregulation of p53.