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11.
《Journal of pharmaceutical sciences》2019,108(10):3425-3433
This study aimed at evaluating how encapsulation in a regular nanocarrier (NC) (providing extended circulation time) or in a brain-targeting NC (providing prolonged circulation time and increased brain uptake) may influence the therapeutic index compared with the unformulated drug and to explore the key parameters affecting therapeutic performance using a model-based approach. Pharmacokinetic (PK) models were built with chosen PK parameters. For a scenario where central effect depends on area under the unbound brain concentration curve and peripheral toxicity relates to peak unbound plasma concentration, dose-effect and drug-side effect curves were constructed, and the therapeutic index was evaluated. Regular NC improved the therapeutic index compared with the unformulated drug due to reduced peripheral toxicity, while brain-targeting NC enhanced the therapeutic index by lowering peripheral toxicity and increasing central effect. Decreasing drug release rate or systemic clearance of NC with drug still encapsulated could increase the therapeutic index. Also, a drug with shorter half-life would therapeutically benefit more from a NC encapsulation. This work provides insights into how a NC for brain delivery should be optimized to maximize the therapeutic performance and is helpful to predict if and to what extent a drug with certain PK properties would obtain therapeutic benefit from nanoencapsulation. 相似文献
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目的利用UPLC-LTQ-Orbitrap-MS技术对刺果番荔枝叶的化学成分进行定性分析。方法采用Waters Acquity UPLC HSS T 3色谱柱(2.1 mm×100 mm,1.8μm),流动相为0.1%甲酸水(A)和乙腈(B)梯度洗脱,流速为0.3 mL/min,进样量2μL,在电喷雾正负离子模式下采集数据。经Reaxys数据库检索番荔枝属类化合物信息,通过质谱信息比对各化合物的m/z值、保留时间、质谱特征碎片等,并结合文献数据对鉴定的化合物进行验证。结果根据各化合物的特征裂解规律,从刺果番荔枝叶中共鉴定出45个化合物,包括16个生物碱类,14个番荔枝内酯类,7个黄酮类和8个其他类化合物,其中以番荔枝内酯类和生物碱类成分居多,与文献报道番荔枝内酯与生物碱类化合物是发挥抗癌的主要活性成分一致。结论利用UPLC-LTQ-Orbitrap-MS技术对刺果番荔枝叶中的化学成分进行了快速、准确的定性分析,为刺果番荔枝叶的提取分离与药效物质基础的研究提供依据。 相似文献
14.
《Drug metabolism and pharmacokinetics》2019,34(5):308-316
LC-MS quantification of drug metabolites is sometimes impeded by the availability of internal standards that often requires customized synthesis and/or extensive purification. Although isotopically labeled internal standards are considered ideal for LC-MS/MS based quantification, de novo synthesis using costly isotope-enriched starting materials makes it impractical for early stage of drug discovery. Therefore, quick access to these isotope-enriched compounds without chemical derivatization and purification will greatly facilitate LC-MS/MS based quantification. Herein, we report a novel 18O-labeling technique using metabolizing enzyme carboxylesterase (CES) and its potential application in metabolites quantification study. Substrates of CES typically undergo a two-step oxygen exchange with H218O in the presence of the enzyme, generating singly- and doubly-18O-labeled carboxylic acids; however, unexpected hydrolytic behavior was observed for three of the test compounds – indomethacin, piperacillin and clopidogrel. These unusual observations led to the discovery of several novel hydrolytic mechanisms. Finally, when used as internal standard for LC-MS/MS based quantification, these in situ labeled compounds generated accurate quantitation comparable to the conventional standard curve method. The preliminary results suggest that this method has potential to eliminate laborious chemical synthesis of isotope-labeled internal standards for carboxylic acid-containing compounds, and can be developed to facilitate quantitative analysis in early-stage drug discovery. 相似文献
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目的:基于网络药理学方法探讨生脉散治疗心房纤颤的作用靶点和相关信号通路并探讨其作用机制。方法:运用中药系统药理学成分分析平台(bioinformatics analysis tool for molecular mechanism of TCM,BATMAN-TCM)数据库获取生脉散的化学成分及作用靶标基因,通过GeneCards,OMIM,DisGeNET数据库收集心房纤颤的靶标基因。将两者取交集后得到生脉散-心房纤颤靶基因交集,运用STRING构建蛋白质间相互作用网络,并将结果进行网络可视化展示。将药物-疾病交集基因导入DAVID6.8数据库,进行基因本体(gene ontology,GO)分析和基于京都基因与基因组百科全书(Kyoto Encyclopedia of Genes and Geomes,KEGG)通路富集分析。结果:生脉散干预房颤的有效活性成分159个,药物靶点与疾病靶点交集后获得206个共有靶点,PPI蛋白互作网络分析发现AKT1,TP53,PRKACA,IL-1B,TNF,INS,PPAR,RXR,F2,CACAN1C,PKC等是生脉散治疗房颤的核心靶点。GO富集分析确定了175个条目(P0.05),其中生物过程主要心脏传导调节心率、动作电位时膜去极化等;分子功能主要包括电压门控钙通道、类固醇激素受体活性、肾上腺素结合等,在细胞组成方面,主要包括钠、钾、钙通道复合物等。KEGG通路富集分析确定了100条相关信号通路,主要有cGMP/PKG信号通路,cAMP信号通路,血清素能突触,肾素分泌,钙信号通路等。结论:生脉散治疗心房纤颤具有多途径、多靶点作用的特点。该研究初步探讨了其作用的关键靶点及涉及的生物学过程和信号通路,为生脉散治疗心房纤颤后续的实验研究提供一定的参考。 相似文献
17.
目的首先确定中毒药物,然后通过测定血药浓度以了解中毒程度,为重度苯妥英钠中毒患者临床抢救治疗提供依据。方法间隔一定时间采集患者静脉血,萃取血中药物,在211 nm处以反相高效液相色谱法定性,明确中毒药物并测定血药浓度。结果在苯妥英中毒患者中最高血药浓度为68.94 mg.L-1,接近治疗浓度上限的3.5倍。结论患者为重度中毒,危及生命,需临床药师与临床医师积极配合,施行全程药学监护。 相似文献
18.
Uptake of Adriamycin in tumour and surrounding brain tissue in patients with malignant gliomas 总被引:1,自引:0,他引:1
H. von Holst E. Knochenhauer H. Blomgren V. P. Collins L. Ehn M. Lindquist G. Norén C. Peterson 《Acta neurochirurgica》1990,104(1-2):13-16
Summary Eight patients with malignant gliomas verified on CT scan, received an intravenous injection of 50 mg of Adriamycin R, 24 hours prior to surgical removal of the tumour. Peroperatively, both tumour and surrounding tissue specimens were obtained for determination of the tissue concentrations of Adriamycin and its reduced metabolite Adriamycinol. It was found that Adriamycin could be detected in tumour tissue from all patients. The concentration varied between 0,9 and 4,6 nmol/g tissue. In contrast, Adriamycin could only be detected in surrounding brain tissue from one patient.In anin vitro study a human malignant glioma cell line (U-251 MG) was exposed to various concentrations of Adriamycin for 24 hours. It was found that an intracellular drug concentration above 30 nmol/g cells caused a concentration dependent inhibition of cell growth. Thus, it is likely that the poor effect of Adriamycin on patients with malignant gliomas is due to an ineffective drug accumulation in the tumour tissue. 相似文献
19.
Neurotransmitter- or neuromodulator-like actions ofl-DOPA were investigated with intracellular recordings from submucous plexus neurons of the guinea-pig caecum.l-DOPA at 30 nM augmented the amplitude of fast EPSPs, but did not affect depolarizations elicited by puff application of acetylcholine (ACh). The augmenting effect ofl-DOPA on the fast EPSPs was counteracted byl-DOPA methyl ester. The fast EPSPs were depressed by 10 μMl-DOPA, but transiently augmented after rinsing the drug.l-DOPA methyl ester did not affect the inhibitory action ofl-DOPA on the fast EPSPs, but antagonized the potentiation following the inhibition. The depolarization elicited by exogenously applied. ACh was inhibited by 10 μMl-DOPA. Intracellular Ca2+ concentrations ([Ca2+]i) of the neuronal soma were measured with fura-2 microfluorophotometry. The transient increase in the [Ca2+]i evoked by the somatic action potential (Δ[Ca2+]AP) was facilitated by 30 nMl-DOPA, but decreased by the drug at 10 μM. It is concluded thatl-DOPA at low concentrations enhances the Δ[Ca2+]AP, increasing the neurotransmitter release, but at high dose diminishes the Δ[Ca2+]AP, inhibiting the neurotransmission. 相似文献
20.