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排序方式: 共有1008条查询结果,搜索用时 125 毫秒
51.
Stephanie Dodd Sivacharan Kollipara Manuel Sanchez-Felix Hyungchul Kim Qingshuo Meng Stefania Beato Tycho Heimbach 《Journal of pharmaceutical sciences》2019,108(1):87-101
Advances in understanding of human disease have prompted the U.S. Food and Drug Administration to classify certain molecules as “break-through therapies,” providing an accelerated review that may potentially enhance the quality of patient lives. With this designation come compressed timelines to develop drug products, which are not only suitable for clinic trials but can also be approved and brought to the market rapidly. Early risk identification for decreased oral absorption due to drug-drug interactions with proton pump inhibitors (PPIs) or acid-reducing agents (ARAs) is paramount to an effective drug product development strategy. An early ARA/PPI drug-drug interaction (DDI) risk identification strategy has been developed using physiologically based absorption modeling that readily integrates ADMET predictor generated in silico estimates or measured in vitro solubility, permeability, and ionization constants. Observed or predicted pH-solubility profile data along with pKas and drug dosing parameters were used to calculate a fraction of drug absorbed ratio in absence and presence of ARAs/PPIs. An integrated physiologically based pharmacokinetic absorption model using GastroPlus? with pKa values fitted to measured pH-solubility profile data along with measured permeability data correctly identified the observed ARA/PPI DDI for 78% (16/22) of the clinical studies. Formulation strategies for compounds with an anticipated pH-mediated DDI risk are presented. 相似文献
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53.
Lipid-based formulations have been an attractive choice among novel drug delivery systems for enhancing the solubility and bioavailability of poorly soluble drugs due to their ability to keep the drug in solubilized state in the gastrointestinal tract. These formulations offer multiple advantages such as reduction in food effect and inter-individual variability, ease of preparation, and the possibility of manufacturing using common excipients available in the market. Despite these advantages, very few products are available in the present market, perhaps due to limited knowledge in the in vitro tests (for prediction of in vivo fate) and lack of understanding of the mechanisms behind pharmacokinetic and biopharmaceutical aspects of lipid formulations after oral administration. The current review aims to provide a detailed understanding of the in vivo processing steps involved after oral administration of lipid formulations, their pharmacokinetic aspects and in vitro in vivo correlation (IVIVC) perspectives. Various pharmacokinetic and biopharmaceutical aspects such as formulation dispersion and lipid digestion, bioavailability enhancement mechanisms, impact of excipients on efflux transporters, and lymphatic transport are discussed with examples. In addition, various IVIVC approaches towards predicting in vivo data from in vitro dispersion/precipitation, in vitro lipolysis and ex vivo permeation studies are also discussed in detail with help of case studies.KEY WORDS: Pharmacokinetics, Lipolysis, IVIVC, Efflux transporters, Lymphatic delivery, Food effectAbbreviations: ADME, absorption/distribution/metabolism/elimination; AUC, area under the curve; BCS, biopharmaceutics classification system; BDDCS, biopharmaceutics drug disposition classification system; CACO, human epithelial colorectal adenocarcinoma cells; Cmax, maximum plasma concentration; CMC, critical micellar concentration; CYP, cytochrome; DDS, drug delivery systems; FaSSGF, fasted-state simulated gastric fluid; FaSSIF, fasted-state simulated intestinal fluid; FeSSIF, fed-state simulated intestinal fluid; GIT, gastrointestinal tract; IVIVC, in vitro in vivo correlation; LCT, long chain triglyceride; LFCS, lipid formulation classification system; log P, n-octanol/water partition coefficient; MCT, medium chain triglyceride; MDCK, Madin–Darby canine kidney cells; NCE, new chemical entity; P-app, apparent permeability; P-gp, permeability glycoprotein; SCT, short chain triglyceride; SEDDS, self-emulsifying drug delivery system; SIF, simulated intestinal fluid; SMEDDS, self-microemulsifying drug delivery system; SNEDDS, self-nanoemulsifying drug delivery system; Vit E, vitamin E 相似文献
54.
目的:通过计算机编程,实现两种宫颈癌后装治疗剂量的调强优化方法,并与传统的A点优化方法进行比较。方法:选择一套已放置3根施源器(1根在宫腔,2根在隆穹)的宫颈癌患者的CT图像,采用VC++编程,读入图像并重建施源器,然后根据靶区器官的限量约束条件(处方剂量为5 Gy),自动激活部分驻点,分别采用模拟退火算法和随机最小二乘法进行调强逆向计算驻点的时间。接着,设A点(宫口上2 cm,旁开2cm)为剂量参考点,取上述相同的驻点,以均等权重方式计算驻点时间。最后比较3种优化方法的剂量分布。结果:在模拟退火法、随机二乘法和A点方法中,5 Gy覆盖靶区的体积分别为84.2%、80.2%和79.5%,靶区的D90分别为4.1 Gy、4.3 Gy和3.7 Gy,直肠D2cc为4.6 Gy、3.2 Gy和3.9 Gy,膀胱的D2cc为5.0 Gy、2.7Gy和4.1 Gy,靶区剂量的均匀度为65%、49%和45%。结论:模拟退火算法可以同时兼顾靶区受量和重要器官限量,剂量均匀性好,能满足个体化后装治疗的需求。随机最小二乘法虽能提高靶区的D90,减少直肠膀胱的受量,但相邻驻点之间的时间梯度变化较大。 相似文献
55.
Ahmed Noah Badr Marwa M. El-Attar Hatem S. Ali Manal F. Elkhadragy Hany M. Yehia Amr Farouk 《Toxins》2022,14(2)
Spent coffee grounds (SCGs), which constitute 75% of original coffee beans, represent an integral part of sustainability. Contamination by toxigenic fungi and their mycotoxins is a hazard that threatens food production. This investigation aimed to examine SCGs extract as antimycotic and anti-ochratoxigenic material. The SCGs were extracted in an eco-friendly way using isopropanol. Bioactive molecules of the extract were determined using the UPLC apparatus. The cytotoxicity on liver cancer cells (Hep-G2) showed moderate activity with selectivity compared with human healthy oral epithelial (OEC) cell lines but still lower than the positive control (Cisplatin). The antibacterial properties were examined against pathogenic strains, and the antifungal was examined against toxigenic fungi using two diffusion assays. Extract potency was investigated by two simulated models, a liquid medium and a food model. The results of the extract showed 15 phenolic acids and 8 flavonoids. Rosmarinic and syringic acids were the most abundant phenolic acids, while apigenin-7-glucoside, naringin, epicatechin, and catechin were the predominant flavonoids in the SCGs extract. The results reflected the degradation efficiency of the extract against the growth of Aspergillus strains. The SCGs recorded detoxification in liquid media for aflatoxins (AFs) and ochratoxin A (OCA). The incubation time of the extract within dough spiked with OCA was affected up to 2 h, where cooking was not affected. Therefore, SCGs in food products could be applied to reduce the mycotoxin contamination of raw materials to the acceptable regulated limits. 相似文献
56.
模拟失重对大鼠肺动脉eNOS表达的影响 总被引:1,自引:1,他引:0
目的通过研究模拟失重对大鼠肺动脉血管内皮型一氧化氮合酶(eNOS)表达的影响,探讨肺动脉反应性改变的发生机制。方法采用尾悬吊大鼠模拟失重,分为模拟失重组(尾悬吊14天)和对照组,每组8只健康雄性Wistar大鼠,用蛋白免疫印迹分析模拟失重组和对照组大鼠肺动脉组织eNOS表达,硝酸还原酶法测定肺动脉组织一氧化氮(NO)含量。结果同对照组相比,模拟失重组大鼠肺动脉组织eNOS表达增强,胶片图像扫描后的相对光密度值为247±2·60,对照组的相对光密度值为141±1·72,两组间有显著性差异(P<0·01)。模拟失重组肺动脉组织NO含量亦增加,其浓度为15·7±4·1μmol/L,对照组为7·6±3·2μmol/L,两组间有显著性差异(P<0·05)。结论模拟失重条件下肺动脉eNOS表达增加可能促进了立位耐力不良的发生。 相似文献
57.
P. Gallagher S. Trappe M. Harber A. Creer S. Mazzetti T. Trappe B. Alkner P. Tesch 《Acta physiologica (Oxford, England)》2005,185(1):61-69
Aim: This investigation determined the effects of 84 days of bedrest on the composition of myosin heavy chain (MHC) in single skeletal muscle fibres with and without a resistance‐training countermeasure programme. Methods: Muscle biopsies were obtained from the m. vastus lateralis (VL) and m. soleus (SOL) before and after 84 days of bedrest. While control (BR) subjects (VL n = 9; SOL n = 3) refrained from exercise, BRE subjects (VL n = 8; SOL n = 3) performed knee extensor and plantar flexor resistance exercise every third day. Approximately 110 fibres per sample were analysed for MHC composition using SDS‐PAGE. Results: BR–VL had 16 and 14% decreases (P < 0.05) in MHC I and IIa fibres, respectively. There were 10% increases (P < 0.05) in MHC I/IIa, IIa/IIx, I/IIa/IIx, and a ~30% increase (P < 0.05) in total hybrid fibres. BRE‐VL showed a 15% reduction (P < 0.05) in MHC I fibres, no change in MHC IIa fibres, and a 13% increase (P < 0.05) in total hybrids. BR–SOL had a 19% decrease (P < 0.05) in MHC I fibres with a 22% increase in total hybrids. BRE–SOL showed no change in MHC composition across all fibre types. Conclusion: These data suggest that the exercise countermeasures programme prevented MHC shifts in the SOL and mitigated MHC shifts in the VL. Furthermore, in the VL it appears that the resistance training programme employed in this investigation during bedrest, emphasized the use of MHC IIa phenotype muscle fibres. 相似文献
58.
Trappe TA Burd NA Louis ES Lee GA Trappe SW 《Acta physiologica (Oxford, England)》2007,191(2):147-159
AIM: The goal of this investigation was to test specific exercise and nutrition countermeasures to lower limb skeletal muscle volume and strength losses during 60 days of simulated weightlessness (6 degrees head-down-tilt bed rest). METHODS: Twenty-four women underwent bed rest only (BR, n = 8), bed rest and a concurrent exercise training countermeasure (thigh and calf resistance training and aerobic treadmill training; BRE, n = 8), or bed rest and a nutrition countermeasure (a leucine-enriched high protein diet; BRN, n = 8). RESULTS: Thigh (quadriceps femoris) muscle volume was decreased (P < 0.05) in BR (-21 +/- 1%) and BRN (-24 +/- 2%), with BRN losing more (P < 0.05) than BR. BRE maintained (P > 0.05) thigh muscle volume. Calf (triceps surae) muscle volume was decreased (P < 0.05) to a similar extent (P > 0.05) in BR (-29 +/- 1%) and BRN (-28 +/- 1%), and this decrease was attenuated (P < 0.05) in BRE (-8 +/- 2%). BR and BRN experienced large (P < 0.05) and similar (P > 0.05) decreases in isometric and dynamic (concentric force, eccentric force, power and work) muscle strength for supine squat (-19 to -33%) and calf press (-26 to -46%). BRE maintained (P > 0.05) or increased (P < 0.05) all measures of muscle strength. CONCLUSION: The nutrition countermeasure was not effective in offsetting lower limb muscle volume or strength loss, and actually promoted thigh muscle volume loss. The concurrent aerobic and resistance exercise protocol was effective at preventing thigh muscle volume loss, and thigh and calf muscle strength loss. While the exercise protocol offset approximately 75% of the calf muscle volume loss, modification of this regimen is needed. 相似文献
59.
目的 研究旋转细胞培养系统(RCCS)模拟微重力环境对小鼠成纤维细胞株L929 lncRNA表达的影响.方法 体外培养L929细胞,随机分为模拟微重力组(SMG组)和正常重力组(NG组),每组3个样本.SMG组回转器轴心与地面平行旋转,NG组回转器轴心与地面垂直旋转,两组转速一致.RCCS培养7d,收集样本,提取样本总RNA,进行荧光标记和芯片杂交.利用Agilent Mouse lncRNA芯片分别检测SMG组和NG组L929细胞的lncRNA和mRNA表达,筛选差异表达显著的lncRNA,RT-qPCR验证芯片结果;利用GO和Pathway分析差异表达lncRNA的功能分布,结合mRNA差异表达谱,进行lncRNA-mRNA联合分析.结果 lncRNA芯片检测分析发现,RCCS模拟微重力环境下小鼠成纤维细胞L929共有238条差异表达的lncRNA,其中134条表达上调,104条表达下调;差异表达的mRNA共有237条,其中53条表达上调,184条表达下调.获取差异表达lncRNA的聚类分析图,对差异表达显著的4条lncRNA芯片结果进行RT-qPCR验证,结果相吻合.GO分析结果显示差异表达的lncRNA与巨噬细胞分化、伤口愈合的负性调节等生物学过程相关,Pathway分析结果显示差异表达的lncRNA与系统性红斑狼疮、TGF-β等信号通路相关.同时成功构建了lncRNA-mR-NA-TF可视化网络图.结论 RCCS模拟微重力环境显著影响L929细胞的lncRNA及mRNA表达谱,基于芯片技术的ln-cRNA靶基因预测和功能富集分析可为失重应激损伤机制探讨和修复措施建立提供理论依据. 相似文献
60.
目的应用同重同位素标记相对与绝对定量技术(iTRAQ),联合液相色谱串联质谱(LC-MS/MS),检测经空间诱变大肠杆菌(T1-13)感染尾吊模拟失重小鼠后,其脾脏组织中的差异蛋白,并探讨其生物学意义。方法 C57BL/6小鼠尾吊模拟失重后以空间诱变大肠杆菌灌胃建立感染模型,采用iTRAQ结合LC-MS/MS技术筛选脾脏组织差异表达蛋白,并对差异蛋白进行GO、pathway富集分析和STRING蛋白互作分析。结果共鉴定出2589个蛋白,尾吊组与对照组相比筛选出378个差异表达蛋白。尾吊染菌后与对照组相比,共筛选出452个差异表达蛋白,STRING蛋白互作网络中有286个差异蛋白间存在相互作用,这些差异蛋白经KEGG分析共得到32条存在显著性的通路,主要为氧化磷酸化通路,代谢通路、蛋白消化和吸收通路、蛋白酶体通路。结论成功筛选出了模拟失重后空间诱变大肠杆菌感染脾脏组织差异表达蛋白,这些差异蛋白可能通过调控代谢通路、不同环境下微生物代谢、颉氨酸/亮氨酸/异亮氨酸降解、溶酶体、碳代谢、吞噬体、丙酸代谢、蛋白酶体参与失重条件下免疫和炎症反应的发生。 相似文献