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《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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Xiaoqing Guo Ji-Eun Seo Xilin Li Nan Mei 《Journal of toxicology and environmental health. Part B, Critical reviews》2020,23(1):27-50
ABSTRACTGenotoxic compounds may be detoxified to non-genotoxic metabolites while many pro-carcinogens require metabolic activation to exert their genotoxicity in vivo. Standard genotoxicity assays were developed and utilized for risk assessment for over 40 years. Most of these assays are conducted in metabolically incompetent rodent or human cell lines. Deficient in normal metabolism and relying on exogenous metabolic activation systems, the current in vitro genotoxicity assays often have yielded high false positive rates, which trigger unnecessary and costly in vivo studies. Metabolically active cells such as hepatocytes have been recognized as a promising cell model in predicting genotoxicity of carcinogens in vivo. In recent years, significant advances in tissue culture and biological technologies provided new opportunities for using hepatocytes in genetic toxicology. This review encompasses published studies (both in vitro and in vivo) using hepatocytes for genotoxicity assessment. Findings from both standard and newly developed genotoxicity assays are summarized. Various liver cell models used for genotoxicity assessment are described, including the potential application of advanced liver cell models such as 3D spheroids, organoids, and engineered hepatocytes. An integrated strategy, that includes the use of human-based cells with enhanced biological relevance and throughput, and applying the quantitative analysis of data, may provide an approach for future genotoxicity risk assessment. 相似文献
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《Journal of Clinical Orthopaedics and Trauma》2021,12(6):976-982
ObjectiveMultiple treatment options for acetabular fractures in geriatric patients exist. However, no large-scale studies have reported the outcomes of acute total hip arthroplasty (THA) in this patient population. We systematically evaluated all available evidence to characterize clinical outcomes, complications, and revisions of acute THA for acetabular fractures in geriatric patients.MethodsMeta-analysis of 21 studies of 430 acetabular fractures with mean follow-up of 44 months (range, 17−97 months). Two independent researchers searched and evaluated the databases of Ovid, Embase, and United States National Library of Medicine using a Boolean search string up to December 2019. Population demographics and complications, including presence of heterotopic ossification (HO), dislocation, infection, revision rate, neurological deficits, and venous thromboembolic event (VTE), were recorded and analyzed.ResultsWeighted mean Harris Hip Score was 83.3 points, and 20% of the patients had reported complications. The most common complication was HO, with a rate of 19.5%. Brooker grade III and IV HO rates were lower at 6.8%. Hip dislocation occurred at a rate of 6.1%, 4.1% of patients developed VTE, deep infection occurred in 3.8%, and neurological complications occurred in 1.9%. Although the revision rate was described in most studies, we were unable to perform a survival analysis because the time to each revision was described in only a few studies. The revision rate was 4.3%.ConclusionsAcute THA is a viable option for treatment of acetabular fracture and can result in acceptable clinical outcomes and survivorship rates in older patients but with an associated complication rate of approximately 20%. Considering the limited treatment options, THA might be a viable alternative for appropriately selected patients. 相似文献
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肾综合征出血热发病机制至今仍未完全阐明,病毒、病毒受体、细胞因子、自由基、特异性CTL反应、HLA差异性均可能与发病有关.此文对近年来的研究进展进行了综述. 相似文献
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[目的]评价后路半椎体切除术治疗半椎体所致脊柱侧后凸畸形的临床效果。[方法]2000年5月~2005年11月,采用后路半椎体切除及矫形固定融合术治疗14例完全分节半椎体所致脊柱侧后凸畸形患者。年龄2.5~14.4岁,平均7.4岁,半椎体均为侧后方半椎体,其中胸椎7例,腰椎7例。[结果]手术时间2~7 h,平均4.7h,术中出血量150~2 500 m l,平均560 m。l固定节段2~8个椎体,平均3.5。术后随访6~36个月。平均15.6个月。术后站立位脊柱正侧位X线片示冠状面Cobb's角由术前46.2°矫正到17.3°,平均矫正率62.6%,矢状面Cobb's角由术前48.3°矫正至术后16.2°,平均矫正率68.7%。终末随访时冠状面Cobb's角平均21.7°,丢失4.4°,矢状面Cobb's角平均18.7°,丢失2.5°。围手术期并发症包括:伤口愈合不良2例,术中术后椎弓根螺钉切割椎体2例。[结论]后路半椎体切除可直接去除致畸因素,在冠状面及矢状面均获得良好的矫形效果,与前后路手术相比可缩短手术时间,减少创伤,适用于从胸段到腰段的半椎体畸形。 相似文献
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AKIKO TANAKA MASAHIRO MATSUMOTO YUJIRO HAYASHI KOJI TAKEUCHI 《Journal of gastroenterology and hepatology》2006,20(1):38-45
Background and Aim: We recently reported that cyclooxygenase (COX)-2 is upregulated in the rat small intestine after administration of indomethacin, and this may be the key to non-steroidal anti-inflammatory drug (NSAID)-induced intestinal damage. The present study investigated the mechanism for COX-2 expression induced in the rat small intestine by indomethacin, in relation with ulcerogenic processes.
Methods: Animals were given indomethacin or SC-560 p.o., and the intestinal mucosa was examined 24 h later.
Results: Indomethacin caused hemorrhagic lesions in the small intestine, accompanied with an increase in intestinal motility, bacterial invasion and inducible nitric oxide synthase (iNOS) activity, as well as the expression of COX-2 mRNA in the mucosa. Although SC-560 did not cause any damage, this agent caused intestinal hypermotility, the bacterial invasion and the upregulation of COX-2 expression. The mucosal PGE2 content was decreased by SC-560 at 3 h but recovered 12 h later, and this recovery of PGE2 was attenuated by both atropine and ampicillin, in addition to rofecoxib. The intestinal hypermotility response to indomethacin was prevented by both 16,16-dimethyl PGE2 and atropine, but not ampicillin. Yet all these agents inhibited not only the bacterial invasion but also the expression of COX-2 and iNOS activity in the intestinal mucosa following indomethacin treatment, resulting in the prevention of intestinal lesions.
Conclusion: These results suggest that COX-2 expression in the intestinal mucosa following the administration of indomethacin is associated with intestinal hypermotility and bacterial invasion. The intestinal hypermotility caused by COX-1 inhibition may be a key to COX-2 expression after administration of NSAIDs and their intestinal ulcerogenic properties. 相似文献
Methods: Animals were given indomethacin or SC-560 p.o., and the intestinal mucosa was examined 24 h later.
Results: Indomethacin caused hemorrhagic lesions in the small intestine, accompanied with an increase in intestinal motility, bacterial invasion and inducible nitric oxide synthase (iNOS) activity, as well as the expression of COX-2 mRNA in the mucosa. Although SC-560 did not cause any damage, this agent caused intestinal hypermotility, the bacterial invasion and the upregulation of COX-2 expression. The mucosal PGE
Conclusion: These results suggest that COX-2 expression in the intestinal mucosa following the administration of indomethacin is associated with intestinal hypermotility and bacterial invasion. The intestinal hypermotility caused by COX-1 inhibition may be a key to COX-2 expression after administration of NSAIDs and their intestinal ulcerogenic properties. 相似文献
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肾综合征出血热患者T细胞亚群数量与白细胞介素2,4水平变化的关系 总被引:2,自引:0,他引:2
采用ABC免疫组化染色法及单克隆抗体夹心法ELISA,同步检测了34例肾综合征出血热(HFRS)患者外周血T细胞亚群数量和血清白细胞介素2和4(IL-2、IL-4)水平。发现HFRS病程中各T细胞亚群数量均有不同程度的升高,其中CDS阳性T细胞在各病期均有升高。IL-4水平升高仅见于发热期.而IL-2的升高主要在低血压期和少尿期。病程中有CD4/CD8比值的下降甚至倒置。这种比值的变化与IL-2和IL-4的动态变化有一定的相关性。结果揭示,在HFRS发病机理中存在Thl型和Th2型免疫反应等多种免疫病理机制。 相似文献