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1.
《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
2.
Abstract The pain of cluster headache attacks is severe, excruciating and selectively responsive to subcutaneous sumatriptan. Serious
cardiovascular events attributed to sumatriptan are extremely rare and have most often been reported in patients at significant
cardiovascular risk, or in overt cardiovascular disease. They also have occurred, however, in patients without evidence of
cardiovascular disease. We describe a 42-year-old man with episodic cluster headache without history of coronary artery disease
who was admitted to our coronary care unit for acute myocardial infarction after 3 h of subcutaneous injection of sumatriptan.
During hospitalisation cluster headache attacks were successfully treated with e.v. indomethacin. 相似文献
3.
Summary The objective of this study was to evaluate the effect of two non-steroid anti-inflammatory drugs, indomethacin and metamizole, on ureteral peristalsis during acute occlusion similar to the situation in renal colic. In 12 pentobarbital anesthetized sheep, both ureters were cannulated and the frequency of ureteral contractions, urine flow, mean ureteral pressure and blood pressure were recorded during 10-min control and i.v. drug administration periods. Both indomethacin (1–2 mg/kg) and metamizole (60–120 mg/kg) showed a dose dependent reduction in peristaltic frequency without reduction of the mean pressure. In addition, the pressure amplitude of the peristaltic waves was also lowered, particularly with indomethacin. Only indomethacin reduced the urine flow. Arterial blood pressure was elevated by both drugs, particularly after the first dose of indomethacin. It can be concluded that indomethacin and metamizole reduce ureteral peristaltic frequency, probably blocking the impulse transmission at the ureteropelvic junction.For the partial fulfillment of a Master's degree in Pharmacology 相似文献
4.
Interleukin-1 inhibits keratan sulfate production by rabbit chondrocytes: Possible role of prostaglandin E2 总被引:2,自引:0,他引:2
We investigated the importance of prostaglandin E2 (PGE2) release in interleukin-1 (IL-1)-induced inhibition of aggrecan synthesis by chondrocytes. Keratan sulfate (KS) production was measured in parallel with PGE2 release in chondrocytes. IL-1 inhibited KS production and stimulated PGE2 release. In the presence of PGE2, there was a dosedependent decrease in baseline KS production. Indomethacin and dexamethasone partially blocked the IL-1-induced PGE2 release while KS production recovered. Our results suggest that IL-1 inhibits KS production, in part, by stimulating the release of PGE2. 相似文献
5.
消炎痛对人胃癌上皮细胞BGC-823的作用 总被引:1,自引:1,他引:0
目的 :探讨非甾体类抗炎药 (NSAIDs)消炎痛 (indomethacin ,IND)对人胃癌细胞BGC - 82 3的作用 ,以期为非甾体类抗炎药对胃癌的防治作用提供理论依据。方法 :采用DNA条带分析以及流式细胞仪分别从定性及定量的角度观察不同浓度的消炎痛引起的BGC - 82 3细胞凋亡情况 ;MTT法分析不同浓度的消炎痛对BGC - 82 3细胞增殖的影响。结果 :低浓度的消炎痛可引起BGC - 82 3细胞的凋亡并且呈现量效关系 ;MTT分析发现 :消炎痛可抑制BGC - 82 3细胞的增殖 (P <0 .0 5)。结论 :NSAIDs有抑制胃癌细胞增殖、诱导其凋亡的作用 ,提示NSAIDs是一类预防胃肠道肿瘤的可行性药物 相似文献
6.
本工作观察了乙酰胆硷(Ach)和电刺激迷走神经对0.6N HCl引起的胃粘膜出血性损伤的保护作用,发现皮下注射50μg/kg的氯化Ach和电刺激膈下迷走神经5min,可明显降低HCl引起的胃粘膜出血量,这一作用可被消炎痛及阿托品所阻断。提示这种保护作用是通过依赖于M-受体的内源性前列腺素。 相似文献
7.
我们曾观察到消炎痛预处理能使大鼠对半乳糖胺肝损伤产生明显的保护作用,本研究利用大鼠肝细胞原代培养的方法进一步观察了达一现象。结果提示,消炎痛整体处理可使肝细胞本身获得抗损伤的能力,而这种抗损伤能力的形成可能有赖于肝细胞外其它因素的参与。 相似文献
8.
Suppressor-cell activity of peripheral blood mononuclear cells were examined and lymphocyte subsets analyzed in children with histocytosis-X and in healthy, age-matched subjects. Suppressor-cell function was assessed by two methods, the indomethacin stimulation of mitogen-activated cultures and the concanavalin A-inducible suppressor-cell assay. The results of these two assays indicate that children with active disease have significantly decreased suppressor-cell activity. Additionally, the percentage and absolute number of OKT8+ lymphocytes were decreased in children with active disease. Suppressor-cell activity and lymphocyte subsets returned to normal, baseline levels with disease remission. This study documents for the first time suppressor-cell dysfunction and supports previous investigations in which suppressor T lymphocytes are deficient in children with active disease. These findings may explain certain clinical manifestations seen in children with histiocytosis-X. 相似文献
9.
10.
Francesco Castelli Bice Conti Davide Maccarrone Olga La Camera Ubaldo Conte 《Drug delivery》1997,4(4):273-279
A comparative study of indomethacin controlled release from poly(lactide-co-glycolide) (50:50, molecular weight 3000) (PLGA) microspheres loaded with two different amounts of drug (10.9 ± 1%, and 34.1 ± 1% w/w) and pure free indomethacin, considering the effects exerted by the drug on the thermotropic behavior of dipalmitoylphosphatidylcholine multilamellar vesicles, was carried out by differential scanning calorimetry (DSC). The release was monitored by comparing the effect exerted by the free indomethacin on lipid thermotropic behavior with that of the drug released by the microspheres and relating these effects to a lipid aqueous dispersion containing the molar ratio of drug able to cause it. By DSC measurements, the pure free indomethacin was found to be able to have a fluidifying effect on the model membrane, causing a shift toward lower values of the transitional temperature (Tm), characteristic of phospholipid liposomes, without variations in the enthalpic changes (ΔH). This shift was found to be modulated by the drug molar fraction with respect to the lipid concentration in the aqueous dispersion. Successively, calorimetric measurements were performed on suspensions of blank liposomes added to weighed amounts of unloaded and indometha-cin-loaded microspheres as well as free powdered indomethacin, and the Tm shifts of the lipid bilayer caused by the drug released from the polymeric system, as well as by the free drug, were compared with that caused by free drug increasing molar fractions dispersed directly on the membrane, employed as a calibration curve to obtain the fraction of drug released. This drug release model could be employed to determine the different kinetics involved in the drug transfer from the microspheres to a membrane. This in vitro study suggests that the kinetic process involved in drug release is influenced by the amount of drug loaded in the microspheres. This calorimetric study shows that the PLGA microspheres are a good delivery system able to sustain drug release. Moreover, the DSC technique applied to the drug interaction with biomembranes constitutes a good tool for determining the drug release representing an innovative alternative in vitro model. 相似文献