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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.
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
5.
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
6.
7.
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
8.
消炎痛对hCG诱发家兔排卵抑制的形态学研究 总被引:3,自引:0,他引:3
应用非甾体抗炎药消炎痛(20mg/kg)抑制hCG 诱发的家兔排卵,注射后的6、9、12、72小时剖腹观察排卵数,并取材进行透射电镜观察和酶组织化学观察。甾体激素合成酶类的组织化学和颗粒细胞内某些细胞器的电镜立体定量学测定结果表明:消炎痛抑制了排卵,却不影响颗粒细胞向黄体细胞的转变。透射电镜观察表明:在排卵前,实验组和对照组最明显的不同是:实验组的外膜和白膜很少见到胶原溶解现象,且表面上皮细胞内含的致密小体不释放其内容物。结果提示:消炎痛主要作用于排卵前卵泡顶部的成纤维细胞和表面上皮细胞,这可能与其抑制了某些与排卵有关的酶的释放有关。 相似文献
9.
ANDERS BILL 《Acta physiologica (Oxford, England)》1979,105(4):437-442
In an attempt to reveal the importance of prostaglandins in the control of regional blood flow 20 mg/kg b.wt. indomethacin was given i.v. in conscious resting rabbits. Regional blood flow determinations were made before and 20 min after the injection using the labelled microsphere technique. The blood flow in the stomach wall was reduced by 0.75 ± 0.17 g·min-1·g-1 from a level of 1.64 ± 0.24 g·min-1·g-1. In jejunum the corresponding figures were 0.44 ± 0.12 and 1.26 ± 0.17 and in the brain 0.29 ± 0.10 and 1.24 ± 0.10. The blood flow in the liver via the hepatic artery increased by 0.20 ± 0.02 g·min-1·g-1 from a level of 0.13 ± 0.02 g·min-1·g-1. In the retina there was a reduction in blood flow by 2.75 ± 1.03 mg·min-1 from a starting level of 15.1 ± 2.3 mg·min-1. In a number of other tissues investigated there were no significant effects of the drug. The results suggest that under resting conditions prostaglandins play a role in the control of blood flow in the gastrointestinal tract, the brain and the retina—tissues which are likely to be rather active under such conditions. 相似文献
10.
CHEN You-fang LIN Xian-fu 《中国生物医学工程学报(英文版)》2007,16(1):8-13
Indomethacin has been encapsulated with polyelectrolyte multilayers for controlled release. Gelatin and alginate were alternatively deposited on indomethacin microcrystals. The released amount of indomethacin from coated microcrystals in pH6. 8 phosphate buffer solution (PBS) was measured with a UV spectrophometer. The polyelectrolyte multilayer capsule thickness was proved to control the release rate. The effects of osmotic pressure existed during the release process of indomethacin from microcapsules coated by (gelatin/alginate) 4. 相似文献