全文获取类型
收费全文 | 269篇 |
免费 | 29篇 |
国内免费 | 8篇 |
专业分类
儿科学 | 1篇 |
妇产科学 | 6篇 |
基础医学 | 7篇 |
临床医学 | 14篇 |
内科学 | 23篇 |
皮肤病学 | 1篇 |
神经病学 | 5篇 |
特种医学 | 15篇 |
外科学 | 9篇 |
综合类 | 10篇 |
预防医学 | 8篇 |
眼科学 | 1篇 |
药学 | 183篇 |
中国医学 | 15篇 |
肿瘤学 | 8篇 |
出版年
2023年 | 5篇 |
2022年 | 4篇 |
2021年 | 8篇 |
2020年 | 6篇 |
2019年 | 8篇 |
2018年 | 13篇 |
2017年 | 13篇 |
2016年 | 10篇 |
2015年 | 9篇 |
2014年 | 8篇 |
2013年 | 22篇 |
2012年 | 10篇 |
2011年 | 17篇 |
2010年 | 11篇 |
2009年 | 15篇 |
2008年 | 18篇 |
2007年 | 10篇 |
2006年 | 15篇 |
2005年 | 14篇 |
2004年 | 6篇 |
2003年 | 11篇 |
2002年 | 12篇 |
2001年 | 4篇 |
2000年 | 4篇 |
1999年 | 7篇 |
1998年 | 3篇 |
1997年 | 7篇 |
1996年 | 2篇 |
1995年 | 1篇 |
1994年 | 3篇 |
1993年 | 2篇 |
1991年 | 5篇 |
1990年 | 4篇 |
1988年 | 2篇 |
1987年 | 1篇 |
1986年 | 2篇 |
1985年 | 1篇 |
1984年 | 3篇 |
1982年 | 1篇 |
1981年 | 1篇 |
1980年 | 2篇 |
1978年 | 3篇 |
1976年 | 1篇 |
1975年 | 1篇 |
1971年 | 1篇 |
排序方式: 共有306条查询结果,搜索用时 31 毫秒
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.
Plasma Concentrations of Mycophenolic Acid Acyl Glucuronide Are Not Associated with Diarrhea in Renal Transplant Recipients 总被引:2,自引:0,他引:2
T. Heller T. van Gelder K. Budde J. W. de Fijter D. Kuypers W. Arns J. Schmidt L. Rostaing S. H. Powis K. Claesson I. A. M. MacPhee E. Pohanka J. Engelmayer G. Brandhorst M. Oellerich V. W. Armstrong 《American journal of transplantation》2007,7(7):1822-1831
The aim of this study was to determine whether plasma concentrations of the acyl (AcMPAG) and phenolic (MPAG) glucuronide metabolites of mycophenolic acid (MPA) were related to diarrhoea in renal transplant patients on mycophenolate mofetil (MMF) with cyclosporine (CsA) or tacrolimus (TCL). Blood samples (0, 30, 120 min) were taken at days 3, 10, week 4, months 3, 6 and 12 for determination of MPA, MPAG and AcMPAG. MPA-AUC was estimated using validated algorithms. Two hour AUCs were calculated for MPAG and AcMPAG. Immunosuppressive therapy consisted of CsA/MMF (n= 110) and of TCL/MMF (n= 180). In 70/290 (24%) patients 86 episodes of diarrhoea were recorded during 12 months. Significantly more patients on TCL (31.1%) suffered from diarrhea compared to CsA (12.7%). MMF dose, MPA-AUC and the 2 h AUCs of MPAG and AcMPAG did not differ between patients with and without diarrhoea. Plasma AcMPAG and MPAG concentrations were substantially higher in patients on CsA compared with TCL, while MPA-AUC was lower in the former group. These data support the concept that CsA inhibits the biliary excretion of MPAG and AcMPAG, thereby potentially reducing the risk of intestinal injury through enterohepatic recycling of MPA and its metabolites. 相似文献
3.
Julia M. Grottenthaler Annette Konzelmann Anette Stiegler Clemens Hinterleitner Sarah M. Bott Thomas Klag Christoph R. Werner Martina Hinterleitner Alfred Königsrainer Anil Batra Nisar P. Malek Silvio Nadalin Christoph P. Berg 《Transplant international》2021,34(11):2257-2265
Alcohol abuse after liver transplantation can seriously impact graft and patient survival. However, to date, there is no defined standard procedure to identify patients consuming alcohol after liver transplantation. The aim of this study was to analyze the diagnostic value and clinical impact of routinely measured urinary ethyl glucuronide (uEtG) – a metabolite of ethanol – in patients after liver transplantation. Data of 362 consecutive patients after liver transplantation who visited the University Hospital of Tuebingen for outpatient follow-up were analyzed. Forty-eight patients (13%) displayed positive uEtG results. The uEtG positive group contained significantly more patients with pretransplant alcoholic liver disease. However, two thirds of the uEtG positive patients had no history of pretransplant alcoholic liver disease. Several clinical parameters were significantly associated with positive uEtG. In order to enable a more cost-effective application of uEtG in the future, a clinical risk score was developed (specificity 0.95). In conclusion, routine testing for uEtG reveals a considerable percentage of patients practicing alcohol intake after liver transplantation. Application of our proposed risk score could help focusing uEtG testing on patients at risk. 相似文献
4.
人血浆中麦考酚酸及其葡糖苷酸代谢物HPLC法测定 总被引:1,自引:0,他引:1
目的:建立HPLC测定人血浆中麦考酚酸(MPA)及其代谢物葡糖醛酸结合物(MPAG)浓度的方法。方法:以安定为内标,血浆经乙腈蛋白沉淀后直接进样。采用Zorbax Eclipse XDB C_(18)(150 mm×4.6 mm,5μm),柱温:30℃,流动相:甲醇-0.1%三氟乙酸(55:45,pH=2.2),流速:1.0 mL·min~(-1),检测波长215 nm。结果:血浆内源性杂质和常用合并用药对样品测定无干扰,MPA和MPAG血药浓度分别在0.5-40μG·mL~(-1)和2.5—200μg·mL~(-1)范围内线性关系良好。MPA和MPAG的日内、日间RSD均小于8%,样品提取后在24 h内及3次冻融后稳定性良好。结论:该法快速,简便,准确,可用于MPA和MPAG的体内分析及常规的治疗药物监测。 相似文献
5.
Ataluren is an aromatic acid derivative with a 1,2,4-oxodiazole moiety. Ataluren-O-1β-acyl glucuronide is a prominent circulatory metabolite in mice, rats, dogs, and humans following oral administration of ataluren. The objective of this paper was to evaluate the stability in vitro and in vivo of ataluren-O-1β-acyl glucuronide metabolite. Ultrahigh performance liquid chromatography-mass spectrometry methods were developed to separate and monitor ataluren-O-1β-acyl glucuronide and its possible migration isomers. In vitro stability was assessed in phosphate buffered saline as well as in control rat and human plasma. The disappearance of ataluren-O-1β-acyl glucuronide and the formation of migration isomers were monitored by the ultrahigh performance liquid chromatography-mass spectrometry methods. In vitro, ataluren-O-1β-acyl glucuronide underwent isomerization with an estimated half-life of approximately 1 h. However, ataluren-O-1β-acyl glucuronide was stable and was the only detectable acyl glucuronide following oral administration of ataluren in mice, rats, dogs, and humans using the same analytical methods. Ataluren acyl glucuronide in mouse, rat, dog, and human plasma could be hydrolyzed by β-glucuronidase, further confirming the structure of O-1β-acyl glucuronide. These results demonstrated that ataluren-O-1β-acyl glucuronide did not undergo migration in vivo. No clinical safety concern related to ataluren-O-1β-acyl glucuronide migration has been detected. 相似文献
6.
《Journal of immunoassay & immunochemistry》2013,34(2):147-163
A radioimmunoassay (RIA) for insulin was validated for reliable measurement of the human insulin analogue, insulin aspart, by correction of non-linear measurements. Specificity was equivalent for several species of insulin, except insulin aspart. A non-linear hyperbolic model fitted insulin aspart with a correction formula for non-linearity of: z = 1503y/(1398 - y), where y denotes measured concentration and z denotes true concentration. Matrix-effects were insignificant for human, porcine, and canine heparin-plasma and for human and porcine serum. The coefficient of variation was below 15% for 80–800 pmol/L human and porcine insulin and for 80–600 pmol/L insulin aspart. The limit of detection for insulin aspart was 11.5 pmol/L with a lower limit of quantification of 17.5 pmol/L. Dilution of serum with Pharmacia dilution media introduced no significant error. In conclusion, this paper demonstrates that a non-parallel radioimmunoassay can be used to estimate accurate concentrations of insulin aspart. 相似文献
7.
8.
9.
Absorption,distribution, metabolism and excretion of novel phosphodiesterase type 4 inhibitor ASP3258 in rats
下载免费PDF全文
![点击此处可从《Biopharmaceutics & drug disposition》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Yoshiaki Ohtsu Takuya Sonoda Yoko Susaki Toshifumi Tohda Yasuhisa Fukunaga Takafumi Iwatsubo Kiyoshi Noguchi 《Biopharmaceutics & drug disposition》2015,36(1):34-48
The potent and selective phosphodiesterase 4 inhibitor ASP3258 is a novel therapeutic agent for asthma and chronic obstructive pulmonary disease (COPD). After a single oral administration to rats, ASP3258 is rapidly absorbed with a bioavailability of 106%. In situ absorption data indicated that ASP3258 is mainly absorbed in the small intestine. Tissue distribution data after oral administration of 14C‐ASP3258 showed rapid and extensive distribution to various tissues. Excluding the gastrointestinal tract, the tissues with the highest concentrations were liver, heart and plasma. Liquid chromatography‐nuclear magnetic resonance spectroscopy data revealed that O‐glucuronidation of the carboxylic acid moiety of ASP3258 (formation of an acyl glucuronide) plays a key role in metabolism. No indication was found that the acyl glucuronide reacted with proteins in plasma or tissues. When 14C‐ASP3258 was orally administered to intact rats, urinary and fecal excretion accounted for 1.3% and 100.6% of the administered radioactivity, respectively. After a single oral administration of 14C‐ASP3258 to bile‐cannulated rats, urinary and biliary excretion accounted for 0.7% and 93.8% of the administered radioactivity, respectively. These findings suggest that fecal excretion via bile plays an important role in the elimination of ASP3258‐derived radioactivity. In vitro metabolic profiles were relatively similar among the species examined, suggesting that our findings in rats may help us to understand pharmacokinetics, efficacy and safety profiles in humans and other species. Copyright © 2014 John Wiley & Sons, Ltd. 相似文献
10.
Gary M. Reisfield Scott A. Teitelbaum Shannon O. Opie Joseph Jones Deborah G. Morrison Ben Lewis 《Drug testing and analysis》2020,12(8):1102-1108
Direct alcohol biomarkers, including urinary ethyl glucuronide (EtG), urinary ethyl sulfate (EtS), and blood phosphatidylethanol (PEth), are used to monitor alcohol abstinence in individuals who are mandated to abstain. In this consecutive case series study, we examined 1000 forensic reports of participants enrolled in a professionals health program who were contractually obligated to abstain from alcohol and who underwent recovery status evaluations. We identified 52 evaluations in which urinary EtG, EtS, and blood PEth were measured and which produced a positive result for at least one of these analytes. PEth, at a cutoff concentration of 20 ng/mL, revealed alcohol use more frequently than EtG or EtS at our laboratory's cutoff concentrations of 100 and 25 ng/mL, respectively. This was true, as well, at alternative EtG/EtS cutoff concentrations of 200/50, 300/75, and 400/100 ng/mL. PEth was more likely than EtG/EtS to be positive in participants previously diagnosed with alcohol use disorders (AUD), whereas EtG/EtS was more likely than PEth to be positive in participants without AUD. In this study, blood PEth was the most sensitive biomarker for evidencing alcohol use. 相似文献