全文获取类型
收费全文 | 260篇 |
免费 | 27篇 |
国内免费 | 4篇 |
专业分类
耳鼻咽喉 | 3篇 |
基础医学 | 18篇 |
口腔科学 | 2篇 |
临床医学 | 14篇 |
内科学 | 13篇 |
神经病学 | 13篇 |
特种医学 | 5篇 |
外科学 | 7篇 |
综合类 | 26篇 |
预防医学 | 13篇 |
药学 | 138篇 |
中国医学 | 34篇 |
肿瘤学 | 5篇 |
出版年
2023年 | 2篇 |
2022年 | 5篇 |
2021年 | 4篇 |
2020年 | 2篇 |
2019年 | 10篇 |
2018年 | 15篇 |
2017年 | 11篇 |
2016年 | 11篇 |
2015年 | 5篇 |
2014年 | 20篇 |
2013年 | 23篇 |
2012年 | 22篇 |
2011年 | 29篇 |
2010年 | 28篇 |
2009年 | 11篇 |
2008年 | 13篇 |
2007年 | 16篇 |
2006年 | 11篇 |
2005年 | 17篇 |
2004年 | 7篇 |
2003年 | 6篇 |
2002年 | 7篇 |
2001年 | 7篇 |
2000年 | 4篇 |
1999年 | 2篇 |
1998年 | 1篇 |
1988年 | 1篇 |
1987年 | 1篇 |
排序方式: 共有291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.
Electron spectroscopic imaging (ESI) was used to analyze the element content of melanin granules in the stria vascularis
seen in ultrathin sections of Spurr-embedded cochleae of the guinea pig. To determine element composition, ESI images were
taken at different ionization edges, and non-specific background signals were subtracted digitally by an image processing
system. The presence of calcium and nitrogen in the melanin granules could be demonstrated clearly. The calcium identified
in the melanin granules was then compared with the spatial distributions of calcium binding sites after the application of
an antimonate precipitation method, which was used to localize loosely bound calcium. Despite a high calcium concentration
within the granules, only very small single scattered calcium precipitates could be detected between these structures as compared
with the amount of calcium precipitates attached to the plasma membrane or located within the cell nuclei. The nearly complete
absence of precipitates within the melanin granules after the application of antimonate suggests differences in calcium binding
and mobility involved in various physiological processes of ion balance regulation within the stria vascularis.
Received: 14 October 1997 / Accepted: 11 February 1998 相似文献
3.
Recently, 2-aminothiazoline-4-carboxylic acid (ATCA), a cyanide (CN) metabolite, has been proposed as a stable diagnostic marker of CN poisoning. In this study, liquid chromatography coupled with electrospray ionization – tandem mass spectrometry was used to quantify ATCA concentrations in human postmortem blood samples, and differences in ATCA concentrations according to age and sex were determined. Both age and sex had significant effects on blood ATCA concentrations. Although ATCA concentrations exhibited an inverted U shape with increasing age in men, in women ATCA concentrations plateaued at around 40–59 years of age. There were significant differences between the sexes in ATCA concentrations for the 20–39 and 40–59 year age groups (P < 0.05 and P < 0.01, respectively). Correlations between ATCA concentrations and carboxyhemoglobin (CO-Hb) saturation were also examined in fire victims. ATCA concentrations increased significantly with increasing CO-Hb saturation (r = 0.382, P < 0.01). In addition, ATCA concentrations were also correlated to CN concentrations (r = 0.309, P < 0.05). The results of our study may provide novel information about the contribution of CN poisoning to the cause of death at fire scenes. 相似文献
4.
Phthalates are suspected to be endocrine disruptors. Di(2-ethylhexyl) phthalate (DEHP) is assumed to have low dermal absorption; however, previous in vitro skin permeation studies have shown large permeation differences. Our aims were to determine DEHP permeation parameters and assess extent of skin DEHP metabolism among workers highly exposed to these lipophilic, low volatile substances. 相似文献
5.
付中静 《中华医学图书情报杂志》2015,24(8):11-16
以ESI数据库为数据来源,采集金砖四国2004-01-01至2014-06-30发表的论文数据,采用科研论文相对产出、相对引文影响指标分析金砖四国科研论文的产出规模及其影响;并采用学科专业化指标和标准引文影响指标,构建“学科专业化-标准引文影响”二维分析框架,分析金砖四国科研产出在全球的相对位置。研究结果表明,金砖四国科研论文绝对产出较多;金砖四国的相对科研产出在学科之间的分布呈现非均衡态势,在很多学科领域相对产出明显低于世界平均水平;金砖四国22个学科的相对引文影响指标均低于世界平均水平;根据专业化指标值,中国、巴西、印度的学科专业化程度低,俄罗斯的学科专业化程度略高;金砖四国的标准引文影响指标值均明显低于世界平均水平,说明科研论文整体质量低于世界平均水平。据此对金砖四国基础研究建设提出建议,以期为有关部门制定科技发展政策、调整学科结构布局提供参考。 相似文献
6.
Alain P. Gobert Olivier Boutaud Mohammad Asim Irene A. Zagol-Ikapitte Alberto G. Delgado Yvonne L. Latour Jordan L. Finley Kshipra Singh Thomas G. Verriere Margaret M. Allaman Daniel P. Barry Kara M. McNamara Johanna C. Sierra Venkataraman Amarnath Mohammed N. Tantawy Diane Bimczok M. Blanca Piazuelo M. Kay Washington Keith T. Wilson 《Gastroenterology》2021,160(4):1256-1268.e9
7.
8.
Julie K. Klint Géza Berecki Thomas Durek Mehdi Mobli Oliver Knapp Glenn F. King David J. Adams Paul F. Alewood Lachlan D. Rash 《Biochemical pharmacology》2014
Spider venoms are replete with peptidic ion channel modulators, often with novel subtype selectivity, making them a rich source of pharmacological tools and drug leads. In a search for subtype-selective blockers of voltage-gated calcium (CaV) channels, we isolated and characterized a novel 39-residue peptide, ω-TRTX-Cc1a (Cc1a), from the venom of the tarantula Citharischius crawshayi (now Pelinobius muticus). Cc1a is 67% identical to the spider toxin ω-TRTX-Hg1a, an inhibitor of CaV2.3 channels. We assembled Cc1a using a combination of Boc solid-phase peptide synthesis and native chemical ligation. Oxidative folding yielded two stable, slowly interconverting isomers. Cc1a preferentially inhibited Ba2+ currents (IBa) mediated by L-type (CaV1.2 and CaV1.3) CaV channels heterologously expressed in Xenopus oocytes, with half-maximal inhibitory concentration (IC50) values of 825 nM and 2.24 μM, respectively. In rat dorsal root ganglion neurons, Cc1a inhibited IBa mediated by high voltage-activated CaV channels but did not affect low voltage-activated T-type CaV channels. Cc1a exhibited weak activity at NaV1.5 and NaV1.7 voltage-gated sodium (NaV) channels stably expressed in mammalian HEK or CHO cells, respectively. Experiments with modified Cc1a peptides, truncated at the N-terminus (ΔG1–E5) or C-terminus (ΔW35–V39), demonstrated that the N- and C-termini are important for voltage-gated ion channel modulation. We conclude that Cc1a represents a novel pharmacological tool for probing the structure and function of L-type CaV channels. 相似文献
9.
Jong Bong Lee Tae Hwan Kim Wanshan Feng Hyeon Gwan Choi Atheer Zgair Soyoung Shin Sun Dong Yoo Pavel Gershkovich Beom Soo Shin 《Journal of pharmaceutical sciences》2019,108(2):1047-1052
For performance assessment of the lipid-based drug delivery systems (LBDDSs), in vitro lipolysis is commonly applied because traditional dissolution tests do not reflect the complicated in vivo micellar formation and solubilization processes. Much of previous research on in vitro lipolysis has mostly focused on rank-ordering formulations for their predicted performances. In this study, we have incorporated in vitro lipolysis with microsomal stability to quantitatively predict the oral bioavailability of a lipophilic antineoplastic drug bexarotene (BEX) administered in LBDDS. Two types of LBDDS were applied: lipid solution and lipid suspension. The predicted oral bioavailability values of BEX from linking in vitro lipolysis with microsomal stability for lipid solution and lipid suspension were 34.2 ± 1.6% and 36.2 ± 2.6%, respectively, whereas the in vivo oral bioavailability of BEX was tested as 31.5 ± 13.4% and 31.4 ± 5.2%, respectively. The predicted oral bioavailability corresponded well with the oral bioavailability for both formulations, demonstrating that the combination of in vitro lipolysis and microsomal stability can quantitatively predict oral bioavailability of BEX. In vivo intestinal lymphatic uptake was also assessed for the formulations and resulted in <1% of the dose, which confirmed that liver microsomal stability was necessary for correct prediction of the bioavailability. 相似文献
10.
Rapid and simple LC‐MS/MS screening of 64 novel psychoactive substances using dried blood spots 下载免费PDF全文
The range of novel psychoactive substances (NPS) including phenethylamines, cathinones, piperazines, tryptamines, etc. is continuously growing. Therefore, fast and reliable screening methods for these compounds are essential and needed. The use of dried blood spots (DBS) for a fast straightforward approach helps to simplify and shorten sample preparation significantly. DBS were produced from 10 µl of whole blood and extracted offline with 500 µl methanol followed by evaporation and reconstitution in mobile phase. Reversed‐phase chromatographic separation and mass spectrometric detection (RP‐LC‐MS/MS) was achieved within a run time of 10 min. The screening method was validated by evaluating the following parameters: limit of detection (LOD), matrix effect, selectivity and specificity, extraction efficiency, and short‐term and long‐term stability. Furthermore, the method was applied to authentic samples and results were compared with those obtained with a validated whole blood method used for routine analysis of NPS. LOD was between 1 and 10 ng/ml. No interference from matrix compounds was observed. The method was proven to be specific and selective for the analytes, although with limitations for 3‐FMC/flephedrone and MDDMA/MDEA. Mean extraction efficiency was 84.6 %. All substances were stable in DBS for at least a week when cooled. Cooling was essential for the stability of cathinones. Prepared samples were stable for at least 3 days. Comparison to the validated whole blood method yielded similar results. DBS were shown to be useful in developing a rapid screening method for NPS with simplified sample preparation. Copyright © 2013 John Wiley & Sons, Ltd. 相似文献