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51.
Gaurav R. Dwivedi Harish C. Upadhyay Dharmendra K. Yadav Vigyasa Singh Santosh K. Srivastava Feroz Khan Nandan S. Darmwal Mahendra P. Darokar 《Chemical biology & drug design》2014,83(4):482-492
The purpose of present investigation was to understand the drug resistance reversal mechanism of 4‐hydroxy‐α‐tetralone ( 1 ) isolated from Ammannia spp. along with its semi‐synthetic derivatives ( 1a – 1e ) using multidrug resistant Escherichia coli (MDREC). The test compounds did not show significant antibacterial activity of their own, but in combination, they reduced the minimum inhibitory concentration (MIC) of tetracycline (TET). In time kill assay, compound 1 and its derivative 1e in combination with TET reduced the cell viability in concentration dependent manner. Compounds 1 and 1e were also able to reduce the mutation prevention concentration of TET. Both compounds showed inhibition of ATP dependent efflux pumps. In real time polymerase chain reaction (RT‐PCR) study, compounds 1 and 1e alone and in combination with TET showed significant down expression of efflux pump gene (yojI) encoding multidrug ATP binding cassettes (ABC) transporter protein. Molecular mechanism was also supported by the in silico docking studies, which revealed significant binding affinity of compounds 1 and 1e with YojI. This study confirms that compound 1 and its derivative 1e are ABC efflux pump inhibitors which may be the basis for development of antibacterial combinations for the management of MDR infections from inexpensive natural product. 相似文献
52.
Eri Hara Motoki Ueda Akira Makino Isao Hara Eiichi Ozeki Shunsaku Kimura 《ACS medicinal chemistry letters》2014,5(8):873-877
l-lactic acid)30 (AB-type), which accumulates in solid
tumors through the enhanced permeability and retention (EPR) effect.
However, lactosome on multiple administrations changed its pharmacokinetics
from accumulation in tumors to liver due to the production of antilactosome
IgM, which was triggered by the first administration. This phenomenon
is called the accelerated blood clearance (ABC). In order to reduce
the production of antilactosome IgM, a novel nanoparticle composed
of (poly(sarcosine)23)3-block-poly(l-lactic acid)30 (A3B-type)
was prepared. The A3B-type lactosome at the second administration
showed an in vivo disposition similar to that at
the first administration due to suppression of antibody production.
This study involving the AB- and A3B-type lactosomes, with
variation of conditions, revealed that the high local density of poly(sarcosine)
chains of the A3B-type lactosome should relate to the prevention
of a polymeric micelle from interacting B-cell receptors. 相似文献
53.
Lipid-based formulations have been an attractive choice among novel drug delivery systems for enhancing the solubility and bioavailability of poorly soluble drugs due to their ability to keep the drug in solubilized state in the gastrointestinal tract. These formulations offer multiple advantages such as reduction in food effect and inter-individual variability, ease of preparation, and the possibility of manufacturing using common excipients available in the market. Despite these advantages, very few products are available in the present market, perhaps due to limited knowledge in the in vitro tests (for prediction of in vivo fate) and lack of understanding of the mechanisms behind pharmacokinetic and biopharmaceutical aspects of lipid formulations after oral administration. The current review aims to provide a detailed understanding of the in vivo processing steps involved after oral administration of lipid formulations, their pharmacokinetic aspects and in vitro in vivo correlation (IVIVC) perspectives. Various pharmacokinetic and biopharmaceutical aspects such as formulation dispersion and lipid digestion, bioavailability enhancement mechanisms, impact of excipients on efflux transporters, and lymphatic transport are discussed with examples. In addition, various IVIVC approaches towards predicting in vivo data from in vitro dispersion/precipitation, in vitro lipolysis and ex vivo permeation studies are also discussed in detail with help of case studies.KEY WORDS: Pharmacokinetics, Lipolysis, IVIVC, Efflux transporters, Lymphatic delivery, Food effectAbbreviations: ADME, absorption/distribution/metabolism/elimination; AUC, area under the curve; BCS, biopharmaceutics classification system; BDDCS, biopharmaceutics drug disposition classification system; CACO, human epithelial colorectal adenocarcinoma cells; Cmax, maximum plasma concentration; CMC, critical micellar concentration; CYP, cytochrome; DDS, drug delivery systems; FaSSGF, fasted-state simulated gastric fluid; FaSSIF, fasted-state simulated intestinal fluid; FeSSIF, fed-state simulated intestinal fluid; GIT, gastrointestinal tract; IVIVC, in vitro in vivo correlation; LCT, long chain triglyceride; LFCS, lipid formulation classification system; log P, n-octanol/water partition coefficient; MCT, medium chain triglyceride; MDCK, Madin–Darby canine kidney cells; NCE, new chemical entity; P-app, apparent permeability; P-gp, permeability glycoprotein; SCT, short chain triglyceride; SEDDS, self-emulsifying drug delivery system; SIF, simulated intestinal fluid; SMEDDS, self-microemulsifying drug delivery system; SNEDDS, self-nanoemulsifying drug delivery system; Vit E, vitamin E 相似文献
54.
肾脏损伤时有机阴离子转运子表达变化及其意义 总被引:1,自引:0,他引:1
有机阴离子转运子(OAT)在机体清除各种内、外源性有机阴离子的过程中发挥极其重要的作用.在肾脏,OAT参与排泄许多外源性有机阴离子,如药物、环境中的化学物质、生物毒素以及许多内源性有机阴离子包括多种尿毒症毒素等.近年研究发现,各种肾脏疾病条件下OAT表达发生变化,并由此而产生相应病理生理效应.本文讨论了OAT在近端肾小管上皮细胞的生物学特征、肾脏病变状态下的表达变化及其病理生理学意义. 相似文献
55.
Fengling Wang Xi Ye Yifan Wu Huihui Wang Chengming Sheng Daiyin Peng Weidong Chen 《Journal of pharmaceutical sciences》2019,108(1):641-651
Repeated injection of PEGylated liposomes can cause the disappearance of long circulating property because of the induction of anti-PEG IgM antibody referred to as “accelerated blood clearance (ABC) phenomenon.” Although ABC phenomenon typically occurs when entrapped drugs are chemotherapeutic agent with low cytotoxic, there is little evidence of accelerated blood clearance of PEGylated herbal-derived compound on repeated injection. Herein, we investigated the blood concentration of PEGylated liposomal gambogenic acid (PEG-GEA-L), a model PEGylated liposomal herbal extract, on its repeated injection to rats. We found time interval between injections had considerable impact on the magnitude of ABC phenomenon induced by PEG-GEA-L. When time interval was prolonged from 3 days to 7 days, ABC phenomenon could be attenuated. Furthermore, its magnitude was enhanced accompanied by a marked rise in the accumulation of PEG-GEA-L in the liver and spleen in a first-dose–dependent manner. Consistently, the level of anti-PEG IgM significantly increased with the first dose of PEG-GEA-L and decreased with the extended time interval between injections, which implies anti-PEG IgM is a major contributor to the ABC phenomenon. Notably, the increased expression of liver anti-PEG IgM was accompanied by an increased expression of efflux transporters in the induction process of the ABC phenomenon. 相似文献
56.
Rei Miyamoto Takashi Nozawa Koichi Shiozuka Kenji Tabata 《Journal of pharmaceutical sciences》2019,108(3):1085-1089
Lilly Laboratories cell porcine kidney 1 (LLC-PK1) cells transfected with human P-glycoprotein (LLC-PK1-P-gp) are widely used in transport assays to identify drug candidates that function as substrates of this efflux transporter. Endogenous transporters expressed in LLC-PK1 cells may complicate the interpretation of findings from P-gp-mediated transport assays. We investigated the impact of porcine breast cancer resistance protein (Bcrp) in P-gp-mediated transport assays in LLC-PK1 cells. Porcine Bcrp mRNA was detected in both LLC-PK1 wildtype (WT) and LLC-PK1-P-gp cells by quantitative RT-PCR. To investigate the activity and impact of porcine Bcrp, we conducted transport assays using 6 typical BCRP substrates in LLC-PK1 cells. Efflux ratios (ER) of the 6 BCRP substrates in LLC-PK1 WT cells were >2, and were reduced in the presence of the BCRP inhibitor Ko143. The efflux activities of the 6 BCRP substrates were confirmed using MDCKII cells transfected with human BCRP. Net ERs of prazosin and fluvastatin, dual substrates of P-gp and BCRP, determined by dividing ERs in LLC-PK1-P-gp cells by those in LLC-PK1 WT cells, were <2, but increased to >2 in the presence of Ko143. These results indicated that endogenous Bcrp in LLC-PK1 cells was involved in the transport of BCRP substrates and may interfere with the identification of P-gp substrates. 相似文献
57.
58.
Heidi Bisgaard Sonia Mazier Amy Hauck Newman Lei Shi Claus J. Loland Ulrik Gether 《Neuropharmacology》2011,60(1):182-190
Analogs of benztropines (BZTs) are potent inhibitors of the dopamine transporter (DAT) but are less effective than cocaine as behavioral stimulants. As a result, there have been efforts to evaluate these compounds as leads for potential medication for cocaine addiction. Here we use computational modeling together with site-directed mutagenesis to characterize the binding site for BZTs in DAT. Docking into molecular models based on the structure of the bacterial homolog LeuT supported a BZT binding site that overlaps with the substrate-binding pocket. In agreement, mutations of residues within the pocket, including2 Val1523.46 to Ala or Ile, Ser4228.60 to Ala and Asn1573.51 to Cys or Ala, resulted in decreased affinity for BZT and the analog JHW007, as assessed in [3H]dopamine uptake inhibition assays and/or [3H]CFT competition binding assay. A putative polar interaction of one of the phenyl ring fluorine substituents in JHW007 with Asn1573.51 was used as a criterion for determining likely binding poses and establish a structural context for the mutagenesis findings. The analysis positioned the other fluorine-substituted phenyl ring of JHW007 in close proximity to Ala47910.51/Ala48010.52 in transmembrane segment (TM) 10. The lack of such an interaction for BZT led to a more tilted orientation, as compared to JHW007, bringing one of the phenyl rings even closer to Ala47910.51/Ala48010.52. Mutation of Ala47910.51 and Ala48010.52 to valines supported these predictions with a larger decrease in the affinity for BZT than for JHW007. Summarized, our data suggest that BZTs display a classical competitive binding mode with binding sites overlapping those of cocaine and dopamine. 相似文献
59.
目的调查新疆维吾尔自治区中医院ICU 2008年和2009年药品使用情况,为临床合理用药及医院内部科室药品比例增减提供参考。方法采用ABC分析法对药品的品种及金额进行统计分析,并对A类药品进行重点分析。结果 2009年A类药品共计22种,金额百分比72.74%,B类药品23种,金额百分比17.45%,C类药品173种,金额百分比9.81%;2008年A类药品共计32种,金额百分比72.51%,B类药品33种,金额百分比18.23%,C类药品203种,金额百分比9.26%。其中A类药品均高度集中在抗菌药物。结论 ICU用药存在不合理现象,应加强抗菌药物及中药注射剂的管理,促进合理用药。 相似文献
60.
M. T. N. Trieu V. Mallet G. Allain M. Rousselot M. Denizot J.‐M. Goujon F. Zal T. Hauet 《American journal of transplantation》2011,11(9):1845-1860
Static preservation is currently the most widely used organ preservation strategy; however, decreased donor organ quality is impacting outcome negatively. M101 is an O2 carrier with high‐oxygen affinity and the capacity to function at low temperatures. We tested the benefits of M101 both in vitro, on cold preserved LLC‐PK1, as well as in vivo, in a large white pig kidney autotransplantation model. In vitro, M101 supplementation reduced cold storage‐induced cell death. In vivo, early follow‐up demonstrated superiority of M101‐supplemented solutions, lowering the peak of serum creatinine and increasing the speed of function recovery. On the longer term, supplementation with M101 reduced kidney inflammation levels and maintained structural integrity, particularly with University of Wisconsin (UW). At the end of the 3‐month follow‐up, M101 supplementation proved beneficial in terms of survival and function, as well as slowing the advance of interstitial fibrosis. We show that addition of M101 to classic organ preservation protocols with UW and Histidine–Tryptophane–Ketoglutarate, the two most widely used solutions worldwide in kidney preservation, provides significant benefits to grafts, both on early function recovery and outcome. Simple supplementation of the solution with M101 is easily translatable to the clinic and shows promises in terms of outcome. 相似文献