全文获取类型
收费全文 | 1562篇 |
免费 | 67篇 |
国内免费 | 8篇 |
专业分类
耳鼻咽喉 | 2篇 |
儿科学 | 43篇 |
妇产科学 | 26篇 |
基础医学 | 172篇 |
口腔科学 | 26篇 |
临床医学 | 124篇 |
内科学 | 358篇 |
皮肤病学 | 31篇 |
神经病学 | 78篇 |
特种医学 | 17篇 |
外科学 | 183篇 |
综合类 | 50篇 |
一般理论 | 2篇 |
预防医学 | 94篇 |
眼科学 | 36篇 |
药学 | 245篇 |
中国医学 | 19篇 |
肿瘤学 | 131篇 |
出版年
2023年 | 9篇 |
2022年 | 25篇 |
2021年 | 47篇 |
2020年 | 33篇 |
2019年 | 42篇 |
2018年 | 46篇 |
2017年 | 56篇 |
2016年 | 30篇 |
2015年 | 38篇 |
2014年 | 77篇 |
2013年 | 108篇 |
2012年 | 113篇 |
2011年 | 125篇 |
2010年 | 74篇 |
2009年 | 47篇 |
2008年 | 88篇 |
2007年 | 104篇 |
2006年 | 67篇 |
2005年 | 92篇 |
2004年 | 70篇 |
2003年 | 79篇 |
2002年 | 83篇 |
2001年 | 27篇 |
2000年 | 16篇 |
1999年 | 26篇 |
1998年 | 8篇 |
1997年 | 8篇 |
1996年 | 15篇 |
1995年 | 8篇 |
1994年 | 11篇 |
1993年 | 11篇 |
1992年 | 8篇 |
1991年 | 4篇 |
1990年 | 4篇 |
1989年 | 4篇 |
1988年 | 4篇 |
1987年 | 3篇 |
1986年 | 7篇 |
1985年 | 2篇 |
1983年 | 1篇 |
1982年 | 3篇 |
1980年 | 1篇 |
1979年 | 1篇 |
1975年 | 1篇 |
1974年 | 2篇 |
1973年 | 2篇 |
1972年 | 1篇 |
1969年 | 2篇 |
1968年 | 3篇 |
1962年 | 1篇 |
排序方式: 共有1637条查询结果,搜索用时 31 毫秒
1.
2.
Hend Kothayer Samy M. Ibrahim Moustafa K. Soltan Samar Rezq Shireen S. Mahmoud 《Drug development research》2019,80(3):343-352
In light of the pharmacophoric structural requirements for achieving anticonvulsant activity, a series of N-(1-methyl-4-oxo-2-un/substituted-1,2-dihydroquinazolin-3[4H]-yl)benzamide (4a-g) and N-(1-methyl-4-oxo-2-un/substituted-1,2-dihydroquinazolin-3[4H]-yl)-2-phenylacetamide (4h-n) derivatives were synthesized in two steps starting from the reaction of N-methyl isatoic anhydride with the appropriate hydrazide and followed by condensation with the appropriate aldehyde. The anticonvulsant activities of the synthesized compounds were evaluated according to the anticonvulsant drug development (ADD) programme protocol. Among the synthesized compounds, 4n showed promising activity in both the maximal electroshock (MES) and pentylenetetrazole (PTZ) tests with median effective dose (ED50) values of 40.7 and 6 mg/kg, respectively. The six most promising derivatives, 4b , 4a , 4c , 4f , 4j , and 4i , showed very low ED50 values in the PTZ test (3.1, 4.96, 8.68, 9.89, 12, and 13.53 mg/kg, respectively). All the tested compounds showed no to low neurotoxicity in the rotarod test with a wide therapeutic index. Docking studies of compound 4n suggested that GABAA binding could be the mechanism of action of these derivatives. The in silico drug likeliness parameters indicated that none of the designed compounds violate Lipinski's rule of five and that they are able to cross the blood–brain barrier.
相似文献
Hit, Lead & Candidate Discovery |
3.
4.
Sarraf S Tejada R Abawi M Oberst M Dennis T Simon KC Blancato J 《Cancer Genetics and Cytogenetics》2005,161(1):63-69
Cell lines derived from tumors contain numerous chromosomal aberrations and are the focus of study in tumor evolution. The ovarian teratocarcinoma cell line PA-1 demonstrates a single chromosomal aberration: a reciprocal t(15;20)(p11.2;q11.2). A complete molecular genetic analysis was undertaken to characterize this cell line. The PA-1 cell line was studied with fluorescence in situ hybridization (FISH), spectral karyotyping (SKY), bacterial artificial chromosome (BAC) microarray, and Western blotting. Amplification of 20q is frequently implicated in both breast and ovarian cancer; this region contains a number of oncogenes including MDM2, ZNF217, and the ovarian tumor marker WFDC2 (alias HE4). FISH revealed gene amplification of AIB1 (now known as NCOA3) but not STK15 (now known as AURKA). Immunoblot analysis demonstrated 3.6-fold overexpression of the AIB1 protein product, but no elevation of the STK15. BAC cancer gene microarray analysis showed gene amplification of > or =1.20 for five oncogenes. The presence of a consistent single change in PA-1, the t(15;20)(p11.2;q11.2), suggests that the aberration is significant with respect to the transformation status of the cell line. This translocation appears to cause overexpression of AIB1 (and perhaps other proteins), which may provide an immortalizing effect on this cell line. 相似文献
5.
A simple numerical simulation of AIDS patient detoxification by a hypothetical extracorporeal device for the removal of viruses, infected white cells, and syncytia has been designed. The mathematical model accounts for healthy blood white cells attacking and destroying the viruses, while at the same time the viruses attack and infect certain white cells. The infected white cells serve as a site for viral growth; eventually the cells lyse, releasing a large number of viruses into the blood stream. The healthy white cells and infected white cells combine to form syncytia, where the virus multiplies, and finally the syncytium ruptures releasing all the virus. This model can be used to predict concentrations over a specified period for the patient. This is a mathematical model to be used as a research and design tool only. 相似文献
6.
Xiaoyu Wang Mingzhen Zhang Regina R. Woloshun Yang Yu Jennifer K. Lee Shireen R. L. Flores Didier Merlin James F. Collins 《Nutrients》2021,13(5)
Intestinal iron transport requires an iron importer (Dmt1) and an iron exporter (Fpn1). The hormone hepcidin regulates iron absorption by modulating Fpn1 protein levels on the basolateral surface of duodenal enterocytes. In the genetic, iron-loading disorder hereditary hemochromatosis (HH), hepcidin production is low and Fpn1 protein expression is elevated. High Fpn1-mediated iron export depletes intracellular iron, causing a paradoxical increase in Dmt1-mediated iron import. Increased activity of both transporters causes excessive iron absorption, thus initiating body iron loading. Logically then, silencing of intestinal Dmt1 or Fpn1 could be an effective therapeutic intervention in HH. It was previously established that Dmt1 knock down prevented iron-loading in weanling Hamp (encoding hepcidin) KO mice (modeling type 2B HH). Here, we tested the hypothesis that Dmt1 silencing combined with dietary iron restriction (which may be recommended for HH patients) will mitigate iron loading once already established. Accordingly, adult Hamp KO mice were switched to a low-iron (LFe) diet and (non-toxic) folic acid-coupled, ginger nanoparticle-derived lipid vectors (FA-GDLVs) were used to deliver negative-control (NC) or Dmt1 siRNA by oral, intragastric gavage daily for 21 days. The LFe diet reduced body iron burden, and experimental interventions potentiated iron losses. For example, Dmt1 siRNA treatment suppressed duodenal Dmt1 mRNA expression (by ~50%) and reduced serum and liver non-heme iron levels (by ~60% and >85%, respectively). Interestingly, some iron-related parameters were repressed similarly by FA-GDLVs carrying either siRNA, including 59Fe (as FeCl3) absorption (~20% lower), pancreatic non-heme iron (reduced by ~65%), and serum ferritin (decreased 40–50%). Ginger may thus contain bioactive lipids that also influence iron homeostasis. In conclusion, the combinatorial approach of FA-GDLV and Dmt1 siRNA treatment, with dietary iron restriction, mitigated pre-existing iron overload in a murine model of HH. 相似文献
7.
Janine Jewanraj Sinaye Ngcapu Farzana Osman Veron Ramsuran Maryam Fish Andile Mtshali Ravesh Singh Leila E Mansoor Salim S Abdool Karim Quarraisha Abdool Karim JoAnn S Passmore Lenine J P Liebenberg 《Journal of the International AIDS Society》2021,24(6)
IntroductionSemen induces mucosal changes in the female reproductive tract to improve pregnancy outcomes. Since semen‐induced alterations are likely short‐lived and genital inflammation is linked to HIV acquisition in women, we investigated the contribution of recent semen exposure on biomarkers of genital inflammation in women at high HIV risk and the persistence of these associations.MethodsWe assessed stored genital specimens from 152 HIV‐negative KwaZulu‐Natal women who participated in the CAPRISA 008 trial between November 2012 and October 2014. During the two‐year study period, 651 vaginal specimens were collected biannually (mean five samples per woman). Cervicovaginal lavage (CVL) was screened for prostate‐specific antigen (PSA) by ELISA, whereas Y‐chromosome DNA (YcDNA) detection and quantification were conducted by RT‐PCR, representing semen exposure within 48 hours (PSA+YcDNA+) and semen exposure within three to fifteen days (PSA−YcDNA+). Soluble protein concentrations were measured in CVLs by multiplexed ELISA. T‐cell frequencies were assessed in cytobrushes by flow‐cytometry, and vulvovaginal swabs were used to detect common vaginal microbes by PCR. Linear mixed models adjusting for factors associated with genital inflammation and HIV risk were used to assess the impact of semen exposure on biomarkers of inflammation over multiple visits.ResultsHere, 19% (125/651) of CVLs were PSA+YcDNA+, 14% (93/651) were PSA−YcDNA+ and 67% (433/651) were PSA−YcDNA−. Semen exposure was associated with how often women saw their partners, the frequency of vaginal sex in the past month, HSV‐2 antibody detection, current gonorrhoea infection and Nugent Score. Both PSA detection (PSA+YcDNA+) and higher cervicovaginal YcDNA concentrations predicted increases in several cytokines, barrier‐related proteins (MMP‐2, TIMP‐1 and TIMP‐4) and activated CD4+CCR5+HLA‐DR+ T cells (β = 0.050; CI 0.001 to 0.098; p = 0.046) and CD4+HLA‐DR+ T cells (β = 0.177; CI 0.016 to 0.339; p = 0.032) respectively. PSA detection was specifically associated with raised pro‐inflammatory cytokines (including IL‐6, TNF‐α, IP‐10 and RANTES), and with the detection of BVAB2 (OR = 1.755; CI 1.116 to 2.760; p = 0.015), P. bivia (OR = 1.886; CI 1.102 to 3.228; p = 0.021) and Gardnerella vaginalis (OR = 1.815; CI 1.093 to 3.015; p = 0.021).ConclusionsMore recent semen exposure was associated with raised levels of inflammatory biomarkers and the detection of BV‐associated microbes, which declined by three to fifteen days of post‐exposure. Although transient, semen‐induced alterations may have implications for HIV susceptibility in women. 相似文献
8.
Preben Jakobsen Bente Søresen Lars Bastholt Mansoor Raza Mirza Susanne B. Gjedde Henning T. Mouridsen Carsten Rose 《Cancer chemotherapy and pharmacology》1994,35(1):45-52
A high-pressure liquid chromatographic method for determination of the bisdioxopiperazine derivative ADR-529 (ICRF-187), a compound proven effective in protection against anthracycline-induced cardiotoxicity, has been developed. The limit of quantitation was 5 ng/ml using a narrow-bore 5-m silica column and UV detection. The method was used for determination of pharmacokinetic profiles of ADR-529 after a 3-weekly i.v. administration of different doses of ADR-529 (600–1000 mg/m2) together with different doses of epirubicin (E, 60–100 mg/m2), fixed-dose cyclophosphamide (C, 600 mg/m2), fixed-dose 5-fluorouracil (F, 600 mg/m2), and daily administration of tamoxifen (T, 30 mg; CEF-T) in the treatment of patients with metastatic breast cancer. Pharmacokinetic parameters for epirubicin were also determined. The aim of the study was to determine (1) whether the pharmacokinetics of ADR-529 as part of a combination with CEF-T changes with increasing doses of ADR-529 and increasing doses of epirubicin and (2) whether the pharmacokinetics of epirubicin in the same combinations is altered with the administration of increasing doses of ADR-529. A total of 82 patients were included. A crossover study including 16 of the patients showed no significant difference in epirubicin pharmacokinetic parameters when epirubicin was given with or without concomitant administration of ADR-529. Apart from minor changes in the distributional half-lives, the pharmacokinetic parameters of epirubicin were not altered with increasing doses of ADR-529, nor were the pharmacokinetic parameters of ADR-529 itself. Escalating doses of epirubicin did not significantly alter the pharmacokinetic parameters of ADR-529 with the exception of a 30% increase in the terminal half-life and a decrease in total body clearance when the epirubicin dose was raised from 60 to 100 mg/m2. We conclude that concomitant administration of ADR-529 does not alter the distribution and elimination of epirubicin in doses suitable for preventing the anthracycline-induced cardiotoxicity. 相似文献
9.
AIMS: To review the availability and quality of data on the epidemiology of diabetes in New Zealand. METHODS: A search was undertaken for all Medline-indexed publications on diabetes in New Zealand. Hospitalisation and mortality data (ICD9 code 250) from the New Zealand Health Information Service (NZHIS) were examined. RESULTS: Information on diabetes in New Zealand has come from community surveys, national surveys, diabetes registers, hospitalisation data and mortality data. Much of this information has been valuable, but there is still inadequate national information on diabetes prevalence, incidence and time trends. CONCLUSION: Information technology provides an opportunity to couple the surveillance of diabetes with improved diabetes care. Medical practitioners need to support the development of their own practice-based registers/recall systems and to contribute to the development of district-based diabetes registers where these have a central focus on improving diabetes care. 相似文献
10.
Purpose: In an attempt to increase the local concentration of tamoxifen in estrogen receptor positive breast cancer cells, we have prepared and characterized poly (ε-caprolactone) (PCL) nanoparticle formulation. Methods: PCL (mol wt 14,800 daltons) nanoparticles were prepared by the solvent displacement method in acetonewater system in the presence of Pluronic F-68. PCL nanoparticles, labeled with rhodamine 123, were incubated with MCF-7 estrogen receptor positive breast cancer cells to determine uptake, intracellular distribution, and localization as a function of time. Intracellular drug concentrations over a specified period of time using different initial doses were examined using tritiated [3H]-tamoxifen. Results: A significant fraction of the administered rhodamine 123-loaded PCL nanoparticles was found in the perinuclear region of the MCF-7 cells, where estrogen receptors are also localized, after 1 hour of incubation. Measurements of the intracellular concentrations revealed that most of the administered nanoparticle dose was internalized within the first 30 minutes of incubation, and the uptake followed saturable transport kinetics. Conclusion: Results of this study show that PCL nanoparticles were rapidly internalized in MCF-7 cells and intracellular tamoxifen concentrations followed a saturable process. This approach may provide better therapeutic benefit by delivering the drug locally, near the tumor cells, for a longer period of time. 相似文献