全文获取类型
收费全文 | 765篇 |
免费 | 56篇 |
国内免费 | 3篇 |
专业分类
耳鼻咽喉 | 21篇 |
儿科学 | 31篇 |
妇产科学 | 6篇 |
基础医学 | 126篇 |
口腔科学 | 15篇 |
临床医学 | 57篇 |
内科学 | 185篇 |
皮肤病学 | 9篇 |
神经病学 | 24篇 |
特种医学 | 9篇 |
外科学 | 127篇 |
综合类 | 2篇 |
预防医学 | 69篇 |
眼科学 | 8篇 |
药学 | 38篇 |
肿瘤学 | 97篇 |
出版年
2023年 | 4篇 |
2021年 | 11篇 |
2020年 | 9篇 |
2019年 | 11篇 |
2018年 | 14篇 |
2017年 | 10篇 |
2016年 | 12篇 |
2015年 | 16篇 |
2014年 | 9篇 |
2013年 | 30篇 |
2012年 | 28篇 |
2011年 | 33篇 |
2010年 | 29篇 |
2009年 | 16篇 |
2008年 | 31篇 |
2007年 | 31篇 |
2006年 | 35篇 |
2005年 | 29篇 |
2004年 | 41篇 |
2003年 | 31篇 |
2002年 | 23篇 |
2001年 | 21篇 |
2000年 | 25篇 |
1999年 | 21篇 |
1998年 | 9篇 |
1997年 | 11篇 |
1996年 | 16篇 |
1995年 | 7篇 |
1994年 | 5篇 |
1993年 | 8篇 |
1992年 | 25篇 |
1991年 | 15篇 |
1990年 | 16篇 |
1989年 | 20篇 |
1988年 | 11篇 |
1987年 | 19篇 |
1986年 | 17篇 |
1985年 | 13篇 |
1984年 | 17篇 |
1983年 | 10篇 |
1982年 | 5篇 |
1981年 | 13篇 |
1980年 | 8篇 |
1979年 | 5篇 |
1973年 | 3篇 |
1970年 | 3篇 |
1968年 | 4篇 |
1966年 | 4篇 |
1964年 | 4篇 |
1963年 | 3篇 |
排序方式: 共有824条查询结果,搜索用时 0 毫秒
1.
Segregation analysis of leprosy in families of northern Thailand 总被引:4,自引:0,他引:4
Sixty-three families with multiple instances of leprosy were identified through a major leprosy treatment center in northern Thailand. Complex segregation analyses for single major genes or polygenic inheritance were performed using the maximum-likelihood routine POINTER to determine the most likely etiologic model of genetic susceptibility. Liability differences between men and women were considered in these models. When individuals were considered to be affected because they had any form of leprosy, a generalized major gene model with nearly dominant parameters on the liability scale, but additive penetrances, was found to be the most likely. When only those individuals who had tuberculoid forms of leprosy were considered to be affected, a recessive model was found to be the most likely; however, the discrimination between various models was poor. Further analyses are necessary to delineate genetic mechanisms to explain these apparently divergent results. In particular, methods of testing two locus models should be considered. 相似文献
2.
In vitro modulation of cisplatin cytotoxicity by sparsomycin inhibition of protein synthesis 总被引:1,自引:0,他引:1
Z Zylicz D J Wagener H van Rennes J M Wessels E van der Kleijn W J de Grip L A van den Broek H C Ottenheijm 《Journal of the National Cancer Institute》1987,78(4):701-705
Inhibition of protein synthesis can alter cellular responsiveness to the classical anticancer drugs. The in vitro response of Chinese hamster ovary (CHO) cells to cisplatin with or without sparsomycin (Sm) was studied with the use of [3H]leucine and [methyl-3H]thymidine incorporation and clonogenic assay. Pretreatment of exponentially growing CHO cells with 1 microgram Sm/ml for 3 or 5 hours decreased [3H]leucine incorporation by 20% and resulted in significant resistance to cisplatin (P = .005). Sm in a concentration of 10 micrograms/ml reduced [3H]leucine and [methyl-3H]thymidine incorporation after 3 hours by 92 and 84%, respectively, and resulted in potentiation of the cisplatin cytotoxicity (P = .004). This effect was the same in the case of nonproliferating cells (P = .005), while protection due to Sm (1 microgram/ml) was seen only during cell proliferation. Simultaneous incubation and postincubation with Sm proved to have much less or no potentiating effect on cisplatin. The mechanisms of both protection and potentiation are still not clear, but our data indicate that Sm is a promising drug for further studies on the modulation of the cancer cell response to classical anticancer drugs. 相似文献
3.
S B Kaye J Wanders M Clavel J Verweij M J Piccart J F Smyth W W Ten Bokkel Huinink D J Wagener I R Judson F Cavalli 《Annals of oncology》1992,3(5):406-408
A total of 91 eligible patients with metastatic cancer have been treated in a series of phase II trials of the novel pentacyclic pyrroloquinone, fosquidone. Tumour types were breast (24), ovary (25), head and neck (21) and melanoma (21). All patients, except those with melanoma had received prior chemotherapy. The drug was given intravenously as a 20 min infusion, at the dose of 120 mg/m2 on days 1 to 5 of a 3 week cycle. Treatment was well tolerated; the only significant side-effects being mild headaches and generalised musculo-skeletal pains. Response was assessed after 2 cycles of therapy. Only one patient (with head and neck cancer) achieved an objective partial response, lasting 6 weeks. A total of 12 patients demonstrated stable disease for a median duration of 15 to 20 weeks. Using this schedule of administration, fosquidone has no significant antitumour activity in this group of tumours. 相似文献
4.
5.
Lipophilic analogues of sparsomycin as strong inhibitors of protein synthesis and tumor growth: a structure-activity relationship study 总被引:2,自引:0,他引:2
L A van den Broek E Lázaro Z Zylicz P J Fennis F A Missler P Lelieveld M Garzotto D J Wagener J P Ballesta H C Ottenheijm 《Journal of medicinal chemistry》1989,32(8):2002-2015
Fourteen derivatives of sparsomycin (1) were synthesized. Six of them were prepared following a novel synthetic route starting from the L-amino acid alanine. Some physicochemical properties, viz. lipophilicity and water solubility, of selected derivatives were measured. The biological activity was tested in vitro in cell-free protein synthesis inhibition assays, in bacterial and tumor cell growth inhibition assays, and in the L1210 leukemia in vivo model in mice. Also for selected drugs the acute toxicity in mice was determined. Ribosomes from both an eukaryotic and a prokaryotic organism were used in the protein synthesis inhibition systems. A linear correlation between the lipophilicity parameters measured was observed. Water solubility and drug toxicity in mice were found to be linearly correlated with lipophilicity. All the derivatives studied are more lipophilic than 1. The deshydroxysparsomycin analogues (30-33) showed an interesting phenomenon: increase in hydrophobicity was accompanied by a considerable increase in water solubility. We found that an increase in hydrophobicity of the drug as a result of replacing the SMe group of 1 with larger alkylthio groups causes an increase in the biological activity of the drug. However, not only the hydrophobicity but also shape and size of the substituent are important; in the homologous series 1-9-10-11-12, 21-22-23-24, and 30-31-32-33, highest protein synthesis inhibitory and in vitro cytostatic activity is found with compounds 11, 23, and 32, respectively, and in comparison with the highly active n-butyl compound 10, the isomeric tert-butyl compound 13 is rather inactive. Polar substituents replacing the SMe group, i.e. Cl in 17 and 35, also render the molecule inactive. Substituting the bivalent sulfur atom for a methylene group decreases the drug's activity. This effect can be compensated for by increasing the length of the alkylsulfinyl side chain. The agreement between the results derived from cell-free and "in vivo" tests is good. The assays using ribosomes of bacterial and eukaryotic organisms give similar results although the latter seem to be more sensitive to changes in hydrophobicity of the drug. Our results confirm the presence of a hydrophobic region at the peptidyl transferase center of the ribosome; the interaction of sparsomycin with this region is more pronounced in the eukaryotic particles. The sparsomycin analogues 11, 23, and 30 show the highest antitumor activity against L1210 leukemia in mice, their median T/C values are 386, 330, and 216%, respectively.(ABSTRACT TRUNCATED AT 400 WORDS) 相似文献
6.
7.
8.
9.
Zbigniew Zylicz D. J. Theo Wagener Marina Garzotto Tom B. Vree Eppo van der Kleijn Leon A. G. M. van den Broek Harry C. J. Ottenheijm 《Investigational new drugs》1990,8(1):25-32
Summary N-pentyl-sparsomycin (PSm) is a lipophilic analogue of sparsomycin (Sm), which is a well known inhibitor of protein synthesis. This compound was selected for preclinical pharmacokinetic studies because of its high in vitro and in vivo antitumor activity. In this study in which the drug was evaluated in beagle dogs under anaesthesia, the drug concentrations in plasma, urine and bile samples were determined using high performance liquid chromatography (HPLC). Plasma protein binding was approximately 54%. The mean t1/2 was 0.2 hours (12 minutes) and t1/2 was 0.75 ± 0.1 hours (45 ± 6 minutes). During continuous infusions up to 5.25 hours, the steady state was reached in 3 out of 6 experiments, suggesting that in some cases the real t1/2 was longer than measured. PSm was actively reabsorbed from the renal tubuli. This process was saturable at the higher doses. Tubular reabsorption played only a minor role in pharmacokinetics as most of the drug (67%) was eliminated by the non-renal clearance. The non-renal clearance was saturable at higher doses of PSm and was the reason for non-linearity of pharmacokinetics. 相似文献
10.
Cytosolic glutathione S-transferases are a family of enzymes involved in the metabolism of drugs, toxins, carcinogens and also of anticancer drugs. Recent studies have indicated that glutathione S-transferases (GSTs) may play an important role in the resistance of cells to toxins and carcinogens but also to anticancer drugs. This report reviews the current literature concerning the role of glutathione S-transferases in anticancer drug resistance. Moreover, the significance of GST pi in carcinogenesis and its role as prognostic factor is discussed. 相似文献