全文获取类型
收费全文 | 107篇 |
免费 | 2篇 |
国内免费 | 1篇 |
专业分类
基础医学 | 14篇 |
临床医学 | 2篇 |
内科学 | 13篇 |
神经病学 | 23篇 |
特种医学 | 1篇 |
外科学 | 12篇 |
综合类 | 11篇 |
眼科学 | 1篇 |
药学 | 23篇 |
中国医学 | 8篇 |
肿瘤学 | 2篇 |
出版年
2023年 | 1篇 |
2021年 | 2篇 |
2020年 | 2篇 |
2018年 | 1篇 |
2016年 | 1篇 |
2014年 | 2篇 |
2013年 | 3篇 |
2012年 | 4篇 |
2011年 | 9篇 |
2010年 | 3篇 |
2009年 | 4篇 |
2008年 | 4篇 |
2007年 | 4篇 |
2006年 | 7篇 |
2005年 | 5篇 |
2004年 | 10篇 |
2003年 | 9篇 |
2002年 | 5篇 |
2001年 | 3篇 |
2000年 | 2篇 |
1999年 | 4篇 |
1998年 | 5篇 |
1996年 | 3篇 |
1995年 | 1篇 |
1994年 | 2篇 |
1992年 | 4篇 |
1991年 | 2篇 |
1990年 | 2篇 |
1988年 | 1篇 |
1985年 | 5篇 |
排序方式: 共有110条查询结果,搜索用时 15 毫秒
1.
Daniele Armaleo Guang-Ning Ye Theodore M. Klein Katherine B. Shark John C. Sanford Stephen Albert Johnston 《Current genetics》1990,17(2):97-103
Summary The yeast Saccharomyces cerevisiae has been engineered to synthesize and secrete desulfato-hirudin (hirudin), a thrombin inhibitor from the leech Hirudo medicinalis. The synthetic gene coding for hirudin was expressed constitutively under the control of four size-variants of the yeast glyceraldehyde-3-phosphate dehydrogenase promoter (GAP) and cloned into a 2 based multicopy yeast vector. The constitutive action of the four promoter variants was confirmed by demonstrating that the expression and secretion of hirudin is growth-related. The different efficiencies of the promoter variants not only affected hirudin expression but also led to changes in several cellular parameters, such as cell growth, average plasmid copy number and plasmid stability. The observed changes show that yeast cells establish a specific equilibrium for each promoter variant. We conclude, that the adjustment of cellular parameters in response to the expression levels of a heterologous protein is regulated by two counteracting selective forces: (1) the need for complementation of the auxotrophic host marker by the plasmid-encoded selection gene which, in the case of dLEU2, requires several plasmid copies; and (2) a selective advantage of cells with a lower copy number enabling them to escape the burden of heterologous protein production. 相似文献
2.
John M. Maraganore 《Perspectives in Drug Discovery and Design》1994,1(3):461-478
Summary Over the past two decades, advances in the prevention and treatment of coronary artery disease, e.g., coronary angioplasty and coronary thrombolysis, have been coupled with the need for improved antithrombotic therapy to prevent acute, life-threatening thrombotic complications. Concurrently, studies on the pathophysiologic mechanisms for the arterial thrombotic process have demonstrated a central, mediating role for thrombin. Brought forward from its identification in the late 19th century, the leech protein hirudin emerged as a model for recombinant DNA engineering and protein-mimetic drug design. Recombinant hirudin (r-hirudin) and Hirulog are the resulting drug candidates which, as direct thrombin inhibitors, offer several potential advances in the management of acute thrombotic disorders. Clinical trials of these drug candidates have already provided evidence for clinical activity and tolerability in thromboembolic disease. Definitive evidence for efficacy is currently sought in large, controlled studies in the settings of coronary angioplasty, coronary thrombolysis and unstable angina.Hirulog antithrombin is a product of Biogen, Inc., Cambridge, MA, U.S.A. 相似文献
3.
4.
Summary The wealth of structural information now available on thrombin, its precursors, its substrates and its inhibitors allows a rationalization of its many roles. -Thrombin exhibits an unusually deep and narrow active-site cleft, formed by loop insertions that are characteristic of thrombin. This canyon structure is one of the prime causes for the narrow specificity of thrombin. As a result of the conjunction of amino acid residues with similar properties such as charge or hydrophobicity, thrombin can be divided up into a number of functional regions. The apposition of the active site to a hydrophobic pocket (the apolar binding site) on one side and a basic patch (the fibrinogen recognition exosite) on the other allows for a fine-tuning of enzymatic activity, as seen for fibrinogen. These two sites are also optimally used by the leech-derived inhibitor hirudin, allowing the very tight binding observed; thrombin inhibition is effected by blocking access to the active site. Interactions with antithrombin III are tightened with the help of heparin, which binds to a second basic site (the heparin binding site). Non-proteolytic cellular properties are attributed to the rigid insertion loop at Tyr60A. The observed rigidity of the thrombin molecule in its complexes makes thrombin ideal for structure-based drug design. Thrombin can be inhibited either at the active site or at the fibrinogen recognition exosite, or both. Structural information shows that binding at the former is enhanced by good fit of aromatic moieties to the aryl and S2 binding sites (the apolar binding site). Binding at the fibrinogen recognition exosite is facilitated by negatively charged groups. The unpredictable nature of inhibitor binding underlines the importance of experimental monitoring of structures of thrombin inhibitors in the drug design process. 相似文献
5.
目的观察双重组RGD肽水蛭素对大鼠冠脉微循环障碍的疗效 ,并探讨其作用机理。方法健康雄性SD大鼠共62只 ,随机分为正常对照组 (n=6)、安慰剂组 (n=18)以及RGD肽水蛭素治疗组(n=36) ,后者根据所用RGD肽水蛭素剂量进一步分为1mg/kg和5mg/kg体质量2个亚组 ,每组各18只。RGD肽水蛭素于建模当日采用腹腔注射的方法给药 ,以注射生理盐水做为安慰剂。分别采用病理切片、超声心动图和彩色微粒子测量技术 ,观察各组大鼠心肌内微血栓和微梗死形成 ,以及心功能和心肌局部血流量变化的情况 ;采用免疫组化和RT -PCR的方法观察心肌组织内IL -18蛋白及mRNA的表达。结果与安慰剂组相比 ,1mg/kg/d及5mg/kg/d的RGD肽水蛭素可显著减少大鼠心肌内微栓塞数量以及局部梗死面积 (P<0.01) ,同时大鼠心功能LVEF和心肌局部血流量也明显得到改善 ;RGD肽水蛭素也显著下调大鼠心肌组织内IL -18蛋白和mRNA的表达 (P<0.05)。结论RGD肽水蛭素能明显改善大鼠因微栓塞所致的冠脉微循环障碍 ,可作为治疗冠脉微循环障碍的重要药物。其中抑制IL -18的分泌表达 ,可能是RGD肽水蛭素抗炎改善冠脉微循环的重要机制之一。 相似文献
6.
S R Mehta J W Eikelboom H-J Rupprecht B S Lewis M K Natarajan C Yi J Pogue S Yusuf 《European heart journal》2002,23(2):117-123
AIMS: Although hirudin is superior to unfractionated heparin for prevention of death, myocardial infarction, or refractory ischaemia in patients with non-ST-elevation acute coronary syndrome, it is not clear whether hirudin is also of benefit in acute coronary syndrome patients undergoing early percutaneous coronary intervention. METHODS AND RESULTS: In the OASIS 2 trial, 10 141 patients with non-ST-elevation acute coronary syndrome were randomized to 72 h of intravenous hirudin or unfractionated heparin. Percutaneous coronary intervention was performed at the discretion of the investigator. One hundred and seventeen patients underwent percutaneous coronary intervention within the first 72 h ("early percutaneous coronary intervention"). In patients undergoing early percutaneous coronary intervention, hirudin compared with unfractionated heparin was associated with a significantly lower incidence of death or myocardial infarction at 96 h (6.4% vs 21.4%, OR 0.30; 95% CI: 0.10-0.88) and 35 days (6.4% vs 22.9%, OR 0.25; 95% CI: 0.07-0.86). In the unfractionated heparin group, death or myocardial infarction was significantly higher at 35 days in patients undergoing early percutaneous coronary intervention compared with those managed conservatively (22.9% vs 7.3%, OR 3.14, P<0.001) but this early percutaneous coronary intervention-related hazard was not observed in hirudin-treated patients (6.4% vs 6.8%, OR 0.94 P=1.0). A time-dependent covariate for percutaneous coronary intervention was not significant in a Cox regression model, suggesting a similar treatment benefit with hirudin before and after percutaneous coronary intervention. After adjustment for percutaneous coronary intervention propensity, the benefits of hirudin remained significant. There were three major bleeds in patients undergoing early percutaneous coronary intervention, all in patients randomized to hirudin. CONCLUSION: In patients with non-ST-elevation acute coronary syndrome undergoing early percutaneous coronary intervention, a direct thrombin inhibitor such as hirudin may be more effective than heparin in reducing the incidence of ischaemic complications. 相似文献
7.
R. Munro R. T. Sawyer F. O. P. Hechtel R. John 《Comparative Haematology International》1992,2(1):27-29
Prolongation of haemostatic parameters in the host achieved by hatchlingHirudo medicinalis differs quantitatively but not qualitatively from those achieved by adult leeches. The duration and the rate of blood loss
from the bite wounds, the gain in body weight of leeches and the duration of feeding each increase with successive feeding
episodes. The mean duration of bleeding from bite wounds of hatchling leeches feeding for the first time on human volunteers
was 43 min compared to 6 min from control incisions and 600 min in adult leeches. The mean ‘whole body’ concentration of hirudin
in 2-week-old hatchlings was 10 antithrombin units (AT-U) compared to 285 AT-U in the head of each adult leech. 相似文献
8.
目的探讨水蛭素活性因子对S180肿瘤及血管新生的影响,为临床用药提供理论依据。方法 (1)S180肿瘤实验:取小鼠44只,随机分组,接种S180瘤细胞。模型对照组给予生理盐水,阳性对照组给予5-FU,实验用药组分别给予不同剂量的水蛭素活性因子,连续用药14天,第15天剥离肿块,比较各组肿瘤生长情况,并计算抑瘤率。(2)血管新生实验:取纯种鸡胚蛋,随机分组,恒温箱中孵育。分别吸取生理盐水、水蛭素活性因子不同浓度的药液,滴于滤膜载体上,将含药载体种植于鸡胚绒毛尿囊(CAM)中,密封后放入恒温箱内孵育96h,滴加甲醛,20m in后立体显微镜下观察药物抑制新生血管的生长情况,并用计算机分析系统对CAM进行扫描,记数血管VN、血管VD、血管VA的多少和大小。结果水蛭素活性因子大小剂量用药组对S180肿瘤具有明显的抑制作用,其抑瘤率分别为43.33%和40.67%。CAM观察发现,水蛭素活性因子大小剂量用药组血管分布稀疏、间距增大,含药载体周围血管减少。而模型对照组则血管分布密集、间距缩小、呈放射状排列。结论实验表明,水蛭素活性因子对S180肿瘤和CAM新生血管具有较强的抑制作用。 相似文献
9.
10.
The influence of direct and antithrombin-dependent thrombin inhibitors on the procoagulant and anticoagulant effects of thrombin 总被引:1,自引:0,他引:1
INTRODUCTION: Clinical trials evaluating direct thrombin inhibitors in unstable coronary artery disease (CAD) have been disappointing. The hypothesis tested in the present study was that these agents may inhibit the anticoagulant effect of thrombin to a further extent than the procoagulant effect of thrombin. MATERIALS AND METHODS: We studied both reversible and irreversible thrombin inhibitors and compared the effects of each inhibitor on activated protein C (APC) generation vs. the effect on fibrinopeptide A (FPA) generation. A mixture of protein C, thrombin inhibitor, fibrinogen, fibrin polymerisation blocker and thrombin was incubated with thrombomodulin (TM)-expressing human saphenous vein endothelial cells (HSVECs). The inhibitors investigated were melagatran, inogatran, hirudin, hirugen, D-Phe-D-Pro-D-arginyl chloromethyl ketone (PPACK), and antithrombin (AT) alone or in combination with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). RESULTS: All agents, except hirugen, inhibited APC and FPA generation in a dose-dependent manner. FPA inhibition/APC inhibition ratios, based on IC50 for inogatran, melagatran, hirudin, PPACK, AT, AT-UFH and AT-LMWH were 1.73, 0.85, 0.55, 2.1, 0.5, 0.65 and 3.1 respectively. CONCLUSIONS: All agents, except hirugen, inhibited APC and FPA generation approximately to a similar extent. Thus, it can be inferred that the poor efficacy of thrombin inhibitors in recent clinical trials in patients with unstable CAD is unlikely to be a consequence of their effects on the protein C system. 相似文献