全文获取类型
收费全文 | 714篇 |
免费 | 60篇 |
国内免费 | 18篇 |
专业分类
儿科学 | 2篇 |
妇产科学 | 4篇 |
基础医学 | 138篇 |
口腔科学 | 6篇 |
临床医学 | 38篇 |
内科学 | 77篇 |
皮肤病学 | 14篇 |
神经病学 | 61篇 |
特种医学 | 17篇 |
外科学 | 19篇 |
综合类 | 40篇 |
预防医学 | 26篇 |
眼科学 | 2篇 |
药学 | 281篇 |
中国医学 | 4篇 |
肿瘤学 | 63篇 |
出版年
2023年 | 8篇 |
2022年 | 7篇 |
2021年 | 18篇 |
2020年 | 27篇 |
2019年 | 14篇 |
2018年 | 23篇 |
2017年 | 26篇 |
2016年 | 23篇 |
2015年 | 30篇 |
2014年 | 38篇 |
2013年 | 85篇 |
2012年 | 30篇 |
2011年 | 44篇 |
2010年 | 42篇 |
2009年 | 28篇 |
2008年 | 41篇 |
2007年 | 29篇 |
2006年 | 25篇 |
2005年 | 25篇 |
2004年 | 29篇 |
2003年 | 31篇 |
2002年 | 17篇 |
2001年 | 11篇 |
2000年 | 14篇 |
1999年 | 12篇 |
1998年 | 10篇 |
1997年 | 14篇 |
1996年 | 9篇 |
1995年 | 11篇 |
1994年 | 12篇 |
1993年 | 3篇 |
1992年 | 10篇 |
1991年 | 6篇 |
1990年 | 1篇 |
1989年 | 4篇 |
1988年 | 2篇 |
1987年 | 7篇 |
1986年 | 3篇 |
1985年 | 5篇 |
1984年 | 7篇 |
1983年 | 1篇 |
1981年 | 2篇 |
1980年 | 2篇 |
1979年 | 2篇 |
1978年 | 2篇 |
1977年 | 2篇 |
排序方式: 共有792条查询结果,搜索用时 31 毫秒
11.
《Expert opinion on drug discovery》2013,8(2):115-129
Introduction: Neurodegenerative diseases have had devastating effects on patients' quality of life. These complex diseases have several pathways that are affected to initiate cell death. Current therapies, designed to address only a single target, fall short in mitigating or preventing disease progression, and disease-modifying drugs are desperately needed. Over the past several years, a new paradigm has emerged which has as a goal the targeting of multiple disease etiological pathways. Such “multi-targeted designed drugs” (MTDD) have shown great promise in preclinical studies as neuroprotective agents, as well as being able to afford symptomatic relief to blunt the day-to-day burden of these illnesses. Areas covered: In this review, the authors evaluate the use of chemical scaffolds that led themselves exquisitely to the development of MTDDs in central nervous system disorders. Some of the examples discussed have also transitioned into the clinic, which underscores the importance of pursuing drug discovery programs within the multifunctional arena. Expert opinion: Currently, very little can be done to slow the progress of neurodegeneration. The multifaceted profile of neurodegeneration necessitates a change in paradigm toward the design of compounds that address several drug targets simultaneously. With successful compounds in clinical trials as well as compounds moving into the clinic, support is growing and the feasibility of this approach is now becoming recognized. This review shows that several small molecule scaffolds can be successfully utilized to design MTDD compounds with good CNS pharmacokinetics. 相似文献
12.
《Expert opinion on therapeutic patents》2013,23(9):1171-1196
Importance of the field: Among the GPCR subclasses that have been discovered to date, 5-HT receptors are especially attractive as key biological targets with enormous clinical importance. In particular, during the last decade, the 5-HT6 receptor has gained increasing attention due to extensive cellular functions. It has also been suggested that its activity can be mediated by inverse agonists.Areas covered in this review: Summarizing the points listed above, the current review primarily focuses on patent literature within the title field, evolution and trends that have not yet been covered in such depth in other published papers.What the reader will gain: To obtain a clear understanding of the situation and dynamics within the field of 5-HT6 ligands, having an obvious pharmaceutical potential in terms of related patents, we provide a comprehensive search through several key patent collections. We have covered promising small molecule compounds which are being evaluated in different clinical trials as well as drugs currently available in the pharmaceutical market. In addition, readers will gain a deep insight into the patent specification, geographic distribution, tendency and patent holders presented.Take home message: Several of 5-HT6-targeted compounds are reasonably regarded as powerful drug candidates for the treatment of a range of neuropathological disorders, including Alzheimer's disease and Huntington's disease. 相似文献
13.
Notch signaling can regulate both hematopoietic progenitors and alloimmune T cells in the setting of allogeneic bone marrow or hematopoietic cell transplantation (allo-HCT). Ex vivo culture of multipotent blood progenitors with immobilized Delta-like ligands induces supraphysiological Notch signals and can markedly enhance progenitor expansion. Infusion of Notch-expanded progenitors shortened myelosuppression in preclinical and early clinical studies, while accelerating T cell reconstitution in preclinical models. Notch also plays an essential role in vivo to regulate pathogenic alloimmune T cells that mediate graft-versus-host disease (GVHD), the most severe complication of allo-HCT. In mouse allo-HCT models, Notch inhibition in donor-derived T cells or transient blockade of Delta-like ligands after transplantation profoundly decreased GVHD incidence and severity, without causing global immunosuppression. These findings identify Notch in T cells as an attractive therapeutic target to control GVHD. In this review, we discuss these contrasting functions of Notch signaling with high translational significance in allo-HCT patients. 相似文献
14.
Tomoya Hirota Hiroto Tsuboi Mana Iizuka-Koga Hiroyuki Takahashi Hiromitsu Asashima Masahiro Yokosawa 《Modern rheumatology / the Japan Rheumatism Association》2017,27(3):457-465
Objective: To investigate the effects of transgenic rice seeds expressing the altered peptide ligand (APL) of human glucose-6-phosphate-isomerase (hGPI325–339) in mice model of GPI-induced arthritis (GIA).Methods: We generated transgenic rice expressing T-cell epitope of hGPI325–339 and APL12 contained in the seed endosperm. The transgenic rice seeds were orally administered prophylactically before the induction of GIA. The severity of arthritis and titers of serum anti-GPI antibodies were evaluated. We examined for IL-17 production in splenocytes and inguinal lymph node (iLN) cells, and analyzed the expression levels of functional molecules in splenocytes.Results: Prophylactic treatment of GIA mice with APL12 transgenic (APL12-TG) rice seeds significantly reduced the severity of arthritis and titers of serum anti-GPI antibodies compared with non-transgenic (Non-TG) rice-treated mice. APL12-TG and hGPI325–339 transgenic (hGPI325–339-TG) rice seeds improved the histopathological arthritis scores and decreased IL-17 production compared with non-TG rice-treated mice. APL12-TG rice-treated GIA mice showed upregulation of Foxp3 and GITR protein in CD4?+?CD25?+?Foxp3+?cells in the spleen compared with non-TG rice- and hGPI325–339-TG rice-treated mice.Conclusion: APL12-TG rice seeds improved the severity of GIA through a decrease in production of IL-17 and anti-GPI antibodies via upregulation of Foxp3 and GITR expression on Treg cells in spleen. 相似文献
15.
《Expert opinion on therapeutic patents》2013,23(8):885-896
Introduction: Farnesoid-X-receptor (FXR) is the receptor for primary bile acids expressed in enterohepatic tissues where it regulates bile acid uptake, metabolism and disposal. For its role as a bile acid sensor, FXR has been thought to be an important target in the treatment of cholestatic disorders, a family of diseases in which endogenous bile acids accumulate in the body. Cholestasis might occur as a consequence of inborn metabolic errors and three major disorders, intra-hepatic cholestasis in pregnancy, primary biliary cirrhosis (PBC) and primary sclerosing cholangitis account for the vast majority of clinical cholestasis occurring in adulthood. In addition, FXR agonists are gaining attention as potential regulators of lipid and glucose metabolism and therefore as new therapeutical approaches to the treatment of fatty liver disease, type 2 diabetes and obesity.Areas covered: New chemical entities as FXR modulators and their in vitro and in vivo efficacy are reviewed with particular focus on patents and peer-reviewed publications in the period 2011 – 2014.Expert opinion: FXR agonists have shown robust therapeutic potential and results from clinical trials have supported their use in the treatment of liver disorders including PBC and fatty liver disease despite side effects. 相似文献
16.
《Expert opinion on therapeutic patents》2013,23(10):1123-1168
Introduction: Among a variety of proteins included in a relatively wide GPCR family, serotonin 5-HT receptors (5-HT6Rs) are highly attractive as important biological targets with enormous clinical importance. Among this sub-class, 5-HT6R is the most recently discovered group. Available biological data clearly indicate that 5-HT6R antagonists can be used as effective regulators in a variety of contexts, including memory formation, age-related cognitive impairments and memory deficits associated with conditions such as schizophrenia, Parkinson's disease (PD) and Alzheimer's disease (AD). Therefore, this receptor has already attracted a considerable attention within the scientific community, due to its versatile therapeutic potential. Areas covered: The current paper is an update to the comprehensive review article published previously in Expert Opinion on Therapeutic Patents Ivashchenko AV, Ivanenkov YA, Tkachenko SE. 5-Hydroxytryptamine subtype 6 receptor modulators: a patent survey. Expert Opin. Ther. Pat, 2010, 20, 1171-1196. Here, the authors mainly focus on small-molecule compounds – 5-HT6 antagonists – which have been described in recent patent literature, since the end of 2009. To obtain a clear understanding of the situation and dynamic development within the field of 5-HT6 ligands, having an obvious pharmaceutical potential in terms of related patents, the authors provide a comprehensive search through several key patent collections. They describe the reported heterocyclic compounds with no sulfonyl moiety in sufficient detail to provide a valuable insight in the 5-HT6R chemistry and pharmacology. Most of the described compounds are currently classified as multimodal agents with high affinity toward 5-HT6R. Expert opinion: Recent progress in the understanding of the 5-HT6 receptor function and structure includes a suggested constitutive activity for the receptor, development of a number of multimodal small-molecule ligands and re-classification of many selective antagonists as pseudo-selective agents. Several heterocylic structures with or without any basic center provide sufficient supramolecular interactions and show high agonistic/antagonistic activity against 5-HT6R. Many ‘multitarget' drugs acting, for instance, against several isoforms of 5-HTR, including 5-HT6R subtype, as well as against dopamine and/or histamine receptors were shown to have beneficial therapeutic effects. At the same time, these ‘unselective' compounds may also increase the side-effect potential. The ensemble of antagonistic activity against 5-HT6R and inhibition potency against BuChE can be regarded as the most promising basis for the development of effective drugs with a sufficient therapeutic window for the treatment of several neurodegenerative diseases, including AD and PD. 相似文献
17.
《Expert opinion on investigational drugs》2013,22(10):1561-1572
PPAR-γ ligands constitute important insulin sensitizers that have already been approved for the treatment of human metabolic disorders. They also exert pleiotropic effects on cell proliferation and cancer and are now being explored in preclinical studies. Angiogenesis constitutes a multifaceted process that is implicated in tumor development and other benign disease states that are associated with diabetes. Recent data have further extended the crucial role of PPAR-γ ligands as potential angiogenesis modulators, in vitro and in vivo. This review summarizes the latest knowledge of the role of PPAR-γ ligands in angiogenesis that are related to both malignant and non-malignant disease states. Taking into careful consideration the data so far, PPAR-γ could be considered as a therapeutic target for diverse disease states in which excessive angiogenesis is implicated, including cancer and diabetes complications. 相似文献
18.
Agnieszka Zagrska Anna Partyka Adam Bucki Marcin Koaczkowski Magdalena Jastrzbska‐Wisek Anna Czopek Agata Siwek Monika Guch‐Lutwin Marek Bednarski Marek Bajda Jakub Joczyk Kamil Piska Paulina Koczurkiewicz Anna Wesoowska Maciej Pawowski 《Chemical biology & drug design》2019,93(4):511-521
A series of 2‐pyrimidinyl‐piperazinyl‐alkyl derivatives of 1H‐imidazo[2,1‐f]purine‐2,4(3H,8H)‐dione has been synthesized in an attempt to discover a new class of psychotropic agents. Compounds were evaluated for their in vitro affinity for serotonin 5‐HT1A, 5‐HT7, and phosphodiesterases PDE4 and PDE10. The most potent compound 2‐pyrimidinyl‐1‐piperazinyl‐butyl‐imidazo[2,1‐f]purine‐2,4‐dione ( 4b ) behaved as strong and selective antagonist of 5‐HT1A. Molecular modeling studies revealed differences in binding mode between compound 4b and buspirone, which might reflect variation of the ligands’ affinity and potency in the 5‐HT1A receptor. Compound 4b in silico models demonstrated drug‐likeness properties and, contrary to buspirone, showed a metabolic stability in mouse liver microsomes system. Experimentally obtained value of apparent permeability coefficient Papp for 4b in parallel artificial permeability assay indicates the possibility of binding weakly to plasma proteins and high intestinal absorption fraction. Evaluation of the antidepressant‐ and anxiolytic‐like activities of 4b revealed both activities at the same dose of 1.25 mg/kg and seemed to be specific. The antidepressant and/or anxiolytic properties of 4b may be related to its first‐pass effect. 相似文献
19.
Synthesis and In Vitro Pharmacological Evaluation of Novel 2‐Hydroxypropyl‐4‐arylpiperazine Derivatives as Serotoninergic Ligands 下载免费PDF全文