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1.
W Amberg S Hergenr?der H Hillen R Jansen G Kettschau A Kling D Klinge M Raschack H Riechers L Unger 《Journal of medicinal chemistry》1999,42(16):3026-3032
Structural variation of the endothelin A-selective antagonist (S)-3-methoxy-2-(4,6-dimethoxypyrimidin-2-yloxy)-3, 3-diphenylpropionic acid (LU 135252) led to analogues which retain ET(A) affinity but exhibit substantial ET(B) affinity as well. The most active derivative obtained is (S)-3-[2-(3, 4-dimethoxyphenyl)ethoxy]-2-(4,6-dimethylpyrimidin-2-yloxy)- 3, 3-diphenylpropionic acid (LU 302872), which can be prepared in enantiomerically pure form in eight steps via an acid-catalyzed transetherification. It has a K(i) = 2.15 nM for binding to the ET(A) receptor and a K(i) = 4.75 nM for binding to the ET(B) receptor, is orally available, and antagonizes the big ET-induced blood pressure increase in rats and the big ET-induced bronchospasm in guinea pigs each time at a dose of 10 mg/kg. 相似文献
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Martin Stroedicke Yacine Bounab Nadine Strempel Konrad Klockmeier Sargon Yigit Ralf P. Friedrich Gautam Chaurasia Shuang Li Franziska Hesse Sean-Patrick Riechers Jenny Russ Cecilia Nicoletti Annett Boeddrich Thomas Wiglenda Christian Haenig Sigrid Schnoegl David Fournier Rona K. Graham Michael R. Hayden Stephan Sigrist Gillian P. Bates Josef Priller Miguel A. Andrade-Navarro Matthias E. Futschik Erich E. Wanker 《Genome research》2015,25(5):701-713
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STUDY DESIGN: Case report. OBJECTIVES: A case report of spinal sarcoidosis improving clinically and radiographically with treatment which correlated with improvement in cerebrospinal fluid T-lymphocyte subpopulation ratios. SETTING: Walter Reed Army Medical Center. CASE REPORT: A 46-year-old man presented with an enhancing spinal cord lesion. Lymph node biopsy confirmed sarcoidosis, and cerebrospinal fluid (CSF) analysis showed elevation in the ratio of two T-lymphocyte subpopulations. Treatment with steroids resulted in clinical resolution and immunocytologic improvement in the CSF. 相似文献
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Brett Theeler MD Sylvia Lucas MD PhD Ronald G Riechers II MD Robert L Ruff MD PhD 《Headache》2013,53(6):881-900
Post‐traumatic headache (PTH) is the most frequent symptom after traumatic brain injury (TBI). We review the epidemiology and characterization of PTH in military and civilian settings. PTH appears to be more likely to develop following mild TBI (concussion) compared with moderate or severe TBI. PTH often clinically resembles primary headache disorders, usually migraine. For migraine‐like PTH, individuals who had the most severe headache pain had the highest headache frequencies. Based on studies to date in both civilian and military settings, we recommend changes to the current definition of PTH. Anxiety disorders such as post‐traumatic stress disorder (PTSD) are frequently associated with TBI, especially in military populations and in combat settings. PTSD can complicate treatment of PTH as a comorbid condition of post‐concussion syndrome. PTH should not be treated as an isolated condition. Comorbid conditions such as PTSD and sleep disturbances also need to be treated. Double‐blind placebo‐controlled trials in PTH population are necessary to see whether similar phenotypes in the primary headache disorders and PTH will respond similarly to treatment. Until blinded treatment trials are completed, we suggest that, when possible, PTH be treated as one would treat the primary headache disorder(s) that the PTH most closely resembles. 相似文献
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Agüero F Al-Lazikani B Aslett M Berriman M Buckner FS Campbell RK Carmona S Carruthers IM Chan AW Chen F Crowther GJ Doyle MA Hertz-Fowler C Hopkins AL McAllister G Nwaka S Overington JP Pain A Paolini GV Pieper U Ralph SA Riechers A Roos DS Sali A Shanmugam D Suzuki T Van Voorhis WC Verlinde CL 《Nature reviews. Drug discovery》2008,7(11):900-907
The increasing availability of genomic data for pathogens that cause tropical diseases has created new opportunities for drug discovery and development. However, if the potential of such data is to be fully exploited, the data must be effectively integrated and be easy to interrogate. Here, we discuss the development of the TDR Targets database (http://tdrtargets.org), which encompasses extensive genetic, biochemical and pharmacological data related to tropical disease pathogens, as well as computationally predicted druggability for potential targets and compound desirability information. By allowing the integration and weighting of this information, this database aims to facilitate the identification and prioritization of candidate drug targets for pathogens. 相似文献
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U. Henkemeier R. Alten B. Bannert X. Baraliakos F. Behrens F. Heldmann U. Kiltz M. Köhm R. König J. Leipe U. Müller-Ladner J. Rech E. Riechers A. Rubbert-Roth R.E. Schmidt H. Schulze-Koops C. Specker A.-K. Tausche S. Wassenberg M. Witt T. Witte J. Zernicke H. Burkhardt 《Zeitschrift für Rheumatologie》2016,75(1):4-10
Despite a large number of approved therapies demonstrating efficacy in the treatment of rheumatic diseases, only 60–85?% of patients with the indications for rheumatoid arthritis are adequately treated in Germany. Additionally, approved therapies for other immune-mediated diseases are often entirely lacking, indicating the great medical need for the development of new innovative therapies in this specialized field. The development of new drugs is expensive due to the high costs of conducting clinical trials in all phases of development up to obtaining approval; therefore, pharmaceutical companies are looking for ways to save costs in the particular developmental stages. Although the classical regions for drug development (i.e. western Europe, the USA and Japan) offer both a high level of data quality and a good infrastructure to conduct clinical trials due to high standards of education and quality, clinical trials are expensive in these regions. Beside high costs, the comparatively low recruitment rates in these regions are one of the main reasons for the shifting of drug developmental stages from classical regions to eastern European, Latin American and Asian countries, which provide services for drug development and high recruitment rates for comparatively less money. However, there are many strong arguments for the participation of regions in western Europe, especially German sites in clinical trials. In this article these arguments are discussed and possible solutions and strategies for conducting and compensation of study centers in Germany for clinical trials in the field of rheumatology are provided. 相似文献
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Analysis of the T cells that are potentially involved in autoantibody production in pemphigus vulgaris 总被引:4,自引:0,他引:4
Pemphigus vulgaris (PV) is a classical example of an antibody-mediated autoimmune disease of the skin. Direct evidence exists that autoantibodies against the desmosomal adhesion molecule, desmoglein 3 (Dsg3), are critical in the pathogenesis of this disease. The transfer of serum IgG antibodies reactive with Dsg3 into newborn mice induces a bullous skin disease resembling PV. Autoreactive T cell responses to Dsg3 may be critical in the pathogenesis of PV because 1) antibody production generally requires T cell help, 2) the involvement of CD4+ T lymphocytes in PV has been suggested by the strong association with distinct HLA class II alleles, and 3) T cell recognition of epitopes of Dsg3 may be crucial for the initiation and perpetuation of the production of Dsg3-specific autoantibodies by B cells. We and others have identified autoreactive T cells recognizing distinct epitopes of the extracellular portion of Dsg3 in PV patients. These autoreactive CD4+ T cells preferentially produced TH2 cytokines such as IL-4, and IL-10. Autoantibodies of the TH2-dependent IgG4 subtype are preferentially seen in active stages of PV disease, while autoantibodies of the TH1-dependent IgG1 subclass are predominant upon remission of PV. Healthy individuals who carried HLA class II alleles similar or identical to those found to be highly prevalent in PV also developed autoreactive T cell responses to Dsg3. Autoreactive T cells from PV patients produced both TH1 and TH2 cytokines; autoreactive T cells from normals produced TH0 cytokines. These observations suggest that Dsg3-specific T cells may provide targets to eventually modulate the T cell-dependent production of pathogenic autoantibodies in PV. 相似文献