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排序方式: 共有592条查询结果,搜索用时 0 毫秒
91.
Joaquin A. Vizcarra lvaro Snchez‐Ferro Walter Maetzler Luca Marsili Lucia Zavala Anthony E. Lang Pablo Martinez‐Martin Tiago A. Mestre Ralf Reilmann Jeffrey M. Hausdorff E. Ray Dorsey Serene S. Paul Judith W. Dexheimer Benjamin D. Wissel Rebecca L. M. Fuller Paolo Bonato Ai Huey Tan Bastiaan R. Bloem Catherine Kopil Margaret Daeschler Lauren Bataille Galit Kleiner Jesse M. Cedarbaum Jochen Klucken Aristide Merola Christopher G. Goetz Glenn T. Stebbins Alberto J. Espay 《Movement disorders》2019,34(5):676-681
92.
Stebbins JL De SK Pavlickova P Chen V Machleidt T Chen LH Kuntzen C Kitada S Karin M Pellecchia M 《Journal of medicinal chemistry》2011,54(18):6206-6214
c-Jun N-terminal kinases (JNKs) represent valuable targets in the development of new therapies. Present on the surface of JNK is a binding pocket for substrates and the scaffolding protein JIP1 in close proximity to the ATP binding pocket. We propose that bidentate compounds linking the binding energies of weakly interacting ATP and substrate mimetics could result in potent and selective JNK inhibitors. We describe here a bidentate molecule, 19, designed against JNK. 19 inhibits JNK kinase activity (IC(50) = 18 nM; K(i) = 1.5 nM) and JNK/substrate association in a displacement assay (IC(50) = 46 nM; K(i) = 2 nM). Our data demonstrate that 19 targets for the ATP and substrate-binding sites on JNK concurrently. Finally, compound 19 successfully inhibits JNK in a variety of cell-based experiments, as well as in vivo where it is shown to protect against Jo-2 induced liver damage and improve glucose tolerance in diabetic mice. 相似文献
93.
Swaney JS Chapman C Correa LD Stebbins KJ Broadhead AR Bain G Santini AM Darlington J King CD Baccei CS Lee C Parr TA Roppe JR Seiders TJ Ziff J Prasit P Hutchinson JH Evans JF Lorrain DS 《The Journal of pharmacology and experimental therapeutics》2011,336(3):693-700
Lysophosphatidic acid (LPA) is a bioactive phospholipid that signals through a family of at least six G protein-coupled receptors designated LPA???. LPA type 1 receptor (LPA?) exhibits widespread tissue distribution and regulates a variety of physiological and pathological cellular functions. Here, we evaluated the in vitro pharmacology, pharmacokinetic, and pharmacodynamic properties of the LPA?-selective antagonist AM095 (sodium, {4'-[3-methyl-4-((R)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-yl]-biphenyl-4-yl}-acetate) and assessed the effects of AM095 in rodent models of lung and kidney fibrosis and dermal wound healing. In vitro, AM095 was a potent LPA? receptor antagonist because it inhibited GTPγS binding to Chinese hamster ovary (CHO) cell membranes overexpressing recombinant human or mouse LPA? with IC?? values of 0.98 and 0.73 μM, respectively, and exhibited no LPA? agonism. In functional assays, AM095 inhibited LPA-driven chemotaxis of CHO cells overexpressing mouse LPA? (IC??= 778 nM) and human A2058 melanoma cells (IC?? = 233 nM). In vivo, we demonstrated that AM095: 1) had high oral bioavailability and a moderate half-life and was well tolerated at the doses tested in rats and dogs after oral and intravenous dosing, 2) dose-dependently reduced LPA-stimulated histamine release, 3) attenuated bleomycin-induced increases in collagen, protein, and inflammatory cell infiltration in bronchalveolar lavage fluid, and 4) decreased kidney fibrosis in a mouse unilateral ureteral obstruction model. Despite its antifibrotic activity, AM095 had no effect on normal wound healing after incisional and excisional wounding in rats. These data demonstrate that AM095 is an LPA? receptor antagonist with good oral exposure and antifibrotic activity in rodent models. 相似文献
94.
Carlo Colosimo MD Pablo Martínez‐Martín MD Giovanni Fabbrini MD Robert A. Hauser MD Marcelo Merello MD PhD Janis Miyasaki MD Werner Poewe MD Cristina Sampaio MD PhD Olivier Rascol MD Glenn T. Stebbins PhD Anette Schrag MD PhD Christopher G. Goetz MD 《Movement disorders》2010,25(9):1131-1142
Drug‐induced dyskinesia is a common phenomenon in Parkinson's disease (PD) and is often socially as well as physically disabling for patients. The Movement Disorders Society commissioned a task force to assess available clinical rating scales, critique their clinimetric properties, and make recommendations regarding their clinical utility. A task force composed six clinical researchers who systematically searched the literature for scales measuring dyskinesia in PD, evaluated the scales' previous use, performance parameters, and quality of validation data (if available). A scale was designated “Recommended” if the scale has been used in clinical studies beyond the group that developed it, has been specifically used in PD reports, and if clinimetric studies have established that it is a valid, reliable, and sensitive. “Suggested” scales met two of the above criteria and those meeting one were “Listed.” Based on the systematic review, eight rating scales for dyskinesia that have either been validated or used in PD were identified. These were the Abnormal Involuntary Movement Scale (AIMS), The Unified Parkinson's Disease Rating Scale (UPDRS) part IV, the Obeso Dyskinesia Rating Scale, the Rush Dyskinesia Rating Scale, the Clinical Dyskinesia Rating Scale (CDRS), the Lang‐Fahn Activities of Daily Living Dyskinesia Scale, the Parkinson Disease Dyskinesia Scale (PDYS‐26), and the Unified Dyskinesia Rating Scale (UDysRS). Based on this review, at present two of the reviewed dyskinesia scales (AIMS and the Rush Dyskinesia Rating Scale) fulfill criteria for Recommended for use in PD populations, albeit weakly so; all of the remaining met criteria to be Suggested. However, the two most recent scales (PDYS‐26 and UDysRS) have excellent clinimetric properties and appear to provide a reliable and valid assessment tool of dyskinesia in PD. If they are used successfully beyond the groups that developed them, both have the potential to be re‐ranked as Recommended. As further testing of these scales in PD is warranted, no new scales are needed until the available scales are fully tested clinimetrically. © 2010 Movement Disorder Society 相似文献
95.
Essential role of LAT in T cell development 总被引:22,自引:0,他引:22
Zhang W Sommers CL Burshtyn DN Stebbins CC DeJarnette JB Trible RP Grinberg A Tsay HC Jacobs HM Kessler CM Long EO Love PE Samelson LE 《Immunity》1999,10(3):323-332
The linker molecule LAT is a substrate of the tyrosine kinases activated following TCR engagement. Phosphorylated LAT binds many critical signaling molecules. The central role of this molecule in TCR-mediated signaling has been demonstrated by experiments in a LAT-deficient cell line. To probe the role of LAT in T cell development, the LAT gene was disrupted by targeting. LAT-deficient mice appeared healthy. Flow cytometric analysis revealed normal B cell populations but the absence of any mature peripheral T cells. Intrathymic development was blocked within the CD4- CD8- stage. No gross abnormality of NK or platelet function was observed. LAT is thus critical to both T cell activation and development. 相似文献
96.
97.
Topiramate as an adjunct to amantadine in the treatment of dyskinesia in parkinson's disease: A randomized,double‐blind,placebo‐controlled multicenter study 下载免费PDF全文
98.
During clinical gait analysis, surface markers are placed over the anterior superior iliac spines (ASIS) of the pelvis. However, this can be problematic in overweight or obese subjects, where excessive adipose tissue can obscure the markers and prevent accurate tracking. A novel solution to this problem has previously been proposed and tested on a limited sample of healthy, adult subjects. This involves use of wand markers on the pelvis, to virtually recreate the ASIS markers. The method was tested here on 20 typical subjects presenting for clinical gait analysis (adults and children, including overweight subjects). The method was found to accurately reproduce ASIS markers, and allow calculation of pelvic angles to within one degree of angles produced by ASIS markers. 相似文献
99.
GT Terézhalmy AR Biesbrock PA Walters JM Grender RD Bartizek 《International journal of dental hygiene》2008,6(4):321-327
Abstract: Aim: To compare plaque removal efficacy of Oral‐B CrossAction (CA) used for 1 min with an American Dental Association (ADA) manual toothbrush used for 2 or 5 min in an examiner‐blind, three‐treatment, six‐period crossover study. Materials and methods: After refraining from all oral hygiene procedures for 23–25 h, subjects were randomly assigned to one of nine possible six‐period (visit) treatment sequences. Plaque was assessed at baseline (Rustogi Modified Navy Plaque Index). Post‐brushing scores were recorded after brushing with a marketed dentifrice and the assigned toothbrush for the specified duration. The same procedure was followed at each of six subsequent visits. Clinical measurements were carried out by the same examiner. Results: Forty subjects completed the study. All three treatments effectively removed plaque from the whole mouth, along the gingival margin and from approximal surfaces. Whole mouth and gingival margin plaque removal scores with CA for 1 min did not differ significantly from scores with the ADA toothbrush used for 2 min. The ADA brush used for 5 min showed significantly greater whole mouth (P < 0.001) and gingival margin (P < 0.001) plaque reduction than the two other treatments. Approximal plaque removal scores did not differ between the three treatments. Conclusions: Efficient plaque removal can be achieved after 1 min of brushing with CA. The amount of plaque removed did not differ significantly from that achieved with the ADA brush after 2 min of brushing. Greater whole mouth and gingival margin plaque removal scores were seen with the ADA brush after 5 min. 相似文献
100.
Biologics in combination with nonbiologics: efficacy and safety 总被引:1,自引:0,他引:1
The mechanisms of action of biologic therapies differ from the currently used systemic therapies by attacking specific steps in the pathogenesis pathway of psoriasis. Preliminary data show that combination therapy using biologics may allow for improved therapeutic efficacy with fewer side effects, including decreased risk of hepatotoxicity and nephrotoxicity commonly associated with the most widely used systemic agents, methotrexate, and cyclosporine. However, some concerns have been raised regarding the increased immunosuppression, increased risk of infection, potential for development of certain types of malignancy, as well as the significant increased cost of therapy. Both potential benefits and toxicities of combination therapy will be reviewed here. Long-term clinical studies are warranted to more accurately quantify the risks and benefits associated with combination therapy. The role of combination therapy will continue to be refined over the next few years to maximize its potential in the treatment of resistant psoriasis. 相似文献