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排序方式: 共有971条查询结果,搜索用时 62 毫秒
961.
962.
Gardell LR Ma JN Seitzberg JG Knapp AE Schiffer HH Tabatabaei A Davis CN Owens M Clemons B Wong KK Lund B Nash NR Gao Y Lameh J Schmelzer K Olsson R Burstein ES 《The Journal of pharmacology and experimental therapeutics》2008,327(3):799-808
We report the first small-molecule protease-activated receptor (PAR) 2 agonists, AC-55541 [N-[[1-(3-bromo-phenyl)-eth-(E)-ylidene-hydrazinocarbonyl]-(4-oxo-3,4-dihydro-phthalazin-1-yl)-methyl]-benzamide] and AC-264613 [2-oxo-4-phenylpyrrolidine-3-carboxylic acid [1-(3-bromo-phenyl)-(E/Z)-ethylidene]-hydrazide], each representing a distinct chemical series. AC-55541 and AC-264613 each activated PAR2 signaling in cellular proliferation assays, phosphatidylinositol hydrolysis assays, and Ca(2+) mobilization assays, with potencies ranging from 200 to 1000 nM for AC-55541 and 30 to 100 nM for AC-264613. In comparison, the PAR2-activating peptide 2-furoyl-LIGRLO-NH(2) had similar potency, whereas SLIGRL-NH(2) was 30 to 300 times less potent. Neither AC-55541 nor AC-264613 had activity at any of the other PAR receptor subtypes, nor did they have any significant affinity for over 30 other molecular targets involved in nociception. Visualization of EYFP-tagged PAR2 receptors showed that each compound stimulated internalization of PAR2 receptors. AC-55541 and AC-264613 were well absorbed when administered intraperitoneally to rats, each reaching micromolar peak plasma concentrations. AC-55541 and AC-264613 were each stable to metabolism by liver microsomes and maintained sustained exposure in rats, with elimination half-lives of 6.1 and 2.5 h, respectively. Intrapaw administration of AC-55541 or AC-264613 elicited robust and persistent thermal hyperalgesia and edema. Coadministration of either a tachykinin 1 (neurokinin 1) receptor antagonist or a transient receptor potential vanilloid (TRPV) 1 antagonist completely blocked these effects. Systemic administration of either AC-55541 or AC-264613 produced a similar degree of hyperalgesia as was observed when the compounds were administered locally. These compounds represent novel small-molecule PAR2 agonists that will be useful in probing the physiological functions of PAR2 receptors. 相似文献
963.
Several antipsychotics are associated with the ventricular tachycardia torsade de pointes (TdP), which may lead to sudden cardiac death (SCD), because of their inhibition of the cardiac delayed potassium rectifier channel. This inhibition extends the repolarization process of the ventricles of the heart, illustrated as a prolongation of the QT interval on a surface ECG. SCD in individuals receiving antipsychotics has an incidence of approximately 15 cases per 10,000 years of drug exposure but the exact association with TdP remains unknown because the diagnosis of TdP is uncertain. Most patients manifesting antipsychotic-associated TdP and subsequently SCD have well established risk factors for SCD, i.e. older age, female gender, hypokalaemia and cardiovascular disease. QT interval prolongation is the most widely used surrogate marker for assessing the risk of TdP but it is considered somewhat imprecise, partly because QT interval changes are subject to measurement error. In particular, drug-induced T-wave changes (e.g. flattening of the T-wave) may complicate the measurement of the QT interval. Furthermore, the QT interval depends on the heart rate and a corrected QT (QTc) interval is often used to compensate for this. Several correction formulas have been suggested, with Bazett's formula the most widely used. However, Bazett's formula overcorrects at a heart rate above 80 beats per minute and, therefore, Fridericia's formula is considered more appropriate to use in these cases. Several other surrogate markers for TdP have been developed but none of them is clinically implemented yet and QT interval prolongation is still considered the most valid surrogate marker. Although automated QT interval determination may offer some assistance, QT interval determination is best performed by a cardiologist skilled in its measurement. A QT interval >500?ms markedly increases the risk for TdP and SCD, and should lead to discontinuation of the offending drug and, if present, correction of underlying electrolyte disturbances, particularly serum potassium and magnesium derangements. Before prescribing antipsychotics that may increase the QTc interval, the clinician should ask about family and personal history of SCD, presyncope, syncope and cardiac arrhythmias, and recommend cardiology consultation if history is positive. 相似文献
964.
Janet Robertson Eric Emerson Chris Hatton M. T. Yasamy 《Journal of Applied Research in Intellectual Disabilities》2012,25(2):143-154
Background Community‐based rehabilitation (CBR) is being implemented in more than 90 countries. Concerns have been voiced about the adequacy of the evidence base regarding the efficacy, effectiveness and efficiency of CBR. This review summarizes evidence on the efficacy of CBR for children with intellectual disabilities. Materials and method Electronic literature database searches were conducted to identify articles in the English language published since 1980 relating to the efficacy of CBR for children with intellectual disabilities. Requests for information were also sent to membership of International Association for the Scientific Study of Intellectual Disabilities and relevant organizations in selected low‐ and middle‐income countries. Results Thirteen studies were identified for inclusion in the review. The quality of evidence for the efficacy of CBR for children with intellectual disabilities was ‘very low’. Conclusion Improving the evidence base will require greater investment in evaluation and addressing the marginalization of people with intellectual disabilities in CBR. 相似文献
965.
Clozapine remains the drug of choice for treatment resistant schizophrenia, but is associated with potentially life threatening side effects, including agranulocytosis and myocarditis. Immunological mechanisms may be involved in the development of these side effects or in the unique antipsychotic efficacy in subgroups of schizophrenia patients. This systematic review presents the immunomodulatory effects of clozapine from human in vitro and in vivo studies and relates these findings to the developments of adverse and therapeutic effects of clozapine. Several studies confirm the immunomodulatory actions of clozapine, but only few studies investigated their relationship to the unique adverse and therapeutic effects of clozapine. During the first month of clozapine treatment, up to 50% of patients develop fever and flu like symptoms, which is seemingly driven by increased cytokines. Within the same time period, the risk of side-effects with a suspected immunological mechanism peaks. Patients developing fever during the first weeks of treatment should have a thorough physical examination, and measurements of white blood cell count, absolute neutrophil count, ECG, C-reactive protein, creatinine kinase, and troponin to exclude infection, agranulocytosis, myocarditis and neuroleptic malignant syndrome. To what degree the unique antipsychotic efficacy of clozapine in subgroups of schizophrenia patients is related to its immunomodulatory effects has not been studied. Research relating the immunomodulatory actions of clozapine and its early markers to clinically relevant adverse and therapeutic outcomes is hoped to provide new leads for the understanding of the pathophysiology of schizophrenia and aid the development of novel treatment targets. 相似文献
966.
Hatton RD 《Immunity》2011,34(3):288-290
As Th17 cell developmental requirements continue to be studied, Gutcher et?al. (2011) demonstrate in this issue of Immunity that autocrine TGF-β cytokine promotes Th17 cell development and maintenance. 相似文献
967.
968.
Beroukhim R Getz G Nghiemphu L Barretina J Hsueh T Linhart D Vivanco I Lee JC Huang JH Alexander S Du J Kau T Thomas RK Shah K Soto H Perner S Prensner J Debiasi RM Demichelis F Hatton C Rubin MA Garraway LA Nelson SF Liau L Mischel PS Cloughesy TF Meyerson M Golub TA Lander ES Mellinghoff IK Sellers WR 《Proceedings of the National Academy of Sciences of the United States of America》2007,104(50):20007-20012
Comprehensive knowledge of the genomic alterations that underlie cancer is a critical foundation for diagnostics, prognostics, and targeted therapeutics. Systematic efforts to analyze cancer genomes are underway, but the analysis is hampered by the lack of a statistical framework to distinguish meaningful events from random background aberrations. Here we describe a systematic method, called Genomic Identification of Significant Targets in Cancer (GISTIC), designed for analyzing chromosomal aberrations in cancer. We use it to study chromosomal aberrations in 141 gliomas and compare the results with two prior studies. Traditional methods highlight hundreds of altered regions with little concordance between studies. The new approach reveals a highly concordant picture involving approximately 35 significant events, including 16-18 broad events near chromosome-arm size and 16-21 focal events. Approximately half of these events correspond to known cancer-related genes, only some of which have been previously tied to glioma. We also show that superimposed broad and focal events may have different biological consequences. Specifically, gliomas with broad amplification of chromosome 7 have properties different from those with overlapping focalEGFR amplification: the broad events act in part through effects on MET and its ligand HGF and correlate with MET dependence in vitro. Our results support the feasibility and utility of systematic characterization of the cancer genome. 相似文献
969.
Shanahan M Roberts J Hatton D Reznick J Goldsmith H 《Journal of intellectual disability research : JIDR》2008,52(10):842-854
Background The phenotype of children and adults with fragile X syndrome (FXS) includes a number of problem behaviours such as inattention, social anxiety and aggressive outbursts. However, very little work has been conducted with young children with FXS less than 5 years of age to examine the developmental pathway of problem behaviours in this population and to determine if later occurring problem behaviours may be rooted in early appearing temperament profiles. Methods Parent ratings and laboratory‐based behavioural observations of negative reactivity were examined in 25 3‐year‐old boys with FXS and compared with 64 typically developing boys matched on age. Results Compared with the typically developing group, boys with FXS were rated by their parents as exhibiting less anger and sadness on the Child Behaviour Questionnaire (CBQ), and they showed less facial sadness on the Laboratory Temperament Assessment Battery (Lab‐TAB). No group differences were found on the Lab‐TAB measures of distress vocalisations, bodily struggle, and facial anger; and anger peaked in the middle of the arm restraint episode for both groups. For boys with FXS, mental age was moderately positively correlated, and autistic behaviour was moderately negatively correlated, with sadness scores from the CBQ. Conclusions Our results show different behavioural profiles in very young children with FXS than reported in older‐aged children with FXS which implies that temperamental differences and elevated problem behaviours reported in older‐aged children with FXS may not be rooted in early temperament. This information is important to develop the phenotype of early development in FXS to facilitate early identification and treatment. 相似文献
970.
The Rural Palliative Care Program (RPCP) is currently being implemented in eight pilot sites across Australia, under the banner of the National Palliative Care Program. It is one of a number of initiatives commissioned by the Department of Health and Ageing that are designed to achieve the goals of the National Palliative Care Strategy. Specifically the RPCP is testing service components that aim to improve access to palliative care for people living in rural and remote communities. With facilitation from the Australian Divisions of General Practice (ADGP), each project and the program as a whole, is undergoing a formal evaluation by the Centre for Health Service Development (CHSD), University of Wollongong. A key question being investigated is whether any systemic improvements in palliative care delivery are sustainable beyond completion of the 3-year program. This paper gives the background to the RPCP. The Adelaide Hills Palliative Care Project is discussed as an example of how strategies are derived and applied in order to test key service components pertinent to the delivery of palliative care in a rural setting. 相似文献