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71.
Peretto I Forlani R Fossati C Giardina GA Giardini A Guala M La Porta E Petrillo P Radaelli S Radice L Raveglia LF Santoro E Scudellaro R Scarpitta F Bigogno C Misiano P Dondio GM Rizzi A Armani E Amari G Civelli M Villetti G Patacchini R Bergamaschi M Delcanale M Salcedo C Fernández AG Imbimbo BP 《Journal of medicinal chemistry》2007,50(7):1571-1583
Pharmacophore-based structural identification, synthesis, and structure-activity relationships of a new class of muscarinic M3 receptor antagonists, the diaryl imidazolidin-2-one derivatives, are described. The versatility of the discovered scaffold allowed for several structural modifications that resulted in the discovery of two distinct classes of compounds, specifically a class of tertiary amine derivatives (potentially useful for the treatment of overactive bladder by oral administration) and a class of quaternary ammonium salt derivatives (potentially useful for the treatment of respiratory diseases by the inhalation route of administration). In this paper, we describe the synthesis and biological activity of tertiary amine derivatives. For these compounds, selectivity for the M3 receptor toward the M2 receptor was crucial, because the M2 receptor subtype is mainly responsible for adverse systemic side effects of currently marketed muscarinic antagonists. Compound 50 showed the highest selectivity versus M2 receptor, with binding affinity for M3 receptor Ki = 4.8 nM and for M2 receptor Ki = 1141 nM. Functional in vitro studies on selected compounds confirmed the antagonist activity toward the M3 receptor and functional selectivity toward the M2 receptor. 相似文献
72.
ObjectivesThe paper evaluates the extent to which the government's policy to encourage the purchase of voluntary health insurance (VHI) may have led to income-related horizontal inequity in access to health care in a universal health care system (NHS).MethodsAd hoc tax return data for the universe of Italian taxpayers for years 2009-2016 are used to estimate the tax benefits granted to taxpayers who hold VHI, the redistributive impact, and the public budget effect. The income elasticity of tax benefits is estimated using tax return data and considering some taxpayers’ characteristics (income class, gender, age, and geographic area). Standard inequality indices are computed to assess income-related horizontal inequity in access to health care.ResultsTax incentives, especially those granted to employer-paid health insurance, have a sizeable impact on tax revenue and introduce into the Italian NHS significant income-related horizontal and vertical inequity in access to health care. The results suggest a distributional profile of tax incentives that is highly concentrated in favor of wealthier taxpayers.ConclusionOur analysis adds novel evidence that may contribute to the current debate on whether and to what extent countries in which all citizens have access to free healthcare and equal standards of healthcare services should subsidize VHI, especially when the coverage doubles the healthcare services provided by universal public insurance. We show that VHI reduces tax revenues and introduces disparities among citizens in terms of access to healthcare services. 相似文献
73.
Filaci G Contini P Fravega M Fenoglio D Azzarone B Julien-Giron M Fiocca R Boggio M Necchi V De Lerma Barbaro A Merlo A Rizzi M Ghio M Setti M Puppo F Zanetti M Indiveri F 《Human immunology》2003,64(1):9-20
Resident macrophages are mainly responsible for the clearance of apoptotic cells from tissue by phagocytosis. Phagocytosis of apoptotic cells is not accompanied by activation of inflammatory mechanisms, unlike what happens when necrotic phenomena occur. We analyzed the effect of phagocytosis of apoptotic bodies on macrophage cell functions. After phagocytosis of apoptotic cells macrophages were unable to present an exogenous antigen to autologous antigen-specific T-cell lines. The inhibition was mediated by different mechanisms including binding of apoptotic DNA to human leukocyte antigen (HLA) class II molecules of macrophages, decreased expression of co-stimulatory molecules and increased secretion of tumor growth factor beta (TGFbeta). When dendritic cells were cultured with macrophages phagocytosing apoptotic cells, or with their supernatant, impaired dendritic cell antigen presenting activity and reduced tumor necrosis factor alpha (TNFalpha) secretion were found. Our results suggest that: (1) the phagocytosis of apoptotic bodies inhibits macrophage antigen presentation; (2) such inhibition is mediated by the binding of apoptotic DNA to macrophage HLA class II molecules as well as by the activation of biological mechanisms that induce an anti-inflammatory functional behavior in macrophages; and (3) macrophages phagocytosing apoptotic cells inhibit antigen presentation of neighboring dendritic cells via TGFbeta secretion. These events are likely related to the preservation of healthy tissues from the onset of inflammation. 相似文献
74.
Elisabeth Salzer MD Aydan Kansu Heiko Sic Peter Májek Aydan Ikincioğullari Figen E. Dogu Nina Kathrin Prengemann Elisangela Santos-Valente Winfried F. Pickl Ivan Bilic Sol A BanZarife Kuloğlu MD Arzu Meltem Demir Arzu Ensari Jacques Colinge Marta Rizzi Hermann Eibel Kaan Boztug 《The Journal of allergy and clinical immunology》2014
75.
Pedro Henrique Rizzi Alves Artur Junio Togneri Ferron Mariane Rvero Costa Fabiana Kurokawa Hasimoto Cristina Schmitt Gregolin Jssica Leite Garcia Dijon Henrique Salom de Campos Antnio Carlos Cicogna Letícia de Mattei Fernando Moreto Silmia Garcia Zanati Bazan Fabiane Valentini Francisqueti-Ferron Camila Renata Corrêa 《Arquivos brasileiros de cardiologia》2021,117(1):91
BackgroundObesity is a chronic low-grade inflammation condition related to cardiac disorders. However, the mechanism responsible for obesity-related cardiac inflammation is unclear. The toll-like receptor 4 (TLR-4) belongs to a receptor of the transmembrane family responsible for the immune response whose activation stimulates the production of proinflammatory cytokines.ObjectiveTo test whether the activation of the TLR-4 receptor participates in the obesity cardiomyopathy process, due to cytokine production through NF-ĸB activation.MethodsMale Wistar rats were randomized into two groups: the control group (C, n= 8 animals) that received standard diet/water and the obese group (OB, n= 8 animals) that were fed a high sugar-fat diet and water plus 25% of sucrose for 30 weeks. Nutritional analysis: body weight, adiposity index, food, water, and caloric intake. Obesity-related disorders analysis: plasma glucose, uric acid and triglycerides, HOMA-IR, systolic blood pressure, TNF-α in adipose tissue. Cardiac analysis included: TLR-4 and NF-ĸB protein expression, TNF-α and IL-6 levels. Comparison by unpaired Student’s t-test or Mann- Whitney test with a p-value < 0.05 as statistically significant.ResultsThe OB group showed obesity, high glucose, triglycerides, uric acid, HOMA, systolic blood pressure, and TNF-α in adipose tissue. OB group presented cardiac remodeling and diastolic dysfunction. TLR-4 and NF-ĸB expression and cytokine levels were higher in OB.ConclusionOur findings conclude that, in an obesogenic condition, the inflammation derived from cardiac TLR-4 activation can be a mechanism able to lead to remodeling and cardiac dysfunction. 相似文献
76.
77.
G Visani S Rizzi P Tosi A Cenacchi B Gamberi R M Lemoli P Papadopulu S Tura 《Haematologica》1990,75(6):527-531
In vitro clonogenic assays may be useful for determining the sensitivity of leukemic cells to chemotherapeutic agents. We evaluated the antileukemic effect of Bisantrene (an anthracene derivative now undergoing phase II clinical trials in relapsed/resistant acute non lymphoid leukemias-ANLL) using the ANLL cell clonogenic assay. Fifteen cases were studied (9 newly diagnosed, 5 relapsed and 1 refractory ANLL). Normal CFU-GM sensitivity was tested in a subset of 10 normal controls. A wide range of concentrations (from 0.01 to 10 micrograms/ml) at 3 durations of exposure (30 min, 120 min, continuous) was employed. Bisantrene proved effective in 12 out of 15 ANLL cases, inhibiting blast colony growth (50% at 1 micrograms/ml; nearly 100% at 10 micrograms/ml) in a dose-dependent, time-independent way. Three cases were unresponsive both in vitro and in vivo. Normal CFU-GM were inhibited at lower doses (50% at 0.5 micrograms/ml; 100% at 5 micrograms/ml). We conclude that: 1) Bisantrene is active in vitro on leukemic clonogenic cells at doses corresponding to plasmatic levels achievable in patients, with a parallel activity in vivo in 3 relapsed cases. It should be tested in vitro before therapeutic use in order to avoid, if possible, improper use in resistant patients. 2) Normal CFU-GM are more sensitive than clonogenic leukemic cells. This must be taken into account, in view of possible prolonged neutropenias after therapy. 3) The time-independent effect of the drug should be evaluated in the design of new therapeutic schedules. 相似文献
78.
79.
R. Rizzi S. Bruno R. Dammacco 《International Journal of Clinical & Laboratory Research》1997,27(2-4):225-232
Behçet’s disease is an immune-mediated vasculitis affecting both small and large vessels. Small-vessel vasculitis is the pathological basis of the multiorgan involvement that results in protean clinical features. However, relapsing aphthous ulcers in the mouth are considered the clinical hallmark and are often also observed over the genitalia. Both manifestations, in association with uveitis, form the typical clinical triad. In addition, skeletal muscles, joints, gastrointestinal, cardiopulmonary, and central nervous systems can be involved. Heterogeneity in incidence, clinical manifestations, course, and seventy are observed according to ethnic background. The natural course is chronic with relapses and remissions, gradually abating over the years, but the illness can also be life or sight threatening. Its origin and cause are still obscure: genetic, infectious, environmental, and immunological factors have been proposed. Owing to the lack of a specific test, diagnosis still relies on recognition of the typical clinical pattern. Treatment usually includes corticosteroids and immunosuppressive drugs. A better understanding of the pathogenesis will hopefully improve both diagnosis and therapy. In addition, the development of tests aimed at monitoring disease activity and response to therapy is certainly desirable. 相似文献
80.