The triple neurokinin-receptor antagonist CS-003 inhibits neurokinin A-induced bronchoconstriction in patients with asthma

peer reviewedNeurokinin A (NKA) causes bronchoconstriction in asthmatic patients. In vitro both NK1 and NK2 receptors can mediate airway contraction. Moreover in guinea pigs, NK3 receptors facilitate cholinergic neurotransmission. Dual tachykinin NK1/NK2 receptor antagonism results in prevention of NKA-induced bronchoconstriction. We have now examined the effect of a single dose of the triple tachykinin receptor antagonist CS-003 on NKA-induced bronchoconstriction in asthmatics. A double blind, crossover, placebo-controlled trial in 16 mild asthmatics was performed. One single dose of CS-003 (200 mg, solution in distilled water) or matched placebo was given orally on the assessment days. NKA-provocation tests were performed pre-dose and 1, 8 and 24h after dosing. There was a significant shift to the right of the dose-response curve at 1 and 8 h after intake of CS-003. PC20 was not reached in 12/16 patients at 1 h post-dose and in 5/16 patients at 8h post-dose. This did not occur under placebo treatment. A single dose of 200 mg CS-003 protected significantly against NKA-induced bronchoconstriction at 1 and 8 h post-dose in mild asthmatics. (c) 2005 Elsevier Ltd. All rights reserved

Tachykinin receptors antagonism for asthma: a systematic review

<p>Abstract</p> <p>Background</p> <p>Tachykinins substance P, neurokinin A and neurokinin B seem to account for asthma pathophysiology by mediating neurogenic inflammation and several aspects of lung mechanics. These neuropeptides act mainly by their receptors NK1, NK2 and NK3, respectively which may be targets for new asthma therapy.</p> <p>Methods</p> <p>This review systematically examines randomized controlled trials evaluating the effect of tachykinins receptors antagonism on asthma. Symptoms, airway inflammation, lung function and airway inflammation were considered as outcomes. We searched the Cochrane Airways Group Specialized Register of Asthma Trials, Cochrane Database of Systematic Reviews, MEDLINE/PubMed and EMBASE. The search is as current as June 2010. Quality rating of included studies followed the Cochrane Collaboration and GRADE Profiler approaches. However, data were not pooled together due to different measures among the studies.</p> <p>Results</p> <p>Our systematic review showed the potential of NK receptor antagonist to decrease airway responsiveness and to improve lung function. However, effects on airway inflammation and asthma symptoms were poorly or not described.</p> <p>Conclusion</p> <p>The limited available evidence suggests that tachykinin receptors antagonists may decrease airway responsiveness and improve lung function in patients with asthma. Further large randomized trials are still required.</p

Efficacy and safety of once-daily aclidinium in chronic obstructive pulmonary disease

BACKGROUND: The long-term efficacy and safety of aclidinium bromide, a novel, long-acting muscarinic antagonist, were investigated in patients with moderate to severe chronic obstructive pulmonary disease (COPD). METHODS: In two double-blind, 52-week studies, ACCLAIM/COPD I (n=843) and II (n=804), patients were randomised to inhaled aclidinium 200 μg or placebo once-daily. Patients were required to have a post-bronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity ratio of ≤70% and FEV1<80% of the predicted value. The primary endpoint was trough FEV1 at 12 and 28 weeks. Secondary endpoints were health status measured by St George's Respiratory Questionnaire (SGRQ) and time to first moderate or severe COPD exacerbation. RESULTS: At 12 and 28 weeks, aclidinium improved trough FEV1 versus placebo in ACCLAIM/COPD I (by 61 and 67 mL; both p<0.001) and ACCLAIM/COPD II (by 63 and 59 mL; both p<0.001). More patients had a SGRQ improvement≥4 units at 52 weeks with aclidinium versus placebo in ACCLAIM/COPD I (48.1% versus 39.5%; p=0.025) and ACCLAIM/COPD II (39.0% versus 32.8%; p=0.074). The time to first exacerbation was significantly delayed by aclidinium in ACCLAIM/COPD II (hazard ratio [HR] 0.7; 95% confidence interval [CI] 0.55 to 0.92; p=0.01), but not ACCLAIM/COPD I (HR 1.0; 95% CI 0.72 to 1.33; p=0.9). Adverse events were minor in both studies. CONCLUSION: Aclidinium is effective and well tolerated in patients with moderate to severe COPD

Diagnostic significance of CK19, TG, Ki67 and galectin-3 expression for papillary thyroid carcinoma in the northeastern region of China

<p>Abstract</p> <p>Background</p> <p>To evaluate the expression and differential diagnostic significance of CK19, TG, Ki67 and galectin-3 in papillary thyroid carcinoma (PTC) (metastatic and non metastatic), follicular adenoma and nodular goiter in patients from the northeastern part of China.</p> <p>Methods</p> <p>441 PTC specimens and 151 other benign thyroid specimens (97 cases of nodular goiter, 54 cases of nonmalignant follicular adenoma) were collected. Immunohistochemistry for CK19, TG, Ki67 and galectin-3 was performed.</p> <p>Results</p> <p>CK19, TG, Ki67 and galectin-3 expression was 96.37% (425/441), 82.77% (365/441), and 40.59% (179/441), 96.82% (427/441), respectively, for the PTC group and the expression of these markers in the benign thyroid lesions group was 25.83% (39/151), 79.47% (120/151), and 37.09% (56/151), 50.99% (77/151), respectively. The expression of CK19 and galectin-3 in PTC was much higher than that in the nonmalignant group (p < 0.05). However, the expression of TG, Ki67 did not differ among these two groups (p > 0.05). The diagnostic efficiency of CK19 and galectin-3 for PTC was 96.37% (537/592) and 84.63% (501/592). CK19 and galectin-3 expression rate in PTC was higher than that in benign disease cases.</p> <p>Conclusions</p> <p>The diagnostic efficiency of CK19 for PTC was slightly better than galectin-3. The utilization of these markers combined with morphologic evaluation may be helpful in the differential diagnosis of papillary thyroid carcinoma in the northeastern region of China.</p

Role of the tachykinin NK1 receptor in a murine model of cigarette smoke-induced pulmonary inflammation

<p>Abstract</p> <p>Background</p> <p>The tachykinins, substance P and neurokinin A, present in sensory nerves and inflammatory cells such as macrophages and dendritic cells, are considered as pro-inflammatory agents. Inflammation of the airways and lung parenchyma plays a major role in the pathogenesis of chronic obstructive pulmonary disease (COPD) and increased tachykinin levels are recovered from the airways of COPD patients. The aim of our study was to clarify the involvement of the tachykinin NK₁receptor, the preferential receptor for substance P, in cigarette smoke (CS)-induced pulmonary inflammation and emphysema in a mouse model of COPD.</p> <p>Methods</p> <p>Tachykinin NK₁receptor knockout (NK₁-R^-/-) mice and their wild type controls (all in a mixed 129/sv-C57BL/6 background) were subjected to sub acute (4 weeks) or chronic (24 weeks) exposure to air or CS. 24 hours after the last exposure, pulmonary inflammation and development of emphysema were evaluated.</p> <p>Results</p> <p>Sub acute and chronic exposure to CS resulted in a substantial accumulation of inflammatory cells in the airways of both WT and NK₁-R^-/-mice. However, the CS-induced increase in macrophages and dendritic cells was significantly impaired in NK₁-R^-/-mice, compared to WT controls, and correlated with an attenuated release of MIP-3α/CCL20 and TGF-β1. Chronic exposure to CS resulted in development of pulmonary emphysema in WT mice. NK₁-R^-/-mice showed already enlarged airspaces upon air-exposure. Upon CS-exposure, the NK₁-R^-/-mice did not develop additional destruction of the lung parenchyma. Moreover, an impaired production of MMP-12 by alveolar macrophages upon CS-exposure was observed in these KO mice. In a pharmacological validation experiment using the NK₁receptor antagonist RP 67580, we confirmed the protective effect of absence of the NK₁receptor on CS-induced pulmonary inflammation.</p> <p>Conclusion</p> <p>These data suggest that the tachykinin NK₁receptor is involved in the accumulation of macrophages and dendritic cells in the airways upon CS-exposure and in the development of smoking-induced emphysema. As both inflammation of the airways and parenchymal destruction are important characteristics of COPD, these findings may have implications in the future treatment of this devastating disease.</p

Aspects of molecular phenotype and its correlations with breast cancer behaviour and taxonomy

The assessment of breast cancer morphology remains an important element in the evaluation of prognosis and therapeutic planning for this disease. The tumour morphology reflects the molecular profile that produced it and consequently each can be predictive of the other

Centralised Design and Production of the Ultra-High Vacuum and Laser-Stabilisation Systems for the AION Ultra-Cold Strontium Laboratories

This paper outlines the centralised design and production of the Ultra-High-Vacuum sidearm and Laser-Stabilisation systems for the AION Ultra-Cold Strontium Laboratories. Commissioning data on the residual gas and steady-state pressures in the sidearm chambers, on magnetic field quality, on laser stabilisation, and on the loading rate for the 3D Magneto-Optical Trap are presented. Streamlining the design and production of the sidearm and laser stabilisation systems enabled the AION Collaboration to build and equip in parallel five state-of-the-art Ultra-Cold Strontium Laboratories within 24 months by leveraging key expertise in the collaboration. This approach could serve as a model for the development and construction of other cold atom experiments, such as atomic clock experiments and neutral atom quantum computing systems, by establishing dedicated design and production units at national laboratories.Comment: 27 pages, 21 figure

Plasma proteins elevated in severe asthma despite oral steroid use and unrelated to Type-2 inflammation

Rationale Asthma phenotyping requires novel biomarker discovery. Objectives To identify plasma biomarkers associated with asthma phenotypes by application of a new proteomic panel to samples from two well-characterised cohorts of severe (SA) and mild-to-moderate (MMA) asthmatics, COPD subjects and healthy controls (HCs). Methods An antibody-based array targeting 177 proteins predominantly involved in pathways relevant to inflammation, lipid metabolism, signal transduction and extracellular matrix was applied to plasma from 525 asthmatics and HCs in the U-BIOPRED cohort, and 142 subjects with asthma and COPD from the validation cohort BIOAIR. Effects of oral corticosteroids (OCS) were determined by a 2-week, placebo-controlled OCS trial in BIOAIR, and confirmed by relation to objective OCS measures in U-BIOPRED. Results In U-BIOPRED, 110 proteins were significantly different, mostly elevated, in SA compared to MMA and HCs. 10 proteins were elevated in SA versus MMA in both U-BIOPRED and BIOAIR (alpha-1-antichymotrypsin, apolipoprotein-E, complement component 9, complement factor I, macrophage inflammatory protein-3, interleukin-6, sphingomyelin phosphodiesterase 3, TNF receptor superfamily member 11a, transforming growth factor-β and glutathione S-transferase). OCS treatment decreased most proteins, yet differences between SA and MMA remained following correction for OCS use. Consensus clustering of U-BIOPRED protein data yielded six clusters associated with asthma control, quality of life, blood neutrophils, high-sensitivity C-reactive protein and body mass index, but not Type-2 inflammatory biomarkers. The mast cell specific enzyme carboxypeptidase A3 was one major contributor to cluster differentiation. Conclusions The plasma proteomic panel revealed previously unexplored yet potentially useful Type-2independent biomarkers and validated several proteins with established involvement in the pathophysiology of SA