Search

Background: Tezepelumab is a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin. SOURCE evaluated the oral corticosteroid-sparing effect of tezepelumab in adults with oral corticosteroid-dependent asthma., Methods: We conducted this phase 3, multicentre, randomised, double-blind, placebo-controlled study across 60 sites in seven countries. Participants aged 18-80 years with physician-diagnosed asthma, who had been receiving medium-dose or high-dose inhaled corticosteroids and had at least one asthma exacerbation in the 12 months before screening were eligible. Patients who were receiving medium-dose inhaled corticosteroids must have had their dose increased to a high dose for at least 3 months before screening. After an oral corticosteroid optimisation phase of up to 8 weeks, participants were randomly assigned according to a computer-generated fixed block randomisation sequence to receive tezepelumab 210 mg or placebo subcutaneously every 4 weeks during a 48 week treatment period (4 week induction phase, 36 week oral corticosteroid reduction phase, and 8 week maintenance phase). Randomisation was stratified by region. Participants, investigators, and site staff were masked to treatment assignment. The primary endpoint was the categorised percentage reduction from baseline in daily oral corticosteroid dose at week 48 without the loss of asthma control. Efficacy and safety endpoints were assessed in all participants who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT03406078., Findings: Between March 5, 2018, and Sept 27, 2019, 150 participants were randomly assigned to receive tezepelumab 210 mg (n=74) or placebo (n=76). The cumulative odds of achieving a category of greater percentage reduction in an oral corticosteroid dose for daily maintenance at week 48 were similar with tezepelumab or placebo in the overall population (odds ratio [OR] 1·28 [95% CI 0·69-2·35], p=0·43; the primary endpoint was not met). The cumulative odds were higher with tezepelumab than with placebo in participants with baseline blood eosinophil counts of at least 150 cells per μL (2·58 [1·16-5·75]), but not in participants with counts below 150 cells per μL (0·40 [0·14-1·13]). Tezepelumab was well tolerated, with no safety concerns identified. 53 (72%) of 74 tezepelumab-assigned participants and 65 (86%) of 76 placebo-assigned participants reported an adverse event. Serious adverse events were reported in 12 (16%) participants in the tezepelumab group and 16 (21%) participants in the placebo group., Interpretation: We did not observe a significant improvement in oral corticosteroid dose reduction with tezepelumab versus placebo in the overall population of this oral corticosteroid-sparing study, although an improvement was observed in participants with baseline blood eosinophil counts of at least 150 cells per μL., Funding: AstraZeneca and Amgen., Competing Interests: Declaration of interests MEW is an employee of US National Jewish Health and has received consultancy fees from AstraZeneca, Equillium, Genentech, GlaxoSmithKline, Novartis, Regeneron, resTORbio, Sanofi, and Teva. AM-G has attended advisory boards for AstraZeneca, GlaxoSmithKline, Novartis, Sanofi, and Teva; has received speaker fees from AstraZeneca, Novartis, Roche, and Teva; participated in research with AstraZeneca, for which his institution has been remunerated; has attended international conferences with Teva; and has consultancy agreements with AstraZeneca, Sanofi, and Vectura. CEB has received grants and consultancy fees from AstraZeneca. PK has received personal fees for lectures from Adamed, Alvogen, AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, HAL Allergy, LEK-AM, Menarini Group, Mylan, Novartis, Polpharma, Sanofi, and Teva. SK has received fees for lectures and advisory board meetings from AstraZeneca, GlaxoSmithKline, Novartis, Roche, Sanofi Aventis, and Teva. TW has received fees for lectures and advisory board meetings from AstraZeneca, Berlin-Chemie, GlaxoSmithKline, MSD, Novartis, Roche, and Sanofi Aventis. JMG, KS, ÅH, GA, HL, TS, and GC are employees of AstraZeneca. PK is an employee of Amgen., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: The coronary sinus ostium (CSO) is covered by the Thebesian valve (ThebV), which has a variable shape when assessed subjectively. The ThebV is an anatomical barrier during CS cannulation, which may be complicated due to the valves' size. The types of valves are: cord, remnant, semilunar, fold, and mesh/fenestrated. The ThebV can be visible using multisliced computed tomography (MSCT), however, this method cannot show the ThebV's morphological shape, only its size., Methods: 301 randomly selected autopsied human hearts were examined. The shape of the valve was subjectively assessed, whereas the ThebV height (H) and the CSO diameter (D) were measured. The H/D-Ratio was computed as the ThebV height divided by the CSO diameter, afterwards k-means cluster analysis was performed to estimate H/D-Ratio's range of values between valves. MSCT scans from 114 patients that underwent CSO cannulation were objectively evaluated based on similar measured parameters in accordance with received H/D-Ratio values., Results: Boundaries of ratio evaluations between remnant and semilunar, and semilunar and fold types were 0.35 and 0.65 respectively. In MSCT scans, the ThebV was recorded in 61 cases (remnant=5.3%, semilunar=24.6%, fold=16.7%, cord=0.0%, mesh/fenestrated=7.9%). Except for the remnant and cord types, the other types appear similarly as in the cadaveric and MSCT studies. There were no differences between ThebV height and the CSO diameter in cadavers and MSCT studies., Conclusion: The H/D-Ratio can be useful in assessing ThebV shape as visualized in MSCT. We give threshold values for the H/D-Ratio which easily allow the ThebV shape to be determined., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Purpose: Opioid peptides provide a link between the neuroendocrine and immune systems. They modify the inflammatory process through their effect on the synthesis and secretion of cytokines and on the proliferation of leukocytes to the inflammatory lesion. The evaluation analyzed changes in free met-enkephalin concentration values in the serum and colon mucosal biopsy specimens of patients with inflammatory bowel disease (IBD)., Material and Methods: In serum and colon mucosal biopsy specimens, free met-enkephalin levels were determined in 43 patients with ulcerative colitis (UC) and 38 individuals with Crohn's disease (CD). The evaluation analyzed the effect of disease activity, inflammatory lesions of the colon and laboratory parameters, on the level of the investigated marker. The control group consisted of 45 healthy volunteers., Results: Serum free met-enkephalin levels were depressed in patients with CD (85.4pg/ml) and UC (101.5pg/ml) as compared to the controls (119.4pg/ml). Met-enkephalin levels in colonic biopsies collected from inflammatory lesions in IBD patients were significantly higher as compared to sections without inflammatory lesions (6.59pg/mg vs. 2.89pg/mg, p < 0.01 in the CD group and 6.12pg/mg vs. 3.47pg/mg, p < 0.05 in the UC group) and their level correlated with disease activity., Conclusions: The present investigation is the first study that demonstrates changes in free met-enkephalin levels in IBD that may play a role in the pathogenesis and course of the disease. Further studies are necessary to assess the anti-inflammatory effect of opioid peptides.