Primary studies included in this broad synthesis

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Estudio primario

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Revista Pediatric pulmonology
Año 2012
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BACKGROUND: We previously performed a randomized placebo-controlled trial to examine the effects of azithromycin in children and adolescents 6-18 years of age with cystic fibrosis uninfected with Pseudomononas aeruginosa and demonstrated that while azithromycin did not acutely improve pulmonary function, azithromycin-reduced pulmonary exacerbations, decreased the initiation of new oral antibiotics, and improved weight gain. We now report the results of the open-label, follow-on study to assess durability of response to azithromycin and continued safety and tolerability. METHODS: Eligible participants were enrolled in a 24-week open-label study of azithromycin to compare efficacy and safety endpoints during the placebo-controlled trial versus open-label study in two groups: participants initially on azithromycin continued azithromycin (azithromycin-azithromycin) and participants initially on placebo who then received azithromycin (placebo-azithromycin). As in the placebo-controlled trial, the azithromycin dose in the open-label study was 250 mg Monday-Wednesday-Friday for participants weighing 18-35.9 kg and 500 mg Monday-Wednesday-Friday for participants weighing 36 kg or greater. RESULTS: Of 174 eligible participants, 146 (83.9%) enrolled in the open-label study. No significant improvements in lung function were observed within either group. There were no differences in outcomes in the placebo-azithromycin group during the placebo-controlled versus open-label phase. The azithromycin-azithromycin group had comparable odds of experiencing an exacerbation during the two phases (OR 1.6, CI(95) 0.8, 3.0) and stable weight gain, but new oral antibiotics were initiated more frequently during the open-label study (OR 1.9, CI(95) 1.0, 3.5). In both groups, adverse event rates were comparable during the placebo-controlled and open-label study and treatment-emergent pathogens were rare. CONCLUSIONS: During the open-label study, we observed continued durability of treatment response to azithromycin, as measured by pulmonary exacerbations and continued weight gain, although use of oral antibiotics increased. There were no new safety concerns. Currently available data suggest that azithromycin reduces exacerbations and improves weight gain for 6-12 months among children and adolescents with CF uninfected with P. aeruginosa.

Estudio primario

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Revista Pediatric pulmonology
Año 2012
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The clinically significant actions of oral azithromycin in modifying progressive cystic fibrosis (CF) lung disease have been well documented. In vitro and clinical data suggests that clarithromycin has immunomodulatory properties similar to other 14-member macrolides, however two previously reported short term, open label trials of clairthromycin in small numbers of patients with CF failed to show significant benefits in modifying lung function or inflammation. We performed an international double blind, cross-over trial in which 63 subjects with CF were studied while receiving either placeo or 500 mg oral clarithromycin twice daily for 5 months, with a 1-month wash-out. The primary efficacy end point was the change in lung function (FEV(1) and FVC) during the clarithromycin treatment period compared to placebo treatment. Secondary efficacy end points included; quality of life, number of pulmonary exacerbations, height and weight, sputum inflammatory mediator content, sputum transportability and surface properties, bacterial flora, nasal potential difference, and breath condensate. No significant difference in either the primary efficacy end point or any secondary end point was seen during the period of clarithromycin treatment compared to those seen during placebo administration. We conclude that clarithromycin is not effective in treating CF lung disease.

Estudio primario

No clasificado

Revista European journal of pharmacology
Año 2012
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Cystic fibrosis is a hereditary disease caused by a mutation in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene that encodes a chloride (Cl(-)) channel. Cystic fibrosis pulmonary pathophysiology is characterised by chronic inflammation and bacterial infections. Azithromycin, a macrolide antibiotic, has shown promising anti-inflammatory properties in some inflammatory pulmonary diseases. Moreover, all clinical studies have presented an improvement of the respiratory condition of cystic fibrosis patients, but the molecular and cellular mechanisms remain unknown. The aim of this study was to investigate, in bronchial epithelial cells, the effects of azithromycin on inflammatory pathways involved in cystic fibrosis. We have analysed the effects of azithromycin on cystic fibrosis and non-cystic fibrosis bronchial epithelial cell lines but also in non-immortalized non-cystic fibrosis human glandular cells. To create an inflammatory context, cells were treated with Tumor Necrosis Factor (TNF)-α or Interleukin (IL)1-β. Activation of the NF-κB pathway was investigated by luciferase assay, western blotting, and by Förster Resonance Energy Transfer imaging, allowing the detection of the interaction between the transcription factor and its inhibitor in live cells. In all conditions tested, azithromycin did not have an anti-inflammatory effect on the cystic fibrosis human bronchial epithelial cells and on CFTR-inhibited primary human bronchial glandular cells. More, our data showed no effect of azithromycin on IL-1β- or TNF-α-induced IL-8 secretion and NF-κB pathway activation. Taken together, these data show that azithromycin is unable to decrease in vitro inflammation in cystic fibrosis cells from airways.

Estudio primario

No clasificado

Revista Clinical transplantation
Año 2012
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BACKGROUND: Bronchiolitis obliterans syndrome (BOS) is the major limitation to long-term survival following lung transplantation and strategies to reduce its incidence have remained elusive. Macrolides may stabilize lung function in patients with established BOS. Their role, however, in prevention of BOS remains unexamined. METHODS: Survival and BOS-free survival of 102 lung allograft recipients (LARs), transplanted at a single center between July 1995 and December 2001 who routinely received clarithromycin, were compared with two different control groups. The first control group consisted of 44 LARs from the same center who were transplanted from January 2002 onwards and did not receive clarithromycin. The second control group consisted of a contemporaneous cohort of 5089 recipients, transplanted between 1995 and 2001, reported to the United Network for Organ Sharing database. RESULTS: When compared with the first control group, BOS-free survival was reduced in LARs receiving clarithromycin. Univariate (hazard ratio [HR] 3.13, p-value = 0.004) and multivariate (HR 3.49, p-value = 0.04) analyses showed that routine use of clarithromycin was associated with an increased risk of developing BOS. When compared with the second control group, the five-yr survival of clarithromycin group was similar (p-value = 0.24). CONCLUSIONS: Routine use of clarithromycin does not delay development of BOS or improve survival.

Estudio primario

No clasificado

Revista The Journal of pediatrics
Año 2012
Objective: To test the hypothesis that azithromycin reduces the length of hospitalization and oxygen requirement in infants with acute viral bronchiolitis (AB). Study design: We performed a randomized, double-blinded, placebo-controlled trial in southern Brazil, from 2009 to 2011. Infants (<12 months of age) hospitalized with AB were recruited in 2 hospitals. Patients were randomized to receive either azithromycin or placebo, administered orally, for 7 days. At enrollment, clinical data were recorded and nasopharyngeal samples were collected for viral identification through immunofluorescence. Main outcomes were duration of oxygen requirement and length of hospitalization. Results: One hundred eighty-four patients were included in the study (azithromycin 88 subjects, placebo 96 subjects). Baseline clinical characteristics and viral identification were not different between the groups studied. A virus was detected in 112 (63%) patients, and of those, 92% were positive for respiratory syncytial virus. The use of azithromycin did not reduce the median number of days of either hospitalization (P =.28) or oxygen requirement (P =.47). Conclusions: Azithromycin did not improve major clinical outcomes in a large sample of hospitalized infants with AB, even when restricting the findings to those with positive respiratory syncytial virus samples. Azithromycin therapy should not be given for AB because it provides no benefit and overuse increases overall antibiotic resistance. Copyright © 2012 Mosby Inc. All rights reserved.

Estudio primario

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Macrolide antibiotics, like erythromycin, clarithromycin, and azithromycin, possess anti-inflammatory properties. These properties are considered fundamental to the efficacy of these three macrolides in the treatment of chronic inflammatory diseases like diffuse panbronchiolitis and cystic fibrosis. However, long-term treatment with macrolide antibiotics presents a considerable risk for promotion of bacterial resistance. We have examined antibacterial and anti-inflammatory effects of a novel macrolide class: N'-substituted 2'-O,3'-N-carbonimidoyl bridged erythromycin-derived 14- and 15-membered macrolides. A small focused library was prepared, and compounds without antimicrobial activity, which inhibited IL-6 production, were selected. Data analysis led to a statistical model that could be used for the design of novel anti-inflammatory macrolides. The most promising compound from this library retained the anti-inflammatory activity observed with azithromycin in lipopolysaccharide-induced pulmonary neutrophilia in vivo. Importantly, this study strongly suggests that antimicrobial and anti-inflammatory activities of macrolides are independent and can be separated, which raises development plausibility of novel anti-inflammatory therapeutics.

Estudio primario

No clasificado

Revista Bone marrow transplantation
Año 2011
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Bronchiolitis obliterans syndrome (BOS) is a devastating pulmonary complication affecting long-term survivors of allogeneic hematopoietic cell transplantation. Treatment of BOS with prolonged courses of high dose corticosteroids is often associated with significant morbidity. Reducing the exposure to corticosteroids may reduce treatment-related morbidity. Our institution has recently begun to treat patients with emerging therapies in an effort to diminish corticosteroid exposure. We retrospectively reviewed the 6-month corticosteroid exposure, lung function and failure rates in eight patients with newly diagnosed BOS who were treated with a combination of fluticasone, azithromycin and montelukast (FAM) and a rapid corticosteroid taper. These patients were compared with 14 matched historical patients who received high-dose corticosteroids, followed by a standard taper. The median 6-month prednisone exposure in FAM-treated patients was 1819 mg (0-4036 mg) compared with 7163 mg (6551-7829 mg) in the control group (P=0.002). The median forced expiratory volume in 1 s (FEV(1)) change in FAM-treated patients was 2% (-3 to 4%] compared with 1% (-4 to 5%) in the control group (P=1.0). Prednisone exposure in FAM patients was one quarter that of a retrospective-matched group of patients, with minimal change in median FEV(1), suggesting that BOS may be spared of the morbidities associated with long-term corticosteroid use by using alternative agents with less side effects.

Estudio primario

No clasificado

Revista Bone marrow transplantation
Año 2011
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Bronchiolitis obliterans syndrome (BOS) is an important complication after hematopoietic SCT (HSCT). Recent observations suggested that azithromycin might improve lung function in BOS after HSCT. We conducted a randomized double-blinded placebo-controlled study on azithromycin in patients with BOS after HSCT. The treatment group (n10) received oral azithromycin 250 mg daily while the control group (n12) received placebo daily for 12 weeks. Respiratory symptoms were assessed by the St George Respiratory Questionnaires and spirometry at baseline (drug commencement), 1, 2, 3 (drug cessation) and 4 months (1 month after drug cessation). There was no significant difference in the baseline demographic characteristics between the treatment and the control groups in age, gender, time from HSCT to BOS, time since diagnosis of BOS, chronic GVHD, baseline respiratory symptom scores and baseline forced expiratory volume in 1 s (FEV 1). Throughout and after 3 months of treatment, there were no significant changes in respiratory symptom scores and FEV 1 measurements between the treatment and the control groups. In conclusion, there was no significant benefit of 3 months of oral azithromycin on the respiratory symptoms and lung function in patients with relatively late BOS after HSCT in this randomized placebo-controlled study. © 2011 Macmillan Publishers Limited.

Estudio primario

No clasificado

Autores Lin SJ , Lee WJ , Liang YW , Yan DC , Cheng PJ , Kuo ML
Revista International archives of allergy and immunology
Año 2011
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BACKGROUND: Childhood asthma is a type 2 helper T (Th2) cell-driven inflammatory airway disease characterized by recurrent episodes of airway obstruction. Azithromycin (AZM), a macrolide antibiotic exhibiting anti-inflammatory activity aside from its antibacterial effect, may prove beneficial for asthmatic children. This study aimed to determine the effect of AZM on Th2 cells from atopic asthmatic children and non-atopic controls. METHODS: CD4+ cells were isolated from peripheral blood mononuclear cells of 9 patients with asthma and 9 non-atopic individuals. Cells were activated as Th0 and differentiated into Th2 cells. The effect of AZM on activated CD4+ cells was evaluated with respective cell proliferation and cytokine production. RESULTS: Th0 and Th2 CD4+ T cells from atopic asthmatic children produced greater interleukin (IL)-5 (Th2 cytokine) but lower interferon (IFN)-γ (Th1 cytokine) compared to the non-atopic controls, respectively. AZM inhibited IL-5 production of Th0 and Th2 cells from atopic asthmatics in a dose-dependent fashion, without significantly affecting their IL-13 and IFN-γ production. A similar effect was observed in non-atopic controls except that AZM did inhibit IFN-γ production of their Th0 cells. AZM at a higher dose decreased cell viability by inhibiting CD4+ T cell proliferation and enhanced their apoptosis, an effect similarly observed in Th0 and Th2 cells, and did not differ between asthmatic children and controls. CONCLUSION: Our finding that AZM preferentially downregulates IL-5 production suggests its therapeutic potentials in controlling childhood asthma.

Estudio primario

No clasificado

Autores Gao X , Ray R , Xiao Y , Ishida K , Ray P
Revista Pulmonary pharmacology & therapeutics
Año 2010
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BACKGROUND: Sulfur mustard (SM) inhalation causes apoptosis and death of airway epithelial cells as well as inflammation in the airway. Efficient clearance of the cell debris by alveolar macrophages is necessitated to reduce the inflammation. Macrolide antibiotics have been reported to have anti-inflammatory properties by modulating the production of proinflammatory cytokines and mediators, and by improving macrophage functions. The present study investigated the effects of four commonly used macrolide antibiotics, namely azithromycin, clarithromycin, erythromycin, and roxithromycin, on chemotactic and phagocytotic function and on inflammatory cytokines/mediators production in vitro in SM-exposed monocyte THP-1 cells. RESULTS: Chemotaxis and phagocytosis of the monocytes reduced upon exposure to 10microM SM (8.1% and 17.5%, respectively) were restored by treatment with 10microM of any of the four macrolides. Overexpression of inflammatory cytokines following SM exposure was decreased by 50-70% with macrolide treatment. Similarly, exaggerated iNOS expression and nitric oxide (NO) production induced by SM exposure was largely inhibited by treatment with macrolides. CONCLUSION: The data demonstrate that macrolide antibiotics were effective in improving the degenerated chemotactic and phagocytotic functions of monocytes following SM exposure, and in reducing SM-induced overproduction of proinflammatory cytokines and mediators. Thus, treatment with macrolide antibiotics may lead to improved clearance of apoptotic material in the airway and ultimately result in reduced airway inflammation and injury caused by SM inhalation, suggesting that macrolide antibiotics may serve as potential vesicant respiratory therapeutics.