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Superior effect of MP-AzeFlu than azelastine or fluticasone propionate alone on reducing inflammatory markers.

ABSTRACT: Background:MP-AzeFlu, intranasal formulation of azelastine hydrochloride (AZE) and fluticasone propionate (FP), is superior to AZE or FP alone for treatment of allergic rhinitis (AR). However, the precise anti-inflammatory mechanism of action of MP-AzeFlu has not been characterized. Objective:To investigate the anti-inflammatory effects of MP-AzeFlu compared with AZE or FP alone in an established in vitro model of eosinophilic inflammation. Methods:Nasal mucosal epithelial cells and peripheral blood eosinophils were obtained from human volunteers. Epithelial cells were stimulated with 10% fetal bovine serum (FBS) in the presence of MP-AzeFlu, AZE, or FP (1:102 to 1:105 dilution). Concentrations of interleukin (IL)-6, IL-8, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were measured by ELISA. Eosinophils were incubated in 10% human epithelial cell-conditioned medium (HECM) and survival assessed by trypan blue dye exclusion. Results are expressed as mean?±?SEM percentage secretion/survival compared with FBS/HECM (respectively). Results:FP and MP-AzeFlu (all dilutions) and AZE (1:102) significantly reduced IL-6 secretion and eosinophil survival compared with positive controls. At 1:102 dilution, IL-6 secretion was significantly lower with MP-AzeFlu (38.3?±?4.2%, compared with FBS?=?100%) than with AZE (76.1?±?4.9%) or FP (53.0?±?4.9%). At 1:102 dilution, eosinophil survival was significantly lower with MP-AzeFlu at day 3 (17.5?±?3.0%) and day 4 (2.4?±?1.4%, compared with HECM?=?100%) than with AZE (day 3: 75.2?±?7.2%; day 4: 44.0?±?9.7%) or FP (day 3: 38.5?±?3.5%; day 4: 14.6?±?4.0%). Conclusion:Greater reductions in cytokine secretion and eosinophil survival observed with MP-AzeFlu in vitro may underlie MP-AzeFlu's superior clinical efficacy vs. AZE or FP alone observed in AR patients.

SUBMITTER: Roca-Ferrer J

PROVIDER: S-EPMC6299636 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Superior effect of MP-AzeFlu than azelastine or fluticasone propionate alone on reducing inflammatory markers.

Roca-Ferrer Jordi J Pujols Laura L Pérez-González Maria M Alobid Isam I Callejas Borja B Vicens-Artés Sònia S Fuentes Mireya M Valero Antonio A Picado César C Castor Dennis D Nguyen DucTung D Mullol Joaquim J

Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology 20181218

<h4>Background</h4>MP-AzeFlu, intranasal formulation of azelastine hydrochloride (AZE) and fluticasone propionate (FP), is superior to AZE or FP alone for treatment of allergic rhinitis (AR). However, the precise anti-inflammatory mechanism of action of MP-AzeFlu has not been characterized.<h4>Objective</h4>To investigate the anti-inflammatory effects of MP-AzeFlu compared with AZE or FP alone in an established in vitro model of eosinophilic inflammation.<h4>Methods</h4>Nasal mucosal epithelial ...[more]

PMID: 30574167

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Project description:• The topical second generation anti-histamine azelastine hydrochloride (AZE) and the potent corticosteroid fluticasone propionate (FP) are well established first-line treatments in allergic rhinitis (AR). • MP29-02, a novel intranasal AZE and FP formulation, has been shown to control AR symptoms faster and better than standard intranasal AZE or FP. • The systemic bioavailabilities of marketed AZE and FP nasal spray products have been established at about 40% and 1% only, respectively. • For new combination medicinal products such as MP29-02, the determination of possible pharmacokinetic (PK) drug-drug interactions between both active components and formulation-based bioavailability alterations is essential.• This paper provides for the first time information on potential drug-drug interactions, AZE and FP bioavailability and disposition characteristics of each component administered by the novel nasal spray formulation MP29-02. • The studies employed highly sensitive FP and AZE LC-MS/MS assays and could therefore be conducted with recommended therapeutic doses, thereby circumventing previously recognized draw-backs that required nasal bioavailability studies to be conducted using supra-therapeutic doses. • No significant PK drug-drug interaction between the active components AZE and FP was noted for MP29-02. • AZE bioavailabilty was equivalent when MP29-02 data were compared with MP29-02-AZE-mono and Astelin®. • Increased FP exposure was observed with MP29-02-based products compared with FP-BI. FP serum concentrations were generally very low with all investigational products suggesting no clinically meaningful pharmacodynamic differences in terms of systemic safety.To determine azelastine hydrochloride (AZE) and fluticasone propionate (FP) bioavailabilities of the novel nasal spray combination product MP 29-02, compared with MP29-02-based products containing only AZE (MP29-02-AZE-mono), FP (MP29-02-FP-mono), marketed AZE and FP single entity products (Astelin® and FP Boehringer-Ingelheim; FP-BI).Two randomized, three period, six sequence, three treatment crossover studies were conducted in healthy subjects. Study 1 administered 200 µg FP as MP29-02, MP29-02-FP-mono or FP-BI. Study 2 administered 548 µg AZE as MP29-02, MP29-02-AZE-mono or Astelin®. Each dose consisted of two sprays/nostril. Serum FP and plasma AZE were followed over 24 (FP) and 120 h (AZE) and quantified by LC-MS/MS. Peak (C(max) ) and total exposures AUC(0,t(last) ) were compared between the treatments by anova.Study 1: Average FP C(max) was very low with all products (? 10 pg ml(-1) ). FP AUC(0,t(last) ) point estimates (90% CIs) for MP29-02 : MP29-02-FP-mono and MP29-02 : FP-BI ratios (%) were 93.6 (83.6, 104.7) and 161.1 (137.1, 189.3). Corresponding ratios for C(max) were 91.0 (82.5, 100.4) and 157.4 (132.5, 187.1). Study 2: AZE AUC(0,t(last) ) point estimates (90% CIs) for MP29-02 : MP29-02-AZE-mono and MP29-02 : Astelin® ratios (%) were 98.8 (91.0, 107.4) and 105.5 (95.6, 116.4). Corresponding outcomes for C(max) were 102.7 (92.1, 114.4) and 107.3 (92.6, 124.3).No interactions of AZE and FP were found with the MP29-02 formulation. Azelastine bioavailability was similar for MP29-02 and Astelin®. Maximum and total FP exposure was higher for MP29-02-based products compared with FP-BI. FP concentrations were generally very low with all investigational products and did not suggest clinically meaningful differences concerning systemic safety.

Project description:Using sputum neutrophils as the primary measure, and other inflammation biomarkers, this study evaluated the anti-inflammatory effects of the combination salmeterol 50 mcg and fluticasone propionate 250 mcg (SFC 250) in Japanese patients with chronic obstructive pulmonary disease (COPD).Patients were treated in a randomized, double-blind, parallel group, placebo-controlled trial with SFC 250 twice daily (n=26) or placebo (n=26) for 12 weeks. At the start and end of treatment, inflammation biomarkers (sputum and serum), lung function, and health status (COPD Assessment Test [CAT] questionnaire) were measured.Although a numerical decrease in differential neutrophil count was observed from baseline, SFC 250 did not significantly reduce sputum neutrophils compared with placebo, nor were there significant changes from baseline in the other biomarkers (sputum or serum), lung function, or CAT, versus placebo. Squamous epithelial cell contamination in some sputum samples rendered them unacceptable for analysis, which reduced the sample size to n=19 (SFC 250) and n=10 (placebo). However, inclusion of contaminated samples did not affect the overall trend of the outcome. Ad hoc bootstrap statistical analysis showed a 27.9% (SFC 250) and 1.3% (placebo) decrease in sputum neutrophils. Sputum IL-8 decreased by 43.2% after SFC 250 but increased by 48.3% with placebo. Responder analyses showed 42% of patients had ?20% decrease in neutrophils from baseline; and 47% of patients had a ?200 pg/mL change in sputum IL-8 following SFC 250 versus 20% after placebo; both changes are considered clinically relevant.This study provides additional information about inflammation in Japanese COPD patients and is the first to study the anti-inflammatory effects of SFC 250 in this context and population. In the primary analysis, SFC 250 did not produce significant changes from baseline in sputum neutrophil levels or other sputum or serum inflammatory markers compared with placebo. Secondary ad hoc statistical analysis showed that SFC 250 reduced the number of sputum neutrophils and IL-8 compared with placebo.

Project description:BackgroundInhaled corticosteroid use is associated with increased rates of pneumonia in COPD patients. The underlying mechanism is unknown, although recent data suggest that pneumonia is more frequent in patients treated with fluticasone propionate (FP) than budesonide. Macrophages and neutrophils from COPD patients are deficient in clearing bacteria, and this might explain increased bacterial colonization in COPD. Inhaled corticosteroid may further suppress this response; therefore, we examined the effect of FP and budesonide on phagocytosis of common respiratory pathogens by monocyte-derived macrophages (MDMs) and neutrophils.MethodsMDMs from COPD patients (n=20-24) were preincubated with FP or budesonide for 1 or 18 hours, after which phagocytosis of fluorescently labeled inert beads or heat-killed Haemophilus influenzae/Streptococcus pneumoniae were measured fluorimetrically after 1 or 4 hours. Additionally, CXCL8, IL6, and TNF? concentrations in supernatants by ELISA, MDM-scavenger-receptor expression by flow cytometry, and MDM ability to kill bacteria were measured. Neutrophils from COPD patients (n=8) were preincubated with corticosteroids for 1 hour and bacteria phagocytosis measured by flow cytometry.ResultsAfter 1 hour's preincubation, neither corticosteroid altered MDM phagocytosis of beads or H. influenzae; however, budesonide (10-7 M) increased S. pneumoniae phagocytosis by 23% (P<0.05). After 18 hours' preincubation, neither corticosteroid altered MDM phagocytosis of any prey, although H. influenzae phagocytosis by budesonide was significantly greater compared to FP at 10-6 and 10-5 M (P<0.05). The 1-hour preincubation with either corticosteroid inhibited bacteria-induced CXCL8 release (at 10-7 and 10-5 M, P<0.05); however, this effect was lost at 18-hour preincubation. There was no change in receptor expression, bacterial killing, or neutrophil phagocytosis by either corticosteroid.ConclusionThese data suggest that dissolved FP and budesonide do not have an overall effect on MDM or neutrophil phagocytosis of bacteria.

Project description:ObjectiveThe aims of this study were (1) to characterise the type of patient prescribed MP-AzeFlu (Dymista, a novel formulation of azelastine hydrochloride, fluticasone propionate and excipients in a single spray) in real life in the UK and physicians' reasons for prescribing it and (2) to quantify the personal and societal burden of allergic rhinitis (AR) in the UK prior to MP-AzeFlu prescription.Design, setting and participantsThis multicentre, non-interventional study enrolled patients (n=193) with moderate-to-severe AR and acute symptoms who were eligible to receive treatment with MP-AzeFlu according to its licensed indications. Information was gathered on patient demographics, AR history and symptom severity, symptomatology and AR treatments in the previous calendar year (prior to MP-AzeFlu prescription). Physicians also recorded the number of previous AR visits, specific reasons for these visits and their reason for prescribing MP-AzeFlu.ResultsMost patients had seasonal AR either alone (10.4%) or in combination with perennial AR (35.2%), but many had AR of unknown origin (35.8%). Prior to MP-AzeFlu prescription, patients reported troublesome symptoms (78.2%) and sleep disturbance (64.8%), with congestion considered the most bothersome (54.4%) and ocular symptoms reported by 68.4% of patients. The most frequent reason for MP-AzeFlu prescription was that other therapies were not sufficient in the past (78.8%) or not sufficient to treat acute symptoms (16.1%). 79.3% of patients reported using ?2 AR therapies in the past year. An average of 1.6 (SD 1.9) doctor visits due to AR were reported prior to MP-AzeFlu prescription.ConclusionsIn the UK, MP-AzeFlu was prescribed for individuals (?12?years) with moderate/severe AR irrespective of (1) previous AR treatment (mono or multiple), (2) previous or likely treatment failure, (3) phenotype, (4) number of previous physician visits for AR and (5) for the relief of both acute symptoms and in anticipation of allergen exposure.

Dataset Information

Superior effect of MP-AzeFlu than azelastine or fluticasone propionate alone on reducing inflammatory markers.

Publications

Superior effect of MP-AzeFlu than azelastine or fluticasone propionate alone on reducing inflammatory markers.

Similar Datasets

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