5 research outputs found
Superior effect of MP-AzeFlu than azelastine or fluticasone propionate alone on reducing inflammatory markers
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
Epinephrine delivery via EpiPenÂź Auto-Injector or manual syringe across participants with a wide range of skin-to-muscle distances
Background Intramuscular (IM) injection of epinephrine (adrenaline) at the mid-anterolateral (AL) thigh is the international standard therapy for acute anaphylaxis. Concerns exist regarding implications of epinephrine auto-injector needles not penetrating the muscle in patients with greater skin-to-muscle-distances (STMD). Methods This open-label, randomized, crossover study investigated pharmacokinetics and pharmacodynamics following injection of epinephrine in healthy volunteers. Individuals were stratified by maximally compressed STMD (low,â<â15Â mm; moderate, 15â20Â mm; high,â>â20Â mm). Participants received epinephrine injections via EpiPenÂź Auto-Injector (EpiPen; 0.3Â mg/0.3Â mL) or IM syringe (0.3Â mg/0.3Â mL) at mid-AL thigh or received saline by IM syringe in a randomized order. Eligible participants received a fourth treatment (EpiPen [0.3Â mg/0.3Â mL] at distal-AL thigh). Model-independent pharmacokinetic parameters and pharmacodynamics were assessed. Results There were numerical trends toward higher peak epinephrine concentrations (0.52 vs 0.35Â ng/mL; geometric mean ratio, 1.40; 90% CI 117.6â164.6%) and more rapid exposure (time to peak concentration, 20 vs 50Â min) for EpiPen vs IM syringe at mid-AL thigh across STMD groups. Absorption was faster over the first 30Â min for EpiPen vs IM syringe (partial area under curve [AUC] over first 30Â min: geometric mean ratio, 2.13; 90% CI 159.0â285.0%). Overall exposure based on AUC to the last measurable concentration was similar for EpiPen vs IM syringe (geometric mean ratio, 1.13; 90% CI 98.8â129.8%). Epinephrine pharmacokinetics after EpiPen injection were similar across STMD groups. Treatments were well tolerated. Conclusions Epinephrine delivery via EpiPen resulted in greater early systemic exposure to epinephrine vs IM syringe as assessed by epinephrine plasma levels. Delivery via EpiPen was consistent across participants with a wide range of STMD, even when the needle may not have penetrated the muscle
Effect of MPâAzeFlu compared to monotherapy on COXâ2, PGE2, and EP2 gene expression in upper airway mucosa
Abstract MPâAzeFlu (intranasal fluticasone and azelastine) has been widely studied and has demonstrated efficacy in Allergic rhinitis with a superior effect compared to these drugs administered individually; however, the mechanism by which MPâAzeFlu produces this improved clinical effect has not yet been fully explained. In this study, we investigated the effect of MPâAzeFlu and fluticasone propionate (FP) on arachidonic acid metabolism as measured by changes in regulation of cyclooxygenase (COX) isoforms, prostaglandin (PG) D2, PGE2, PGE2 receptor (EP) 2, and EP3. Expression of these key inflammation markers was assessed through an in vitro model of upper airway inflammation using fibroblasts derived from both healthy and inflamed upper airway mucosa. Both MPâAzeFlu and FP inhibited interleukinâ1ÎČâinduced COXâ2 messenger RNA (mRNA) and protein expression and PGE2 secretion in vitro. MPâAzeFlu and FP both upregulated EP2 mRNA expression, though neither upregulated EP2 protein expression. This downregulation of COXâ2 and PGE2 coupled with upregulation of EP2 receptor expression reinforces the antiâinflammatory effect of MPâAzeFlu in upper airway inflammation
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 granulocyteâmacrophage colony-stimulating factor (GM-CSF) were measured by ELISA. Eosinophils were incubated in 10% human epithelial cellâconditioned medium (HECM) and survival assessed by trypan blue dye exclusion. Results are expressed as meanâ±âSEM 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 (38.3â±â4.2%, compared with FBSâ=â100%) than with AZE (76.1â±â4.9%) or FP (53.0â±â4.9%). At 1:102 dilution, eosinophil survival was significantly lower with MP-AzeFlu at day 3 (17.5â±â3.0%) and day 4 (2.4â±â1.4%, compared with HECMâ=â100%) than with AZE (day 3: 75.2â±â7.2%; day 4: 44.0â±â9.7%) or FP (day 3: 38.5â±â3.5%; day 4: 14.6â±â4.0%). Conclusion Greater reductions in cytokine secretion and eosinophil survival observed with MP-AzeFlu in vitro may underlie MP-AzeFluâs superior clinical efficacy vs. AZE or FP alone observed in AR patients