MP29-02 reduces nasal hyperreactivity and nasal mediators in patients with house dust mite-allergic rhinitis.

BACKGROUND: Nasal hyperreactivity (NHR) is an important clinical feature of allergic rhinitis (AR). The efficacy of MP29-02 (azelastine hydrochloride (AZE) and fluticasone propionate [FP]) nasal spray on local inflammatory mediators and NHR in AR is unknown. We tested if MP29-02 decreases inflammatory mediators and NHR in AR and if this effect is due to restoration of nasal epithelial barrier function. METHODS: A 4-week double-blinded placebo-controlled trial with MP29-02 treatment was conducted in 28 patients with house dust mite (HDM) AR. The presence of NHR was evaluated by measuring reduction in nasal flow upon cold dry air exposure. The effects of AZE ± FP on barrier integrity and airway inflammation were studied in a murine model of HDM-induced NHR and on reduced activation of murine sensory neurons and human mast cells. RESULTS: MP29-02 but not placebo reduced NHR (P < .0001 vs P = .21), levels of substance P (P = .026 vs P = .941), and ß-hexosaminidase (P = .036 vs P = .632) in human nasal secretions. In wild-type C57BL6 mice, the reduction in ß-hexosaminidase levels (P < .0001) by AZE + FP treatment upon HDM challenge was found in parallel with a decreased transmucosal passage (P = .0012) and completely reversed eosinophilic inflammation (P = .0013). In vitro, repeated applications of AZE + FP desensitized sensory neurons expressing the transient receptor potential channels TRPA1 and TRPV1. AZE + FP reduced MC degranulation to the same extent as AZE alone. CONCLUSION: MP29-02 treatment reduces inflammatory mediators and NHR in AR. The effects of AZE + FP on MC degranulation, nasal epithelial barrier integrity, and TRP channels provide novel insights into the pathophysiology of allergic rhinitis.

Effect of nasal antihistamine on secretory IgA in nasal lavage of rats.

The humoral IgA is an immunoglobulin which plays a defensive role for organisms on mucosal surfaces. Today, intranasal antihistamines are effectively used in the treatment of allergic rhinitis. In our study, the effect of azelastine hydrochloride-a nasal antihistaminic-on humoral IgA of the nasal mucosa has been reviewed empirically. Twenty-four female Sprague-Dawley rats were included in our study. The rats were divided into three groups randomly. Group 1(azelastine hydrochloride): rats in this group had nasal azelastine hydrochloride (0.05%) applied for 30 days at 10 µl/nostril dosage. Group 2 (saline): saline (0.09%) was applied to the rats in this group for 30 days at 10 µl/nostril dosage. Group 3 (control): no application was made throughout the study. The chemicals applied in Groups 1 and 2 were applied to both nostrils by mounting a flexible micropipette to the end of an insulin injector. At the beginning of the study, nasal lavage was performed to both nostrils of the rats in every group on the 15th and 30th day to aspirate irrigation solution (distilled water). The aspirated liquids were kept at - 80° temperature and reviewed together at the end of study. Within-group comparisons: in Group 1 (azelastine hydrochloride), the humoral IgA value on the 15th day was significantly higher than the basal value (p = 0.037). There is a significant difference between humoral IgA value on the 30th day and humoral IgA value on the 15th day (p = 0.045). In Group 2 (saline), no significant difference is available between basal, 15th day and 30th day humoral IgA values (p = 0.265). In Group 3 (control), no significant difference is available between basal, 15th day and 30th day humoral IgA values (p = 0.374). Between-group comparison: there is no significant difference in between-group humoral IgA basal values (p = 0.714). On days 15 and 30, Humoral IgA value of Group 1 was significantly higher than that of Groups 2 and 3 (p = 0.013, p = 0.024, respectively). According to the results we achieved in our study, nasal antihistaminic (azelastine hydrochloride) significantly increases the level of humoral IgA. Our study is the first one in the literature to reveal a relation between nasal antihistaminic and humoral IgA and there is a further need for clinical, randomized and prospective studies.

[The effectiveness of the combination of azelastine hydrochloride and mometasone furoate for the intranasal application in the patients presenting with seasonal allergic rhinitis]. / Éffektivnost' kombinatsii azelastina gidrokhlorida i mometazona furoata dlia intranazal'nogo primeneniia u bol'nykh sezonnym allergicheskim rinitom.

The objective of the present work was to evaluate the effectiveness of the combination of azelastine hydrochloride and mometasone furoate for the intranasal application to treat the patients presenting with seasonal allergic rhinitis. A total of 60 subjects suffering from seasonal allergic rhinitis were available for the observation. All the patients were allocated to three groups comprised of 20 individuals each. The patients of the first group received the fixed combination of azelastine hydrochloride and mometasone furoate for the intranasal application, those in the second group were given mometasone furoate administered intranasally together with an oral antihistamine preparation of the third generation, and the patients of the third group were treated with intranasal mometasone furoate alone. The effectiveness of the treatment was evaluated on days 7 and 14 after its initiation. It was found that the treatment with the use of the combination of azelastine hydrochloride and mometasone furoate resulted in a more pronounced alleviation of rhinological symptoms and improvement of the quality of life at the early stages of therapy in comparison with mometasone furoate monotherapy. It is concluded that the patients with moderate and severe seasonal allergic rhinitis can be recommended to use the combination of azelastine hydrochloride and mometasone furoate as качестве the initial treatment.

Cytological Study of Topical Effect of Azelastine Hydrochloride on the Nasal Mucous Membrane Cells in Various Nasal Rhinitis Types.

Previous reports on the benefits of using local therapy with azelastine in rhinitis focus on the assessment of clinical symptoms and the analysis of nasal lavage for the presence of inflammatory cells and the expression of adhesion molecules. Little attention has been paid to studies assessing the effect of azelastine on individual cytotypes of the nasal mucosa, especially epithelial cells, also in the context of inducing morphological changes. The aim of this study was the cytological analysis of swabs taken from the surface of the nasal mucosa of patients with allergic rhinitis (AR) and nonallergic/vasomotor rhinitis (NAR/VMR) who were subjected to 4 weeks of therapy with azelastine and then comparing the obtained results with the pre-treatment condition. The technique of obtaining materials for cytoanalysis included sampling, staining of smears, microscopic analysis, and preparation of cytograms. Our studies confirmed the therapeutic benefits of azelastine in both study groups. Significant changes were demonstrated, confirming the regeneration of ciliated cells and the induction of autophagy and apoptosis in epithelial cells. Such changes indicate new mechanisms of action of azelastine, which play a significant role in restoring homeostasis in the nasal mucosa. The presented research also results in a detailed description of cytological changes in both studied rhinitis types, which complements the knowledge regarding prognostic indicators.

A double-blind, placebo-controlled trial of the efficacy and safety of two doses of azelastine hydrochloride in perennial allergic rhinitis.

Background: Azelastine hydrochloride (AZE) is a selective, non-sedating H1 antagonist with anti-inflammatory and mast cell stabilizing properties, which can be used as an alternative to intranasal corticosteroids. The objective of this study was to evaluate the efficacy of the new formulation of 0.15% AZE compared to that of the placebo at a dosage of two sprays per nostril twice daily for 4 weeks in patients with perennial allergic rhinitis (PAR). Materials and methods: A total of 581 subjects were randomized in this double-blind (DB) placebo-controlled trial (NCT00712920) that compared 0.10% (1,096 µg daily) and 0.15% AZE (1,644 µg daily) to the placebo in PAR patients. The study consisted of a 7-day single-blind placebo lead-in period and a 28-day DB treatment period. The primary endpoint was the change from baseline in the 12-h reflective total nasal symptom score (rTNSS) for the entire 28-day study period of 0.15% AZE, two sprays per nostril BID compared to the placebo. The efficacy and safety of 0.15% AZE were compared to the placebo. Results: Least square (LS) mean improvement from baseline in the morning (AM) and evening (PM) combined rTNSS was statistically significant for the 0.15% AZE group (p = 0.04) compared to the placebo group. LS mean improvement from baseline in the AM and PM combined rTNSS was 4.10 (4.26) units for 0.15% AZE and 3.81 (3.99) for 0.10% AZE. For individual symptoms, there was a statistically significant change in the LS mean (p = 0.04) improvement from baseline on the 12-h reflective assessment for the 0.15% AZE group for runny nose. Further numerical improvements were shown for itchy nose, nasal congestion, runny nose, and sneezing compared to the placebo. No deaths or serious adverse events related to the study medication were reported. Conclusion: The present formulation of 0.15% AZE is safe and effective in relieving PAR symptoms. It effectively relieves nasal and non-nasal symptoms. Clinical Trial Registration: ClinicalTrials.gov, identifier: NCT00712920.

Effect of azelastine hydrochloride combined with montelukast sodium in the treatment of patients with allergic rhinitis.

OBJECTIVE: To investigate efficacy of azelastine hydrochloride combined with montelukast sodium in the treatment of patients with allergic rhinitis. METHODS: A total of 137 patients with allergic rhinitis in our hospital were divided into two groups, 70 patients in the experimental group received azelastine hydrochloride combined with montelukast sodium treatment, while 67 patients in the control group were given only azelastine hydrochloride treatment. The clinical therapeutic effect, clinical symptom score and serum levels of inflammatory factors were recorded. RESULTS: The clinical therapeutic effect of the two groups after treatment were improved compared to those without intervention (P < 0.05), and the total effective rate of the experimental group was 94.3% (66/70), which was higher than that of the control group (83.6%). The clinical symptom score (nasal itching, nasal congestion and runny nose) of two groups was decreased after receiving the intervention, and the scores in the experimental group were much lower than the control group after receiving the intervention (P < 0.05). The serum levels of inflammatory factors (IL-6, IL-8 and hsCRP) were obviously lower in the two groups after treatment, and those levels in the experimental group were much lower than the control group after receiving the intervention. Furthermore, after the receiving treatment, the levels of each of the inflammatory and anti-inflammatory factors in the experimental group were significantly ameliorated compared to those in the control group (P < 0.05). CONCLUSION: Azelastine hydrochloride combined with montelukast sodium can effectively improve clinical symptoms and inflammatory reactions in patients with allergic rhinitis; furthermore, this research provides ideas for clinical practice.

Quantitative proton nuclear magnetic resonance method for simultaneous analysis of fluticasone propionate and azelastine hydrochloride in nasal spray formulation.

A facile, rapid, accurate and selective quantitative proton nuclear magnetic resonance (1H-qNMR) method was developed for the simultaneous determination of fluticasone propionate (FLP) and azelastine hydrochloride (AZH) in pharmaceutical nasal spray for the first time. The 1H-qNMR analysis of the studied analytes was performed using inositol as the internal standard and dimethyl sulfoxide-d6 (DMSO-d6) as the solvent. The quantitative selective proton signal of FLP was doublet of doublet at 6.290, 6.294, 6.316 and 6.319 ppm, while that of AZH was doublet at 8.292 and 8.310 ppm. The internal standard (inositol) produced a doublet signal at 3.70 and 3.71 ppm. The method was rectilinear over the concentration ranges of 0.25-20.0 and 0.2-15.0 mg ml-1 for FLP and AZH, respectively. No labelling or pretreatment steps were required for NMR analysis of the studied analytes. The proposed 1H-qNMR method was validated efficiently according to the International Council on Harmonisation guidelines in terms of linearity, limit of detection, limit of quantification, accuracy, precision, specificity and stability. Moreover, the method was applied to assay the analytes in their combined nasal spray formulation. The results ensured the linearity (r 2 > 0.999), precision (% RSD < 1.5), stability, specificity and selectivity of the developed method.

Comparative study of the efficacy and safety of intranasal azelastine hydrochloride and fluticasone furoate in the treatment of allergic rhinitis.

BACKGROUND: Allergic rhinitis (AR) is characterized by nasal itch, sneezing, watery or mucous rhinorrhea, nasal obstruction, and nasal or pharyngeal irritation. If untreated, AR can impair patients' quality of life (QOL). Azelastine hydrochloride (AH), histamine receptor antagonists, has anti-inflammatory and mast cell stabilizing properties. Fluticasone furoate (FF) is an anti-inflammatory agent with action on mast cells, eosinophils, neutrophils, macrophages, and lymphocytes. This study compares the efficacy and safety of these medications in AR. MATERIALS AND METHODS: Patients in the study had been clinically diagnosed with AR. In each group, there were 75 randomized patients who were to receive either FF (27.5 µg/spray) or AH (0.10%) intranasally twice daily. Assessment in terms of symptoms (total nasal symptom score), signs (endoscopic staging), QOL, eosinophil count, and sensory attributes was done at baseline, day 7, and day 15. Adverse effects were recorded, and the cost incurred was analyzed. Paired and umpaired t-test were used to compare symptom scores, QOL scores, and absolute eosinophil count within and between the groups, respectively. RESULTS: The total number of patients was 150 (76 males and 74 females); the mean age for FF group was 26.23 ± 5.2 years, and 26.96 ± 4.8 years for AH group. By day 7, there was a reduction of all scores in both medications, but the reduction in reduction was highly significant with FF (P = 0.001). There was a significant reduction (P = 0.001) in absolute eosinophil count both in blood and nasal smears by day 15 in both the groups; the reduction was significant (P = 0.001) with fluticasone. Adverse reactions were reported by 33.3% of patients receiving FF and 28% patients receiving AH. CONCLUSION: Fluticasone furoate produced sustained relief of symptoms, signs, and sensory attributes with a greater reduction in eosinophil count in comparison with AH in patients with allergic rhinitis.

MP-AzeFlu Improves the Quality-of-Life of Patients with Allergic Rhinitis.

PURPOSE: Patients with poorly controlled allergic rhinitis (AR) experience nasal symptoms, sleep disturbances, activity impairment, and decreased quality-of-life (QoL). MP-AzeFlu is safe and effective for moderate-to-severe seasonal and perennial AR, but its impact on QoL requires investigation in the real-world, especially among phenotypes of immunoglobulin (Ig)E-mediated AR. This subanalysis of an observational study evaluated response to MP-AzeFlu via assessment of sleep quality and trouble with daily activities. PATIENTS AND METHODS: This multicenter, prospective, non-interventional, real-life study included a convenience sample of patients with a history of moderate-to-severe AR presenting with acute AR symptoms (visual analog scale [VAS] ≥50 mm). Over approximately 14 days of treatment with MP-AzeFlu (137 µg azelastine HCL and 50 µg fluticasone propionate administered via single 0.137-mL spray in each nostril twice daily), changes in sleep quality and trouble with daily work, school, social, and outdoor activities were evaluated using a VAS for the entire study population and for four subgroups based on IgE response phenotype. VAS scores ranged from "not at all troubled" (0 mm) to "extremely troubled" (100 mm). RESULTS: Following MP-AzeFlu treatment, mean VAS scores for sleep quality impairment and work or school impairment decreased from 55.2 mm at baseline to 22.1 mm and 57.6 mm at baseline to 23.0 mm, respectively, after ~14 days. Similar results were observed for mean VAS scores for impairment of social activity (55.1 mm to 22.4 mm) and impairment of outdoor activity (64.4 mm to 25.0 mm). For all VAS scores, results were similar across populations, regardless of phenotype of IgE-mediated disease, comorbidity, age, and sex. CONCLUSION: MP-AzeFlu relieves symptoms and improves patient-reported QoL, illustrated by better sleep quality and less impairment of work, school, social, and outdoor activities after 14 days. The QoL benefits of MP-AzeFlu were consistent regardless of the phenotype of IgE-mediated disease. REGISTRATION: Clinical Trial Registration (CTR) Number: EUPAS23075. Trial Register Date: March 12, 2018. First patient visit; Last patient visit: February 2018; April 2019.

Evaluation of in vitro Penetration of Fluticasone Propionate from MP-AzeFlu and Fluticasone Propionate Nasal Spray Through EpiAirway™606 Tissues Using Vertical Diffusion Cells.

PURPOSE: Most patients with allergic rhinitis (AR) have moderate-to-severe disease, requiring complete and prompt relief when symptoms occur. The time course of fluticasone propionate (FP) penetration into nasal tissues after intranasal administration is not well characterized. The goal of this proof-of-concept study was to evaluate the mucosal penetration of FP from fixed-combination FP-azelastine nasal spray (MP-AzeFlu) compared with an FP-only nasal spray in an in vitro, 3-dimensional human bronchial tissue model. MATERIALS AND METHODS: Absorption of FP from MP-AzeFlu and FP nasal spray was modeled using EpiAirway™606 (MatTek Corporation; Ashland, MA, USA) tissue cultured in vertical diffusion cells. The dosing amount of MP-AzeFlu was optimized in a pilot study. Based on the results of the pilot study, 10 µL of MP-AzeFlu (3.65 µg; n = 8) and 10 µL of FP nasal spray (5.00 µg; n = 8) were evaluated for penetration of tissue. Tissue integrity was monitored with Lucifer yellow. FP in the receiving media was quantified for each sample using liquid chromatography with tandem mass spectrometry. RESULTS: MP-AzeFlu and FP nasal spray were associated with similar FP accumulation profiles in the receiving media, but the permeability of FP was greater for MP-AzeFlu during hours 0 to 6, suggesting faster absorption for MP-AzeFlu. No indications of compromised tissue integrity were found in any of the tested cells. CONCLUSION: The higher and more rapid penetration of FP from MP-AzeFlu supports the use of MP-AzeFlu for patients with AR, particularly when prioritizing fast and pronounced symptom relief.

[Clinical observation of nasal spray allergen blocker combined with antihistamines in treatment of allergic rhinitis children].

Objective:To investigate the clinical effect and safety of nasal spray allergen blocker combined with antihistamines in children with allergic rhinitis. Method:Eighty-four children with mild-severe allergic rhinitis were randomly divided into observation group（42 cases） and control group（42 cases）. Children in control group were treated with azelastine hydrochloride nasal spray, while children in observation group added with nasal spray allergen blocker on the basis of control group. Both groups were treated for 4 weeks. The changes of symptoms and signs integral in both groups were compared and analyzed after 1, 2 and 4 weeks treatment. And Clinical efficacy and adverse reactions between two groups were compared after treatment. Result:Among 4 weeks treatment, the symptoms and signs integral of the two groups showed a significant decreasing trend（P<0.01）. The reduction in the observation group was greater than that in the control group, there were statistical differences in the variation trends of symptoms and signs integral between the two groups（P<0.01, P<0.05）. And there were significant differences in symptoms and signs integral between the two groups（P<0.05）. The total effective rate of observation group（90.5%） was significantly higher than that of control group（64.3%）（P<0.05）. There was no statistically significant difference in the incidence of adverse reactions between the two groups（9.5%vs 4.8%, P>0.05）. Conclusion:The effect of nasal spray allergen blocker combined with antihistamines on allergic rhinitis children is remarkable. They can alleviate the symptoms and signs of allergic rhinitis with rapidity and safety.

Real-life effectiveness of MP-AzeFlu in Irish patients with persistent allergic rhinitis, assessed by visual analogue scale and endoscopy.

INTRODUCTION: Most allergic rhinitis (AR) patients have moderate-to-severe, persistent disease. Meda Pharma's AzeFlu (MP-AzeFlu) combines intranasal azelastine hydrochloride (AZE) and fluticasone propionate (FP) in a novel formulation in a single device to treat AR. This prospective, noninterventional study sought to assess the effectiveness of MP-AzeFlu (one spray/nostril twice daily; 548 µg AZE/200 µg FP daily dose) in relieving AR symptom severity. METHODS: A visual analogue scale (VAS) was used prior to MP-AzeFlu treatment on days 0, 1, 3, 7, 14, 21, 28, 35, and 42 by 53 persistent AR (PER) patients seen in routine clinical practice in Ireland. An endoscopy was performed on days 0 and 28, and symptoms of edema, discharge, and redness were scored on a three-point scale (for both nostrils). RESULTS: Patients using MP-AzeFlu experienced rapid VAS score reduction from 73.4 mm (standard deviation [SD], 20.3) at Day 0 to 31.5 mm (SD, 25.0) at day 28 (P < 0.0001) to 28.1 mm (SD, 24.1) at day 42 (P < 0.0001), a 45.3-mm reduction. On average, patients achieved a clinically relevant VAS score cutoff of 50 mm before Day 7. Total endoscopy score decreased from 7.5 mm (SD, 3.1) at baseline to 3.5 mm (SD, 2.5) at Day 28. The incidence of severe edema on endoscopy decreased from 53.1% at baseline to 3.8% at Day 28. A similar reduction in the incidence of thick/mucousy discharge (from 28.3% to 4.8%) and severe redness (from 34.9% to 0%) was also observed. CONCLUSIONS: MP-AzeFlu provided effective, rapid control of PER as assessed by VAS in a real-world clinical setting in Ireland. Symptom improvement was observed at Day 1, sustained for 42 days, and associated with improved mucosal appearance after 28 days. These results confirm the safety of MP-AzeFlu and exceed the efficacy demonstrated in phase 3 clinical studies for controlling AR in PER patients.

Simultaneous determination of Fluticasone propionate and Azelastine hydrochloride in the presence of pharmaceutical dosage form additives.

Fluticasone propionate (FLU) and Azelastine hydrochloride (AZE) are co-formulated with phenylethyl alcohol (PEA) and Benzalkonium chloride (BENZ) (as preservatives) in pharmaceutical dosage form for treatment of seasonal allergies. Different spectrophotometric methods were used for the simultaneous determination of cited drugs in the dosage form. Direct spectrophotometric method was used for determining of AZE, while Derivative of double divisor of ratio spectra (DD-RS), Ratio subtraction coupled with ratio difference method (RS-RD) and Mean centering of the ratio spectra (MCR) are used for the determination of FLU. The linearity of the proposed methods was investigated in the range of 5.00-40.00 and 5.00-80.00µg/mL for FLU and AZE, respectively. The specificity of the developed methods was investigated by analyzing laboratory prepared mixtures containing different ratios of cited drugs in addition to PEA and their pharmaceutical dosage form. The validity of the proposed methods was assessed using the standard addition technique. The obtained results were statistically compared with those obtained by official or the reported method for FLU or AZE, respectively showing no significant difference with respect to accuracy and precision at p=0.05.

Clinical development of an advanced intranasal delivery system of azelastine hydrochloride and fluticasone propionate.

There is no shortage of pharmacologic treatments available for the management of allergic rhinitis (AR), but none regularly provide full relief from all symptoms. MP29-02 (Dymista®) is a novel intranasal formulation of azelastine hydrochloride (AZE) and fluticasone propionate (FP), benefiting from an enhanced formulation and improved device characteristics compared to marketed intranasal corticosteroid (INS) formulations. Results from large, randomized, double-blind, placebo-controlled, head-to-head trials versus first-line therapies, confirmed MP29-02 as the evidence-based drug-of-choice for AR treatment. MP29-02 was twice as effective as AZE or FP for nasal and ocular symptom relief in moderate to severe seasonal AR patients, with superiority documented regardless of season, and in more severe patients. More MP29-02-treated patients experienced clinically relevant responses (i.e., halving of nasal symptom burden and complete/near-to-complete relief) days faster than those on INS or intranasal antihistamine monotherapy. MP29-02's efficacy was sustained long-term versus FP (up to 52 weeks) in chronic rhinitis patients (perennial AR or nonallergic rhinitis), with 7 out of 10 patients first becoming symptom-free following 1 month's treatment with MP29-02, and days faster than with the INS. These results confirm MP29-02's superiority over the historical gold-standard therapy for AR (i.e., INS), and position it now as first-line treatment for moderate to severe AR patients, the majority of whom are uncontrolled on existing medications.