Indacaterol, glycopyrronium, and mometasone: Pharmacological interaction and anti-inflammatory profile in hyperresponsive airways.

LABA/ICS and LABA/LAMA/ICS combinations elicit beneficial effects in asthma. Specific evidence concerning the impact of combining indacaterol acetate (IND), glycopyrronium bromide (GLY), and mometasone furoate (MF) on human airway hyperresponsiveness (AHR) and airway inflammation is still missing. The aim of this study was to characterize the synergy of IND/MF and IND/GLY/MF combinations, both once-daily treatments for asthma, in hyperresponsive airways. Passively sensitized human medium and small airways were stimulated by histamine and treated with IND/MF (molar ratio: 100/45, 100/90) and IND/GLY/MF (molar ratio: 100/37/45, 100/37/90). The effect on contractility and airway inflammation was tested. Drug interaction was assessed by Bliss Independence equation and Unified Theory. IND/MF 100/90 elicited middle-to-very strong synergistic relaxation in medium and small airways (+≈20-30% vs. additive effect, P < 0.05), for IND/MF 100/45 the synergy was middle-to-very strong in small airways (+≈20% vs. additive effect, P < 0.05), and additive in medium bronchi (P > 0.05 vs. additive effect). IND/GLY/MF 100/37/45 and 100/37/90 induced very strong synergistic relaxation in medium and small airways (+≈30-50% vs. additive effect, P < 0.05). Synergy was related with significant (P < 0.05) reduction in IL-4, IL-5, IL-6, IL-9, IL-13, TNF-α, TSLP, NKA, SP, and non-neuronal ACh, and enhancement in cAMP. IND/MF and IND/GLY/MF combinations synergistically interact in hyperresponsive medium and small airways and modulate the levels of cytokines, neurokinins, ACh, and intracellular cAMP. The concentrations of MF in the combinations modulate the effects in the target tissue.

P-glycoprotein inhibition with verapamil overcomes mometasone resistance in Chronic Sinusitis with Nasal Polyps.

BACKGROUND: P-glycoprotein (P-gp) is a membrane efflux pump which is overexpressed in Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) and promotes Type 2 inflammation. Glucocorticoids (GC) are substrates of P-gp suggesting that overexpression may additionally contribute to GC resistance in CRSwNP. This study aims to determine whether P-gp inhibition using verapamil enhances mometasone retention and efficacy in nasal polyp explants. METHODOLOGY: IRB approved study in which organotypic polyp explants were exposed to mometasone (4.15 µg/mL) and verapa- mil (125 µg/mL) as mono and combination therapy. The effect of verapamil on mometasone tissue retention over time was deter- mined using HPLC. The effect of verapamil on mometasone anti-inflammatory function was determined using ELISA for secreted IL-5. Groups were compared using Kruskal-Wallis test. RESULTS: P-gp expression strongly and significantly inversely correlated with mometasone retention 1hr after exposure, with a ne- arly 6-fold reduction in tissue retention between the lowest and highest P-gp expressing polyp explants. P-gp inhibition reversed this effect and significantly improved mometasone retention at 1hr relative to mometasone alone. The combination of mome- tasone and verapamil significantly reduced IL-5 secretion relative to vehicle control and outperformed either treatment alone. CONCLUSIONS: Our study confirms that P-gp contributes to mometasone resistance. This P-gp mediated resistance was successfully reversed by addition of the P-gp inhibitor verapamil. Verapamil further significantly enhanced the anti-inflammatory effect of mometasone when given as a combination therapy.

Mometasone furoate sinus implant - a new targeted approach to treating recurrent nasal polyp disease.

Introduction: Chronic rhinosinusitis (CRS) is a broad heterogeneous inflammatory disorder of the nose and paranasal sinuses, resulting from the dysfunctional interplay between host immunity, defective epithelial barrier, and environmental factors. CRS with nasal polyps (CRSwNP) is considered a more severe clinical phenotype with greater burden of symptoms and higher relapse rate, especially with comorbid asthma or aspirin sensitivity. Available treatment options after endoscopic sinus surgery (ESS) - systemic corticosteroids or revision surgery - have significant risks and limitations. Areas covered: Bioabsorbable, steroid-eluting implants have been studied extensively for the ability to dilate and re-establish sinus patency by the localized, controlled delivery of topical corticosteroids to diseased sinonasal lining and nasal polyps. This review provides a comprehensive, up to date analysis of the literature regarding a novel, office-based, mometasone furoate (MF) sinus implant that may treat patients with recurrent CRSwNP after ESS. Expert commentary: Clinical evidence has demonstrated the safety and efficacy of steroid-eluting implant in the reduction of polyp size, symptom burden, and the need for revision sinus surgery. MF sinus implants may play an important role in the management of patients with recurrent polyposis after sinus surgery.

Mometasone furoate inhibits growth of acute leukemia cells in childhood by regulating PI3K signaling pathway.

OBJECTIVES: Acute lymphoblastic leukemia (ALL) is the most common cancer before the age of 15 years, seriously endangering the health of children. The main treatment for Childhood ALL was pharmacotherapy. But these drugs have many side effects and some of them could develop drug resistance quickly. Mometasone furoate (MF) is an efficient glucocorticoid for topical treatment of inflammation on the skin, lung and nose. METHODS: In this study, we investigated whether the MF had effects on ALL cells proliferation and migration. RESULTS: The CCK-8 proliferation test showed that the cell viability was the lowest at 25 nM MF treatment and the increased OD value was time-dependent. In transwell assay, the number of CCRF-CEM cells was reduced in MF treated group. We found the expression of anti-apoptotic protein bcl-2 decreased the expression of pro-apoptotic protein caspase3 and bax increased in CCRF-CEM cell line treated with MF. The expression of p-AKT, p-mTOR, p70S6 K, vascular endothelial growth factor and CyclinD1 were decreased in MF treated group. CONCLUSION: This study reveals that MF can inhibit proliferation and invasion/migration and induce apoptosis in Childhood ALL cells, which may be regulated by Phosphatidylinositol 3-kinase signaling pathway. These results suggest MF may be a potential new drug target for clinical ALL treatment.

Effectiveness of quercetin in an experimental rat model of allergic rhinitis.

We aimed to investigate whether quercetin had a therapeutic effect in an experimental rat model of allergic rhinitis. The study was conducted with 35 rats, which were randomly assigned into 4 groups: group 1 (n = 5), sham group; group 2 (quercetin group, n = 10) received 80 mg/kg day quercetin; group 3 (steroid group, n = 10) received steroid (mometasone furoate); and group 4 (control group, n = 10), received ovalbumin alone. Rats were sensitized by administration of ovalbumin on alternate days over 14 days via an intraperitoneal route. On day 15, in addition to ovalbumin via an intranasal route, quercetin and steroid were given over 7 days to the corresponding groups. All rats were then sacrificed and nasal turbinates were evaluated histopathologically, and serum total IgE and ovalbumin (OVA)-specific IgE values were measured before and after treatment. A significant increase in OVA-specific IgE values was detected in all groups except sham group. A significant increase was detected in post-treatment total IgE levels in the control group, while no significant change was detected in the sham, quercetin, and intranasal steroid groups. On histopathological evaluation, it was observed that findings of allergic rhinitis were suppressed in the quercetin group when compared to the control group. In immunohistochemical evaluation, it was detected that COX-2 and VIP expressions were weaker in the quercetin group compared to the control group. Based on these findings, we conclude that quercetin was effective in allergic rhinitis induced by ovalbumin in rats both histopathologically and serologically.

Antibiofilm effects of topical corticosteroids and intranasal saline in patients with chronic rhinosinusitis with nasal polyps depend on bacterial species and their biofilm-forming capacity.

Microbial biofilms have been implicated in the pathogenesis of chronic rhinosinusitis with nasal polyposis (CRSwNP). Intranasal application of corticosteroids and saline is a reliable option for their management. The aim of our study was to evaluate in vitro antibiofilm effects of corticosteroids and isotonic and hypertonic nasal saline in CRSwNP patients. The sinus mucosal specimens were harvested from the ethmoid cavity of 48 patients with CRSwNP and further subjected to hematoxylin-eosin staining and microbiology analysis. The biofilm-forming capacity of isolated bacterial strains was detected by microtiter-plate method and the effects of therapeutic doses of mometasone, fluticasone, isotonic and hypertonic saline on biofilm production were investigated. Bacterial strains were isolated in 42 (87.5%) patients: one organism in 34 (80.9%) and two organisms in 8 (19.1%). Staphylococcus epidermidis (34%) and Staphylococcus aureus (28%) were the most prevalent bacteria in biofilms of CRSwNP patients. Corticosteroids and saline solutions significantly reduced biofilm formation (p < 0.01 and p < 0.05, respectively) with better efficacy of fluticasone and isotonic nasal saline. Treatment with fluticasone, mometasone, isotonic and hypertonic nasal saline completely prevented biofilm production in 66, 50, 84 and 38% of bacterial strains, respectively. The most significant density reduction was observed in biofilm formed by Staphylococcus aureus, Pseudomonas aeruginosa and Streptococcus pneumoniae compared to other bacterial species (p < 0.01, p < 0.05, p < 0.05, respectively). The antibiofilm effects of corticosteroids and saline solutions also greatly depended on bacterial biomass (p < 0.05), with the most significant effect on high compared to small amount of formed biofilm. The topical steroids and nasal saline are shown to be potent antibiofilm agents in patients with CRSwNP. The effects of tested compounds depend on bacterial species and volume of formed biofilm.

Combination of mometasone furoate and oxymetazoline for the treatment of adenoid hypertrophy concomitant with allergic rhinitis: A randomized controlled trial.

In the clinic, approximately 30% of children with adenoid hypertrophy (AH) concomitant with allergic rhinitis (AR) report poor responses to intranasal steroids. To determine whether the combination of mometasone furoate (MF) and oxymetazoline (OXY) is more effective than either agent alone, we performed a two-stage, parallel, randomized, double-blind, double-dummy, clinical trial with 240 AH children with concomitant perennial AR. During the first stage, all children were randomly assigned to the MF or control group for six weeks of treatment. During the second stage, the non-responders from stage one were randomly assigned to 4 groups for 8 weeks of treatment that involved receiving the following treatments: MF/OXY, MF/placebo, placebo/OXY, or placebo/placebo. During the first stage of treatment, 39% of the responders treated with MF achieved greater reductions in total and individual symptom scores than did those on placebo. During the second stage of treatment, the nasal congestion scores of the MF/OXY group significantly decreased. The adenoid/choana ratio of the MF/OXY-treated group decreased and the nasal volume increased significantly. Our results suggest that the combination of OXY and MF is effective and safe for the treatment of AH children with concomitant AR and has a rapid onset of action.

[The use of intranasal glucocorticosteroids in the treatment of rhinosinusitis: Focus on mometasone furoate]. / Intranazal'nye glyukokortikosteroidy v terapii rinosinusita: fokus na mometazona furoat.

The authors discuss the mechanism of action, effectiveness, and safety of intranasal glucocorticosteroids (inGCS) used to treat acute, recurrent and chronic rhinosinusitis (RS). The last version of the European guidelines concerning the application of inGCS assigns the highest level of evidence-Ia and the highest strength of recommendations-A to these medications when applied for the treatment of acute and polypoid rhinosinusitis. Moreover, they acquire the status of the agents of choice for the therapy of chronic RS without polyps. Mometasone furoate is one of the best explored preparations of this group of medicines. It is possessed of favourable pharmacodynamic and pharmacokinetic properties when prescribed for local application. The new mometasone furoate preparation in the form of an intranasal spray Dezrinit produced by "Teva" Ltd. was registered in the Russian Federation. In a comparative randomized clinical trial (RCT), the preparation was shown to be an equivalent to the Nasonex spray.

[Polypous rhinosinusitis in the children].

We present an overview of the modern literature concerningpolypous rhinosinusitis (PRS) in the children. The information thus derived is compared with the available results of the clinical investigations involving the adults patients with this pathology. Allergic diseases and mucoviscidosis appear to be the pathological conditions most likely leading to the development of polyps in the nasal cavity. The patients suffering from rhinosinusitis associated with the disorders of arachidonic acid metabolismare very rarely encountered in the pediatric practice unlike those among the adult population. Intranasal glucocorticosteroids (INGCS), especially in the form of the mometasonefuroate nasal spray, are considered to be the most promising medications for the treatment of the children presenting with PRS. However, further clinical studies are needed to confirm the effectiveness and safety of this therapeutic modality.

Is the effect of topical intranasal steroids on obstructive adenoids transient or long-lasting? Case series and systematic review of literature.

OBJECTIVES: To study and review the short- and long-term effects of intranasal steroids on obstructive adenoids. METHODS: In this prospective cohort study, 19 children previously treated with mometasone furoate for 3 months were contacted at 3, 6 and 12 months after cessation of treatment. Main outcome measures included: change in severity of nasal obstruction, allergic rhinitis and obstructive symptoms. A systematic review of literature was also performed. RESULTS: By one year, 25 per cent of patients required adenoidectomy; the remaining children had no significant change in clinical score (p = 0.464), obstruction severity (p = 0.191) or allergic symptoms (p = 0.284). Fourteen pertinent studies were identified; all but one study showed improvement in the patients' symptoms and/or degree of obstruction. Two studies with follow up reaching 25 months showed positive effects. CONCLUSION: The short-term positive effect of some intranasal steroids on obstructive adenoids seems to persist in a significant number of patients after the cessation of treatment.

The glucocorticoid mometasone furoate is a novel FXR ligand that decreases inflammatory but not metabolic gene expression.

The Farnesoid X receptor (FXR) regulates bile salt, glucose and cholesterol homeostasis by binding to DNA response elements, thereby activating gene expression (direct transactivation). FXR also inhibits the immune response via tethering to NF-κB (tethering transrepression). FXR activation therefore has therapeutic potential for liver and intestinal inflammatory diseases. We aim to identify and develop gene-selective FXR modulators, which repress inflammation, but do not interfere with its metabolic capacity. In a high-throughput reporter-based screen, mometasone furoate (MF) was identified as a compound that reduced NF-κB reporter activity in an FXR-dependent manner. MF reduced mRNA expression of pro-inflammatory cytokines, and induction of direct FXR target genes in HepG2-GFP-FXR cells and intestinal organoids was minor. Computational studies disclosed three putative binding modes of the compound within the ligand binding domain of the receptor. Interestingly, mutation of W469A residue within the FXR ligand binding domain abrogated the decrease in NF-κB activity. Finally, we show that MF-bound FXR inhibits NF-κB subunit p65 recruitment to the DNA of pro-inflammatory genes CXCL2 and IL8. Although MF is not suitable as selective anti-inflammatory FXR ligand due to nanomolar affinity for the glucocorticoid receptor, we show that separation between metabolic and anti-inflammatory functions of FXR can be achieved.

Mometasone furoate-loaded cold processed oil-in-water emulsions: in vitro and in vivo studies.

Over the years, research has focused on strategies to increase benefit/risk ratio of corticoids. However, vehicles intended for topical glucocorticoids delivery with an improved benefit/risk ratio are still on demand. The aim of this work was the in vitro and in vivo characterization of cold processed oil-in-water (o/w) emulsions intended for mometasone furoate (MF) delivery to induce drug targeting to upper skin strata, decreasing adverse effects. Two o/w emulsions, containing 0.1% of MF, were developed differing in the glycol used (2-methyl-2,4-pentanediol - PT and ethoxydiglycol - TC emulsions). In vitro permeation studies revealed that these emulsions are suitable vehicles for the delivery of MF containing ingredients which are responsible for a drastically increased on the permeability coefficients of MF from a theoretical value of 1.18 × 10(-4 )cm/h to 5.20 × 10(-4) ± 2.05 × 10(-4 )cm/h and 6.30 × 10(-4) ± 2.94 × 10(-4 )cm/h, for PT and TC, respectively. The tape stripping results showed that the amount of drug that reached the viable skin layers was very low (1.99 %) and the amount that remained in the stratum corneum (SC) was 10.61%. The in vivo studies showed that the developed formulations decreased the edema and erythema in mice skin in more that 90%, assuring, at least, the same anti-inflammatory effect compared with the commercial cream. PT placebo demonstrated to contribute to restore the skin barrier by increasing the amount of lipids within the human skin.

3M Cavilon No-Sting Barrier Film or topical corticosteroid (mometasone furoate) for protection against radiation dermatitis: A clinical trial.

BACKGROUND/PURPOSE: Evidence on the prevention of radiation dermatitis is lacking. The aim of this study was to investigate the effect of 3M Cavilon No Sting Barrier Film and topical corticosteroids on irradiated skin. METHODS: Thirty-nine postoperative breast cancer patients were randomized into three groups for intraindividual comparison (skin to be irradiated was divided into 2 parts): (1) 3M No Sting Barrier Film versus no treatment; (2) corticosteroid versus no treatment; and (3) corticosteroid versus 3M No Sting Barrier Film. The primary end points monitored were the time to first occurrence of grade 1 pruritus, pain score of 3 and grade 2 radiation dermatitis. The secondary end points studied were the incidence of grade 3 radiation dermatitis and total pain scores. Data analysis was done using the SPSS software version 10. RESULTS: Skin given the 3M barrier film experienced a later occurrence of pruritus compared to both corticosteroids and untreated, although this was statistically insignificant. Corticosteroids delayed the time to occurrence of grade 2 dermatitis compared to both untreated skin and 3M barrier film, (mean day of onset = corticosteroid: 52 vs. untreated: 43, p = 0.092; corticosteroid: 53.4 vs. 3M barrier film: 44.5, p = 0.002, t test). Skin given corticosteroids had the lowest incidence of grade 3 dermatitis among all three conditions, although the differences were statistically insignificant. No statistically significant differences were noted in total pain scores. CONCLUSION: The 3M barrier film may be helpful against dermatitis associated pruritus. Corticosteroids may delay the time of onset of severe skin reactions and also reduce the incidence of severe radiation dermatitis.