mometasone-furoate and Inflammation

Exhaled nitric oxide (F(ENO)) and exhaled breath condensate (EBC) are noninvasive markers that directly measure airway inflammation and may potentially be useful in assessing asthma control and response to therapy.. To examine the time-dependent effects of inhaled corticosteroids on F(ENO) and EBC markers concomitantly with lung function and bronchial hyperresponsiveness.. Eleven steroid-naive adults with mild-to-moderate persistent asthma were treated with mometasone furoate dry powder inhaler, 400 microg/d, for 8 weeks, followed by a 4-week washout. Forced expiratory volume in 1 second (FEV1), the concentration of methacholine calculated to cause a 20% decline in FEV1 (PC20), F(ENO), EBC pH, and EBC nitrite measurements before, during, and after treatment were analyzed and compared.. The mean (SEM) FEV1 increased from 3.01 (0.13) L (82% predicted) to 3.24 (0.18) L (87% predicted) by week 8 (P < .05). The PC20 level increased from 1.28 (0.31) mg/mL to 2.99 (0.51) mg/mL by treatment week 8 (P < .05) and remained relatively stable through washout week 4 (P < .05). The F(ENO) level decreased from 31.1 (4.1) ppb to 20.6 (4.5) ppb by treatment week 1 (P < .01), remained low through treatment week 8 (P < .01), then trended back to the baseline level by washout week 1 (P < .01). The median EBC pH increased from 7.81 (interquartile range, 7.49-8.09) to 8.02 (interquartile range, 7.87-8.12) by treatment week 4, but did not achieve statistical significance. The EBC nitrite level decreased from 17.6 (1.6) microM to 9.3 (0.9) microM by treatment week 8 (P < .01), and remained low throughout washout week 4 (P < .05). There was a negative correlation between F(ENO) and PC20 (Spearman rank correlation coefficient = -0.50, P < .001).. The F(ENO) level responded the earliest to treatment and withdrawal of inhaled corticosteroids, whereas changes in EBC markers were delayed but more sustained.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adult; Anti-Allergic Agents; Anti-Inflammatory Agents; Asthma; Breath Tests; Bronchial Hyperreactivity; Bronchial Provocation Tests; Female; Forced Expiratory Volume; Humans; Hydrogen-Ion Concentration; Inflammation; Lung; Male; Methacholine Chloride; Middle Aged; Mometasone Furoate; Nitrates; Nitric Oxide; Pregnadienediols; Young Adult

Comparisons of the potency of different inhaled corticosteroids, delivery devices, and treatment regimens in the management of asthma can only be made when outcome measurements display a dose-dependent effect. These outcomes have been difficult to identify. In this study, we compared in a randomized, double-blind, crossover design, the effects of 6 d treatment with placebo and three doses (50, 100, and 400 microg, twice daily) of mometasone furoate delivered by dry powder inhaler (MF-DPI) on responses after allergen inhalation challenge. Twelve mild asthmatic subjects with dual responses after allergen inhalation were studied. Outcome measurements included early and late asthmatic responses, the change in methacholine airway responsiveness 24 h after challenge, and sputum eosinophilia measured 7 and 24 h after challenge. All three doses of MF-DPI demonstrated similar attenuation of early responses and allergen-induced airway hyperresponsiveness relative to placebo (p < 0.05). The late maximal %fall in FEV(1) after placebo treatment was 23.5% and was significantly reduced in a dose-dependent manner to 12.3%, 11.0%, and 5.9% for the 50-, 100-, and 400-microg twice-daily treatments (p = 0.007). The allergen-induced increase in sputum eosinophilia (x10(4) cells/ml) 24 h after challenge during placebo treatment was 60.2 and was significantly reduced to 24.0, 15.3, and 6.2 for the 50-, 100-, and 400-microg twice-daily treatments. MF-DPI is effective at attenuating allergen-induced early and late responses, airway hyperresponsiveness, and sputum eosinophilia, and dose-response effects exist for the attenuation of the late response.

Topics: Administration, Inhalation; Adolescent; Adult; Airway Resistance; Allergens; Anti-Inflammatory Agents; Asthma; Bronchoconstrictor Agents; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Eosinophils; Female; Forced Expiratory Volume; Humans; Inflammation; Male; Methacholine Chloride; Middle Aged; Mometasone Furoate; Pregnadienediols; Severity of Illness Index; Sputum; Time Factors; Treatment Outcome

Intranasal delivery is the most preferred route of drug administration for treatment of a range of nasal conditions including chronic rhinosinusitis (CRS), caused by an infection and inflammation of the nasal mucosa. However, localised delivery of lipophilic drugs for persistent nasal inflammation is a challenge especially with traditional topical nasal sprays. In this study, a composite thermoresponsive hydrogel is developed and tuned to obtain desired rheological and physiochemical properties suitable for intranasal administration of lipophilic drugs. The composite is comprised of drug-loaded porous silicon (pSi) particles embedded in a poloxamer 407 (P407) hydrogel matrix. Mometasone Furoate (MF), a lipophilic corticosteroid (log P of 4.11), is used as the drug, which is loaded onto pSi particles at a loading capacity of 28 wt%. The MF-loaded pSi particles (MF@pSi) are incorporated into the P407-based thermoresponsive hydrogel (HG) matrix to form the composite hydrogel (MF@pSi-HG) with a final drug content ranging between 0.1 wt% to 0.5 wt%. Rheomechanical studies indicate that the MF@pSi component exerts a minimal impact on gelation temperature or strength of the hydrogel host. The in-vitro release of the MF payload from MF@pSi-HG shows a pronounced increase in the amount of drug released over 8 h (4.5 to 21-fold) in comparison to controls consisting of pure MF incorporated in hydrogel (MF@HG), indicating an improvement in kinetic solubility of MF upon loading into pSi. Ex-vivo toxicity studies conducted on human nasal mucosal tissue show no adverse effect from exposure to either pure HG or the MF@pSi-HG formulation, even at the highest drug content of 0.5 wt%. Experiments on human nasal mucosal tissue show the MF@pSi-HG formulation deposits a quantity of MF into the tissues within 8 h that is >19 times greater than the MF@HG control (194 ± 7 μg of MF/g of tissue vs. <10 μg of MF/g of tissue, respectively).

Topics: Administration, Intranasal; Humans; Hydrogels; Inflammation; Mometasone Furoate; Porosity; Silicon

Seasonal allergic rhinitis (SAR) is a common disease of childhood and is characterized by type 2 inflammation, bothersome symptoms, and impaired quality of life (QoL). Intranasal corticosteroids are effective medications in managing SAR. In addition, mometasone furoate nasal spray (MFNS) is a well-known therapeutic option. However, the literature provided no data about the effects of MFNS in European children with SAR. Thus, this study addressed this unmet requirement.. MFNS was compared to isotonic saline. Both treatments were prescribed: one drop of spray per nostril, twice a day, for 3 weeks. Nasal cytology, total symptom score (TSS), visual analogic scale concerning the parental perception of severity of symptoms, and the Pediatric Rhinoconjunctivitis Quality of Life Questionnaire (PRQLQ) were assessed at baseline, after 7 and 21 days, and 1 month after discontinuation.. MFNS significantly reduced eosinophil and mast cell counts, improved QoL, and relieved symptoms, as assessed by doctors and perceived by parents. These effects persisted over time, even after discontinuation. Both treatments were safe and well-tolerated.. The present study documented that a 3-week MFNS treatment was able to significantly dampen type 2 inflammation, improve QoL, and reduce severity of symptoms in Italian children with SAR, and was safe.

Topics: Child; Double-Blind Method; Humans; Inflammation; Mometasone Furoate; Nasal Obstruction; Nasal Sprays; Pregnadienediols; Quality of Life; Rhinitis, Allergic, Seasonal

Lichen sclerosus (LS) is a disease of the skin of unclear etiology that can occur in the foreskin. Topical therapy with corticosteroids is recommended, but they can have side effects.. We aimed to compare the effects of ozonides with vitamin E acetate (OZOILE) versus topical corticosteroid in children undergoing circumcision.. Twenty children undergoing circumcision were treated before surgery: 10 children with OZOILE cream and 10 with 0.1% mometasone furoate once a day for 7 days. Ten age-matched patients with LS of the foreskin without any treatment were recruited as controls. Transcript levels of proinflammatory and anti-inflammatory cytokines and e-cadherin were evaluated in removed foreskins by qRT-PCR.. OZOILE and steroid topical treatment produced a similar reduction of TNF-α and IL-1β mRNA levels in foreskins from patients with LS when compared to untreated patients (p < 0.001). OZOILE and steroid treatment caused an increase in the transcript levels of IL-13 and e-cadherin in the foreskin of patients affected by LS in comparison to untreated foreskin (p < 0.001).. On the basis of our biochemical data, a randomized clinical trial might be useful to verify the actual clinical effect of OZOILE as alternative treatment to corticosteroids in children affected by LS of the foreskin.

Topics: Administration, Topical; Adolescent; Adrenal Cortex Hormones; Anti-Inflammatory Agents; Child; Child, Preschool; Foreskin; Genital Diseases, Male; Humans; Inflammation; Lichen Sclerosus et Atrophicus; Male; Mometasone Furoate; Olive Oil; Ozone; Retrospective Studies; Vitamin E

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.

Topics: Administration, Cutaneous; Adolescent; Adult; Animals; Anti-Inflammatory Agents; Disease Models, Animal; Drug Delivery Systems; Emulsions; Female; Humans; Inflammation; Mice; Middle Aged; Mometasone Furoate; Permeability; Skin; Skin Absorption; Young Adult

Traumatic spinal cord injury (SCI) represents one of the most disabling injuries of the human body causing temporary or permanent sensory and/or motor system deficit, particularly hind limb locomotor function impairment. At present, steroidal inflammatory drugs, in particular methylprednisolone sodium succinate (MPSS) are the first line choice treatment of acute SCI. Despite progress in pharmacological, surgical and rehabilitative treatment approaches, SCI still remains a very complex medical and psychological challenge, with no curative therapy available. The aim of the present study was to compare the efficacy of MPSS in respect to other GCs such as dexamethasone (Dex) and mometasone furoate (MF) in an in vitro suitable model of LPS-induced inflammation in J774 cells as well as in an in vivo experimental mouse SCI (compression model). In both the in vitro and in vivo experiments, MF resulted surprisingly more potent than Dex and MPSS. In detail, mice sacrificed seven days after induction of SCI trauma resulted not only in tissue damage, cellular infiltration, fibrosis, astrocyte activation, iNOS expression, extracellular signal regulated kinase 1/2 phosphorylation in injured tissue, poly (ADP-ribose) polymerase 1 (PARP-1) activation but also apoptosis (Bax and Bcl-2 expression). All three GCs demonstrated the ability to modulate inflammatory, oxidative as well as apoptotic pathways, but MF demonstrated the best efficacy, while Dex and MPSS showed alternative potency with a different degree of protection. Therefore, we can conclude that MF is the best candidate for post-traumatic chronic treatment, since it ameliorates different molecular pathways involved in the damage's propagation to the surrounding areas of the injured spinal cord.

Topics: Animals; Apoptosis; Cell Line; Dexamethasone; Disease Models, Animal; Glucocorticoids; Inflammation; Male; MAP Kinase Signaling System; Methylprednisolone Hemisuccinate; Mice; Mometasone Furoate; Nitric Oxide Synthase Type II; Poly(ADP-ribose) Polymerases; Spinal Cord; Spinal Cord Injuries

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.

Topics: Animals; Anti-Inflammatory Agents; Gene Expression; Gene Expression Regulation; Genes, Reporter; Hep G2 Cells; Humans; Inflammation; Ligands; Mice; Models, Molecular; Molecular Conformation; Molecular Docking Simulation; Mometasone Furoate; NF-kappa B; Promoter Regions, Genetic; Protein Binding; Receptors, Cytoplasmic and Nuclear; Transcription Factor RelA; Tumor Necrosis Factor-alpha

We aimed to evaluate nasal mucosal changes and efficiency of nasal steroids and diclofenac on nasal mucosa during hyperbaric oxygen (HBO) treatment. Forty adult Albino-Wistar rats were randomized into four groups. Group 1 (control group) (n = 10) not exposed to hyperbaric or enhanced oxygen concentrations; group 2 (HBO group) (n = 10) underwent only HBO treatment; group 3 (n = 10) received HBO and intranasal mometasone furoate (10 μl/day); group 4 (n = 10) treated with HBO and diclofenac sodium (10 mg/kg/day ip). Specimens of nasal mucosa were collected after sacrificing and dissection of animals. The specimens were processed for light microscopic evaluation, and then evaluated histopathologically for fibroblastic proliferation and inflammation. Regarding the scores of inflammation, the level of inflammation in the control group was significantly less severe than the other groups (p < 0.05). Evaluation of the fibrosis scores showed that the scores of both groups 2 and 4 were significantly increased (p < 0.05). There were no statistically significant differences between groups 2, 3, and 4 as for fibrosis and inflammation (p > 0.05). Chronic HBO treatment induced mild inflammation of the nasal mucosa. These effects cannot be prevented adequately by administration of nasal steroids and diclofenac.

Topics: Administration, Intranasal; Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Diclofenac; Double-Blind Method; Fibrosis; Hyperbaric Oxygenation; Inflammation; Male; Mometasone Furoate; Nasal Mucosa; Pregnadienediols; Random Allocation; Rats, Wistar

This protocol describes microsphere-based protease assays for use in flow cytometry and high-throughput screening. This platform measures a loss of fluorescence from the surface of a microsphere due to the cleavage of an attached fluorescent protease substrate by a suitable protease enzyme. The assay format can be adapted to any site or protein-specific protease of interest and results can be measured in both real time and as endpoint fluorescence assays on a flow cytometer. Endpoint assays are easily adapted to microplate format for flow cytometry high-throughput analysis and inhibitor screening.

Topics: Animals; Biotinylation; Flow Cytometry; Fluorescence Resonance Energy Transfer; Green Fluorescent Proteins; High-Throughput Screening Assays; Humans; Inflammation; Kinetics; Microspheres; Peptide Hydrolases; Peptides; Reproducibility of Results; Temperature

Exhaled nitric oxide (NO) measurement at multiple exhalation flow rates allows calculation of flow-independent NO parameters: alveolar NO concentration, bronchial NO flux, bronchial diffusing capacity of NO and bronchial wall NO concentration.. In the present study, we measured the flow-independent NO parameters and inflammatory markers in exhaled breath condensate (EBC) and in serum in 14 patients with seasonal allergic rhinitis (AR) without asthma, and in 14 age- and sex-matched healthy volunteers.. At symptomatic stage before the treatment, patients with AR had higher bronchial wall diffusing capacity of NO than healthy volunteers (p = 0.024), but there were no differences in bronchial wall NO concentration or alveolar NO concentration. Patients with AR had also increased 8-isoprostane levels in the EBC (p = 0.040), and increased serum levels of IgE (p = 0.002) and eosinophil cationic protein (ECP; p = 0.027). Two-week treatment with nasal glucocorticoid mometasone decreased symptom scores and serum ECP levels but had no effect on NO parameters or 8-isoprostane levels in EBC.. Noninvasive markers of airway inflammation showed subclinical lower airway inflammation in patients with AR without asthma, but short-term treatment with nasal glucocorticoids did not affect most of the markers of lower airway inflammation.

Topics: Adult; Biomarkers; Breath Tests; Bronchi; Dinoprost; Eosinophil Cationic Protein; Female; Glucocorticoids; Humans; Inflammation; Male; Mometasone Furoate; Nitric Oxide; Pregnadienediols; Respiratory Function Tests; Rhinitis, Allergic, Perennial; Young Adult

The permeabilities of normal human and normal, inflamed, or corticosteroid (CS) pretreated skin of young domestic pigs for pimecrolimus and tacrolimus were compared in vitro, using Franz-type diffusion cells. The test articles were either used as 1.0% solutions or as the marketed formulations (Elidel 1% cream, Protopic 0.1%, and 0.03% ointment). In normal human skin, the permeation rate of pimecrolimus from the 1% cream was about sixfold lower than that of tacrolimus from 0.1% ointment and by a factor of 4.3 lower compared with tacrolimus from Protopic 0.03%. In pigs, sodium laurylsulfate-induced irritant contact dermatitis resulted in significantly faster skin permeation of both drugs from applied solutions. The permeation rate for pimecrolimus was lower than that for tacrolimus. Thus, at 24 h, pimecrolimus concentrations in the receptor fluid were 2.8-fold lower than the tacrolimus levels. Compared with normal porcine skin, permeation of drugs through hydrocortisone (1.0%)-, mometasone (0.1%)-, or clobetasol-17-butyrate (0.05%)-pretreated skin was increased by factors of 3.6 (pimecrolimus, applied as 1% cream) and 1.7 (tacrolimus, applied as 0.1% ointment). In normal pig skin, the permeation rate of tacrolimus was found to be 11.2 times higher than that of pimecrolimus and 3.5- to 7.1-fold higher in CS-pretreated skin, independent of the potency of the CSs. The present in vitro data suggest that in patients with acute skin inflammation or after therapy with topical CSs, percutaneous absorption and, as a consequence, systemic drug exposure will be lower with Elidel 1% cream as compared with Protopic 0.1% and 0.03% ointment.

Topics: Adrenal Cortex Hormones; Animals; Anti-Inflammatory Agents, Non-Steroidal; Clobetasol; Dermatologic Agents; Disease Models, Animal; Humans; Hydrocortisone; Inflammation; Models, Animal; Mometasone Furoate; Pregnadienediols; Skin; Skin Physiological Phenomena; Swine; Tacrolimus

Topics: Acute Disease; Administration, Inhalation; Aerosols; Anti-Allergic Agents; Anti-Bacterial Agents; Anti-Inflammatory Agents; Drug Therapy, Combination; Humans; Inflammation; Mometasone Furoate; Pregnadienediols; Recurrence; Severity of Illness Index; Sinusitis; Treatment Outcome