(9R)-9-chloro-11-17-dihydroxy-17-(2-hydroxy-1-oxoethyl)-10-13-16-trimethyl-6-7-8-11-12-14-15-16-octahydrocyclopenta[a]phenanthren-3-one and Disease-Models--Animal

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adult; Animals; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Anti-Idiotypic; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Asthma; Beclomethasone; Biological Therapy; Child; Controlled Clinical Trials as Topic; Disease Models, Animal; Eosinophilia; Etanercept; Forecasting; Glucocorticoids; Haplorhini; Humans; Hypereosinophilic Syndrome; Immunoglobulin E; Immunoglobulin G; Immunosuppressive Agents; Interleukin-5; Omalizumab; Receptors, Tumor Necrosis Factor; Time Factors; Tumor Necrosis Factor-alpha

Asthma is a chronic lung disease that injures and constricts the airways. This study evaluates the effects of agmatine on ovalbumin (OVA)-induced allergic inflammation of the airways.. OVA sensitization by intraperitoneal injection was used to induce airway inflammation in mice on days 0 and 7; then the mice were challenged using beclomethasone (150 µg/kg, inhalation), a standard anti-asthmatic drug, from day 14 to day 16. Furthermore, agmatine (200 mg/kg) was intraperitoneally injected on day 0 and then daily for 16 days, followed by OVA challenge. The lung weight ratio, total and differential cell counts, TNF-α, interleukin-5 (IL-5) and IL-13 in bronchoalveolar lavage fluid (BALF), lung nitrite/nitrate (NO), and oxidative parameters were determined. Moreover, histopathological and immunohistochemical staining was employed.. Injection of agmatine (200 mg/kg) for 16 days significantly attenuated inflammation of the airways. The levels of BALF inflammatory cells, TNF-α, IL-5, IL-13, lung NO, and malondialdehyde (MDA), significantly decreased with concomitant elevation of superoxide dismutase (SOD) levels. Histological and immunohistochemical analyses of mast cells paralleled to biochemical improvements.. Finally, this study illustrated that agmatine attenuates the allergic inflammation of airways caused by OVA by mitigating cytokines release, NO expression, and oxidative stress.

Topics: Agmatine; Animals; Anti-Asthmatic Agents; Beclomethasone; Cytokines; Disease Models, Animal; Inflammation; Interleukin-13; Interleukin-5; Lung; Malondialdehyde; Mice; Mice, Inbred BALB C; Nitrates; Nitrites; Ovalbumin; Superoxide Dismutase; Tumor Necrosis Factor-alpha

The current study is concerned with the development and characterization of mixed micelles intended for the dermal delivery of beclomethasone dipropionate, which is a topical corticosteroid used in the management of atopic dermatitis. Mixed micelles were prepared using thin-film hydration technique, employing different concentrations of pluronic L121 with either poloxamer P84 or pluronic F127 with different surfactant mixture-to-drug ratios. The prepared formulae were characterized concerning entrapment efficiency, particle size, and zeta potential. Two formulae were chosen for ex vivo skin deposition studies: one formulated using pluronic L121/poloxamer P84 mixture while the other using pluronic L121/pluronic F127 mixture. The optimum formula with the highest dermal deposition was subjected to morphological examination and was formulated as hydroxypropyl methylcellulose hydrogel. The hydrogel was evaluated regarding viscosity and was subjected to ex vivo deposition study in comparison with the commercially available cream Beclozone®. In vivo histopathological study was conducted for both the hydrogel and Beclozone® in order to evaluate their healing efficiency. In vivo histopathological study results showed that the prepared hydrogel successfully treated sub-chronic dermatitis in an animal model within a shorter period of time compared to Beclozone®, resulting in better patient compliance and fewer side effects.

Topics: Animals; Animals, Newborn; Anti-Inflammatory Agents; Beclomethasone; Biocompatible Materials; Dermatitis; Disease Models, Animal; Drug Carriers; Drug Evaluation, Preclinical; Hydrogels; Male; Mice; Micelles; Particle Size; Rats; Rats, Wistar; Skin Absorption; Surface-Active Agents

The current investigation was taken to scrutinize the action of tranilast on the airway remodeling in chronic asthma in mice.. Intraperitoneal injection of ovalbumin was applied to mice for sensitization and subsequent inhalation of 1% ovalbumin three times week for 10 weeks for challenge. Beclomethasone or tranilast were given daily for the 10 week challenge period. At the end of the study, lung weight index, total collagen content, bronchoalveolar lavage level of total and differential cell counts, interleukin-13, in addition to lung tissue nitrate/nitrite and transforming growth beta-1 were measured. Also, histological analysis was done.. Asthmatic mice demonstrated apparent fibrotic changes. Significant airway fibrosis was demonstrated by hyperplasia of goblet cells and thickening of airway epithelium, increased content of lung collagen, lung and bronchoalveolar lavage of transforming growth factor beta-1 and interleukin-13 mutually accompanied by reduction in nitrate/nitrite generation.. Beclomethasone influence on airway remodeling was mediated mainly via suppression of eosinophilic recruitment into the airways and reduction of interleukin-13 cytokine levels. Whereas, tranilast effects on airway remodeling was found to be mainly mediated via its inhibitory effect on transforming growth beta-1. Both beclomethasone and tranilast influence airway remodeling by different degrees and mechanisms.

Topics: Airway Remodeling; Animals; Anti-Allergic Agents; Anti-Asthmatic Agents; Asthma; Beclomethasone; Bronchoalveolar Lavage Fluid; Chronic Disease; Collagen; Disease Models, Animal; Drug Evaluation, Preclinical; Interleukin-13; Leukocyte Count; Lung; Male; Mice; Nitric Oxide; ortho-Aminobenzoates; Transforming Growth Factor beta1

To evaluate the acute effects of insulin on airway reactivity and the protective effects of beclomethasone and ipratropium against insulin-induced airway hyperresponsiveness on isolated tracheal smooth muscle in a guinea pig model.. The trachea of each guinea pig was excised; one end of the tracheal strip was attached to the hook of the oxygen tube of a tissue bath and the other end was connected to a research-grade isometric force displacement transducer. The effects of varying concentrations of insulin (10(-7) to 10(-3)M) and insulin pretreated with a fixed concentration of beclomethasone (10(-6)M) and ipratropium (10(-6)M) on the isolated tracheal tissue were studied by constructing cumulative concentration-response curves. Changes in tracheal smooth muscle contractions were recorded on a 4-channel oscillograph.. The means ± standard error of the mean of the maximum amplitude of contraction with increasing concentrations of insulin and of insulin pretreated with fixed concentrations of beclomethasone and ipratropium were 35 ± 1.13, 22 ± 1.15 and 27.8 ± 1.27 mm, respectively.. The data showed that beclomethasone inhibited the contractile response of insulin to a greater extent than ipratropium. Thus we suggest that inhalational insulin pretreated with beclomethasone may be more efficacious than with ipratropium for the amelioration of potential respiratory adverse effects such as bronchoconstriction.

Topics: Animals; Anti-Asthmatic Agents; Beclomethasone; Bronchodilator Agents; Disease Models, Animal; Guinea Pigs; Insulin; Ipratropium; Muscle Contraction; Muscle, Smooth; Random Allocation; Trachea; Tracheal Diseases

This study examined the effect of montelukast and beclomethasone on airway remodeling in murine model of asthma. Mice were sensitized by i.p. injection of ovalbumin (OVA) on days 0 and 14, and then challenged by nebulization of 1% OVA 3 days/week for 6 or 10 weeks. Results of 6-week OVA-challenged group showed moderate inflammation, but the 10-week OVA-challenged group exhibited mild inflammation. The OVA challenge (6 and 10 weeks) exhibited marked airway fibrosis, illustrated by significant increase in goblet cell hyperplasia and epithelial thickness, increased lung content of collagen and transforming growth factor-β(1), together with a decrease in nitric oxide production; also, there was an increase in bronchoalveolar lavage fluid level of interleukin-13. Administration of montelukast or beclomethasone before each OVA challenge was capable of restoring most of the measured parameters to near normal levels. Inhalation of beclomethasone has a similar role in airway remodeling as montelukast, but its effects in regulating inflammatory changes is less pronounced than montelukast.

Topics: Acetates; Administration, Inhalation; Airway Remodeling; Animals; Anti-Asthmatic Agents; Asthma; Beclomethasone; Cyclopropanes; Disease Models, Animal; Inflammation; Male; Mice; Ovalbumin; Quinolines; Severity of Illness Index; Sulfides; Time Factors

Inhibition of VEGF signalling effectively suppresses localized tumour growth but accelerates tumour invasiveness and micrometastasis by unknown mechanisms. To study the dynamic and reciprocal interactions between tumour cells and their microenvironment during these processes, we established a xenograft model by injecting tumour cells into the blood circulation of transparent zebrafish embryos. This reproducibly results in rapid simultaneous formation of a localized tumour and experimental micrometastasis, allowing time-resolved imaging of both processes at single-cell resolution within 1 week. The tumour vasculature was initiated de novo by remodelling of primitive endothelial cells into a functional network. Roles of myeloid cells in critical tumourigenesis steps such as vascularization and invasion were revealed by genetic and pharmaceutical approaches. We discovered that the physiological migration of neutrophils controlled tumour invasion by conditioning the collagen matrix and forming the metastatic niche, as detected by two-photon confocal microscopy and second harmonic generation. Administration of VEGFR inhibitors blocked tumour vascularization and a localized tumour growth but enhanced migration of neutrophils, which in turn promoted tumour invasion and formation of micrometastasis. This demonstrates the in vivo cooperation between VEGF signalling and myeloid cells in metastasis and provides a new mechanism underlying the recent findings that VEGFR targeting can promote tumour invasiveness.

Topics: Animals; Beclomethasone; Breast Neoplasms; Cell Movement; Cell Transformation, Neoplastic; Disease Models, Animal; Endothelial Cells; Humans; Indoles; Mice; Myeloid Cells; Neoplasm Metastasis; Neutrophils; Pyrroles; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Sunitinib; Xenograft Model Antitumor Assays; Zebrafish

Natural surfactant combined with beclomethasone decreases pulmonary oxidative stress in preterm lambs with respiratory distress syndrome (RDS).. To test the hypothesis that this occurs through a decrease in pulmonary inflammation.. Preterm lambs received 200 mg/kg of natural surfactant or 200 mg/kg of natural surfactant combined with 400 or 800 μg/kg of beclomethasone. Interleukin 8 (IL-8) and macrophage migration inhibitory factor (MIF) were assayed in bronchial aspirate samples and lung mechanics were evaluated.. IL-8 increased in all the groups, but the increase was lower in the groups treated with surfactant plus 400 and 800 μg/kg of beclomethasone. MIF decreased in the surfactant group, did not vary in the surfactant plus 400 μg/kg beclomethasone group, and decreased in the surfactant plus 800 μg/kg beclomethasone group. MIF concentration was higher in the surfactant plus 800 μg/kg beclomethasone group than in the other groups.. Natural surfactant combined with beclomethasone at 800 μg/kg is effective in reducing lung inflammation in an animal model of RDS, thus explaining the associated decrease in lung oxidative stress. The increase in MIF in animals treated with surfactant plus 800 μg/kg of beclomethasone might be an important maturative and protective factor for neonatal lungs.

Topics: Animals; Animals, Newborn; Anti-Inflammatory Agents; Beclomethasone; Disease Models, Animal; Female; Humans; Infant, Newborn; Interleukin-8; Macrophage Migration-Inhibitory Factors; Oxidative Stress; Pneumonia; Pregnancy; Pulmonary Surfactants; Respiratory Distress Syndrome, Newborn; Sheep

Mometasone furoate (MF) is a topical glucocorticoid used for atopic dermatitis, allergic rhinitis, and bronchial asthma. To elucidate the usefulness of MF, the dissociation between local anti-inflammatory effects and systemic effects of MF was compared with that of beclomethasone 17,21-dipropionate (BDP). MF was more potent than BDP in croton oil-induced ear edema tests in mice. Oral systemic effects of MF were inversely lower than that of BDP on thymolysis, plasma corticosterone lowering, and suppression of body weight gain in mice. These results indicate that MF has a higher therapeutic index and superior clinical usefulness as a topical glucocorticoid compared to BDP.

Topics: Administration, Oral; Administration, Topical; Animals; Anti-Inflammatory Agents; Beclomethasone; Corticosterone; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Male; Mice; Mice, Inbred ICR; Mometasone Furoate; Pituitary-Adrenal System; Pregnadienediols; Thymus Gland; Weight Gain

We performed a randomized study in preterm lambs to assess the hypothesis that the treatment with natural surfactant combined with beclomethasone might decrease pulmonary oxidative stress in an animal model of respiratory distress syndrome (RDS). Animals received 200 mg/kg of porcine natural surfactant or 200 mg/kg of natural surfactant combined with 400 or 800 microg/kg of beclomethasone. Lung tissue oxidation was studied by measuring total hydroperoxide (TH), advanced oxidation protein products (AOPP), and non-protein bound iron (NPBI) in bronchial aspirate samples. In addition, lung mechanics was evaluated. TH was lower in the groups treated with surfactant plus 400 or 800 microg/kg of beclomethasone than in the surfactant group; AOPP was lower in the group treated with surfactant plus 800 microg/kg of beclomethasone than in the other groups; NPBI was similar in all groups. Surfactant treatment was followed by a sustained improvement of tidal volume (TV) and airway resistance, while dynamic compliance did not vary. However, the mean airway pressure needed to obtain similar values of TV was lower in the group treated with surfactant plus 800 microg/kg of beclomethasone than in other groups. We concluded that natural surfactant combined with beclomethasone at 800 microg/kg is effective in reducing the oxidative lung stress and improving the respiratory function in an animal model of RDS.

Topics: Animals; Beclomethasone; Disease Models, Animal; Drug Therapy, Combination; Glucocorticoids; Humans; Infant, Newborn; Oxidative Stress; Pulmonary Surfactants; Respiratory Distress Syndrome, Newborn; Sheep; Treatment Outcome

The best delivery of a drug in ventilated neonates is obtained when using a small particle diameter solution administered via a spacer. Lung deposition of hydrofluoroalkane beclomethasone dipropionate (QVAR, 1.3 microm particles), delivered via an Aerochamber-MV15, was measured in piglets under conditions mimicking ventilated severely ill neonates (uncuffed 2.5 mm endotracheal tube; peak pressure 16 cm H2O; respiratory rate 40/min). After determining the mass and particle size distribution of the 99mTc-labeled and unlabeled drug, three lung deposition studies were performed: after 1 h of ventilation (controls, n = 18), after 48 h aggressive ventilation inducing an acute lung injury (nine piglets out of the controls), and after increasing the pressure to 24 cm H2O during drug delivery (five piglets out of the nine with acute lung injury). All piglets were then killed for lung histology. Results (median, range), expressed as a percentage of the delivered dose, were compared using an inferential or the Friedman test. While lung deposition was low, it was greater (p = 0.003) in controls (2.66%, 0.50-7.70) than in piglets with histologically confirmed acute lung injury (0.26%, 0.06-1.28) or under a high-pressure ventilation (1.01%, 0.30-2.15). Lung deposition of QVAR in an animal model of ventilated neonates is low, variable, and dramatically affected by lung injury.

Topics: Aerosol Propellants; Animals; Animals, Newborn; Beclomethasone; Bronchopulmonary Dysplasia; Disease Models, Animal; Glucocorticoids; Humans; Hydrocarbons, Fluorinated; Infant, Newborn; Lung; Male; Swine

These studies were designed to assess the pharmacodynamic interaction between formoterol and beclomethasone dipropionate (BDP) in controlling the bronchoconstriction and inflammatory response induced by various challenges in guinea-pigs and rats. In anaesthetised guinea-pigs, superfusion of the formoterol/BDP combination into the tracheal lumen had significantly more effect than the single components in antagonising the bronchoconstricting and inflammatory responses to acetylcholine or ovalbumin in a standard model of airway hyper-responsiveness. After ovalbumin challenge, the combination completely protected animals from death at doses lower than those effective when given separately. The combination, at doses ineffective individually, even counteracted the development of lung oedema induced by sephadex in the rat. Finally, in tracheal strips from ovalbumin-sensitised guinea-pigs pre-treatment with BDP (30 mg kg(-1) i.m.) completely reversed the rightward shift of the formoterol dose-response curve due to beta(2)-receptor desensitisation. In conclusion, these results indicate that formoterol and BDP together induce a favourable pharmacodynamic interaction which can be considered more than additive, at least in these experimental settings.

Topics: Acetylcholine; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Albuterol; Animals; Anti-Inflammatory Agents; Beclomethasone; Bronchial Hyperreactivity; Bronchoconstriction; Bronchodilator Agents; Dextrans; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Combinations; Drug Synergism; Ethanolamines; Formoterol Fumarate; Guinea Pigs; Inflammation; Male; Ovalbumin; Pulmonary Edema; Rats; Receptors, Adrenergic, beta-2; Trachea

We established a novel murine model of pharyngeal candidiasis maintaining stable yeast population and local symptoms characteristic of pharyngeal thrush. The persistent Candida-infection was prolonged by inhalation of beclomethasone dipropionate corticosteroid. The severity of infection lesions was evaluated by determining viable cell number of Candia albicans and scores representing symptomatic curd-like white patch on pharyngeal tissue. The utility of this model was shown by the disappearance of lesions and fungal cells after treatment with fluconazole (FLCZ). The model would be useful for evaluating new chemotherapeutic or immunotherapeutic approaches against pharyngeal candidiasis, as well as in pathological studies.

Topics: Administration, Inhalation; Animals; Antifungal Agents; Beclomethasone; Candida albicans; Candidiasis, Oral; Colony Count, Microbial; Disease Models, Animal; Female; Fluconazole; Histocytochemistry; Immunosuppressive Agents; Mice; Mice, Inbred ICR; Pharynx

To assess the effects of treatment with nebulized corticosteroids immediately after chlorine gas injury.. Eighteen anesthetized and mechanically ventilated pigs were exposed to chlorine gas (140 ppm for 10 minutes) and observed for 6 hours. Nine pigs were treated with nebulized beclomethasone-dipropionate 20 microg/kg (BDP group), and nine pigs were given no treatment (control group).. All animals developed severe pulmonary dysfunction. The initial decrease in PaO2 was similar in both groups, but BDP-treated animals improved whereas control animals deteriorated (p < 0.005; analysis of variance). Pulmonary vascular resistance increased in both groups but less in the BDP group (p < 0.01). Lung-thorax compliance was better preserved in the BDP group (p < 0.01), and oxygen delivery was significantly better in the BDP group (p < 0.01). One animal died in the BDP group, as did three animals in the control group.. Immediate treatment with nebulized BDP improved pulmonary and cardiovascular function after experimental chlorine gas injury.

Topics: Administration, Inhalation; Aerosols; Analysis of Variance; Animals; Anti-Inflammatory Agents; Beclomethasone; Blood Gas Analysis; Chlorine; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Monitoring; Gases; Hemodynamics; Lung Compliance; Pulmonary Circulation; Pulmonary Edema; Respiration, Artificial; Swine; Vascular Resistance

Representative glucocorticosteroids (GCS) and phosphodiesterase IV (PDE4) inhibitors were compared in several models of pulmonary inflammation ranging in severity. Lung tissue eosinophil peroxidase (EPO) levels rather than bronchoalveolar lavage fluid (BALF) EPO or eosinophil percentages were used to indicate eosinophil recruitment after intratracheal instillation of sephadex beads in rats or nebulized ovalbumin in sensitized guinea pigs. A single oral or intratracheal administration of a GCS was effective against mild and robust sephadex-induced eosinophilia whereas the PDE4 inhibitors evaluated appeared more effective in the milder sephadex models. The GCS were also more effective against sephadex-induced than ovalbumin-induced eosinophilia. The effectiveness of the GCS and PDE4 inhibitors improved when the severity of the ovalbumin-induced eosinophilia was decreased. Multiple day dosing also improved activity. These studies indicated that activity was influenced greatly by administration protocols, the severity of the inflammatory response and possibly the method used for estimating eosinophil recruitment.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Androstadienes; Animals; Asthma; Beclomethasone; Benzamides; Budesonide; Cyclic Nucleotide Phosphodiesterases, Type 4; Dexamethasone; Dextrans; Disease Models, Animal; Enzyme Inhibitors; Eosinophil Peroxidase; Eosinophils; Fluticasone; Glucocorticoids; Guinea Pigs; Inflammation; Lung; Male; Ovalbumin; Peroxidases; Pyridines; Rats; Rats, Sprague-Dawley; Rolipram

In an attempt to study the pathogenesis of mucosal hypersensitivity in allergic rhinitis, we investigated the suppressive effects of cyclosporin A (CyA) and glucocorticosteroids on ovalbumin (OA)-induced hypersensitivity to topical histamine challenge.. Actively sensitized Dunkin-Hartley guinea pigs.. OA and alum were applied to guinea pigs intraperitoneally 3 times at two-week intervals. After general sensitization, OA inhalation was performed every day for 6 days as topical sensitization. Before inhalation, treatment with CyA (50 mg/kg, p.o.), glucocorticosteroids (beclomethasone propionate (1.0 mg/kg, i.p.), fluticasone propionate (FP, 0.5 mg/kg, i.p.)) or vehicle were performed, and the sensitivity to histamine was measured before and after the inhalation. Moreover, in actively (general and topical) sensitized guinea pigs, FP (0.5 mg/kg, i.p.) was applied every day for 5 days and histamine sensitivity was evaluated before and after the application.. We found that histamine sensitivity was significantly increased by nasal antigen challenge in this guinea pig model, and that the occurrence of histamine hypersensitivity was inhibited by the pretreatment with CyA and glucocorticosteroids. Although multiple administration of FP gradually reduced the histamine hypersensitivity according to the period of administration, it did not significantly alter the histamine hypersensitivity after the occurrence of hypersensitivity.. It is concluded that CyA and glucocorticosteroids suppress antigen-induced histamine hypersensitivity in a guinea pig model of allergic rhinitis.

Topics: Administration, Inhalation; Androstadienes; Animals; Anti-Allergic Agents; Anti-Inflammatory Agents; Beclomethasone; Cyclosporine; Disease Models, Animal; Drug Hypersensitivity; Fluticasone; Glucocorticoids; Guinea Pigs; Histamine; Immunosuppressive Agents; Injections, Intraperitoneal; Male; Ovalbumin; Rhinitis, Allergic, Perennial

The effects of beclomethasone dipropionate (BDP) enemas on ulcerative colitis were investigated by administrating BDP enemas to Fischer male rats with an inflammatory bowel disease induced by 2,4,6-trinitrobenzensulfonic acid (TNB). After administration of a TNB ethanol solution to rats, diarrhea and melena were found in all rats, and the wet tissue weights of the colons in the rats increased by erosion and thickness of epithelial mucous membranes with edema. BDP enemas were administered to the rats one time a day at a dose of 20 or 50 micrograms of BDP for 4 or 11 days from the day 3 after TNB treatment, respectively. After dosing of BDP, the rate of rats developing diarrhea and melena decreased more with time in comparison with that of BDP-free rats, and the symptoms of all rats developing the diseases were improved on the day 4 after administration of a dose of 50 micrograms of BDP. A dose dependent recovery in the wet tissue weights and scores of damages, and the myeloperoxidase (MPO) activity in the tissue were found at the early days (until the day 4). However, their measurements on the day 11 at each dose of BDP were not different from those of control rats significantly, as the damages in the colons of the control rats were recovered naturally with time. In conclusion, the clinical usefulness of BDP enemas was supported by elucidating the dose dependent effect of BDP at the early days in the model rats with an inflammatory bowel disease induced by TNB.

Topics: Animals; Anti-Inflammatory Agents; Beclomethasone; Colon; Disease Models, Animal; Dose-Response Relationship, Drug; Enema; Inflammatory Bowel Diseases; Male; Organ Size; Rats; Rats, Inbred F344; Trinitrobenzenesulfonic Acid