mometasone-furoate and flunisolide

Treatment guidelines for asthma recommend inhaled corticosteroids (ICS) as first-line therapy for children with persistent asthma. Although ICS treatment is generally considered safe in children, the potential systemic adverse effects related to regular use of these drugs have been and continue to be a matter of concern, especially the effects on linear growth.. To assess the impact of ICS on the linear growth of children with persistent asthma and to explore potential effect modifiers such as characteristics of available treatments (molecule, dose, length of exposure, inhalation device) and of treated children (age, disease severity, compliance with treatment).. We searched the Cochrane Airways Group Specialised Register of trials (CAGR), which is derived from systematic searches of bibliographic databases including CENTRAL, MEDLINE, EMBASE, CINAHL, AMED and PsycINFO; we handsearched respiratory journals and meeting abstracts. We also conducted a search of ClinicalTrials.gov and manufacturers' clinical trial databases to look for potential relevant unpublished studies. The literature search was conducted in January 2014.. Parallel-group randomised controlled trials comparing daily use of ICS, delivered by any type of inhalation device for at least three months, versus placebo or non-steroidal drugs in children up to 18 years of age with persistent asthma.. Two review authors independently performed study selection, data extraction and assessment of risk of bias in included studies. We conducted meta-analyses using the Cochrane statistical package RevMan 5.2 and Stata version 11.0. We used the random-effects model for meta-analyses. We used mean differences (MDs) and 95% CIs as the metrics for treatment effects. A negative value for MD indicates that ICS have suppressive effects on linear growth compared with controls. We performed a priori planned subgroup analyses to explore potential effect modifiers, such as ICS molecule, daily dose, inhalation device and age of the treated child.. We included 25 trials involving 8471 (5128 ICS-treated and 3343 control) children with mild to moderate persistent asthma. Six molecules (beclomethasone dipropionate, budesonide, ciclesonide, flunisolide, fluticasone propionate and mometasone furoate) [corrected] given at low or medium daily doses were used during a period of three months to four to six years. Most trials were blinded and over half of the trials had drop out rates of over 20%.Compared with placebo or non-steroidal drugs, ICS produced a statistically significant reduction in linear growth velocity (14 trials with 5717 participants, MD -0.48 cm/y, 95% CI -0.65 to -0.30, moderate quality evidence) and in the change from baseline in height (15 trials with 3275 participants; MD -0.61 cm/y, 95% CI -0.83 to -0.38, moderate quality evidence) during a one-year treatment period.Subgroup analysis showed a statistically significant group difference between six molecules in the mean reduction of linear growth velocity during one-year treatment (Chi² = 26.1, degrees of freedom (df) = 5, P value < 0.0001). The group difference persisted even when analysis was restricted to the trials using doses equivalent to 200 μg/d hydrofluoroalkane (HFA)-beclomethasone. Subgroup analyses did not show a statistically significant impact of daily dose (low vs medium), inhalation device or participant age on the magnitude of ICS-induced suppression of linear growth velocity during a one-year treatment period. However, head-to-head comparisons are needed to assess the effects of different drug molecules, dose, inhalation device or patient age. No statistically significant difference in linear growth velocity was found between participants treated with ICS and controls during the second year of treatment (five trials with 3174 participants; MD -0.19 cm/y, 95% CI -0.48 to 0.11, P value 0.22). Of two trials that reported linear growth velocity in the third year of treatment, one trial involving 667 participants showed similar growth velocity between the budesonide and placebo groups (5.34 cm/y vs 5.34 cm/y), and another trial involving 1974 participants showed lower growth velocity in the budesonide group compared with the placebo group (MD -0.33 cm/y, 95% CI -0.52 to -0.14, P value 0.0005). Among four trials reporting data on linear growth after treatment cessation, three did not describe statistically significant catch-up growth in the ICS group two to four months after treatment cessation. One trial showed accelerated li. Regular use of ICS at low or medium daily doses is associated with a mean reduction of 0.48 cm/y in linear growth velocity and a 0.61-cm change from baseline in height during a one-year treatment period in children with mild to moderate persistent asthma. The effect size of ICS on linear growth velocity appears to be associated more strongly with the ICS molecule than with the device or dose (low to medium dose range). ICS-induced growth suppression seems to be maximal during the first year of therapy and less pronounced in subsequent years of treatment. However, additional studies are needed to better characterise the molecule dependency of growth suppression, particularly with newer molecules (mometasone, ciclesonide), to specify the respective role of molecule, daily dose, inhalation device and patient age on the effect size of ICS, and to define the growth suppression effect of ICS treatment over a period of several years in children with persistent asthma.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Androstadienes; Anti-Asthmatic Agents; Asthma; Beclomethasone; Budesonide; Child; Child, Preschool; Fluocinolone Acetonide; Fluticasone; Growth; Growth Disorders; Humans; Mometasone Furoate; Patient Dropouts; Pregnadienediols; Pregnenediones

The introduction of nasal glucocorticosteroids, 30 years ago, has been the most important therapeutic progress in rhinitis management since the introduction of the first generation of antihistamines. Our knowledge of the mode of action of glucocorticosteroids in the nose has improved as the airway mucous membrane of the nose is easily accessible for investigation. However, the exact mechanism behind the marked clinical effect remains unclear. Topical glucocorticosteroids are highly effective in diseases characterized by eosinophil-dominated inflammation (allergic rhinitis, nasal polyposis), but not in diseases characterized by neutrophil-dominated inflammation (common cold, infectious rhinosinusitis). Experience for 30 years and a long series of controlled studies have shown that the treatment is highly effective and that the side effects are few and benign. Intranasal glucocorticosteroids can therefore be considered as first-line treatment for allergic and non-allergic, non-infectious rhinitis and nasal polyps.

Topics: Administration, Topical; Androstadienes; Animals; Beclomethasone; Budesonide; Dexamethasone; Eosinophils; Fluocinolone Acetonide; Fluticasone; Glucocorticoids; Humans; Mometasone Furoate; Nasal Mucosa; Nasal Polyps; Pregnadienediols; Randomized Controlled Trials as Topic; Rhinitis; Treatment Outcome; Triamcinolone Acetonide

Topical administration of corticosteroids can reduce the total dose of corticosteroid required to treat the patient and minimize side effects. This logic has led to the development of intranasal corticosteroids (INCS) for allergic and perennial rhinitis. The second generation of these compounds includes beclomethasone dipropionate, budesonide, flunisolide, fluticasone propionate, mometasone furoate, and triamcinolone acetonide. There is evidence that the INCS are effective in rhinitis; however, there is concern about the potential for these compounds to cause growth suppression. In one study, beclomethasone dipropionate significantly reduced growth in children; however, treatment of children with mometasone furoate nasal spray for 1 year showed no signs of growth suppression. It is evident that the differences among INCS lie in their pharmacokinetics. Structural differences among the various INCS influence their metabolism. The goal of INCS therapy is to have a high ratio of topical to systemic activity. The drug delivery device, absorption of the drug, and drug distribution all contribute to effective topical activity of an INCS. In addition, individual drug metabolism and elimination (half-life and drug clearance) also contribute to the therapeutic index of a drug. Overall, the second-generation INCS cause minimal systemic effects at recommended doses.

Topics: Absorption; Administration, Intranasal; Adrenal Cortex Hormones; Adult; Androstadienes; Anti-Allergic Agents; Anti-Inflammatory Agents; Beclomethasone; Budesonide; Child; Drug Delivery Systems; Fluocinolone Acetonide; Fluticasone; Humans; Mometasone Furoate; Pregnadienediols; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal; Structure-Activity Relationship; Tissue Distribution; Triamcinolone Acetonide

Intranasal steroids (INSs) are established as first-line treatment for allergic rhinitis. Extensive use of INSs with few reported adverse events supports the safety of these medications. Nevertheless, the prescription of more potent INSs for consistent and more prolonged use to younger and older patients, often in combination with inhaled corticosteroids, justifies the careful examination of their potential adverse systemic effects. Systemic bioavailability of INSs, by way of nasal and intestinal absorption, can be substantial; but current INSs vary significantly in their degree of first-pass hepatic inactivation and clearance from the body of the swallowed drug. For safety studies of INSs, distinguishing detectable physiologic perturbations from important adverse events is aided by an understanding of normal endocrine physiology and the methods used to test these systems. A review of available information indicates that (1) sensitive tests can measure the effects of INSs on biologic feedback systems, but they do not accurately predict clinically relevant adverse effects; (2) the primary factors that influence the relationship between therapeutic and adverse systemic effects of INSs are dosing frequency and efficiency of hepatic inactivation of swallowed drug; (3) INS treatment in recommended doses does not cause clinically significant hypothalamic-pituitary-adrenal axis suppression; (4) growth suppression can occur with twice-daily administration of certain INSs but does not appear to occur with once-daily dosing or with agents with more complete first-pass hepatic inactivation; (5) harmful effects of INSs on bone metabolism have not yet been adequately studied but would not be expected with the use of an INS dose and dosing frequency that do not suppress basal hypothalamic-pituitary-adrenal axis function or growth; and (6) these conclusions apply to INS treatment alone and in recommended doses-the risk of adverse effects in individual patients who are treated with INSs is increased by excessive dosing or concomitant inhaled corticosteroid or other topical corticosteroid therapy.

Topics: Administration, Intranasal; Androstadienes; Beclomethasone; Budesonide; Endocrinology; Fluocinolone Acetonide; Fluticasone; Humans; Mometasone Furoate; Pregnadienediols; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal; Steroids; Triamcinolone Acetonide

Intranasal corticosteroids (INS) are the first line treatment for allergic rhinitis (AR). To guide clinical decision-making, we created a therapeutic index (TIX) for INS reflecting efficacy and safety.. A Medline search (1966 to June 2009) was carried out to identify all placebo-controlled randomized trials, and observational reports for safety issues, with Dexamethasone, Budesonide (BUD), Fluticasone propionate (FP), Fluticasone furoate (FF), Flunisolide, Mometasone furoate (MF), Triamcinolone (TRIAM), and Beclomethasone dipropionate (BDP) as treatment for AR. Data on three efficacy (nasal symptoms, ocular symptoms, global assessment) and three safety outcomes (epistaxis, growth, systemic ocular effects) were extracted. Meta analyses were performed for each INS and outcome and results were categorised into scores by quartiles. Scores of the three efficacy and safety outcomes were summed up to create summation scores for efficacy (ES) and side effects (AES), respectively with a maximum of 9 points. The TIX was then defined as the ratio of ES and AES.. Data of 84 studies were extracted. Based on availability of data, a TIX was calculated for 6 substances. BUD showed the highest efficacy score followed by MF and TRIAM. The lowest scores for side effects were achieved by MF and TRIAM followed by FP. These findings resulted in TIX scores of 7 and 5 for MF and TRIAM, respectively, indicating a high efficacy and low potential of adverse events. Medium scores were reached by BUD and FP and lower scores by BDP and FF.. Although safety and efficacy is proven for all available INS by multiple studies, the systematic aggregation and analysis of data allows for a differentiated summary on clinically important features.

Topics: Administration, Intranasal; Androstadienes; Anti-Inflammatory Agents; Beclomethasone; Budesonide; Fluocinolone Acetonide; Fluticasone; Glucocorticoids; Humans; Mometasone Furoate; Pregnadienediols; Rhinitis, Allergic, Perennial; Treatment Outcome; Triamcinolone

The purpose of this study was to compare the toxicity of three marketed corticosteroid receptor agonists (mometasone furoate, budesonide, or flunisolide) to the stomach of female CD-1 mice following oral administration via the diet for up to 52 weeks, with a 16-week recovery period (budesonide and flunisolide). A range of tissues was examined by light microscopy, accompanied by clinical pathology measurements to assess anticipated corticosteroid effects as a surrogate marker of systemic drug exposure. Microscopic changes seen in the stomach with each corticosteroid included pyloric hyalinization. This previously unreported finding was investigated using histochemical and immunohistochemical techniques and was found to consist of hyalinized collagen, in association with increased immunohistochemical signal for transglutaminase-2 and osteopontin. The significance of the osteopontin finding is unclear; however, the ability of transglutaminase-2 to facilitate the formation of degradation resistant protein bonds implies this protein may be involved in the pathogenesis of this change. Furthermore, published evidence that transglutaminase-2 may be induced by a corticosteroid agonist raises the possibility that pyloric stomach hyalinization may be a class effect of corticosteroids via the action of this enzyme.

Topics: Administration, Oral; Adrenal Cortex Hormones; Animals; Anti-Inflammatory Agents; Budesonide; Female; Fluocinolone Acetonide; GTP-Binding Proteins; Hyalin; Mice; Mice, Inbred Strains; Microscopy, Electron; Mometasone Furoate; Osteopontin; Pregnadienediols; Protein Glutamine gamma Glutamyltransferase 2; Pylorus; Transglutaminases