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Bronchial nitric oxide is related to symptom relief during fluticasone treatment in COPD.
Eur Respir J. 2009 Jul 2;
Lehtimäki L, Kankaanranta H, Saarelainen S, Annila I, Aine T, Nieminen R, Moilanen E
High levels of exhaled nitric oxide (NO) predict favorable response to inhaled corticosteroids in asthma, but the ability of exhaled NO or inflammatory markers in exhaled breath condensate (EBC) to predict steroid-responsiveness in COPD is not known.We measured alveolar and bronchial NO output, levels of leukotriene B4 (LTB4), cysteinyl leukotrienes (cysLTs) and 8-isoprostane in EBC, spirometry, body plethysmography and symptoms in 40 subjects with COPD before and after 4 weeks of treatment with inhaled fluticasone (500 microg b.i.d.).Five subjects (12.5 %) with COPD had significant improvement in lung function during fluticasone treatment, while 20 subjects (50 %) had significant decrease in symptoms. High baseline bronchial NO flux was associated with higher increase in FEV1/FVC (r=0.334, p=0.038) and more symptom relief (r= -0.317, p=0.049) during the treatment. Baseline EBC levels of LTB4, cysLTs or 8-isoprostane were not related to response to fluticasone treatment. Inhaled fluticasone decreased bronchial NO flux but not alveolar NO concentration or markers in EBC.High levels of bronchial NO flux are related to symptom relief and improvement of airway obstruction during treatment with inhaled fluticasone in COPD. Markers of inflammation or oxidative stress in EBC are not related to steroid-responsiveness in COPD.
Intranasal corticosteroids and adrenal suppression.
Neuroimmunomodulation. 2009; 16(5): 353-62
Bruni FM, De Luca G, Venturoli V, Boner AL
Allergic rhinitis is a common condition that frequently coexists with asthma and atopic dermatitis. It is commonly treated with intranasal corticosteroids which may increase the potential inception of side effects of the same type of drugs used for the treatment of other allergic diseases. A method to assess the systemic effect of corticosteroids is the evaluation of their effect on the hypothalamic-pituitary-adrenal (HPA) axis. However, it is not clear which test is best for detection of clinically relevant HPA axis suppression in children Morning plasma cortisol levels are twice that of late afternoon and evening values and a delay in the time of onset in peak cortisol levels has been observed in children treated with inhaled corticosteroids. Single morning cortisol level has a low sensitivity for detecting adrenal insufficiency in children. 24-Hour plasma cortisol is a good test because it is a non-invasive measure of the biologically active free cortisol levels for the entire day. For research purposes, the 24-hour integrated concentration plasma cortisol test is preferred. Studies that have looked at HPA axis suppression with intranasal corticosteroids indicate that overall, intranasal corticosteroids have a minimal effect on the HPA axis. A review of the literature reveals one study in which there was a decreased output of urinary cortisol during treatment with either budesonide or fluticasone propionate in adults. Other studies with fluticasone propionate or budesonide have shown no effect on the HPA axis in children. Beclomethasone dipropionate was shown to affect urinary cortisol output in one study on healthy volunteers. However, in a long-term study in children, no effect on the HPA axis was found. Mometasone furoate has been extensively studied in more than 20 trials of adults and children. No effects on the HPA axis were detected in either children or adults. Fluticasone furoate nasal spray was not associated with HPA axis suppression. It is unlikely that children are more sensitive to corticosteroids than adults. There is no reason to perform routine monitoring of adrenal function in children who are treated with intranasal corticosteroid unless those drugs are used concomitantly with inhaled corticosteroids and/or steroid ointments for the possible concomitant presence of asthma and/or atopic dermatitis.
Curr Med Res Opin. 2009 Jul 2;
Keith PK, Scadding GK
ABSTRACT Background: Nasal and ocular symptoms of allergic rhinitis (AR) are reported by >70% of patients and have a profound impact on quality of life while also incurring substantial healthcare costs. It has been suggested that intranasal corticosteroids (INS), in addition to effectively treating the nasal components of AR, are effective in treating the ocular symptoms. Objective: This review provides a comprehensive, updated assessment of available data in the public domain to determine the consistency of INS efficacy in treating ocular AR symptoms. Methods: MEDLINE and EMBASE searches, and research of governmental and regulatory institution sources identified 35 randomised, placebo-controlled trials of INS and seasonal AR (SAR) published between 1990 and May 2009 that specifically contained ocular efficacy as part of the study analyses. Results: Examination of these studies reveals substantial inconsistency of effect of some INS across, and even within, trials, casting doubt on the suggestion that ocular efficacy is a class effect of INS. Conflicting, inconsistent or even negative effects were observed for most INS examined including mometasone furoate and fluticasone propionate. Only fluticasone furoate nasal spray, in addition to established efficacy in treating nasal symptoms, demonstrated a consistent positive effect on ocular symptoms of SAR compared with placebo in a large number of patients across all of its prospective studies. Moreover, these results were consistent across different allergy seasons, including grass, ragweed, and mountain cedar seasons, and different geographical locations throughout Europe and the USA. Conclusion: While additional prospective head-to-head clinical trials comparing the efficacy of INS in treating ocular symptoms of AR are needed to fully elucidate the benefits of one INS compared with another, data available to date suggest that not all INS are equally consistent in managing ocular symptoms of SAR. Fluticasone furoate is currently the most consistent.
Respir Res. 2009 Jun 30; 10(1): 59
Jenkins CR, Jones PW, Calverley PM, Celli B, Anderson JA, Ferguson GT, Yates JC, Willits LR, Vestbo J
ABSTRACT: BACKGROUND: The efficacy of inhaled salmeterol plus fluticasone propionate (SFC) in patients with severe or very severe COPD is well documented. However, there are only limited data about the influence of GOLD severity staging on the effectiveness of SFC, particularly in patients with milder disease. METHODS: TORCH was a 3-year, double-blind, placebo-controlled trial of 6112 patients with moderate/severe COPD with pre-bronchodilator FEV1 < 60% predicted (mean age 65 years, 76% male, mean 44% predicted FEV1, 43% current smokers). To understand the relative efficacy of SFC and its components by GOLD stages, we conducted a post-hoc analysis of the TORCH dataset using baseline post-bronchodilator FEV1 to segment patients into three groups: moderate COPD (GOLD stage II and above: [greater than or equal to] 50%; n = 2156), severe COPD (GOLD stage III: 30% to < 50%; n = 3019) and very severe COPD (GOLD stage IV: < 30%; n = 937). RESULTS: Compared with placebo, SFC improved post-bronchodilator FEV1: 101 ml (95% confidence interval [CI]: 71, 132) in GOLD stage II, 82 ml (95% CI: 60, 104) in GOLD stage III and 96 ml (95% CI: 54, 138) in GOLD stage IV patients, and reduced the rate of exacerbations: 31% (95% CI: 19, 40) in GOLD stage II, 26% (95% CI: 17, 34) in GOLD stage III and 14% (95% CI: -4, 29) in GOLD stage IV. SFC improved health status to a greater extent than other treatments regardless of baseline GOLD stage. Similarly, SFC reduced the risk of death by 33% (hazard ratio [HR] 0.67; 95% CI: 0.45, 0.98) for GOLD stage II, 5% (HR 0.95; 95% CI: 0.73, 1.24) for GOLD stage III, and 30% (HR 0.70; 95% CI: 0.47, 1.05) for GOLD stage IV. The rates of adverse events were similar across treatment arms and increased with disease severity. Overall, there was a higher incidence of pneumonia in the fluticasone propionate and SFC arms, compared with other treatments in all GOLD stages. CONCLUSIONS: In the TORCH study, SFC reduced moderate-to-severe exacerbations and improved health status and FEV1 across GOLD stages. Treatment with SFC may be associated with reduced mortality compared with placebo in patients with GOLD stage II disease. The effects were similar to those reported for the study as a whole. Thus, SFC is an effective treatment option for patients with GOLD stage II COPD. Trial registration Clinicaltrial.gov registration NCT00268216; Study number: SCO30003.
Pediatr Allergy Immunol. 2009 Jun 26;
Doss N, Kamoun MR, Dubertret L, Cambazard F, Remitz A, Lahfa M, de Prost Y
Tacrolimus 0.03% ointment is licensed for second-line treatment of children with atopic dermatitis (AD). Although data are available from clinical trials, no study has enrolled only second-line patients. This double-blind, non-inferiority study compared tacrolimus 0.03% and fluticasone 0.005% ointments in children with moderate-to-severe AD, who had responded insufficiently to conventional therapies. Children (aged 2-15 yr) were randomized to tacrolimus ointment (n = 240) or fluticasone ointment (n = 239), twice daily until clearance or for a maximum of 3 wk and, if lesions remained, once daily for up to 3 wk further. Primary end-point was week 3 response rate (improvement of >/=60% in modified Eczema Area and Severity Index and not withdrawn for lack of efficacy). Secondary end-points included pruritus and sleep quality, global assessment of clinical response, incidence of new flares and safety. Response rates were 86.3% with tacrolimus ointment and 91.5% with fluticasone. Lower limit of the 95% confidence interval was -11.8%, exceeding the non-inferiority limit of -15% and meeting the primary end-point. Moderate or better improvement on the physicians' global assessment occurred in 93.6% and 92.4% of patients in the tacrolimus ointment and fluticasone arms, respectively, while median pruritus scores improved by 84.0% and 91.5%. Sleep quality improved by approximately 92% in both treatment arms. After day 21, new flare-up occurred in 5.5% and 11.3% of patients receiving tacrolimus ointment and fluticasone, respectively; mean times to new flares were 6.5 +/- 5.0 and 8.6 +/- 5.2 days. Adverse events were similar between the two arms, with the exception of application-site skin burning sensation in the tacrolimus ointment group. In conclusion, efficacy of tacrolimus 0.03% ointment as second-line treatment was not inferior to that of fluticasone 0.005% ointment, with similar benefits on global disease improvement and quality of sleep.
Eur J Clin Pharmacol. 2009 Jun 26;
Chung KF, Caramori G, Adcock IM
Inhaled corticosteroid (ICS) therapy in combination with long-acting beta-adrenergic agonists represents the most important treatment for chronic airways diseases such as asthma and chronic obstructive pulmonary disease (COPD). ICS therapy forms the basis for treatment of asthma of all severities, improving asthma control, lung function and preventing exacerbations of disease. Use of ICS has also been established in the treatment of COPD, particularly symptomatic patients, who experience useful gains in quality of life, likely from an improvement in symptoms such as breathlessness and in reduction in exacerbations, and an attenuation of the yearly rate of deterioration in lung function. The addition of long-acting beta-agonist (LABA) therapy with ICS increases the efficacy of ICS effects in moderate-to-severe asthma. Thus, a 800 mug daily dose of the ICS budesonide reduced severe exacerbation rates by 49% compared to a low dose of 200 mug daily, and addition of the LABA formoterol to budesonide (800 mug) led to a 63% reduction. In COPD, the effects of ICS are less prominent but there are beneficial effects on the decline in FEV(1) and the rate of exacerbations. A reduction in the rate of decline in FEV(1) of 16 ml/year with a 25% reduction in exacerbation rate has been reported with the salmeterol and fluticasone combination. A non-significant 17.5% reduction in all-cause mortality rate with ICS and LABA is reported. Chronic inflammation is a feature of both asthma and COPD, although there are site and characteristic differences. ICS targets this inflammation although this effect of ICS is less effective in patients with severe asthma and with COPD; however, addition of LABA may potentiate the anti-inflammatory effects of ICS. An important consideration is the presence of corticosteroid insensitivity in these patients. Currently available ICS have variably potent binding activities to specific glucocorticoid receptors, leading to inhibition of gene expression by either binding to DNA and inducing anti-inflammatory genes or by repressing the induction of pro-inflammatory mediators. Local side effects of ICS include oral candidiasis, hoarseness and dysphonia, while systemic side effects, such as easy bruising and reduction in growth velocity or bone mineral densitometry, are usually restricted to doses above maximally recommended doses. Use of LABA alone in patients with asthma increases the risk of asthma-related events including deaths, but this is less observed with the combination of ICS and LABA. Therefore, use of LABA alone is not recommended for asthma therapy. Future progress in ICS development will be characterised by the introduction of ICS with greater efficacy with a limited side-effect profile, and by longer-acting ICS that can be used in combination with once-daily LABAs. Other agents that could improve the efficacy of corticosteroids or reverse corticosteroid insensitivity may be added to ICS. ICS in combination with LABAs will continue to remain the main focus of treatment of airways diseases.
Allergy Asthma Proc. 2009 May-Jun; 30(3): 255-62
Kaliner MA, Storms W, Tilles S, Spector S, Tan R, Laforce C, Lanier BQ, Chipps B
The efficacy of nasal antihistamines (NAHs) for allergic rhinitis (AR) is comparable with or better than second-generation oral antihistamines, with faster onset of action and greater effect on congestion. Limited data suggest that NAHs may be equivalent to intranasal corticosteroids at reducing the full range of nasal seasonal AR (SAR) symptoms, including congestion. The efficacy of olopatadine 0.6% nasal spray (2 sprays/nostril b.i.d.) for symptoms of SAR was compared with fluticasone 50 microg nasal spray (2 sprays/nostril q.d.) in a double-blind, randomized, parallel-group, 2-week noninferiority trial. A total of 130 symptomatic patients were randomized to treatment and they recorded nasal and ocular allergy symptom scores b.i.d. (morning and evening) in a diary. Both treatments reduced reflective and instantaneous assessments of nasal and ocular symptoms from baseline throughout the 2-week study period (p < 0.05). The reflective total nasal symptom score (the primary efficacy variable) decreased by an average of -45.4% for patients treated with olopatadine 0.6% and by -47.4% for those treated with fluticasone; statistical significance favoring olopatadine was demonstrated at day 1. No significant between-treatment differences were determined for the average 2-week percent changes from baseline for congestion, runny nose, sneezing, itchy nose, and ocular symptoms, although olopatadine had a faster onset of action for reducing all symptoms. Both treatments were safe and well tolerated. Olopatadine and fluticasone nasal sprays both reduced nasal and ocular SAR symptoms with no significant between-treatment differences except for a faster and greater onset of action with olopatadine.
Leptin and leptin receptor expression in asthma.
J Allergy Clin Immunol. 2009 Jun 17;
Bruno A, Pace E, Chanez P, Gras D, Vachier I, Chiappara G, La Guardia M, Gerbino S, Profita M, Gjomarkaj M
BACKGROUND: The adipokine leptin is a potential new mediator for bronchial epithelial homeostasis. Asthma is a chronic inflammatory disease characterized by airway remodeling that might affect disease chronicity and severity. TGF-beta is a tissue growth factor the dysregulation of which is associated with airway remodeling. OBJECTIVE: We sought to determine whether a bronchial epithelial dysfunction of the leptin/leptin receptor pathway contributes to asthma pathogenesis and severity. METHODS: We investigated in vitro the presence of leptin/leptin receptor on human bronchial epithelial cells. Then we studied the effect of TGF-beta and fluticasone propionate on leptin receptor expression. Finally, the role of leptin on TGF-beta release and cell proliferation was analyzed. Ex vivo we investigated the presence of leptin/leptin receptor in the epithelium of bronchial biopsy specimens from subjects with asthma of various severities and from healthy volunteers, and some features of airway remodeling, such as reticular basement membrane (RBM) thickness and TGF-beta expression in the epithelium, were assessed. RESULTS: In vitro bronchial epithelial cells express leptin/leptin receptor. TGF-beta decreased and fluticasone propionate increased leptin receptor expression, and leptin decreased the spontaneous release of TGF-beta and increased cell proliferation. Ex vivo the bronchial epithelium of subjects with mild, uncontrolled, untreated asthma showed a decrease expression of leptin and its receptor and an increased RBM thickness and TGF-beta expression when compared with values seen in healthy volunteers. Furthermore, severe asthma was associated with a reduced expression of leptin and its receptor and an increased RBM thickness with unaltered TGF-beta expression. CONCLUSIONS: Decreased expression of leptin/leptin receptor characterizes severe asthma and is associated with airway remodeling features.
Clin Ther. 2009 May; 31(5): 1056-63
Friedman HS, Eid NS, Crespi S, Wilcox TK, Reardon G
Background: According to current asthma treatment guidelines, single-entity inhaled corticosteroids (ICSs) should be used as initial controller therapy in children with mild to moderate persistent asthma. Long-acting beta(2)-agonists (LABAs) can be added to therapy for those patients whose asthma is not well controlled with a single-entity ICS. Objectives: The goal of this study was to examine whether the claims history for children in a US insured population indicate proper fluticasone propionate/ salmeterol (FPS) fixed-dose combination use in accordance with recommended asthma guidelines and a US Food and Drug Administration (FDA) advisory and black box warning regarding LABA use. A comparison of study-drug charges was also conducted. Methods: Data from a US commercial insurance database were used in this retrospective study to evaluate pharmacy and medical claims for children between October 2004 and September 2006 (ie, the index period). An index date corresponding to the date of the first FPS claim was assigned to each patient. Eligible patients were aged 4 to 11 years and had >/=1 pharmacy claim for FPS during the index period. Those patients receiving 1 FPS prescription dose strength on the index date who were continuously enrolled for benefits during the preindex period (ie, the 365 days before the index date) were included in the study. Disease severity was assigned based on asthma-related pharmacy (frequency and/or incidence of oral corticosteroid, LABA, montelukast, and >365 doses of a short-acting beta(2)-agonist) and medical (asthma-related urgent care clinic or emergency department visits or hospitalizations) claim histories during the preindex period. Results: A total of 13,306 patients between the ages of 4 and 11 years on the index date were included in the study; their mean (SD) age was 8.9 (1.9) years. The majority of the patients were male (60.7%). Of the total FPS claims, 55.2% were for patients with no evidence of pharmacy or medical claims in the 365 days before the first FPS claim that would warrant ICS/LABA combination therapy according to asthma treatment guidelines. There were no large changes in preindex ICS claims over the course of the study in response to an FDA-issued advisory and black box warning regarding the use of LABAs. Median drug charges for single-entity ICS use were $98 compared with $168 for FPS therapy. Conclusions: ICS/LABA combination treatment was used as initial therapy in 55.2% of children with mild to moderate asthma in this claims database population, contrary to the recommendations of current asthma treatment guidelines. The FDA advisory and black box warning for LABA use had little observed impact on the number of single-entity ICS claims.
Clin Exp Allergy. 2009 Jun 17;
Baumann D, Bachert C, Högger P
Summary Background Intranasal glucocorticoids represent the most effective pharmacologic treatment of allergic rhinitis. So far, no clinical data are available that compare fluticasone furoate (FF) with other intranasally applied glucocorticoids. Objective Because the pharmacokinetic behaviour of drugs governs their presence at the therapeutic target site we analysed selected in vitro properties of FF in comparison with triamcinolone acetonide (TCA), budesonide (Bud), fluticasone propionate (FP) and mometasone furoate (MF). Additionally, we determined the anti-inflammatory activity of the glucocorticoid fraction residing in human nasal tissue samples after washing. Methods We analysed the solubility of the compounds in artificial human nasal fluid and the retention in human nasal tissue as well as typical spray volumes of commercially available drug preparations. As an anti-inflammatory measure, we evaluated the inhibition of IL-8 release from epithelial cells. Results FF is delivered in the smallest application volume per spray. Despite the low aqueous solubility of glucocorticoids, a fraction of the compounds is already dissolved in the aqueous supernatants of drug preparations (Bud>TCA>FP>MF>FF). The dissolution of FP, MF and FF was significantly enhanced in artificial nasal fluid and FF displayed the most pronounced enhancement of solubility in the presence of proteins. Consistent with this result, the highest retention in nasal tissue was observed for FF, followed by FP>MF>Bud>TCA. After washing of the nasal tissue samples, all compounds inhibited IL-8 release, with FF displaying the highest activity. Conclusion FF displayed beneficial properties for nasal application. Its low application volume per spray is a prerequisite for effective drug utilization by avoiding immediate loss by nose runoff or drip down the throat. Sustained dissolution and high tissue binding of FF should contribute towards an extended presence of compounds in nasal tissue as a basis for a prolonged pharmacologic activity.