Effects of ciclesonide and fluticasone propionate on allergen-induced airway inflammation and remodeling features

Leung, Suet Yi; Eynott, Paul R.; Nath, Puneeta; Chung, Kian Fan

doi:10.1016/j.jaci.2005.01.036

Cited by 56 publications

(33 citation statements)

References 33 publications

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“…Furthermore, given the lipophilic nature of ciclesonide and des-CIC (Nave et al, 2004) as well as the ability of des-CIC to form lipid conjugates within the lung (properties that prolong residency time and local anti-inflammatory activity), any minor differences in potency between ciclesonide and fluticasone may be effectively negated with chronic therapy. These points are supported by recent investigations in which daily administration for 21 days with ciclesonide inhibited both bronchial hyperresponsiveness and airway inflammation in an allergic asthma model, whereas fluticasone inhibited airway inflammation but not bronchial hyper-responsiveness (Leung et al, 2003). Furthermore, fluticasone caused systemic side effects at higher doses, although there was no effect on body weight or the HPA axis with ciclesonide.…”

Section: Ciclesonide a Novel Corticosteroid 571supporting

confidence: 58%

Preclinical Profile of Ciclesonide, a Novel Corticosteroid for the Treatment of Asthma

Belvisi¹,

Bundschuh²,

Stoeck³

et al. 2005

J Pharmacol Exp Ther

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Ciclesonide is a novel, inhaled corticosteroid under development for the treatment of asthma. Ciclesonide is activated to desisobutyryl-ciclesonide (des-CIC) in the lungs to provide potent anti-inflammatory activity. The investigations herein compared the activity of ciclesonide with fluticasone in animal models to assess efficacy/potency as an airway anti-inflammatory and the comparative side effect potential to consider the therapeutic ratio of each compound. In radioligand binding assays, des-CIC and fluticasone exhibited comparable high-affinity binding to the glucocorticoid receptor, whereas ciclesonide exhibited 100-fold less binding affinity. In the Brown Norway rat model of antigen-induced airway eosinophilia and in a model of Sephadex-induced lung edema, ciclesonide and fluticasone exhibited comparable efficacy. Interestingly, following 7-day intratracheal administration, ciclesonide elicited adrenal involution with a potency that was 44-fold less than fluticasone. Furthermore, ciclesonide was 22-fold less active than fluticasone in eliciting hypoplasia of the femoral growth plate. These data support the concept that ciclesonide acts as a parent compound that, when delivered to the airways, can be transformed into the active metabolite des-CIC, resulting in local high anti-inflammatory activity. Furthermore, ciclesonide possesses equivalent anti-inflammatory efficacy through pulmonary activation with a significantly improved safety profile in preclinical animal models compared with fluticasone.

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Section: Ciclesonide a Novel Corticosteroid 571supporting

confidence: 58%

Preclinical Profile of Ciclesonide, a Novel Corticosteroid for the Treatment of Asthma

Belvisi¹,

Bundschuh²,

Stoeck³

et al. 2005

J Pharmacol Exp Ther

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“…In a murine model of asthma, inhaled corticosteroids decrease goblet cell hyperplasia (102). Dexamethasone has also been shown to decrease epithelial mucin gene MUC5AC gene expression in human bronchial epithelial cells (103).…”

Section: Glucocorticoidsmentioning

confidence: 99%

Chronic Bronchitis and Chronic Obstructive Pulmonary Disease

Kim

Criner

2013

Am J Respir Crit Care Med

388

276

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Chronic bronchitis (CB) is a common but variable phenomenon in chronic obstructive pulmonary disease (COPD). It has numerous clinical consequences, including an accelerated decline in lung function, greater risk of the development of airflow obstruction in smokers, a predisposition to lower respiratory tract infection, higher exacerbation frequency, and worse overall mortality. CB is caused by overproduction and hypersecretion of mucus by goblet cells, which leads to worsening airflow obstruction by luminal obstruction of small airways, epithelial remodeling, and alteration of airway surface tension predisposing to collapse. Despite its clinical sequelae, little is known about the pathophysiology of CB and goblet cell hyperplasia in COPD, and treatment options are limited. In addition, it is becoming increasingly apparent that in the classic COPD spectrum, with emphysema on one end and CB on the other, most patients lie somewhere in the middle. It is known now that many patients with severe emphysema can develop CB, and small airway pathology has been linked to worse clinical outcomes, such as increased mortality and lesser improvement in lung function after lung volume reduction surgery. However, in recent years, a greater understanding of the importance of CB as a phenotype to identify patients with a beneficial response to therapy has been described. Herein we review the epidemiology of CB, the evidence behind its clinical consequences, the current understanding of the pathophysiology of goblet cell hyperplasia in COPD, and current therapies for CB.Keywords: chronic obstructive pulmonary disease; chronic bronchitis; goblet cell hyperplasia; N-acetylcysteine; roflumilast Chronic obstructive pulmonary disease (COPD) is a common disease characterized by irreversible airflow obstruction and persistent inflammation to noxious environmental stimuli, usually cigarette smoke. It affects 12 to 16 million people in the United States and is the third leading cause of death and disease burden worldwide (1). COPD encompasses a spectrum of diseases, with chronic bronchitis (CB) at one end and emphysema at the other, with most individuals having some characteristics of both. The CB definition used in epidemiologic studies has been variable, but the classic definition is chronic cough and sputum production for at least 3 months per year for two consecutive years (2). CB has numerous clinical consequences, including an increased exacerbation rate, accelerated decline in lung function, worse health-related quality of life (HRQoL), and possibly increased mortality (3-6). We review the clinical phenotype of CB, the current understanding of its pathophysiology, and treatment options. EPIDEMIOLOGYCB is common in the general population. Table 1 provides an overview of the prevalence of cough and sputum production in population-based studies. CB is seen in 3.4 to 22.0% of adults (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). This wide range of prevalence estimates may be due to varying definitions of CB (i.e., chronic phlegm ver...

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“…The specimens (3 m thick) of the lung were stained with H&E and periodic acid-Schiff (PAS) according to standard protocols. The number of goblet cells was counted on PAS-stained lung sections as described elsewhere (19). The numbers of eosinophils, lymphocytes, and neutrophils recovered in the bronchoalveolar lavage fluid (BALF) and the levels of cytokines in the BALF were evaluated at 48 h after OVA inhalation as described previously (20).…”

Section: Ag-induced Allergic Airway Inflammationmentioning

confidence: 99%

Overlapping and Distinct Roles of STAT4 and T-bet in the Regulation of T Cell Differentiation and Allergic Airway Inflammation

Furuta

Kagami

Tamachi

et al. 2008

The Journal of Immunology

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T-bet and STAT4 play critical roles in helper T cell differentiation, especially for Th1 cells. However, it is still unknown about the relative importance and redundancy of T-bet and STAT4 for Th1 differentiation. It is also unknown about their independent role of T-bet and STAT4 in the regulation of allergic airway inflammation. In this study, we addressed these issues by comparing T-bet-deficient (T-bet−/−) mice, STAT4−/− mice, and T-bet- and STAT4-double-deficient (T-bet−/−STAT4−/−) mice on the same genetic background. Th1 differentiation was severely decreased in T-bet−/− mice and STAT4−/− mice as compared with that in wild-type mice, but Th1 differentiation was still observed in T-bet−/− mice and STAT4−/− mice. However, Th1 cells were hardly detected in T-bet−/−STAT4−/− mice. In contrast, the maintenance of Th17 cells was enhanced in T-bet−/− mice but was reduced in STAT4−/− mice and T-bet−/−STAT4−/− mice. In vivo, Ag-induced eosinophil and neutrophil recruitment into the airways was enhanced in T-bet−/− mice but was attenuated in STAT4−/− mice and T-bet−/−STAT4−/− mice. Ag-induced IL-17 production in the airways was also diminished in STAT4−/− mice and T-bet−/−STAT4−/− mice. These results indicate that STAT4 not only plays an indispensable role in T-bet-independent Th1 differentiation but also is involved in the maintenance of Th17 cells and the enhancement of allergic airway inflammation.

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Effects of ciclesonide and fluticasone propionate on allergen-induced airway inflammation and remodeling features

Cited by 56 publications

References 33 publications

Preclinical Profile of Ciclesonide, a Novel Corticosteroid for the Treatment of Asthma

Preclinical Profile of Ciclesonide, a Novel Corticosteroid for the Treatment of Asthma

Chronic Bronchitis and Chronic Obstructive Pulmonary Disease

Overlapping and Distinct Roles of STAT4 and T-bet in the Regulation of T Cell Differentiation and Allergic Airway Inflammation

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