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

Belvisi, Maria G.; Bundschuh, Daniela S.; Stoeck, Michael; Wicks, Sharon; Underwood, Stephen L.; Battram, Clifford H.; Haddad, El-Bdaoui; Webber, S. E.; Foster, Martyn

doi:10.1124/jpet.105.085217

“…An earlier study of INSs that used competition assay methodology reported a similar rank order of relative binding potency: mometasone furoate > fluticasone propionate > budesonide > triamcinolone acetonide > dexamethasone (15). Studies conducted before the development of mometasone furoate consistently described the same relative binding affinity order (15,(21)(22)(23)(24); the binding affinity of desciclesonide (the active metabolite of the prodrug ciclesonide) is slightly less than that of fluticasone propionate (7,19).…”

Section: Derendorf and Meltzermentioning

confidence: 79%

“…lung/nasal tissue). Subsequent intracellular esterification of desciclesonide with endogenous fatty acids produces reversible lipid conjugates of des-ciclesonide that become a reservoir of the drug in the lung or nasal mucosa (7,8).…”

mentioning

confidence: 99%

Molecular and clinical pharmacology of intranasal corticosteroids: clinical and therapeutic implications

Derendorf

¹

,

Meltzer

²

2008

Allergy

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Intranasal corticosteroids (INSs) are effective treatments for allergic rhinitis, rhinosinusitis, and nasal polyposis. In recent years, increased understanding of corticosteroid and glucocorticoid receptor pharmacology has enabled the development of molecules designed specifically to achieve potent, localized activity with minimal risk of systemic exposure. Pharmacologic potency studies using affinity and other assessments have produced similar rank orders of potency, with the most potent being mometasone furoate, fluticasone propionate, and its modification, fluticasone furoate. The furoate and propionate ester side chains render these agents highly lipophilic, which may facilitate their absorption through nasal mucosa and uptake across phospholipid cell membranes. These compounds demonstrate negligible systemic absorption. Systemic absorption rates are higher among the older corticosteroids (flunisolide, beclomethasone dipropionate, triamcinolone acetonide, and budesonide), which have bioavailabilities in the range of 34–49%. Studies, including 1‐year studies with mometasone furoate, fluticasone propionate, and budesonide that evaluated potential systemic effects of INSs in children have generally found no adverse effects on hypothalamic–pituitary–adrenal axis function or growth. Clinical data suggest no significant differences in efficacy between the INSs. Theoretically, newer agents with lower systemic availability may be preferable, and may come closer to the pharmacokinetic/pharmacologic criteria for the ideal therapeutic choice.

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“…Entretanto, mudanças no conteúdo mineral ósseo total em crianças tratadas com doses elevadas de DPB ou BUD ou PF foram recentemente documentadas durante tratamento por período de 12 meses 42,43 . Estudo experimental documentou a ausência de efeito sobre o metabolismo ósseo com ciclesonida, mesmo em doses elevadas 20 .…”

Section: Metabolismo óSseounclassified

Inhaled corticosteroids in the treatment of respiratory allergy: safety vs. efficacy

Rizzo

¹

,

Solé

²

2006

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Objective: Review the molecular mechanisms of action, efficacy, and potential side effects associated with inhaled corticosteroids (ICS) in children with persistent asthma.Sources: Articles in English from MEDLINE. The following terms were used: corticosteroids, inhaled corticosteroids, asthma, children, beclomethasone, fluticasone, budesonide, ciclesonide, growth, adrenal insufficiency, bone mineral density, and oral candidiasis. Treatment guidelines, review articles, controlled trials, meta-analyses, and systematic reviews evaluating the efficacy and the adverse events of treatment with ICS were selected.Summary of the findings: In vivo and in vitro studies show that t h e a v a i l a b l e I C S h a v e d i f f e r e n t p h a r m a c o k i n e t i c a n d pharmacodynamic properties that result in different action potentials. ICS also differ as to the systemic and local side effects. The bioavailability of these products is essential in order to determine the incidence of side effects. In general, ICS are capable of controlling asthma, reducing the number of exacerbations, medical consultations, hospitalizations, and the need of oral corticosteroid (applications) bursts. Improvement can also be seen in pulmonary function, especially in patients with recent onset asthma. The most documented adverse effect is transitory decrease of growth rate.Conclusions: ICS are the main anti-inflammatory agent used to treat persistent asthma. When administered in low doses, they seem to be safe and effective. Patient monitoring allows for early detection of possible side effects associated with ICS.J Pediatr (Rio J). 2006;82(5 Suppl):S198-205: Children, asthma, inhaled corticosteroids, budesonide, beclomethasone, fluticasone, ciclesonide. ResumoObjetivo: Revisar os mecanismos moleculares de ação, eficácia e potenciais efeitos adversos relacionados aos corticosteróides inalados (CEI) em crianças com asma persistente.Fontes dos dados: Artigos de língua inglesa da base de dados MEDLINE. Foram empregados os termos: corticosteroids, inhaled corticosteroids, asthma, children, beclomethasone, fluticasone, budesonide, ciclesonide, growth, adrenal insufficiency, bone mineral density, oral candidiasis. Foram selecionados guias de tratamento, artigos de revisão, estudos controlados, meta-análises e revisões sistemáticas que avaliaram a eficácia e os eventos adversos do tratamento com CEI. Síntese dos dados:Estudos in vivo e in vitro mostram que os CEI disponíveis apresentam diferentes características farmacociné-ticas e farmacodinâmicas que lhes conferem diferentes potenciais de ação. Os CEI também diferem quanto aos efeitos adversos sistêmicos e locais. Salienta-se a biodisponibilidade desses produtos como essencial para determinar a incidência de efeitos colaterais. Em linhas gerais, os CEI são capazes de controlar a asma, reduzindo o número de exacerbações, atendimentos médicos, hospitalizações e a necessidade de pulsos de corticosteróides orais. Também se observa melhora da função pulmonar, sobretudo nos pacientes com asma ...

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“…42,43 An experimental assay has documented the absence of effect on bone metabolism with ciclesonide, even in elevated doses. 20 …”

Section: Clinical Efficacymentioning

confidence: 99%

Corticosteróides inalados no tratamento da alergia respiratória: segurança versus eficácia

Rizzo¹,

Solé²

2006

J. Pediatr. (Rio J.)

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Objective: Review the molecular mechanisms of action, efficacy, and potential side effects associated with inhaled corticosteroids (ICS) in children with persistent asthma.Sources: Articles in English from MEDLINE. The following terms were used: corticosteroids, inhaled corticosteroids, asthma, children, beclomethasone, fluticasone, budesonide, ciclesonide, growth, adrenal insufficiency, bone mineral density, and oral candidiasis. Treatment guidelines, review articles, controlled trials, meta-analyses, and systematic reviews evaluating the efficacy and the adverse events of treatment with ICS were selected.Summary of the findings: In vivo and in vitro studies show that the available ICS have different pharmacokinetic and pharmacodynamic properties that result in different action potentials. ICS also differ as to the systemic and local side effects. The bioavailability of these products is essential in order to determine the incidence of side effects. In general, ICS are capable of controlling asthma, reducing the number of exacerbations, medical consultations, hospitalizations, and the need of oral corticosteroid (applications) bursts. Improvement can also be seen in pulmonary function, especially in patients with recent onset asthma. The most documented adverse effect is transitory decrease of growth rate.

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

Cited by 45 publications

References 34 publications

Molecular and clinical pharmacology of intranasal corticosteroids: clinical and therapeutic implications

Molecular and clinical pharmacology of intranasal corticosteroids: clinical and therapeutic implications

Inhaled corticosteroids in the treatment of respiratory allergy: safety vs. efficacy

Corticosteróides inalados no tratamento da alergia respiratória: segurança versus eficácia

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