Ciclesonide: A Pro-Soft Drug Approach for Mitigation of Side Effects of Inhaled Corticosteroids

Mukker, Jatinder Kaur; Singh, Ravi Shankar Prasad; Derendorf, Hartmut

doi:10.1016/j.xphs.2016.05.004

Cited by 18 publications

(15 citation statements)

References 56 publications

(84 reference statements)

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“…Des-CIC has anti-inflammatory activity with affinity for the glucocorticoid receptor that is 100-120 times higher than the parent compound. The anti-inflammatory effects of des-CIC in human asthma are thought to be primarily mediated via inhibition of tumour necrosis factoralpha and the Th-2 cytokine interleukin-4 in airway epithelial cells [12], two cytokines implicated in the pathogenesis of equine asthma [20,21]. The maximal dose of ciclesonide to be tested in the first study was based on the clinical equivalence observed in human patients between fluticasone propionate and ciclesonide (80 lg of ciclesonide are considered clinically equivalent to 100 lg of fluticasone [22]) and on previous experiments performed in horses during which fluticasone propionate was shown to be effective at doses ≥2000 lg/day [1,3,4].…”

Section: Discussionmentioning

confidence: 99%

“…It displays high plasma protein binding (~99% vs. 71-98% of most ICSs) and rapid systemic clearance. As systemic side effects of inhaled corticosteroids result from the interaction of unbound systemically available fraction of inhaled corticosteroids with glucocorticoid receptors expressed by non-pulmonary cells, ciclesonide has an excellent safety profile [12]. Suppression of endogenous cortisol levels following inhaled corticosteroid therapy is indicative of an effect on the hypothalamicpituitary-adrenal axis and represents undesired systemic activity.…”

Section: Discussionmentioning

confidence: 99%

“…For this reason, it is considered an inhaled corticosteroid with an excellent safety profile. Ciclesonide enzymatic activation occurs within the lungs and increases the affinity of the drug for glucocorticoid receptors as much as 100-120 times [12]. Due to its favourable safety profile, ciclesonide might be a valuable drug for asthma-affected horses.…”

Section: Introductionmentioning

confidence: 99%

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Effect of different doses of inhaled ciclesonide on lung function, clinical signs related to airflow limitation and serum cortisol levels in horses with experimentally induced mild to severe airway obstruction

Lavoie

Bullone

Rodrigues

et al. 2019

Equine Veterinary Journal

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Summary Background Inhaled corticosteroids are effective for the treatment of equine asthma but they induce cortisol suppression with potential side effects. Objectives To study the efficacy of ciclesonide, an inhaled corticosteroid with an improved safety profile, on lung function, clinical signs related to airway obstruction, and serum cortisol levels in asthmatic horses exposed to a mouldy hay challenge. Study design Cross‐over placebo controlled, blinded, randomised experiment. Methods Sixteen horses were enrolled in three subsequent dose‐titration studies (8 horses/study) to investigate the effects of inhaled ciclesonide administered for 2 weeks at doses ranging from 450 to 2700 μg twice daily or 3712.5 μg once daily. Systemic dexamethasone (0.066 mg/kg per os) was our positive control. A placebo group was also studied. Lung function and clinical scores were blindly performed before and after 7 and 14 days of treatment. Serum cortisol was measured before and after 3, 5, 7, 10, 14 days of treatment as well as 3 and 7 days post treatment. Results After 7 days, dexamethasone induced a significant reduction in pulmonary resistance (from 2.5 ± 0.6 at day 0 to 1.1 ± 0.7 cm H2O/L/s), pulmonary elastance (5.0 ± 2.6 to 1.2 ± 1.0 cm H2O/L), and of the weighted clinical score (14.8 ± 4.7 to 8.0 ± 4.4). Similarly, ciclesonide 1687.5 μg twice daily significantly improved pulmonary resistance (2.7 ± 1.1 to 1.6 ± 0.8 cm H2O/L/s), pulmonary elastance (5.2 ± 3.1 to 2.2 ± 1.3 cm H2O/L), and weighted clinical score (13 ± 2.9 to 10.8 ± 4.2). Serum cortisol suppression (<50 nmol/L) systematically occurred with dexamethasone from day 3 of treatment up to day 3 post treatment, but not with ciclesonide at any tested doses. Placebo did not exert any significant beneficial effect. Main limitations Experimentally induced asthma exacerbations in horses might respond differently to treatment than naturally occurring exacerbations. Conclusions Inhaled ciclesonide is an effective treatment for horses with equine asthma. Serum cortisol was unaffected by treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effect of different doses of inhaled ciclesonide on lung function, clinical signs related to airflow limitation and serum cortisol levels in horses with experimentally induced mild to severe airway obstruction

Lavoie

Bullone

Rodrigues

et al. 2019

Equine Veterinary Journal

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“…Ciclesonide is also a prodrug which is activated by metabolism after oral inhalation [53]. Ciclesonide has been shown to be metabolized in vitro both in nasal mucosal cells and in various models (precision cut lung slices, primary bronchial epithelial cells, A549 type II alveolar cells), which are used to represent the lungs [45,54].…”

Section: Inhaled Prodrugsmentioning

confidence: 99%

Drug metabolism in the lungs: opportunities for optimising inhaled medicines

Enlo-Scott

Bäckström

Mudway

et al. 2021

Expert Opinion on Drug Metabolism & Toxicology

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Introduction:The lungs possess many xenobiotic metabolizing enzymes which influence the pharmacokinetics and safety of inhaled medicines. Anticipating metabolism in the lungs provides an opportunity to optimize new inhaled medicines and overcome challenges in their development.Areas covered: This article summarizes current knowledge on xenobiotic metabolizing enzymes in the lungs. The impact of metabolism on inhaled medicines is considered with examples of how this impacts small molecules, biologics and macromolecular formulation excipients. Methods for measuring and predicting xenobiotic lung metabolism are critically reviewed and the potential for metabolism to influence inhalation toxicology is acknowledged. Expert opinion: Drugs can be optimized by molecular modification to (i) reduce systemic exposure using a 'soft drug' approach, (ii) improve bioavailability by resisting metabolism, or (iii) use a prodrug approach to overcome pharmacokinetic limitations. Drugs that are very labile in the lungs may require a protective formulation. Some drug carriers being investigated for PK-modification rely on lung enzymes to trigger drug release or biodegrade. Lung enzyme activity varies with age, race, smoking status, diet, drug exposure and preexisting lung disease. New experimental technologies to study lung metabolism include tissue engineered models, improved analytical capability and in silico models.

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“…Alternatively, for IBD the corticosteroid can be altered to reduce gastrointestinal absorption and/ or enhance first-pass hepatic metabolism. Prolonged retention in the tissue can be achieved by increasing lipophilicity, as with fluticasone propionate (FP) and fluticasone furoate (FF) and mometasone furoate, or by forming soluble intracellular fatty acid esters, as with budesonide and ciclesonide [9,15,63,72,73].…”

Section: Pharmacokinetics Of Corticosteroidsmentioning

confidence: 99%