Visualizing the spatial localization of ciclesonide and its metabolites in rat lungs after inhalation of 1-μm aerosol of ciclesonide by desorption electrospray ionization-time of flight mass spectrometry imaging

Yamamoto, Eiichi; Taquahashi, Yuhji; Kuwagata, Makiko; Saito, Hayato; Matsushita, Kohei; Toyoda, Takeshi; Sato, Futoshi; Kitajima, Satoshi; Ogawa, Kumiko; Izutsu, Ken‐ichi; Saito, Yoshiro; Hirabayashi, Yoko; Iimura, Yasuo; Honma, Masamitsu; Okuda, Haruhiro; Goda, Yukihiro

doi:10.1016/j.ijpharm.2021.120241

Cited by 14 publications

(17 citation statements)

References 36 publications

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“…However, some studies have suggested that ciclesonide might suppress viral replication by inhibiting viral endoribonuclease (NSP15), p21 activated kinase-1, or viral RNA replication-transcription complex [9,12,15]. Ciclesonide is a prodrug that is converted to the active metabolite desisobutyryl-ciclesonide (des-CIC) by tissue esterases in the lung [15,16]. Although both ciclesonide and des-CIC are capable of interacting with NSP15, des-CIC has larger binding energy [9,15].…”

Section: Discussionmentioning

confidence: 99%

“…Considering that ciclesonide is an inhalant, we expected a viral inhibitory effect in saliva during the early stage of infection, but contrary to expectations, the ciclesonide group did not display any difference in salivary SARS-CoV-2 suppression compared with the standard care group. Since ciclesonide is inhaled into the lower airways, the exposure time in the oral cavity is short, and the active metabolites generated in the lung tissue mainly exert antiviral effects [9,16]. Thus, ciclesonide inhalation may not sufficiently suppress salivary SARS-CoV-2.…”

Section: Discussionmentioning

confidence: 99%

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Ciclesonide Inhaler Treatment for Mild-to-Moderate COVID-19: A Randomized, Open-Label, Phase 2 Trial

Song

Yoon

Seo

et al. 2021

JCM

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Although some intravenous drugs have been used to treat coronavirus disease 2019 (COVID-19), no effective antiviral agents are currently available in the outpatient setting. We aimed to evaluate the efficacy and adverse events of 14-day ciclesonide treatment vs. standard care for patients with mild-to-moderate COVID-19. A randomized, open-label, multicenter clinical trial of ciclesonide inhalers was conducted in patients with mild-to-moderate COVID-19. Patients were enrolled within 3 days of diagnosis or within 7 days from symptom onset and randomly assigned to receive either ciclesonide (320 µg inhalation twice per day for 14 days) or standard care. The primary endpoint was the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) eradication rate on day 14 from study enrollment. Clinical status was assessed once daily, and serial nasopharyngeal viral load was evaluated by quantitative reverse transcription polymerase chain reaction. There were 35 and 26 patients in the ciclesonide and standard care groups, respectively. The SARS-CoV-2 eradication rate at day 14 was significantly higher in the ciclesonide group (p = 0.021). In multivariate analysis, SARS-CoV-2 negative conversion within 14 days was 12 times more likely in the ciclesonide group (95% confidence interval, 1.187–125.240). Additionally, the clinical failure rate (high-flow nasal oxygen therapy or mechanical ventilation) was significantly lower in the ciclesonide group (p = 0.034). In conclusion, ciclesonide inhalation shortened SARS-CoV-2 viral shedding duration, and it may inhibit the progression to acute respiratory failure in patients with mild-to-moderate COVID-19. Clinical Trial Registration NCT04330586.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Ciclesonide Inhaler Treatment for Mild-to-Moderate COVID-19: A Randomized, Open-Label, Phase 2 Trial

Song

Yoon

Seo

et al. 2021

JCM

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“…Recently, Yamamoto et al (2021), evaluated if 1-μm aerosol particles of inhaled corticosteroid, ciclesonide, routinely used for asthma treatment, can be efficiently delivered to the lungs. The drug was given to rats as a single aerosol dose, and the distributions of the drug, its desisobutyryl metabolite, and oleate ester of desisobutyryl-ciclesonide formed in the lungs were imaged by DESI-MSI in MS and MS/MS modes.…”

Section: Tissue Drug Distributionmentioning

confidence: 99%

Desorption electrospray ionization mass spectrometry imaging in discovery and development of novel therapies

Soudah

Zoabi

Margulis

2021

Mass Spectrometry Reviews

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Desorption electrospray ionization mass spectrometry imaging (DESI‐MSI) is one of the least specimen destructive ambient ionization mass spectrometry tissue imaging methods. It enables rapid simultaneous mapping, measurement, and identification of hundreds of molecules from an unmodified tissue sample. Over the years, since its first introduction as an imaging technique in 2005, DESI‐MSI has been extensively developed as a tool for separating tissue regions of various histopathologic classes for diagnostic applications. Recently, DESI‐MSI has also emerged as a versatile technique that enables drug discovery and can guide the efficient development of drug delivery systems. For example, it has been increasingly employed for uncovering unique patterns of in vivo drug distribution, the discovery of potentially treatable biochemical pathways, revealing novel druggable targets, predicting therapeutic sensitivity of diseased tissues, and identifying early tissue response to pharmacological treatment. These and other recent advances in implementing DESI‐MSI as the tool for the development of novel therapies are highlighted in this review.

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“…(iii) Analytical methods: more sensitive or insightful methods for application to metabolism studies, e.g. mass spectrometry imaging [110,111].…”

Section: Development and Adoption Of New Technologiesmentioning

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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Visualizing the spatial localization of ciclesonide and its metabolites in rat lungs after inhalation of 1-μm aerosol of ciclesonide by desorption electrospray ionization-time of flight mass spectrometry imaging

Cited by 14 publications

References 36 publications

Ciclesonide Inhaler Treatment for Mild-to-Moderate COVID-19: A Randomized, Open-Label, Phase 2 Trial

Ciclesonide Inhaler Treatment for Mild-to-Moderate COVID-19: A Randomized, Open-Label, Phase 2 Trial

Desorption electrospray ionization mass spectrometry imaging in discovery and development of novel therapies

Drug metabolism in the lungs: opportunities for optimising inhaled medicines

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