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Current clinical management of pregnancies at risk of preterm delivery includes maternal antenatal corticosteroid (ACS) treatment. ACS activate the glucocorticoid receptor (GR) in all fetal tissues, maturing the lungs at the cost of impaired brain development, creating a need for novel treatments. The prodrug ciclesonide (CIC) activates the GR only when converted to des-CIC by specific enzymes, including acetylcholinesterase (ACHE) and carboxylesterase 1 and 2 (CES1, CES2). Importantly, the human placenta expresses ACHE and CES, and could potentially produce des-CIC, resulting in systemic fetal exposure and GR activation in all fetal tissues. We therefore investigated CES gene expression and conversion of CIC to des-CIC in human placentae collected during the second trimester (Tri2), and at preterm and term birth. Differential expression analysis was performed in Tri2 (n = 27), preterm (n = 34), and term (n = 40) placentae using the DESeq2 R -package. Conversion of CIC to des-CIC was measured in a subset of placenta samples (Tri2 n = 7, preterm n = 26, term n = 20) using functional assays. ACHE mRNA expression was higher in Tri2 male than preterm and term male placentae only, whereas CES1 mRNA expression was higher in Tri2 than preterm or term placentae of both sexes. Conversion of CIC to des-CIC did not differ between gestational ages. Conversion of CIC to des-CIC by the human placenta may preclude its use as a novel GR-agonist in threatened preterm birth. In vivo studies are required to confirm the extent to which placental activation occurs after maternal treatment. • Human placental ciclesonide activation decreased with increasing gestational age. • Human placenta activated ciclesonide at rates greater than reported in human lung. • Placental CES1 and ACHE expression was higher at Tri2 than later gestations. • Placental activation of ciclesonide may expose the fetus to active metabolite. [ABSTRACT FROM AUTHOR]

Background: Long-term COVID-19 symptoms are a serious health concern and impact medical resource utilization. Lung involvement in this pandemic due to the transmission trajectory elicits appropriate therapeutic management of pre-and post-viral infection. This aspect must cover both in terms of mitigation of disease by inhibiting the coronavirus RNA replication and in terms of repairing underlying tissues that are inflamed. This review article explores ciclesonide's treatment efficacy in patients with symptomatic COVID-19 infections supported by clinical findings. Methodology: A literature search was done using databases like PubMed and Science Direct to evaluate published works of literature from December 2019, when the outbreak of the new coronavirus was reported to date by using the following search terms; 'COVID -19 pneumonia, and corticosteroid', 'COVID-19 pneumonia and Ciclesonide', 'Coronavirus disease and corticosteroid/ciclesonide.' Both retrospective and randomized controlled trials (RCTs) highlighting the role of ciclesonide in COVID-19 pneumonia were eligible for inclusion. The search terms focused on studies conducted about local anti-inflammatory treatments and their use in managing long COVID-19 symptoms. Results: An inhaled ciclesonide is a standard drug that provides a local anti-inflammatory effect with the additional inhibition of viral proliferation recently indicated and researched for post-acute COVID-19 syndrome. Eight studies were included in the analysis. Among them, five studies have documented insufficient evidence to establish the clinical benefit of ciclesonide in COVID-19 in achieving the outcomes such as resolution/ alleviation of all COVID-19 symptoms, reduced hospitalization or mortality, exacerbation of pneumonia and reduction in duration of oxygen therapy. Three studies, however, have indicated that ciclesonide, alone or in combination, reduces hospital stays, lowers the risk of in-hospital mortality, reduces the length of COVID-19 viral shedding, and delays the progression to acute respiratory failure in patients with mild-to-severe COVID-19. Conclusion: Despite demographic limitations, early use of ciclesonide in COVID-19 patients has shown promising results in date research. However, a lack of studies with level-1 evidence is crucial to proving ciclesonide's efficacy and safety for long COVID-19 symptoms. [ABSTRACT FROM AUTHOR]

IntroductionDespite the advances in perinatal care, bronchopulmonary dysplasia (BPD) continues to be a highly prevalent chronic lung disease that affects newborns, especially affecting premature newborns. There is no specific cure for BPD, and treatments aimed at reducing the risk of developing BPD focus mainly on lung-protective ventilation strategies, surfactant therapy, and/or corticosteroid administration. Our objective was to evaluate whether systemic postnatal administration of a new glucocorticoid, ciclesonide, can attenuate the alteration of lung structure and pulmonary hypertension in a rat model of chorioamnionitis-induced BPD, with minimal adverse effects on the developing brain.MethodsEndotoxin (ETX) or saline was administered to pregnant rats by intra-amniotic (i.a.) injection on day 20 of pregnancy, and pups were delivered by cesarean section on day 22. Ciclesonide (0.5 mg/kg) was administered postnatally for five consecutive days to pups previously exposed to i.a. ETX. On postnatal day 14, we assessed lung function (compliance), lung structure (radial alveolar count, mean linear intercept, pulmonary vessel density), pulmonary hypertension, and brain histology (edema, inflammation, apoptosis, hemorrhage, and infarction).ResultOn postnatal day 14, the effects of i.a. ETX administration were evident in neonatal rats not receiving treatment; these animals showed impaired lung compliance, disrupted lung structure, and developing pulmonary hypertension compared to those receiving i.a. saline. Postnatal administration of ciclesonide for 5 days was associated with significantly better outcomes in terms of lung compliance, alveolarization, lung vascular growth, and pulmonary hypertension, without affecting the brain histological parameters evaluated.ConclusionPostnatal ciclesonide administration preserved lung function and structure and prevented pulmonary hypertension in a BPD model induced by antenatal i.a. ETX administration, without causing any adverse effects on brain development. These findings suggest that the new glucocorticoid, ciclesonide, may provide a novel strategy for the prevention of BPD; however, more long-term studies are required.

Background Coronavirus disease 2019 (COVID-19) is an ongoing global pandemic. Although systemic steroids play an important role in treating patients with severe COVID-19, the role of inhaled corticosteroids in non–critically ill, hospitalized patients with COVID-19 remains unclear. Methods We analyzed findings in non–critically ill, hospitalized patients with COVID-19 who were >18 years old and were admitted to 64 Japanese hospitals between January and September 2020. We performed propensity score matching analysis to evaluate 28-day and in-hospital mortality rates with or without inhaled ciclesonide within 2 days of admission. Sensitivity analyses using inverse probability weighting analysis, and generalized estimating equation method were also performed. Results Eligible patients (n = 3638) were divided into ciclesonide (n = 290) and control (n = 3, 393) groups. The 1-to-4 propensity score matching analysis included 271 ciclesonide users and 1084 nonusers. There were no significant differences between the 2 groups for 28-day (3.3% vs 2.3%; risk difference, 1.0% [95% confidence interval, −1.2 to 3.3]) or in-hospital (4.8% vs 2.6%; risk difference, 2.2 [−.5 to 4.9]) mortality rates. The sensitivity analysis showed similar outcomes. Conclusions From this multicenter observational study in Japan, inhaled ciclesonide did not decrease 28-day or in-hospital mortality rates in non–critically ill, hospitalized patients with COVID-19. Future large, multinational, randomized trials are required to confirm our results. [ABSTRACT FROM AUTHOR]

Background: The efficacy of inhaled corticosteroid (ICS) in the treatment of patients with COVID-19 has been evaluated in randomized controlled trials (RCTs), however, their findings are not consistent. Methods: PubMed, Embase, Cochrane Library, ClinicalTrials.gov, Scopus, Web of Science and Google Scholar were searched to June 10, 2023. Only RCTs that investigated the clinical efficacy and safety of ICS for patients with COVID-19 were included. Results: Eleven RCTs were included. ICS users had significantly higher rate of symptom alleviation at day 14 than the control group (risk ratio [RR], 1.13; 95% CI, 1.04–1.23; I2 = 42%). Additionally, no significant difference between the ICS users and the control group was observed in the composite outcome of urgent care, emergency department (ED) visit or hospitalization (RR, 0.43; 95% CI, 0.08–2.48; I2 = 85%) and hospitalization or death (RR, 0.85; 95% CI, 0.64–1.12; I2 = 0%). Finally, ICS user had a non-significantly lower risk of death at day 28 than the control group (0.63% vs 0.99%; RR, 0.82; 95% CI, 0.43–1.56; I2 = 0%). Conclusions: Additional ICS use, particularly inhaled budesonide may help symptom relief in patients with COVID-19. However, ICS use did not help reduce the risk of urgent care, ED visit, hospitalization, or death.

Abstract Background Despite the introduction of vaccination, there remains a need for pre-exposure prophylactic agents against SARS-CoV-2. Several patient groups are more vulnerable to SARS-CoV-2 infection by virtue of underlying health conditions, treatments received or suboptimal responses to vaccination. Methods PROTECT-V is a platform trial testing pre-exposure prophylactic interventions against SARS-CoV-2 infection in vulnerable patient populations (organ transplant recipients; individuals with oncological/haematological diagnoses, immune deficiency or autoimmune diseases requiring immunosuppression or on dialysis). Multiple agents can be evaluated across multiple vulnerable populations sharing placebo groups, with the option of adding additional treatments at later time points as these become available. The primary endpoint is symptomatic SARS-CoV-2 infection, and each agent will be independently evaluated in real time when the required number of events occurs. Presently, three agents are approved in the platform: intranasal niclosamide, nasal and inhaled ciclesonide and intravenous sotrovimab. Discussion Despite the introduction of vaccination, there remains a need for pre-exposure prophylactic agents against SARS-CoV-2. Several patient groups are more vulnerable to COVID-19 disease by virtue of underlying health conditions, treatments received or suboptimal responses to vaccination. Trial registration ClinicalTrials.gov NCT04870333. EudraCT 2020-004144-28

Abstract Background The successful management of patients infected with coronavirus disease 2019 (COVID-19) with inhaled ciclesonide has been reported, however few studies have investigated its application among hospitalized patients. Methods This retrospective cohort study enrolled all adult patients admitted to our hospital with confirmed COVID-19 infection from May to June 2021. Critical patients who received mechanical ventilation within 24 h after admission and those who started ciclesonide more than 14 days after symptom onset were excluded. The in-hospital mortality rate was compared between those who did and did not receive inhaled ciclesonide. Results A total of 269 patients were enrolled, of whom 184 received inhaled ciclesonide and 85 did not. The use of ciclesonide was associated with lower in-hospital mortality (7.6% vs. 23.5%, p = 0.0003) and a trend of shorter hospital stay (12.0 (10.0–18.0) days vs. 13.0 (10.0–25.3) days, p = 0.0577). In subgroup analysis, the use of inhaled ciclesonide significantly reduced mortality in the patients with severe COVID-19 infection (6.8% vs. 50.0%, p

SARS-CoV-2 viremia is associated with increased acute lung injury (ALI) and mortality in children and adults. The mechanisms by which viral components in the circulation mediate ALI in COVID-19 remain unclear. We tested the hypothesis that the SARS-CoV-2 envelope (E) protein induces Toll-like receptor (TLR)-mediated ALI and lung remodeling in a model of neonatal COVID-19. Neonatal C57BL6 mice given intraperitoneal E protein injections revealed a dose-dependent increase in lung cytokines [interleukin 6 (Il6), tumor necrosis factor (Tnfa), and interleukin 1 beta (Il1b)] and canonical proinflammatory TLR signaling. Systemic E protein induced endothelial immune activation, immune cell influx, and TGFb signaling and lung matrix remodeling inhibited alveolarization in the developing lung. E protein-mediated ALI and transforming growth factor beta (TGFb) signaling was repressed in Tlr2-/-, but not Tlr4-/- mice. A single dose of intraperitoneal E protein injection induced chronic alveolar remodeling as evidenced by a decrease in radial alveolar counts and increase in mean linear intercepts. Ciclesonide, a synthetic glucocorticoid, inhibited E protein-induced proinflammatory TLR signaling and ALI. In vitro, E protein-mediated inflammation and cell death were TLR2-dependent in human primary neonatal lung endothelial cells and were rescued by ciclesonide. This study provides insight into the pathogenesis of ALI and alveolar remodeling with SARS-CoV-2 viremia in children, whereas revealing the efficacy of steroids. NEW & NOTEWORTHY We reveal that the envelope protein of SARS-CoV-2 mediates acute lung injury (ALI) and alveolar remodeling through Toll-like receptor activation, which is rescued by the glucocorticoid, ciclesonide. [ABSTRACT FROM AUTHOR]

Background: Despite the introduction of vaccination, there remains a need for pre-exposure prophylactic agents against SARS-CoV-2. Several patient groups are more vulnerable to SARS-CoV-2 infection by virtue of underlying health conditions, treatments received or suboptimal responses to vaccination. Methods: PROTECT-V is a platform trial testing pre-exposure prophylactic interventions against SARS-CoV-2 infection in vulnerable patient populations (organ transplant recipients; individuals with oncological/haematological diagnoses, immune deficiency or autoimmune diseases requiring immunosuppression or on dialysis). Multiple agents can be evaluated across multiple vulnerable populations sharing placebo groups, with the option of adding additional treatments at later time points as these become available. The primary endpoint is symptomatic SARS-CoV-2 infection, and each agent will be independently evaluated in real time when the required number of events occurs. Presently, three agents are approved in the platform: intranasal niclosamide, nasal and inhaled ciclesonide and intravenous sotrovimab. Discussion: Despite the introduction of vaccination, there remains a need for pre-exposure prophylactic agents against SARS-CoV-2. Several patient groups are more vulnerable to COVID-19 disease by virtue of underlying health conditions, treatments received or suboptimal responses to vaccination. Trial registration: ClinicalTrials.gov NCT04870333. EudraCT 2020-004144-28 [ABSTRACT FROM AUTHOR]

Ciclesonide (Cic) is approved as an inhalant for asthma and was clinically tested as a candidate therapy for coronavirus disease 2019 (COVID-19). Its active metabolite Cic2 was recently reported to suppress genomic RNA replication of severe acute respiratory syndrome coronavirus 2. In this study, we designed and synthesized a set of ciclesonide-acetal (Cic-acetal) derivatives. Among designated compounds, some Cic-acetal derivatives with a linear alkyl chain exhibited strong viral copy-number reduction activities compared with Cic2. These compounds might serve as lead compounds for developing novel anti-COVID-19 agents.

The aim of this study was to determine the efficacy and safety of ciclesonide in the treatment of novel coronavirus disease 2019 (COVID-19) as gauged by pneumonia progression. This multi-center, open-label randomized trial was conducted with patients recruited from 22 hospitals across Japan. Participants were patients admitted with mild or asymptomatic COVID-19 without signs of pneumonia on chest X-rays. Asymptomatic participants were diagnosed after identification through contact tracing. Trial participants were randomized to either the ciclesonide or control arm. Participants in the treatment arm were administered 400 µg of ciclesonide three times a day over seven consecutive days. The primary endpoint was exacerbated pneumonia within seven days. Secondary outcomes were changes in clinical findings, laboratory findings, and changes over time in the amount of the viral genome. In the treatment group, 16 patients (39.0%) were classified as having exacerbated pneumonia compared to 9 (18.8%) in the control group. The risk ratio (RR) was 2.08 (95% confidence interval (CI): 1.15-3.75), indicating a worsening of pneumonia in the ciclesonide group. Significant differences were noted in participants with a fever on admission (RR: 2.62, 90% CI: 1.17-5.85, 95% CI: 1.00-6.82) and individuals 60 years of age or older (RR: 8.80, 90% CI: 1.76-44.06, 95% CI: 1.29-59.99). The current results indicated that ciclesonide exacerbates signs of pneumonia on images in individuals with mild or asymptomatic symptoms of COVID-19 without worsening clinical symptoms. [ABSTRACT FROM AUTHOR]

Background: The successful management of patients infected with coronavirus disease 2019 (COVID-19) with inhaled ciclesonide has been reported, however few studies have investigated its application among hospitalized patients.Methods: This retrospective cohort study enrolled all adult patients admitted to our hospital with confirmed COVID-19 infection from May to June 2021. Critical patients who received mechanical ventilation within 24 h after admission and those who started ciclesonide more than 14 days after symptom onset were excluded. The in-hospital mortality rate was compared between those who did and did not receive inhaled ciclesonide.Results: A total of 269 patients were enrolled, of whom 184 received inhaled ciclesonide and 85 did not. The use of ciclesonide was associated with lower in-hospital mortality (7.6% vs. 23.5%, p = 0.0003) and a trend of shorter hospital stay (12.0 (10.0-18.0) days vs. 13.0 (10.0-25.3) days, p = 0.0577). In subgroup analysis, the use of inhaled ciclesonide significantly reduced mortality in the patients with severe COVID-19 infection (6.8% vs. 50.0%, p < 0.0001) and in those with a high risk of mortality (16.4% vs. 43.2%, p = 0.0037). The use of inhaled ciclesonide also reduced the likelihood of receiving mechanical ventilation in the patients with severe COVID-19 infection. After multivariate analysis, inhaled ciclesonide remained positively correlated with a lower risk of in-hospital mortality (odds ratio: 0.2724, 95% confidence interval: 0.087-0.8763, p = 0.0291).Conclusions: The use of inhaled ciclesonide in hospitalized patients with COVID-19 infection can reduce in-hospital mortality. Further randomized studies in patients with moderate to severe COVID-19 infection are urgently needed. [ABSTRACT FROM AUTHOR]

Introduction: Despite the advances in perinatal care, bronchopulmonary dysplasia (BPD) continues to be a highly prevalent chronic lung disease that affects newborns, especially affecting premature newborns. There is no specific cure for BPD, and treatments aimed at reducing the risk of developing BPD focus mainly on lung-protective ventilation strategies, surfactant therapy, and/or corticosteroid administration. Our objective was to evaluate whether systemic postnatal administration of a new glucocorticoid, ciclesonide, can attenuate the alteration of lung structure and pulmonary hypertension in a rat model of chorioamnionitis-induced BPD, with minimal adverse effects on the developing brain., Methods: Endotoxin (ETX) or saline was administered to pregnant rats by intra-amniotic (i.a.) injection on day 20 of pregnancy, and pups were delivered by cesarean section on day 22. Ciclesonide (0.5 mg/kg) was administered postnatally for five consecutive days to pups previously exposed to i.a. ETX. On postnatal day 14, we assessed lung function (compliance), lung structure (radial alveolar count, mean linear intercept, pulmonary vessel density), pulmonary hypertension, and brain histology (edema, inflammation, apoptosis, hemorrhage, and infarction)., Result: On postnatal day 14, the effects of i.a. ETX administration were evident in neonatal rats not receiving treatment; these animals showed impaired lung compliance, disrupted lung structure, and developing pulmonary hypertension compared to those receiving i.a. saline. Postnatal administration of ciclesonide for 5 days was associated with significantly better outcomes in terms of lung compliance, alveolarization, lung vascular growth, and pulmonary hypertension, without affecting the brain histological parameters evaluated., Conclusion: Postnatal ciclesonide administration preserved lung function and structure and prevented pulmonary hypertension in a BPD model induced by antenatal i.a. ETX administration, without causing any adverse effects on brain development. These findings suggest that the new glucocorticoid, ciclesonide, may provide a novel strategy for the prevention of BPD; however, more long-term studies are required., Competing Interests: CC and FR disclose that they are Chiesi employees. XM served as a consultant for this study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Mielgo, Gastiasoro, Catozzi, Ricci, Gomez-Solaetxe, Murgia and Rey-Santano.)

The recent outbreak "Coronavirus Disease 2019 (COVID-19)" is caused by fast-spreading and highly contagious severe acute respiratory syndrome coronavirus 2 (SARS-CoV2). This virus enters into the human respiratory system by binding of the viral surface spike glycoprotein (S-protein) to an angiotensin-converting enzyme2 (ACE2) receptor that is found in the nasal passage and oral cavity of a human. Both spike protein and the ACE2 receptor have been identified as promising therapeutic targets to develop anti-SARS-CoV2 drugs. No therapeutic drugs have been developed as of today except for some vaccines. Therefore, potent therapeutic agents are urgently needed to combat the COVID-19 infections. This goal would be achieved only by applying drug repurposing and computational approaches. Thus, based on drug repurposing approach, we have investigated 16 bioactive components (1–16) from different nasal spray solutions to check their efficacies against human ACE2 and SARS-CoV2 spike proteins by performing molecular docking and molecular dynamic (MD) simulation studies. In this study, three bioactive components namely ciclesonide (8), levocabastine (13), and triamcinolone acetonide (16) have been found as promising inhibitory agents against SARS-CoV2 spike and human ACE2 receptor proteins with excellent binding affinities, comparing to reference drugs such as nafamostat, arbidol, losartan, and benazepril. Furthermore, MD simulations were performed (triplicate) for 100 ns to confirm the stability of 8, 13, and 16 with said protein targets and to compute MM-PBSA-based binding-free energy calculations. Thus, bioactive components 8, 13, and 16 open the door for researchers and scientist globally to investigate them against SARS-CoV2 through in vitro and in vivo analysis. [ABSTRACT FROM AUTHOR]

Ciclesonide is an inhaled corticosteroid used to treat asthma and has been repurposed as a treatment for mildly ill COVID-19 patients, but its precise mechanism of action is unclear. Herein, we report that ciclesonide blocks the coronavirus-induced production of the cytokines IL-6, IL-8, and MCP-1 by increasing IκBα protein levels and significantly decreasing p65 nuclear translocation. Furthermore, we found that the combination of ciclesonide and dbq33b, a potent tylophorine-based coronavirus inhibitor that affects coronavirus-induced NF-κB activation a little, additively and synergistically decreased coronavirus-induced IL-6, IL-8, and MCP-1 cytokine levels, and synergistically inhibited the replication of both HCoV-OC43 and SARS-CoV-2. Collectively, the combination of ciclesonide and dbq33b merits consideration as a treatment for COVID-19 patients who may otherwise be overwhelmed by high viral loads and an NF-κB-mediated cytokine storm. [ABSTRACT FROM AUTHOR]

To assess the efficacy of inhaled ciclesonide in reducing the risk of adverse outcomes in COVID-19 outpatients at risk of developing severe illness. COVERAGE is an open-label, randomized controlled trial. Outpatients with documented COVID-19, risk factors for aggravation, symptoms for ≤7 days, and absence of criteria for hospitalization are randomly allocated to either a control arm or one of several experimental arms, including inhaled ciclesonide. The primary efficacy endpoint is COVID-19 worsening (hospitalization, oxygen therapy at home, or death) by Day 14. Other endpoints are adverse events, maximal follow-up score on the WHO Ordinal Scale for Clinical Improvement, sustained alleviation of symptoms, cure, and RT-PCR and blood parameter evolution at Day 7. The trial's Safety Monitoring Board reviewed the first interim analysis of the ciclesonide arm and recommended halting it for futility. The results of this analysis are reported here. The analysis involved 217 participants (control 107, ciclesonide 110), including 111 women and 106 men. Their median age was 63 years (interquartile range 59–68), and 157 of 217 (72.4%) had at least one comorbidity. The median time since first symptom was 4 days (interquartile range 3–5). During the 28-day follow-up, 2 participants died (control 2/107 [1.9%], ciclesonide 0), 4 received oxygen therapy at home and were not hospitalized (control 2/107 [1.9%], ciclesonide 2/110 [1.8%]), and 24 were hospitalized (control 10/107 [9.3%], ciclesonide 14/110 [12.7%]). In intent-to-treat analysis of observed data, 26 participants reached the composite primary endpoint by Day 14, including 12 of 106 (11.3%, 95% CI: 6.0%–18.9%) in the control arm and 14 of 106 (13.2%; 95% CI: 7.4–21.2%) in the ciclesonide arm. Secondary outcomes were similar for both arms. Our findings are consistent with the European Medicines Agency's COVID-19 task force statement that there is currently insufficient evidence that inhaled corticosteroids are beneficial for patients with COVID-19. [ABSTRACT FROM AUTHOR]

Purpose To characterize the clinical features and outcome of patients treated at a specialized hospital for coronavirus disease 2019 (COVID-19). Methods We retrospectively reviewed the symptoms on admission, treatment, and outcome of a total of 300 patients with mild (peripheral oxygen saturation (SpO.sub.2) [greater than or equal to] 96%), moderate I (93% < SpO.sub.2 < 96%), moderate II (SpO.sub.2 [less than or equal to] 93%) and severe (requiring admission to the ICU or mechanical ventilation) COVID-19. Results Median age was 53 (interquartile range [IQR] 33-72) years and 57% was male. The number of patients with mild, moderate I, II and severe condition was 85, 138, 61 and 16, respectively. Common presenting symptoms were cough (n = 71), loss of taste (42), loss of smell (39), fever [greater than or equal to] 37.5 °C (36). Dyspnea was observed only 21 cases; 57 reported no symptoms on admission. Favipiravir, ciclesonide, dexamethasone, and heparin were administered in 106, 168, 65, and 38 patients, respectively, but not remdesivir. The median duration of hospitalization was 10 (7-15) days. All patients with mild and moderate I severity were discharged. Among the 77 patients classified as moderate II or severe, 3 were transferred to tertiary hospitals for further treatment on the day of admission. The respiratory condition worsened in 21 patients; 18 required transfer to tertiary hospitals 3 (median) days after admission and 3 died. Conclusion Respiratory condition recovered in 92%; whereas it worsened in 7% and the mortality rate was 1%. The ratios of male patients, of patients with diabetes mellitus in those with the decreased respiratory condition, were significantly higher than recovered., Author(s): Yutaka Oda [sup.1], Satoshi Shiraishi [sup.2], Motoko Shimada [sup.1], Osamu Kurai [sup.3] Author Affiliations: (1) Department of Anesthesiology, Osaka City Juso Hospital, , 2-12-27 Nonaka-kita, Yodogawa-ku, 532-0034, Osaka, Japan [...]

Summary: Background: The effectiveness of combination therapy for COVID-19 pneumonia remains unclear. We evaluated favipiravir, camostat, and ciclesonide combination therapy in patients with moderate COVID-19 pneumonia. Methods: In this open-label phase 3 study, hospitalized adults who were positive for SARS-CoV-2 and had COVID-19 pneumonia were enrolled prior to official vaccination drive in Japan. Participants were randomly assigned to favipiravir monotherapy or favipiravir + camostat + ciclesonide combination therapy. The primary outcome was the length of hospitalization due to COVID-19 infection after study treatment. The hospitalization period was calculated from the time of admission to the time of patient discharge using the clinical management guide of COVID-19 for front-line healthcare workers developed by the Japanese Ministry of Health, Labour, and Welfare (Version 3). Cases were registered between November 11, 2020, and May 31, 2021. Japan Registry of Clinical Trials registration: jRCTs031200196. Findings: Of 121 enrolled patients, 56 received monotherapy and 61 received combination therapy. Baseline characteristics were balanced between the groups. The median time of hospitalization was 10 days for the combination and 11 days for the monotherapy group. The median time to discharge was statistically significantly lower in the combination therapy vs monotherapy group (HR, 1·67 (95% CI 1·03–2·7; P = 0·035). The hospital discharge rate was statistically significantly higher in the combination therapy vs monotherapy group in patients with less severe COVID-19 infections and those who were ≤60 years. There were no significant differences in clinical findings between the groups at 4, 8, 11, 15, and 29 days. Adverse events were comparable between the groups. There were two deaths, with one in each group. Interpretation: Combination oral favipiravir, camostat and, ciclesonide therapy could decrease the length of hospitalization stays without safety concerns in patients with moderate COVID-19 pneumonia. However, lack of hard clinical primary outcome is one of the major limitations of the study. Funding: This research was supported by Japan Agency for Medical Research and Development (AMED) under Grant Number 20fk0108261h0001.

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No specific therapy is available for COVID-19. We report the effectiveness and adverse effects of triple therapy with hydroxychloroquine, azithromycin, and ciclesonide in patients with COVID-19 pneumonia. The clinical condition of the patients improved within 5 days in response to the therapy.

Ciclesonide (CIC), an inhaled corticosteroid for bronchial asthma is currently available as metered dose inhaler (CIC–MDI) which possesses a major challenge in the management of the elderly, critically ill patients and children. In this work, nebulized CIC nano-structure lipid particles (CIC-NLPs) were prepared and evaluated for their deep pulmonary delivery and cytotoxicity to provide additional clinical benefits to patients in controlled manner and lower dose. The bio-efficacy following nebulization in ovalbumin (OVA) induced asthma Balb/c mice compared to commercial (CIC–MDI) was also assessed. The developed NLPs of 222.6 nm successfully entrapped CIC (entrapment efficiency 93.3%) and exhibited favorable aerosolization efficiency (mass median aerodynamic diameter (MMAD) 2.03 μm and fine particle fraction (FPF) of 84.51%) at lower impactor stages indicating deep lung deposition without imparting any cytotoxic effect up to a concentration of 100 μg/ml. The nebulization of 40 µg dose of the developed CIC-NLPs revealed significant therapeutic impact in the mitigation of the allergic airways inflammations when compared to 80 µg dose of the commercial CIC–MDI inhaler (Alvesco®). Superior anti-inflammatory and antioxidative stress effects characterized by significant decrease (p