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2.
Lancet ; 398(10303): 843-855, 2021 09 04.
Article in English | MEDLINE | ID: covidwho-2106189

ABSTRACT

BACKGROUND: A previous efficacy trial found benefit from inhaled budesonide for COVID-19 in patients not admitted to hospital, but effectiveness in high-risk individuals is unknown. We aimed to establish whether inhaled budesonide reduces time to recovery and COVID-19-related hospital admissions or deaths among people at high risk of complications in the community. METHODS: PRINCIPLE is a multicentre, open-label, multi-arm, randomised, controlled, adaptive platform trial done remotely from a central trial site and at primary care centres in the UK. Eligible participants were aged 65 years or older or 50 years or older with comorbidities, and unwell for up to 14 days with suspected COVID-19 but not admitted to hospital. Participants were randomly assigned to usual care, usual care plus inhaled budesonide (800 µg twice daily for 14 days), or usual care plus other interventions, and followed up for 28 days. Participants were aware of group assignment. The coprimary endpoints are time to first self-reported recovery and hospital admission or death related to COVID-19, within 28 days, analysed using Bayesian models. The primary analysis population included all eligible SARS-CoV-2-positive participants randomly assigned to budesonide, usual care, and other interventions, from the start of the platform trial until the budesonide group was closed. This trial is registered at the ISRCTN registry (ISRCTN86534580) and is ongoing. FINDINGS: The trial began enrolment on April 2, 2020, with randomisation to budesonide from Nov 27, 2020, until March 31, 2021, when the prespecified time to recovery superiority criterion was met. 4700 participants were randomly assigned to budesonide (n=1073), usual care alone (n=1988), or other treatments (n=1639). The primary analysis model includes 2530 SARS-CoV-2-positive participants, with 787 in the budesonide group, 1069 in the usual care group, and 974 receiving other treatments. There was a benefit in time to first self-reported recovery of an estimated 2·94 days (95% Bayesian credible interval [BCI] 1·19 to 5·12) in the budesonide group versus the usual care group (11·8 days [95% BCI 10·0 to 14·1] vs 14·7 days [12·3 to 18·0]; hazard ratio 1·21 [95% BCI 1·08 to 1·36]), with a probability of superiority greater than 0·999, meeting the prespecified superiority threshold of 0·99. For the hospital admission or death outcome, the estimated rate was 6·8% (95% BCI 4·1 to 10·2) in the budesonide group versus 8·8% (5·5 to 12·7) in the usual care group (estimated absolute difference 2·0% [95% BCI -0·2 to 4·5]; odds ratio 0·75 [95% BCI 0·55 to 1·03]), with a probability of superiority 0·963, below the prespecified superiority threshold of 0·975. Two participants in the budesonide group and four in the usual care group had serious adverse events (hospital admissions unrelated to COVID-19). INTERPRETATION: Inhaled budesonide improves time to recovery, with a chance of also reducing hospital admissions or deaths (although our results did not meet the superiority threshold), in people with COVID-19 in the community who are at higher risk of complications. FUNDING: National Institute of Health Research and United Kingdom Research Innovation.


Subject(s)
Budesonide/administration & dosage , COVID-19/drug therapy , Glucocorticoids/administration & dosage , Administration, Inhalation , Aged , Bayes Theorem , COVID-19/mortality , Female , Hospitalization , Humans , Male , Middle Aged , Prospective Studies , Risk Factors , SARS-CoV-2 , Treatment Outcome
3.
Eur Respir Rev ; 31(166)2022 Dec 31.
Article in English | MEDLINE | ID: covidwho-2098296

ABSTRACT

BACKGROUND: The Joint Committee on Vaccination and Immunisation in the United Kingdom requested an evidence synthesis to investigate the relationship between asthma and coronavirus disease 2019 (COVID-19) outcomes. OBJECTIVE: We conducted a systematic review and meta-analysis to summarise evidence on the risk of severe COVID-19 outcomes in people with uncontrolled asthma or markers of asthma severity. METHODS: High-dose inhaled corticosteroids (ICS) or oral corticosteroids (OCS) were used as markers of asthma severity, following international or national asthma guidelines. Risk of bias was assessed using Joanna Briggs Institute tools. Adjusted point estimates were extracted for random-effects meta-analyses and subgroup analyses. RESULTS: After screening, 12 studies (11 in adults and one in children) met the eligibility criteria. Adults using high-dose ICS or OCS had a pooled adjusted hazard ratio (aHR) of 1.33 (95% CI 1.06-1.67, I2=0%) for hospitalisation and an aHR of 1.22 (95% CI 0.90-1.65, I2=70%) for mortality for COVID-19. We found insufficient evidence for associations between markers on COVID-19 mortality in the subgroup analyses. CONCLUSIONS: Adults with severe asthma are at increased risk of COVID-19 hospitalisation compared to nonusers. Our analysis highlighted the dearth of studies in children with asthma investigating serious COVID-19 outcomes.


Subject(s)
Anti-Asthmatic Agents , Asthma , COVID-19 , Adult , Child , Humans , Anti-Asthmatic Agents/adverse effects , Administration, Inhalation , Asthma/diagnosis , Asthma/drug therapy , Asthma/epidemiology , Adrenal Cortex Hormones/therapeutic use
4.
Am J Case Rep ; 23: e937147, 2022 Oct 25.
Article in English | MEDLINE | ID: covidwho-2090898

ABSTRACT

BACKGROUND Inhaled nitric oxide (iNO) is used as a treatment for pulmonary arterial hypertension (PAH). Severe hypoxia with hypoxic vasoconstriction caused by severe acute respiratory distress syndrome (ARDS) can induce pulmonary hypertension with hemodynamic implications, mainly secondary to right ventricle (RV) systolic function impairment. We report the case of the use of iNO in a critically ill patient with bilateral SARS-CoV-2 pneumonia and severe ARDS and hypoxemia leading to acute severe PAH, causing a ventilation/perfusion mismatch, RV pressure overload, and RV systolic dysfunction. CASE REPORT A 36-year-old woman was admitted to the Intensive Care Unit with a severe ARDS associated with SARS-CoV-2 pneumonia requiring invasive mechanical ventilation. Severe hypoxia and hypoxic vasoconstriction developed, leading to an acute increase in pulmonary vascular resistance, severe to moderate tricuspid regurgitation, RV pressure overload, RV systolic function impairment, and RV dilatation. Following 24 h of treatment with iNO at 15 ppm, significant oxygenation and hemodynamic improvement were noted, allowing vasopressors to be stopped. After 24 h of iNO treatment, echocardiography showed very mild tricuspid regurgitation, a non-dilated RV, no impairment of transverse free wall contractility, and no paradoxical septal motion. iNO was maintained for 7 days. The dose of iNO was progressively decreased with no adverse effects and maintaining an improvement of oxygenation and hemodynamic status, allowing respiratory weaning. CONCLUSIONS Sustained acute hypoxia in ARDS secondary to SARS-CoV-2 pneumonia can lead to PAH, causing a ventilation/perfusion mismatch and RV systolic impairment. iNO can be considered in patients with significant PAH causing hypoxemia and RV dysfunction.


Subject(s)
COVID-19 , Hypertension, Pulmonary , Respiratory Distress Syndrome , Tricuspid Valve Insufficiency , Female , Humans , Adult , Nitric Oxide/therapeutic use , Hypertension, Pulmonary/drug therapy , Hypertension, Pulmonary/etiology , COVID-19/complications , Administration, Inhalation , SARS-CoV-2 , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/therapy , Hypoxia/etiology
5.
PLoS One ; 17(8): e0272034, 2022.
Article in English | MEDLINE | ID: covidwho-2079709

ABSTRACT

RATIONALE: Inhaled antimicrobials enable high local concentrations where needed and, compared to orally administration, greatly reduce the potential for systemic side effects. In SARS-CoV-2 infections, hydroxychloroquine sulphate (HCQ) administered as dry powder via inhalation could be safer than oral HCQ allowing higher and therefore more effective pulmonary concentrations without dose limiting toxic effects. OBJECTIVES: To assess the local tolerability, safety and pharmacokinetic parameters of HCQ inhalations in single ascending doses of 5, 10 and 20 mg using the Cyclops dry powder inhaler. METHODS: Twelve healthy volunteers were included in the study. Local tolerability and safety were assessed by pulmonary function tests, electrocardiogram and recording adverse events. To estimate systemic exposure, serum samples were collected before and 0.5, 2 and 3.5 h after inhalation. RESULTS AND DISCUSSION: Dry powder HCQ inhalations were well tolerated by the participants, except for transient bitter taste in all participants and minor coughing irritation. There was no significant change in QTc-interval or drop in FEV1 post inhalation. The serum HCQ concentration remained below 10 µg/L in all samples. CONCLUSION: Single doses of inhaled dry powder HCQ up to 20 mg are safe and well tolerated. Our data support that further studies with inhaled HCQ dry powder to evaluate pulmonary pharmacokinetics and efficacy are warranted.


Subject(s)
COVID-19 , Hydroxychloroquine , Administration, Inhalation , COVID-19/drug therapy , Dry Powder Inhalers , Healthy Volunteers , Humans , Hydroxychloroquine/adverse effects , Powders , SARS-CoV-2
6.
Int J Environ Res Public Health ; 19(19)2022 Oct 06.
Article in English | MEDLINE | ID: covidwho-2066063

ABSTRACT

BACKGROUND: Severe COVID-19 is associated with hypoxemia and acute respiratory distress syndrome (ARDS), which may predispose multiorgan failure and death. Inhaled nitric oxide (iNO) is a clinical vasodilator used in the management of acute respiratory distress syndrome (ARDS). This study evaluated the response rate to iNO in patients with COVID-19-ARDS. METHOD: We searched Medline and Embase databases in May 2022, and data on the use of iNO in the treatment of ARDS in COVID-19 patients were synthesized from studies that satisfied predefined inclusion criteria. A systematic synthesis of data was performed followed by meta-analysis. We performed the funnel plot and leave-one-out sensitivity test on the included studies to assess publication bias and possible exaggerated effect size. We compared the effect size of the studies from the Unites States with those from other countries and performed meta-regression to assess the effect of age, year of publication, and concomitant vasodilator use on the effect size. RESULTS: A total of 17 studies (including 712 COVID-19 patients) were included in this systematic review of which 8 studies (involving 265 COVID-19 patients) were subjected to meta-analysis. The overall response rate was 66% (95% CI, 47-84%) with significantly high between-studies heterogeneity (I2 = 94%, p < 0.001). The funnel plot showed publication bias, although the sensitivity test using leave-one-out analysis showed that removing any of the study does not remove the significance of the result. The response rate was higher in the Unites States, and meta-regression showed that age, year of publication, and use of concomitant vasodilators did not influence the response rate to iNO. CONCLUSION: iNO therapy is valuable in the treatment of hypoxemia in COVID-19 patients and may improve systemic oxygenation in patients with COVID-19-ARDS. Future studies should investigate the mechanism of the activity of iNO in COVID-19 patients to provide insight into the unexplored potential of iNO in general ARDS.


Subject(s)
COVID-19 , Respiratory Distress Syndrome , Administration, Inhalation , COVID-19/drug therapy , Humans , Hypoxia/drug therapy , Nitric Oxide/therapeutic use , Respiratory Distress Syndrome/drug therapy , Vasodilator Agents/adverse effects , Vasodilator Agents/therapeutic use
7.
J Aerosol Med Pulm Drug Deliv ; 35(5): 239-251, 2022 10.
Article in English | MEDLINE | ID: covidwho-2062819

ABSTRACT

Background: Ivermectin has received worldwide attention as a potential COVID-19 treatment after showing antiviral activity against SARS-CoV-2 in vitro. However, the pharmacokinetic limitations associated with oral administration have been postulated as limiting factors to its bioavailability and efficacy. These limitations can be overcome by targeted delivery to the lungs. In this study, inhalable dry powders of ivermectin and lactose crystals were prepared and characterized for the potential treatment of COVID-19. Methods: Ivermectin was co-spray dried with lactose monohydrate crystals and conditioned by storage at two different relative humidity points (43% and 58% RH) for a week. The in vitro dispersion performance of the stored powders was examined using a medium-high resistance Osmohaler connecting to a next-generation impactor at 60 L/min flow rate. The solid-state characteristics including particle size distribution and morphology, crystallinity, and moisture sorption profiles of raw and spray-dried ivermectin samples were assessed by laser diffraction, scanning electron microscopy, Raman spectroscopy, X-ray powder diffraction, thermogravimetric analysis, differential scanning calorimetry, and dynamic vapor sorption. Results: All the freshly spray-dried formulation (T0) and the conditioned samples could achieve the anticipated therapeutic dose with fine particle dose of 300 µg, FPFrecovered of 70%, and FPFemitted of 83%. In addition, the formulations showed a similar volume median diameter of 4.3 µm and span of 1.9. The spray-dried formulations were stable even after conditioning and exposing to different RH points as ivermectin remained amorphous with predominantly crystalline lactose. Conclusion: An inhalable and stable dry powder of ivermectin and lactose crystals was successfully formulated. This powder inhaler ivermectin candidate therapy appears to be able to deliver doses that could be safe and effective to treat the SARS-COV-2 infection. Further development of this therapy is warranted.


Subject(s)
COVID-19 , Administration, Inhalation , Antiviral Agents , COVID-19/drug therapy , Dry Powder Inhalers , Humans , Ivermectin , Lactose , Particle Size , Powders/chemistry , Respiratory Aerosols and Droplets , SARS-CoV-2
8.
Adv Drug Deliv Rev ; 189: 114527, 2022 Oct.
Article in English | MEDLINE | ID: covidwho-2060293

ABSTRACT

Lactose is the most commonly used excipient in carrier-based dry powder inhalation (DPI) formulations. Numerous inhalation therapies have been developed using lactose as a carrier material. Several theories have described the role of carriers in DPI formulations. Although these theories are valuable, each DPI formulation is unique and are not described by any single theory. For each new formulation, a specific development trajectory is required, and the versatility of lactose can be exploited to optimize each formulation. In this review, recent developments in lactose-based DPI formulations are discussed. The effects of varying the material properties of lactose carrier particles, such as particle size, shape, and morphology are reviewed. Owing to the complex interactions between the particles in a formulation, processing adhesive mixtures of lactose with the active ingredient is crucial. Therefore, blending and filling processes for DPI formulations are also reviewed. While the role of ternary agents, such as magnesium stearate, has increased, lactose remains the excipient of choice in carrier-based DPI formulations. Therefore, new developments in lactose-based DPI formulations are crucial in the optimization of inhalable medicine performance.


Subject(s)
Excipients , Lactose , Administration, Inhalation , Aerosols , Chemistry, Pharmaceutical , Drug Carriers , Dry Powder Inhalers , Humans , Particle Size , Powders
9.
Crit Care ; 26(1): 304, 2022 10 03.
Article in English | MEDLINE | ID: covidwho-2053942

ABSTRACT

BACKGROUND: Inhaled nitric oxide (iNO) is used as rescue therapy in patients with refractory hypoxemia due to severe COVID-19 acute respiratory distress syndrome (ARDS) despite the recommendation against the use of this treatment. To date, the effect of iNO on the clinical outcomes of critically ill COVID-19 patients with moderate-to-severe ARDS remains arguable. Therefore, this study aimed to evaluate the use of iNO in critically ill COVID-19 patients with moderate-to-severe ARDS. METHODS: This multicenter, retrospective cohort study included critically ill adult patients with confirmed COVID-19 treated from March 01, 2020, until July 31, 2021. Eligible patients with moderate-to-severe ARDS were subsequently categorized into two groups based on inhaled nitric oxide (iNO) use throughout their ICU stay. The primary endpoint was the improvement in oxygenation parameters 24 h after iNO use. Other outcomes were considered secondary. Propensity score matching (1:2) was used based on the predefined criteria. RESULTS: A total of 1598 patients were screened, and 815 were included based on the eligibility criteria. Among them, 210 patients were matched based on predefined criteria. Oxygenation parameters (PaO2, FiO2 requirement, P/F ratio, oxygenation index) were significantly improved 24 h after iNO administration within a median of six days of ICU admission. However, the risk of 30-day and in-hospital mortality were found to be similar between the two groups (HR: 1.18; 95% CI: 0.77, 1.82; p = 0.45 and HR: 1.40; 95% CI: 0.94, 2.11; p= 0.10, respectively). On the other hand, ventilator-free days (VFDs) were significantly fewer, and  ICU and hospital LOS were significantly longer in the iNO group. In addition, patients who received iNO had higher odds of acute kidney injury (AKI) (OR (95% CI): 2.35 (1.30, 4.26), p value = 0.005) and hospital/ventilator-acquired pneumonia (OR (95% CI): 3.2 (1.76, 5.83), p value = 0.001). CONCLUSION: In critically ill COVID-19 patients with moderate-to-severe ARDS, iNO rescue therapy is associated with improved oxygenation parameters but no mortality benefits. Moreover, iNO use is associated with higher odds of AKI, pneumonia, longer LOS, and fewer VFDs.


Subject(s)
Acute Kidney Injury , COVID-19 , Respiratory Distress Syndrome , Acute Kidney Injury/drug therapy , Administration, Inhalation , Adult , COVID-19/complications , COVID-19/drug therapy , Cohort Studies , Critical Illness/therapy , Humans , Nitric Oxide , Respiratory Distress Syndrome/drug therapy , Retrospective Studies
11.
Adv Ther ; 39(11): 5216-5228, 2022 Nov.
Article in English | MEDLINE | ID: covidwho-2035373

ABSTRACT

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) and asthma are treatable but greatly underdiagnosed disorders. Telemedicine made it possible to continue diagnosis, follow-up visits and treatment modifications during the COVID-19 pandemic. The present study describes the management of patients with COPD and asthma, and their treatments during the pandemic from the pulmonologist's perspective. METHODS: NEUMOBIAL was an ecological study with aggregated data. A total of 279 Spanish pulmonologists answered a 60-question survey about their last 10 patients, focused on the characterisation and changes in visits and treatments during the pandemic. RESULTS: Most pulmonologists (72.0%) considered that the pandemic negatively altered the diagnosis and follow-up of patients with asthma or COPD. Diagnostic tests were reduced during the pandemic, mainly because they were not recommended by pulmonologists (68.1% and 72.7% in the case of COPD and asthma tests, respectively). Moreover, 17.3% of the COPD and 19.1% of the asthma visits were remote visits. According to pulmonologists, low adherence to treatment was mainly due to a lack of patient knowledge about their disease (75.3% and 81.7% in COPD and asthma, respectively). Other factors that also influenced adherence were inadequate use of the inhaler (59.5% for COPD and 57.7% for asthma) and a lack of knowledge about the device (57.3% for COPD and 57.7% for asthma). Pulmonologists chose Zonda® for COPD because of the ease of use of the device (73.1%) and the ability to check whether the entire dose was inhaled (69.5%). For asthma, Spiromax® was chosen because of the ease of use of the device (85.7%) and the possibility of using a single device for maintenance and reliever treatment (82.4%). CONCLUSION: According to pulmonologists, during the pandemic, treatments for COPD and asthma were mainly chosen on the basis of their ease of use; treatment adherence was good; and the number of remote visits increased.


Subject(s)
Asthma , COVID-19 , Pulmonary Disease, Chronic Obstructive , Administration, Inhalation , Asthma/drug therapy , Humans , Pandemics , Pulmonary Disease, Chronic Obstructive/diagnosis , Pulmonary Disease, Chronic Obstructive/drug therapy , Pulmonologists
13.
Br J Clin Pharmacol ; 88(12): 5083-5092, 2022 12.
Article in English | MEDLINE | ID: covidwho-2001607

ABSTRACT

AIMS: Pressurised metered-dose inhalers (MDIs) have a much higher carbon footprint than dry powder inhalers (DPIs). We aimed to describe variations of inhaler options in local adult asthma prescribing guidance. METHODS: We reviewed local clinical commissioning group (CCG) adult asthma prescribing guidance for primary care in England in 2019 and recorded DPI and MDI inclusion. The relationship to prescribing data from OpenPrescribing.net was examined. RESULTS: In total, 58 unique guidance documents were analysed covering 144 out of 191 CCGs in England. Only 3% of CCG guidelines expressed an overall preference for DPIs, while 12% explicitly preferred MDIs. The inclusion of DPIs first-line was 77% for short-acting ß-agonists, 78% for low-dose inhaled corticosteroid (ICS) inhalers and 90-96% for combination long-acting ß-agonist/ICS inhalers. MDIs were included first-line in 98-100% of these classes. In 26% of CCGs, there was no first-line DPI option for at least 1 asthma management step. Ten percent of CCGs had no DPI included first-line for any of the 5 classes examined. Many CCGs recommended higher carbon footprint options; Ventolin MDI (25.6%), inhalers containing HFA227ea (57.9%) and ICS regimes recommending 2 puffs of a lower dose over 1 puff of higher dose (94.2%). MDIs were prescribed more in CCGs that recommended them. CONCLUSION: Before the COVID pandemic, there was substantial variation between CCGs in adult asthma prescribing guidance regarding higher and lower carbon footprint options. There may still be scope to amend local guidance to improve clinical and environmental outcomes. This study provides a method and baseline for further investigation of this.


Subject(s)
Asthma , COVID-19 , Humans , Adult , Carbon Footprint , Administration, Inhalation , Pandemics , COVID-19/drug therapy , COVID-19/epidemiology , Metered Dose Inhalers , Asthma/drug therapy , Dry Powder Inhalers , Adrenal Cortex Hormones , Primary Health Care
14.
MMW Fortschr Med ; 164(13): 26, 2022 07.
Article in German | MEDLINE | ID: covidwho-1995919
15.
Sci Rep ; 12(1): 11186, 2022 07 01.
Article in English | MEDLINE | ID: covidwho-1972641

ABSTRACT

The dose-response model has been widely used for quantifying the risk of infection of airborne diseases like COVID-19. The model has been used in the room-average analysis of infection risk and analysis using passive scalars as a proxy for aerosol transport. However, it has not been employed for risk estimation in numerical simulations of droplet dispersion. In this work, we develop a framework for the evaluation of the probability of infection in droplet dispersion simulations using the dose-response model. We introduce a version of the model that can incorporate the higher transmissibility of variant strains of SARS-CoV2 and the effect of vaccination in evaluating the probability of infection. Numerical simulations of droplet dispersion during speech are carried out to investigate the infection risk over space and time using the model. The advantage of droplet dispersion simulations for risk evaluation is demonstrated through the analysis of the effect of ambient wind, humidity on infection risk, and through a comparison with risk evaluation based on passive scalars as a proxy for aerosol transport.


Subject(s)
COVID-19 , Infections , Administration, Inhalation , Aerosols/adverse effects , Humans , RNA, Viral , SARS-CoV-2
16.
J Aerosol Med Pulm Drug Deliv ; 35(3): 121-138, 2022 06.
Article in English | MEDLINE | ID: covidwho-1927267

ABSTRACT

Vaccines are a very important tool in the effort to reduce the global burden of infectious diseases. Modern vaccines can be formulated in several ways to induce specific immunity, including through the use of live bacteria, subunit antigens, and even genetic material. However, vaccines typically need to be transported and stored under controlled refrigerated or frozen conditions to maintain potency. This strict temperature control is incompatible with the available infrastructure in many developing countries. One method of improving the thermostability of a vaccine is through drying of a liquid presentation into a dry dosage form. In addition to enhancing the capability for distribution in resource-poor settings, these dry vaccine forms are more suitable for long-term stockpiling. Spray drying is a drying method that has been successfully used to stabilize many experimental vaccines into a dry form for storage above refrigerated temperatures. Additionally, the use of spray drying allows for the production of engineered particles suitable for respiratory administration. These particles can be further designed for increased out-of-package robustness against high humidity. Furthermore, there are already commercial dry powder delivery devices available that can be used to safely deliver vaccines to the respiratory system. The research in this field demonstrates that the resources to develop highly stable vaccines in flexible dosage forms are available and that these presentations offer many advantages for global vaccination campaigns.


Subject(s)
Spray Drying , Vaccines , Administration, Inhalation , Drug Compounding , Particle Size , Powders/chemistry , Vaccines/chemistry
17.
PLoS One ; 17(5): e0268822, 2022.
Article in English | MEDLINE | ID: covidwho-1923695

ABSTRACT

BACKGROUND: In March 2020, WHO announced the COVID-19 a pandemic and a major global public health emergency. Mortality from COVID-19 is rapidly increasing globally, with acute respiratory failure as the predominant cause of death. Many patients experience severe hypoxia and life-threatening respiratory failure often requiring mechanical ventilation. To increase safety margins during emergency anaesthesia and rapid sequence intubation (RSI), patients are preoxygenated with a closed facemask with high-flow oxygen and positive end-expiratory pressure (PEEP). Due to the high shunt fraction of deoxygenated blood through the lungs frequently described in COVID-19 however, these measures may be insufficient to avoid harmful hypoxemia. Preoxygenation with inhaled nitric oxide (iNO) potentially reduces the shunt fraction and may thus allow for the necessary margins of safety during RSI. METHODS AND DESIGN: The INOCOV protocol describes a phase II pharmacological trial of inhaled nitric oxide (iNO) as an adjunct to standard of care with medical oxygen in initial airway and ventilation management of patients with known or suspected COVID-19 in acute respiratory failure. The trial is parallel two-arm, randomized, controlled, blinded trial. The primary outcome measure is the change in oxygen saturation (SpO2), and the null hypothesis is that there is no difference in the change in SpO2 following initiation of iNO. TRIAL REGISTRATION: EudraCT number 2020-001656-18; WHO UTN: U1111-1250-1698. Protocol version: 2.0 (June 25th, 2021).


Subject(s)
COVID-19 , Respiratory Distress Syndrome , Respiratory Insufficiency , Administration, Inhalation , Humans , Hypoxia/drug therapy , Nitric Oxide/therapeutic use , Oxygen , Randomized Controlled Trials as Topic , Respiratory Insufficiency/complications
18.
Expert Rev Clin Pharmacol ; 15(5): 593-600, 2022 May.
Article in English | MEDLINE | ID: covidwho-1915460

ABSTRACT

BACKGROUND: The effect of inhaled corticosteroids (ICS) on the clinical outcomes of patients with coronavirus disease 2019 (COVID-19) was not known. RESEARCH DESIGN AND METHODS: Only phase 2 and 3 randomized clinical trials (RCTs) from electronic databases that investigated ICS in the treatment of COVID-19 patients were included. The outcomes of interest were the resolution of symptoms, risk of hospitalization or urgent medical visit, mortality, and the incidence of adverse events (AEs). RESULTS: Five RCTs involving 1243 patients who received ICS and 1526 patients with placebo or usual care were included. The ICS group had a higher rate of symptom resolution than the control group at day 14 (risk ratio [RR], 1.21; 95% confidence interval [CI], 1.12-1.30, p < 0.00001) and day 28 (RR, 1.12; 95% CI, 1.06-1.18, p < 0.0001). Additionally, the ICS group had a significantly lower risk of needing urgent medical care or hospitalization than the control group (RR, 0.15; 95% CI, 0.05-0.50; I2 = 0, p = 0.002). However, no significant difference in the 28-day mortality rate. CONCLUSIONS: In patients with mild-to-moderate COVID-19, ICS therapy improved symptom resolution, and decreased the risk of needing urgent medical care or hospitalization.


Subject(s)
Anti-Asthmatic Agents , Asthma , COVID-19 , Administration, Inhalation , Adrenal Cortex Hormones , Anti-Asthmatic Agents/therapeutic use , Asthma/drug therapy , COVID-19/drug therapy , Humans , Randomized Controlled Trials as Topic
19.
Pharm Dev Technol ; 27(6): 635-645, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1915404

ABSTRACT

Remdesivir is one of the effective drugs proposed for the treatment of coronavirus disease 2019 (COVID-19). However, the study on inhalable regimen is currently limited though COVID-19 is respiratory diseases and infects lung area. This work aims to prepare inhalable remdesivir formulations and verify their effectiveness through in vitro evaluations. Formulations containing different ratios of jet-milled inhalable remdesivir (5, 10, 20,40, and 70%) with excipients were produced and characterized in terms of the particle size distribution, particle morphology, flowability, water content, crystallinity, the water sorption and desorption capabilities, and the aerodynamic performance. Results indicating that drug loading are a vital factor in facilitating the dispersion of remdesivir dry powder, and the ternary excipient plays a negligible role in improving aerosol performance. Besides, the 70% remdesivir with lactose carrier (70% RD-Lac) was physically stable and retain high aerosol performance after conditioned at 40 °C and 75% RH for a month. Therefore, formulation 70% RD-Lac might be recommended as a candidate product for the potential treatment of COVID-19.


Subject(s)
COVID-19 , Excipients , Adenosine Monophosphate/analogs & derivatives , Administration, Inhalation , Alanine/analogs & derivatives , COVID-19/drug therapy , Dry Powder Inhalers/methods , Humans , Lactose , Particle Size , Powders , Respiratory Aerosols and Droplets , Water
20.
PLoS One ; 17(6): e0270646, 2022.
Article in English | MEDLINE | ID: covidwho-1910691

ABSTRACT

OBJECTIVE: To compare the efficacy and outcomes with inhaled nitric oxide (iNO) and inhaled epoprostenol (iEPO) in patients with refractory hypoxemia due to COVID-19. DESIGN: Retrospective Cohort Study. SETTING: Single health system multicenter academic teaching hospitals. PATIENTS OR SUBJECTS: Age group of 18-80 years admitted to the medical ICU. INTERVENTIONS: Mechanically ventilated patients with COVID-19 infection, who received either iNO or iEPO between March 1st, 2020, and June 30th, 2020. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the change in the PaO2/FiO2 (P/F) ratio 1 hour after initiation of pulmonary vasodilator therapy. Secondary outcomes include P/F ratios on days 1-3 after initiation, positive response in P/F ratio (increase of at least 20% in PaO2), total days of treatment, rebound hypoxemia (if there was a drop in oxygen saturation after treatment was stopped), ventilator free days (if any patient was extubated), days in ICU, days to extubation, days to tracheostomy, mortality days after intubation, 30-day survival and mortality. 183 patients were excluded, as they received both iNO and iEPO. Of the remaining 103 patients, 62 received iEPO and 41 received iNO. The severity of ARDS was similar in both groups. Change in P/F ratio at one hour was 116 (70.3) with iNO and 107 (57.6) with iEPO (Mean/SD). Twenty-two (53.7%) patients in the iNO group and 25 (40.3%) in the iEPO group were responders to pulmonary vasodilators n(%)(p = 0.152) (more than 20% increase in partial pressure of oxygen, Pao2), and 18 (43.9%) and 31 (50%) patients in the iNO and iEPO group (p = 0.685), respectively, had rebound hypoxemia. Only 7 patients in the cohort achieved ventilator free days (3 in the iEPO group and 4 in iNO group). CONCLUSIONS: We found no significant difference between iNO and iEPO in terms of change in P/F ratio, duration of mechanical ventilation, ICU, in-hospital mortality in this cohort of mechanically ventilated patients with COVID-19. Larger, prospective studies are necessary to validate these results.


Subject(s)
COVID-19 , Epoprostenol , Administration, Inhalation , Adolescent , Adult , Aged , Aged, 80 and over , COVID-19/complications , COVID-19/drug therapy , Epoprostenol/therapeutic use , Humans , Hypoxia/drug therapy , Middle Aged , Nitric Oxide/therapeutic use , Oxygen/therapeutic use , Prospective Studies , Retrospective Studies , Vasodilator Agents/therapeutic use , Young Adult
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