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1.
Nitric Oxide ; 121: 20-33, 2022 04 01.
Article in English | MEDLINE | ID: covidwho-1665319

ABSTRACT

Inhaled nitric oxide (iNO) acts as a selective pulmonary vasodilator and it is currently approved by the FDA for the treatment of persistent pulmonary hypertension of the newborn. iNO has been demonstrated to effectively decrease pulmonary artery pressure and improve oxygenation, while decreasing extracorporeal life support use in hypoxic newborns affected by persistent pulmonary hypertension. Also, iNO seems a safe treatment with limited side effects. Despite the promising beneficial effects of NO in the preclinical literature, there is still a lack of high quality evidence for the use of iNO in clinical settings. A variety of clinical applications have been suggested in and out of the critical care environment, aiming to use iNO in respiratory failure and pulmonary hypertension of adults or as a preventative measure of hemolysis-induced vasoconstriction, ischemia/reperfusion injury and as a potential treatment of renal failure associated with cardiopulmonary bypass. In this narrative review we aim to present a comprehensive summary of the potential use of iNO in several clinical conditions with its suggested benefits, including its recent application in the scenario of the COVID-19 pandemic. Randomized controlled trials, meta-analyses, guidelines, observational studies and case-series were reported and the main findings summarized. Furthermore, we will describe the toxicity profile of NO and discuss an innovative proposed strategy to produce iNO. Overall, iNO exhibits a wide range of potential clinical benefits, that certainly warrants further efforts with randomized clinical trials to determine specific therapeutic roles of iNO.


Subject(s)
Critical Illness , Hypertension, Pulmonary/drug therapy , Infant, Newborn, Diseases/drug therapy , Nitric Oxide/therapeutic use , Vasodilator Agents/therapeutic use , Adult , COVID-19/complications , COVID-19/drug therapy , COVID-19/virology , Humans , Hypertension, Pulmonary/etiology , Infant, Newborn , Infant, Newborn, Diseases/etiology , Nitric Oxide/pharmacology , SARS-CoV-2/drug effects , SARS-CoV-2/isolation & purification , Vasodilator Agents/pharmacology
2.
PLoS One ; 17(1): e0262737, 2022.
Article in English | MEDLINE | ID: covidwho-1631070

ABSTRACT

INTRODUCTION: The coronavirus disease 2019 (COVID-19), emerged in late 2019, was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The risk factors for idiopathic pulmonary fibrosis (IPF) and COVID-19 are reported to be common. This study aimed to determine the potential role of differentially expressed genes (DEGs) common in IPF and COVID-19. MATERIALS AND METHODS: Based on GEO database, we obtained DEGs from one SARS-CoV-2 dataset and five IPF datasets. A series of enrichment analysis were performed to identify the function of upregulated and downregulated DEGs, respectively. Two plugins in Cytoscape, Cytohubba and MCODE, were utilized to identify hub genes after a protein-protein interaction (PPI) network. Finally, candidate drugs were predicted to target the upregulated DEGs. RESULTS: A total of 188 DEGs were found between COVID-19 and IPF, out of which 117 were upregulated and 71 were downregulated. The upregulated DEGs were involved in cytokine function, while downregulated DEGs were associated with extracellular matrix disassembly. Twenty-two hub genes were upregulated in COVID-19 and IPF, for which 155 candidate drugs were predicted (adj.P.value < 0.01). CONCLUSION: Identifying the hub genes aberrantly regulated in both COVID-19 and IPF may enable development of molecules, encoded by those genes, as therapeutic targets for preventing IPF progression and SARS-CoV-2 infections.


Subject(s)
COVID-19/genetics , Idiopathic Pulmonary Fibrosis/genetics , COVID-19/pathology , COVID-19/virology , Databases, Genetic , Down-Regulation/drug effects , Down-Regulation/genetics , Humans , Idiopathic Pulmonary Fibrosis/drug therapy , Idiopathic Pulmonary Fibrosis/pathology , Protein Interaction Maps/drug effects , Protein Interaction Maps/genetics , SARS-CoV-2/isolation & purification , Suloctidil/pharmacology , Suloctidil/therapeutic use , Up-Regulation/drug effects , Up-Regulation/genetics , Vasodilator Agents/pharmacology , Vasodilator Agents/therapeutic use
3.
J Med Internet Res ; 23(10): e25163, 2021 10 08.
Article in English | MEDLINE | ID: covidwho-1496813

ABSTRACT

BACKGROUND: Pulmonary arterial hypertension restricts the ability of patients to perform routine physical activities. As part of pulmonary arterial hypertension treatment, inhaled iloprost can be administered via a nebulizer that tracks inhalation behavior. Pulmonary arterial hypertension treatment is guided by intermittent clinical measurements, such as 6-minute walk distance, assessed during regular physician visits. Continuous digital monitoring of physical activity may facilitate more complete assessment of the impact of pulmonary arterial hypertension on daily life. Physical activity tracking with a wearable has not yet been assessed with simultaneous tracking of pulmonary arterial hypertension medication intake. OBJECTIVE: We aimed to digitally track the physical parameters of patients with pulmonary arterial hypertension who were starting treatment with iloprost using a Breelib nebulizer. The primary objective was to investigate correlations between changes in digital physical activity measures and changes in traditional clinical measures and health-related quality of life over 3 months. Secondary objectives were to evaluate inhalation behavior, adverse events, and changes in heart rate and sleep quality. METHODS: We conducted a prospective, multicenter observational study of adults with pulmonary arterial hypertension in World Health Organization functional class III who were adding inhaled iloprost to existing pulmonary arterial hypertension therapy. Daily distance walked, step count, number of standing-up events, heart rate, and 6-minute walk distance were digitally captured using smartwatch (Apple Watch Series 2) and smartphone (iPhone 6S) apps during a 3-month observation period (which began when iloprost treatment began). Before and at the end of the observation period (within 2 weeks), we also evaluated 6-minute walk distance, Borg dyspnea, functional class, B-type natriuretic peptide (or N-terminal pro-B-type natriuretic peptide) levels, health-related quality of life (EQ-5D questionnaire), and sleep quality (Pittsburgh Sleep Quality Index). RESULTS: Of 31 patients, 18 were included in the full analysis (observation period: median 91.5 days, IQR 88.0 to 92.0). Changes from baseline in traditional and digital 6-minute walk distance were moderately correlated (r=0.57). Physical activity (daily distance walked: median 0.4 km, IQR -0.2 to 1.9; daily step count: median 591, IQR -509 to 2413) and clinical measures (traditional 6-minute walk distance: median 26 m, IQR 0 to 40) changed concordantly from baseline to the end of the observation period. Health-related quality of life showed little change. Total sleep score and resting heart rate slightly decreased. Distance walked and step count showed short-term increases after each iloprost inhalation. No new safety signals were identified (safety analysis set: n=30). CONCLUSIONS: Our results suggest that despite challenges, parallel monitoring of physical activity, heart rate, and iloprost inhalation is feasible in patients with pulmonary arterial hypertension and may complement traditional measures in guiding treatment; however, the sample size of this study limits generalizability. TRIAL REGISTRATION: ClinicalTrials.gov NCT03293407; https://clinicaltrials.gov/ct2/show/NCT03293407. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/12144.


Subject(s)
Hypertension, Pulmonary , Pulmonary Arterial Hypertension , Administration, Inhalation , Adult , Heart Rate , Humans , Hypertension, Pulmonary/drug therapy , Iloprost/therapeutic use , Prospective Studies , Quality of Life , Treatment Outcome , Vasodilator Agents/therapeutic use , Walking
6.
PLoS One ; 16(5): e0251048, 2021.
Article in English | MEDLINE | ID: covidwho-1242245

ABSTRACT

BACKGROUND: COVID-19 is a multisystemic disorder that frequently causes acute kidney injury (AKI). However, the precise clinical and biochemical variables associated with AKI progression in patients with severe COVID-19 remain unclear. METHODS: We performed a retrospective study on 278 hospitalized patients who were admitted to the ward and intensive care unit (ICU) with COVID-19 between March 2020 and June 2020, at the University Hospital, São Paulo, Brazil. Patients aged ≥ 18 years with COVID-19 confirmed on RT-PCR were included. AKI was defined according to the Kidney Disease Improving Global Outcomes (KDIGO) criteria. We evaluated the incidence of AKI, several clinical variables, medicines used, and outcomes in two sub-groups: COVID-19 patients with AKI (Cov-AKI), and COVID-19 patients without AKI (non-AKI). Univariate and multivariate analyses were performed. RESULTS: First, an elevated incidence of AKI (71.2%) was identified, distributed across different stages of the KDIGO criteria. We further observed higher levels of creatinine, C-reactive protein (CRP), leukocytes, neutrophils, monocytes, and neutrophil-to-lymphocyte ratio (NLR) in the Cov-AKI group than in the non-AKI group, at hospital admission. On univariate analysis, Cov-AKI was associated with older age (>62 years), hypertension, CRP, MCV, leucocytes, neutrophils, NLR, combined hydroxychloroquine and azithromycin treatment, use of mechanical ventilation, and vasoactive drugs. Multivariate analysis showed that hypertension and the use of vasoactive drugs were independently associated with a risk of higher AKI in COVID-19 patients. Finally, we preferentially found an altered erythrocyte and leukocyte cellular profile in the Cov-AKI group compared to the non-AKI group, at hospital discharge. CONCLUSIONS: In our study, the development of AKI in patients with severe COVID-19 was related to inflammatory blood markers and therapy with hydroxychloroquine/azithromycin, with vasopressor requirement and hypertension considered potential risk factors. Thus, attention to the protocol, hypertension, and some blood markers may help assist doctors with decision-making for the management of COVID-19 patients with AKI.


Subject(s)
Acute Kidney Injury/diagnosis , COVID-19/pathology , Acute Kidney Injury/epidemiology , Acute Kidney Injury/etiology , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , Azithromycin/therapeutic use , Brazil/epidemiology , COVID-19/complications , COVID-19/drug therapy , COVID-19/virology , Creatinine/blood , Female , Glomerular Filtration Rate , Humans , Hydroxychloroquine/therapeutic use , Male , Middle Aged , Respiration, Artificial , Retrospective Studies , Risk Factors , SARS-CoV-2/isolation & purification , Severity of Illness Index , Vasodilator Agents/adverse effects , Vasodilator Agents/therapeutic use , Young Adult
7.
Prog Urol ; 31(8-9): 495-502, 2021.
Article in French | MEDLINE | ID: covidwho-1213486

ABSTRACT

OBJECTIVE: To assist urologists in the management of andrological and sexual medicine pathologies during the COVID-19 crisis. MATERIAL AND METHOD: Use of the formalized consensus method. RESULTS: The medical and surgical management of patients in andrology and sexual medicine must be adapted. Consultations should, as far as possible, be carried out by tele-consultation. For operative procedures, the delay between the operative decision and the date of (re)scheduling of the procedure will depend on: (1) the level of criticality of the clinical situation; (2) the type of intervention; (3) the functional and psychological repercussions, including quality of life while waiting for the procedure; (4) the notion of losing the chance of having an optimal outcome; (5) the risk of potential complications from delaying a procedure for too long; and (6) taking into account the patient's risk factors for severe forms of COVID-19. The protection of urologists from COVID-19 should be considered. Each urologist must make the best decision for the patient, taking into account the acceptable time frame and quality of life impact before surgical management, the COVID risk parameters, the technical and anesthetic feasibility and the structural possibility of the health care institution to ensure a specific dedicated pathway during the COVID-19 health crisis. CONCLUSION: The management of andrological and sexual medicine pathologies must be adapted to the COVID-19 crisis context. Some patients may require surgery, including in emergency. These recommendations are transitional and will end with the COVID-19 crisis.


Subject(s)
Penile Induration/diagnosis , Penile Induration/therapy , COVID-19 , Collagenases/therapeutic use , Combined Modality Therapy , Erectile Dysfunction/drug therapy , Humans , Injections , Male , Pandemics , Penile Implantation , Phosphodiesterase 5 Inhibitors/therapeutic use , Traction , Urologic Surgical Procedures, Male , Vacuum , Vasodilator Agents/therapeutic use , Verapamil/therapeutic use
8.
J Stroke Cerebrovasc Dis ; 30(7): 105822, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1179851

ABSTRACT

There have been limited cases linking SARS-CoV-2 infection with the development of reversible cerebral vasoconstriction syndrome (RCVS). We hereby report a rare case of RCVS in the setting of mild SARS-CoV-2 respiratory infection successfully treated with nimodipine and aspirin. SARS-CoV-2 attacks the ACE2-receptors, which are expressed in various body organs including the lungs, kidneys, and blood vessels. Vasoconstriction can result from down-regulation of the ACE2-receptors that can lead to sympathetic hypertonia of the cerebral blood vessel walls and/or over-activation of the renin-angiotensin axis.


Subject(s)
Aspirin/therapeutic use , COVID-19/complications , Cerebral Arteries/drug effects , Nimodipine/therapeutic use , Vasoconstriction/drug effects , Vasodilator Agents/therapeutic use , Vasospasm, Intracranial/drug therapy , Adult , COVID-19/diagnosis , Cerebral Arteries/diagnostic imaging , Cerebral Arteries/physiopathology , Female , Humans , Syndrome , Treatment Outcome , Vasospasm, Intracranial/diagnostic imaging , Vasospasm, Intracranial/etiology , Vasospasm, Intracranial/physiopathology
9.
Am J Cardiovasc Drugs ; 21(6): 589-593, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1144418

ABSTRACT

The purpose of this current opinion article is to illustrate a novel approach to the treatment of acute decompensated heart failure (ADHF) in coronavirus disease 2019 (COVID-19) patients. The approach described herein relies on a reformulation of intravenous nitroglycerin in 5% glutathione, itself novel, and is felt to have the potential to not only improve the rate of resolution of ADHF, but also reduce the risk of complications of heart failure seen in patients with COVID-19.


Subject(s)
COVID-19/complications , Heart Failure/diagnosis , Heart Failure/etiology , Nitroglycerin/therapeutic use , Vasodilator Agents/therapeutic use , Administration, Intravenous , Drug Compounding , Glutathione/chemistry , Humans , Infusions, Intravenous , Nitroglycerin/chemistry , Vasodilator Agents/chemistry
10.
J Intensive Care Med ; 36(3): 327-333, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-945132

ABSTRACT

BACKGROUND: Inhaled pulmonary vasodilators are used as adjunctive therapies for the treatment of refractory hypoxemia. Available evidence suggest they improve oxygenation in a subset of patients without changing long-term trajectory. Given the differences in respiratory failure due to COVID-19 and "traditional" ARDS, we sought to identify their physiologic impact. METHODS: This is a retrospective observational study of patients mechanically ventilated for COVID-19, from the ICUs of 2 tertiary care centers, who received inhaled epoprostenol (iEpo) for the management of hypoxemia. The primary outcome is change in PaO2/FiO2. Additionally, we measured several patient level features to predict iEpo responsiveness (or lack thereof). RESULTS: Eighty patients with laboratory confirmed SARS-CoV2 received iEpo while mechanically ventilated and had PaO2/FiO2 measured before and after. The median PaO2/FiO2 prior to receiving iEpo was 92 mmHg and interquartile range (74 - 122). The median change in PaO2/FiO2 was 9 mmHg (-9 - 37) corresponding to a 10% improvement (-8 - 41). Fifty-percent (40 / 80) met our a priori definition of a clinically significant improvement in PaO2/FiO2 (increase in 10% from the baseline value). Prone position and lower PaO2/FiO2 when iEpo was started predicted a more robust response, which held after multivariate adjustment. For proned individuals, improvement in PaO2/FiO2 was 14 mmHg (-6 to 45) vs. 3 mmHg (-11 - 20), p = 0.04 for supine individuals; for those with severe ARDS (PaO2/FiO2 < 100, n = 49) the median improvement was 16 mmHg (-2 - 46). CONCLUSION: Fifty percent of patients have a clinically significant improvement in PaO2/FiO2 after the initiation of iEpo. This suggests it is worth trying as a rescue therapy; although generally the benefit was modest with a wide variability. Those who were prone and had lower PaO2/FiO2 were more likely to respond.


Subject(s)
COVID-19/therapy , Epoprostenol/therapeutic use , Hypoxia/therapy , Respiration, Artificial , Respiratory Insufficiency/therapy , Vasodilator Agents/therapeutic use , Administration, Inhalation , Aged , Female , Humans , Hypoxia/metabolism , Male , Middle Aged , Oxygen/metabolism , Partial Pressure , Patient Positioning , Prone Position , Retrospective Studies , SARS-CoV-2 , Severity of Illness Index , Tertiary Care Centers , Treatment Outcome
11.
Nat Rev Cardiol ; 18(3): 194-209, 2021 03.
Article in English | MEDLINE | ID: covidwho-936141

ABSTRACT

The core pathology of coronavirus disease 2019 (COVID-19) is infection of airway cells by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that results in excessive inflammation and respiratory disease, with cytokine storm and acute respiratory distress syndrome implicated in the most severe cases. Thrombotic complications are a major cause of morbidity and mortality in patients with COVID-19. Patients with pre-existing cardiovascular disease and/or traditional cardiovascular risk factors, including obesity, diabetes mellitus, hypertension and advanced age, are at the highest risk of death from COVID-19. In this Review, we summarize new lines of evidence that point to both platelet and endothelial dysfunction as essential components of COVID-19 pathology and describe the mechanisms that might account for the contribution of cardiovascular risk factors to the most severe outcomes in COVID-19. We highlight the distinct contributions of coagulopathy, thrombocytopathy and endotheliopathy to the pathogenesis of COVID-19 and discuss potential therapeutic strategies in the management of patients with COVD-19. Harnessing the expertise of the biomedical and clinical communities is imperative to expand the available therapeutics beyond anticoagulants and to target both thrombocytopathy and endotheliopathy. Only with such collaborative efforts can we better prepare for further waves and for future coronavirus-related pandemics.


Subject(s)
Blood Coagulation Disorders/blood , Blood Platelet Disorders/blood , COVID-19/blood , Endothelium, Vascular/physiopathology , Inflammation/blood , Thrombosis/blood , Administration, Inhalation , Anticoagulants/therapeutic use , Blood Coagulation Disorders/drug therapy , Blood Coagulation Disorders/etiology , Blood Coagulation Disorders/physiopathology , Blood Platelet Disorders/drug therapy , Blood Platelet Disorders/etiology , Blood Platelet Disorders/physiopathology , COVID-19/complications , COVID-19/drug therapy , COVID-19/physiopathology , Endothelium-Dependent Relaxing Factors/therapeutic use , Epoprostenol/therapeutic use , Heart Disease Risk Factors , Humans , Iloprost/therapeutic use , Inflammation/etiology , Inflammation/physiopathology , Nitric Oxide/therapeutic use , Platelet Aggregation Inhibitors/therapeutic use , SARS-CoV-2 , Systemic Inflammatory Response Syndrome/blood , Systemic Inflammatory Response Syndrome/drug therapy , Systemic Inflammatory Response Syndrome/physiopathology , Thrombosis/etiology , Thrombosis/immunology , Thrombotic Microangiopathies/blood , Thrombotic Microangiopathies/drug therapy , Thrombotic Microangiopathies/etiology , Thrombotic Microangiopathies/physiopathology , Vascular Diseases/blood , Vascular Diseases/drug therapy , Vascular Diseases/etiology , Vascular Diseases/physiopathology , Vasodilator Agents/therapeutic use , Venous Thromboembolism/blood , Venous Thromboembolism/drug therapy , Venous Thromboembolism/etiology , Venous Thromboembolism/physiopathology
13.
Am Heart J ; 232: 105-115, 2021 02.
Article in English | MEDLINE | ID: covidwho-893406

ABSTRACT

Morbidity and mortality associated with COVID-19 has increased exponentially, and patients with cardiovascular (CV) disease are at risk for poor outcomes. Several lines of evidence suggest a potential role for CV therapies in COVID-19 treatment. Characteristics of clinical trials of CV therapies related to COVID-19 registered on ClinicalTrials.gov have not been described. METHODS: ClinicalTrials.gov was queried on August 7, 2020 for COVID-19 related trials. Studies evaluating established CV drugs, other fibrinolytics (defibrotide), and extracorporeal membrane oxygenation were included. Studies evaluating anti-microbial, convalescent plasma, non-colchicine anti-inflammatory, and other therapies were excluded. Trial characteristics were tabulated from study-specific entries. RESULTS: A total of 2,935 studies related to COVID-19 were registered as of August 7, 2020. Of these, 1,645 were interventional studies, and the final analytic cohort consisted of 114 studies evaluating 10 CV therapeutic categories. Antithrombotics (32.5%; n = 37) were most commonly evaluated, followed by pulmonary vasodilators (14.0%; n = 16), renin-angiotensin-aldosterone system-related therapies (12.3%; n = 14), and colchicine (8.8%; n = 10). Trials evaluating multiple CV therapy categories and CV therapies in combination with non-CV therapies encompassed 4.4% (n = 5) and 9.6% (n = 11) of studies, respectively. Most studies were designed for randomized allocation (87.7%; n = 100), enrollment of less than 1000 participants (86.8%; n = 99), single site implementation (55.3%; n = 63), and had a primary outcome of mortality or a composite including mortality (56.1%; n = 64). Most study populations consisted of patients hospitalized with COVID-19 (81.6%; n = 93). At the time of database query, 28.9% (n = 33) of studies were not yet recruiting and the majority were estimated to be completed after December 2020 (67.8%; n = 78). Most lead sponsors were located in North America (43.9%; n = 50) or Europe (36.0%; n = 41). CONCLUSIONS: A minority (7%) of clinical trials related to COVID-19 registered on ClinicalTrials.gov plan to evaluate CV therapies. Of CV therapy studies, most were planned to be single center, enroll less than 1000 inpatients, sponsored by European or North American academic institutions, and estimated to complete after December 2020. Collectively, these findings underscore the need for a network of sites with a platform protocol for rapid evaluation of multiple therapies and generalizability to inform clinical care and health policy for COVID-19 moving forward.


Subject(s)
COVID-19/drug therapy , Cardiovascular Diseases/drug therapy , Clinical Trials as Topic/statistics & numerical data , National Library of Medicine (U.S.) , Registries/statistics & numerical data , SARS-CoV-2 , COVID-19/complications , COVID-19/mortality , Cardiovascular Agents/therapeutic use , Cardiovascular Diseases/complications , Cardiovascular Diseases/mortality , Colchicine/therapeutic use , Combined Modality Therapy/statistics & numerical data , Databases, Factual/statistics & numerical data , Extracorporeal Membrane Oxygenation/statistics & numerical data , Fibrinolytic Agents/therapeutic use , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hypoglycemic Agents/therapeutic use , Patient Participation/statistics & numerical data , Randomized Controlled Trials as Topic/statistics & numerical data , Renin-Angiotensin System , Treatment Outcome , United States , Vasodilator Agents/therapeutic use
14.
Trials ; 21(1): 746, 2020 Aug 26.
Article in English | MEDLINE | ID: covidwho-731235

ABSTRACT

OBJECTIVES: To investigate the effect of continuous infusion of the potential endothelial cytoprotective agent prostacyclin (Iloprost) 1 ng/kg/min vs. placebo for 72 hours on pulmonary endotheliopathy in mechanically ventilated COVID-19 patients. TRIAL DESIGN: A multicenter, randomized (1:1, active: placebo), blinded, parallel group exploratory trial PARTICIPANTS: Inclusion criteria are: Adult patients (>18 years); Confirmed COVID-19 infection; Need for mechanical interventions; Endothelial biomarker soluble thrombomodulin >4ng/ml. EXCLUSION CRITERIA: Withdrawal from active therapy; Pregnancy (non-pregnancy confirmed by patient being postmenopausal (age 60 or above) or having a negative urine- or plasma-hCG); Known hypersensitivity to iloprost or to any of the other ingredients; Previously included in this trial or a prostacyclin trial within 30 days; Consent cannot be obtained; Life-threatening bleeding defined by the treating physician; Known severe heart failure (NYHA class IV); Suspected acute coronary syndrome The study is conducted at five intensive care units in the Capital Region of Denmark at Rigshospitalet, Herlev Hospital, Hvidovre Hospital, Bispebjerg Hospital, Nordsjællands Hospital. INTERVENTION AND COMPARATOR: The patients are randomized to 72-hours continuous infusion of either prostacyclin (Iloprost/Ilomedin) at a dose of 1 ng/kg/min or Placebo (normal saline). MAIN OUTCOMES: Primary endpoint: Days alive without mechanical ventilation in the intensive care units within 28 days RANDOMISATION: The randomisation sequence is performed in permuted blocks of variable sizes stratified for trial site using centralised, concealed allocation. The randomisation sequence is generated 1:1 (active/placebo) using the online randomisation software 'Sealed Envelope' ( https://www.sealedenvelope.com/ ). Once generated the randomisation sequence is formatted and uploaded into Research Electronic Data Capture system (REDCap) to facilitate centralised, web-based allocation according to local written instruction. BLINDING (MASKING): The following are blinded: all clinicians, patients, investigators, and those assessing the outcomes including the statisticians. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): Forty patients are planned to be randomized to each group, with a total sample size of 80 patients. TRIAL STATUS: Protocol version 1.4 dated May 25, 2020. Recruitment is ongoing. The recruitment was started June 15, 2020 and the anticipated finish of recruitment is February 28, 2021 with 90 days follow up hereafter. TRIAL REGISTRATION: Trial registration at clinicaltrialregisters.eu; EudraCT no. 2020-001296-33 on 3 April 2020 and at ClinicalTrials.gov Identifier: NCT04420741 on 9 June 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1).In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Subject(s)
Coronavirus Infections/therapy , Iloprost/therapeutic use , Pneumonia, Viral/therapy , Respiration, Artificial , Vasodilator Agents/therapeutic use , Betacoronavirus , COVID-19 , Coronavirus Infections/blood , Coronavirus Infections/drug therapy , Denmark , Endothelium, Vascular/metabolism , Endothelium, Vascular/physiopathology , Humans , Infusions, Intravenous , Intensive Care Units , Pandemics , Pneumonia, Viral/blood , SARS-CoV-2 , Thrombomodulin/metabolism
15.
Clin Exp Pharmacol Physiol ; 47(11): 1791-1797, 2020 11.
Article in English | MEDLINE | ID: covidwho-695227

ABSTRACT

At present, there is yet no specific antiviral treatment or immunization against the newly identified human severe acute respiratory syndrome virus (SARS-CoV2) that results in a rapidly progressive pandemic coronavirus disease 2019 (COVID-19). We believe in a crucial need for a clinical strategy to counteract this viral pandemic based on the known pathogenesis throughout the disease course. Evidence suggests that exaggerated patient's inflammatory response and oxidative stress are likely to aggravate the disease pathology. The resulting endothelial dysfunction further induces fibrosis and coagulopathy. These disturbances can generate severe acute respiratory distress syndrome (ARDS) that can progress into respiratory and circulatory failure. Nicorandil is an anti-anginal vasodilator drug acts by increasing nitric oxide bioavailability and opening of the KATP channel. Recently, nicorandil has been recognized to possess multiple protective effects against tissue injury. Here, we address a possible modulatory role of nicorandil against COVID-19 pathogenesis. We hypothesise nicorandil would be an effective form of adjuvant therapy against COVID-19.


Subject(s)
Coronavirus Infections/drug therapy , Nicorandil/therapeutic use , Pneumonia, Viral/drug therapy , Vasodilator Agents/therapeutic use , Anti-Inflammatory Agents/therapeutic use , Anticoagulants/therapeutic use , Antioxidants/therapeutic use , COVID-19 , Coronavirus Infections/physiopathology , Fibrosis/prevention & control , Humans , Pandemics , Pneumonia, Viral/physiopathology
16.
Br J Pharmacol ; 177(17): 3898-3904, 2020 09.
Article in English | MEDLINE | ID: covidwho-669062

ABSTRACT

Inflammation is generally accepted as a component of the host defence system and a protective response in the context of infectious diseases. However, altered inflammatory responses can contribute to disease in infected individuals. Many endogenous mediators that drive the resolution of inflammation are now known. Overall, mediators of resolution tend to decrease inflammatory responses and provide normal or greater ability of the host to deal with infection. In the lung, it seems that pro-resolution molecules, or strategies that promote their increase, tend to suppress inflammation and lung injury and facilitate control of bacterial or viral burden. Here, we argue that the demonstrated anti-inflammatory, pro-resolving, anti-thrombogenic and anti-microbial effects of such endogenous mediators of resolution may be useful in the treatment of the late stages of the disease in patients with COVID-19.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , COVID-19/drug therapy , Inflammation/drug therapy , Acetates/therapeutic use , Angiotensin I/therapeutic use , Animals , Annexin A1/therapeutic use , COVID-19/immunology , Disease Models, Animal , Docosahexaenoic Acids/therapeutic use , Humans , Hydrogen Peroxide/therapeutic use , Inflammation/immunology , Inflammation Mediators/immunology , Mice , Orthomyxoviridae Infections/drug therapy , Orthomyxoviridae Infections/immunology , Oxidants/therapeutic use , Peptide Fragments/therapeutic use , Peptides/therapeutic use , Phosphodiesterase 4 Inhibitors/therapeutic use , Pneumonia, Viral/drug therapy , Pneumonia, Viral/immunology , Rolipram/therapeutic use , Vasodilator Agents/therapeutic use
17.
BMC Anesthesiol ; 20(1): 177, 2020 07 20.
Article in English | MEDLINE | ID: covidwho-656789

ABSTRACT

The management of Acute Respiratory Distress Syndrome (ARDS) secondary to the novel Coronavirus Disease 2019 (COVID-19) proves to be challenging and controversial. Multiple studies have suggested the likelihood of an atypical pathophysiology to explain the spectrum of pulmonary and systemic manifestations caused by the virus. The principal paradox of COVID-19 pneumonia is the presence of severe hypoxemia with preserved pulmonary mechanics. Data derived from the experience of multiple centers around the world have demonstrated that initial clinical efforts should be focused into avoid intubation and mechanical ventilation in hypoxemic COVID-19 patients. On the other hand, COVID-19 patients progressing or presenting into frank ARDS with typical decreased pulmonary compliance, represents another clinical enigma to many clinicians, since routine therapeutic interventions for ARDS are still a subject of debate.


Subject(s)
Betacoronavirus , Coronavirus Infections/therapy , Critical Care/methods , Pneumonia, Viral/therapy , Respiratory Distress Syndrome/therapy , Adrenal Cortex Hormones/therapeutic use , Biomarkers/metabolism , COVID-19 , COVID-19 Testing , Clinical Laboratory Techniques/methods , Coronavirus Infections/diagnosis , Coronavirus Infections/drug therapy , Coronavirus Infections/transmission , Cross Infection/transmission , Cytokines/metabolism , Diagnostic Imaging , Extracorporeal Membrane Oxygenation/methods , Humans , Hypoxia/virology , Immune System Diseases/virology , Intubation, Intratracheal , Neuromuscular Blockade/methods , Pandemics , Patient Positioning/methods , Pneumonia, Viral/diagnosis , Pneumonia, Viral/transmission , Pneumonia, Viral/virology , Prone Position/physiology , Respiration, Artificial/methods , Respiratory Distress Syndrome/virology , SARS-CoV-2 , Thrombophilia/virology , Vasodilator Agents/therapeutic use
19.
Turk Kardiyol Dern Ars ; 48(4): 410-424, 2020 06.
Article in English | MEDLINE | ID: covidwho-622990

ABSTRACT

OBJECTIVE: The aim of this study was to evaluate the effectiveness of plants used in the formulations of traditional Chinese medicine (TCM), which were also used in clinical trials to treat patients with the novel coronavirus COVID-19, and to assess their effects on the cardiovascular system. METHODS: A literature review of PubMed, ResearchGate, ScienceDirect, the Cochrane Library, and TCM monographs was conducted and the effects of the plants on the cardiovascular system and the mechanisms of action in COVID-19 treatment were evaluated. RESULTS: The mechanism of action, cardiovascular effects, and possible toxicity of 10 plants frequently found in TCM formulations that were used in the clinical treatment of COVID-19 were examined. CONCLUSION: TCM formulations that had been originally developed for earlier viral diseases have been used in COVID-19 treatment. Despite the effectiveness seen in laboratory and animal studies with the most commonly used plants in these formulations, the clinical studies are currently insufficient according to standard operating procedures. More clinical studies are needed to understand the safe clinical use of traditional plants.


Subject(s)
Cardiovascular System/drug effects , Coronavirus Infections/therapy , Drugs, Chinese Herbal/therapeutic use , Medicine, Chinese Traditional , Pneumonia, Viral/therapy , Animals , Anti-Arrhythmia Agents/pharmacology , Anti-Arrhythmia Agents/therapeutic use , Anti-Arrhythmia Agents/toxicity , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Anti-Inflammatory Agents/toxicity , Anticholesteremic Agents/pharmacology , Anticholesteremic Agents/therapeutic use , Anticholesteremic Agents/toxicity , Antihypertensive Agents/pharmacology , Antihypertensive Agents/therapeutic use , Antihypertensive Agents/toxicity , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Antiviral Agents/toxicity , COVID-19 , Calcium Channel Blockers/pharmacology , Calcium Channel Blockers/therapeutic use , Calcium Channel Blockers/toxicity , Drug Interactions , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/toxicity , Humans , Pandemics , Platelet Aggregation Inhibitors/pharmacology , Platelet Aggregation Inhibitors/therapeutic use , Platelet Aggregation Inhibitors/toxicity , Vasodilator Agents/pharmacology , Vasodilator Agents/therapeutic use , Vasodilator Agents/toxicity
20.
Am J Respir Crit Care Med ; 201(12): 1560-1564, 2020 06 15.
Article in English | MEDLINE | ID: covidwho-155108
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