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1.
PLoS One ; 17(5): e0268822, 2022.
Article in English | MEDLINE | ID: covidwho-1869203

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
2.
BMJ Case Rep ; 15(5)2022 May 10.
Article in English | MEDLINE | ID: covidwho-1832381

ABSTRACT

Multisystem inflammatory syndrome in adults (MIS-A) has been reported as a rare but severe consequence of COVID-19 infection. Adult patients were more likely to present with hypotension and cardiac illness when compared with multisystem inflammatory syndrome in children. Although the exact prevalence of MIS-A is unknown, more cases have been observed in men and younger adults. The pathophysiology of MIS-A is also unclear, but is thought to be caused by a delayed, dysregulated immune response. Given no established guideline for treatment of MIS-A, treatment has been based on case reports. We present a case of MIS-A in a woman in her 60s who had severe hypotension, progressive dyspnoea, massive pleural effusion, hypoxaemia, thyroiditis and multiple organ failure, which dramatically improved after treatment with corticosteroid and interleukin 6 inhibitor.


Subject(s)
COVID-19 , Hypotension , Thyroiditis , Adrenal Cortex Hormones/therapeutic use , Adult , COVID-19/complications , COVID-19/drug therapy , Child , Female , Humans , Hypoxia/drug therapy , Hypoxia/etiology , Interleukin-6 , Male , SARS-CoV-2 , Systemic Inflammatory Response Syndrome/drug therapy
3.
Intensive Care Med ; 48(5): 580-589, 2022 05.
Article in English | MEDLINE | ID: covidwho-1797659

ABSTRACT

PURPOSE: We assessed long-term outcomes of dexamethasone 12 mg versus 6 mg given daily for up to 10 days in patients with coronavirus disease 2019 (COVID-19) and severe hypoxaemia. METHODS: We assessed 180-day mortality and health-related quality of life (HRQoL) using EuroQoL (EQ)-5D-5L index values and EQ visual analogue scale (VAS) in the international, stratified, blinded COVID STEROID 2 trial, which randomised 1000 adults with confirmed COVID-19 receiving at least 10 L/min of oxygen or mechanical ventilation in 26 hospitals in Europe and India. In the HRQoL analyses, higher values indicated better outcomes, and deceased patients were given a score of zero. RESULTS: We obtained vital status at 180 days for 963 of 982 patients (98.1%) in the intention-to-treat population, EQ-5D-5L index value data for 922 (93.9%) and EQ VAS data for 924 (94.1%). At 180 days, 164 of 486 patients (33.7%) had died in the 12 mg group versus 184 of 477 (38.6%) in the 6 mg group [adjusted risk difference - 4.3%; 99% confidence interval (CI) - 11.7-3.0; relative risk 0.89; 0.72-1.09; P = 0.13]. The adjusted mean differences between the 12 mg and the 6 mg groups in EQ-5D-5L index values were 0.06 (99% CI - 0.01 to 0.12; P = 0.10) and in EQ VAS scores 4 (- 3 to 10; P = 0.22). CONCLUSION: Among patients with COVID-19 and severe hypoxaemia, dexamethasone 12 mg compared with 6 mg did not result in statistically significant improvements in mortality or HRQoL at 180 days, but the results were most compatible with benefit from the higher dose.


Subject(s)
COVID-19 , Dexamethasone , Hypoxia , Adult , COVID-19/complications , COVID-19/drug therapy , Dexamethasone/administration & dosage , Dose-Response Relationship, Drug , Humans , Hypoxia/complications , Hypoxia/drug therapy , Patient Acuity , Quality of Life , Surveys and Questionnaires , Treatment Outcome
4.
Comput Math Methods Med ; 2022: 9612548, 2022.
Article in English | MEDLINE | ID: covidwho-1765204

ABSTRACT

Objective: To investigate the differences between inhaled nitric oxide (iNO) treatment and conventional therapy in the treatment of postoperative hypoxemia in obese patients with acute type A aortic dissection (ATAAD). Methods: ATAAD patients diagnosed and treated with emergency surgery in our hospital from June 2017 to December 2019 were retrospectively analyzed. Patients with postoperative hypoxemia were divided into the iNO group and control group. Propensity score matching was used to analyze clinical characteristics and results of the two groups. Results: A total of 218 ATAAD patients with BMI ≥ 25 were treated with surgery. Among them, 115 patients developed refractory hypoxemia (64 in the control group and 51 in the iNO group). Patients in the iNO group had significantly shorter invasive mechanical ventilation time, intensive care unit (ICU) stay, and hospital stay. After 6 h of iNO treatment, the PaO2/FiO2 ratio in the iNO group increased significantly, and this ratio was higher than that in the control group at 6, 12, 24, 48, and 72 h after treatment. Conclusion: Low-dose iNO could improve oxygenation and shorten mechanical ventilation and ICU stay in patients with hypoxemia after ATAAD surgery, but without significant side effects or increase in postoperative mortality or morbidity. These findings provide a basis for a randomized multicenter controlled trial to assess the efficacy of iNO in the treatment of hypoxemia after ATAAD surgery.


Subject(s)
Aneurysm, Dissecting , Nitric Oxide , Aneurysm, Dissecting/complications , Aneurysm, Dissecting/surgery , Humans , Hypoxia/drug therapy , Hypoxia/etiology , Nitric Oxide/therapeutic use , Obesity/complications , Respiratory Therapy , Retrospective Studies
5.
Environ Sci Pollut Res Int ; 29(26): 38657-38672, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1729363

ABSTRACT

COVID-19 is a serious respiratory infection caused by a beta-coronavirus that is closely linked to SARS. Hypoxemia is a symptom of infection, which is accompanied by acute respiratory distress syndrome (ARDS). Augmenting supplementary oxygen may not always improve oxygen saturation; reversing hypoxemia in COVID-19 necessitates sophisticated means to promote oxygen transfer from alveoli to blood. Inhaled nitric oxide (iNO) has been shown to inhibit the multiplication of the respiratory coronavirus, a property that distinguishes it from other vasodilators. These findings imply that NO may have a crucial role in the therapy of COVID-19, indicating research into optimal methods to restore pulmonary physiology. According to clinical and experimental data, NO is a selective vasodilator proven to restore oxygenation by helping to normalize shunts and ventilation/perfusion mismatches. This study examines the role of NO in COVID-19 in terms of its specific physiological and biochemical properties, as well as the possibility of using inhaled NO as a standard therapy. We have also discussed how NO could be used to prevent and cure COVID-19, in addition to the limitations of NO.


Subject(s)
COVID-19 , Administration, Inhalation , Humans , Hypoxia/drug therapy , Nitric Oxide , Oxygen
6.
Hosp Pract (1995) ; 50(2): 118-123, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1713461

ABSTRACT

OBJECTIVES: Patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) frequently present with a febrile illness that may progress to pneumonia and hypoxic respiratory failure. Aerosolized epoprostenol (aEPO) has been evaluated in patients with acute respiratory distress syndrome and refractory hypoxemia. A paucity of literature has assessed the impact of aEPO in patients with SARS-CoV-2 receiving oxygen support with high flow nasal cannula (HFNC). The objective of this study was to evaluate whether aEPO added to HFNC prevents intubation and/or prolong time to intubation compared to controls only treated with HFNC, guided by oxygen saturation goals. METHODS: This was a single-center, retrospective study of adult patients infected with coronavirus 2019 (COVID-19) and admitted to the medical intensive care unit. A total of 60 patients were included. Thirty patients were included in the treatment, and 30 in the control group, respectively. Among patients included in the treatment group, response to therapy was assessed. The need for mechanical ventilation and hospital mortality between responders vs. non-responders was evaluated. RESULTS: The primary outcome of mechanical ventilation was not statistically different between groups. Time from HFNC initiation to intubation was significantly prolonged in the treatment group compared to the control group (5.7 days vs. 2.3 days, P = 0.001). There was no statistically significant difference between groups in mortality or length of stay. Patients deemed responders to aEPO had a lower rate of mechanical ventilation (50% vs 88%, P = 0.025) and mortality (21% vs 63%, P = 0.024), compared with non-responders. CONCLUSION: The utilization of aEPO in COVID-19 patients treated with HFNC is not associated with a reduction in the rate of mechanical ventilation. Nevertheless, the application of this strategy may prolong the time to invasive mechanical ventilation, without affecting other clinical outcomes.


Subject(s)
COVID-19 , Noninvasive Ventilation , Respiratory Insufficiency , Adult , Epoprostenol/therapeutic use , Humans , Hypoxia/drug therapy , Oxygen Inhalation Therapy , Respiratory Insufficiency/therapy , Retrospective Studies , SARS-CoV-2
7.
Future Microbiol ; 17: 339-350, 2022 03.
Article in English | MEDLINE | ID: covidwho-1686353

ABSTRACT

Aims: Ivermectin is a safe, inexpensive and effective early COVID-19 treatment validated in 20+ random, controlled trials. Having developed combination therapies for Helicobacter pylori, the authors present a highly effective COVID-19 therapeutic combination, stemming from clinical observations. Patients & methods: In 24 COVID-19 subjects refusing hospitalization with high-risk features, hypoxia and untreated moderate to severe symptoms averaging 9 days, the authors administered this novel combination of ivermectin, doxycycline, zinc and vitamins D and C. Results & conclusions: All subjects resolved symptoms (in 11 days on average), and oxygen saturation improved in 24 h (87.4% to 93.1%; p = 0.001). There were no hospitalizations or deaths, less than (p < 0.002 or 0.05, respectively) background-matched CDC database controls. Triple combination therapy is safe and effective even when used in outpatients with moderate to severe symptoms. Clinical Trial Registration: NCT04482686 (ClinicalTrial.gov).


Subject(s)
COVID-19 , Ivermectin , COVID-19/drug therapy , Drug Therapy, Combination , Humans , Hypoxia/drug therapy , Ivermectin/therapeutic use , Leprostatic Agents/therapeutic use , SARS-CoV-2 , Treatment Outcome
8.
Intern Med ; 61(8): 1219-1223, 2022 Apr 15.
Article in English | MEDLINE | ID: covidwho-1677612

ABSTRACT

A 44-year-old man developed coronavirus disease 2019 (COVID-19) pneumonia during immunochemotherapy consisting of carboplatin, paclitaxel, and pembrolizumab for non-small cell lung cancer. Low-grade fever, followed by mild hypoxemia, and febrile neutropenia, were observed, and granulocyte colony-stimulating factor (G-CSF) was administered until the recovery of neutropenia, when he developed a high fever, severe hypoxemia, and hypotension accompanied by consolidation in the bilateral lungs. His conditions promptly improved after treatment including hydrocortisone and the primary and metastatic tumors remained regressed for 10 months without further treatment. Post-COVID-19 organizing pneumonia during cancer immunochemotherapy can be aggravated by immune-checkpoint inhibitors and G-CSF.


Subject(s)
COVID-19 , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Adult , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Non-Small-Cell Lung/drug therapy , Granulocyte Colony-Stimulating Factor/therapeutic use , Humans , Hypoxia/drug therapy , Lung Neoplasms/complications , Lung Neoplasms/drug therapy , Male
9.
Immunopharmacol Immunotoxicol ; 44(2): 141-146, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1671877

ABSTRACT

Over the last twenty months, the attention of the world has been focusing on managing the unprecedented and devastating wave of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV 2) and mitigating its impacts. Recent findings indicated that high levels of pro-inflammatory cytokines are leading cause of poor prognosis in severely ill COVID-19 patients. Presently, the multiple variants and highly contagious nature of virus makes challenge humongous. The shortage and vaccine hesitancy also prompted to develop antiviral therapeutic agents to manage this pandemic. Nanocurcumin has potential antiviral activities and also beneficial in post COVID inflammatory complications. We have developed nanocurcumin based formulation using pyrroloquinoline quinone (PQQ) which protects cardio-pulmonary function and mitochondrial homeostasis in hypobaric hypoxia induced right ventricular hypertrophy in animal model and human ventricular cardiomyocytes. Nanocurcumin based formulation (NCF) with improved bioavailability, has proven several holistic therapeutic effects including myocardial protection, and prevents edema formation, anti-inflammatory and antioxidant properties, maintaining metabolic and mitochondrial homeostasis under hypoxic condition. The post COVID-inflammatory syndrome also reported to cause impaired heart function, lung injuries and increased C-reactive protein level in severely ill patients. Thus, we speculate that NCF could be a new treatment option to manage post COVID-19 inflammatory syndrome.


Subject(s)
COVID-19 , Animals , Antioxidants/pharmacology , COVID-19/drug therapy , Humans , Hypoxia/drug therapy , Hypoxia/metabolism , Mitochondria , Pandemics
10.
Drug Discov Ther ; 15(5): 273-277, 2021 Nov 21.
Article in English | MEDLINE | ID: covidwho-1542926

ABSTRACT

Use of systemic corticosteroids is well-established in COVID-19 patients with hypoxia; however, there is scant data on its role in patients with mild disease and prolonged symptoms as a measure to prevent disease progression. The aim of this study is to evaluate the role of systemic corticosteroids in preventing hypoxia (SpO2 ≤ 93% on room-air) among mild COVID-19 patients. An observational study was conducted among symptomatic COVID-19 patients taking oral corticosteroids and attending institute teleconsultation facility between 10th-30th June 2021. Patients who were already on corticosteroids for other indication or required oxygen supplementation before or within 24-hours of initiation of corticosteroids were excluded. A total of 140 consecutive symptomatic COVID-19 patients were included. Higher baseline C-reactive protein (OR: 1.03, 95% CI: 1.02-1.06, p < 0.001) and early systemic corticosteroid (within 7 days) initiation (OR: 6.5, 95% CI: 2.1-20.1, p = 0.001) were independent risk factors for developing hypoxia (SpO2 ≤ 93%). Progression to hypoxia was significantly higher in patients who received corticosteroids before day 7 of illness (36.7%, 95% CI, 23.4-51.7%) compared to ≥ 7 of illness (14.3%, 95% CI, 7.8-23.2%) for persistent fever. Systemic corticosteroids within 7 days from symptom-onset were harmful and increased the risk of progression to hypoxia, whereas it may decrease the risk of progression when administered on or beyond 7 days in patients with mild COVID-19 and persistent symptoms. A well-designed randomised controlled trial is required to validate the findings.


Subject(s)
Adrenal Cortex Hormones/therapeutic use , COVID-19/drug therapy , Hypoxia/prevention & control , Administration, Oral , Adrenal Cortex Hormones/administration & dosage , Adult , COVID-19/complications , Disease Progression , Female , Humans , Hypoxia/drug therapy , Hypoxia/etiology , Kaplan-Meier Estimate , Male , Middle Aged , Treatment Outcome
11.
J Infect Chemother ; 28(2): 321-325, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1521285

ABSTRACT

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which leads to critical pneumonia, although the clinical courses vary. In some cases, COVID-19 pneumonia causes secondary pulmonary fibrosis, which can retain radiological changes and prolong respiratory symptoms. Interstitial lung disease (ILD) secondary to COVID-19 is thought to be caused by multiple pathologies, such as excessive cytokines and abnormal repair processes elaborated by lung cells (epithelium, mesenchyme, and alveolar macrophages) after lung injury rather than viral invasion itself. Immunosuppression therapy may improve chronic respiratory symptoms and radiological changes in post-COVID-19 ILD, although the treatment is not yet established. Herein, we report three patients with post-COVID-19 ILD who presented with profound hypoxemia that had a good response to high-dose corticosteroid therapy. Further and larger studies are needed to establish post-COVID-19 ILD.


Subject(s)
COVID-19 , Lung Diseases, Interstitial , Adrenal Cortex Hormones/therapeutic use , Humans , Hypoxia/drug therapy , Lung , Lung Diseases, Interstitial/drug therapy , SARS-CoV-2
12.
Free Radic Biol Med ; 177: 189-200, 2021 12.
Article in English | MEDLINE | ID: covidwho-1466351

ABSTRACT

As hypoxia is a major driver for the pathophysiology of COVID-19, it is crucial to characterize the hypoxic response at the cellular and molecular levels. In order to augment drug repurposing with the identification of appropriate molecular targets, investigations on therapeutics preventing hypoxic cell damage is required. In this work, we propose a hypoxia model based on alveolar lung epithelial cells line using chemical inducer, CoCl2 that can be used for testing calcium channel blockers (CCBs). Since recent studies suggested that CCBs may reduce the infectivity of SARS-Cov-2, we specifically select FDA approved calcium channel blocker, nifedipine for the study. First, we examined hypoxia-induced cell morphology and found a significant increase in cytosolic calcium levels, mitochondrial calcium overload as well as ROS production in hypoxic A549 cells. Secondly, we demonstrate the protective behaviour of nifedipine for cells that are already subjected to hypoxia through measurement of cell viability as well as 4D imaging of cellular morphology and nuclear condensation. Thirdly, we show that the protective effect of nifedipine is achieved through the reduction of cytosolic calcium, mitochondrial calcium, and ROS generation. Overall, we outline a framework for quantitative analysis of mitochondrial calcium and ROS using 3D imaging in laser scanning confocal microscopy and the open-source image analysis platform ImageJ. The proposed pipeline was used to visualize mitochondrial calcium and ROS level in individual cells that provide an understanding of molecular targets. Our findings suggest that the therapeutic value of nifedipine may potentially be evaluated in the context of COVID-19 therapeutic trials.


Subject(s)
COVID-19 , Nifedipine , A549 Cells , Calcium , Calcium Channel Blockers/pharmacology , Calcium Channel Blockers/therapeutic use , Cell Death , Humans , Hypoxia/drug therapy , Nifedipine/pharmacology , SARS-CoV-2 , Superoxides
13.
Lipids Health Dis ; 20(1): 126, 2021 Oct 03.
Article in English | MEDLINE | ID: covidwho-1448237

ABSTRACT

The coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). At present, the COVID-19 has been prevalent worldwide for more than a year and caused more than four million deaths. Liver injury was frequently observed in patients with COVID-19. Recently, a new definition of metabolic dysfunction associated fatty liver disease (MAFLD) was proposed by a panel of international experts, and the relationship between MAFLD and COVID-19 has been actively investigated. Several previous studies indicated that the patients with MAFLD had a higher prevalence of COVID-19 and a tendency to develop severe type of respiratory infection, and others indicated that liver injury would be exacerbated in the patients with MAFLD once infected with COVID-19. The mechanism underlying the relationship between MAFLD and COVID-19 infection has not been thoroughly investigated, and recent studies indicated that multifactorial mechanisms, such as altered host angiotensin converting enzyme 2 (ACE2) receptor expression, direct viral attack, disruption of cholangiocyte function, systemic inflammatory reaction, drug-induced liver injury, hepatic ischemic and hypoxic injury, and MAFLD-related glucose and lipid metabolic disorders, might jointly contribute to both of the adverse hepatic and respiratory outcomes. In this review, we discussed the relationship between MAFLD and COVID-19 based on current available literature, and summarized the recommendations for clinical management of MAFLD patients during the pandemic of COVID-19.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , COVID-19/complications , Chemical and Drug Induced Liver Injury/complications , Hypoxia/complications , Liver/metabolism , Non-alcoholic Fatty Liver Disease/complications , SARS-CoV-2/pathogenicity , Age Factors , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/drug therapy , COVID-19/pathology , COVID-19/virology , Chemical and Drug Induced Liver Injury/drug therapy , Chemical and Drug Induced Liver Injury/pathology , Chemical and Drug Induced Liver Injury/virology , Cytokines/genetics , Cytokines/metabolism , Dipeptides/therapeutic use , Gene Expression Regulation , Glucose/metabolism , Glycyrrhizic Acid/therapeutic use , Humans , Hypoxia/drug therapy , Hypoxia/pathology , Hypoxia/virology , Liver/drug effects , Liver/pathology , Liver/virology , Lung/drug effects , Lung/metabolism , Lung/pathology , Lung/virology , Non-alcoholic Fatty Liver Disease/drug therapy , Non-alcoholic Fatty Liver Disease/pathology , Non-alcoholic Fatty Liver Disease/virology , Receptors, Virus/genetics , Receptors, Virus/metabolism , Severity of Illness Index
14.
Mol Med ; 27(1): 120, 2021 09 26.
Article in English | MEDLINE | ID: covidwho-1440900

ABSTRACT

BACKGROUND: Since fall 2019, SARS-CoV-2 spread world-wide, causing a major pandemic with estimated ~ 220 million subjects affected as of September 2021. Severe COVID-19 is associated with multiple organ failure, particularly of lung and kidney, but also grave neuropsychiatric manifestations. Overall mortality reaches > 2%. Vaccine development has thrived in thus far unreached dimensions and will be one prerequisite to terminate the pandemic. Despite intensive research, however, few treatment options for modifying COVID-19 course/outcome have emerged since the pandemic outbreak. Additionally, the substantial threat of serious downstream sequelae, called 'long COVID' and 'neuroCOVID', becomes increasingly evident. Among candidates that were suggested but did not yet receive appropriate funding for clinical trials is recombinant human erythropoietin. Based on accumulating experimental and clinical evidence, erythropoietin is expected to (1) improve respiration/organ function, (2) counteract overshooting inflammation, (3) act sustainably neuroprotective/neuroregenerative. Recent counterintuitive findings of decreased serum erythropoietin levels in severe COVID-19 not only support a relative deficiency of erythropoietin in this condition, which can be therapeutically addressed, but also made us coin the term 'hypoxia paradox'. As we review here, this paradox is likely due to uncoupling of physiological hypoxia signaling circuits, mediated by detrimental gene products of SARS-CoV-2 or unfavorable host responses, including microRNAs or dysfunctional mitochondria. Substitution of erythropoietin might overcome this 'hypoxia paradox' caused by deranged signaling and improve survival/functional status of COVID-19 patients and their long-term outcome. As supporting hints, embedded in this review, we present 4 male patients with severe COVID-19 and unfavorable prognosis, including predicted high lethality, who all profoundly improved upon treatment which included erythropoietin analogues. SHORT CONCLUSION: Substitution of EPO may-among other beneficial EPO effects in severe COVID-19-circumvent downstream consequences of the 'hypoxia paradox'. A double-blind, placebo-controlled, randomized clinical trial for proof-of-concept is warranted.


Subject(s)
COVID-19/complications , COVID-19/drug therapy , Erythropoietin/genetics , Hypoxia/drug therapy , Lung/drug effects , COVID-19/genetics , COVID-19/pathology , COVID-19/virology , Erythropoietin/analogs & derivatives , Erythropoietin/therapeutic use , Humans , Hypoxia/genetics , Hypoxia/pathology , Hypoxia/virology , Lung/pathology , Lung/virology , Pandemics , Recombinant Proteins/genetics , Recombinant Proteins/therapeutic use , SARS-CoV-2/drug effects
16.
Pharmacol Res ; 158: 104950, 2020 08.
Article in English | MEDLINE | ID: covidwho-1318942

ABSTRACT

Patients affected by severe coronavirus induced disease-2019 (Covid-19) often experience hypoxemia due to alveolar involvement and endothelial dysfunction, which leads to the formation of micro thrombi in the pulmonary capillary vessels. Both hypoxemia and a prothrombotic diathesis have been associated with more severe disease and increased risk of death. To date, specific indications to treat this condition are lacking. This was a single center, investigator initiated, compassionate use, proof of concept, case control, phase IIb study (NCT04368377) conducted in the Intermediate Respiratory Care Unit of L. Sacco University Hospital in Milano, Italy. Our objective was to explore the effects of the administration of anti-platelet therapy on arterial oxygenation and clinical outcomes in patients with severe Covid-19 with hypercoagulability. We enrolled five consecutive patients with laboratory confirmed SARS-CoV-2 infection, severe respiratory failure requiring helmet continuous positive airway pressure (CPAP), bilateral pulmonary infiltrates and a pro-thrombotic state identified as a D-dimer > 3 times the upper limit of normal. Five patients matched for age, D-dimer value and SOFA score formed the control group. Beyond standard of care, treated patients received 25 µg/Kg/body weight tirofiban as bolus infusion, followed by a continuous infusion of 0.15 µg/Kg/body weight per minute for 48 hours. Before tirofiban, patients received acetylsalicylic acid 250 mg infusion and oral clopidogrel 300 mg; both were continued at a dose of 75 mg daily for 30 days. Fondaparinux2.5 mg/day sub-cutaneous was given for the duration of the hospital stay. All controls were receiving prophylactic or therapeutic dose heparin, according to local standard operating procedures. Treated patients consistently experienced a mean (SD) reduction in A-a O2 gradient of -32.6 mmHg (61.9, P = 0.154), -52.4 mmHg (59.4, P = 0.016) and -151.1 mmHg (56.6, P = 0.011; P = 0.047 vs. controls) at 24, 48 hours and 7 days after treatment. PaO2/FiO2 ratio increased by 52 mmHg (50, P = 0.172), 64 mmHg (47, P = 0.040) and 112 mmHg (51, P = 0.036) after 24, 48 hours and 7 days, respectively. All patients but one were successfully weaned from CPAP after 3 days. This was not true for the control group. No major adverse events were observed. Antiplatelet therapy might be effective in improving the ventilation/perfusion ratio in Covid-19 patients with severe respiratory failure. The effects might be sustained by the prevention and interference on forming clots in lung capillary vessels and by modulating megakaryocytes' function and platelet adhesion. Randomized clinical trials are urgently needed to confirm these results.


Subject(s)
Betacoronavirus , Coronavirus Infections/drug therapy , Hypoxia/drug therapy , Platelet Aggregation Inhibitors/therapeutic use , Pneumonia, Viral/drug therapy , Thrombophilia/drug therapy , Aged , Aspirin/therapeutic use , COVID-19 , Clopidogrel/therapeutic use , Compassionate Use Trials , Coronavirus Infections/complications , Female , Fibrin Fibrinogen Degradation Products/metabolism , Humans , Hypoxia/complications , Male , Middle Aged , Pandemics , Pneumonia, Viral/complications , Proof of Concept Study , SARS-CoV-2 , Thrombophilia/blood , Thrombophilia/complications , Tirofiban/therapeutic use
17.
Ann Pharmacother ; 56(3): 237-244, 2022 03.
Article in English | MEDLINE | ID: covidwho-1285161

ABSTRACT

BACKGROUND: Severe hypoxic respiratory failure from COVID-19 pneumonia carries a high mortality risk. There is uncertainty surrounding which patients benefit from corticosteroids in combination with tocilizumab and the dosage and timing of these agents. The balance of controlling inflammation without increasing the risk of secondary infection is difficult. At present, dexamethasone 6 mg is the standard of care in COVID-19 hypoxia; whether this is the ideal choice of steroid or dosage remains to be proven. OBJECTIVES: The primary objective was to assess the impact on mortality of tocilizumab only, corticosteroids only, and combination therapy in patients with COVID-19 respiratory failure. METHODS: A multihospital, retrospective study of adult patients with severe respiratory failure from COVID-19 who received supportive therapy, corticosteroids, tocilizumab, or combination therapy were assessed for 28-day mortality, biomarker improvement, and relative risk of infection. Propensity-matched analysis was performed between corticosteroid alone and combination therapies to further assess mortality benefit. RESULTS: The steroid-only, tocilizumab-only, and combination groups showed hazard reduction in mortality at 28 days when compared with supportive therapy. In a propensity-matched analysis, the combination group (daily equivalent dexamethasone 10 mg and tocilizumab 400 mg) had an improved 28-day mortality compared with the steroid-only group (daily equivalent dexamethasone 10 mg; hazard ratio (95% CI) = 0.56 (0.38-0.84), P = 0.005] without increasing the risk of infection. CONCLUSION AND RELEVANCE: Combination of tocilizumab and corticosteroids was associated with improved 28-day survival when compared with corticosteroids alone. Modification of steroid dosing strategy as well as steroid type may further optimize therapeutic effect of the COVID-19 treatment.


Subject(s)
Adrenal Cortex Hormones/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19 , Respiratory Insufficiency , Adult , COVID-19/drug therapy , COVID-19/mortality , Hospital Mortality , Humans , Hypoxia/drug therapy , Hypoxia/virology , Respiratory Insufficiency/drug therapy , Respiratory Insufficiency/virology , Retrospective Studies , Treatment Outcome
18.
Inflamm Res ; 70(7): 749-752, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1281256

ABSTRACT

Coronavirus disease 2019 (COVID-19) pandemic is still a world-class challenge. Inflammation, especially its severe form with excess release of pro-inflammatory cytokines (cytokine storm) which is a life-threatening condition, is among the most important suspects involved in COVID-19 pathogenesis. It has been shown that cytokine storm could cause notable morbidities such as acute respiratory distress syndrome (ARDS) which leads to hypoxia which is significantly associated with mortality of patients with COVID-19. Hypoxia-inducible factor 1α (HIF-1α) which activates following ARDS-induced hypoxia plays a crucial role in pathogenesis of cytokine storm. The expression of tumor necrosis factor α (TNF-α), interleukin 1 ß (IL-1ß), and IL-6 which are key elements of cytokine storm are by nuclear factor κß (NFκB). Interestingly, during the hypoxia, HIF-1α activates NFκB to induce expression of pro-angiogenic and pro-inflammatory factors. These released factors starts a autocrine/paracrine loop and causes deterioration of their etiological pathways of expression: cytokine storm and ARDS. To sum up, it seems HIF-1α is an important target to hit to ameliorate the mentioned pathways. Herein, we suggest perfluorocarbons (PFCs) which are among the organofluorine compounds as a possible co-treatment to reduce hypoxemia and then hypoxia. These substances are known for their high gas solving potential that make them able to be used as a synthetic artificial blood product. Due to the potential of PFCs to affect the fountain of important physiopathological pathway such as inflammation a hypoxia through affecting NFκB, they could be considered as multi-target co-treatment for ARD individuals with COVID-19. It is highly suggested to evaluate this hypothesis in following researches.


Subject(s)
COVID-19/drug therapy , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/etiology , Fluorocarbons/therapeutic use , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/etiology , Animals , Cytokines/biosynthesis , Humans , Hypoxia/drug therapy , Hypoxia/etiology , NF-kappa B/drug effects , Protective Agents/therapeutic use , Respiratory Distress Syndrome/drug therapy , Respiratory Distress Syndrome/etiology
19.
J Aerosol Med Pulm Drug Deliv ; 34(4): 262-264, 2021 08.
Article in English | MEDLINE | ID: covidwho-1276115

ABSTRACT

Despite the various parenchymal presentation of coronavirus disease 2019 (COVID-19) pneumonia, the involvement of the vascular component, the reduction of perfusion in noninjured part of the lung and secondary right to left shunt play an important role in the genesis of the respiratory insufficiency. We present the case of a 72-year-old woman admitted to Livorno Hospital for severe respiratory insufficiency due to SARS-CoV-2 infection unresponsive to noninvasive in whom administration of nebulized phosphodiesterase 3 (PDE3) inhibitor enoximone was able to improve oxygenation avoiding tracheal intubation. Intravenous infusions of phosphodiesterase inhibitors are commonly used as pulmonary vasodilators in the management of pulmonary hypertension. This is the first case showing that inhaled route administration of PDE3 inhibitor enoximone could be important in the management of COVID-19 hypoxemia, to restore perfusion in noninjured part of the lung, improving oxygenation and avoiding risks of systemic infusion.


Subject(s)
COVID-19/drug therapy , Enoximone/administration & dosage , Hypoxia/drug therapy , Lung/blood supply , Phosphodiesterase 3 Inhibitors/administration & dosage , Pulmonary Circulation/drug effects , Administration, Inhalation , Aerosols , Aged , COVID-19/physiopathology , COVID-19/virology , Female , Humans , Hypoxia/physiopathology , Hypoxia/virology , Nebulizers and Vaporizers , Treatment Outcome
20.
Acta Pharmacol Sin ; 41(12): 1539-1546, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-1269381

ABSTRACT

The pandemic of coronavirus disease 2019 (COVID-19) and its pathogen, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have become the greatest current threat to global public health. The highly infectious SARS-CoV-2 virus primarily attacks pulmonary tissues and impairs gas exchange leading to acute respiratory distress syndrome (ARDS) and systemic hypoxia. The current pharmacotherapies for COVID-19 largely rely on supportive and anti-thrombi treatment and the repurposing of antimalarial and antiviral drugs such as hydroxychloroquine and remdesivir. For a better mechanistic understanding of COVID-19, our present review focuses on its primary pathophysiologic features: hypoxia and cytokine storm, which are a prelude to multiple organ failure and lethality. We discussed a possible link between the activation of hypoxia inducible factor 1α (HIF-1α) and cell entry of SARS-CoV-2, since HIF-1α is shown to suppress the angiotensin-converting enzyme 2 (ACE2) receptor and transmembrane protease serine 2 (TMPRSS2) and upregulate disintegrin and metalloproteinase domain-containing protein 17 (ADAM17). In addition, the protein targets of HIF-1α are involved with the activation of pro-inflammatory cytokine expression and the subsequent inflammatory process. Furthermore, we hypothesized a potential utility of so-called "hypoxic conditioning" to activate HIF-1α-induced cytoprotective signaling for reduction of illness severity and improvement of vital organ function in patients with COVID-19. Taken together, we would propose further investigations into the hypoxia-related molecular mechanisms, from which novel targeted therapies can be developed for the improved management of COVID-19.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Animals , COVID-19/physiopathology , COVID-19/virology , Cytokine Release Syndrome/virology , Drug Development , Drug Repositioning , Humans , Hypoxia/drug therapy , Hypoxia/virology , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Molecular Targeted Therapy , SARS-CoV-2/isolation & purification , SARS-CoV-2/pathogenicity
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