scholarly journals Treatment of COVID-19 pneumonia and acute respiratory distress with ramatroban, a thromboxane A2 and prostaglandin D2 receptor antagonist: A 4-Patient Case Series Report

2021 ◽  
Author(s):  
Martin L. Ogletree ◽  
Kate Chander Chiang ◽  
Rashmi Kulshreshta ◽  
Aditya Agarwal ◽  
Ashutosh Agarwal ◽  
...  
Keyword(s):  
Respiratory Distress ◽  
Organ Failure ◽  
Viral Infections ◽  
Pulmonary Veins ◽  
D2 Receptor ◽  
Case Series ◽  
Acute Onset ◽  
Lipid Mediator ◽  
Prostaglandin D2 ◽  
Th2 Immune Response

Abstract COVID-19 associated pneumonia and acute respiratory distress syndrome are characterized by a lipid mediator storm with massive increases in lung and systemic thromboxane A2 >> prostaglandin D2. Thromboxane A2 is a potent vasoconstrictor of pulmonary veins >> arteries, and thereby promotes an increase in pulmonary capillary pressures, transudation of fluid into the alveolar space, pulmonary edema and ARDS. Thromboxane A2 also increases vascular permeability, contracts bronchial smooth muscle, triggers and amplifies platelet activation, and promotes a prothrombotic state. PGD2 promotes a Th2 immune response that is atypical for viral infections and inhibits antiviral defense by suppressing interferon λ expression. D-dimers, urinary 11-dehydro-TxB2, and IL-13, a Th2 cytokine, have emerged as key biomarkers of severity and organ failure in COVID-19. Ramatroban is an orally bioavailable, potent, dual antagonist of the thromboxane A2 (TPr) and PGD2 (DPr2) receptors. We report use of ramatroban in 4 COVID-19 outpatients, 22 to 87 years of age, with acute onset / worsening of respiratory distress and hypoxemia. All four patients experienced decrease in respiratory distress and increase in SpO2, within hours of the first dose and thereby avoided hospitalization. By the 5th day all 4 patients had complete resolution of respiratory distress and hypoxemia. Ramatroban (Baynas®, Bayer Yakuhin Ltd., Japan) has an established safety profile, having been indicated in Japan for the treatment of allergic rhinitis for over 20 years. As a broncho-relaxant, anti-vasospastic, anti-thrombotic and immunomodulator, ramatroban addresses the fundamental pathophysiologic mechanisms underlying respiratory and critical organ failure in COVID-19, and therefore merits urgent clinical trials that might impact the ongoing pandemic.

scholarly journals Treatment of COVID-19 pneumonia and acute respiratory distress with ramatroban, a thromboxane A2 and prostaglandin D2 receptor antagonist: A 4-Patient Case Series Report

2021 ◽  
Author(s):  
Martin L. Ogletree ◽  
Kate Chander Chiang ◽  
Rashmi Kulshreshta ◽  
Aditya Agarwal ◽  
Ashutosh Agarwal ◽  
...  
Keyword(s):  
Respiratory Distress ◽  
Organ Failure ◽  
Viral Infections ◽  
Pulmonary Veins ◽  
D2 Receptor ◽  
Case Series ◽  
Acute Onset ◽  
Lipid Mediator ◽  
Prostaglandin D2 ◽  
Th2 Immune Response

Abstract COVID-19 associated pneumonia and acute respiratory distress syndrome are characterized by a lipid mediator storm with massive increases in lung and systemic thromboxane A2 >> prostaglandin D2. Thromboxane A2 is a potent vasoconstrictor of pulmonary veins >> arteries, and thereby promotes an increase in pulmonary capillary pressures, transudation of fluid into the alveolar space, pulmonary edema and ARDS. Thromboxane A2 also increases vascular permeability, contracts bronchial smooth muscle, triggers and amplifies platelet activation, and promotes a prothrombotic state. PGD2 promotes a Th2 immune response that is atypical for viral infections and inhibits antiviral defense by suppressing interferon λ expression. D-dimers, urinary 11-dehydro-TxB2, and IL-13, a Th2 cytokine, have emerged as key biomarkers of severity and organ failure in COVID-19. Ramatroban is an orally bioavailable, potent, dual antagonist of the thromboxane A2 (TPr) and PGD2 (DPr2) receptors. We report use of ramatroban in 4 COVID-19 outpatients, 22 to 87 years of age, with acute onset / worsening of respiratory distress and hypoxemia. All four patients experienced decrease in respiratory distress and increase in SpO2, within hours of the first dose and thereby avoided hospitalization. By the 5th day all 4 patients had complete resolution of respiratory distress and hypoxemia. Ramatroban (Baynas®, Bayer Yakuhin Ltd., Japan) has an established safety profile, having been indicated in Japan for the treatment of allergic rhinitis for over 20 years. As a broncho-relaxant, anti-vasospastic, anti-thrombotic and immunomodulator, ramatroban addresses the fundamental pathophysiologic mechanisms underlying respiratory and critical organ failure in COVID-19, and therefore merits urgent clinical trials that might impact the ongoing pandemic.

scholarly journals Treatment of COVID-19 pneumonia and acute respiratory distress with ramatroban, a thromboxane A2 and prostaglandin D2 receptor antagonist: A 4-Patient Case Series Report

2021 ◽  
Author(s):  
Martin L. Ogletree ◽  
Kate Chander Chiang ◽  
Rashmi Kulshreshta ◽  
Aditya Agarwal ◽  
Ashutosh Agarwal ◽  
...  
Keyword(s):  
Respiratory Distress ◽  
Organ Failure ◽  
Viral Infections ◽  
Pulmonary Veins ◽  
D2 Receptor ◽  
Case Series ◽  
Acute Onset ◽  
Lipid Mediator ◽  
Prostaglandin D2 ◽  
Th2 Immune Response

Abstract COVID-19 associated pneumonia and acute respiratory distress syndrome are characterized by a lipid mediator storm with massive increases in lung and systemic thromboxane A2 >> prostaglandin D2. Thromboxane A2 is a potent vasoconstrictor of pulmonary veins >> arteries, and thereby promotes an increase in pulmonary capillary pressures, transudation of fluid into the alveolar space, pulmonary edema and ARDS. Thromboxane A2 also increases vascular permeability, contracts bronchial smooth muscle, triggers and amplifies platelet activation, and promotes a prothrombotic state. PGD2 promotes a Th2 immune response that is atypical for viral infections and inhibits antiviral defense by suppressing interferon λ expression. D-dimers, urinary 11-dehydro-TxB2, and IL-13, a Th2 cytokine, have emerged as key biomarkers of severity and organ failure in COVID-19. Ramatroban is an orally bioavailable, potent, dual antagonist of the thromboxane A2 (TPr) and PGD2 (DPr2) receptors. We report use of ramatroban in 4 COVID-19 outpatients, 22 to 87 years of age, with acute onset / worsening of respiratory distress and hypoxemia. All four patients experienced decrease in respiratory distress and increase in SpO2, within hours of the first dose and thereby avoided hospitalization. By the 5th day all 4 patients had complete resolution of respiratory distress and hypoxemia. Ramatroban (Baynas®, Bayer Yakuhin Ltd., Japan) has an established safety profile, having been indicated in Japan for the treatment of allergic rhinitis for over 20 years. As a broncho-relaxant, anti-vasospastic, anti-thrombotic and immunomodulator, ramatroban addresses the fundamental pathophysiologic mechanisms underlying respiratory and critical organ failure in COVID-19, and therefore merits urgent clinical trials that might impact the ongoing pandemic.

scholarly journals Treatment of COVID-19 pneumonia and acute respiratory distress with ramatroban, a thromboxane A2 and prostaglandin D2 receptor antagonist: A 4-Patient Case Series Report

2021 ◽  
Author(s):  
Martin L. Ogletree ◽  
Kate Chander Chiang ◽  
Rashmi Kulshreshta ◽  
Aditya Agarwal ◽  
Ashutosh Agarwal ◽  
...  
Keyword(s):  
Respiratory Distress ◽  
Viral Infections ◽  
Pulmonary Veins ◽  
D2 Receptor ◽  
Case Series ◽  
Acute Onset ◽  
Prostaglandin D2 ◽  
Th2 Immune Response ◽  
Case Series Report ◽  
Orally Bioavailable

Abstract COVID-19 associated pneumonia and acute respiratory distress syndrome are accompanied by a massive and sustained increase in lung and systemic thromboxane (Tx) A2. TxA2 is a short-lived, potent vasoconstrictor of pulmonary veins > arteries, and thereby selectively increases pulmonary venous resistance, promoting an increase in pulmonary capillary pressure. TxA2 also increases vascular permeability which, in the lungs, exaggerates pressure-mediated transudation into the alveolar space, causing pulmonary edema and ARDS. Also relevant to COVID-19 pathophysiology, TxA2 contracts bronchial smooth muscle, triggers and amplifies platelet activation, mediates apoptosis of immature thymocytes, and promotes a procoagulant state, all of which are mediated by TxA2 receptor (TPr) activation. The stable TxA2 metabolite, 11-dehydro-TxB2, is elevated in direct proportion to COVID-19 severity. Though inactive at TPr, 11-dehydro-TxB2 activates PGD2 / DP2 receptors (DPr2) which promote a Th2 immune response that is atypical for viral infections and inhibits antiviral defense by suppressing interferon λ expression. Ramatroban is an orally bioavailable, potent, dual antagonist of TPr and DPr2 receptors. We report use of ramatroban (Baynas®, Bayer Yakuhin Ltd., Japan) in 4 COVID-19 outpatients, 22 to 87 years of age, with acute onset / worsening of respiratory distress and hypoxemia. All four patients experienced a decrease in respiratory distress and increase in SpO2, within hours of the first dose of ramatroban and, thereby, avoided hospitalization. By the 5th day all 4 patients had complete resolution of respiratory distress and hypoxemia. Ramatroban has an established safety profile, having been indicated in Japan for the treatment of allergic rhinitis for over 20 years. As an anti-vasospastic, broncho-relaxant, anti-thrombotic and immunomodulator, ramatroban addresses the fundamental host response mechanisms underlying respiratory and critical organ failure in COVID-19, and merits urgent clinical trials that might impact the ongoing pandemic.

scholarly journals Mesenchymal stem cells derived from perinatal tissues for treatment of critically ill COVID-19-induced ARDS patients: a case series

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Seyed-Mohammad Reza Hashemian ◽  
Rasoul Aliannejad ◽  
Morteza Zarrabi ◽  
Masoud Soleimani ◽  
Massoud Vosough ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Respiratory Distress ◽  
Organ Failure ◽  
Critically Ill ◽  
Umbilical Cord ◽  
Case Series ◽  
High Dose ◽  
Human Umbilical Cord ◽  
Multi Organ Failure

Abstract Background Acute respiratory distress syndrome (ARDS) is a fatal complication of coronavirus disease 2019 (COVID-19). There are a few reports of allogeneic human mesenchymal stem cells (MSCs) as a potential treatment for ARDS. In this phase 1 clinical trial, we present the safety, feasibility, and tolerability of the multiple infusions of high dose MSCs, which originated from the placenta and umbilical cord, in critically ill COVID-19-induced ARDS patients. Methods A total of 11 patients diagnosed with COVID-19-induced ARDS who were admitted to the intensive care units (ICUs) of two hospitals enrolled in this study. The patients were critically ill with severe hypoxemia and required mechanical ventilation. The patients received three intravenous infusions (200 × 106 cells) every other day for a total of 600 × 106 human umbilical cord MSCs (UC-MSCs; 6 cases) or placental MSCs (PL-MSCs; 5 cases). Findings There were eight men and three women who were 42 to 66 years of age. Of these, six (55%) patients had comorbidities of diabetes, hypertension, chronic lymphocytic leukemia (CLL), and cardiomyopathy (CMP). There were no serious adverse events reported 24–48 h after the cell infusions. We observed reduced dyspnea and increased SpO2 within 48–96 h after the first infusion in seven patients. Of these seven patients, five were discharged from the ICU within 2–7 days (average: 4 days), one patient who had signs of acute renal and hepatic failure was discharged from the ICU on day 18, and the last patient suddenly developed cardiac arrest on day 7 of the cell infusion. Significant reductions in serum levels of tumor necrosis factor-alpha (TNF-α; P < 0.01), IL-8 (P < 0.05), and C-reactive protein (CRP) (P < 0.01) were seen in all six survivors. IL-6 levels decreased in five (P = 0.06) patients and interferon gamma (IFN-γ) levels decreased in four (P = 0.14) patients. Four patients who had signs of multi-organ failure or sepsis died in 5–19 days (average: 10 days) after the first MSC infusion. A low percentage of lymphocytes (< 10%) and leukocytosis were associated with poor outcome (P = 0.02). All six survivors were well with no complaints of dyspnea on day 60 post-infusion. Radiological parameters of the lung computed tomography (CT) scans showed remarkable signs of recovery. Interpretation We suggest that multiple infusions of high dose allogeneic prenatal MSCs are safe and can rapidly improve respiratory distress and reduce inflammatory biomarkers in some critically ill COVID-19-induced ARDS cases. Patients that develop sepsis or multi-organ failure may not be good candidates for stem cell therapy. Large randomized multicenter clinical trials are needed to discern the exact therapeutic potentials of MSC in COVID-19-induced ARDS.

scholarly journals Treatment of COVID-19 pneumonia and acute respiratory distress with ramatroban, a thromboxane A2 and prostaglandin D2 receptor antagonist: A 4-Patient Case Series Report

2022 ◽  
Author(s):  
Martin L. Ogletree ◽  
Kate Chander Chiang ◽  
Rashmi Kulshreshta ◽  
Aditya Agarwal ◽  
Ashutosh Agarwal ◽  
...  
Keyword(s):  
Respiratory Failure ◽  
Respiratory Distress ◽  
Receptor Antagonist ◽  
Randomized Clinical Trials ◽  
Clinical Symptoms ◽  
Case Series ◽  
Secondary Outcome ◽  
Prostaglandin D2 ◽  
Retrospective Case ◽  
Blood Oxygen Saturation

Abstract Importance Hypoxemia in COVID-19 pneumonia is dispositive for hospitalization and mechanical ventilation and contributes to mortality. Other than oxygen supplementation, there is no treatment that resolves hypoxemia in COVID-19 pneumonia. Objective COVID-19 pneumonia sustains a massive increase in lipid mediators, especially thromboxane A2 >> PGE2 > PGD2. Thromboxane A2 induces pulmonary venoconstriction, increases pulmonary capillary pressure and contributes to pulmonary edema. High thromboxane A2 metabolite levels are strongly associated with respiratory failure and mortality in hospitalized COVID-19 patients. Ramatroban (Baynas®, Bayer Yakuhin Ltd., Japan) is an inexpensive, orally bioavailable, thromboxane A2 receptor antagonist. Ramatroban was administered to patients with COVID-19 pneumonia and hypoxemia to explore the effect of thromboxane A2 antagonism on clinical symptoms and outcomes. Design, Setting, and Participants A retrospective case series comprising 4 consecutive outpatients, 22 to 87 years of age, with COVID-19 pneumonia and hypoxemia treated with ramatroban between April and July 2021 in India. Main Outcomes and Measures The primary outcome measure was blood oxygen saturation using pulse oximetry (SpO2). Secondary outcome measures were respiratory distress and need for hospitalization. Results Four COVID-19 outpatients had developed progressive respiratory distress and hypoxemia. Within 12-36 hours of the first dose of ramatroban, all four patients experienced increase in SpO2 and decrease in respiratory distress, which obviated hospitalization. Continued treatment for 5 days was associated with complete resolution of respiratory distress and hypoxemia. Conclusions and Relevance There is an unmet medical need for drugs that target the hemodynamic, prothrombotic, and maladaptive immune responses that lead to pneumonia and respiratory failure following SARS-CoV-2 infection. As an anti-vasospastic, broncho-relaxant, anti-thrombotic and immunomodulatory agent, ramatroban addresses the fundamental host response mechanisms underlying respiratory and critical organ failure in COVID-19. Ramatroban merits study in randomized clinical trials that might offer hope for a cost-effective pandemic treatment.

scholarly journals Treatment of COVID-19 pneumonia and acute respiratory distress with ramatroban, a thromboxane A2 and prostaglandin D2 receptor antagonist: A 4-Patient Case Series Report

2022 ◽  
Author(s):  
Martin L. Ogletree ◽  
Kate Chander Chiang ◽  
Rashmi Kulshreshta ◽  
Aditya Agarwal ◽  
Ashutosh Agarwal ◽  
...  
Keyword(s):  
Respiratory Failure ◽  
Respiratory Distress ◽  
Receptor Antagonist ◽  
Randomized Clinical Trials ◽  
Clinical Symptoms ◽  
Case Series ◽  
Secondary Outcome ◽  
Prostaglandin D2 ◽  
Retrospective Case ◽  
Blood Oxygen Saturation

Abstract Importance Hypoxemia in COVID-19 pneumonia is dispositive for hospitalization and mechanical ventilation and contributes to mortality. Other than oxygen supplementation, there is no treatment that resolves hypoxemia in COVID-19 pneumonia. Objective COVID-19 pneumonia sustains a massive increase in lipid mediators, especially thromboxane A2 >> PGE2 > PGD2. Thromboxane A2 induces pulmonary venoconstriction, increases pulmonary capillary pressure and contributes to pulmonary edema. High thromboxane A2 metabolite levels are strongly associated with respiratory failure and mortality in hospitalized COVID-19 patients. Ramatroban (Baynas®, Bayer Yakuhin Ltd., Japan) is an inexpensive, orally bioavailable, thromboxane A2 receptor antagonist. Ramatroban was administered to patients with COVID-19 pneumonia and hypoxemia to explore the effect of thromboxane A2 antagonism on clinical symptoms and outcomes. Design, Setting, and Participants A retrospective case series comprising 4 consecutive outpatients, 22 to 87 years of age, with COVID-19 pneumonia and hypoxemia treated with ramatroban between April and July 2021 in India. Main Outcomes and Measures The primary outcome measure was blood oxygen saturation using pulse oximetry (SpO2). Secondary outcome measures were respiratory distress and need for hospitalization. Results Four COVID-19 outpatients had developed progressive respiratory distress and hypoxemia. Within 12-36 hours of the first dose of ramatroban, all four patients experienced increase in SpO2 and decrease in respiratory distress, which obviated hospitalization. Continued treatment for 5 days was associated with complete resolution of respiratory distress and hypoxemia. Conclusions and Relevance There is an unmet medical need for drugs that target the hemodynamic, prothrombotic, and maladaptive immune responses that lead to pneumonia and respiratory failure following SARS-CoV-2 infection. As an anti-vasospastic, broncho-relaxant, anti-thrombotic and immunomodulatory agent, ramatroban addresses the fundamental host response mechanisms underlying respiratory and critical organ failure in COVID-19. Ramatroban merits study in randomized clinical trials that might offer hope for a cost-effective pandemic treatment.

scholarly journals Endocrine Dysfunction in Children with Zika-Related Microcephaly Who Were Born during the 2015 Epidemic in the State of Pernambuco, Brazil

Viruses ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 1
Author(s):  
Andréia Veras Gonçalves ◽  
Demócrito de B. Miranda-Filho ◽  
Líbia Cristina Rocha Vilela ◽  
Regina Coeli Ferreira Ramos ◽  
Thalia V. B. de Araújo ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Viral Infections ◽  
Case Series ◽  
Optic Nerve Hypoplasia ◽  
Endocrine Dysfunction ◽  
Careful Monitoring ◽  
Early Puberty ◽  
Growth Impairment ◽  
Appropriate Treatment ◽  
The Brain

Congenital viral infections and the occurrence of septo-optic dysplasia, which is a combination of optic nerve hypoplasia, abnormal formation of structures along the midline of the brain, and pituitary hypofunction, support the biological plausibility of endocrine dysfunction in Zika-related microcephaly. In this case series we ascertained the presence and describe endocrine dysfunction in 30 children with severe Zika-related microcephaly from the MERG Pediatric Cohort, referred for endocrinological evaluation between February and August 2019. Of the 30 children, 97% had severe microcephaly. The average age at the endocrinological consultation was 41 months and 53% were female. The most frequently observed endocrine dysfunctions comprised short stature, hypothyroidism, obesity and variants early puberty. These dysfunctions occurred alone 57% or in combination 43%. We found optic nerve hypoplasia (6/21) and corpus callosum hypoplasia (20/21). Seizure crises were reported in 86% of the children. The most common—and clinically important—endocrine dysfunctions were pubertal dysfunctions, thyroid disease, growth impairment, and obesity. These dysfunctions require careful monitoring and signal the need for endocrinological evaluation in children with Zika-related microcephaly, in order to make early diagnoses and implement appropriate treatment when necessary.

scholarly journals Immunohistochemical and qPCR Detection of SARS-CoV-2 in the Human Middle Ear Versus the Nasal Cavity: Case Series

2021 ◽  
Author(s):  
Arwa Kurabi ◽  
Kwang Pak ◽  
Adam S. DeConde ◽  
Allen F. Ryan ◽  
Carol H. Yan
Keyword(s):  
Nasal Cavity ◽  
Middle Ear ◽  
Viral Infections ◽  
Case Series ◽  
Middle Ear Mucosa ◽  
Viral Receptor ◽  
Tissue Samples ◽  
Angiotensin Converting Enzyme 2 ◽  
Nasal Tissue ◽  
Human Middle Ear

AbstractViral infections have already been implicated with otitis media and sudden sensorineural hearing loss. However, the pathophysiology of COVID-19 as it relates to otologic disorders is not well-defined. With the spread of SARS-CoV-2, it is important to evaluate its colonization of middle ear mucosa. Middle ear and nasal tissue samples for quantitative RT-PCR and histologic evaluations were obtained from post-mortem COVID-19 patients and non-diseased control patients. Here we present evidence that SARS-CoV-2 colonizes the middle ear epithelium and co-localizes with the primary viral receptor, angiotensin-converting enzyme 2 (ACE2). Both middle ear and nasal epithelial cells show relatively high expression of ACE2, required for SARS-CoV-2 entry. The epithelial cell adhesion molecule (EpCAM) was use as a biomarker of epithelia. Furthermore, we found that the viral load in the middle ear is lower than that present in the nasal cavity.

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