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

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.

Tetracyclines Diminish In Vitro IFN-γ and IL-17-Producing Adaptive and Innate Immune Cells in Multiple Sclerosis

IntroductionLimited data from clinical trials in multiple sclerosis (MS) reported that minocycline, a widely used antibiotic belonging to the family of tetracyclines (TCs), exerts a beneficial short-lived clinical effect A similar anti-inflammatory effect of minocycline attributed to a deviation from Th1 to Th2 immune response has been reported in experimental models of MS. Whether such an immunomodulatory mechanism is operated in the human disease remains largely unknown.AimTo assess the in vitro immunomodulatory effect of tetracyclines, and in particular minocycline and doxycycline, in naïve and treated patients with MS.Material and MethodsPeripheral blood mononuclear cells from 45 individuals (35 MS patients, amongst which 15 naïve patients and 10 healthy controls, HCs) were cultured with minocycline or doxycycline and conventional stimulants (PMA/Ionomycin or IL-12/IL-18). IFN-γ and IL-17 producing T-, NK- and NKT cells were assessed by flow cytometry. The effect of TCs on cell viability and apoptosis was further assessed by flow cytometry with Annexin V staining.ResultsBoth tetracyclines significantly decreased, in a dose dependent manner, IFN-γ production in NKT and CD4+ T lymphocytes from MS patients (naïve or treated) stimulated with IL-12/IL-18 but did not decrease IFN-γ producing CD8+ T cells from naive MS or treated RRMS patients. They also decreased IL-17+ T and NKT cells following PMA and Ionomycin-stimulation. Tetracyclines did not affect the viability of cell subsets.ConclusionTetracyclines can in vitro suppress IFN-γ and IL-17- producing cells from MS patients, and this may explain their potential therapeutic effect in vivo.

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

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.

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

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.

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

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.

Synthesis of N-Glycans Implicated in Asthma and Allergy

<p><b>Asthma and allergies affect a large number of people, with over 300 million people worldwide suffering from asthma alone. Although, on the ‟macroscopic‟ level, it is known how allergens trigger allergic reactions, it is not known how an allergen's ‟micro‟ structure causes such a profound allergic response in sensitised individuals. A review of inter-species carbohydrate motifs revealed a striking similarity between carbohydrate moieties (N-glycans) present on antigens derived from species known to give an allergic T helper (Th) 2 response in humans (such as pollen, schistosomes, and food allergens). Preliminary studies on mixtures of allergen extracts have suggested that these carbohydrate motifs (glycoproteins) bias the immune response to an allergic (Th2) response.</b></p> <p>This project presents work conducted towards the synthesis of three fragments of a larger N-glycan found on allergens. The synthesis of these N-glycans will allow the first detailed study regarding the relationship between N-glycan structure and Th2 bias to be performed and thereby aid in our understanding of the molecular triggers of asthma. Ultimately, this could lead to the elucidation of the mechanisms of the allergic Th2 immune response.</p>

Synthesis of N-Glycans Implicated in Asthma and Allergy

<p><b>Asthma and allergies affect a large number of people, with over 300 million people worldwide suffering from asthma alone. Although, on the ‟macroscopic‟ level, it is known how allergens trigger allergic reactions, it is not known how an allergen's ‟micro‟ structure causes such a profound allergic response in sensitised individuals. A review of inter-species carbohydrate motifs revealed a striking similarity between carbohydrate moieties (N-glycans) present on antigens derived from species known to give an allergic T helper (Th) 2 response in humans (such as pollen, schistosomes, and food allergens). Preliminary studies on mixtures of allergen extracts have suggested that these carbohydrate motifs (glycoproteins) bias the immune response to an allergic (Th2) response.</b></p> <p>This project presents work conducted towards the synthesis of three fragments of a larger N-glycan found on allergens. The synthesis of these N-glycans will allow the first detailed study regarding the relationship between N-glycan structure and Th2 bias to be performed and thereby aid in our understanding of the molecular triggers of asthma. Ultimately, this could lead to the elucidation of the mechanisms of the allergic Th2 immune response.</p>

Synthesis of N-glycans implicated in asthma and allergy

<p>Asthma and allergies affect a large number of people, with over 300 million people worldwide suffering from asthma alone. Although, on the ‟macroscopic‟ level, it is known how allergens trigger allergic reactions, it is not known how an allergen's ‟micro‟ structure causes such a profound allergic response in sensitised individuals. A review of inter-species carbohydrate motifs revealed a striking similarity between carbohydrate moieties (N-glycans) present on antigens derived from species known to give an allergic T helper (Th) 2 response in humans (such as pollen, schistosomes, and food allergens). Preliminary studies on mixtures of allergen extracts have suggested that these carbohydrate motifs (glycoproteins) bias the immune response to an allergic (Th2) response. This project presents work conducted towards the synthesis of three fragments of a larger N-glycan found on allergens. The synthesis of these N-glycans will allow the first detailed study regarding the relationship between N-glycan structure and Th2 bias to be performed and thereby aid in our understanding of the molecular triggers of asthma. Ultimately, this could lead to the elucidation of the mechanisms of the allergic Th2 immune response.</p>

Synthesis of N-glycans implicated in asthma and allergy

<p>Asthma and allergies affect a large number of people, with over 300 million people worldwide suffering from asthma alone. Although, on the ‟macroscopic‟ level, it is known how allergens trigger allergic reactions, it is not known how an allergen's ‟micro‟ structure causes such a profound allergic response in sensitised individuals. A review of inter-species carbohydrate motifs revealed a striking similarity between carbohydrate moieties (N-glycans) present on antigens derived from species known to give an allergic T helper (Th) 2 response in humans (such as pollen, schistosomes, and food allergens). Preliminary studies on mixtures of allergen extracts have suggested that these carbohydrate motifs (glycoproteins) bias the immune response to an allergic (Th2) response. This project presents work conducted towards the synthesis of three fragments of a larger N-glycan found on allergens. The synthesis of these N-glycans will allow the first detailed study regarding the relationship between N-glycan structure and Th2 bias to be performed and thereby aid in our understanding of the molecular triggers of asthma. Ultimately, this could lead to the elucidation of the mechanisms of the allergic Th2 immune response.</p>

Biomarkers of Gut Microbiota in Chronic Spontaneous Urticaria and Symptomatic Dermographism

BackgroundChronic urticaria (CU) is a chronic inflammatory skin disease associated with Th2 immune response. The two most common subtypes of CU, i.e., chronic spontaneous urticaria and symptomatic dermographism (CSD), often coexist. However, the pathogenesis of CSD is still unclear. Gut microbiota plays an important role in immune-related inflammatory diseases. The purpose of this study was to explore the correlation between gut microbiota and CSD.MethodsA case-control study was conducted on CSD patients as well as gender- and age-matched normal controls (NCs). The 16S ribosomal DNA sequencing of fecal samples was used to detect the gut microbiota of all subjects. QPCR was used to further verify the species with differences between the two groups.ResultsThe alpha diversity of gut microbiota decreased in CSD patients, accompanied by significant changes of the structure of gut microbiota. Subdoligranulum and Ruminococcus bromii decreased significantly in CSD patients and had a potential diagnostic value for CSD according to receiver operating characteristic curve (ROC) analysis. Enterobacteriaceae and Klebsiella were found to be positively correlated with the duration of CSD, while Clostridium disporicum was positively correlated with the dermatology life quality index (DLQI).ConclusionsThe gut microbiota of CSD patients is imbalanced. Subdoligranulum and Ruminococcus bromii are the gut microbiota biomarkers in CSD.