Treatment of COVID-19 Pneumonia and Acute Respiratory Distress With Ramatroban, a Thromboxane A2 and Prostaglandin D2 Receptor Antagonist: A Four-Patient Case Series Report.

Hypoxemia in COVID-19 pneumonia is associated with hospitalization, mechanical ventilation, and mortality. COVID-19 patients exhibit marked increases in fatty acid levels and inflammatory lipid mediators, predominantly arachidonic acid metabolites, notably thromboxane B2 >> prostaglandin E2 > prostaglandin D2. Thromboxane A2 increases pulmonary capillary pressure and microvascular permeability, leading to pulmonary edema, and causes bronchoconstriction contributing to ventilation/perfusion mismatch. Prostaglandin D2-stimulated IL-13 production is associated with respiratory failure, possibly due to hyaluronan accumulation in the lungs. Ramatroban is an orally bioavailable, dual thromboxane A2/TP and prostaglandin D2/DP2 receptor antagonist used in Japan for allergic rhinitis. Four consecutive outpatients with COVID-19 pneumonia treated with ramatroban exhibited rapid relief of dyspnea and hypoxemia within 12-36 h and complete resolution over 5 days, thereby avoiding hospitalization. Therefore, ramatroban as an antivasospastic, broncho-relaxant, antithrombotic, and immunomodulatory agent merits study in randomized clinical trials that might offer hope for a cost-effective pandemic treatment.

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

Lungs in COVID-19 patients produce lipid mediators measured in bronchoalveolar lavage fluid (BALF), notably thromboxane B2 (TxB2) >> prostaglandin E2 > prostaglandin D2 (PGD2).1 High levels of TxA2 metabolites in BALF from COVID-19 associated ARDS,1 and systemically in non- ICU COVID-19 patients2,3 led us to propose a critical role for TxA2 prostanoid receptors (TPr) in COVID-19 respiratory distress. We hypothesized that TxA2/TPr signaling in airways, pulmonary microvasculature, and veins contributes to pulmonary edema and hypoxemia in COVID-19 pneumonia. TPr signaling contracts intrapulmonary veins with 10-fold higher potency than arteries.4 High concentrations of TxA2 impede pulmonary venous blood flow, increase microvascular pressure, and force fluid into alveoli.4 TPr signaling also activates platelets and triggers tissue factor expression on monocytes, which may contribute to thrombosis in COVID-19. A TPr antagonist was previously reported to decrease pulmonary capillary pressure by selectively reducing post-capillary resistance in patients with acute lung injury.5 PGD2 stimulation of Dprostanoid receptor 2 (DPr2, aka CRTH2) suppresses interferon lambda (IFN-λ) transcription in the upper respiratory tract in response to respiratory viruses. PGD2/DPr2 antagonism boosts local IFN- λ antiviral responses and limits viral replication.6 Antagonism of TxA2/TPr and PGD2/DPr2 signaling has been proposed for antiviral, antithrombotic and immunomodulatory action in COVID- 19.7 Ramatroban is an oral, dual receptor antagonist of TxA2/TPr and PGD2/DPr2 and a potential candidate for chemoprophylaxis and treatment of COVID-19.1,7 With well-established safety, ramatroban has been used since 2000 in Japan for the treatment of allergic rhinitis.8 We report here a small case series of four consecutive outpatients with COVID-19 with new onset or worsening respiratory distress and hypoxemia who were treated with oral ramatroban (Baynas®, Bayer Yakuhin, Japan). Summarized below, ramatroban afforded rapid improvement in respiratory distress and hypoxemia, followed by complete recovery, successfully avoiding hospitalization. Conclusion: Four consecutive outpatients with COVID-19 were treated with ramatroban. Improvement within hours was followed by gradual complete recovery, thereby avoiding hospitalization. As a safe, oral drug, ramatroban merits clinical trials for both outpatients and hospitalized patients with SARS-CoV-2 infection and COVID-19.

DESCARTE DE PLASMA RICO EM PLAQUETAS EM RAZÃO DA UTILIZAÇÃO DE FÁRMACOS COM ATIVIDADE ANTIPLAQUETÁRIA NO HEMOCENTRO REGIONAL DE SANTA MARIA DURANTE A PANDEMIA DE COVID-19

Objetivos: Analisar o número de plasma rico em plaquetas desprezados em razão do uso de medicamentos com atividade antiagregante plaquetária no Hemocentro Regional de Santa Maria (HEMOSM) no período da pandemia de COVID-19. Material e métodos: Trata-se de um estudo observacional retrospectivo realizado pela investigação de dados do Sistema HEMOVIDA (Sistema Nacional de Gerenciamento em Serviços de Hemoterapia) no HEMOSM durante o período de fevereiro/2020 a Julho/2021. Resultados: Durante o período da pandemia, foram descartadas 35 bolsas de plasma rico em plaquetas porque os doadores relataram na triagem clínica que haviam feito uso de alguma medicação com atividade antiagregante plaquetária. Discussão: A triagem clínica é uma etapa muito importante na garantia da qualidade dos hemocomponentes porque, através de uma entrevista privada com um profissional da saúde, o doador pode fornecer informações relevantes para que este seja considerado apto ou inapto para a doação. Durante a entrevista, uma das questões postas ao candidato à doação é se este faz ou fez o uso de algum medicamento, isto porque alguns medicamentos podem tornar o doador inapto para a doação de forma permanente (uso contínuo) ou temporariamente, caso o uso do medicamento ocorra de forma esporádica mas tenha antecedido a doação de sangue. A Aspirina®, por exemplo, é um medicamento amplamente difundido, de venda livre e empregado na automedicação. O ácido acetilsalicílico (AAS) é o fármaco (componente ativo) presente na formulação deste medicamento utilizado como analgésico, antitérmico e inclusive (em doses baixas como 75 mg/dia) para evitar eventos trombóticos. A propriedade do AAS que justifica seu uso como profilaxia da trombose é a inibição da síntese de TXA2 plaquetário, e este é justamente o motivo pelo qual doadores que fizeram uso recente do AAS não tem suas plaquetas fracionadas, aproveitando-se apenas o concentrado de hemácias oriundo da doação. A inibição da síntese de TXA2 plaquetário (>95%) implica na deficiência dessas plaquetas em estimular a ativação de novas plaquetas e aumentar a agregação plaquetária, tornando os trombóticos desse doador não funcionais, e, portanto, não efetivos no controle de eventos hemorrágicos quando transfundidos em pacientes plaquetopênicos. O uso de medicamento com atividade antiplaquetários, mesmo não representando um número muito elevado dentre as causas de desprezo de hemocomponentes, representa uma preocupação em relação à automedicação. Ainda, o número de plaquetas randômicas que poderiam ter sido fracionadas destes doadores seria suficiente para atender a aproximadamente 5 prescrições de transfusão de plaquetas (número dependente da quantidade de bolsas solicitadas para a formação do pool de plaquetas randômicas). Conclusão: Considerando o cenário da redução de aproximadamente 10% das doações no HEMOSM e a alta demanda destes hemocomponentes por solicitação dos serviços de saúde atendidos pelo hemocentro, faz-se importante uma orientação mais efetiva para os doadores quanto aos requisitos necessários para a realização da doação e para a garantia da qualidade dos hemocomponentes produzidos.

The effects of acetylsalicylic acid among latino patients of COVID-19

Purpose of Study Retrospective Observational Study. The novel coronavirus SARS-CoV-2, responsible for the Covid-19 pandemic, has led to the death of over 4.8 million people worldwide and over 700 thousand people in the United States. The Latino population has been especially vulnerable and is counted among those most affected by the pandemic. Many fatalities of this novel infection have occurred due to an unknown mechanism causing increased thrombotic activity. Acetylsalicylic Acid (ASA) or aspirin which in low doses functions as an antiplatelet drug by inhibiting thromboxane A2, could be of potential benefit due to its anti-inflammatory and antithrombotic qualities. Methods Used We collected data from the medical charts of 1,039 Latino patients hospitalized to treat COVID-19. We then assessed the outcomes of patients who have been treated with ASA (332) in comparison to those who had not been treated with ASA (707). The main parameter for our study was mortality. Length of hospitalization, ICU admission, and need for supplemental oxygen upon discharge were among the secondary outcomes also analyzed. We investigated further by then selecting for patients who suffered myocardial infarction (MI), stroke, or pneumothorax, and again comparing the two groups. Summary of Results In this study, we found significant evidence that including ASA in COVID-19 treatment regimen decreases the mortality among patients who also suffered a myocardial infarction, stroke, or pneumothorax. These patients were 62% less likely to have a fatality (P=.019) during their stay in the hospital as compared to those who did not receive aspirin. We also found significant evidence suggesting that a treatment regimen including ASA decreased the admission to ICU and the need for oxygen supplementation upon discharge. Patients who were given Aspirin as part of their treatment regimen were 31% less likely of being transferred to the ICU (P=0.036). Patients were also found to be 42% less likely of being discharged with supplemental oxygen if given aspirin as part of their treatment regimen (P=0.003). Conclusions We conclude that our study has shown how aspirin could possibly influence the course of the SARS-CoV-2 viral infection by decreasing thrombotic activity. ASA can have significant health affects among minority populations by improving mortality among patients who also suffered a MI, stroke, or pneumothorax as well as decreasing the strain on hospital ICUs and saving health resources such as oxygen. This important information will be helpful in guiding doctors and other healthcare workers as we continue to battle the COVID-19 pandemic and care for future COVID patients. Further research involving randomized control studies and larger samples sizes must be pursued.

Ramatroban for chemoprophylaxis and treatment of COVID-19: David takes on Goliath.

INTRODUCTION: In COVID-19 pneumonia, there is a massive increase in fatty acid levels and lipid mediators with a predominance of cyclooxygenase metabolites, notably TxB2 ≫ PGE2 > PGD2 in the lungs, and 11-dehydro-TxB2, a TxA2 metabolite, in the systemic circulation. While TxA2 stimulates thromboxane prostanoid (TP) receptors, 11-dehydro-TxB2 is a full agonist of DP2 (formerly known as the CRTh2) receptors for PGD2. Anecdotal experience of using ramatroban, a dual receptor antagonist of the TxA2/TP and PGD2/DP2 receptors, demonstrated rapid symptomatic relief from acute respiratory distress and hypoxemia while avoiding hospitalization. AREAS COVERED: Evidence supporting the role of TxA2/TP receptors and PGD2/DP2 receptors in causing rapidly progressive lung injury associated with hypoxemia, a maladaptive immune response and thromboinflammation is discussed. An innovative perspective on the dual antagonism of TxA2/TP and PGD2/DP2 receptor signaling as a therapeutic approach in COVID-19 is presented. This paper examines ramatroban an anti-platelet, immunomodulator, and antifibrotic agent for acute and long-haul COVID-19. EXPERT OPINION: Ramatroban, a dual blocker of TP and DP2 receptors, has demonstrated efficacy in animal models of respiratory dysfunction, atherosclerosis, thrombosis, and sepsis, as well as preliminary evidence for rapid relief from dyspnea and hypoxemia in COVID-19 pneumonia. Ramatroban merits investigation as a promising antithrombotic and immunomodulatory agent for chemoprophylaxis and treatment.

The combination of bromelain and curcumin as an immune-boosting nutraceutical in the prevention of severe COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic is still ongoing, while no treatment has been proven effective. COVID-19 pathophysiology involves the activation of three main pathways: the inflammatory, the coagulation and the bradykinin cascades. Here, we highlight for the first time the joint potential therapeutic role of bromelain and curcumin, two well-known nutraceuticals, in the prevention of severe COVID-19. Bromelain (a cysteine protease isolated from the pineapple stem) and curcumin (a natural phenol found in turmeric) exert important immunomodulatory actions interfering in the crucial steps of COVID-19 pathophysiology. Their anti-inflammatory properties include inhibition of transcription factors and subsequent downregulation of proinflammatory mediators. They also present fibrinolytic and anticoagulant properties. Additionally, bromelain inhibits cyclooxygenase and modulates prostaglandins and thromboxane, affecting both inflammation and coagulation, and also hydrolyzes bradykinin. Interestingly, curcumin has been shown in silico studies to prevent entry of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into cells as well as viral replication, while a recent experimental study has demonstrated that bromelain may also inhibit viral entry into cells. Notably, bromelain substantially increases the absorption of curcumin after oral administration. To the best of our knowledge, this is the first report highlighting the significance of bromelain and, most importantly, the potential preventive value of the synergistic effects of bromelain and curcumin against severe COVID-19.