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

ABSTRACT

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.