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

Abstract

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.

Impact of COVID-19 pneumonia on pulmonary vascular volume

“…could be involved in this process ( 38 – 41 ). Thromboxane A2 and F2-isoprostanes are two other important vasomediators known to induce venoconstriction via activation of TP receptors in COVID-19 patients ( 42 – 44 ), It is relevant that the TP receptor blocker, ramatroban, was found in anecdotal clinical experience to relieve respiratory distress and hypoxemia in COVID-19 patients ( 45 ).…”

COVID-19, Blood Lipid Changes, and Thrombosis

“…Preliminary evidence indicates that a dual blocker of TP and the PGD2 receptor, ramatroban, can produce rapid relief from dyspnoea and hypoxemia in patients with COVID-19 [ 101 , 102 ]. In another study, treatment of four COVID-19 outpatients with ramatroban resulted in rapid relief of dyspnoea and hypoxaemia within 12–36 h and complete resolution over 5 days [ 103 ] ( Figure 1 and Figure 2 ).…”

The effect of ramatroban on cytokine and thrombotic storms in Covid-19

“…Bioactive lipids and other polyunsaturated fatty acids play a critical task in the process of viral infections including severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection (Di Costanzo et al 2019 ; Batiha et al 2022b ). One of the most important classes of bioactive lipids are prostaglandins (PGs) which act as cytokine amplifiers (Ogletree et al 2022 ). PGs trigger the release of pro-inflammatory cytokines, activation of Th cells (Th1 and Th17), recruitment of immune cells, and increase expression of pro-inflammatory genes (Ogletree et al 2022 ).…”

“…One of the most important classes of bioactive lipids are prostaglandins (PGs) which act as cytokine amplifiers (Ogletree et al 2022 ). PGs trigger the release of pro-inflammatory cytokines, activation of Th cells (Th1 and Th17), recruitment of immune cells, and increase expression of pro-inflammatory genes (Ogletree et al 2022 ). PGs are chiefly inhibited by non-steroidal anti-inflammatory drugs (NSAIDs) through the blocking of cyclooxygenase enzymes (COXs), which are involved in the synthesis of PGs (Shekhar et al 2022 ).…”

“…NSAIDs reduce inflammation by selective or non-selective blocking activity of COX2 or COX1/2, respectively (Shekhar et al 2022 ). COX2 is stimulated and up-regulated during SARS-CoV-2 infection (Ogletree et al 2022 ). Activated COX in Covid-19 increases the expression and release of PGD2 and thromboxane A2 (TXA2).…”