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.

Kidney in the net of acute and long-haul coronavirus disease 2019: a potential role for lipid mediators in causing renal injury and fibrosis.

PURPOSE OF REVIEW: Severe COVID-19 disease is often complicated by acute kidney injury (AKI), which may transition to chronic kidney disease (CKD). Better understanding of underlying mechanisms is important in advancing therapeutic approaches. RECENT FINDINGS: SARS-CoV-2-induced endothelial injury initiates platelet activation, platelet-neutrophil partnership and release of neutrophil extracellular traps. The resulting thromboinflammation causes ischemia-reperfusion (I/R) injury to end organs. Severe COVID-19 induces a lipid-mediator storm with massive increases in thromboxane A2 (TxA2) and PGD2, which promote thromboinflammation and apoptosis of renal tubular cells, respectively, and thereby enhance renal fibrosis. COVID-19-associated AKI improves rapidly in the majority. However, 15-30% have protracted renal injury, raising the specter of transition from AKI to CKD. SUMMARY: In COVID-19, the lipid-mediator storm promotes thromboinflammation, ischemia-reperfusion injury and cytotoxicity. The thromboxane A2 and PGD2 signaling presents a therapeutic target with potential to mitigate AKI and transition to CKD. Ramatroban, the only dual antagonist of the thromboxane A2/TPr and PGD2/DPr2 signaling could potentially mitigate renal injury in acute and long-haul COVID. Urgent studies targeting the lipid-mediator storm are needed to potentially reduce the heavy burden of kidney disease emerging in the wake of the current pandemic.