A small clinical study conducted by researchers from the Charak Foundation-California-USA, Regulatory Wisdom-India, the EyeSight Eye Hospital and Retina Centre-India and the University of California Irvine-USA has found that the drug Ramatroban, which is a thromboxane A2 & prostaglandin D2 receptor antagonist can be used to treat COVID respiratory distress and hypoxemia.
The study findings were published on a preprint server and are currently being peer reviewed.
After symptomatic SARS-CoV-2 infection, 10-20% of patients require hospitalization for respiratory distress and hypoxemia.1 Currently, anti-SARS-CoV-2 monoclonal antibodies are approved for treatment of ambulatory patients with COVID-19,2 and antiviral treatments have recently been approved, but they are expensive and effective only early after symptom onset.
There is an unmet medical need for inexpensive, safe, orally bioavailable drugs that can reduce hypoxemia, provide symptomatic relief, and minimize hospitalization in patients with COVID-19. Identifying the correct therapeutic target is critical to discovering such a drug.
Lungs in COVID-19 patients with acute respiratory distress syndrome (ARDS) produce proinflammatory lipid mediators with predominance of cyclooxygenase metabolites in bronchoalveolar lavage fluid (BALF), notably thromboxane B2 (TxB2) >> prostaglandin E2 (PGE2) > prostaglandin D2 (PGD2).3
The massive increase in TxA2 metabolites in BALF3 and systemically in hospitalized COVID-19 patients,4,5 suggests a critical role for TxA2 / TxA2 prostanoid receptors (TPr) in COVID-19 respiratory distress. We hypothesized that TxA2/TPr induced contraction of pulmonary veins elevates pulmonary capillary pressure and contributes to pulmonary edema and hypoxemia in COVID-19 pneumonia (Fig. 1).
TPr signaling leads to selective constriction of intrapulmonary veins and small airways with 10-fold higher potency and greater reduction in luminal area than intrapulmonary arteries.6 High local concentrations of TxA2 can effectively divert pulmonary blood flow, increase microvascular pressure and permeability, and force fluid and plasma proteins into alveoli.6
A selective TPr antagonist was previously reported to decrease pulmonary capillary pressure by selectively reducing post-capillary resistance in patients with acute lung injury.7 TxA2 and isoprostanes stimulate TPr-mediated activation of the TGFβ pathway,8 and early, untimely TGFβ responses in SARS-CoV-2 infection limit antiviral function of natural killer (NK) cells and promote progression to severe COVID-19 disease.9
Theken and FitzGerald proposed early administration of a TxA2 antagonist as an antithrombotic agent, and a D-prostanoid receptor 2 (DPr2, formerly referred to as CRTH2) antagonist to boost interferon lambda (IFN-λ) in the upper respiratory tract, thereby limiting SARS-CoV-2 replication and transmission.10,11
Ramatroban, the only dual TxA2/TPr and PGD2/DPr2 receptor antagonist available for clinical study, has been proposed as an antithrombotic and immunomodulator agent in COVID-19.12,13 In their report showing very high levels of TxB2 >> PGD2 in BALF, Archambault and colleagues also suggested ramatroban to block the deleterious effects of TxA2 and PGD2 in COVID-19.3
We report here a small case series of four consecutive COVID-19 patients with worsening respiratory distress and hypoxemia who were treated with ramatroban. Surprisingly, this led to rapid improvement in both respiratory distress and hypoxemia, thereby avoiding hospitalization and promoting recovery from acute disease.