CALIFORNIA, US: The severity of Covid-19 infection is primarily determined by the body’s various responses to the virus, and these responses vary from patient to patient. In the majority of cases, immune response is able to respond adequately, leading to recovery after a mild to moderately severe illness. However, in about 10-20% of patients, the body’s immune response to the virus is inappropriate or maladaptive, and such patients develop severe disease with inadequate oxygenation that may require hospitalization.
Such an inappropriate response can have one or more of the following characteristics. First, the immune response is inadequate allowing the virus to proliferate. Second, the body responds by mounting an immune response better suited to fighting a worm rather than a virus. Third, in about 5% of hospitalized patients, there is an exuberant cytokine response, often referred to as a cytokine storm that causes severe inflammation. Fourth, there is excessive clotting leading to impaired exchange of oxygen in the lungs, or clots in veins or arteries of heart, brain, or limbs leading to heart attack, stroke or gangrene, respectively.
While corticosteroids such as dexamethasone or prednisone may be helpful in about 5% of hospitalized patients with the cytokine storm, for the rest of the patients, effective therapy remains elusive. More specifically, there is no effective treatment for over 90% of patients who have mild or moderate Covid being treated at home. There is an urgent unmet need for a drug that can help prevent progression of milder disease to a severe form that requires hospitalization.
Flamand and colleagues from Laval University in Quebec, Canada have described a response by the body involving release of lipid mediators that offers a target for drug treatment, and thereby hope for patients with mild to moderate Covid.
These scientists studied lung washings from patients with severe Covid-19, and found massive increase in breakdown products of lipids released from the cell wall. These lipid breakdown products include thromboxane and prostaglandin D2. Thromboxane activates its receptor TPr leading to thrombosis (clotting) while prostaglandin D2 activates its receptor DPr2 and leads to a maladaptive immune response characterized by poor anti-viral activity.
Flamand and colleagues state that “blocking the deleterious effects of prostaglandin D2 and thromboxane A2 with the dual DPr2/TPr antagonist Ramatroban might be beneficial in Covid-19”.1
Garrett FitzGerald, a renowned scientist from University of Pennsylvania has recently proposed that a blocker of PGD2 action has the potential to decrease viral load and mitigate the severity of Covid-19 disease by enhancing anti-viral responses while a blocker of the thromboxane receptor (TPr) can prevent adult respiratory distress syndrome (ARDS). Professor FitzGerald states “early administration of well-tolerated TPr antagonists may limit progress to severe Covid-19.2 A case report describing successful treatment of moderately severe Covid-19 with ramatroban further fuels such hopes.3 Additionally, scientists from Beijing have recently reported that ramatroban significantly alleviated pulmonary inflammation, fibrosis, and cardiopulmonary dysfunction in a mouse model of lung fibrosis.”4 This offers hope that ramatroban can potentially reduce lung scarring (fibrosis) in Covid-19 and thereby diminish long term lung damage.
Ramatroban (pronounced as rama-tro-ban) is a very safe drug having been used to treat allergies in Japan for the past 20 years. Ramatroban holds great potential as an immune booster and anti-clotting agent in Covid-19, and merits urgent clinical trials. This author has filed patents on the use of ramatroban for Covid-19 in March 20205, and offered royalty-free use to any non-profit organization or government. The scientific rationale notwithstanding, only clinical trials will show if ramatroban is indeed a baan (arrow) that can target various facets of this enigmatic disease.
Dr Ajay Gupta, MBBS (AIIMS), MD (AIIMS) is Clinical Professor of Medicine at University of California Irvine, USA; and inventor of two US FDA approved drugs. Dr Gupta has filed patents on the use of ramatroban in Covid-19.
Footnotes:
1. Archambault AS, Zaid Y, Rakotoarivelo V, et al. High levels of eicosanoids and docosanoids in the lungs of intubated Covid-19 patients. The FASEB Journal. 2021;35(6)doi:10.1096/fj.202100540r
2. Theken KN, Fitzgerald GA. Bioactive lipids in antiviral immunity. Science. 2021;371(6526):237-238. doi:10.1126/science.abf3192
3. Agarwal MMA, Chiang KC, Agarwal MMA. Ramatroban, an orally bioavailable immunomodulator and antithrombotic agent for treatment of Covid-19 disease: A Case Report. Research Square Platform LLC; 2021.
4. Pang J, Qi X, Luo Y, et al. Multi-omics study of silicosis reveals the potential therapeutic targets PGD2 and TXA2. Research Paper. Theranostics. 2021;11(5):2381-2394. doi:10.7150/thno.47627
5. Gupta A, Kamyar K-Z, Reddy ST. Ramatroban as a Novel Immunotherapy for Covid-19. Molecular and Genetic Medicine. 2020;14(3)doi:10.37421/jmgm.2020.14.457