COVID-19 Drugs: Canadian Study Indicates That Asthma Drugs Zileuton And Montelukast Could Be Repurposed To Prevent COVID-19’s Cytokine Storm
: Canadian researchers from Queen’s University-Ontario Novateur Ventures Inc.-Vancouver in a new study propose that two generic anti-inflammatory drugs, zileuton and montelukast typically used in asthma treatments, be used to treat COVID-19 patients because of their potential to dampen disease progression and severity.
The research findings were published in the journal: Frontiers in Pharmacology. https://www.frontiersin.org/articles/10.3389/fphar.2020.01214/full
The research basically explores the role of leukotrienes in the hyperinflammatory response that occurs in severe COVID-19 cases and often leads to multi-organ failure.
The study team suggests that combining the controlled release formulation of the leukotriene biosynthesis blocker zileuton (Zyflo®) with montelukast (Singulair®), which inhibits the cysteinyl leukotriene 1 receptor, could prevent the cytokine storm from forming.
As both drugs zileuton and montelukast were developed decades ago and now are generic medications, their safety and efficacy already are well-documented in humans.
Hence, it appears possible that the combined therapeutics can go directly into Phase III trials to prove their efficacy in combination and against the hyperimmune response that occurs in acute respiratory distress syndrome (ARDS) associated with COVID-19.
Dr Ali Ardakani, founder and managing director of Novateur Ventures, Thailand Medical News, “Leukotrienes are lipid mediators. We are talking with researchers globally to advance the idea into clinical trials, and are looking at sites and potential drug development partners.”
Dr Colin Funk, Ph.D., scientific lead at Novateur Ventures added, “Leukotrienes have some of the most potent impacts on immune cell trafficking and vascular leakage in biological systems. They are made de novo ie only when there is an infection or other stimulus and are derived from the fatty acids in cells. In small amounts, they help the host fight the infection. In COVID-19, when the inflammatory response gets out of control, leukotrienes are churned out, where they affect blood vessels, making them leaky. Then fluid can get into the lungs and the virus can get into the blood stream.”
Surprisingly, despite their importance, leukotrienes have been overlooked as a potential strategy against COVID-19.
It has been monitored that of more than 20,000 papers listed on PubMed mentioning COVID-19, only three also discussed leukotriene modifier drugs as a potential treatment.
Dr Funk said, “One of the reasons leukotrienes have been overlooked is that they are very difficult to measure. In hospitals and labs, you cannot just take a blood test because there are no routine leukotriene assays. Instead, measuring them usually requires sophisticated equipment, like mass spectrometers.”
However, as more awareness is growing in the scientific community about leukotrienes role in COVID-19, it merits investigation as possible COVID-19 therapy targets.
Dr Funk and Dr Ardakani suggest c
ombining the drugs because they target separate sites and have different mechanisms of action.
It it known that Zileuton blocks the formation of leukotriene B4 (LTB4), one of the most potent known chemoattractants for neutrophils and lymphocyte subsets. Dr Funk and Dr Ardakani suggest LTB4 probably is a key mediator in terms of carrying white blood cells to the site of inflammation. Dampening its action could reduce the lymphocytopenia and neutrophilia observed in severe cases of COVID-19.
Dr Ardakani added, “Moreover, the cysteinyl leukotrienes (cysLTs) LTC4 and LTD4 are among the most profound vascular leakage promoting agents in man and animal models, so blocking the formation of those leukotrienes with montelukast would have a significant effect on vascular leakage.”
Dr Funk further added, “Ideally, Zileuton would block leukotriene synthesis. If it works extremely well, patients probably would only need (the one drug). But, it has poor pharmacokinetics and a short half-life.”
The improvised controlled release formula, for instance must be taken twice daily.
He added, “Montelukast only acts on the Cys LT1 receptor. It’s very specific and can block vascular leakage. It is very potent and could be taken once daily.”
Both drugs likely would be most effective early in the onset of disease, before the hyperinflammatory cell recruitment to the lungs and before pulmonary edema sets in.
Dr Funk said, “Therapy, ideally, would begin shortly after a positive test is confirmed.”
While clinical trials have not yet begun, Dr Funk and Dr Ardakani speculate the drugs could be administered alone or with other therapies during a one- to three-week period until symptoms resolve and tests for SARS-CoV-2 are negative.
Significantly, because both drugs are generic, their costs for a full treatment cycle are relatively low. Montelukast, for example, costs less than US$1 per day. Zileutron costs about US$50 per day (generic versions from India are far much cheaper than even this.) or about US$350 to US$1,050 for one to three-week treatment cycle. (Usage against COVID-19 still depends on the outcome of clinical trials, they stressed). Remdesivir, in contrast, costs approximately US$3,600 for a five-day course of treatment but its efficacy is still being questioned by many physicians who have used it coupled with the fact that there have not been any long term safety studies on the drug.
Dr Ardakani said, “Overall, SARS-CoV-2 appears to promulgate a novel clinical presentation never before seen in the human population. Pathogenesis is multifocal. For instance, the virus may attack blood vessel endothelial cells, leading to coagulopathy and strokes, damage to the kidneys and perhaps pancreatic islet cells, and neurological problems. The unmet need is high, with only two therapies authorized for emergency use as COVID-19 therapies by the U.S. FDA.
He stresses, zileuton and montelukast have the potential to meet at least some of those needs. Dr Ardakani likens the combination of zileuton and montelukast to a dam that prevents water from gushing over during the rainy season. In the same way, he says, this combination could prevent a hyperinflammatory response from overwhelming the immune system and creating a condition that, he said, is worse than the SARS-CoV-2 coronavirus itself.
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