Researchers Propose Use of N-acetylcysteine as Prophylactic and Treatment for COVID-19; Memorial Sloan-Kettering Recruiting Now to See if it Works

Researchers Propose Use of N-acetylcysteine as Prophylactic and Treatment for COVID-19; Memorial Sloan-Kettering Recruiting Now to See if it Works TrialsiteN

The FASEB Journal, put out by The Federation of American Societies for Experimental Biology, published a manuscript on August 11 regarding the, “Rationale for the use of N-acetylcysteine in both prevention and adjuvant therapy of COVID-19.” Noting that COVID-19 can cause, “pneumonia, acute respiratory distress syndrome, cardiovascular alterations, and multiple organ failure,” most think that much of the damage is due to a “cytokine storm, systematic inflammatory response, and an attack on the immune system.” Also, an oxidative stress imbalance has been seen consistently in COVID-19 patients. N-Acetyl-L-cysteine (NAC) is, “a precursor of reduced glutathione (GSH).” Based on its high tolerability, this “pleiotropic” drug has been proposed, in addition to its mucolytic (anti-mucous) effects, as a preventative and therapeutic drug, “in a variety of disorders involving GSH depletion and oxidative stress.” Thiols, like NAC, “block the angiotensin‐converting enzyme 2 thereby hampering penetration of SARS‐CoV‐2 into cells.” Based on a wide range of “antioxidant and anti-inflammatory mechanisms,” NAC is likely to lessen the risk of catching COVID-19. Prior research has shown this reduced risk for influenza and influenza-like conditions with use.

NAC’s Mechanisms

About 15% of COVID-19 patients get pneumonia, and about 5%, “undergo acute respiratory distress syndrome (ARDS), septic shock and/or multiple organ failure” that require ICU-level care. ARDS is the top cause of death in COVID-19 patients, and it involves a, “cytokine storm and a systemic inflammatory response” caused by, “the large amounts of pro-inflammatory cytokines and chemokines that trigger an attack by the immune system.” COVID-19 also affects the cardiovascular system, “and diffuse thrombosis” is a significant contributor to bad outcomes. Based on the literature, reduced GSH during the disease may underlie the fatalities. Since NAC is used in a wide range of conditions to correct GSH depletion, it might limit lung damage in COVID-19 patients, and as noted it has a wide safety margin. The paper then details several separate mechanisms by which NAC can reduce the risk of death, and argues that it is, “more likely to be effective as compared with drugs having a single target.” Based on these “mechanistic premises,” NAC may be useful for both the prevention and treatment of COVID-19.

On July 14, prior to the FASEB article, Future Medicine weighed in with a very similar analysis and concluded that health care workers are one of the at-risk groups who could most benefit from prophylactic use of NAC. And Memorial Sloan Kettering’s currently-recruiting, “A Study of N-acetylcysteine in Patients With COVID-19 Infection” that will help us see if the hypotheses and mechanisms proposed in FACEB are true.

The Researchers

A key researcher driving this hypothesis is Silvio De Flora, Department of Health Sciences, University of Genoa.  Professor De Flora along with his colleague out of Genoa Sebastiano La Maestra and Roumen Balansky National Center Oncology, Bulgaria, offered the intellectual foundation for this hypothesis.

Dr. De Flora has authored 460 full length papers, 308 of which are available in PubMed. The overall impact factor is 1500. With almost 1,400 citations, the h-index is 58. He is published in collaboration with 140 laboratories in European countries, China, Japan, India, New Zealand and the USA.

FDA Approval

The U.S. Food and Drug Administration (FDA) has approved N-acetylcysteine to treat the liver side effects resulting from an overdose of the anti-inflammatory medication acetaminophen. Moreover, it is used to loosen the thick mucus in the lungs of patients with cystic fibrosis or chronic obstructive pulmonary disease (COPD). More on the drug can be viewed here

Memorial Sloan Kettering Cancer Center Study

This hypothesis is currently under investigation at New York’s prestigious Memorial Sloan Kettering Cancer Center. It is led by principal investigator Dr. Santosha Vardhana and team to validate the hypothesis that NAC can help fight the COVID-19 virus helping the immune system fight the virus. This Phase 2 study involves severe or critically ill patients with refractory COVID-19 infection.

A two-armed study, patients in both arms receive N-acetylcysteine IV 6g/day in addition to supportive and/or COVID-19 directed treatments at the discretion of the treating physician. More on study NCT04374461 can be read here

Note that with the decline of SARS-CoV-2 cases in New York, it may be difficult to complete this study.

Lead Research/Investigator

Santosha Vardhana, MD, PhD, medical oncologist with expertise in Hodgkin lymphoma, Non-Hodgkin lymphoma