Dr. Paul Marik is a critical care physician who teaches medicine at Eastern Virginia Medical School. Known for a vitamin C sepsis cocktail currently under clinical investigation, he recently posted an in depth YouTube lecture with a dire warning for Americans and the world. Disclosing that he has no affiliation with any commercial interests, the academic researcher and doctor suggests that, “the U.S. is in big trouble.” Now with over 9 million cases and 232,101 deaths according to most recent sources, Dr. Marik notes “the [COVID] cases are increasing at a remarkable rate.” Marik declares something must be done as Americans collectively move into winter, otherwise the outcomes could be “catastrophic.” He goes on to explain SARS-CoV-2 and the viral lifecycle as well as introduces the listener to possible ways that Ivermectin may inhibit SARS-CoV-2. He does a clinical study “meta-analysis” and pleads to health authorities to take this drug seriously. Although the National Institute of Health (NIH) Guidelines declares Ivermectin should only be used in clinical trials for COVID-19, they do now include the anti-parasite drug in the guidelines which wasn’t the case months ago. A growing tension mounts between research and regulatory authorities on the one side, and a rising number of independent-minded researchers and clinicians on the other side declaring sufficient data is in place for public funding in support of this economical and widely available generic drug.
Failed and Successful Rx
Interestingly, at 9:14 in his talk Dr. Marik presents a table titled: “Failed and Successful Rx for COVID-19 by Phase of Illness,” and includes a number of therapies that have been tested in COVID-19 patients. They include hydroxychloroquine, Remdesivir, Lopivnar-Ritonavir, Interferon Ab, Tocilizumab, convalescent plasma, and corticosteroids. Of these, Marik is doubtful except for corticosteroids which he acknowledges shows benefit (based on RECOVERY trial) at the “pulmonary/Inflammatory” stage of the illness. As to Remdesivir, he suggests there isn’t sufficient data to tell if there is any benefit at the pre-exposure/post-exposure and incubation phases of the illness. And the use of question marks indicates he at least wonders about the declared benefit of “reduced time to recovery” during the symptomatic phase. He notes Remdesivir doesn’t reduce mortality. Remdesivir is the only drug approved by the U.S. Food and Drug Administration (FDA) for use against COVID-19. TrialSite, although critical of how Remdesivir was approved, certainly has accumulated significant data points that the drug helps. Convalescent plasma, for which the FDA controversially awarded an emergency use authorization (EUA), has questionable benefit, according to Marik. He suggests that the benefit of interferon alpha beta is uncertain at the pre-exposure/post-exposure incubation phase, while this therapy provides no benefit during the symptomatic phase and potentially harm during the pulmonary/inflammatory phase. The National Institutes of Health guidelines recommends against use of interferon Alpha Beta except for in clinical trials.
Some Hypotheses as to How Ivermectin may Inhibit SARS-CoV-2
The FDA approved drug Ivermectin was first demonstrated to inhibit SARS-CoV-2 by University of Monash, causing a 5000-fold reduction in viral RNA at 48 hours. The Australian researchers (Caly et al.) suggested that SARS-CoV-2 proteins, most importantly Orf6 and nucleocapsid proteins, need to bind to something to get into the human cell. This is accomplished by binding to importin proteins (alpha and beta), and this combined entity then penetrates the Nuclear Pore Complex allowing the SARS-CoV-2 proteins into the nucleus. Marik says that once these two proteins associated with COVID-19 enter the cell nucleus, “they cause havoc, cell arrest, they interfere with DNA transcription and promote viral replication.” He notes Ivermectin binds to the importin complex and prevents SARS-CoV-2 proteins from binding to this importin mechanisms; therefore, the SARS-CoV-2 proteins cannot penetrate the nuclear core. Marik also introduces NF-kB and suggests some intriguing information. First, it was recently identified by a research team at Boston University and published in peer-reviewed Cell Stem Cell that SARS-CoV-2 causes major inflammatory trouble in the lungs via the activation of a biological pathway in the body known as NFkB (the k is pronounced “kappa”).
Marik suggests NFkB is an importin inflammatory-transcription vector that transcribes a host of inflammatory proteins. Made in the cytoplasm, it works in the nucleus and can penetrate the nuclear pore. Marik and the Monash hypothesis suggest that Ivermectin may prevent NFkB from binding to the key importins and hence inhibit entry into the nucleus. Marik introduces other possible benefits, such as docking to the SARS-CoV-2 “Spike receptor-binding Domain attached to ACE2.” The Eastern Virginia Medical School professor and doctor goes on to review four clinical studies (also chronicled by TrialSite) including Mahmud, Rajter, Kahn, and Gorial and performs what he describes as a “meta-analysis” with mortality as an endpoint. He argues that the results indicate a “highly significant reduction in mortality.”
Critique of TrialSite Article
At 49:24 Dr. Marik refers to a TrialSite article titled, “India’s ICMR Excludes Ivermectin from National Guidelines for COVID-19: Not Sufficient Evidence via RCTs,” and he responds that there is in fact sufficient data via randomized studies, observational studies, and in vitro studies, as well as safety studies. He pleads: “What more do you need?” Dr. Marik suggests a major crisis is unfolding and calls for more observational studies in large groups of patients, even suggesting it could be unethical to conduct randomized studies with placebo given the number of deaths in this pandemic. TrialSite first and foremost is an independent and unbiased digital media. At present, we have no evidence that the Indian ICMR study was wrong based on their own internal decision making policies. There does appear to be a split in India between the national authorities and at least some state’s treatment guidelines that accept Ivermectin, however. Moreover, the National Institutes of Health (NIH) is clear about their recommended guidelines for Ivermectin—it can only be used in a clinical trial. TrialSite has been on the record numerous times arguing that an Ivermectin-based study should be funded by the NIH, and in fact one of our founders sent an email to Dr. Francis Collins recommending that NIH consider funding a clinical trial led by the physician/research authors of the ICON study—recently published in Chest.
Paul Marik, MD, Professor, Internal Medicine
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