Monday, November 16, 2020

Is IVERMECTIN the New Covid-19 Game-Changer?

November, 2020-  The world is almost one year deep into the CoronaVirus pandemic, falling into a third infection surge.  The global health community floats the latest report of a near-ready deployment of the Covid vaccine while ICU reports a new spike in cases in all 50 states.

 According to health officials at the FLCCC (Front Line Covid-19 Care Alliance), a new report of a prophylactic solution & a treatment protocol for Covid-19 infection is available in the global market NOW. This community of intensivists in FLCCC expresses tremendous confidence in this clinical strategy with climbing evidence of success domestically and abroad., "... in keeping with the robust and emerging evidence reviewed above, the Front Line COVID-19 Critical Care Alliance recently created a prophylaxis and early treatment approach for COVID-19 called “I-MASK+”. This protocol includes IVERMECTIN as a core therapy in both early treatment and prophylaxis of both high-risk patients and post-exposure to household members with COVID-19 . The Front Line COVID-19 Critical Care Alliance is committed to measuring outcomes in those treated with ivermectin and reviewing all emerging results from the current and any future clinical trials of Ivermectin in COVID19"

The following overview is a repost of the current feature published by the FLCCC Alliance and Dr. Pierre Kory.



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REVIEW OF THE EMERGING EVIDENCE SUPPORTING THE USE OF IVERMECTIN IN THE PROPHYLAXIS AND TREATMENT OF COVID-19

In March 2020, an expert panel called the Front Line COVID-19 Critical Care Alliance (FLCCC) was created and led by Professor Paul E. Marik with the goal of continuously reviewing the rapidly emerging basic science, translational, and clinical data in order to gain insight into and to develop a treatment protocol for, COVID-19. At the same time, many centers and groups employed a multitude of novel therapeutic agents empirically and within clinical trials, often during inappropriate time points during this now well-described multi-phase disease. Either as a result of these frequent trial design failures or due to the lack of their insufficient anti-viral or anti-inflammatory properties, nearly all trialed agents have proven ineffective in reducing the mortality of COVID-19. Based on a recent series of negative published therapeutic trial results, in particular the SOLIDARITY trial, virtually eliminates any treatment role for Remdesivir, hydroxychloroquine, lopinavir/ritonavir, interferon, convalescent plasma, tocilizumab, and mono-clonal antibody therapy.


Despite this growing list of failed therapeutics in COVID-19, the FLCCC recently discovered that ivermectin, an anti-parasitic medicine, has highly potent real-world, anti-viral, and anti-inflammatory properties against SARS-CoV-2 and COVID-19. This conclusion is based on the increasing numbers of study results reporting effectiveness, not only within in-vitro and animal models, but also in numerous randomized and observational controlled clinical trials. Repeated, consistent, large magnitude improvements in clinical outcomes have now been reported when ivermectin is used not only as a prophylactic agent but also in mild, moderate, and even severe disease states from multiple, large, randomized and observational controlled trials. However, the review that follows of the existing evidence for ivermectin relies on “emerging” data in that, although convincing, as of November 14, 2020, only a minority of studies have been published in peer-reviewed publications with the majority of results compiled from manuscripts uploaded to medicine pre-print servers or posted on clinicaltrials.gov. 
The most recent paper, currently in production, reports a 6.1% hospital mortality rate in COVID-19 patients measured in the two U.S hospitals that systematically adopted the MATH+ protocol, a markedly decreased mortality rate compared to the 23.9% hospital mortality rate calculated from a review of 39 studies including over 165,000 patients (unpublished data; available on request). For a review of the therapeutic interventions comprising the current MATH+ protocol.

Although the adoption of MATH+ has been considerable, it largely occurred only after the RECOVERY and other trials were published which supported one of the main components (corticosteroids) of the combination therapy approach created at the onset of the pandemic.4-9 Despite the plethora of supportive evidence, the MATH+ protocol for hospitalized patients has not yet become widespread. Further, the world is in a worsening crisis with the potential of again overwhelming hospitals and ICU’s. As of November 10th, 2020, the number of deaths attributed to COVID-19 in the United States reached 245,799 with over 3.7 million active cases, the highest number to date. Multiple European countries have now begun to impose new rounds of restrictions and lockdowns. Further compounding these alarming developments was a wave of recently published negative results from therapeutic trials done on medicines thought effective for COVID-19, that now virtually eliminate any treatment role for remdesivir, hydroxychloroquine, lopinavir/ritonavir, interferon, convalescent plasma, tocilizumab, and mono-clonal antibody therapy, particularly in later phases.

One year into the pandemic, the only therapy considered “proven” as an effective treatment in COVID-19 is the use of corticosteroids in patients with moderate to severe illness.18 Similarly most concerning is the fact that little has proven effective to prevent disease progression to prevent hospitalization.



Despite this growing list of failed therapeutics in COVID-19, it now appears that ivermectin, a widely used anti-parasitic medicine with known anti-viral and anti-inflammatory properties is proving a highly potent and multi-phase effective treatment against COVID-19. Although much of the trials data supporting this conclusion is available on medical pre-print servers or posted on clinicaltrials.gov, most have not yet undergone peer-review. Despite this limitation, the FLCCC expert panel, in their prolonged and continued commitment to reviewing the emerging medical evidence base, and considering the impact of the recent surge, has now reached a consensus in recommending that ivermectin for both prophylaxis and treatment of COVID-19 should be systematically and globally adopted.

The FLCCC recommendation is based on the following set of conclusions derived from the existing data, which will be comprehensively reviewed below:

1) Since 2012, multiple in-vitro studies have demonstrated that Ivermectin inhibits the replication of many viruses, including influenza, Zika, Dengue and others 

2) Ivermectin inhibits SARS-CoV-2 replication, leading to absence of nearly all viral material by 48h in infected cell cultures

3) Ivermectin has potent anti-inflammatory properties with in-vitro data demonstrating profound inhibition of both cytokine production and transcription of nuclear factor-κB (NF-κB), the most potent mediator of inflammation 

4) Ivermectin significantly diminishes viral load and protects against organ damage when administered to mice upon infection with a virus similar to SARS-CoV-232

5) Ivermectin prevents transmission and development of COVID-19 disease in those exposed to infected patients

6) Ivermectin hastens recovery and prevents deterioration in patients with mild to moderate disease treated early after symptoms 




7) Ivermectin hastens recovery and avoidance of ICU admission and death in hospitalized patients 

8) Ivermectin reduces mortality in critically ill patients with COVID-19

9) Ivermectin leads to striking reductions in case-fatality rates in regions with widespread use

10) The safety, availability, and cost of ivermectin is nearly unparalleled given its near nil drug interactions along with only mild and rare side effects observed in almost 40 years of use and billions of doses administered 

11) The World Health Organization has long included ivermectin on its “List of Essential Medicines”

Exposure prophylaxis studies of Ivermectin’s ability to prevent transmission of COVID-19

Data is also now available showing large and statistically significant decreases in the transmission of COVID-19 among human subjects based on data from three randomized controlled trials (RCT) and one retrospective observational study (OCT); however, none of the studies have been peer-reviewed yet.

The largest RCT was posted on the Research Square pre-print server on November 13, 2020 while the two other RCT’s have submitted data to clinicaltrials.gov, which then performed a quality control review and posted the results. The OCT was posted on the pre-print server medRxiv on November 3, 2020.

The largest RCT by Elgazzar and colleagues at Benha University in Egypt randomized 200 health care and households contacts of COVID-19 patients where 100 patients took a high dose of 0.4mg/kg on day 1 and repeated the dose on day 7 in addition to wearing personal protective equipment (PPE), while the control group of 100 contacts wore PPE only.52 There was a large and statistically significant reduction in contacts tesing positive by RT-PCR when treated with ivermectin vs. controls, 2% vs 10%, p<.05.

The second largest RCT, conducted in Egypt by Shouman et al. at Zagazig University, included 340 (228 treated, 112 control) family members of patients positive for SARS-CoV-2 via PCR.

Ivermectin, (approximately 0.25mg/kg) was administered twice, on the day of the positive test and 72 hours later. After a two-week follow up, a large and statistically significant decrease in COVID-19 symptoms among household members treated with ivermectin was found, 7.4% vs. 58.4%. Similarly, in another RCT conducted by Carvallo et al. in Argentina involving 229 healthy citizens, 131 were randomized to treatment with 0.2mg of ivermectin drops taken by mouth five times per day. After 28 days, none of those receiving ivermectin prophylaxis group had tested positive for SARS-COV-2 versus 11.2% of patients in the control arm (p<.001).53 More recently, in a large retrospective observational case-control study from India, Behara et al. reported that among 186 casecontrol pairs (n=372) of health care workers, they identified 169 participants that had taken some form of prophylaxis, with 115 that had taken ivermectin prophylaxis (n=38 of the COVID-19 cases and n=77 of the controls). After matched pair analysis, they reported that in the workers who had taken two dose ivermectin prophylaxis, the odds ratio for contracting COVID-19 was markedly decreased (0.27, 95% CI, 0.15–0.51). Notably, one dose prophylaxis was not found to be protective in this study.

Based on both their study finding and the Egyptian prophylaxis study, the All India Institute of Medical Sciences included a consensus statement in the manuscript recommending health care workers take two 0.3mg/kg doses of ivermectin 72 hours apart and to repeat monthly.

Further data supporting a role for ivermectin in decreasing transmission rates can be found from South American countries where, in retrospect, large “natural experiments” appear to have occurred. For instance, beginning as early as May, various regional health ministries and governmental authorities within Peru, Brazil, and Paraguay initiated “ivermectin distribution” campaigns to their citizen populations. In one such example from Brazil, the cities of Itajai, Macapa, and Natal distributed massive amounts of ivermectin doses to the city’s population, where, in the case of Natal, 1 million doses were distributed.45 The data in Table 2 below was compiled on September 14, 2020 and was obtained from the official Brazilian government site (https://covid.saude.gov.br) and the national press consortium by an engineer named Alan Cannel whose findings were published on the website TrialSiteNews and are thus not peer-reviewed. 

For the complete report, visit: www.covid19criticalcare.com




COUNTERPOINT

FROM THE NIH

COVID-19 TREATMENT GUIDELINES: IVERMECTIN Last Updated: August 27, 2020

Ivermectin is a Food and Drug Administration (FDA)-approved antiparasitic drug that is used to treat several neglected tropical diseases, including onchocerciasis, helminthiases, and scabies.1 It is also being evaluated for its potential to reduce the rate of malaria transmission by killing mosquitoes that feed on treated humans and livestock.2 For these indications, ivermectin has been widely used and has demonstrated an excellent safety profile.

Recommendation: The COVID-19 Treatment Guidelines Panel recommends against the use of ivermectin for the treatment of COVID-19, except in a clinical trial (AIII). The available clinical data on the use of ivermectin to treat COVID-19 are limited.

Results

  • Ivermectin administration was reportedly consistent with hospital guidelines: a single dose of 200 µg/kg, with repeat dosing on Day 7 if the patient was still hospitalized (13 patients received a second dose). Ninety percent of the ivermectin group and 97% of the usual care group received hydroxychloroquine (the majority received hydroxychloroquine in conjunction with azithromycin).
  • All-cause mortality was lower among the patients in the ivermectin group than among patients in the usual care group (OR 0.27; P = 0.03). The mortality benefit appeared to be limited to the subgroup of patients with severe disease.
  • There was no difference between the groups for the median length of hospital stay (7 days in both groups) or the proportion of mechanically ventilated patients who were successfully extubated (36% in the ivermectin group vs. 15% in the usual care group; P = 0.07).

Limitations

  • This was a retrospective analysis.
  • The study included little or no information on oxygen saturation or radiographic findings. It was also unclear whether therapeutic interventions other than hydroxychloroquine, such as remdesivir or dexamethasone, were used in the study.
  • The timing of therapeutic interventions was not standardized; if the timing is not accounted for, it can bias the survival comparison.
  • The analyses of the durations of ventilation and hospitalization do not appear to account for death as a competing risk.
  • No virologic assessments were performed.
See complete NIH report and references: https://www.covid19treatmentguidelines.nih.gov/antiviral-therapy/ivermectin/

 




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METHYLPREDNISOLONE OR DEXALMETHAZONE?: STRATEGIC TREATMENT CHALLENGE FROM THE FIELD Teams of American physicians like Dr. Pierre Kory, Pulmonary and Critical Care Specialist (Milwaukee, WI) and his team of front-line Covid care providers (the Front Line Covid-19 Critical Care Alliance) challenged Dexamethasone as the exalted panacea of the pandemic.  Dr. Kory’s team dedicated their life’s work to the research and treatment of infectious diseases in critical illness, and recently published a battle-tested and proven Hospital Treatment Protocol called MATH+,  a combination of medicines designed to counteract the injurious hyperinflammation, hypercoagulability, and hypoxemia in COVID-19 using synergistic actions. Their group strongly recommends a different corticosteroid called METHYLPREDNISOLONE.   Work done by members of the group, in particular, Dr. G. Umberto Meduri, one of the worlds experts on the use of corticosteroids in critical illness, discovered key findings establishing the rationale in support of the preferred use of Methylprednisolone, while also providing a wider scope of evidence supporting corticosteroid therapy for Covid-19 critical cases.


VIEWPOINTS: "The incredible work that has emerged from the group of scholars working on the MATH+ formula for patient care reminds me of the importance of collaboration in medicine.  This treatment formula was designed with patient care in mind, during an unprecedented time in our history.  The formula has clearly been shown to be an effective treatment to combat the virus.  The combination of Corticosteroids, Ascorbic acid and the Heperin has effectively been shown to reduce severity of patient symptoms and greatly reduce the need for the ventilator.  This is certainly a step forward in treatment options for COVID19 patients."   Dr. Noelle Cutter (Molloy College | Associate Professor of Biology and Chemistry) 


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