Real-Life Practice of Kelleni’s Protocol in Treatment and Post Exposure Prophylaxis of SARS CoV-2 Omicron HV.1 and JN.1 Subvariants (preprint)

This brief report discusses the ongoing real-world practice using nitazxoanide, NSAIDs and/or azithromycin (Kelleni’s protocol) to manage the evolving manifestations of SARS CoV-2 Omicron EG.5.1, its descendant HV.1 as well as BA.2.86 and its descendant JN.1 subvariants in Egypt. These subvariants are well-known for their highly evolved immune-evasive properties and the manifestations include some peculiar manifestations as persistent cough besides high fever in young children as well as persistent severe cough, high fever, change of voice and marked bone aches in high risk groups of adults. It’s suggested that the ongoing SARS CoV-2 evolution is continuing to mostly affect the high risk groups of patients, to some of whom we’ve also successfully prescribed nitazoxanide and/or NSAIDs for post-exposure prophylaxis of all household contacts. We also continue to recommend starting the immune-modulatory antiviral Kelleni’s protocol as soon as possible in the course of infection and adjusting it in a personalized manner to be more aggressive from the beginning for the high risk patients, at least until the currently encountered surge of infections subsides.

Potential Crucial Role of COX-1 and/or COX-2 Inhibition, NSAIDs or Aspirin Triggered Lipoxins and Resolvins in Amelioration of COVID-19 Mortality (preprint)

Aspirin has been recently suggested to be independently associated with reduced risk of mechanical ventilation, ICU admission and in-hospital mortality of COVID-19. However, we claim that the molecular interpretation of these important results was not scientifically valid, and we provide our academic interpretation that is also basing on our real-life practice using non-steroidal anti-inflammatory drugs in management of COVID-19 and we suggest that inhibition of COX-1 and/or COX-2 enzymes might play a lifesaving role in COVID-19 management, and we further discuss the potential of aspirin triggered lipoxins and resolivns in the same context.

Autoimmunity and Antibody Dependent COVID-19 Enhancement of SARS CoV-2 Vaccination: A Global Human Right to Know then Decide. (preprint)

Nucleic acid based - mRNA based and adenovirus vectored - vaccines, were first ever or first commercially ever approved for the public, respectively. However, these newly emergency approved types possess a potential risk to induce auto-immune diseases e.g., thrombocytopenia, myocarditis and immune induced thrombosis and thromboembolism that might be fatal and could reason for some of the post vaccination sudden death reports. Moreover, all SARS CoV-2 types of vaccines, depending on the spike protein immunogenicity, especially the conventional inactivated ones might increase the likelihood of COVID-19 severity upon re-infection through antibody dependent enhancement which might reason for the recently described abundance of hospital admissions within seven days of vaccination and might also reason for some of the serious adverse effects encountered with administration of convalescent plasma to COVID-19 patients as well as they might share in development of some lethal SARS CoV-2 variants. Importantly, we suggest that SARS CoV-2 mass vaccination campaigns were the worst ever decision made and that making these COVID-19 vaccines compulsory or administering them to children or pregnant participants might be considered as a crime against humanity to the extent that no prior companies- governmental agreements would ever secure impunity. Finally, a full informed personalized risk benefit ratio especially for some described high-risk groups must be secured while suggesting that the subunit vaccines are the least hazardous ones.

SARS CoV-2 adenovirus and RNA based vaccines potential autoimmune complications: could we lower the chances? (preprint)

Nucleic acid based - mRNA based and adenovirus vectored - vaccines, were first ever or first commercially ever approved for the public, respectively. However, these newly emergency approved types possess a potential risk to induce auto-immune diseases e.g., thrombocytopenia, myocarditis and immune induced thrombosis and thromboembolism that might be fatal and could reason for some of the post vaccination sudden death reports. Moreover, all SARS CoV-2 types of vaccines, depending on the spike protein immunogenicity, especially the conventional inactivated ones might increase the likelihood of COVID-19 severity upon re-infection through antibody dependent enhancement which might reason for the recently described abundance of hospital admissions within seven days of vaccination and might also reason for some of the serious adverse effects encountered with administration of convalescent plasma to COVID-19 patients as well as they might share in development of some lethal SARS CoV-2 variants. Importantly, we suggest that SARS CoV-2 mass vaccination campaigns were the worst ever decision made and that making these COVID-19 vaccines compulsory or administering them to children or pregnant participants might be considered as a crime against humanity to the extent that no prior companies- governmental agreements would ever secure impunity. Finally, a full informed personalized risk benefit ratio especially for some described high-risk groups must be secured while suggesting that the subunit vaccines are the least hazardous ones.

NSAIDs Immunomodulation in COVID-19 Might Inhibit SARS CoV-2 ORF Proteins Induced Caspase Activation, Necroptosis and Endoplasmic Reticulum Stress. (preprint)

We have previously suggested numerous immunomodulatory and anti-inflammatory benefits when NSAIDs are administered to manage COVID-19 and in this commentary, we add other potential benefits related to SARS CoV-2 ORF proteins dependent activation of caspases with subsequent mitochondrial dysfunction, endoplasmic reticulum stress and necroptosis that were described with complicated COVID-19 as NSAIDs are known to be caspase inhibitors. Moreover, NSAIDs might independently inhibit other COVID-19 associated downstream pathological signaling mechanisms. We also postulate that CARD-14, a caspase recruitment domain-containing protein, polymorphisms might play a role in development of severe and critical COVID-19. We believe that it is very unfortunate that for more than one year of relentless struggle, our recommendation to adopt NSAIDs as first choice COVID-19 therapy has not adopted while lives are lost are succumbed every day.

SARS CoV-2 Vaccines, Remdesivir and Favipiravir Might Have Led to SARS CoV-2 B.1.617 Variants: India First but We Can Intervene (preprint)

In the first version, I have made a mistake SARS COV-2 Vaccines have not shared in development of the original SARS CoV-2 B.1.617 variants in India (yet they might have shared in the evolution of the more virulent delta plus variant). I have updated the manuscript, thanks to Authorea, and in the updated versions Remdesivir, Favipiravir and Dexamethasone are suggested as potential crucial causes that led to B.1.617 variants in India and elsewhere. Moreover, SARS CoV-2 mass vaccination programs and the unfortunately anticipated Molnupiravir are suggested to share in evolution of potentially more virulent variants e.g. delta plus and the catastrophic Indian surge of mortality is also anticipated to be repeated elsewhere unless some prompt interventions are considered.

NSAIDs/Nitazoxanide/Azithromycin Immunomodulatory Protocol Used in Adults, Geriatric, Pediatric, Pregnant, and Immunocompromised COVID-19 Patients: A Prospective Observational Study and Case-Series (preprint)

Introduction: COVID-19 management still lacks a protocol of proven efficacy and we present a novel COVID-19 immunomodulatory protocol basing on our early pioneering article that justified repurposing nitazoxanide/azithromycin combination for early COVID-19 which was followed by two articles to justify addition of non-steroidal anti-inflammatory drugs to nitazoxanide/azithromycin as well as by our recent article that illustrates the potential immunomodulatory mechanisms by which all the drugs used in this manuscript might benefit COVID-19 patients. Methods: : We present a case series of 38 confirmed and highly suspected COVID-19 consented native Arabic speaking patients, including 12 confirmed by PCR, and the others diagnosed by other measures who were managed by telemedicine. The patients included 15 adult males including an immunocompromised patient, 16 adult females including one lactating, 3 pregnant patients including one confirmed by PCR as well as 4 children. All patients have received a short 5-day-regimen of NSAIDs / nitazoxanide/ azithromycin +/- cefoperazone either in full or in part. The primary endpoint of this protocol was a full relief of all serious COVID-19 clinical manifestations. Results: : The primary endpoint was fully achieved within two weeks. Most of the patients who were treated early, have fully recovered during its described five days; the leucocytic/lymphocytic count was significantly improved for those with prior leucopenia or leucocytosis/lymphopenia. Neither significant adverse effects, nor post/para COVID syndrome was reported. Conclusions: : a novel 5-day-protocol to safely and effectively cure COVID-19 using repurposed immunomodulatory safe and inexpensive FDA approved drugs is illustrated and we recommend performing sufficiently powered double-blind randomized clinical trials.

ACE2 Polymorphisms Reflected on the Immune and Apelinergic Peptide Systems: Potential COVID-19 Tools for Risk Stratification and Therapy. (preprint)

ACE2 polymorphisms have been previously linked to increased susceptibility to multiple diseases and are currently linked to SARS CoV-2 susceptibility and complications. Notably, ACE2 transcribed or regulated proteins include the activity of metaloproteinsase-2 and apelin-13 and 36, might be linked to abnormal immune responses and complications. Potential genetic or serological tests might be developed to detect the higher vulnerable groups to SARS CoV-2 complications and/or mortality. Moreover, we postulate that diabetic and obese patients suffer from exhausted and/or abnormally functioning apelinergic peptides that predispose them to a higher severe COVID-19 risk. Finally, infusion of apelin-13 to treat selected critical cases of COVID-19, especially those complaining of refractory advanced heart failure, might be considered for clinical trials.

NSAIDs/Nitazoxanide/Azithromycin Repurposed for COVID-19: Potential Mitigation of the Cytokine Storm Interleukin-6 Amplifier via Immunomodulatory Effects (preprint)

Introduction: Mediators of immunity and inflammation are playing a crucial role in COVID-19 pathogenesis and complications as demonstrated by several genetic and clinical studies. Moreover, a weak, irregular, or inhibited early interferon response to SARS CoV-2 infection was shown to trigger an exaggerated inflammatory response leading to the COVID-19 associated mortality. Thus, repurposing of drugs that possess anti-inflammatory and/or immune-modulatory effects for COVID-19 is considered a rational approach. Areas covered We present a concise analysis and interpretations of selected studies that correlated COVID-19 with dysregulated interferon and inflammatory responses while reflecting on our academic and real-life experience using non-steroidal anti-inflammatory drugs, nitazoxanide and azithromycin for management of COVID-19. Moreover, we interpret the recent results that suggested a potential survival benefit of low dose aspirin and colchicine when used for COVID-19. Expert opinion Nitazoxanide/azithromycin combination has been first hypothesized by the author and practiced by him and several researchers to benefit COVID-19 patients due to a potential ability to augment the natural interferon response as well as their positive immunomodulatory effects on several cytokines. Furthermore, NSAIDs, that were unfortunately almost globally avoided early in the COVID-19 era and still avoided in many developing ones or at best of second choice in the developed ones, have been early postulated and clinically practiced by the author to prevent or ameliorate COVID-19 complications and mortality due to their ability to prevent, constrain or reverse COVID-19 associated dysregulated immune and hyper-inflammatory responses through mitigating the formation of several inflammatory cytokines and pathways including the interleukin-6 amplifier and its NF-kB component, as well as modulation of a described monocytic immunological dysrhythmia, which is also known to trigger the COVID-19 cytokine storm. Finally, we repeat our previous call to adopt our observational study that used these drugs in sufficiently powered double blind randomized clinical trials as COVID-19 potential safe and economic cure might be available and unfortunately repeatedly ignored for one year.

Diclofenac potassium/nitazoxanide/azithromycin novel COVID-19 protocol used in adults, children and pregnant patients: could it be the magic bullet? (preprint)

Background: The current pandemic of coronavirus disease 2019 has necessitated trial of several drugs searching for a potential cure. We have published an article to justify adoption of nitazoxanide/azithromycin for early cases of COVID-19 followed by two other articles providing the theoretical basis to add non-steroidal anti-inflammatory drugs to the protocol which is described in this manuscript. Patients and methods: Twenty-two consented confirmed and highly suspected COVID-19 Egyptian patients including 11 adult males, 6 adult females, 2 pregnant patients as well as 3 children. All patients have received a 5-day-regimen of NSAIDs (diclofenac potassium, ibuprofen or ketoprofen)/nitazoxanide/azithromycin either in full or in part as illustrated in the manuscript. The primary endpoint of this protocol was full relief of all significant/hazardous COVID-19 symptoms and signs like fever, progressive cough, moderate/severe dyspnea or disturbed level of consciousness. Results: : The primary endpoint of this protocol was fully achieved in all patients within two weeks. Most of the patients treated early with the protocol have recovered during the five days; the lymphocytic count was significantly improved for those with prior lymphopenia. No significant adverse effects were reported. Conclusion: A novel short course COVID-19 protocol using inexpensive FDA approved drugs is illustrated.

Does the RECOVERY dexamethasone improve COVID-19 mortality? (preprint)

On the same day the results of the RECOVERY study was published; July 17, 2020, we have submitted a letter to New England Journal of Medicine (NEJM, ID 20-25534) representing some concerns about this study and its status was with editor until November 29, 2020 on which a withdrawal request has been sent to NEJM and was promptly accepted on the following day. Notably, four emails were sent to NEJM, once every month wondering about this unprecedent delay in publishing a short letter and the response was that the editor has been contacted on multiple occasions but he/she is busy because of the large number of COVID-19 related submissions.

Remdesivir is least likely to be effective for safe treatment of COVID-19: A pharmacovigilant point of view (preprint)

This manuscript has been published on the 29 th of May 2020 by the honorable BMJ as a rapid response to a related article. However since a DOI has not been assigned and two subsequent manuscripts have cited it, I’m preprinting a copy wishing it might reach all the interested colleagues and researchers in an easier way.

Nitazoxanide/Azithromycin Combination for COVID-19: A Suggested New Protocol for COVID-19 Early Management (preprint)

Azithromycin has been shown to have a clinical efficacy against severe acute respiratory syndrome coronavirus 2 (SARS CoV-2); ivermectin has also demonstrated a remarkable experimental efficacy with a potential to be used for Coronavirus disease 2019 (COVID-19). Further, BCG vaccination is being considered for clinical trials aiming to test its potential for lowering COVID-19 morbidity and mortality. This article illustrates some structural and functional relationships that may gather these drugs and the author, basing on a combined pathophysiological and pharmacological approach, recommends the FDA-approved antidiarrhea drug; nitazoxanide, which has been previously suggested but unfortunately ignored, to be tested in combination with azithromycin for their potential activity against SARS CoV-2 soonest. The author recommends testing their combined administration as early during the clinical course of COVID-19 as possible. Further, basing on the same represented concept, the author recommends more trials for interferons to be tested against SARS CoV-2 especially in severe and critical cases.