key: cord-0750407-rogv6xtv authors: Kelleni, Mina T. title: Nitazoxanide/Azithromycin combination for COVID-19: A suggested new protocol for COVID-19 early management date: 2020-04-30 journal: Pharmacol Res DOI: 10.1016/j.phrs.2020.104874 sha: 4e5fc42ca14b51407e0e8e137e23e2ffa7f0115f doc_id: 750407 cord_uid: rogv6xtv Abstract Azithromycin has been shown to have a clinical efficacy against severe acute respiratory syndrome coronavirus 2; ivermectin has also demonstrated a remarkable experimental efficacy with a potential to be used for Coronavirus disease 2019. 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 also 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 suggests more trials for interferons to be tested against SARS CoV-2, especially in severe and critical cases. 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 also 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 suggests more trials for interferons to be tested against SARS CoV-2, especially in severe and critical cases. Keywords: SARS CoV-2, COVID-19, Nitazoxanide, Azithromycin, Interferons Ivermectin ( Fig. 1) is a broad spectrum macrolide endectocide macrocyclic lactone produced by Streptomyces avermitilis and it's widely used for treatment of pediculosis, scabies, onchocerciasis and lymphatic filariasis 1-3 . It's also been shown to possess an invitro antiviral activity against influenza A, dengue and Venezuelan equine encephalitis viruses. Importantly, Ivermectin has been recently proved, in an invitro experiment, to produce approximately 5000-fold reduction in the RNA of severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) causing Coronavirus disease 2019 (COVID-19) at 48 h of its single addition 4 . Interestingly, ivermectin therapy has been shown to reverse onchocerciasis-associated immunosuppression through sustained production of IFN-γ in amicrofilaridermic individuals 5 , to be also noted that it was previously shown that recombinant human IFN-γ had a particular effect on the incidence of herpes simplex, and 7 8 . Noteworthy, only azithromycin which is a synthetic derivative of erythromycin; the prototype of macrolides antibiotics first isolated from the soil bacterium Streptomyces erythraeus, but not erythromycin or telithromycin, has been shown to significantly increase rhinovirus 1B-and rhinovirus 16-induced interferons and interferon-stimulated gene mRNA expression as well as protein production leading to a significant reduction of rhinovirus replication and release in bronchial epithelial cells 9 . This differential peculiarity associated with azithromycin should be properly investigated as regards to its structure activity relationship. Further, it's also been recently reported that when azithromycin was added to hydroxychloroquine, the efficiency of SARS CoV-2 elimination was significantly improved leading to a significant more rapid virologic cure as evident by a negative nasopharyngeal PCR, and healing in COVID-19 patients 7 . Surprisingly, a recent study has suggested an association of increased overall mortality that was identified in patients treated with hydroxychloroquine without azithromycin as compared to the standard care alone and it's also pointed no evidence that the use of hydroxychloroquine, either with or without azithromycin, reduced the risk of mechanical ventilation in patients hospitalized with Covid-19 10 . The author wonders if the previous reported beneficial effects might be more properly attributed to azithromycin alone; further studies might explore this potential and hopefully this manuscript might also help other colleagues in their search for answers. Taken together, ivermectin and azithromycin share a potential structural similarity and more importantly both drugs are potentiating the interferons' immune response which is essential to combat viral infections. Noteworthy, BCG vaccination which is currently being considered for clinical trials to test its potential against COVID-19, was previously shown when given once a month for 3 consecutive months to produce a significant reduction on the prevalence of adult upper respiratory tract infections in the elderly, at least partially through its induced significant increase of IFN-γ level as compared to the placebo group 11 . Taken together, the author agrees that ivermectin J o u r n a l P r e -p r o o f deserves its enrollment for clinical trials to explore its potential for COVID-19 treatment and suggests that BCG vaccination might not be the proper fast response we need. On the other hand, more research for other macrolides to assess their potential antiviral effect might be fertile, not only for this COVID-19 pandemic but also afterwards. Similarly, the author recommends more COVID-19 clinical trials for recombinant human IFN-γ, interferon alfa-1, recombinant interferon beta and while a preliminary version of this manuscript was being submitted on the 8 th of April, 2020 elsewhere; other colleagues have also been pointing out, both clinically and theoretically, the significance of interferons as potential drug candidates for COVID-19 [12] [13] [14] . Further, it might also be beneficial to test the related possibility that SARS CoV-2 may produce interferon antagonist activities similar to the effect Middle East respiratory syndrome coronavirus (MERS-CoV) has previously exhibited 15 16 . Most importantly, the author basing on the same concept, would like to recommend the start of clinical trials for the widely available FDA-approved, for both adults and immunocompetent children, antidiarrhea drug; nitazoxanide, 17 in combination with azithromycin 18 , soonest. Nitazoxanide (Fig. 3) , is an orally active nitrothiazolysalicylamide broad-spectrum antiparasitic and antiviral prodrug that is converted rapidly to the active metabolites tizoxanide and tizoxanide conjugates and unlike metronidazole, these metabolites appear to be safer and free of mutagenic effects 19 . Similarly, nitazoxanide is also known to potentiate interferon alfa and interferon beta production and it has been previously shown to exhibit an in vitro activity against MERS-CoV and other coronaviruses 20 . Moreover, when nitazoxanide was given as 600 mg twice daily for 5 days, it's proved to reduce of the duration of symptoms in patients with acute uncomplicated influenza with minor adverse effects 21 and this dose regimen might be reasonably considered to be used combined with azithromycin in a suggested new COVID-19 protocol aiming to test their integrated potential to decrease SARS CoV-2 morbidity and mortality. Noteworthy, the author would like to stress that on the 9 th of March, 2020, nitazoxanide was previously suggested, among other drugs, by French colleagues to be evaluated for its potential against SARS CoV-2; unfortunately, their recommendation wasn't popular and has been practically ignored 22 . Similarly, the author has recently found another research, though also unpopular and ignored, that has been published on the 15 th of March, 2020 to J o u r n a l P r e -p r o o f recommend nitazoxanide to be used with hydroxychloroquine for COVID-19 patients pointing to some links with the interferon immune system 23 . The author suggests that nitazoxanide/azithromycin combination has a potential that should be properly tested. The author humbly suggests the approach represented in this manuscript might be considered a first of its kind as regards to its combined pathophysiological as well as pharmacological COVID-19 displayed concept just to raise an Afro-Egyptian voice on behalf of COVID-19 patients that nitazoxanide/azithromycin should be considered as a safe and available regimen to be tested immediately; if proved right many lives might be saved as wished but if, after the recent disappointing results regarding chloroquine efficacy against SARS CoV-2, proved wrong, then the author wishes to finally declare: we, humans, will never lose hope, abandon courage, or stop researching and we can't afford to do so. The author wishes to thank Prof. Emilio Clementi, Editor in Chief of Pharmacological as well as Prof. Elaine Leung, guest editor of the special issue: "Pharmacoepidemiology and pathogenetics of 2019-nCoV" for their precious remarks and their integrative extraordinary and highly professional handling of this manuscript in such a timely manner. 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