Protective Effect of Melatonin Administration against SARS-CoV-2 Infection: A Systematic Review

Round 1

Reviewer 1 Report

This paper entitled “Protective effect of melatonin administration against SARS-CoV-2 infection: A systematic review” is interesting and provides new information on the protective role of melatonin in COVID-19 disease. The paper is well written, is concise, and shows results with potential therapeutic interest.
Minor request:

• Line 13: names of the authors, write number 6 before “Biosanitary Research Institute...”
• Line 33: write “Web of Science
• Line 37: it should be written “197 papers selected and 40 often were finally used”
• Line 41: repetition of the results 4), 5) and 6)
• Page 2, line 79, repetition of the sentence: “The genome of this coronavirus…”
• Page 3, line 104, repetition of the sentence: “…for further research to find treatmente that are effective,…”
• Page 4, in figure 2, change for the word “Neurogenesis”
• Line 146: write “Google Scholar”
• Page 5, line 152, it should be written as “Comparation”
• Page 5, line 173, add one final point.
• Line 181: write SARS-CoV-2 infection
• Page 6, figure 3: close he parentheses “(n=197)”
• Figure 3: remove the line in red under Inclusion, Suitability, Screening, Identified
• Page 6, Table 1: it should be written “GOOGLE SCHOLAR”
• Page 7, table 2: increase the font size of “Reiter RJ, et al”
• Page 7, in table 2: change the “H” for “A”
• Page 8, remove the year 2020, behind the autor “Feitosa EL, et al. Int J Med Sci.”
• Page 8, table 2, correct SARC for SARS-CoV-2
• Page 9, table 2, repetition of the paragraph “Intravenous administration of 60 mg/d…”
• Page 10, line 231 until line 264, review the cites written as “22 (Reiter et al), 23 (Karimitri), 24 (Alghamdi), Zhang et al (25), Brusco L et al (26), and Cardinali D, et al (27)”, they correspond another numbers in references.
• Page 10, line 262, indicate which dose of 9 mg is.
• Page 10, line 264, change for “Cardinali D et al”.
• Page 10, line 266, indicate the dose of melatonin of 2 weeks
• Line 277: add “figure 4”
• Page 11, line 284, change for “Reiter RJ, et al”
• Page 11, line 288, behind “In figure 5”, change the text for “to use”
• Page 12, line 311, change for the expression “In the same sense…”
• Page 13, line 369, change for “Acuña-Castroviejo D, et al”
• Page 14, line 387, remove the final sign “among the antiviral activities´…”
• Page 14, line 408, change for “ Conclusions”
• Page 14, line 424, change for “SARS-CoV-2 infection”
• Page 15, line 432, change in letter “c) Because its security profile”
• Please, check references style.

Author Response

We are very grateful for the comments of reviewer 1 and as can be seen in the final version of the manuscript, the advice given has been followed. As it was suggested, Any revision to the manuscript should be marked up using the “Track Changes” function if you are using MS Word such that any changes can be easily viewed by the editors and reviewers. 

Best regards

Reviewer 2 Report

The authors present a short review article that summarizes studies into the treatment of COVID19 with melatonin therapies and categorically rank their contributions. The review article lacks proper academic research convention and seems to include too much information regarding the aggregation of cited documents. It would be beneficial for the authors to use normal conventions (i.e., flow charts and figures rather than in-text bullet points and number lists). More importantly, I find the assertions made, mostly in the discussion and conclusion, to be of concern. The authors should be extremely cautious calling for the approval of drugs that, at best, have modest effects against the virus. I would try to contextualize the efficacy of melatonin more as an adjuvant therapy or modality for symptom alleviation rather than as a preventative medicine. 

Reviews like this are important, but they should be as unbiased as possible. I urge the authors to dramatically revise assertive claims and overzealous verbiage and subscribe to a more formal review style.

Author Response

We really appreciate your comments. Actually, your remark has provided us the chance to add some new clarification points as following we included:

• It is a systematic review, for which the well-known and accepted “PRISMA Declaration” 1 has been followed, which consists of a scientifically-based methodology precisely to update the evidence of a specific aspect, using the articles that have focused on the subject of study. In our case, the use of melatonin in patients infected with COVID-19. In any case, and following your recommendations, we have modified the bullets for flowcharts.
• The work has the extension that allows including the works published so far.
• Regarding your comments on the discussion and the conclusions, without pretending to be categorical, we can tell you that we have only limited ourselves to reproducing the comments and contributions that the selected works contribute. In addition, they are endorsed by renowned authors and high impact magazines (Dr. Reiter, Dr. Cardinali, Dr. Dario Acuña, etc.). Although, as you well say, in the discussion we make the following comment “… we do not understand how it has not been implemented in the clinic in a generalized way so that its usefulness, recommended dose, administration schedule based on circadian rhythm, etc. "
• Along the same lines, you may notice that among our comments that appeared in the discussion we say: “The antiviral protective efficacy in mice has been demonstrated with the administration of melatonin, even with a certain dose / dependence, an essential issue in humans. in which there is still a long way to go”.
• In any case, the authors who have published on the use of melatonin in COVID-19 infection all agree that it is a recommendation as adjuvant therapy at the moment.
• In fact, there are already many hospitals where it is being used for such problems. With respect to the conclusions that have been drawn from the analyzed articles, it seems to us that they conform to what is described in them, with phrases that you indicate should be underlined, such as the following: a) In conclusion 1, "... which would make it a therapeutic alternative to consider against various infectious diseases". b) Conclusion 5, “We believe that there is a sufficient level of scientific evidence to authorize its use as a preventive medicine against COVID-19 infection, due to its proven physiological actions, although it must be said that the exact dose to achieve the preventive effects have yet to be determine”. In fact, there are already many hospitals where it is being used in this type of problem.
• Finally, and agreeing with your observations, you will see how in conclusion 7, where it is stated: “Although several administration guidelines have already been published in patients infected with SARS-CoV-2, it would be advisable to launch new clinical trials to define what is the best administration protocol, especially with regard to the dose and the times when it should be administered, to respect its circadian rhythmicity ”. What we understand goes in the same direction as your successful comments.

Round 2

Reviewer 2 Report

I believe the authors have adequately addressed my concerns. I feel that the manuscript is well-prepared.