The manuscript by Grzegorz W. Przybyła et al. entitled “Paracetamol - an old drug with new mechanisms of action“ summarizes literature on the mechanisms of action of paracetamol. Thereby, this adds to a long list of reviews on paracetamol (e.g. Prescott et al, 2000, Am J Therapeutics 7:143-147; Anderson, 2008, Pediatric Anesthesia 18: 915–921; Hinson et al, 2010, Handb Exp Pharmacol 196: 369–405; Kis et al, 2006, JPET 315:1–7; Toussaint et al, 2010, J Clin Pharm Ther 35, 617–638; Graham et al, 2013, Inflammopharmacol 21:201–232; Ghanem et al, 2016, Pharmacol Res 109: 119–131). All the authors of these previous reviews agree that paracetamol cannot be viewed as NSAID because it has much less peripheral antiinflammatory activity than NSAIDs (or almost none), it shows much less propensity to cause gastric ulcers than NSAIDs, and it does not block platelet aggregation as NSAIDs do. Hence, in this respect, the present manuscripts presents paracetamol as part of a drug category which it doesn’t belong to. As a consequence, the focus of the entire review is centered too much on COX enzymes and prostaglandins. Nevertheless, other targets described more recently, such as TRP channels, are listed in this manuscripts which renders it a potentially useful addition to the list of reviews presented above. However, some targets and mechanisms described within the last few years (such as anticonvulsant activity and opening of Kv7 channels, with both mechanisms being highly relevant for analgesia) are ignored. Hence, the present manuscript might become attractive to an audience interested in pharmacology once the shortcomings described above are overcome.
Additional points:
Figure 1 is identical to figure 1 of Anderson BJ, 2008, Pediatric Anesthesia 18: 915–921, but this fact is not mentioned in the legend. This is a form of plagiarism and is unacceptable! Likewise, table1 of this manuscript is largely congruent with table 1 of Anderson BJ, 2008, Pediatric Anesthesia 18: 915–921.

The revised version of the manuscript by Przybyła et al. entitled “Paracetamol - an old drug with new mechanisms of action“ has been improved along the suggestions provided by both reviewers. Nevertheless, some shortcomings remain and need to be accounted for:
Abstract:
Line 88: “The mechanism of paracetamol action currently considered to include the involvement of inhibition of cyclooxygenases (COX-1, COX-2, and COX-3), participation in the endocannabinoid system and serotonergic pathways, an influence on the transient receptor potential (TRP) channels, voltage-gated Kv7 potassium channels, inhibition of the T-type Cav3.2 calcium channels, and an impact on the L-arginine in nitric oxide (NO) synthesis pathway.” This sentence is too long and suffers from incorrect syntax: where is the verb?
Line 95: “However, with its serious side effects, paracetamol…” Which serious side effects? In this context it should be mentioned that there is no list of adverse effects of paracetamol within the entire manuscript. Moreover, one should differentiate between adverse (at therapeutic doses) and toxic (higher doses) effects.
1, Introduction:
Line 101: “For many years, nonsteroid anti-inflammatory drugs (NSAIDs) have been used by a wide human population. However, their mechanism of action has not been fully elucidated.” Considering that paracetamol is NOT categorized as NSAID, it appears rather inappropriate to start the review by using such a statement. Moreover, the mechanism of action of NSAIDs are by far less controversial than those of paracetamol. Moreover, the reference used to support this statement is mainly relevant for COX3.
Line 105: “However, due to some similarities, it is often compared with NSAIDs”. Which similarities? There are not that many. Either explain these similarities and provide an according reference or omit this statement. Instead, one might allude to differences between NSAIDs and paracetamol.
Language:
Line 326: “For instance, paracetamol in combination with a COX inhibitor, such as ibuprofen, provides additional improved analgesia and exhibits antipyretic activity, compared to both these compounds given separately, which suggests that they act through different mechanisms”. The meaning of this sentence is hard (if not impossible) to understand; please reword!
Line 377: “It gives the opportunity to control the increasing nociceptive signal from the spinal cord with feedback 139, with subsequent serotonergic activation 140”. Impossible to understand: which opportunity? I assume the authors mean “ascending” instead of increasing. Please reword the entire sentence!
Line 408: “Nevertheless, TRP channels are best known for their action in the peripheral nervous system (Moran 2018).” Incorrect citation.
Line 539: “Therefore, a relationship of TRPV1 channels in the mobilization of Cav3.2 in the analgesic action of paracetamol was hypothesized”. What do you mean by “relationship of TRPV1 channels in the mobilization of Cav3.2…”?
Line549: “After a harmful stimuli,…” Either “a harmful stimulus…” or plural!

In the second revision of the manuscript “Paracetamol - an old drug with new mechanisms of action“, Przybyła et al. have considered the points of critique provided by both reviewers. Nevertheless, there is one problem remaining that needs to be overcome.

1. Introduction:
   Line 95: According to my previous critique, the first sentence has been rephrased and nor reads as “In the light of current scientific research, paracetamol (which is a recommended international nonproprietary name of acetaminophen (acetyl-p-aminophenol; APAP)), is generally not considered as nonsteroidal anti-inflammatory drugs (NSAIDs) because it has only minor anti-inflammatory activity”. Why would one start an article on a drug by stating what this drug does not do? Please change!