A Narrative Review of Pharmacotherapy of Glaucoma
Round 1
Reviewer 1 Report (New Reviewer)
Comments and Suggestions for Authors
This review summarizes the current literature comprehensively. In the choice of therapy section (section 10), authors should elaborate on combination therapy and review studies which have been performed using combination therapies. I think this will strengthen the manuscript.
Comments on the Quality of English Language
The English language was adequate for scientific understanding.
Author Response
Thanks for your suggestion. A paragraph on fixed drug combinations has been added to adjuvant therapy section.
Reviewer 2 Report (New Reviewer)
Comments and Suggestions for Authors
The authors well describe the anatomy of aqueous secretion and drainage, and related pathophysiology of glaucoma. A list of IOP-related therapeutic modes is presented with detailed and thorough descriptions of mechanisms of action. There are several comments to be raised:
1. There is no reference to Figure 1. Were those pictures taken by authors or re-used with permission from other sources? Please clarify.
2. The presentation of IOP-related treatments is well performed and described well in details. However, a chapter on ongoing clinical trials, e.g. neuroprotection in glaucoma using nicotinamide and pyruvate in several ongoing clinical trials (NCT05695027, NCT05275738), and future perspectives using novel treatment modalities (gene therapy, stem cell therapy) is expected to be addressed.
Author Response
- The figure 1 is from one of the author’s personal collection of images, and has not been sourced from third party.
-
Thanks for your suggestion. A paragraph on future perspectives related to ongoing drug trials and encapsulated cell therapy has been added.
Reviewer 3 Report (New Reviewer)
Comments and Suggestions for Authors
The authors fail to mention the phase 2 clinical trials ongoing for QLS-111 (Qlaris Bio), a potassium channel modulator. This ATP-sensitive potassium channel modulator is designed to lower IOP by targeting episcleral venous pressure and distal outflow resistance.
Comments on the Quality of English Language
Recommend re-review of the article once QLS-111 is added to the text.
Author Response
Thanks for your suggestion. A paragraph on future perspectives related to ongoing drug trials and encapsulated cell therapy has been added.
Round 2
Reviewer 3 Report (New Reviewer)
Comments and Suggestions for Authors
The revisions to the manuscript are acceptable.
This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.
Round 1
Reviewer 1 Report
Comments and Suggestions for Authors
This is an excellent and very thorough review of the pharmacotherapy of glaucoma with lots of references. The main concern I have is that there seems to be some confusion over trabecular outflow and outflow facility. These are two different terms with different units of measure. They are not interchangeable.
I have listed some suggestions for the authors’ consideration.
Page 2, paragraph 1.
1. The discussion of IOP in this paragraph should include the resistance to drainage (inverse of facility) which is the factor that is most affected by glaucoma.
2. In the healthy eye there is more uveoscleral outflow than 25%. There are more recent publications on this topic than ref 12 published in 1989. Consider citing the more recent references.
3. There are better references than #13-14 in the Discussion section of aging changes in human eyes. Please include one or two of them.
4. In the paragraph titled Targets for pharmacotherapy, change line 7 to read “approved in the USA by the FDA.” OMPI was approved in Japan years before 2022.
Table 2:
1. The formatting of Table 2 makes it hard to read. Consider changing.
2. There needs to be a column of outflow facility, not trabecular meshwork outflow. Since it is not possible to separate trabecular from uveoscleral outflow facility, it is best just to label it ‘outflow facility’.
3. The beta blockers also have been found to reduce outflow facility. Consider adding a reference to this effect.
4. It is true that there are papers reporting an increase in aqueous humor secretion with the prostaglandin F2alpha analogues, but there are other papers that report no effect. Consider citing these too.
5. The PGF2alpha analogues do not necessarily increase trabecular outflow. They sometimes but not always are shown to change outflow facility. These analogues increase uveoscleral outflow and if they don’t have an effect on aqueous production, they actually decrease trabecular outflow. Please change the table accordingly.
6. Consider limiting the table to currently approved and prescribed drugs. I don’t think unoprostone is still prescribed in the USA. Also indicate that some of the studies were done in animals and not humans.
Page 5
1. In the paragraph header beta-adrenergic antagonists, change ‘in non-primate animal studies’ to ‘in rabbits’.
2. On the last sentence of the paragraph entitled adrenergic agonists, change ‘did not show cause any’ to ‘did not show any’
Page 6
1. paragraph on cholinergic drugs:
Another reference on pilocarpine’s mechanism of IOP lowering is one that found no reduction in uveoscleral outflow when given in clinical doses. Consider adding this reference.
TORIS, C. B., ZHAN, G. L., ZHAO, J., CAMRAS, C. B. & YABLONSKI, M. E. 2001. Potential mechanism for the additivity of pilocarpine and latanoprost. Am J Ophthalmol, 131, 722-8.
2. Paragraph on Nitric oxide donors
NO does not enhance trabecular outflow but rather trabecular outflow facility. Please correct.
3. Paragraph on Rho kinase inhibitors
ROCK inhibitors do not increase trabecular outflow but rather trabecular outflow facility. Please correct.
Page 7,
1. Paragraph on IOP lowering effect
There are nonresponders to timolol as well as latanoprost. Add a discussion of timolol’s nonresponse. See reference:
CAMRAS, C. B. & HEDMAN, K. 2003. Rate of response to latanoprost or timolol in patients with ocular hypertension or glaucoma. J Glaucoma, 12, 466-9.
2. Are there publications on nonresponse to other IOP lowering drugs? Please expand on this topic.
Page 8, 24-hour IOP control, consider adding a discussion of the iCare Home, a tonometer that patients can take home and measure IOP any time of the day and night.
Page 12, consider adding a table of local and systemic side effects of the drugs.
Page 13, consider adding a table summarizing adjunctive therapy including fixed combinations.
Figure 1. change ‘doted’ to ‘dotted’.
There are a few other typos to be corrected.
Comments on the Quality of English Language
For the most part the English is very good. There are just a few errors that need to be corrected.
Author Response
Please see the attachment
Author Response File: 
Author Response.pdf
Reviewer 2 Report
Comments and Suggestions for Authors
The review article by Virani and Rewri about pharmacotherapy of glaucoma is timely and important. The article has covered many seminal findings and therapies aimed at lowering IOP. The authors have done a good job of covering various classes of IOP lowering drugs, their mechanism of action and side-effects. Overall the article is well written, however there are many confusing or poorly worded sentences that need to be modified. Here are some of the points that need to be addressed:
1. The abstract has several ambiguous statements that need to be re-worded to improve their clarity. The first sentence should be modified as follows: “Degeneration of optic nerve axons and progressive loss of retinal ganglion cells are key contributors to vision loss in glaucoma.” The statement, “With an evolving understanding…..is also recognized” must be changed to “With an evolving understanding…..is also being actively studied in the clinic and in preclinical models of glaucoma”
2. In the paragraph on pathophysiology of glaucoma, the authors state that “RGC death is mostly due to elevated IOP”. This must be changed to “RGC death is mostly due to elevated IOP even though it occur over a range of IOPs.” In the same paragraph, the sentence, “The pressure-induced changes at the level of lamina cribrosa……which culminates in apoptosis and RGC death” must be changed to “The pressure-induced changes at the level of lamina cribrosa……which culminates RGC death mainly via apoptosis”
3. The sentence: “It is the drainage of aqueous humor that is almost always impaired in all types of glaucoma” must be changed to “It is the drainage of aqueous humor that is almost always impaired in all types of glaucoma, with the exception of normal tension glaucoma”.
4. “In open angle conditions…the resistance to aqueous outflow is at the biochemical or molecular level of the trabecular meshwork.
5. In the beginning of the section on Targets for Pharmacotherapy, mention the class of drug for Omidenepag Isopropyl (prostaglandin E2 receptor agonist).
6. Table 2 must be improved by properly aligning the words “decrease” and “increase” under the aqueous secretion heading. Similar alignments must be made under all the other heading to make it more presentable and readable.
7. In the section of aqueous suppressant drugs, under the beta-adrenergic antagonist sub-heading, after stating that the precise mechanism of b-adrenergic receptor mechanism is not understood, include the reference of Caprioli et al., (1984) Invest. Ophthalmol. Vis. Sci. 25: 268-277, who showed that agents that increase cAMP such as forskolin and cholera toxin also lower IOP.
8. In the section on adrenergic receptors, the authors mention the presence of a2-A receptors in the outflow pathway: the tissues where they are expressed must be mentioned.
9. Under Rho kinase inhibitors, the authors must clarify how inhibition of LIM kinase and myosin light chain phosphatase could facilitate actin fibre relaxation and polymerization.
10. In the section entitled “IOP-related”, the authors must provide some numbers to indicate how bimatoprost 0.03% and travoprost 0.004% reduced IOP slightly more than latanoprost.
11. In the sub-section of long term efficacy, the authors discuss long-term drift as a kind of drug tolerance. Is there any evidence for receptor desensitization or downregulation for receptors of pilocarpine and apoclonidine?
12. The section of neuroprotection needs to be developed further with additional findings from the pre-clinical models of glaucoma and several exciting targets including complement C1q, endothelin (Howell et al. 2011, J Clin Invest. 121:1429-1444) and neuroprotective effects of vitamin B3 (De Moraes et al., 2022, JAMA Ophthalmol. 140:11-18). The challenges with adverse side-effects and poor patient compliance for IOP lowering therapies and gradual loss of vision despite IOP lowering, necessitate the development of neuroprotective therapies. This point must be emphasized in the neuroprotection section and this section must be moved to the end of the article after the sections on local side effects and adjunctive therapy.
Comments on the Quality of English Language
Need to enhance the writing is some places in the manuscript.
Author Response
Please see the attachment
Author Response File: Author Response.pdf
Reviewer 3 Report
Comments and Suggestions for Authors
Although this is a well-written article, it contains too much basic knowledge to be regarded as an updated piece of literature. It would be better if the author could put more emphasis on the new classes of glaucoma medications, such as ROCK inhibitor, LBN, and omidenepag isopropyl, and discuss them in detail. In addition, the neuroprotection part was too concise for readers to draw any conclusion on the role of each glaucoma medication in terms of neuroprotection.
Author Response
Please see the attachment
Author Response File: Author Response.pdf
Round 2
Reviewer 1 Report
Comments and Suggestions for Authors
Comments for author File: Comments.pdf
Reviewer 3 Report
Comments and Suggestions for Authors
Although the authors made some amendments in the revised manuscript, details regarding newer classes of drugs are too scarce. For instance, how does the EP-2 pathway modulate intraocular pressure? A comprehensive update on medications other than a review of conventional drugs would be of higher value in the scientific field.
Comments on the Quality of English Language
Minor editing of English language required
