Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The paper is interesting and provides valuable conclusions, and the intervention itself was successful. In my opinion, this work provides evidence of a problem that is currently being analyzed in my country. A very interesting concept and well-selected patient. However, I have several comments that should be considered:

1. What does this case report contribute to the current state of knowledge? The aim of the work should be well structurized.
2. Why was the Naranjo algorithm or WHO criteria not used to assess the probability that a specific event was caused by a specific drug? On what basis did the authors evaluate ADRs, for example regarding clonazepam and semaglutide?
3. Please specify that semaglutide was administered orally - this is crucial. Doses of 7 and 14 mg refer to the oral form, not the weekly injectable form. Please verify this. The dosage form should be provided for all medications used to avoid confusion. At this stage, it is unclear whether the drug was given weekly or daily.
4. Please include a detailed timeline - information such as “a few days later” is insufficient and does not allow consideration of half-life, washout periods, and other key pharmacokinetic aspects.
5. The statement “Suspecting a urinary tract infection, she attended the emergency department” is imprecise. It should be clarified who made this assumption (the patient, pharmacist, or physician) and on what basis.
6. The description of replacing diazepam with clonazepam lacks information about the previously used diazepam dose.
7. What was the renal function? Was eGFR measured? The patient is 70 years old; in my opinion, this is crucial and impacts data interpretation.
8. If no validated tool was used to assess ADR probability, the discussion should be modified accordingly. Moreover, the discussion lacks an analysis of how exactly the Personalized Dosage System contributed to identifying the problem.
9. Please expand the analysis and discussion to include the drug mechanisms, as this is important to support your observations.
10. In my opinion, the conclusions must be formulated cautiously, as this is a single-patient case.

The manuscript addresses a clinically relevant topic regarding the pharmacist’s role in managing polypharmacy, but in its current form, it requires revision.

Author Response

Response to Reviewer 1

General Response

We thank the reviewer for the constructive comments and for highlighting the clinical relevance of the manuscript. All comments have been carefully considered and the manuscript has been revised accordingly. The modifications introduced in the manuscript are detailed below.

Comment 1

What does this case report contribute to the current state of knowledge? The aim of the work should be well structured.

Response:
The objective of the study has been clarified at the end of the Introduction section.

Modified text:
The objective of this study is to describe the detection and management of suspected adverse drug reactions in a polymedicated older patient through structured pharmacotherapeutic follow-up in community pharmacy, highlighting the role of the Personalized Dosage System (PDS) in identifying medication-related problems and improving medication safety.

Comment 2

Why was the Naranjo algorithm or WHO criteria not used to assess ADR probability?

Response:
The Naranjo algorithm has now been applied to evaluate the probability of adverse drug reactions associated with clonazepam and semaglutide. Corresponding tables have been added in the Evaluation section.

Comment 3

Please specify that semaglutide was administered orally.

Response:
The manuscript has been revised to clearly specify that semaglutide was administered in its oral formulation (7 mg increased to 14 mg once daily). The dosage form has also been specified for all medications in Table 1.

Comment 4

Please include a detailed timeline.

Response:
A detailed timeline has been incorporated describing medication changes, symptom onset, intervention, and clinical outcomes.

Modified text:
On September 15, 2023, the primary care physician replaced diazepam with clonazepam and increased oral semaglutide from 7 mg to 14 mg daily. Five days later (September 20, 2023), the patient reported nausea, abdominal pain and urinary incontinence. On September 27, 2023 the patient consulted the community pharmacy due to persistent symptoms.

Comment 5

Clarify who suspected urinary infection.

Response:
The text has been clarified.

Modified text:
The patient herself suspected a urinary tract infection due to the sudden onset of urinary incontinence and therefore attended the emergency department, where a urine culture was performed and resulted negative.

Comment 6

The previous dose of diazepam is missing.

Response:
This information has been added: Diazepam 10 mg once daily at night was replaced with clonazepam 2 mg nightly.

Comment 7

What was the renal function? Was eGFR measured?

Response:
The estimated glomerular filtration rate (eGFR) was not available at the time of the intervention. This limitation has been added to the Discussion section.

Comment 8

The discussion lacks explanation of the Personalized Dosage System.

Response:
The discussion has been expanded to describe how the Personalized Dosage System allowed verification of real medication use, identification of treatment changes, and assessment of adherence.

Comment 9

Expand discussion including drug mechanisms.

Response:
Pharmacological mechanisms have been added explaining clonazepam effects on GABA-A receptors and the gastrointestinal mechanism associated with semaglutide.

Comment 10

Conclusions must be cautious.

Response:
The conclusions have been revised to avoid overinterpretation and emphasize the role of community pharmacy in detecting medication-related problems.

Reviewer 2 Report

Comments and Suggestions for Authors

1. The authors should clarify whether the pharmacist’s intervention followed a validated protocol or was performed ad hoc.
2. Please include the timeline of drug changes, symptom onset, intervention, and resolution to demonstrate causal association.
3. The authors should present quantitative outcome data, including symptom scores, adherence rates, or biochemical improvement, to support conclusions.
4. The authors should justify the clinical significance of the omeprazole+semaglutide interaction and provide supporting references.
5. Please describe follow-up duration and confirm whether symptom resolution was sustained over time.
6. The authors should avoid overinterpretation—claims of “pharmacotherapy optimization” should be supported by measurable outcomes.
7. The authors should revise Tables to be presented as three line format.
8. The authors should revise the Conclusion to focus on practical implications rather than restating results.

Author Response

Response to Reviewer 2

General Response

We thank the reviewer for the valuable comments and suggestions, which helped improve the clarity and methodological rigor of the manuscript.

Comment 1

Clarify whether the pharmacist intervention followed a validated protocol.

Response:
The intervention followed the methodology proposed by the Community Pharmacy Pharmaceutical Care Forum (Foro AF-FC), which provides a structured approach for identifying medication-related problems and negative outcomes associated with medication.

Comment 2

Include a detailed timeline.

Response:
A detailed timeline has been incorporated into the case presentation to demonstrate the temporal relationship between medication changes and symptom onset.

Comment 3

Include quantitative outcome data.

Response:
Although formal symptom scores were not collected, clinical improvement was documented through patient reported symptom reduction, medication adjustments and adherence verification using the Personalized Dosage System.

Comment 4

Justify the omeprazole + semaglutide interaction.

Response:
The discussion now includes pharmacokinetic information from the Summary of Product Characteristics explaining the reduction in semaglutide absorption when multiple tablets are taken simultaneously.

Comment 5

Describe follow-up duration.

Response:
Follow-up performed approximately one month after the intervention confirmed sustained improvement in symptoms without recurrence of urinary incontinence.

Comment 6

Avoid overinterpretation.

Response:
The manuscript conclusions were revised to present findings more cautiously and focus on medication safety improvements.

Comment 7

Tables should follow three-line format.

Response:
All tables have been reformatted according to the three-line table format required by the journal.

Comment 8

Revise conclusion to focus on practical implications.

Response:
The conclusion now emphasizes the role of community pharmacy interventions in detecting medication-related problems and improving safety in polymedicated patients.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Dear Authors,

Thank you. I have reviewed the revised version of the manuscript and must admit that the introduced corrections are satisfactory. However, the manuscript was not submitted in track changes mode, which significantly hindered my ability to assess the revisions.

Unfortunately, it appears that some statements included in the response letter are not reflected in the revised manuscript submitted to the editorial office. For example, the response to Comment 1 does not appear in the manuscript in the indicated section. I suggest completing this accordingly.

I also note an inconsistency: Table 2 classifies both clonazepam-related urinary incontinence and semaglutide-related gastrointestinal symptoms as “Confirmed NOM”, while the Naranjo scores (presented in Tables 3 and 4) indicate only a possible causal relationship (1–4) for both cases. These classifications are contradictory and should be aligned. The most straightforward solution would be to revise Table 2 to “Suspected NOM”.

The remaining comments have been addressed very thoroughly. I also noticed some minor typographical errors; the manuscript would benefit from another careful proofreading or the use of a grammar-check function in a text editor.

In summary, I recommend the manuscript for publication after minor revisions.

Yours sincerely,

Author Response

RESPONSE TO REVIEWER

 

General Response

 

We thank the reviewer for the constructive comments and for the positive evaluation of the revised manuscript. All comments have been carefully considered, and the corresponding modifications have been implemented in the manuscript. The changes introduced have been highlighted in yellow to facilitate their identification. The main revisions are detailed below.

 

Comment 1

Some statements included in the response letter are not reflected in the revised manuscript.

 

Response:

The manuscript has been carefully revised to ensure that all modifications described in the response letter are properly incorporated into the text. In particular, the objective of the study has been explicitly added at the end of the Introduction section, as previously indicated.

 

In addition, the methodological description has been strengthened in the case presentation section by specifying that the intervention was conducted following the methodology proposed by the Community Pharmacy Pharmaceutical Care Forum (AF-FC), including a brief explanation of its structured approach for identifying medication-related problems and negative outcomes associated with medication.

 

Comment 2

Inconsistency between NOM classification and Naranjo algorithm results.

 

Response:

The inconsistency pointed out by the reviewer has been corrected. The classification in Table 2 has been modified from “Confirmed NOM” to “Suspected NOM” in order to align it with the results obtained using the Naranjo algorithm, which indicate a possible causal relationship in both cases.

 

Comment 3

Minor typographical errors.

 

Response:

The manuscript has been carefully proofread to correct minor typographical errors and improve the overall language quality.