Comparison of the efficacy of aescin and diclofenac sodium in the management of postoperative sequelae and their effect on salivary Prostaglandin E2 and serum C–reactive protein levels after surgical removal of impacted mandibular third molar: a randomized, double-blind, controlled clinical trial.

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The postoperative phase is often associated with severe inflammation. Non-steroidal anti-inflammatory drugs (NSAIDs) are usually prescribed to manage postoperative discomfort. NSAIDs have been associated with gastrointestinal bleeding, renal function disturbances, and platelet count reductions. Thus, the present study demonstrates the utility of aescin in managing postoperative discomfort after the surgical removal of impacted mandibular third molars. This study aimed to correlate and compare the impact of aescin and diclofenac on salivary PGE2 levels and serum C-reactive protein levels after surgical extraction of the mandibular third molar. The study will also evaluate and compare the effectiveness of individual drug therapy in managing postoperative pain, swelling and mouth opening. Methods The planned study is a single-center, double-blind, randomized, parallel, prospective clinical trial. Each patient will be prescribed either diclofenac sodium 150 mg/day or aescin (escin) 120 mg/day to be taken orally in divided doses for five days after surgically removing the impacted mandibular third molar. Pain will be assessed using a visual analog scale. Facial swelling and mouth opening will be recorded using a metric scale with standardized reference points. ELISA (enzyme-linked immunosorbent assay (ELISA) will be employed to measure salivary Prostaglandin E2 and serum C–reactive protein levels. All parameters will be recorded preoperatively (T0) on the second postoperative day (T1) and fifth postoperative day (T2). Conclusion The proposed study is expected to show a clinically acceptable response to the administration of aescin for the management of postoperative discomfort compared to diclofenac sodium after third molar surgery. The proposed study is expected to positively manipulate the levels of salivary Prostaglandin E2 and serum C–reactive protein, which are reliable inflammatory markers. The outcome of this study may provide an efficacious and safe alternative to conventional nonsteroidal anti-inflammatory drugs for managing postoperative discomfort following third molar surgery. " } { "@context": "http://schema.org", "@type": "BreadcrumbList", "itemListElement": [ { "@type": "ListItem", "position": "1", "item": { "@id": "https://f1000research.com/", "name": "Home" } }, { "@type": "ListItem", "position": "2", "item": { "@id": "https://f1000research.com/browse/articles", "name": "Browse" } }, { "@type": "ListItem", "position": "3", "item": { "@id": "https://f1000research.com/articles/13-106/v3", "name": "Comparison of the efficacy of aescin and diclofenac sodium in the..." } } ] } Home Browse Comparison of the efficacy of aescin and diclofenac sodium in the... ALL Metrics - Views Downloads Get PDF Get XML Cite How to cite this article Singhai A, Kambala R and Bhola N. Comparison of the efficacy of aescin and diclofenac sodium in the management of postoperative sequelae and their effect on salivary Prostaglandin E2 and serum C–reactive protein levels after surgical removal of impacted mandibular third molar: a randomized, double-blind, controlled clinical trial. [version 3; peer review: 2 approved] . F1000Research 2024, 13 :106 ( https://doi.org/10.12688/f1000research.145643.3 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Study Protocol Revised Comparison of the efficacy of aescin and diclofenac sodium in the management of postoperative sequelae and their effect on salivary Prostaglandin E2 and serum C–reactive protein levels after surgical removal of impacted mandibular third molar: a randomized, double-blind, controlled clinical trial. [version 3; peer review: 2 approved] Anuroop Singhai https://orcid.org/0000-0002-8806-1283 1,2 , Rajanikanth Kambala https://orcid.org/0000-0001-7695-3770 2 , Nitin Bhola 2 Anuroop Singhai https://orcid.org/0000-0002-8806-1283 1,2 , Rajanikanth Kambala https://orcid.org/0000-0001-7695-3770 2 , Nitin Bhola 2 PUBLISHED 30 Oct 2024 Author details Author details 1 Oral Surgery, General Dentistry Program, Batterjee Medical College, Jeddah, Makkah, 21442, Saudi Arabia 2 Oral and Maxillofacial Surgery, Datta Meghe Institute of Higher Education and Research, Wardha, Maharashtra, 442001, India Anuroop Singhai Roles: Conceptualization, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Rajanikanth Kambala Roles: Supervision, Validation Nitin Bhola Roles: Validation OPEN PEER REVIEW DETAILS REVIEWER STATUS This article is included in the Datta Meghe Institute of Higher Education and Research collection. Abstract Introduction Surgical removal of an impacted third molar is one of the most common oral surgical procedures performed in dental offices. The postoperative phase is often associated with severe inflammation. Non-steroidal anti-inflammatory drugs (NSAIDs) are usually prescribed to manage postoperative discomfort. NSAIDs have been associated with gastrointestinal bleeding, renal function disturbances, and platelet count reductions. Thus, the present study demonstrates the utility of aescin in managing postoperative discomfort after the surgical removal of impacted mandibular third molars. This study aimed to correlate and compare the impact of aescin and diclofenac on salivary PGE2 levels and serum C-reactive protein levels after surgical extraction of the mandibular third molar. The study will also evaluate and compare the effectiveness of individual drug therapy in managing postoperative pain, swelling and mouth opening. Methods The planned study is a single-center, double-blind, randomized, parallel, prospective clinical trial. Each patient will be prescribed either diclofenac sodium 150 mg/day or aescin (escin) 120 mg/day to be taken orally in divided doses for five days after surgically removing the impacted mandibular third molar. Pain will be assessed using a visual analog scale. Facial swelling and mouth opening will be recorded using a metric scale with standardized reference points. ELISA (enzyme-linked immunosorbent assay (ELISA) will be employed to measure salivary Prostaglandin E2 and serum C–reactive protein levels. All parameters will be recorded preoperatively (T0) on the second postoperative day (T1) and fifth postoperative day (T2). Conclusion The proposed study is expected to show a clinically acceptable response to the administration of aescin for the management of postoperative discomfort compared to diclofenac sodium after third molar surgery. The proposed study is expected to positively manipulate the levels of salivary Prostaglandin E2 and serum C–reactive protein, which are reliable inflammatory markers. The outcome of this study may provide an efficacious and safe alternative to conventional nonsteroidal anti-inflammatory drugs for managing postoperative discomfort following third molar surgery. READ ALL READ LESS Keywords Aescin, Diclofenac, pain, swelling, C-reactive protein, prostaglandin E2, third molar Corresponding Author(s) Anuroop Singhai ( [email protected] ) Close Corresponding author: Anuroop Singhai Competing interests: No competing interests were disclosed. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2024 Singhai A et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Singhai A, Kambala R and Bhola N. Comparison of the efficacy of aescin and diclofenac sodium in the management of postoperative sequelae and their effect on salivary Prostaglandin E2 and serum C–reactive protein levels after surgical removal of impacted mandibular third molar: a randomized, double-blind, controlled clinical trial. [version 3; peer review: 2 approved] . F1000Research 2024, 13 :106 ( https://doi.org/10.12688/f1000research.145643.3 ) First published: 16 Feb 2024, 13 :106 ( https://doi.org/10.12688/f1000research.145643.1 ) Latest published: 30 Oct 2024, 13 :106 ( https://doi.org/10.12688/f1000research.145643.3 ) Revised Amendments from Version 2 The following sections of the article have been updated: 1. Trial Design 2. Inclusion Criteria 3. Discussion 4. References The following sections of the article have been updated: 1. Trial Design 2. Inclusion Criteria 3. Discussion 4. References See the authors' detailed response to the review by Gaetano Isola See the authors' detailed response to the review by Ahmed Saaduddin READ REVIEWER RESPONSES Introduction Background and rationale The backbone of most oral surgical practices worldwide is the extraction of impacted third molars. It is the most common oral surgical procedure 1 performed in dental offices. However, the postoperative phase is often concomitant with severe pain, reduced mouth opening, and marked facial inflammation. Most patients are prescribed corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs) to manage their postoperative discomfort. NSAIDS have been associated with gastrointestinal bleeding, disturbance in renal function, and a reduction in platelet count. 2 Certain newer NSAIDs like lornoxicam have been evaluated for their efficacy in managing pain after third molar surgery due to lesser incidences of gastrointestinal lesions as compared to other NSAIDs. 3 However, this untoward still poses a challenge to clinicians. Because of these limitations, many phytotherapeutic alternatives have been suggested. Aescin (Escin) has generated interest among researchers over the years. It is a practical part of Aesculus hippocastanum and was first isolated in 1953. It combines triterpene saponins and has demonstrated anti-inflammatory, antiedematous, and venotonic properties in various preparations. 4 Thus, the present study demonstrates the utility of aescin in managing postoperative discomfort after the surgical removal of impacted mandibular third molars. Another concern over the years has been the selection of NSAIDs, which predominantly depends on subjective factors, including the surgeon’s preference and personal experience. The need for an hour is to use a measurable marker of inflammation that can be quantitatively controlled by drug administration. Prostaglandin E2 (PGE2) is a reliable marker of inflammation, which has been isolated from various body fluids, including saliva. 5 Owing to inflammation, C-reactive protein (CRP) emerges in the blood. Various studies have used CRP concentrations to monitor the healing process after drug therapy because of its sensitivity. 6 This study aimed to correlate salivary PGE2 levels and serum C-reactive protein levels with subjective and objective symptoms after surgical extraction of the mandibular third molar and their relationship with therapeutic use of aescin and diclofenac. The objectives of the study is to compare the efficacy of aescin and diclofenac for managing pain, swelling, mouth opening and the need for rescue analgesics. The study will also evaluate the patient satisfaction regarding each drug therapy. Background and rationale: choice of comparators Diclofenac was chosen for comparison because it has dose equivalence to aescin and is widely used to manage postoperative sequelae associated with third molar surgery. Protocol Aim of the study To compare the efficacy of aescin (escin) and diclofenac in managing postoperative sequelae following surgical removal of impacted mandibular third molars and their effects on salivary Prostaglandin E2 and serum C-reactive protein levels. Objectives The objectives of the present study are as follows: 1. To compare the efficacy of aescin and diclofenac sodium in managing postoperative sequelae following surgical removal of impacted mandibular third molars. 2. To compare the efficacy of aescin and diclofenac sodium in manipulating salivary Prostaglandin E2 (PGE2) and serum C-reactive protein (CRP) levels in patients undergoing surgical removal of the impacted mandibular third molar. 3. To assess patient satisfaction regarding therapy. 4. To evaluate the need for rescue analgesics in the postoperative period. Trial design A single-center, double-blind, randomized, parallel, prospective clinical trial will be conducted at the Sharad Pawar Dental College, Datta Meghe Institute of Higher Education and Research (DMIHER), Sawangi, Wardha. Two groups will be created: Group A – Diclofenac sodium Group B – Aescin (escin) The randomization process will be performed using a computer-generated subject allocation list. Trial participants and outcome assessors will be blinded. The study will be a double-blinded clinical trial where the participant and the principal investigator will not be aware of the drug being used in the postoperative period. The double-blinded study minimizes the risk of various types of biases, such as observer bias or confirmation bias, which may influence the results of the investigation. Study setting A total of 50 patients presenting to the outpatient department of oral and maxillofacial surgery, Sharad Pawar Dental College and Hospital, Sawangi, Wardha, India, with impacted mandibular third molars with a definitive indication for extraction will be enrolled in the study. Eligibility criteria Inclusion criteria 1. Patients giving informed written consent. 2. Age group 18-40 yrs. The age range is selected to have homogeneity, reduced comorbidities, relevance to the target population and better baseline functionality. 3. ASA I and healthy ASA II physical status. 4. Patients presenting with impacted mandibular third molars that are indicated for removal. 5. Slightly or moderately difficult impacted mandibular third molars, according to the Pederson difficulty index with the difficulty score in the range of 3 to 7. Exclusion criteria 1. Presence of oral mucosal comorbid conditions that may affect salivary inflammatory markers. 2. Patients not reporting for follow-up as per study protocol. 3. Presence of systemic infections that may alter the levels of serum C-reactive protein. 4. Presence of acute infection that necessitates the use of antibiotic therapy. 5. Known allergies to drugs under study and local anesthetic agents. 6. Patients with a history of xerostomia or hypersalivation. Methods Interventions: description A clinical trial will be conducted with approval from the institutional ethics committee. The Consolidated Standards of Reporting Trials (CONSORT) statement guidelines will be used for this study. Patients will be prescribed either diclofenac sodium 150 mg/day or aescin (escin) 120 mg/day 7 to be taken orally in divided doses for five days. Each patient will be subjected to one of the drugs after the procedure. Saliva collection will be done using a sterile polystyrene tube. A kit specific to PGE2 will be used to measure PGE2 levels in each specimen. 5 Venous blood will be subjected to a C-reactive protein (CRP) test to measure C-reactive protein 8 levels in blood serum. Saliva and serum samples will be processed in Central Research Laboratory. Surgical procedure All patients will be administered 1 g of oral amoxicillin 1 h before the procedure. The standard surgical protocol for the removal of impacted mandibular third molars under local anesthesia will be followed. Interventions: modifications Drug therapy will be discontinued in cases of adverse reactions reported by the patient. Interventions: adherence Patients will be recalled on the second and fifth postoperative days. The number of tablets remaining will be calculated to assess compliance with the trial protocol. Interventions: concomitant care Patients will be required to adhere to the standard postoperative instructions following extraction. Tramadol 50 mg will be prescribed as a rescue analgesic for the postoperative period. Outcomes Postoperative sequelae after surgical removal of the impacted mandibular third molar will be estimated by assessing pain, facial swelling, and mouth opening. Pain: The visual analog scale (VAS) 9 will be used to assess pain on a scale ranging from 0 to 10. The worst imaginable pain will be graded as 10, and the absence of pain will be graded as 0. Facial swelling will be measured using a metric tape and standard reference points. 7 The following reference points will be used for the measurement: • Soft tissue pogonion - Tragus • The angle of the mandible - Corner of the eye • Corner of mouth - Tragus Mouth opening: The maximum interincisal distance will be recorded using a metric scale with standardized ruler and a digital Vernier caliper. 10 Salivary Prostaglandin E2 and serum C-reactive protein levels will be measured by ELISA (enzyme-linked immunosorbent assay (ELISA) preoperatively (T0) on the second postoperative day (T1) and fifth postoperative day (T2). Patient satisfaction regarding therapy: Study subjects will classify their experience from 1 to 5, where 1 = poor, 2 = fair, 3 = good, 4 = very good, and 5 = excellent. The need for rescue analgesics will be evaluated by counting the number of tramadol capsules or tablets required by the patient until the fifth postoperative day (T2). Participant timeline Pain, facial swelling, mouth opening, serum C-reactive protein, and salivary prostaglandin E2 levels will be recorded preoperatively (T0) on the second postoperative day (T1) and fifth postoperative day (T2). Patient satisfaction regarding therapy and the need for rescue analgesics will be recorded on the fifth postoperative day. Sample size The study will be a non-inferiority trial with a continuous outcome. The sample size was established based on data obtained from a previous study conducted by Salgia et al. 11 Serum C-reactive protein level was chosen as the primary outcome variable. Formula using mean difference n 1 = n 2 = 2 Z α + Z β 2 σ 2 δ 2 Z α = 1.96 α = Type I error at 5% at both sides two tailed Z β = 0.84 = Power at 80% Primary Variable = CRP (C-reactive protein) levels The mean difference after treatment CRP (mean ± SD) for the diclofenac group was 16.305 ± 3.977 (as per the reference article). 10 Considering 20% clinically relevant margin for aescin = ( 16.305 ∗ 20 ) / 100 = 3.26 Sample size: N = n 1 = n 2 = 2 1.96 + 0.84 2 3.977 2 3.261 2 = 23 Assuming 10% dropout = 2 Total sample size required = 23 + 2 = 25 each group. Thus, a total sample size of 50 subjects presenting with impacted mandibular third molars will be enrolled in the study. Recruitment All patients presenting to the outpatient unit of the Oral and Maxillofacial Department and fulfilling the enrolment criteria of the study will be recruited. The principal investigator coordinated with each patient to achieve the desired sample size. Methods: Assignment of interventions (for controlled trials) Allocation: sequence generation Study participants will be randomized using the SCIENCER application. As a specific age range was chosen for the study, further stratification and subset creation will not be performed. Allocation concealment mechanism All the patients will be sequentially numbered for the purpose of allocation concealment. Allocation: implementation The principal investigator will then enrol the participants. The research supervisor allocate the sequence and assign the participants to the intervention. Blinding Trial participants and the principal investigator will be blinded. Blinding (masking): emergency unblinding Unblinding will be performed if a patient reports adverse side effects to the emergency unit during the follow-up period. Data collection plan Demographic, clinical, and laboratory data for each patient will be collected using the JOTFORM application. Data collection plan: retention Telephonic reminders will be administered to each patient, according to the follow-up protocol. The research supervisor will directly dispense medication to the participants to promote retention. Data management Demographic, clinical, and laboratory data will be segregated in the JOTFORM application based on patient codes. The filtered data will be downloaded and stored in an Excel spreadsheet for statistical analysis. Statistical analysis plan Statistics: outcomes Statistics: additional analyses Statistics: analysis population and missing data Primary variable Inferential statistics will be used to compare the two groups for measurement scores, resulting in their mean change in a primary variable (visual analog scale, facial swelling, mouth opening, salivary prostaglandin E2, serum C-reactive protein) between baseline and end visits. Baseline variables will be tested for significance in the mean using ANOVA or Kruskal-Wallis test for more than two assessment periods. A post-hoc (Tukey’s or Duncan’s) test will be used to find a significant difference between the two groups for pair-wise comparison. Outcome variables Outcome variables will be tested for intra-difference in measurement at pre- and post-visits using a paired t-test to determine the mean’s significance. The unpaired t-test for comparison of two groups and ANOVA for comparison of three groups will be used for intergroup differences. Statistical analysis will be carried out using R-software free version. Methods: monitoring Data monitoring: formal committee Data monitoring will be carried out under the aegis of DSCC at DMIHER, Sawangi, and Wardha. Data monitoring: interim analysis The interim analysis and review will be carried out by a member of the institutional ethics committee. Trial termination rights were reserved by the Institutional Ethical Committee. Harms Telephonic conversations will be conducted prior to follow-up visits to inquire about any untoward events. In case of any adverse events, patients will be managed at the institutional hospital, and the necessary care will be rendered free of cost. All adverse events will be reported to the Institutional Ethical Committee. Auditing An interim audit of the trial will be conducted by the research supervisor. A final audit will be carried out by nominated members of the DSCC at the DMIHER, Sawangi, and Wardha. Ethics and dissemination Research ethics approval Ethical approval has been obtained from the Institutional Review Board of the Datta Meghe Institute of Medical Sciences (now renamed as Datta Meghe Institute of Higher Education and Research) Sawangi, Wardha. (Reference number: DMIMS (DU)/IEC/2022/842 on 05/04/2022). Protocol amendments Amendments to the protocol will be carried out only after approval from the Institutional Ethical Committee and DSCC at DMIHER, Sawangi, Wardha. Consent or assent The Principal investigator will be required to answer any queries by the patient regarding the trial, and will be responsible for obtaining informed consent. Consent or assent: ancillary studies No biological specimen will be stored for ancillary studies and hence, ancillary study consent is not applicable. Confidentiality Access to information from individual participants will be restricted to the principal investigator and research supervisor. Declaration of interests There are no financial or competing interests for the principal investigators for the overall trial or each study site. Data access The principal investigator and research supervisor will be custodian of the final trial data. The IEC and DSCC have access to the final trial dataset. Ancillary and post-trial care The trial will be conducted in accordance with good clinical practice and a strong adverse event-monitoring protocol. The safety of the procedures and drugs used in this study has been established. However, in case of any harm, compensation will be carried out according to institutional policy. Dissemination policy: trial results This clinical trial will be published as an original research article in an indexed journal. Open access release of the trial results will be performed to ensure optimum exposure of the scientific community. Dissemination policy: authorship The final trial data will be published as postdoctoral research (PHD thesis). The authorship associated with this trial will be limited to the principal investigator and research supervisor, with acknowledgements to individuals involved at various stages of the trial. Dissemination policy: reproducible research The PHD thesis will be made public after approval from DSCC. Study status The study is currently in the stage of a pilot project. Discussion There is growing interest in medical fraternity to find safer alternatives to NSAIDs. Despite advances in pharmaceutical technology, the pharmacokinetic properties of NSAIDs, such as diclofenac, have improved, however the dose-dependent gastrointestinal severe, renal, and cardiovascular adverse effects remain a cause of concern with the use of NSAIDs. Previous studies have indicated that phytotherapeutic drugs have a favorable impact on inflammatory parameters and are safe for managing pain and discomfort following surgical removal of the third molar. Aescin (escin) is a phytotherapeutic drug that has been recognized for its anti-inflammatory properties. Previous studies have also suggested the glucocorticoid-like activity of aescin along with its gastroprotective action. However, further research is needed to examine the effectiveness of aescin in managing postoperative pain, facial swelling, and mouth opening following surgical removal of the third molar. Isola et al. (2024) conducted a parallel-arm, randomised clinical trial on forty-two periodontitis patients to compare the outcome of minimally invasive non-surgical therapy (MINST) with quadrant-wise subgingival instrumentation (Q-SI) on C-reactive protein (CRP) and lipoprotein-associated phospholipase A2 (Lp-PLA2) levels, and their association with clinical implications. The study suggested that lower levels of C-reactive protein and Lp-PLA2 were seen in patients receiving MINST after 1-year follow-up. 12 Marciano et al. (2024) present a compelling narrative review that elucidates the remarkable clinical benefits of aescin in modulating the bradykinin pathway. They draw attention to a critical gap in scientific literature, noting a scarcity of human studies on aescin’s effects. Alarmingly, no comparative research has been conducted between aescin—a natural compound—and the mentioned nutraceuticals. Overall, aescin stands out as a drug with an impressive safety profile and versatile pharmacodynamics, positioning it for optimal anti-inflammatory and anti-edema effects through bradykinin pathway suppression. However, to fully unlock its potential, robust human studies are essential to assess aescin’s impact on bradykinin. 13 Singh et al. (2021) conducted a study on 90 patients that aimed to compare the efficacy of diclofenac sodium and mefenamic acid in managing pain after mandibular impacted third molar surgery and to assess changes in C-reactive protein (CRP) levels as an inflammation marker. The study involved surgical removal using standardized procedures, with patients divided into two groups: one receiving diclofenac sodium (50 mg) and the other mefenamic acid (500 mg) for three days. Pain was evaluated using the visual analog scale (VAS), revealing a mean VAS of 2.58 for diclofenac and 3.46 for mefenamic acid (p < 0.05). Postoperative CRP levels increased significantly in both groups. However, diclofenac showed lower CRP levels compared to mefenamic acid. The findings suggested that diclofenac sodium is effective for pain relief and that CRP evaluation can serve as a useful indicator of postoperative inflammation. 14 Nowak et al. (2021) conducted a study of 60 patients to assess the impact of A-PRF application during third molar surgery and its effect on C-reactive protein concentrations and wound healing. Patients who received A-PRF after the procedure had a faster rate of decreased CRP levels. They also suggested that A-PRF application significantly reduced the symptoms of regional inflammation and incidence of dry socket. 6 In a detailed review of escin, Gallelli (2019) suggested that it has potent anti-inflammatory, antiedematous, venotonic, and endothelial protective properties. They described the basic mechanism of action of escin. Oral escin and its topical gel have been demonstrated to increase venous tone and reduce edema, resulting in quantifiable clinical progress in patients with blunt injury and chronic venous insufficiency. 4 Isola et al. (2018) conducted a clinical trial of eighty-two patients needing mandibular third molar extraction surgery. The study participants were randomly allocated into three groups. Group 1, placebo; Group 2, ibuprofen; Group 3, a phytotherapeutic drug (baicalin 190 mg, bromelain 50 mg, and escin 30 mg). All medications were prescribed twice daily for five days after tooth extraction. A visual analog scale was used to assess pain. A metric scale was used to record alterations in facial contours and mouth opening in millimeters. The outcome of this clinical trial implies that phytotherapeutic drug therapy effectively manages postoperative pain and discomfort. 9 Graziani et al. (2017) enrolled 40 patients in a case-control study demonstrating systemic inflammation following third molar removal. Patients who underwent third molar removal had more significant systemic inflammation, oxidative stress, and triglyceride levels than controls, and the first postoperative week had increased WBC counts and serum C-reactive protein and fibrinogen levels. The baseline values of the markers were observed three months after extraction. Higher systemic inflammation is associated with impacted third molars, and their elimination may signify a novel method for investigating acute inflammation and defining favorable systemic outcomes in humans. 8 Mehra et al. (2013) conducted a double-blind, randomized clinical trial of 80 patients to assess the effect of four different pharmacological regimens on prostaglandin E2 (PGE2) levels in urine and saliva. Saliva and urine samples were collected at planned intervals. After removing the impacted lower third molars, the findings were compared with clinical progression. Patients who received ibuprofen fared significantly better in terms of most parameters. They further concluded that PGE2 is measurable in saliva and urine, and its rise and fall can be detected in both saliva and urine. They further suggested that PGE2 correlates with subjective and objective clinical symptomatology and that administration of anti-inflammatory drugs manipulates its levels in the body. 5 The current scientific literature must be more extensive in demonstrating the correlation of the drug’s efficacy with reliable inflammation markers and associated clinical symptomatology. Considering this, the present study will be a randomized, double-blind, non-inferiority trial to compare the efficacy of aescin and diclofenac sodium in the management of postoperative pain, swelling, and mouth opening, as well as their effects on salivary Prostaglandin E2 and serum C-reactive protein levels after surgical removal of the impacted mandibular third molar. The trial will be conducted as per SPIRIT guidelines. 15 In conclusion, the proposed study is expected to positively manipulate the levels of salivary Prostaglandin E2 and serum C–reactive protein, which are reliable inflammatory markers. The study may show clinically acceptable responses in the management of postoperative pain, swelling and mouth opening with administration of aescin. The outcome of this study may provide an efficacious and safe alternative to conventional nonsteroidal anti-inflammatory drugs for managing postoperative discomfort following third molar surgery. Trial registration www.ctri.nic.in Trial Registration Number is: CTRI/2023/09/058004 Trial registration: data set Not applicable Protocol version v1 dated 26/07/2023 Identifier: Dr. Rajanikanth Kambala Roles and responsibilities: sponsor and funder Study planning, data collection, research management, analysis, preparation of report and publication Roles and responsibilities: committees The study will be carried out under the aegis of the Institutional Ethical Committee and the DSCC at DMIHER, Sawangi, Wardha, Maharashtra, India. Data availability No data is associated with this article. Extended data Zenodo: Extended data sheet for “Comparison of the efficacy of aescin and diclofenac sodium in the management of postoperative sequelae and their effect on salivary Prostaglandin E2 and serum C–reactive protein levels after surgical removal of impacted mandibular third molars: a randomized, double-blind, controlled clinical trial.”. Zenodo. https://doi.org/10.5281/zenodo.10605612 . 15 This project contains the following extended data: • Model Consent form • Biological specimen • Patient Case Record form Reporting guidelines Zenodo: SPIRIT checklist for “Comparison of the efficacy of aescin and diclofenac sodium in the management of postoperative sequelae and their effect on salivary Prostaglandin E2 and serum C–reactive protein levels after surgical removal of impacted mandibular third molars: a randomized, double-blind, controlled clinical trial.” https://doi.org/10.5281/zenodo.10605565 . 16 Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0). References 1. Brkovic B, Andric M, Calasan D, et al. : Efficacy and safety of 1% ropivacaine for postoperative analgesia after lower third molar surgery: a prospective, randomized, double-blind clinical study. Clin. Oral Investig. 2017; 21 : 779–785. PubMed Abstract | Publisher Full Text 2. Piecuch JF: What strategies are helpful in the operative management of third molars? J. Oral Maxillofac. Surg. 2012; 70 (9 Suppl 1): S25–S32. PubMed Abstract | Publisher Full Text 3. Isola G, Alibrandi A, Pedullà E, et al. : Analysis of the Effectiveness of Lornoxicam and Flurbiprofen on Management of Pain and Sequelae Following Third Molar Surgery: A Randomized, Controlled, Clinical Trial. J. Clin. Med. 2019; 8 (3): 325. PubMed Abstract | Publisher Full Text | Free Full Text 4. Gallelli L: Escin: a review of its anti-edematous, anti-inflammatory, and venotonic properties. Drug Des. Devel. Ther. 2019; 13 : 3425–3437. PubMed Abstract | Publisher Full Text | Free Full Text 5. Mehra P, Reebye U, Nadershah M, et al. : Efficacy of anti-inflammatory drugs in third molar surgery: a randomized clinical trial. Int. J. Oral Maxillofac. Surg. 2013; 42 (7): 835–842. Publisher Full Text 6. Nowak JM, Surma S, Romańczyk M, et al. : Assessment of the Effect of A-PRF Application during the Surgical Extraction of Third Molars on Healing and the Concentration of C-Reactive Protein. Pharmaceutics. 2021; 13 (9): 1471. PubMed Abstract | Publisher Full Text | Free Full Text 7. Landim FS, Filho JRL, Nascimento J, et al. : Effectiveness of nicotine patch for the control of pain, oedema, and trismus following third molar surgery: a randomized clinical trial. Int. J. Oral Maxillofac. Surg. 2020; 49 (11): 1508–1517. PubMed Abstract | Publisher Full Text 8. Graziani F, D’Aiuto F, Gennai S, et al. : Systemic Inflammation after Third Molar Removal: A Case-Control Study. J. Dent. Res. 2017; 96 (13): 1505–1512. PubMed Abstract | Publisher Full Text 9. Isola G, Matarese M, Ramaglia L, et al. : Efficacy of a drug composed of herbal extracts on postoperative discomfort after surgical removal of impacted mandibular third molar: a randomized, triple-blind, controlled clinical trial. Clin. Oral Investig. 2019; 23 (5): 2443–2453. PubMed Abstract | Publisher Full Text 10. Ali AA, Belgasem KA: Maximum Mouth Opening among Libyan Population. J. Oral Health Dent. Sci. 2021; 5 : 102–109. 11. Salgia G, Kulkarni DG, Shetty L: C-reactive protein estimation: A quantitative analysis for three nonsteroidal anti-inflammatory drugs: A randomized control trial. Indian J. Dent. Res. 2015; 26 : 43–47. PubMed Abstract | Publisher Full Text 12. Isola G, Pesce P, Polizzi A, et al. : Effects of minimally invasive non-surgical therapy on C-reactive protein, lipoprotein-associated phospholipase A 2 , and clinical outcomes in periodontitis patients: A 1-year randomized, controlled clinical trial. J. Periodontol. 2024. Epub ahead of print. PubMed Abstract | Publisher Full Text 13. Marcianò G, Vocca C, Dıraçoğlu D, et al. : Escin’s Action on Bradykinin Pathway: Advantageous Clinical Properties for an Unknown Mechanism? Antioxidants (Basel). 2024; 13 (9). Publisher Full Text 14. Singh R, Jayam C, Singh R, et al. : Assessment of C-reactive Protein Level and Efficacy of Diclofenac Sodium and Mefenamic Acid in Relieving Pain in Mandibular Impacted Third Molar Surgery. J. Contemp. Dent. Pract. 2021; 22 (1): 39–41. PubMed Abstract | Publisher Full Text 15. Singhai A: Extended data sheet for “Comparison of the efficacy of aescin and diclofenac sodium in the management of postoperative sequelae and their effect on salivary Prostaglandin E2 and serum C–reactive protein levels after surgical removal of impacted mandibular third molars: a randomized, double-blind, controlled clinical trial.”. Zenodo. 2024. Publisher Full Text 16. Singhai A: SPIRIT checklist for “Comparison of the efficacy of aescin and diclofenac sodium in the management of postoperative sequelae and their effect on salivary Prostaglandin E2 and serum C–reactive protein levels after surgical removal of impacted mandibular third molar: a randomized, double-blind, controlled clinical trial.”. Zenodo. 2023. Publisher Full Text Comments on this article Comments (0) Version 3 VERSION 3 PUBLISHED 16 Feb 2024 ADD YOUR COMMENT Comment Author details Author details 1 Oral Surgery, General Dentistry Program, Batterjee Medical College, Jeddah, Makkah, 21442, Saudi Arabia 2 Oral and Maxillofacial Surgery, Datta Meghe Institute of Higher Education and Research, Wardha, Maharashtra, 442001, India Anuroop Singhai Roles: Conceptualization, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Rajanikanth Kambala Roles: Supervision, Validation Nitin Bhola Roles: Validation Competing interests No competing interests were disclosed. Grant information The author(s) declared that no grants were involved in supporting this work. Article Versions (3) version 3 Revised Published: 30 Oct 2024, 13:106 https://doi.org/10.12688/f1000research.145643.3 version 2 Revised Published: 07 Jun 2024, 13:106 https://doi.org/10.12688/f1000research.145643.2 version 1 Published: 16 Feb 2024, 13:106 https://doi.org/10.12688/f1000research.145643.1 Copyright © 2024 Singhai A et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Singhai A, Kambala R and Bhola N. Comparison of the efficacy of aescin and diclofenac sodium in the management of postoperative sequelae and their effect on salivary Prostaglandin E2 and serum C–reactive protein levels after surgical removal of impacted mandibular third molar: a randomized, double-blind, controlled clinical trial. [version 3; peer review: 2 approved] . F1000Research 2024, 13 :106 ( https://doi.org/10.12688/f1000research.145643.3 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 3 VERSION 3 PUBLISHED 30 Oct 2024 Revised Views 0 Cite How to cite this report: Isola G. Reviewer Report For: Comparison of the efficacy of aescin and diclofenac sodium in the management of postoperative sequelae and their effect on salivary Prostaglandin E2 and serum C–reactive protein levels after surgical removal of impacted mandibular third molar: a randomized, double-blind, controlled clinical trial. [version 3; peer review: 2 approved] . F1000Research 2024, 13 :106 ( https://doi.org/10.5256/f1000research.173977.r336513 ) The direct URL for this report is: https://f1000research.com/articles/13-106/v3#referee-response-336513 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 06 Nov 2024 Gaetano Isola , University of Catania, Catania, Italy Approved VIEWS 0 https://doi.org/10.5256/f1000research.173977.r336513 The authors have well modified the protocol based on the issues ... Continue reading READ ALL The authors have well modified the protocol based on the issues raised by the reviewer. The protocol can be indexed in this form. Competing Interests: No competing interests were disclosed. Reviewer Expertise: Oral surgery, periodontitis I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Isola G. Reviewer Report For: Comparison of the efficacy of aescin and diclofenac sodium in the management of postoperative sequelae and their effect on salivary Prostaglandin E2 and serum C–reactive protein levels after surgical removal of impacted mandibular third molar: a randomized, double-blind, controlled clinical trial. [version 3; peer review: 2 approved] . F1000Research 2024, 13 :106 ( https://doi.org/10.5256/f1000research.173977.r336513 ) The direct URL for this report is: https://f1000research.com/articles/13-106/v3#referee-response-336513 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Saaduddin A. Reviewer Report For: Comparison of the efficacy of aescin and diclofenac sodium in the management of postoperative sequelae and their effect on salivary Prostaglandin E2 and serum C–reactive protein levels after surgical removal of impacted mandibular third molar: a randomized, double-blind, controlled clinical trial. [version 3; peer review: 2 approved] . F1000Research 2024, 13 :106 ( https://doi.org/10.5256/f1000research.173977.r336514 ) The direct URL for this report is: https://f1000research.com/articles/13-106/v3#referee-response-336514 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 05 Nov 2024 Ahmed Saaduddin , Mansoura University, Mansoura, Egypt Approved VIEWS 0 https://doi.org/10.5256/f1000research.173977.r336514 I appreciate the efforts of the authors in addressing the feedback from the initial review. Your revisions have significantly strengthened the overall clarity and impact of the paper. I was particularly impressed by the following improvements: ... Continue reading READ ALL I appreciate the efforts of the authors in addressing the feedback from the initial review. Your revisions have significantly strengthened the overall clarity and impact of the paper. I was particularly impressed by the following improvements: Expanded discussion : The inclusion of recent studies enhances the context of your work and demonstrates a thorough engagement with existing literature. This addition enriches your arguments and positions your research within the current discourse. Methodological rigour : The clarifications regarding your methodology address earlier concerns and add credibility to your objectives. It is now evident how your approach effectively supports your conclusions. Overall, I am satisfied with the revisions made and believe the article is now ready for indexing. I commend your responsiveness to feedback and your commitment to enhancing the quality of your work. Competing Interests: No competing interests were disclosed. Reviewer Expertise: I am an Oral and Maxillofacial Surgeon whose primary research is in the field of minor oral surgery, clinical implantology and dental traumatology. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Saaduddin A. Reviewer Report For: Comparison of the efficacy of aescin and diclofenac sodium in the management of postoperative sequelae and their effect on salivary Prostaglandin E2 and serum C–reactive protein levels after surgical removal of impacted mandibular third molar: a randomized, double-blind, controlled clinical trial. [version 3; peer review: 2 approved] . F1000Research 2024, 13 :106 ( https://doi.org/10.5256/f1000research.173977.r336514 ) The direct URL for this report is: https://f1000research.com/articles/13-106/v3#referee-response-336514 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Version 2 VERSION 2 PUBLISHED 07 Jun 2024 Revised Views 0 Cite How to cite this report: Saaduddin A. Reviewer Report For: Comparison of the efficacy of aescin and diclofenac sodium in the management of postoperative sequelae and their effect on salivary Prostaglandin E2 and serum C–reactive protein levels after surgical removal of impacted mandibular third molar: a randomized, double-blind, controlled clinical trial. [version 3; peer review: 2 approved] . F1000Research 2024, 13 :106 ( https://doi.org/10.5256/f1000research.167297.r332167 ) The direct URL for this report is: https://f1000research.com/articles/13-106/v2#referee-response-332167 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 24 Oct 2024 Ahmed Saaduddin , Mansoura University, Mansoura, Egypt Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.167297.r332167 Objectives The authors have clearly defined objectives with a focus on both subjective (pain, satisfaction) and objective (PGE2, CRP levels) outcomes. Including additional patient-reported outcomes, such as satisfaction with therapy. Study Design The protocol outlines ... Continue reading READ ALL Objectives The authors have clearly defined objectives with a focus on both subjective (pain, satisfaction) and objective (PGE2, CRP levels) outcomes. Including additional patient-reported outcomes, such as satisfaction with therapy. Study Design The protocol outlines a single-center, double-blind, randomized, parallel, prospective clinical trial, which is appropriate for this type of comparative study. The use of a non-inferiority design is justified, especially since the aim is to assess aescin as a safer alternative to diclofenac. Methods Participants: The inclusion and exclusion criteria are comprehensive. However, the rationale for the age restriction (18-40 years) should be elaborated. Why not include a broader age range? Randomization and Blinding: The randomization process using a computer-generated allocation is a robust method. However, further details on the blinding process (e.g., how blinding will be maintained) would add clarity. Discussion and Literature Review The literature review provides good context for the study, though the author can add suggested references that are more current and directly related to the specific outcomes being measured. Overall, Clarity and Structure The protocol is well-structured and generally clear. However, it could benefit from adding the appropriate responses to the queries raised in the above sections. Is the rationale for, and objectives of, the study clearly described? Yes Is the study design appropriate for the research question? Yes Are sufficient details of the methods provided to allow replication by others? Partly Are the datasets clearly presented in a useable and accessible format? Not applicable References 1. Singh R, Jayam C, Singh R, Nazeer J, et al.: Assessment of C-reactive Protein Level and Efficacy of Diclofenac Sodium and Mefenamic Acid in Relieving Pain in Mandibular Impacted Third Molar Surgery. J Contemp Dent Pract . 2021; 22 (1): 39-41 PubMed Abstract 2. Marcianò G, Vocca C, Dıraçoğlu D, Sevgin RÖ, et al.: Escin's Action on Bradykinin Pathway: Advantageous Clinical Properties for an Unknown Mechanism?. Antioxidants (Basel) . 2024; 13 (9). PubMed Abstract | Publisher Full Text Competing Interests: No competing interests were disclosed. Reviewer Expertise: I am an Oral and Maxillofacial Surgeon whose primary research is in the field of minor oral surgery, clinical implantology and dental traumatology. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Saaduddin A. Reviewer Report For: Comparison of the efficacy of aescin and diclofenac sodium in the management of postoperative sequelae and their effect on salivary Prostaglandin E2 and serum C–reactive protein levels after surgical removal of impacted mandibular third molar: a randomized, double-blind, controlled clinical trial. [version 3; peer review: 2 approved] . F1000Research 2024, 13 :106 ( https://doi.org/10.5256/f1000research.167297.r332167 ) The direct URL for this report is: https://f1000research.com/articles/13-106/v2#referee-response-332167 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 30 Oct 2024 Anuroop Singhai , Oral and Maxillofacial Surgery, Datta Meghe Institute of Higher Education and Research, Wardha, 442001, India 30 Oct 2024 Author Response Dear Dr. Ahmed Thank you for your insightful comments and constructive feedback on our manuscript. We appreciate the time you took to evaluate our study, and we have addressed your ... Continue reading Dear Dr. Ahmed Thank you for your insightful comments and constructive feedback on our manuscript. We appreciate the time you took to evaluate our study, and we have addressed your points as follows: Participants: Thank you for highlighting the need for clarification regarding our age restrictions. We have elaborated on this rationale in the revised manuscript, explaining that our focus on the 18-40 age range is intended to minimize variability related to age-related physiological differences and comorbidities that could affect the study outcomes. Randomization and Blinding: We acknowledge that additional details on our blinding process would enhance clarity. We have included a more thorough explanation of how blinding will be maintained throughout the study to ensure the integrity of the results. Discussion and Literature Review: We appreciate your feedback on the literature review. We have incorporated the studies suggested by you in the discussion section in our study to provide a stronger context for our findings. Thank you for your positive remarks regarding the clarity and structure of our protocol. We have tried to address all queries appropriately in the revised manuscript. We believe that these revisions will strengthen our manuscript and better address the valuable concerns you have raised. Thank you once again for your thorough review and support in improving our work. We look forward to submitting our revised manuscript for your consideration. Dear Dr. Ahmed Thank you for your insightful comments and constructive feedback on our manuscript. We appreciate the time you took to evaluate our study, and we have addressed your points as follows: Participants: Thank you for highlighting the need for clarification regarding our age restrictions. We have elaborated on this rationale in the revised manuscript, explaining that our focus on the 18-40 age range is intended to minimize variability related to age-related physiological differences and comorbidities that could affect the study outcomes. Randomization and Blinding: We acknowledge that additional details on our blinding process would enhance clarity. We have included a more thorough explanation of how blinding will be maintained throughout the study to ensure the integrity of the results. Discussion and Literature Review: We appreciate your feedback on the literature review. We have incorporated the studies suggested by you in the discussion section in our study to provide a stronger context for our findings. Thank you for your positive remarks regarding the clarity and structure of our protocol. We have tried to address all queries appropriately in the revised manuscript. We believe that these revisions will strengthen our manuscript and better address the valuable concerns you have raised. Thank you once again for your thorough review and support in improving our work. We look forward to submitting our revised manuscript for your consideration. Competing Interests: None Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 30 Oct 2024 Anuroop Singhai , Oral and Maxillofacial Surgery, Datta Meghe Institute of Higher Education and Research, Wardha, 442001, India 30 Oct 2024 Author Response Dear Dr. Ahmed Thank you for your insightful comments and constructive feedback on our manuscript. We appreciate the time you took to evaluate our study, and we have addressed your ... Continue reading Dear Dr. Ahmed Thank you for your insightful comments and constructive feedback on our manuscript. We appreciate the time you took to evaluate our study, and we have addressed your points as follows: Participants: Thank you for highlighting the need for clarification regarding our age restrictions. We have elaborated on this rationale in the revised manuscript, explaining that our focus on the 18-40 age range is intended to minimize variability related to age-related physiological differences and comorbidities that could affect the study outcomes. Randomization and Blinding: We acknowledge that additional details on our blinding process would enhance clarity. We have included a more thorough explanation of how blinding will be maintained throughout the study to ensure the integrity of the results. Discussion and Literature Review: We appreciate your feedback on the literature review. We have incorporated the studies suggested by you in the discussion section in our study to provide a stronger context for our findings. Thank you for your positive remarks regarding the clarity and structure of our protocol. We have tried to address all queries appropriately in the revised manuscript. We believe that these revisions will strengthen our manuscript and better address the valuable concerns you have raised. Thank you once again for your thorough review and support in improving our work. We look forward to submitting our revised manuscript for your consideration. Dear Dr. Ahmed Thank you for your insightful comments and constructive feedback on our manuscript. We appreciate the time you took to evaluate our study, and we have addressed your points as follows: Participants: Thank you for highlighting the need for clarification regarding our age restrictions. We have elaborated on this rationale in the revised manuscript, explaining that our focus on the 18-40 age range is intended to minimize variability related to age-related physiological differences and comorbidities that could affect the study outcomes. Randomization and Blinding: We acknowledge that additional details on our blinding process would enhance clarity. We have included a more thorough explanation of how blinding will be maintained throughout the study to ensure the integrity of the results. Discussion and Literature Review: We appreciate your feedback on the literature review. We have incorporated the studies suggested by you in the discussion section in our study to provide a stronger context for our findings. Thank you for your positive remarks regarding the clarity and structure of our protocol. We have tried to address all queries appropriately in the revised manuscript. We believe that these revisions will strengthen our manuscript and better address the valuable concerns you have raised. Thank you once again for your thorough review and support in improving our work. We look forward to submitting our revised manuscript for your consideration. Competing Interests: None Close Report a concern COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Isola G. Reviewer Report For: Comparison of the efficacy of aescin and diclofenac sodium in the management of postoperative sequelae and their effect on salivary Prostaglandin E2 and serum C–reactive protein levels after surgical removal of impacted mandibular third molar: a randomized, double-blind, controlled clinical trial. [version 3; peer review: 2 approved] . F1000Research 2024, 13 :106 ( https://doi.org/10.5256/f1000research.167297.r288083 ) The direct URL for this report is: https://f1000research.com/articles/13-106/v2#referee-response-288083 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 08 Jun 2024 Gaetano Isola , University of Catania, Catania, Italy Approved VIEWS 0 https://doi.org/10.5256/f1000research.167297.r288083 In this revised version of the protocol, the authors have well ... Continue reading READ ALL In this revised version of the protocol, the authors have well addressed all issues raised by the reviewer. The protocol can be indexed. Competing Interests: No competing interests were disclosed. Reviewer Expertise: Oral surgery, periodontitis I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Isola G. Reviewer Report For: Comparison of the efficacy of aescin and diclofenac sodium in the management of postoperative sequelae and their effect on salivary Prostaglandin E2 and serum C–reactive protein levels after surgical removal of impacted mandibular third molar: a randomized, double-blind, controlled clinical trial. [version 3; peer review: 2 approved] . F1000Research 2024, 13 :106 ( https://doi.org/10.5256/f1000research.167297.r288083 ) The direct URL for this report is: https://f1000research.com/articles/13-106/v2#referee-response-288083 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Version 1 VERSION 1 PUBLISHED 16 Feb 2024 Views 0 Cite How to cite this report: Isola G. Reviewer Report For: Comparison of the efficacy of aescin and diclofenac sodium in the management of postoperative sequelae and their effect on salivary Prostaglandin E2 and serum C–reactive protein levels after surgical removal of impacted mandibular third molar: a randomized, double-blind, controlled clinical trial. [version 3; peer review: 2 approved] . F1000Research 2024, 13 :106 ( https://doi.org/10.5256/f1000research.159617.r272570 ) The direct URL for this report is: https://f1000research.com/articles/13-106/v1#referee-response-272570 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 22 May 2024 Gaetano Isola , University of Catania, Catania, Italy Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.159617.r272570 In the manuscript entitled: " Comparison of the efficacy of aescin and diclofenac sodium in the management of postoperative sequelae and their effect on salivary Prostaglandin E2 and serum C–reactive protein levels after surgical removal of impacted mandibular third molar: ... Continue reading READ ALL In the manuscript entitled: " Comparison of the efficacy of aescin and diclofenac sodium in the management of postoperative sequelae and their effect on salivary Prostaglandin E2 and serum C–reactive protein levels after surgical removal of impacted mandibular third molar: a randomized, double-blind, controlled clinical trial" the authors aimed to assess salivary PGE2 levels and serum Creactive protein levels with subjective and objective symptoms after surgical extraction of the mandibular third molar and their relationship with drug therapy. The proposed study is expected to show a favorable response to the administration of aescin for the management of postoperative discomfort compared to diclofenac sodium after third molar surgery. The proposed study is expected to positively manipulate the levels of salivary Prostaglandin E2 and serum C–reactive protein, which are reliable inflammatory markers. Major comments: In general, the idea and innovation of this study regards the analysis of perioperative effects of third molar and biomarkers is interesting and novel because the role these aspects in medicine are validated but further studies on this topic could be an innovative issue in this field could be open a creative matter of debate in literature by adding new information. The study was well conducted by the authors; However, there are some concerns to revise that are described below. The introduction section resumes the existing knowledge regarding the important factor linked with the impact mediators involved together with biomarkers in dentistry. However, as the importance of the topic, the reviewer recommends to update the literature through read, discuss some recent interesting articles, that helps the authors to better introduce and discuss the role of CRP in periodontal treatment (similar to third molar) and on NSAIDs approaches (Isola G, et al., 2024 [Ref 1]) , (Isola G, et al., 2019 [Ref 2]) The authors should be better specified, at the end of the introduction section, the rationale of the study and the aim of the protocol. In the central section, should better clarify inclusions and exclusions criteria of the selected sample. Please better state the results obtained in the abstract. The discussion section appears well organized with the relevant paper that support the conclusions, even if the authors should better discuss the relationship regarding the periodontitis and risk of oxidative stress evolution and periodontal treatment that could improve the quality of life in oral diseases patients with impacted third molar. The conclusion should reinforce in light of the discussions. In conclusion, I am sure that the authors are fine clinicians who achieve very nice results with their adopted protocol. Minor Comments: Abstract: Better formulate the abstract section by better describing the aim of the study Introduction: Please refer to major comments Discussion Please add a specific sentence that clarifies the results obtained in the first part of the discussion Is the rationale for, and objectives of, the study clearly described? Partly Is the study design appropriate for the research question? Yes Are sufficient details of the methods provided to allow replication by others? Partly Are the datasets clearly presented in a useable and accessible format? Yes References 1. Isola G, Pesce P, Polizzi A, Lo Giudice A, et al.: Effects of minimally invasive non-surgical therapy on C-reactive protein, lipoprotein-associated phospholipase A2, and clinical outcomes in periodontitis patients: A 1-year randomized, controlled clinical trial. J Periodontol . 2024. PubMed Abstract | Publisher Full Text 2. Isola G, Alibrandi A, Pedullà E, Grassia V, et al.: Analysis of the Effectiveness of Lornoxicam and Flurbiprofen on Management of Pain and Sequelae Following Third Molar Surgery: A Randomized, Controlled, Clinical Trial. J Clin Med . 2019; 8 (3). PubMed Abstract | Publisher Full Text Competing Interests: No competing interests were disclosed. Reviewer Expertise: Oral surgery, periodontitis I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Isola G. Reviewer Report For: Comparison of the efficacy of aescin and diclofenac sodium in the management of postoperative sequelae and their effect on salivary Prostaglandin E2 and serum C–reactive protein levels after surgical removal of impacted mandibular third molar: a randomized, double-blind, controlled clinical trial. [version 3; peer review: 2 approved] . F1000Research 2024, 13 :106 ( https://doi.org/10.5256/f1000research.159617.r272570 ) The direct URL for this report is: https://f1000research.com/articles/13-106/v1#referee-response-272570 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 21 Jun 2024 Anuroop Singhai , Oral and Maxillofacial Surgery, Datta Meghe Institute of Higher Education and Research, Wardha, 442001, India 21 Jun 2024 Author Response Dear Dr. Isola Thank you for taking the time to review our manuscript submitted to F1000research. We greatly appreciate your valuable feedback and constructive comments, which have undoubtedly enhanced the ... Continue reading Dear Dr. Isola Thank you for taking the time to review our manuscript submitted to F1000research. We greatly appreciate your valuable feedback and constructive comments, which have undoubtedly enhanced the quality of our work. We have carefully considered each of your suggestions and have made the necessary revisions to address the concerns raised. Below, we outline the changes made in response to your comments: Introduction Section: We have provided a more comprehensive rationale for the study and explicitly stated the aim of the protocol at the end of the introduction section. This aims to offer readers a clear understanding of the objectives and purpose of our research. Methods Section: In the central section, we have meticulously clarified the inclusion and exclusion criteria of the selected sample. This ensures transparency and assists readers in understanding the criteria used for participant selection. Abstract: We have revised the abstract however as this is a study protocol in preliminary stage and data collection is still going on. So the results will be published after the completion of study. Discussion Section: We have reorganized the discussion section to further elucidate the relationship between periodontitis, periodontal therapy and inflammatory markers. Additionally, we have incorporated relevant literature to support our conclusions effectively. Conclusion: The conclusion has been strengthened to reinforce key insights gleaned from the discussion. By aligning the conclusion with the broader implications discussed, we aim to provide readers with a more robust and conclusive summary of our study approach and relevance. We are grateful for your acknowledgment of our clinical expertise and the positive assessment of our adopted protocol. Your encouraging words serve as motivation to continually strive for excellence in our research endeavors. Once again, we extend our sincere gratitude for your insightful review and invaluable input. We believe that the revisions made have significantly improved the manuscript and hope that it now meets the standards for publication in F1000research. Thank you for your continued support and consideration. Dear Dr. Isola Thank you for taking the time to review our manuscript submitted to F1000research. We greatly appreciate your valuable feedback and constructive comments, which have undoubtedly enhanced the quality of our work. We have carefully considered each of your suggestions and have made the necessary revisions to address the concerns raised. Below, we outline the changes made in response to your comments: Introduction Section: We have provided a more comprehensive rationale for the study and explicitly stated the aim of the protocol at the end of the introduction section. This aims to offer readers a clear understanding of the objectives and purpose of our research. Methods Section: In the central section, we have meticulously clarified the inclusion and exclusion criteria of the selected sample. This ensures transparency and assists readers in understanding the criteria used for participant selection. Abstract: We have revised the abstract however as this is a study protocol in preliminary stage and data collection is still going on. So the results will be published after the completion of study. Discussion Section: We have reorganized the discussion section to further elucidate the relationship between periodontitis, periodontal therapy and inflammatory markers. Additionally, we have incorporated relevant literature to support our conclusions effectively. Conclusion: The conclusion has been strengthened to reinforce key insights gleaned from the discussion. By aligning the conclusion with the broader implications discussed, we aim to provide readers with a more robust and conclusive summary of our study approach and relevance. We are grateful for your acknowledgment of our clinical expertise and the positive assessment of our adopted protocol. Your encouraging words serve as motivation to continually strive for excellence in our research endeavors. Once again, we extend our sincere gratitude for your insightful review and invaluable input. We believe that the revisions made have significantly improved the manuscript and hope that it now meets the standards for publication in F1000research. Thank you for your continued support and consideration. Competing Interests: None Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 21 Jun 2024 Anuroop Singhai , Oral and Maxillofacial Surgery, Datta Meghe Institute of Higher Education and Research, Wardha, 442001, India 21 Jun 2024 Author Response Dear Dr. Isola Thank you for taking the time to review our manuscript submitted to F1000research. We greatly appreciate your valuable feedback and constructive comments, which have undoubtedly enhanced the ... Continue reading Dear Dr. Isola Thank you for taking the time to review our manuscript submitted to F1000research. We greatly appreciate your valuable feedback and constructive comments, which have undoubtedly enhanced the quality of our work. We have carefully considered each of your suggestions and have made the necessary revisions to address the concerns raised. Below, we outline the changes made in response to your comments: Introduction Section: We have provided a more comprehensive rationale for the study and explicitly stated the aim of the protocol at the end of the introduction section. This aims to offer readers a clear understanding of the objectives and purpose of our research. Methods Section: In the central section, we have meticulously clarified the inclusion and exclusion criteria of the selected sample. This ensures transparency and assists readers in understanding the criteria used for participant selection. Abstract: We have revised the abstract however as this is a study protocol in preliminary stage and data collection is still going on. So the results will be published after the completion of study. Discussion Section: We have reorganized the discussion section to further elucidate the relationship between periodontitis, periodontal therapy and inflammatory markers. Additionally, we have incorporated relevant literature to support our conclusions effectively. Conclusion: The conclusion has been strengthened to reinforce key insights gleaned from the discussion. By aligning the conclusion with the broader implications discussed, we aim to provide readers with a more robust and conclusive summary of our study approach and relevance. We are grateful for your acknowledgment of our clinical expertise and the positive assessment of our adopted protocol. Your encouraging words serve as motivation to continually strive for excellence in our research endeavors. Once again, we extend our sincere gratitude for your insightful review and invaluable input. We believe that the revisions made have significantly improved the manuscript and hope that it now meets the standards for publication in F1000research. Thank you for your continued support and consideration. Dear Dr. Isola Thank you for taking the time to review our manuscript submitted to F1000research. We greatly appreciate your valuable feedback and constructive comments, which have undoubtedly enhanced the quality of our work. We have carefully considered each of your suggestions and have made the necessary revisions to address the concerns raised. Below, we outline the changes made in response to your comments: Introduction Section: We have provided a more comprehensive rationale for the study and explicitly stated the aim of the protocol at the end of the introduction section. This aims to offer readers a clear understanding of the objectives and purpose of our research. Methods Section: In the central section, we have meticulously clarified the inclusion and exclusion criteria of the selected sample. This ensures transparency and assists readers in understanding the criteria used for participant selection. Abstract: We have revised the abstract however as this is a study protocol in preliminary stage and data collection is still going on. So the results will be published after the completion of study. Discussion Section: We have reorganized the discussion section to further elucidate the relationship between periodontitis, periodontal therapy and inflammatory markers. Additionally, we have incorporated relevant literature to support our conclusions effectively. Conclusion: The conclusion has been strengthened to reinforce key insights gleaned from the discussion. By aligning the conclusion with the broader implications discussed, we aim to provide readers with a more robust and conclusive summary of our study approach and relevance. We are grateful for your acknowledgment of our clinical expertise and the positive assessment of our adopted protocol. Your encouraging words serve as motivation to continually strive for excellence in our research endeavors. Once again, we extend our sincere gratitude for your insightful review and invaluable input. We believe that the revisions made have significantly improved the manuscript and hope that it now meets the standards for publication in F1000research. Thank you for your continued support and consideration. Competing Interests: None Close Report a concern COMMENT ON THIS REPORT Comments on this article Comments (0) Version 3 VERSION 3 PUBLISHED 16 Feb 2024 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 Version 3 (revision) 30 Oct 24 read read Version 2 (revision) 07 Jun 24 read read Version 1 16 Feb 24 read Gaetano Isola , University of Catania, Catania, Italy Ahmed Saaduddin , Mansoura University, Mansoura, Egypt Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Isola G. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 06 Nov 2024 | for Version 3 Gaetano Isola , University of Catania, Catania, Italy 0 Views copyright © 2024 Isola G. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The authors have well modified the protocol based on the issues raised by the reviewer. The protocol can be indexed in this form. Competing Interests No competing interests were disclosed. Reviewer Expertise Oral surgery, periodontitis I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (0) Isola G. Peer Review Report For: Comparison of the efficacy of aescin and diclofenac sodium in the management of postoperative sequelae and their effect on salivary Prostaglandin E2 and serum C–reactive protein levels after surgical removal of impacted mandibular third molar: a randomized, double-blind, controlled clinical trial. [version 3; peer review: 2 approved] . F1000Research 2024, 13 :106 ( https://doi.org/10.5256/f1000research.173977.r336513) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/13-106/v3#referee-response-336513 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Saaduddin A. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 05 Nov 2024 | for Version 3 Ahmed Saaduddin , Mansoura University, Mansoura, Egypt 0 Views copyright © 2024 Saaduddin A. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions I appreciate the efforts of the authors in addressing the feedback from the initial review. Your revisions have significantly strengthened the overall clarity and impact of the paper. I was particularly impressed by the following improvements: Expanded discussion : The inclusion of recent studies enhances the context of your work and demonstrates a thorough engagement with existing literature. This addition enriches your arguments and positions your research within the current discourse. Methodological rigour : The clarifications regarding your methodology address earlier concerns and add credibility to your objectives. It is now evident how your approach effectively supports your conclusions. Overall, I am satisfied with the revisions made and believe the article is now ready for indexing. I commend your responsiveness to feedback and your commitment to enhancing the quality of your work. Competing Interests No competing interests were disclosed. Reviewer Expertise I am an Oral and Maxillofacial Surgeon whose primary research is in the field of minor oral surgery, clinical implantology and dental traumatology. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (0) Saaduddin A. Peer Review Report For: Comparison of the efficacy of aescin and diclofenac sodium in the management of postoperative sequelae and their effect on salivary Prostaglandin E2 and serum C–reactive protein levels after surgical removal of impacted mandibular third molar: a randomized, double-blind, controlled clinical trial. [version 3; peer review: 2 approved] . F1000Research 2024, 13 :106 ( https://doi.org/10.5256/f1000research.173977.r336514) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/13-106/v3#referee-response-336514 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Saaduddin A. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 24 Oct 2024 | for Version 2 Ahmed Saaduddin , Mansoura University, Mansoura, Egypt 0 Views copyright © 2024 Saaduddin A. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Objectives The authors have clearly defined objectives with a focus on both subjective (pain, satisfaction) and objective (PGE2, CRP levels) outcomes. Including additional patient-reported outcomes, such as satisfaction with therapy. Study Design The protocol outlines a single-center, double-blind, randomized, parallel, prospective clinical trial, which is appropriate for this type of comparative study. The use of a non-inferiority design is justified, especially since the aim is to assess aescin as a safer alternative to diclofenac. Methods Participants: The inclusion and exclusion criteria are comprehensive. However, the rationale for the age restriction (18-40 years) should be elaborated. Why not include a broader age range? Randomization and Blinding: The randomization process using a computer-generated allocation is a robust method. However, further details on the blinding process (e.g., how blinding will be maintained) would add clarity. Discussion and Literature Review The literature review provides good context for the study, though the author can add suggested references that are more current and directly related to the specific outcomes being measured. Overall, Clarity and Structure The protocol is well-structured and generally clear. However, it could benefit from adding the appropriate responses to the queries raised in the above sections. Is the rationale for, and objectives of, the study clearly described? Yes Is the study design appropriate for the research question? Yes Are sufficient details of the methods provided to allow replication by others? Partly Are the datasets clearly presented in a useable and accessible format? Not applicable References 1. Singh R, Jayam C, Singh R, Nazeer J, et al.: Assessment of C-reactive Protein Level and Efficacy of Diclofenac Sodium and Mefenamic Acid in Relieving Pain in Mandibular Impacted Third Molar Surgery. J Contemp Dent Pract . 2021; 22 (1): 39-41 PubMed Abstract 2. Marcianò G, Vocca C, Dıraçoğlu D, Sevgin RÖ, et al.: Escin's Action on Bradykinin Pathway: Advantageous Clinical Properties for an Unknown Mechanism?. Antioxidants (Basel) . 2024; 13 (9). PubMed Abstract | Publisher Full Text Competing Interests No competing interests were disclosed. Reviewer Expertise I am an Oral and Maxillofacial Surgeon whose primary research is in the field of minor oral surgery, clinical implantology and dental traumatology. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (1) Author Response 30 Oct 2024 Anuroop Singhai, Oral and Maxillofacial Surgery, Datta Meghe Institute of Higher Education and Research, Wardha, 442001, India Dear Dr. Ahmed Thank you for your insightful comments and constructive feedback on our manuscript. We appreciate the time you took to evaluate our study, and we have addressed your points as follows: Participants: Thank you for highlighting the need for clarification regarding our age restrictions. We have elaborated on this rationale in the revised manuscript, explaining that our focus on the 18-40 age range is intended to minimize variability related to age-related physiological differences and comorbidities that could affect the study outcomes. Randomization and Blinding: We acknowledge that additional details on our blinding process would enhance clarity. We have included a more thorough explanation of how blinding will be maintained throughout the study to ensure the integrity of the results. Discussion and Literature Review: We appreciate your feedback on the literature review. We have incorporated the studies suggested by you in the discussion section in our study to provide a stronger context for our findings. Thank you for your positive remarks regarding the clarity and structure of our protocol. We have tried to address all queries appropriately in the revised manuscript. We believe that these revisions will strengthen our manuscript and better address the valuable concerns you have raised. Thank you once again for your thorough review and support in improving our work. We look forward to submitting our revised manuscript for your consideration. View more View less Competing Interests None reply Respond Report a concern Saaduddin A. Peer Review Report For: Comparison of the efficacy of aescin and diclofenac sodium in the management of postoperative sequelae and their effect on salivary Prostaglandin E2 and serum C–reactive protein levels after surgical removal of impacted mandibular third molar: a randomized, double-blind, controlled clinical trial. [version 3; peer review: 2 approved] . F1000Research 2024, 13 :106 ( https://doi.org/10.5256/f1000research.167297.r332167) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/13-106/v2#referee-response-332167 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Isola G. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 08 Jun 2024 | for Version 2 Gaetano Isola , University of Catania, Catania, Italy 0 Views copyright © 2024 Isola G. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions In this revised version of the protocol, the authors have well addressed all issues raised by the reviewer. The protocol can be indexed. Competing Interests No competing interests were disclosed. Reviewer Expertise Oral surgery, periodontitis I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (0) Isola G. Peer Review Report For: Comparison of the efficacy of aescin and diclofenac sodium in the management of postoperative sequelae and their effect on salivary Prostaglandin E2 and serum C–reactive protein levels after surgical removal of impacted mandibular third molar: a randomized, double-blind, controlled clinical trial. [version 3; peer review: 2 approved] . F1000Research 2024, 13 :106 ( https://doi.org/10.5256/f1000research.167297.r288083) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/13-106/v2#referee-response-288083 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Isola G. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 22 May 2024 | for Version 1 Gaetano Isola , University of Catania, Catania, Italy 0 Views copyright © 2024 Isola G. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions In the manuscript entitled: " Comparison of the efficacy of aescin and diclofenac sodium in the management of postoperative sequelae and their effect on salivary Prostaglandin E2 and serum C–reactive protein levels after surgical removal of impacted mandibular third molar: a randomized, double-blind, controlled clinical trial" the authors aimed to assess salivary PGE2 levels and serum Creactive protein levels with subjective and objective symptoms after surgical extraction of the mandibular third molar and their relationship with drug therapy. The proposed study is expected to show a favorable response to the administration of aescin for the management of postoperative discomfort compared to diclofenac sodium after third molar surgery. The proposed study is expected to positively manipulate the levels of salivary Prostaglandin E2 and serum C–reactive protein, which are reliable inflammatory markers. Major comments: In general, the idea and innovation of this study regards the analysis of perioperative effects of third molar and biomarkers is interesting and novel because the role these aspects in medicine are validated but further studies on this topic could be an innovative issue in this field could be open a creative matter of debate in literature by adding new information. The study was well conducted by the authors; However, there are some concerns to revise that are described below. The introduction section resumes the existing knowledge regarding the important factor linked with the impact mediators involved together with biomarkers in dentistry. However, as the importance of the topic, the reviewer recommends to update the literature through read, discuss some recent interesting articles, that helps the authors to better introduce and discuss the role of CRP in periodontal treatment (similar to third molar) and on NSAIDs approaches (Isola G, et al., 2024 [Ref 1]) , (Isola G, et al., 2019 [Ref 2]) The authors should be better specified, at the end of the introduction section, the rationale of the study and the aim of the protocol. In the central section, should better clarify inclusions and exclusions criteria of the selected sample. Please better state the results obtained in the abstract. The discussion section appears well organized with the relevant paper that support the conclusions, even if the authors should better discuss the relationship regarding the periodontitis and risk of oxidative stress evolution and periodontal treatment that could improve the quality of life in oral diseases patients with impacted third molar. The conclusion should reinforce in light of the discussions. In conclusion, I am sure that the authors are fine clinicians who achieve very nice results with their adopted protocol. Minor Comments: Abstract: Better formulate the abstract section by better describing the aim of the study Introduction: Please refer to major comments Discussion Please add a specific sentence that clarifies the results obtained in the first part of the discussion Is the rationale for, and objectives of, the study clearly described? Partly Is the study design appropriate for the research question? Yes Are sufficient details of the methods provided to allow replication by others? Partly Are the datasets clearly presented in a useable and accessible format? Yes References 1. Isola G, Pesce P, Polizzi A, Lo Giudice A, et al.: Effects of minimally invasive non-surgical therapy on C-reactive protein, lipoprotein-associated phospholipase A2, and clinical outcomes in periodontitis patients: A 1-year randomized, controlled clinical trial. J Periodontol . 2024. PubMed Abstract | Publisher Full Text 2. Isola G, Alibrandi A, Pedullà E, Grassia V, et al.: Analysis of the Effectiveness of Lornoxicam and Flurbiprofen on Management of Pain and Sequelae Following Third Molar Surgery: A Randomized, Controlled, Clinical Trial. J Clin Med . 2019; 8 (3). PubMed Abstract | Publisher Full Text Competing Interests No competing interests were disclosed. Reviewer Expertise Oral surgery, periodontitis I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (1) Author Response 21 Jun 2024 Anuroop Singhai, Oral and Maxillofacial Surgery, Datta Meghe Institute of Higher Education and Research, Wardha, 442001, India Dear Dr. Isola Thank you for taking the time to review our manuscript submitted to F1000research. We greatly appreciate your valuable feedback and constructive comments, which have undoubtedly enhanced the quality of our work. We have carefully considered each of your suggestions and have made the necessary revisions to address the concerns raised. Below, we outline the changes made in response to your comments: Introduction Section: We have provided a more comprehensive rationale for the study and explicitly stated the aim of the protocol at the end of the introduction section. This aims to offer readers a clear understanding of the objectives and purpose of our research. Methods Section: In the central section, we have meticulously clarified the inclusion and exclusion criteria of the selected sample. This ensures transparency and assists readers in understanding the criteria used for participant selection. Abstract: We have revised the abstract however as this is a study protocol in preliminary stage and data collection is still going on. So the results will be published after the completion of study. Discussion Section: We have reorganized the discussion section to further elucidate the relationship between periodontitis, periodontal therapy and inflammatory markers. Additionally, we have incorporated relevant literature to support our conclusions effectively. Conclusion: The conclusion has been strengthened to reinforce key insights gleaned from the discussion. By aligning the conclusion with the broader implications discussed, we aim to provide readers with a more robust and conclusive summary of our study approach and relevance. We are grateful for your acknowledgment of our clinical expertise and the positive assessment of our adopted protocol. Your encouraging words serve as motivation to continually strive for excellence in our research endeavors. Once again, we extend our sincere gratitude for your insightful review and invaluable input. We believe that the revisions made have significantly improved the manuscript and hope that it now meets the standards for publication in F1000research. Thank you for your continued support and consideration. View more View less Competing Interests None reply Respond Report a concern Isola G. Peer Review Report For: Comparison of the efficacy of aescin and diclofenac sodium in the management of postoperative sequelae and their effect on salivary Prostaglandin E2 and serum C–reactive protein levels after surgical removal of impacted mandibular third molar: a randomized, double-blind, controlled clinical trial. [version 3; peer review: 2 approved] . F1000Research 2024, 13 :106 ( https://doi.org/10.5256/f1000research.159617.r272570) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/13-106/v1#referee-response-272570 Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions Adjust parameters to alter display View on desktop for interactive features Includes Interactive Elements View on desktop for interactive features Competing Interests Policy Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. 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