Benzydamine hydrochloride: an overview on a well-established drug with news in mechanisms of action

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Benzydamine hydrochloride (HCl) is a topical indolic nonsteroidal anti-inflammatory drug, endowed with analgesic and anesthetic activity, and with antimicrobial (including both gram-positive and gram-negative bacteria) and antifungal properties (targeting Candida albicans and non-albicans strains), used in odontostomatology, otorhinolaryngology, and gynecology for its properties. This molecule has a lipophilic nature, showing high affinity with cell membranes and exhibiting membrane stabilization properties, resulting in local anesthesia, an effect related also to the interaction of the drug with cationic channels. In addition, benzydamine HCl is able to inhibit the production of pro-inflammatory cytokines, with consequent analgesia. Moreover, benzydamine HCl is able to inhibit leukocyte-endothelial interactions and platelet aggregation. Unlike other non-steroidal anti-inflammatory drugs, benzydamine HCl does not inhibit cyclooxygenase or lipoxygenase. Here we review the most updated clinical data available on benzydamine HCl local application as spray, mouthwash or gargling and evidence of its effectiveness in inflammatory and/or septic conditions in the otorhinolaryngology and odontostomatology settings, with particular reference to sore throat, oral inflammation, dental plaque, tonsillitis/tonsillectomy and chemo- or radiotherapy-induced oral mucositis. Novel formulations for oral administration of benzydamine HCl are also reviewed, including in situ gelling formulations to be sprayed onto the damaged oral mucosa. Finally, novel data on the potential role of benzydamine HCl in nociceptor excitability are introduced." } { "@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/13-350/v1", "name": "Benzydamine hydrochloride: an overview on a well-established drug..." } } ] } Home Browse Benzydamine hydrochloride: an overview on a well-established drug... ALL Metrics - Views Downloads Get PDF Get XML Cite How to cite this article Ferrer-Montiel A. Benzydamine hydrochloride: an overview on a well-established drug with news in mechanisms of action [version 1; peer review: 2 approved with reservations] . F1000Research 2024, 13 :350 ( https://doi.org/10.12688/f1000research.144067.1 ) 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 ▬ ✚ Review Benzydamine hydrochloride: an overview on a well-established drug with news in mechanisms of action [version 1; peer review: 2 approved with reservations] Antonio Ferrer-Montiel https://orcid.org/0000-0002-2973-6607 Antonio Ferrer-Montiel https://orcid.org/0000-0002-2973-6607 PUBLISHED 23 Apr 2024 Author details Author details Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Miguel Hernandez University, Alicante, 03202, Spain Antonio Ferrer-Montiel Roles: Conceptualization, Writing – Original Draft Preparation, Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS Abstract Pain and inflammation are the consequences of sore throat, dental and oral procedures, infections, ulcers and head and neck chemotherapy/radiotherapy, and their management is of fundamental importance to avoid distress in patients. Benzydamine hydrochloride (HCl) is a topical indolic nonsteroidal anti-inflammatory drug, endowed with analgesic and anesthetic activity, and with antimicrobial (including both gram-positive and gram-negative bacteria) and antifungal properties (targeting Candida albicans and non-albicans strains), used in odontostomatology, otorhinolaryngology, and gynecology for its properties. This molecule has a lipophilic nature, showing high affinity with cell membranes and exhibiting membrane stabilization properties, resulting in local anesthesia, an effect related also to the interaction of the drug with cationic channels. In addition, benzydamine HCl is able to inhibit the production of pro-inflammatory cytokines, with consequent analgesia. Moreover, benzydamine HCl is able to inhibit leukocyte-endothelial interactions and platelet aggregation. Unlike other non-steroidal anti-inflammatory drugs, benzydamine HCl does not inhibit cyclooxygenase or lipoxygenase. Here we review the most updated clinical data available on benzydamine HCl local application as spray, mouthwash or gargling and evidence of its effectiveness in inflammatory and/or septic conditions in the otorhinolaryngology and odontostomatology settings, with particular reference to sore throat, oral inflammation, dental plaque, tonsillitis/tonsillectomy and chemo- or radiotherapy-induced oral mucositis. Novel formulations for oral administration of benzydamine HCl are also reviewed, including in situ gelling formulations to be sprayed onto the damaged oral mucosa. Finally, novel data on the potential role of benzydamine HCl in nociceptor excitability are introduced. READ ALL READ LESS Keywords Benzydamine hydrochloride, sore throat, oropharyngeal disorders, inflammation, pain relief, nociceptor excitability Corresponding Author(s) Antonio Ferrer-Montiel ( [email protected] ) Close Corresponding author: Antonio Ferrer-Montiel Competing interests: Antonio Ferrer-Montiel has received research funding from Angelini Pharma S.p.A. Grant information: The editorial assistance for this work was supported by Angelini Pharma S.p.A (unconditioned contribution without grant number). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Copyright: © 2024 Ferrer-Montiel A. 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: Ferrer-Montiel A. Benzydamine hydrochloride: an overview on a well-established drug with news in mechanisms of action [version 1; peer review: 2 approved with reservations] . F1000Research 2024, 13 :350 ( https://doi.org/10.12688/f1000research.144067.1 ) First published: 23 Apr 2024, 13 :350 ( https://doi.org/10.12688/f1000research.144067.1 ) Latest published: 22 May 2025, 13 :350 ( https://doi.org/10.12688/f1000research.144067.2 )  There is a newer version of this article available. Suppress this message for one day. Introduction Benzydamine, available as hydrochloride (HCl) salt, is an indolic nonsteroidal anti-inflammatory drug (NSAID) that shares properties with other NSAIDs, but displays also some peculiar characteristics, including local anaesthetic and analgesic activities, as well as antimicrobial and antifungal properties ( Figure 1 ). 1 Benzydamine HCl is currently formulated as topical preparations for the treatment of oropharyngeal and gynaecological conditions. 2 It has been approved also for pediatric use in oropharyngeal conditions. The main characteristics of this molecule, as well as the main available clinical data and perspectives in its use and effectiveness are summarized in this narrative review. Figure 1. Schematic overview of the main targets and effects of benzydamine HCl on inflammation, microbial infection, membrane stabilization and cell aggregation. Benzydamine HCl shares some properties with other nonsteroidal antiinflammatory drugs, but also displays some unique characteristics. (↓) indicates downregulation; (↑) indicates upregulation. A comprehensive search and critical review have been conducted in PubMed database using the keywords benzydamine hydrochloride, sore throat, oropharyngeal disorders, inflammation, oral mucositis, pain relief through the use of the Boolean operators AND, OR, and identifying the articles relevant to this review. The literature search has been limited to English language articles. Manual search for related articles has been performed as well. Pharmacology of benzydamine hydrochloride Pharmacokinetics of benzydamine HCl Benzydamine HCl has high lipid solubility in the unionized form, but low protein-binding capacity, and is consequently taken up by cells with high efficiency. 1 Benzydamine HCl is metabolized mainly by conjugation, dealkylation and oxidation, with benzydamine N-oxide as the major metabolite. 2 Benzydamine HCl is characterized by a high volume of distribution and a relatively low systemic clearance. 2 Plasma drug concentrations of oral benzydamine HCl reach a peak rapidly and decline with a half-life of about 13 h. Less than 20% of the drug results to be bound to plasma proteins. 3 The systemic absorption of benzydamine HCl through the skin and non-specialized mucosae is relatively low compared to oral administration, 2 thereby limiting unrequired systemic exposure to this drug and the potential for any systemic side-effect. The mechanisms of action of benzydamine HCl Benzydamine HCl shares some properties with other NSAIDs, but exhibits also some distinctive characteristics. Benzydamine HCl has several properties that may contribute to its anti-inflammatory activity, as summarized in Figure 1 . Among others, it may exert an anti-inflammatory activity by decreasing the release of pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), but not IL-6 and IL-8, without affecting the production of anti-inflammatory molecules, such as IL-10 and IL-1 receptor antagonist (IL-1ra). 4 At lower concentrations (3–30 μmol/L), this drug is also able to inhibit leukocyte-endothelial interactions, while at concentration of 10–100 μmol/L, benzydamine HCl may stabilize the mucosal membrane by virtue of its general high affinity for membranes, and may inhibit the release of azurophilic granules from neutrophils, rich in serine proteases, further contributing to its anti-inflammatory effects. 1 , 5 Benzydamine HCl also reduces the histamine-induced vasodilation and vascular permeability. 6 Benzydamine HCl shows antithrombotic activity 7 and the inhibition of the collagen-induced aggregation appears to be rather selective vs. other NSAIDs. 4 Finally, benzydamine HCl is a weak inhibitor of cyclooxygenase and lipoxygenase, and needs high concentrations to inhibit effectively prostaglandin and thromboxane biosynthesis. 4 Benzydamine HCl has also anti-microbial properties, supporting its anti-inflammatory activity when applied to the mouth. It proved to be effective in growth inhibition of Candida albicans and non-albicans strains, with minimal inhibitory concentrations ranging from 12.5 to 50.0 μg/mL, and with cytotoxic activity at higher concentration, through a membrane-damaging action, consistently with the lipophilic properties of this drug. 8 A very recent study confirmed the effectiveness of benzydamine HCl on Candida albicans inhibition through the impairment of its adhesion, biofilm formation, regrowth and persistence in vitro. 9 Benzydamine HCl proved to be effective also against gram-negative and gram-positive bacteria in vitro within a few minutes from exposure, at concentrations equal to or lower than those generally used to exert an anti-inflammatory action. 10 The role of benzydamine hydrochloride in prevention and treatment of sore throat: insights from the clinical data Acute sore throat is a symptom often caused by an inflammation of pharynx, tonsils or nasopharynx and can occur as a part of a common cold of viral origin or can be due to pharyngeal bacterial infections. 11 The effectiveness of benzydamine HCl oral rinse for pain relief in acute sore throat has been initially supported by a double-blind study involving 44 patients, where it showed a greater effect on hyperemia and edema at 24 hours vs. the placebo solution. 12 More recently, a study revealed that chlorhexidine gluconate and benzydamine HCl mouth spray, added to standard antibiotic treatment with penicillin, significantly alleviated the intensity of clinical signs in patients with streptococcal tonsillopharyngitis. 13 Of major interest, a novel multicenter, phase IV randomized study proved that both benzydamine HCl 0.3% oromucosal spray and benzydamine HCl 3 mg lozenges were effective in providing a sore throat relief in patients with at least one symptom of upper respiratory tract infection already 2 minutes after a single drug administration, thus addressing the patients’ priority of rapid symptoms’ relief in the setting of upper respiratory tract infections. Clinical efficacy after 7 days of treatment and a good safety profile were also demonstrated. 14 Sore throat following tonsillectomy both in adults and children can cause discomfort in the immediate post-operative period. Moreover, since the nerve supplying the tonsil has a branch in the ear, otalgia, i.e. pain along the glossopharyngeal nerve, is commonly referred by patients submitted to tonsillectomy. Benzydamine HCl spray was more effective than placebo in the control of post-operative pain in patients submitted to tonsillectomy in a double-blind trial. 15 Another double-blind study confirmed the effectiveness of benzydamine HCl as a local agent in alleviating symptoms of dysphagia and sore throat, but not the earache, thus reducing the requirement of analgesic medication in adult post-tonsillectomy patients. 16 However, a prospective, double-blind randomized clinical trial (RCT) did not reveal any difference between mouthwash benzydamine HCl and placebo in intensity and duration of post operative pain, 17 suggesting the need for further research studies. Post-operative sore throat (POST) is an adverse outcome of intubation for general anesthesia that can affect patient’s condition and the care quality, with multifactorial etiology and an incidence ranging from 21% to 66%, in function of the different surgical and anesthetic procedures. 18 Different methods have been applied to alleviate POST. Among them, different studies tested the effectiveness of benzydamine HCl by virtue of its analgesic, anesthetic and anti-inflammatory properties. A prospective, double-blind study verified the effectiveness of an approach based on spraying the endotracheal tube cuff and/or the oropharyngeal cavity with benzydamine HCl. The results clearly indicated that spraying benzydamine HCl on the endotracheal tube lowers the incidence and severity of POST without increased benzydamine-related adverse effects. 18 These data are consistent with the results of a subsequent meta-analysis of five trials that included 824 patients, showing that the incidence of POST was significantly reduced in the group treated with benzydamine HCl, without major benzydamine-related complications. 19 A prospective randomized double-blind comparative study also confirmed the effectiveness of a gargle with benzydamine HCl for 30 seconds before undergoing surgery under general anaesthesia in alleviating the POST, the severity of cough and the voice hoarseness vs. a control group treated with placebo. 20 Of note, benzydamine HCl gargle proved to be effective in reducing the consumption of propofol, an agent of choice used for sedation during endoscopic retrograde cholangiopancreatography. The combination of propofol and benzydamine HCl mouthwash reduced POST, cumulative propofol consumption/min/kg body weight and desaturation vs. the control group that received propofol and water mouthwash. 21 These results are of particular interest, as they support the use of a combination of propofol and benzydamine HCl as topical analgesic to reduce propofol consumption and to provide adequate sedation while avoiding propofol side effects, including hypotension and respiratory depression, with a relevant advantage for patients. The combination of sedation with topical anaesthetics in endoscopic procedures is not new and has been tested also in previous studies, where lidocaine in the form of spray or gel was locally applied. 22 However, benzydamine HCl mouthwash is becoming an alternative for this approach in the clinical practice as it can induce lower side effects than lidocaine. Only a few studies did not confirm the effectiveness of prophylactic benzydamine HCl spray on POST following endotracheal intubation. 23 The role of benzydamine hydrochloride in prevention and treatment of chemoradiotherapy-induced oral mucositis: insights from the clinical data Oropharyngeal mucositis is one of the main adverse events of cancer treatment with chemotherapy or radiation therapy, and is characterized by generalized inflammation, erythema, atrophy and ulceration of oral mucosa. 24 , 25 Oral mucositis can also follow hematopoietic stem cell transplantation, and can be caused by infections, diabetes and smoking as well. Oropharyngeal mucositis can induce several debilitating symptoms and functional impairment, with consequences on body weight and nutritional status. Moreover, cancer patients could need an unscheduled temporary stop of treatments due to severe oral mucositis, with the risk of a negative impact both on treatment outcome and on survival rates. Oral care is of great importance for prevention or limitation of oropharyngeal mucositis, as it can have an interplay with microbiota and oral infections, including candidiasis and herpes simplex virus-1 infections. 25 Benzydamine HCl is widely used in the control of oral mucositis, thanks to its capacity to interact with different inflammation pathways and at the same time to act on pain. The Clinical Practice Guidelines for mucositis issued by the Multinational Association of Supportive Care in Cancer and by the International Society of Oral Oncology recommend the use of benzydamine HCl mouthwash for the prevention of oral mucositis in head and neck cancer (HNC) patients receiving radiotherapy, without concomitant chemotherapy. A recent systematic review of 11 papers further supported the use of benzydamine HCl mouthwash in the prevention and/or treatment of oral mucositis in patients submitted to radiotherapy while also adding chemotherapy. 26 , 27 However, another systematic review of interventions used to mitigate the radiotherapy-induced oral mucositis in HNC patients did not support the use of benzydamine HCl or other interventions, such as honey and oral glutamine, in radiation-induced oral mucositis. This discrepancy highlights the need for additional high-quality studies with a consensus on the methodology to reduce heterogeneity, and an examination of the cost effectiveness of the interventions. 28 Indeed, the discrepancies among study results may be due to dosing and timing of product administration, type of cancer and of patients characteristics, as well as to heterogeneity in anticancer treatments. Several other clinical studies supported the positive effects of benzydamine HCl in preventing and/or reducing the severity of oral mucositis in cancer submitted to radiotherapy. Among others, Chitapanarux et al . demonstrated the superiority of benzydamine HCl vs. sodium bicarbonate in reducing the severity of oral mucositis in locally advanced HNC patients treated with high-dose radiotherapy concurrently with platinum-based chemotherapy. 29 Similar positive results have been obtained by Rastogi et al. in the prevention of oral mucositis in HNC patients treated with radiotherapy (>50 Gy) without chemotherapy, while the efficacy of benzydamine HCl in patients receiving concurrent chemotherapy was not confirmed. 30 Positive results have been obtained also in pediatric patients affected by chemotherapy-induced oropharyngeal mucositis. 31 This overview mostly supports the beneficial effect of benzydamine HCl in oral mucositis following anticancer treatments. Importantly, to the best of our knowledge, there is no evidence of any interference of benzydamine HCl with the activity of anticancer treatments. Moreover, the treatment with benzydamine HCl has been proved not only effective, but also safe and well tolerated in the setting of radiation-induced oral mucositis. 32 The role of benzydamine hydrochloride in prevention and treatment of oral disorders: insights from the clinical data Aphthous stomatitis Recurrent aphthous stomatitis (RAS) is a common and painful disease of oral mucosa of unknown etiology and pathogenesis, not associated with systemic diseases and characterized by the formation of round or oval mouth ulcers. Since the underlying cause triggering RAS remains to be elucidated, at present the emergence of new lesions cannot be prevented, and therapy focuses mainly on pain reduction, through corticosteroids and topical analgesics plus antiseptics. 33 A trial involving patients with minor RAS and comparing the effectiveness of 0.15% benzydamine HCl, 0.2% aqueous chlorhexidine and placebo mouthwashes administered consecutively for 3 months/each, for a total of 9 months, did not reveal any difference between the treatments tested. However, a subgroup of patients preferred the benzydamine HCl preparation because of the temporary topical anesthetic effect, which gave some pain relief. 34 A greater control of pain by benzydamine HCl vs. other proprietary agents was also highlighted in a study involving hospital out-patients with aphthae in the UK. 35 More recently, a prospective, parallel, double-blind, active control, preliminary study compared the flavonoid quercetin with 0.15% benzydamine HCl (Tantum oral rinse) in patients with RAS. The study revealed that both the drugs led to a similar reduction in pain scores from baseline up to day 7 during the treatment period, despite quercetin was able to significantly accelerate ulcer healing vs. benzydamine HCl. 36 Dental plaque Dental plaque is a microbial biofilm adhering to the tooth surfaces and composed by microorganisms and by an extracellular matrix, i.e. a mix of molecules derived from both the biofilm microorganisms and from the host. 37 Dental plaque is the most important etiological factor for oral diseases and is known to have also systemic effects on health. Oral antiseptics in mouth-rinse formulations are often used to reduce the microbial load in the oral cavity and can play an important role in preservation of oral health, together with mechanical oral hygiene procedures. 38 Benzydamine HCl 0.15% as a mouthwash was well tolerated with no reported side effects in a double-blind RCT, and was as effective as chlorhexidine digluconate 0.2% in reducing gingival inflammation due to plaque accumulation, thus controlling further disease progression. 39 However, these data were not confirmed by another study comparing chlorhexidine and benzydamine HCl administered as oral sprays to patients affected by gingival inflammation. 40 Oral antiseptics can potentially cause irritation and have cytotoxic effects on cells of oral mucosa. The cytotoxic effect of benzydamine HCl has been recently assessed on primary human gingival fibroblasts in parallel with other oral antiseptics. The 2,3-bis (2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino) carbonyl]-2H-tetrazo-lium hydroxide (XTT) cytotoxicity test revealed low cytotoxic effects of benzydamine HCl on fibroblasts, suggesting that it can be used safely to achieve faster wound healing for conditions such as post-operative period. 41 Periodontal surgery Periodontal surgery aims to prevent or improve different types of defects in the bone, gingiva or alveolar mucosa. Acute pain is one of the most frequent postoperative complications after periodontal surgery, and several analgesics have been tested so far. In this setting, a recent RCT compared the efficacy of 0.15% benzydamine HCl mouthwash vs. 400 mg ibruprofen tablets in the reduction of postoperative pain in a period of 24 hours following the crown lengthening, a surgical procedure that addresses excessive gingival display. The trial revealed comparable results for the level of pain in the two groups of patients treated with either benzydamine HCl or ibruprofen; however the investigators supported the use of benzydamine HCl mouthwash to decrease pain after periodontal surgery, because of its fewer side effects and lower price vs. ibuprofen. 42 Another double-blind RCT involving patients affected by periodontitis demonstrated the superiority of 0.15% benzydamine HCl vs. 50 mg diclofenac sodium tablets in reduction of pain perceived by patients submitted to periodontal surgery. 43 The potential role of benzydamine hydrochloride in nociceptor excitability: insights from novel preclinical data In addition to the anti-inflammatory, analgesic and antimicrobial effects described above ( Figure 1 ), some studies are revealing the ability of benzydamine HCl to block the neuronal excitability as well. A first indication came from a study investigating the effect of four different NSAIDs, including benzydamine HCl, on neuronally evoked contractile responses to a submaximal dose of prostaglandin E1 (PGE1) or cholecystokinin-octapeptide (CCK-8) in isolated guinea-pig ileum. All the four NSAIDs tested in the study were able to inhibit the CCK-8- or PGE1-induced contractile response in the isolated guinea-pig ileum at very low concentration, thus indicating their ability to interfere with a neuronally-evoked response. Moreover, all the NSAIDs tested were able to depress the opioid system activated by PGE1 or CCK-8. 44 A more recent study verified the effect of benzydamine HCl on nociceptor excitability in primary cultures of sensitized rat nociceptors treated with the anti-mycotic compound econazole. This drug, belonging to the imidazole class, is able, at a clinically relevant concentration, to modulate directly the cytosolic Ca 2+ homeostasis. Overall, the consequence of econazole action on sensory neurons is an increase in their excitability, augmenting the triggering of action potentials in silent nociceptors and, more evidently, in ATP-sensitized nociceptors, consistently with the higher Ca 2+ fluxes. Of interest, a treatment with benzydamine HCl in vitro was able to inhibit the econazole-induced nociceptor excitability through the blockade of voltage-gated Na + (Na v ) channels. 45 These data suggest an alternative pathway to inflammatory cytokine inhibition for the analgesic activity of benzydamine HCl. Additional studies tested the capacity of benzydamine HCl to decrease the neuronal activity in an inflammatory sensitized neuronal model through electrophysiological recordings. Nociceptors were sensitized through a 24-hours incubation with an inflammatory soup containing histamine, serotonin, ATP and Prostaglandin E2. Action potential firing was induced by acute exposure to an identical inflammatory soup and acid pH, in order to mimic a local inflammatory process. Benzydamine HCl showed a dose-related inhibition of neuronal excitability mediated by either the inflammatory cocktail or the acidic pH in sensitized nociceptors and in basal conditions. Of note, higher potency was shown under inflammatory sensitized conditions compared to basal conditions. 46 These novel results support the idea of complementary and synergistic effects of benzydamine HCl in the treatment of local inflammatory symptoms as well as in the painful processes, not only by reducing the inflammation cascade but also by reducing the inflammatory-mediated neuronal signaling. The safety of benzydamine HCl administration as spray, mouthwash or gargling: insights from the clinical studies The safety of benzydamine HCl when administered as spray, mouthwash or gargling in the setting of otorhinolaryngology and odontostomatology, has been verified by several studies. Among them, a multicenter phase IV study showed that both benzydamine HCl 0.3% spray and benzydamine HCl 3 mg lozenges formulations were well tolerated and showed a good safety profile, without any clinically significant abnormality when administered to patients with acute sore throat. 14 The absence of significant adverse events related to benzydamine HCl has been showed also by a systematic review and meta-analysis of 13 RCT assessing the efficacy and safety of topical application of benzydamine HCl to prevent POST. 47 The safety of benzydamine HCl oral spray administered as adjuvant therapy was further confirmed in a study including 210 children and adults submitted to tonsillectomy, adenoidectomy, or both, when compared to a similar group receiving a Salvia officinalis preparation. 48 Finally, benzydamine HCl oral spray showed proper safety and was well tolerated, with no serious adverse events reported, when administered to patients with an acute tonsillopharyngitis associated with a common cold. 49 Generally, the most commonly reported adverse effects after a topical administration of benzydamine HCl were mild numbness in tissues and tingling sensation in oral cavity after the rinse. These effects are presumably related to the mechanism of action of benzydamine HCl, characterized by a marked, local anesthetic activity, with a rapid onset and transience. 50 , 51 Research insights for novel benzydamine HCl formulations Some studies are testing novel formulations for the administration of benzydamine HCl. An in-situ gelling formulation of benzydamine HCl, whose composition includes a thermosensitive polymer to be sprayed onto the damaged oral mucosa by self-administration, showed a sustained drug release and reduced the number of daily administrations of benzydamine HCl, while protecting the damaged mucosa from mechanical and chemical solicitations. 52 The chemical and physical characteristics of benzydamine HCl also make this drug ideal for nanosponge complexes, i.e. stable nanostructures able to cross multiple barriers, as the pore size of the oral cavity is 2 μm, and particles that are less than this pore size can cross the mucus membrane. 53 A recent study tested in the oral mucosa of murine models the local administration of benzydamine HCl in nanosponge-loaded hydrogels, able to increase the drug stability and to make its release more target-specific, for a potential application to mouth ulcers. 54 A mucoadhesive buccal film for the mucosal delivery of benzydamine HCl has been recently developed for the treatment of aphthous stomatitis. The film showed adequate physicochemical properties and was able to provide prolonged residence time and sustained delivery vs. conventional therapies. 40 Finally, nanoparticles composed by chitosan, a linear polysaccharide, have been recently developed and tested in vitro for benzydamine HCl delivery. 55 An easier application and a higher contact time of benzydamine HCl with the oral mucosa thanks to the novel formulations described above could lead to a greater local bioavailability of the drug with a consequent grater control of pain and inflammation and/or infection, greater management of drug administration and a decrease of potential side effects. Conclusions Pain and inflammation are the consequences of sore throat, dental and oral procedures, infections, ulcers and HNC chemotherapy/radiotherapy, and their management is of fundamental importance to avoid distress in patients. 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Sharma D, Sharma A, Garg R: Design, Development and In vitro/Ex vivo Evaluation of Mucoadhesive Buccal Film of Benzydamine Hydrochloride for the Effective Treatment of Aphthous Stomatitis. Recent Pat. Drug Deliv. Formul. 2018; 12 (4): 277–294. PubMed Abstract | Publisher Full Text 55. Marudova M, Zahariev N, Milenkova S, et al. : Development and In-Vitro Characterization of Benzydamine-Loaded Chitosan Nanoparticles. Macromol. Symp. 2021; 395 (1): 2000279. Publisher Full Text Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 23 Apr 2024 ADD YOUR COMMENT Comment Author details Author details Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Miguel Hernandez University, Alicante, 03202, Spain Antonio Ferrer-Montiel Roles: Conceptualization, Writing – Original Draft Preparation, Writing – Review & Editing Competing interests Antonio Ferrer-Montiel has received research funding from Angelini Pharma S.p.A. Grant information The editorial assistance for this work was supported by Angelini Pharma S.p.A (unconditioned contribution without grant number). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Article Versions (2) version 2 Revised Published: 22 May 2025, 13:350 https://doi.org/10.12688/f1000research.144067.2 version 1 Published: 23 Apr 2024, 13:350 https://doi.org/10.12688/f1000research.144067.1 Copyright © 2024 Ferrer-Montiel A. 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 Ferrer-Montiel A. Benzydamine hydrochloride: an overview on a well-established drug with news in mechanisms of action [version 1; peer review: 2 approved with reservations] . F1000Research 2024, 13 :350 ( https://doi.org/10.12688/f1000research.144067.1 ) 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 1 VERSION 1 PUBLISHED 23 Apr 2024 Views 0 Cite How to cite this report: Arpa MD. Reviewer Report For: Benzydamine hydrochloride: an overview on a well-established drug with news in mechanisms of action [version 1; peer review: 2 approved with reservations] . F1000Research 2024, 13 :350 ( https://doi.org/10.5256/f1000research.157806.r368800 ) The direct URL for this report is: https://f1000research.com/articles/13-350/v1#referee-response-368800 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 27 Mar 2025 Muhammet Davut Arpa , Istanbul Medipol University, Istanbul, Turkey Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.157806.r368800 This review provides a comprehensive overview of the pharmacological properties, mechanisms of action, clinical efficacy, and novel formulations of benzydamine hydrochloride (HCl). The effects of topical use are discussed in detail, particularly in conditions such as oral and throat inflammations ... Continue reading READ ALL This review provides a comprehensive overview of the pharmacological properties, mechanisms of action, clinical efficacy, and novel formulations of benzydamine hydrochloride (HCl). The effects of topical use are discussed in detail, particularly in conditions such as oral and throat inflammations and chemotherapy-induced oral mucositis. The article is generally well-structured, clearly written, and supported by relevant literature. However, there are several points I would like to highlight: Oral administration is typically associated with gastrointestinal (GI) delivery of a drug. However, the current review focuses on both oral and oromucosal/buccal/intraoral routes of administration. Therefore, I suggest reviewing the terminology used to ensure consistency and clarity in this context. Including more recent publications (post-2020) is essential to enhance the timeliness and relevance of the review. Although clinical trials are described in the text, they are not presented in a tabular format. Summarizing key details such as effect size, sample size, and statistical significance in a table would significantly improve readability and provide added value for the reader. Most of the clinical data emphasize positive outcomes, while negative or inconclusive results (e.g., studies showing a lack of efficacy) are rarely discussed. It would be beneficial to include a discussion on studies where the treatment was ineffective and possible reasons behind those outcomes. While novel formulations such as nanoparticles, gels, or films are briefly mentioned, experimental or clinical data supporting these formulations are limited. The review would be strengthened by a more detailed discussion of the advantages and limitations of these newer delivery systems. Additionally, recent formulation studies should be incorporated to reflect current research trends. Examples include (refer 1to 3). Is the topic of the review discussed comprehensively in the context of the current literature? Partly Are all factual statements correct and adequately supported by citations? Partly Is the review written in accessible language? Yes Are the conclusions drawn appropriate in the context of the current research literature? Yes References 1. Arpa M, Yağcılar A, Biltekin S: Novel benzydamine hydrochloride and chlorhexidine gluconate loaded bioadhesive films for local treatment of buccal infections. Journal of Drug Delivery Science and Technology . 2023; 84 . Publisher Full Text 2. Yenilmez E, Öztürk A, Başaran E: Preparation and In vitro, Ex vivo Evaluation of Benzidamine Hydrochloride Loaded Fast Dissolving Oral Strip Formulations: Treatment of Oral Mucositis Due to Side Effects of Chemotherapy and Radiotherapy. Letters in Drug Design & Discovery . 2023; 20 (8): 1147-1157 Publisher Full Text 3. Milenkova S, Ambrus R, Mukhtar M, Pilicheva B, et al.: Spray-Dried Chitosan Hydrogel Particles as a Potential Delivery System for Benzydamine Hydrochloride. Gels . 2024; 10 (3). PubMed Abstract | Publisher Full Text Competing Interests: No competing interests were disclosed. Reviewer Expertise: Pharmaceutical technology, oromucosal administration 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 Arpa MD. Reviewer Report For: Benzydamine hydrochloride: an overview on a well-established drug with news in mechanisms of action [version 1; peer review: 2 approved with reservations] . F1000Research 2024, 13 :350 ( https://doi.org/10.5256/f1000research.157806.r368800 ) The direct URL for this report is: https://f1000research.com/articles/13-350/v1#referee-response-368800 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 09 Aug 2025 Antonio Ferrer-Montiel , Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Miguel Hernandez University, Alicante, 03202, Spain 09 Aug 2025 Author Response I kindly thank the reviewer for the valuable comments. I have revised the manuscript in according to the suggestions and I provide below the point-by-point responses. Comment #1 Oral ... Continue reading I kindly thank the reviewer for the valuable comments. I have revised the manuscript in according to the suggestions and I provide below the point-by-point responses. Comment #1 Oral administration is typically associated with gastrointestinal (GI) delivery of a drug. However, the current review focuses on both oral and oromucosal/buccal/intraoral routes of administration. Therefore, I suggest reviewing the terminology used to ensure consistency and clarity in this context. REPLY : I followed the Reviewer suggestion and modified the terminology used in the review with reference to the route of administration. Comment #2 Including more recent publications (post-2020) is essential to enhance the timeliness and relevance of the review. REPLY : I thank the reviewer for the suggestion. The revised version of the manuscript now includes also recent studies on novel formulations and novel systematic reviews as well as clinical trials assessing the effectiveness of benzydamine HCl in oral disorders (changes and integrations are highlighted in TC). Comment #3 Although clinical trials are described in the text, they are not presented in a tabular format. Summarizing key details such as effect size, sample size, and statistical significance in a table would significantly improve readability and provide added value for the reader. REPLY : I thank the reviewer for this valuable suggestion. As an alternative, I implemented additional information in the text. Comment #4 Most of the clinical data emphasize positive outcomes, while negative or inconclusive results (e.g., studies showing a lack of efficacy) are rarely discussed. It would be beneficial to include a discussion on studies where the treatment was ineffective and possible reasons behind those outcomes. REPLY : I thank the reviewer for the suggestion. The review was implemented with studies where the treatment with benzydamine HCl was ineffective. Changes are highlighted in TC. Comment #5 While novel formulations such as nanoparticles, gels, or films are briefly mentioned, experimental or clinical data supporting these formulations are limited. The review would be strengthened by a more detailed discussion of the advantages and limitations of these newer delivery systems. Additionally, recent formulation studies should be incorporated to reflect current research trends. Examples include (refer 1 to 3). REPLY : I thank the reviewer for the suggestion. Studies focusing on formulations have been implemented in the revised version of the manuscript. Changes are highlighted in TC. References on novel formulations: Arpa M, Yağcılar A, Biltekin S: Novel benzydamine hydrochloride and chlorhexidine gluconate loaded bioadhesive films for local treatment of buccal infections. Journal of Drug Delivery Science and Technology. 2023; 84. Publisher Full Text Yenilmez E, Öztürk A, Başaran E: Preparation and In vitro, Ex vivo Evaluation of Benzidamine Hydrochloride Loaded Fast Dissolving Oral Strip Formulations: Treatment of Oral Mucositis Due to Side Effects of Chemotherapy and Radiotherapy. Letters in Drug Design & Discovery. 2023; 20 (8): 1147-1157 Publisher Full Text I kindly thank the reviewer for the valuable comments. I have revised the manuscript in according to the suggestions and I provide below the point-by-point responses. Comment #1 Oral administration is typically associated with gastrointestinal (GI) delivery of a drug. However, the current review focuses on both oral and oromucosal/buccal/intraoral routes of administration. Therefore, I suggest reviewing the terminology used to ensure consistency and clarity in this context. REPLY : I followed the Reviewer suggestion and modified the terminology used in the review with reference to the route of administration. Comment #2 Including more recent publications (post-2020) is essential to enhance the timeliness and relevance of the review. REPLY : I thank the reviewer for the suggestion. The revised version of the manuscript now includes also recent studies on novel formulations and novel systematic reviews as well as clinical trials assessing the effectiveness of benzydamine HCl in oral disorders (changes and integrations are highlighted in TC). Comment #3 Although clinical trials are described in the text, they are not presented in a tabular format. Summarizing key details such as effect size, sample size, and statistical significance in a table would significantly improve readability and provide added value for the reader. REPLY : I thank the reviewer for this valuable suggestion. As an alternative, I implemented additional information in the text. Comment #4 Most of the clinical data emphasize positive outcomes, while negative or inconclusive results (e.g., studies showing a lack of efficacy) are rarely discussed. It would be beneficial to include a discussion on studies where the treatment was ineffective and possible reasons behind those outcomes. REPLY : I thank the reviewer for the suggestion. The review was implemented with studies where the treatment with benzydamine HCl was ineffective. Changes are highlighted in TC. Comment #5 While novel formulations such as nanoparticles, gels, or films are briefly mentioned, experimental or clinical data supporting these formulations are limited. The review would be strengthened by a more detailed discussion of the advantages and limitations of these newer delivery systems. Additionally, recent formulation studies should be incorporated to reflect current research trends. Examples include (refer 1 to 3). REPLY : I thank the reviewer for the suggestion. Studies focusing on formulations have been implemented in the revised version of the manuscript. Changes are highlighted in TC. References on novel formulations: Arpa M, Yağcılar A, Biltekin S: Novel benzydamine hydrochloride and chlorhexidine gluconate loaded bioadhesive films for local treatment of buccal infections. Journal of Drug Delivery Science and Technology. 2023; 84. Publisher Full Text Yenilmez E, Öztürk A, Başaran E: Preparation and In vitro, Ex vivo Evaluation of Benzidamine Hydrochloride Loaded Fast Dissolving Oral Strip Formulations: Treatment of Oral Mucositis Due to Side Effects of Chemotherapy and Radiotherapy. Letters in Drug Design & Discovery. 2023; 20 (8): 1147-1157 Publisher Full Text Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 09 Aug 2025 Antonio Ferrer-Montiel , Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Miguel Hernandez University, Alicante, 03202, Spain 09 Aug 2025 Author Response I kindly thank the reviewer for the valuable comments. I have revised the manuscript in according to the suggestions and I provide below the point-by-point responses. Comment #1 Oral ... Continue reading I kindly thank the reviewer for the valuable comments. I have revised the manuscript in according to the suggestions and I provide below the point-by-point responses. Comment #1 Oral administration is typically associated with gastrointestinal (GI) delivery of a drug. However, the current review focuses on both oral and oromucosal/buccal/intraoral routes of administration. Therefore, I suggest reviewing the terminology used to ensure consistency and clarity in this context. REPLY : I followed the Reviewer suggestion and modified the terminology used in the review with reference to the route of administration. Comment #2 Including more recent publications (post-2020) is essential to enhance the timeliness and relevance of the review. REPLY : I thank the reviewer for the suggestion. The revised version of the manuscript now includes also recent studies on novel formulations and novel systematic reviews as well as clinical trials assessing the effectiveness of benzydamine HCl in oral disorders (changes and integrations are highlighted in TC). Comment #3 Although clinical trials are described in the text, they are not presented in a tabular format. Summarizing key details such as effect size, sample size, and statistical significance in a table would significantly improve readability and provide added value for the reader. REPLY : I thank the reviewer for this valuable suggestion. As an alternative, I implemented additional information in the text. Comment #4 Most of the clinical data emphasize positive outcomes, while negative or inconclusive results (e.g., studies showing a lack of efficacy) are rarely discussed. It would be beneficial to include a discussion on studies where the treatment was ineffective and possible reasons behind those outcomes. REPLY : I thank the reviewer for the suggestion. The review was implemented with studies where the treatment with benzydamine HCl was ineffective. Changes are highlighted in TC. Comment #5 While novel formulations such as nanoparticles, gels, or films are briefly mentioned, experimental or clinical data supporting these formulations are limited. The review would be strengthened by a more detailed discussion of the advantages and limitations of these newer delivery systems. Additionally, recent formulation studies should be incorporated to reflect current research trends. Examples include (refer 1 to 3). REPLY : I thank the reviewer for the suggestion. Studies focusing on formulations have been implemented in the revised version of the manuscript. Changes are highlighted in TC. References on novel formulations: Arpa M, Yağcılar A, Biltekin S: Novel benzydamine hydrochloride and chlorhexidine gluconate loaded bioadhesive films for local treatment of buccal infections. Journal of Drug Delivery Science and Technology. 2023; 84. Publisher Full Text Yenilmez E, Öztürk A, Başaran E: Preparation and In vitro, Ex vivo Evaluation of Benzidamine Hydrochloride Loaded Fast Dissolving Oral Strip Formulations: Treatment of Oral Mucositis Due to Side Effects of Chemotherapy and Radiotherapy. Letters in Drug Design & Discovery. 2023; 20 (8): 1147-1157 Publisher Full Text I kindly thank the reviewer for the valuable comments. I have revised the manuscript in according to the suggestions and I provide below the point-by-point responses. Comment #1 Oral administration is typically associated with gastrointestinal (GI) delivery of a drug. However, the current review focuses on both oral and oromucosal/buccal/intraoral routes of administration. Therefore, I suggest reviewing the terminology used to ensure consistency and clarity in this context. REPLY : I followed the Reviewer suggestion and modified the terminology used in the review with reference to the route of administration. Comment #2 Including more recent publications (post-2020) is essential to enhance the timeliness and relevance of the review. REPLY : I thank the reviewer for the suggestion. The revised version of the manuscript now includes also recent studies on novel formulations and novel systematic reviews as well as clinical trials assessing the effectiveness of benzydamine HCl in oral disorders (changes and integrations are highlighted in TC). Comment #3 Although clinical trials are described in the text, they are not presented in a tabular format. Summarizing key details such as effect size, sample size, and statistical significance in a table would significantly improve readability and provide added value for the reader. REPLY : I thank the reviewer for this valuable suggestion. As an alternative, I implemented additional information in the text. Comment #4 Most of the clinical data emphasize positive outcomes, while negative or inconclusive results (e.g., studies showing a lack of efficacy) are rarely discussed. It would be beneficial to include a discussion on studies where the treatment was ineffective and possible reasons behind those outcomes. REPLY : I thank the reviewer for the suggestion. The review was implemented with studies where the treatment with benzydamine HCl was ineffective. Changes are highlighted in TC. Comment #5 While novel formulations such as nanoparticles, gels, or films are briefly mentioned, experimental or clinical data supporting these formulations are limited. The review would be strengthened by a more detailed discussion of the advantages and limitations of these newer delivery systems. Additionally, recent formulation studies should be incorporated to reflect current research trends. Examples include (refer 1 to 3). REPLY : I thank the reviewer for the suggestion. Studies focusing on formulations have been implemented in the revised version of the manuscript. Changes are highlighted in TC. References on novel formulations: Arpa M, Yağcılar A, Biltekin S: Novel benzydamine hydrochloride and chlorhexidine gluconate loaded bioadhesive films for local treatment of buccal infections. Journal of Drug Delivery Science and Technology. 2023; 84. Publisher Full Text Yenilmez E, Öztürk A, Başaran E: Preparation and In vitro, Ex vivo Evaluation of Benzidamine Hydrochloride Loaded Fast Dissolving Oral Strip Formulations: Treatment of Oral Mucositis Due to Side Effects of Chemotherapy and Radiotherapy. Letters in Drug Design & Discovery. 2023; 20 (8): 1147-1157 Publisher Full Text Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Liu JX. Reviewer Report For: Benzydamine hydrochloride: an overview on a well-established drug with news in mechanisms of action [version 1; peer review: 2 approved with reservations] . F1000Research 2024, 13 :350 ( https://doi.org/10.5256/f1000research.157806.r279009 ) The direct URL for this report is: https://f1000research.com/articles/13-350/v1#referee-response-279009 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 Jun 2024 Jian-Xin Liu , College of Pharmacy, Hunan University of Medicine, Huaihua,, China Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.157806.r279009 This article provides an overview of benzydamine hydrochloride and a detailed analysis of its mechanism of action. Benzamine hydrochloride has been proven to be safe and effective in anti-inflammatory, antibacterial, and pain relief, and its research is an interesting topic. ... Continue reading READ ALL This article provides an overview of benzydamine hydrochloride and a detailed analysis of its mechanism of action. Benzamine hydrochloride has been proven to be safe and effective in anti-inflammatory, antibacterial, and pain relief, and its research is an interesting topic. However, the article still has the following issues to consider. Comment 1 “ Unlike other non-steroidal anti inflammatory drugs, benzydamine HCl does not inhibit cyclooxygenase or lipoxygenase. ” The ending with " Unlike other non-steroidal antiinflammatory drugs, benzydamine HCl does not inhibit cyclooxygenase or lipoxygenase." in the abstract is too abrupt, and a sentence can be added at the end. Unlike other nonsteroidal anti-inflammatory drugs, what happens if cyclooxygenase is not inhibited, and whether it improves or deteriorates. Comment 2 “ The mechanisms of action of benzydamine HCl ” The description of the mechanism of action of benzydamine HCl in "The mechanisms of action of benzydamine HCl" is too simplistic. Comment 3 “The role of benzydamine hydrochloride in prevention and treatment of sore throat: insights from the clinical data ” It is best to add a table to make it clearer and more clear. How does benzidine hydrochloride affect these diseases of throat pain, and what data supports this viewpoint, presented in a table format for a more intuitive understanding. Comment 4 As a review paper, the literature cited in this paper is too outdated to reflect the latest research progress. Is there any literature support from the past three years. Comment 5 “Only a few studies did not confirm the effectiveness of prophylactic benzydamine HCl spray on POST following endotracheal intubation.” Is there any other literature here that proves this drug is ineffective? Comment 6 "The role of benzydamine hydrochloride in prevention and treatment of sore throat ” There is a lack of more in-depth insights into the clinical data here, and it is recommended to delete 1~2 articles inserted into the literature. Comment 7 “ Research insights for novel benzydamine HCl formulations ” There is little description of the new dosage form here, and there is a lack of recent advances. Abstract Pain and inflammation are the consequences of sore throat, dental and oral procedures, infections, ulcers and head and neck chemotherapy/radiotherapy, and their management is of fundamental importance to avoid distress in patients. Benzydamine hydrochloride (HCl) is a topical indolic nonsteroidal anti-inflammatory drug, endowed with analgesic and anesthetic activity, and with antimicrobial (including both gram-positive and gram-negative bacteria) and antifungal properties (targeting Candida albicans and non-albicans strains), used in odontostomatology, otorhinolaryngology, and gynecology for its properties. This molecule has a lipophilic nature, showing high affinity with cell membranes and exhibiting membrane stabilization properties, resulting in local anesthesia, an effect related also to the interaction of the drug with cationic channels. In addition, benzydamine HCl is able to inhibit the production of pro-inflammatory cytokines, with consequent analgesia. Moreover, benzydamine HCl is able to inhibit leukocyte-endothelial interactions and platelet aggregation. Unlike other non-steroidal anti-inflammatory drugs, benzydamine HCl does not inhibit cyclooxygenase or lipoxygenase. Here we review the most updated clinical data available on benzydamine HCl local application as spray, mouthwash or gargling and evidence of its effectiveness in inflammatory and/or septic conditions in the otorhinolaryngology and odontostomatology settings, with particular reference to sore throat, oral inflammation, dental plaque, tonsillitis/tonsillectomy and chemo- or radiotherapy-induced oral mucositis. Novel formulations for oral administration of benzydamine HCl are also reviewed, including in situ gelling formulations to be sprayed onto the damaged oral mucosa. Finally, novel data on the potential role of benzydamine HCl in nociceptor excitability are introduced. Is the topic of the review discussed comprehensively in the context of the current literature? Yes Are all factual statements correct and adequately supported by citations? Partly Is the review written in accessible language? Yes Are the conclusions drawn appropriate in the context of the current research literature? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: Kidney disease and inflammation 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 Liu JX. Reviewer Report For: Benzydamine hydrochloride: an overview on a well-established drug with news in mechanisms of action [version 1; peer review: 2 approved with reservations] . F1000Research 2024, 13 :350 ( https://doi.org/10.5256/f1000research.157806.r279009 ) The direct URL for this report is: https://f1000research.com/articles/13-350/v1#referee-response-279009 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 09 Aug 2025 Antonio Ferrer-Montiel , Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Miguel Hernandez University, Alicante, 03202, Spain 09 Aug 2025 Author Response I kindly thank the reviewer for the valuable comments. I have revised the manuscript in according to the suggestions, and I provide below the point-by-point responses. Comment 1 “Unlike ... Continue reading I kindly thank the reviewer for the valuable comments. I have revised the manuscript in according to the suggestions, and I provide below the point-by-point responses. Comment 1 “Unlike other non-steroidal anti inflammatory drugs, benzydamine HCl does not inhibit cyclooxygenase or lipoxygenase.” The ending with " Unlike other non-steroidal anti inflammatory drugs, benzydamine HCl does not inhibit cyclooxygenase or lipoxygenase." in the abstract is too abrupt, and a sentence can be added at the end. Unlike other nonsteroidal anti-inflammatory drugs, what happens if cyclooxygenase is not inhibited, and whether it improves or deteriorates. REPLY : We followed the reviewer suggestion and modified this sentence in the abstract (highlights in TC). Comment 2 “The mechanisms of action of benzydamine HCl” The description of the mechanism of action of benzydamine HCl in "The mechanisms of action of benzydamine HCl" is too simplistic. REPLY : We followed the reviewer suggestion and added further information about the mechanism of action of benzydamine HCl in the corresponding section (highlights in TC). Comment 3 “The role of benzydamine hydrochloride in prevention and treatment of sore throat: insights from the clinical data” It is best to add a table to make it clearer and more clear. How does benzidine hydrochloride affect these diseases of throat pain, and what data supports this viewpoint, presented in a table format for a more intuitive understanding. REPLY : I thank the reviewer for this observation. I modified this section with a more schematic description of the different types of sore throat aimed at an improved presentation of the data. Comment 4 As a review paper, the literature cited in this paper is too outdated to reflect the latest research progress. Is there any literature support from the past three years. REPLY : I thank the reviewer for the suggestion. Additional studies on novel formulations and novel studies on benzydamine HCl effectiveness in oral disorders have been implemented in the revised version of the manuscript (highlights in TC). Comment 5 “Only a few studies did not confirm the effectiveness of prophylactic benzydamine HCl spray on POST following endotracheal intubation.” Is there any other literature here that proves this drug is ineffective? REPLY : We thank the reviewer for this comment. We added another recently published study revealing that benzydamine HCl has no beneficial effect on POST (changes highlighted in TC). Comment 6 "The role of benzydamine hydrochloride in prevention and treatment of sore throat” There is a lack of more in-depth insights into the clinical data here, and it is recommended to delete 1~2 articles inserted into the literature. REPLY : We thank the reviewer for this comment. We provided more in-depth insights into the clinical data in the section describing the role of nebzydamine HCl in treatment of sore throat. Comment 7 “Research insights for novel benzydamine HCl formulations” There is little description of the new dosage form here, and there is a lack of recent advances. REPLY : I thank the reviewer for the suggestion. Additional studies on novel formulations have been implemented in the revised version of the manuscript (Arpa M et al., 2023; Yenilmez E et al., 2023; Milenkova S et al., 2024). I kindly thank the reviewer for the valuable comments. I have revised the manuscript in according to the suggestions, and I provide below the point-by-point responses. Comment 1 “Unlike other non-steroidal anti inflammatory drugs, benzydamine HCl does not inhibit cyclooxygenase or lipoxygenase.” The ending with " Unlike other non-steroidal anti inflammatory drugs, benzydamine HCl does not inhibit cyclooxygenase or lipoxygenase." in the abstract is too abrupt, and a sentence can be added at the end. Unlike other nonsteroidal anti-inflammatory drugs, what happens if cyclooxygenase is not inhibited, and whether it improves or deteriorates. REPLY : We followed the reviewer suggestion and modified this sentence in the abstract (highlights in TC). Comment 2 “The mechanisms of action of benzydamine HCl” The description of the mechanism of action of benzydamine HCl in "The mechanisms of action of benzydamine HCl" is too simplistic. REPLY : We followed the reviewer suggestion and added further information about the mechanism of action of benzydamine HCl in the corresponding section (highlights in TC). Comment 3 “The role of benzydamine hydrochloride in prevention and treatment of sore throat: insights from the clinical data” It is best to add a table to make it clearer and more clear. How does benzidine hydrochloride affect these diseases of throat pain, and what data supports this viewpoint, presented in a table format for a more intuitive understanding. REPLY : I thank the reviewer for this observation. I modified this section with a more schematic description of the different types of sore throat aimed at an improved presentation of the data. Comment 4 As a review paper, the literature cited in this paper is too outdated to reflect the latest research progress. Is there any literature support from the past three years. REPLY : I thank the reviewer for the suggestion. Additional studies on novel formulations and novel studies on benzydamine HCl effectiveness in oral disorders have been implemented in the revised version of the manuscript (highlights in TC). Comment 5 “Only a few studies did not confirm the effectiveness of prophylactic benzydamine HCl spray on POST following endotracheal intubation.” Is there any other literature here that proves this drug is ineffective? REPLY : We thank the reviewer for this comment. We added another recently published study revealing that benzydamine HCl has no beneficial effect on POST (changes highlighted in TC). Comment 6 "The role of benzydamine hydrochloride in prevention and treatment of sore throat” There is a lack of more in-depth insights into the clinical data here, and it is recommended to delete 1~2 articles inserted into the literature. REPLY : We thank the reviewer for this comment. We provided more in-depth insights into the clinical data in the section describing the role of nebzydamine HCl in treatment of sore throat. Comment 7 “Research insights for novel benzydamine HCl formulations” There is little description of the new dosage form here, and there is a lack of recent advances. REPLY : I thank the reviewer for the suggestion. Additional studies on novel formulations have been implemented in the revised version of the manuscript (Arpa M et al., 2023; Yenilmez E et al., 2023; Milenkova S et al., 2024). Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 09 Aug 2025 Antonio Ferrer-Montiel , Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Miguel Hernandez University, Alicante, 03202, Spain 09 Aug 2025 Author Response I kindly thank the reviewer for the valuable comments. I have revised the manuscript in according to the suggestions, and I provide below the point-by-point responses. Comment 1 “Unlike ... Continue reading I kindly thank the reviewer for the valuable comments. I have revised the manuscript in according to the suggestions, and I provide below the point-by-point responses. Comment 1 “Unlike other non-steroidal anti inflammatory drugs, benzydamine HCl does not inhibit cyclooxygenase or lipoxygenase.” The ending with " Unlike other non-steroidal anti inflammatory drugs, benzydamine HCl does not inhibit cyclooxygenase or lipoxygenase." in the abstract is too abrupt, and a sentence can be added at the end. Unlike other nonsteroidal anti-inflammatory drugs, what happens if cyclooxygenase is not inhibited, and whether it improves or deteriorates. REPLY : We followed the reviewer suggestion and modified this sentence in the abstract (highlights in TC). Comment 2 “The mechanisms of action of benzydamine HCl” The description of the mechanism of action of benzydamine HCl in "The mechanisms of action of benzydamine HCl" is too simplistic. REPLY : We followed the reviewer suggestion and added further information about the mechanism of action of benzydamine HCl in the corresponding section (highlights in TC). Comment 3 “The role of benzydamine hydrochloride in prevention and treatment of sore throat: insights from the clinical data” It is best to add a table to make it clearer and more clear. How does benzidine hydrochloride affect these diseases of throat pain, and what data supports this viewpoint, presented in a table format for a more intuitive understanding. REPLY : I thank the reviewer for this observation. I modified this section with a more schematic description of the different types of sore throat aimed at an improved presentation of the data. Comment 4 As a review paper, the literature cited in this paper is too outdated to reflect the latest research progress. Is there any literature support from the past three years. REPLY : I thank the reviewer for the suggestion. Additional studies on novel formulations and novel studies on benzydamine HCl effectiveness in oral disorders have been implemented in the revised version of the manuscript (highlights in TC). Comment 5 “Only a few studies did not confirm the effectiveness of prophylactic benzydamine HCl spray on POST following endotracheal intubation.” Is there any other literature here that proves this drug is ineffective? REPLY : We thank the reviewer for this comment. We added another recently published study revealing that benzydamine HCl has no beneficial effect on POST (changes highlighted in TC). Comment 6 "The role of benzydamine hydrochloride in prevention and treatment of sore throat” There is a lack of more in-depth insights into the clinical data here, and it is recommended to delete 1~2 articles inserted into the literature. REPLY : We thank the reviewer for this comment. We provided more in-depth insights into the clinical data in the section describing the role of nebzydamine HCl in treatment of sore throat. Comment 7 “Research insights for novel benzydamine HCl formulations” There is little description of the new dosage form here, and there is a lack of recent advances. REPLY : I thank the reviewer for the suggestion. Additional studies on novel formulations have been implemented in the revised version of the manuscript (Arpa M et al., 2023; Yenilmez E et al., 2023; Milenkova S et al., 2024). I kindly thank the reviewer for the valuable comments. I have revised the manuscript in according to the suggestions, and I provide below the point-by-point responses. Comment 1 “Unlike other non-steroidal anti inflammatory drugs, benzydamine HCl does not inhibit cyclooxygenase or lipoxygenase.” The ending with " Unlike other non-steroidal anti inflammatory drugs, benzydamine HCl does not inhibit cyclooxygenase or lipoxygenase." in the abstract is too abrupt, and a sentence can be added at the end. Unlike other nonsteroidal anti-inflammatory drugs, what happens if cyclooxygenase is not inhibited, and whether it improves or deteriorates. REPLY : We followed the reviewer suggestion and modified this sentence in the abstract (highlights in TC). Comment 2 “The mechanisms of action of benzydamine HCl” The description of the mechanism of action of benzydamine HCl in "The mechanisms of action of benzydamine HCl" is too simplistic. REPLY : We followed the reviewer suggestion and added further information about the mechanism of action of benzydamine HCl in the corresponding section (highlights in TC). Comment 3 “The role of benzydamine hydrochloride in prevention and treatment of sore throat: insights from the clinical data” It is best to add a table to make it clearer and more clear. How does benzidine hydrochloride affect these diseases of throat pain, and what data supports this viewpoint, presented in a table format for a more intuitive understanding. REPLY : I thank the reviewer for this observation. I modified this section with a more schematic description of the different types of sore throat aimed at an improved presentation of the data. Comment 4 As a review paper, the literature cited in this paper is too outdated to reflect the latest research progress. Is there any literature support from the past three years. REPLY : I thank the reviewer for the suggestion. Additional studies on novel formulations and novel studies on benzydamine HCl effectiveness in oral disorders have been implemented in the revised version of the manuscript (highlights in TC). Comment 5 “Only a few studies did not confirm the effectiveness of prophylactic benzydamine HCl spray on POST following endotracheal intubation.” Is there any other literature here that proves this drug is ineffective? REPLY : We thank the reviewer for this comment. We added another recently published study revealing that benzydamine HCl has no beneficial effect on POST (changes highlighted in TC). Comment 6 "The role of benzydamine hydrochloride in prevention and treatment of sore throat” There is a lack of more in-depth insights into the clinical data here, and it is recommended to delete 1~2 articles inserted into the literature. REPLY : We thank the reviewer for this comment. We provided more in-depth insights into the clinical data in the section describing the role of nebzydamine HCl in treatment of sore throat. Comment 7 “Research insights for novel benzydamine HCl formulations” There is little description of the new dosage form here, and there is a lack of recent advances. REPLY : I thank the reviewer for the suggestion. Additional studies on novel formulations have been implemented in the revised version of the manuscript (Arpa M et al., 2023; Yenilmez E et al., 2023; Milenkova S et al., 2024). Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 23 Apr 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 3 Version 2 (revision) 22 May 25 read Version 1 23 Apr 24 read read Jian-Xin Liu , Hunan University of Medicine, Huaihua,, China Muhammet Davut Arpa , Istanbul Medipol University, Istanbul, Turkey Saai Ram Thejas , RVM Institute of Medical Sciences, Telangana, India 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 © 2025 Thejas S. 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. 26 Jun 2025 | for Version 2 Saai Ram Thejas , RVM Institute of Medical Sciences, Telangana, India 0 Views copyright © 2025 Thejas S. 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 SUMMARY The article is well written and encompasses a whole lot of points about various uses of Benzydamine. Usage in oral cavity inflammation/infection, mucositis, surgery, POST has been explained. Various ways of administration have also been explained. It has been compared to chlorhexidine and lidocaine and the pros and cons have been explained too. What could be added here is the use of Benzydamine in Post Operative Nausea and Vomiting (PONV). Otherwise, excellent article. Is the topic of the review discussed comprehensively in the context of the current literature? Yes Are all factual statements correct and adequately supported by citations? Yes Is the review written in accessible language? Yes Are the conclusions drawn appropriate in the context of the current research literature? Yes Competing Interests No competing interests were disclosed. Reviewer Expertise Rhinology, Laryngology, Otology, Newer advances in management of medical conditions 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) Thejas SR. Peer Review Report For: Benzydamine hydrochloride: an overview on a well-established drug with news in mechanisms of action [version 1; peer review: 2 approved with reservations] . F1000Research 2024, 13 :350 ( https://doi.org/10.5256/f1000research.182442.r393573) 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/13-350/v2#referee-response-393573 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Arpa M. 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. 27 Mar 2025 | for Version 1 Muhammet Davut Arpa , Istanbul Medipol University, Istanbul, Turkey 0 Views copyright © 2025 Arpa M. 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 This review provides a comprehensive overview of the pharmacological properties, mechanisms of action, clinical efficacy, and novel formulations of benzydamine hydrochloride (HCl). The effects of topical use are discussed in detail, particularly in conditions such as oral and throat inflammations and chemotherapy-induced oral mucositis. The article is generally well-structured, clearly written, and supported by relevant literature. However, there are several points I would like to highlight: Oral administration is typically associated with gastrointestinal (GI) delivery of a drug. However, the current review focuses on both oral and oromucosal/buccal/intraoral routes of administration. Therefore, I suggest reviewing the terminology used to ensure consistency and clarity in this context. Including more recent publications (post-2020) is essential to enhance the timeliness and relevance of the review. Although clinical trials are described in the text, they are not presented in a tabular format. Summarizing key details such as effect size, sample size, and statistical significance in a table would significantly improve readability and provide added value for the reader. Most of the clinical data emphasize positive outcomes, while negative or inconclusive results (e.g., studies showing a lack of efficacy) are rarely discussed. It would be beneficial to include a discussion on studies where the treatment was ineffective and possible reasons behind those outcomes. While novel formulations such as nanoparticles, gels, or films are briefly mentioned, experimental or clinical data supporting these formulations are limited. The review would be strengthened by a more detailed discussion of the advantages and limitations of these newer delivery systems. Additionally, recent formulation studies should be incorporated to reflect current research trends. Examples include (refer 1to 3). Is the topic of the review discussed comprehensively in the context of the current literature? Partly Are all factual statements correct and adequately supported by citations? Partly Is the review written in accessible language? Yes Are the conclusions drawn appropriate in the context of the current research literature? Yes References 1. Arpa M, Yağcılar A, Biltekin S: Novel benzydamine hydrochloride and chlorhexidine gluconate loaded bioadhesive films for local treatment of buccal infections. Journal of Drug Delivery Science and Technology . 2023; 84 . Publisher Full Text 2. Yenilmez E, Öztürk A, Başaran E: Preparation and In vitro, Ex vivo Evaluation of Benzidamine Hydrochloride Loaded Fast Dissolving Oral Strip Formulations: Treatment of Oral Mucositis Due to Side Effects of Chemotherapy and Radiotherapy. Letters in Drug Design & Discovery . 2023; 20 (8): 1147-1157 Publisher Full Text 3. Milenkova S, Ambrus R, Mukhtar M, Pilicheva B, et al.: Spray-Dried Chitosan Hydrogel Particles as a Potential Delivery System for Benzydamine Hydrochloride. Gels . 2024; 10 (3). PubMed Abstract | Publisher Full Text Competing Interests No competing interests were disclosed. Reviewer Expertise Pharmaceutical technology, oromucosal administration 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 09 Aug 2025 Antonio Ferrer-Montiel, Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Miguel Hernandez University, Alicante, 03202, Spain I kindly thank the reviewer for the valuable comments. I have revised the manuscript in according to the suggestions and I provide below the point-by-point responses. Comment #1 Oral administration is typically associated with gastrointestinal (GI) delivery of a drug. However, the current review focuses on both oral and oromucosal/buccal/intraoral routes of administration. Therefore, I suggest reviewing the terminology used to ensure consistency and clarity in this context. REPLY : I followed the Reviewer suggestion and modified the terminology used in the review with reference to the route of administration. Comment #2 Including more recent publications (post-2020) is essential to enhance the timeliness and relevance of the review. REPLY : I thank the reviewer for the suggestion. The revised version of the manuscript now includes also recent studies on novel formulations and novel systematic reviews as well as clinical trials assessing the effectiveness of benzydamine HCl in oral disorders (changes and integrations are highlighted in TC). Comment #3 Although clinical trials are described in the text, they are not presented in a tabular format. Summarizing key details such as effect size, sample size, and statistical significance in a table would significantly improve readability and provide added value for the reader. REPLY : I thank the reviewer for this valuable suggestion. As an alternative, I implemented additional information in the text. Comment #4 Most of the clinical data emphasize positive outcomes, while negative or inconclusive results (e.g., studies showing a lack of efficacy) are rarely discussed. It would be beneficial to include a discussion on studies where the treatment was ineffective and possible reasons behind those outcomes. REPLY : I thank the reviewer for the suggestion. The review was implemented with studies where the treatment with benzydamine HCl was ineffective. Changes are highlighted in TC. Comment #5 While novel formulations such as nanoparticles, gels, or films are briefly mentioned, experimental or clinical data supporting these formulations are limited. The review would be strengthened by a more detailed discussion of the advantages and limitations of these newer delivery systems. Additionally, recent formulation studies should be incorporated to reflect current research trends. Examples include (refer 1 to 3). REPLY : I thank the reviewer for the suggestion. Studies focusing on formulations have been implemented in the revised version of the manuscript. Changes are highlighted in TC. References on novel formulations: Arpa M, Yağcılar A, Biltekin S: Novel benzydamine hydrochloride and chlorhexidine gluconate loaded bioadhesive films for local treatment of buccal infections. Journal of Drug Delivery Science and Technology. 2023; 84. Publisher Full Text Yenilmez E, Öztürk A, Başaran E: Preparation and In vitro, Ex vivo Evaluation of Benzidamine Hydrochloride Loaded Fast Dissolving Oral Strip Formulations: Treatment of Oral Mucositis Due to Side Effects of Chemotherapy and Radiotherapy. Letters in Drug Design & Discovery. 2023; 20 (8): 1147-1157 Publisher Full Text View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Arpa MD. Peer Review Report For: Benzydamine hydrochloride: an overview on a well-established drug with news in mechanisms of action [version 1; peer review: 2 approved with reservations] . F1000Research 2024, 13 :350 ( https://doi.org/10.5256/f1000research.157806.r368800) 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/13-350/v1#referee-response-368800 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Liu J. 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 Jun 2024 | for Version 1 Jian-Xin Liu , College of Pharmacy, Hunan University of Medicine, Huaihua,, China 0 Views copyright © 2024 Liu J. 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 This article provides an overview of benzydamine hydrochloride and a detailed analysis of its mechanism of action. Benzamine hydrochloride has been proven to be safe and effective in anti-inflammatory, antibacterial, and pain relief, and its research is an interesting topic. However, the article still has the following issues to consider. Comment 1 “ Unlike other non-steroidal anti inflammatory drugs, benzydamine HCl does not inhibit cyclooxygenase or lipoxygenase. ” The ending with " Unlike other non-steroidal antiinflammatory drugs, benzydamine HCl does not inhibit cyclooxygenase or lipoxygenase." in the abstract is too abrupt, and a sentence can be added at the end. Unlike other nonsteroidal anti-inflammatory drugs, what happens if cyclooxygenase is not inhibited, and whether it improves or deteriorates. Comment 2 “ The mechanisms of action of benzydamine HCl ” The description of the mechanism of action of benzydamine HCl in "The mechanisms of action of benzydamine HCl" is too simplistic. Comment 3 “The role of benzydamine hydrochloride in prevention and treatment of sore throat: insights from the clinical data ” It is best to add a table to make it clearer and more clear. How does benzidine hydrochloride affect these diseases of throat pain, and what data supports this viewpoint, presented in a table format for a more intuitive understanding. Comment 4 As a review paper, the literature cited in this paper is too outdated to reflect the latest research progress. Is there any literature support from the past three years. Comment 5 “Only a few studies did not confirm the effectiveness of prophylactic benzydamine HCl spray on POST following endotracheal intubation.” Is there any other literature here that proves this drug is ineffective? Comment 6 "The role of benzydamine hydrochloride in prevention and treatment of sore throat ” There is a lack of more in-depth insights into the clinical data here, and it is recommended to delete 1~2 articles inserted into the literature. Comment 7 “ Research insights for novel benzydamine HCl formulations ” There is little description of the new dosage form here, and there is a lack of recent advances. Abstract Pain and inflammation are the consequences of sore throat, dental and oral procedures, infections, ulcers and head and neck chemotherapy/radiotherapy, and their management is of fundamental importance to avoid distress in patients. Benzydamine hydrochloride (HCl) is a topical indolic nonsteroidal anti-inflammatory drug, endowed with analgesic and anesthetic activity, and with antimicrobial (including both gram-positive and gram-negative bacteria) and antifungal properties (targeting Candida albicans and non-albicans strains), used in odontostomatology, otorhinolaryngology, and gynecology for its properties. This molecule has a lipophilic nature, showing high affinity with cell membranes and exhibiting membrane stabilization properties, resulting in local anesthesia, an effect related also to the interaction of the drug with cationic channels. In addition, benzydamine HCl is able to inhibit the production of pro-inflammatory cytokines, with consequent analgesia. Moreover, benzydamine HCl is able to inhibit leukocyte-endothelial interactions and platelet aggregation. Unlike other non-steroidal anti-inflammatory drugs, benzydamine HCl does not inhibit cyclooxygenase or lipoxygenase. Here we review the most updated clinical data available on benzydamine HCl local application as spray, mouthwash or gargling and evidence of its effectiveness in inflammatory and/or septic conditions in the otorhinolaryngology and odontostomatology settings, with particular reference to sore throat, oral inflammation, dental plaque, tonsillitis/tonsillectomy and chemo- or radiotherapy-induced oral mucositis. Novel formulations for oral administration of benzydamine HCl are also reviewed, including in situ gelling formulations to be sprayed onto the damaged oral mucosa. Finally, novel data on the potential role of benzydamine HCl in nociceptor excitability are introduced. Is the topic of the review discussed comprehensively in the context of the current literature? Yes Are all factual statements correct and adequately supported by citations? Partly Is the review written in accessible language? Yes Are the conclusions drawn appropriate in the context of the current research literature? Yes Competing Interests No competing interests were disclosed. Reviewer Expertise Kidney disease and inflammation 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 09 Aug 2025 Antonio Ferrer-Montiel, Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Miguel Hernandez University, Alicante, 03202, Spain I kindly thank the reviewer for the valuable comments. I have revised the manuscript in according to the suggestions, and I provide below the point-by-point responses. Comment 1 “Unlike other non-steroidal anti inflammatory drugs, benzydamine HCl does not inhibit cyclooxygenase or lipoxygenase.” The ending with " Unlike other non-steroidal anti inflammatory drugs, benzydamine HCl does not inhibit cyclooxygenase or lipoxygenase." in the abstract is too abrupt, and a sentence can be added at the end. Unlike other nonsteroidal anti-inflammatory drugs, what happens if cyclooxygenase is not inhibited, and whether it improves or deteriorates. REPLY : We followed the reviewer suggestion and modified this sentence in the abstract (highlights in TC). Comment 2 “The mechanisms of action of benzydamine HCl” The description of the mechanism of action of benzydamine HCl in "The mechanisms of action of benzydamine HCl" is too simplistic. REPLY : We followed the reviewer suggestion and added further information about the mechanism of action of benzydamine HCl in the corresponding section (highlights in TC). Comment 3 “The role of benzydamine hydrochloride in prevention and treatment of sore throat: insights from the clinical data” It is best to add a table to make it clearer and more clear. How does benzidine hydrochloride affect these diseases of throat pain, and what data supports this viewpoint, presented in a table format for a more intuitive understanding. REPLY : I thank the reviewer for this observation. I modified this section with a more schematic description of the different types of sore throat aimed at an improved presentation of the data. Comment 4 As a review paper, the literature cited in this paper is too outdated to reflect the latest research progress. Is there any literature support from the past three years. REPLY : I thank the reviewer for the suggestion. Additional studies on novel formulations and novel studies on benzydamine HCl effectiveness in oral disorders have been implemented in the revised version of the manuscript (highlights in TC). Comment 5 “Only a few studies did not confirm the effectiveness of prophylactic benzydamine HCl spray on POST following endotracheal intubation.” Is there any other literature here that proves this drug is ineffective? REPLY : We thank the reviewer for this comment. We added another recently published study revealing that benzydamine HCl has no beneficial effect on POST (changes highlighted in TC). Comment 6 "The role of benzydamine hydrochloride in prevention and treatment of sore throat” There is a lack of more in-depth insights into the clinical data here, and it is recommended to delete 1~2 articles inserted into the literature. REPLY : We thank the reviewer for this comment. We provided more in-depth insights into the clinical data in the section describing the role of nebzydamine HCl in treatment of sore throat. Comment 7 “Research insights for novel benzydamine HCl formulations” There is little description of the new dosage form here, and there is a lack of recent advances. REPLY : I thank the reviewer for the suggestion. Additional studies on novel formulations have been implemented in the revised version of the manuscript (Arpa M et al., 2023; Yenilmez E et al., 2023; Milenkova S et al., 2024). View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Liu JX. Peer Review Report For: Benzydamine hydrochloride: an overview on a well-established drug with news in mechanisms of action [version 1; peer review: 2 approved with reservations] . F1000Research 2024, 13 :350 ( https://doi.org/10.5256/f1000research.157806.r279009) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. 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