Natural and Synthetic Drugs Approached for the Treatment of Recurrent Aphthous Stomatitis Over the Last Decade.

Recurrent aphthous stomatitis (RAS) refers to a sore and frequently recurring inflammation of the oral tissues, distinguished by the presence of small ulcers that cause significant discomfort and cannot be attributed to any underlying disease. Different treatments have been used for RAS. This review aims to provide a comprehensive overview of the treatment options over the past decade for recurrent aphthous stomatitis (RAS), encompassing both natural and synthetic treatments. It will utilize clinical efficacy studies conducted in vivo and in vitro, along with a focus on the pharmaceutical approach through advancements in drug delivery development. We conducted a thorough literature search from 2013 to 2023 in prominent databases such as PubMed, Scopus, and Cochrane, utilizing appropriate keywords of recurrent aphthous stomatitis, and treatment. A total of 53 clinical trials with 3022 patients were included, with 35 using natural materials in their research and a total of 16 articles discussing RAS treatment using synthetic materials. All the clinical trials showed that natural and synthetic medicines seemed to benefit RAS patients by reducing pain score, ulcer size, and number of ulcers and shortening the healing duration.

Network pharmacology-based strategy combined with molecular docking to explore the potential mechanism of agarwood against recurrent aphthous stomatitis.

To explore the antiinflammatory mechanism of agarwood on recurrent aphthous stomatitis (RAS). RAS is the most common mucosal disease in the oral cavity. The clinical application of traditional Chinese medicine found that agarwood has significant curative effect on peptic ulcer, but the effect and mechanism of agarwood on RAS remain unclear. This study is intended to predict the potential antiinflammatory mechanisms by which agarwood acts on RAS through network pharmacology and molecular docking. TCMSP database was used to screen the active components of agarwood. RAS targets were screened in Genecards, DisGeNET, and OMIM database. Venny, an online tool, screens for interacting genes between the two. Cytoscape software was used to construct the gene regulation map of active compounds target of agarwood. String Database building protein-protein interaction network. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathways were enriched in DAVID database. The key active ingredients and core targets were further verified by molecular docking. There were 9 effective compounds and 186 target genes in agarwood; RAS has 793 target genes. There were 41 interacting genes between agarwood and RAS. Interleukin 6, tumor necrosis factor, interleukin 1 beta, and cellular component motif ligand 2 may be key targets. Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses predicted multiple pathways associated with RAS. Molecular docking results showed that the active compounds of agarwood combined well and stably with the target. The Chinese herbal medicine agarwood can relieve the inflammation of RAS through multiple targets and various ways. Its active compounds may be nominated as candidates for antiinflammatory drugs of RAS.

Propolis Use in Dentistry: A Narrative Review of Its Preventive and Therapeutic Applications.

Propolis is a resinous substance produced naturally by bees, and it consists of the exudates of plants mixed with enzymes, wax, and pollen. Propolis continues to gain considerable scientific interest due to its potential health benefits. The modern-day use of propolis in pharmaceutical preparations, such as toothpastes, mouthwashes, chewable tablets, mucoadhesive gels, and sprays, is increasing. However, the effectiveness of using propolis-containing pharmaceuticals in dentistry is not clear. The present paper aims to review the literature on the dental applications of propolis in preventive dentistry, periodontics, oral medicine, and restorative dentistry and discuss its clinical effectiveness. A literature search was conducted using Scopus, PubMed, and Web of Science databases. In total, 104 studies were included, of which 46 were laboratory studies, 5 animal studies, and 53 human clinical studies. Overall, the laboratory studies revealed a range of antimicrobial effects of propolis on oral pathogens. Clinical investigations of propolis in biofilm and dental caries control as well as adjuvant periodontal therapies reported positive outcomes in terms of plaque control, pathogenic microbial count reduction, and periodontal tissue inflammation control. Additional investigations included the use of propolis for the management of recurrent aphthous stomatitis, oral mucositis, and cavity disinfection after caries removal as well as the development of a range of restorative dental materials. Based on the reported outcomes of the studies, the clinical usage of propolis has potential. However, the majority of the evidence is derived from studies with flaws in their methodological design, making their results and conclusions questionable. As a consequence, properly designed and well-reported clinical studies are required to affirm the effectiveness of propolis for dental applications. Additionally, the safety of propolis and the optimal concentrations and extraction methods for its clinical use warrant further investigation. Utilisation of standardised propolis extracts will help in quality control of propolis-based products and lead to the achievement of reproducible outcomes in research studies.

Thalidomide for management of refractory oral mucosal diseases.

BACKGROUND: Thalidomide has anti-inflammatory properties and has been used off-label for multiple mucocutaneous disorders, but its application in managing refractory oral mucosal diseases is unclear. This study aimed to review the efficacy and safety of thalidomide in treating various oral mucosal disorders refractory to conventional therapies. METHODS: The medical records of patients who were prescribed thalidomide from 2002 through 2021 for oral mucosal disorders were reviewed. Data collected included demographic characteristics, oral mucosal disease diagnosis, treatment courses, and thalidomide dose, duration, response, and side effects. RESULTS: Thalidomide was prescribed for 28 patients with diagnoses of recurrent aphthous stomatitis (n = 14), inflammatory oral lichenoid lesions (n = 6), traumatic ulcerative granuloma with stroma eosinophilia (n = 5), chronic radiation-induced mucositis (n = 2), and orofacial granulomatosis (n = 1). Patients were treated for a median duration of 84 days (range 2-1,582). Clinical improvement was observed in 19 of 22 patients who completed at least 1 cycle of thalidomide (86.4%), with complete resolution in 12 patients (54.5%). Adverse events occurred in 75% of patients (n = 21), with 8 requiring thalidomide discontinuation. The most common adverse events included peripheral neuropathy (42.9%), drowsiness (28.6%), and constipation (21.4%). CONCLUSIONS: Thalidomide may be considered for the management of refractory oral mucosal disorders. Drug side effects are common and need monitoring closely during use.

Evaluation of caffeic acid mucoadhesive tablets on minor recurrent aphthous stomatitis: a randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: Oral aphthous stomatitis is a chronic inflammatory condition. Numerous medications have been investigated to treat the symptoms of the disease. However, these days patients prefer herbal medicines due to lower side effects. Considering the anti-inflammatory, analgesic, and anti-oxidant properties of Caffeic acid and its few side effects, the aim of this study was to assess the impact of Caffeic acid on recurrent aphthous stomatitis (RAS). investigating the effect of caffeic acid mucoadhesive tablets on the size and pain intensity of the aphthous lesions. METHODS: in this double-blinded clinical trial study, 47 patients who met the inclusion criteria were selected by convenient sampling method. The patients were assigned to two groups randomly; the control group (placebo recipients) and the intervention group (Caffeic acid recipients). Patients were followed up for 7 days following the intervention. The diameter of the inflammatory lesion was measured in millimeters, and the pain intensity was recorded based on the VAS scale (Visual Analogue Scale). This trial was approved by the medical ethics committee of Mazandaran University of Medical Sciences (Ethical code: IR.MAZUMS.REC.1401.261) and received IRCT code of IRCT20220815055700N1on 03/09/2022. RESULTS: the diameter of the lesion in both groups decreased over time, and there was no significant difference between the intervention and control groups, except on the fifth day when the diameter of the lesion was significantly greater in the control group (P = 0.012). From the second day, the control group's average pain intensity was significantly higher than the intervention group's pain intensity (P < 0.05). CONCLUSIONS: when comparing mucoadhesive tablets containing Caffeic acid and placebo, the findings demonstrated that Caffeic acid has a significant efficacy in reducing aphthous lesions' diameter and pain intensity of the patients and are suggested for palliative oral aphthous lesions treatment since they showed significant anti-inflammatory and analgesic effects on recurrent aphthous stomatitis.

Plants with Anti-Ulcer Activity and Mechanism: A Review of Preclinical and Clinical Studies.

Ulcer disorders including the oral mucosa, large intestine, and stomach mucosa, cause significant global health burdens. Conventional treatments such as non-steroid anti-inflammatory drugs (NSAIDs), proton pump inhibitors (PPIs), histamine H2 receptor antagonists (H2RAs), and cytoprotective agents have drawbacks like mucosal injury, diminish gastric acid secretion, and interact with concurrent medications. Therefore, alternative therapeutic approaches are needed to tackle this health concern. Plants are rich in active metabolites in the bark, roots, leaves, fruits, and seeds, and have been utilized for medicinal purposes since ancient times. The use of herbal therapy is crucial, and regulations are necessary to ensure the quality of products, particularly in randomized studies, to assess their efficacy and safety in treating ulcer disorders. This study aims to explore the anti-ulcer activity of medicinal plants in treating peptic ulcer disease, ulcerative colitis, and aphthous ulcers. Articles were searched in Scopus and PubMed, and filtered for publication from 2013 to 2023, resulting in a total of 460 from Scopus and 239 from PubMed. The articles were further screened by title and abstract and resulted in 55 articles. Natural products, rich in active metabolites, were described to manage ulcer disease by protecting the mucosa, reducing ulcer effects, inhibiting pro-inflammatory factors, and reducing bacterial load, thus improving patients' quality of life. Natural extracts have proven effective in managing other health problems, including ulcers by reducing pain and decreasing lesions. This review provides an overview of preclinical and clinical studies on medicinal plants, focusing on their effectiveness in treating conditions like peptic ulcers, ulcerative colitis, and aphthous ulcers.

Dynamic salivary cytokine profile of recurrent aphthous stomatitis patients in thalidomide maintenance treatment.

OBJECTIVE: To dynamically compare the longitudinal (time axis) and transverse (between groups) differences of the salivary cytokines during thalidomide maintenance treatment of recurrent aphthous stomatitis. METHODS: A randomized, controlled, clinical trial was performed. After the initial prednisone treatment, thalidomide (50 mg/d vs. 25 mg/d) was used as a maintenance drug for 4 or 8 weeks. The salivary IL-4, 5, 6, 10, TNF-α, and IFN-γ were dynamically detected with a cytometric bead array. RESULTS: Overall, the level of six elevated salivary cytokines after prednisone treatment was significantly downregulated, remained low during thalidomide maintenance, and rebounded at recurrence. The effect of 50 mg/d thalidomide on the salivary cytokines was not superior to 25 mg/d medication. The relapse-free period following drug withdrawal was the longest in the subgroup using 25 mg/d thalidomide for 8 weeks. The order of magnitude of IL-6 was the most obvious, and at week 8, only the level of IL-6 in the group (25 mg/d thalidomide for 8 weeks) continued to decline compared with the other groups. CONCLUSION: Thalidomide maintenance treatment can effectively sustain low levels of salivary IL-4, 5, 6, 10, TNF-α, and IFN-γ of recurrent aphthous stomatitis patients. IL-6 displayed a good correlation with the disease and is expected to become an index for diagnosis and follow-up. CLINICAL RELEVANCE: Low-dose long-term thalidomide maintenance treatment was supported for recurrent aphthous stomatitis. TRIAL REGISTRATION: Trial registration number of ChiCTR-IPR-16009759 at http://www.chictr.org/index.aspx .

Elevated serum fibrinogen levels in Chinese patients with minor recurrent aphthous stomatitis: An observational study.

Fibrinogen is a protein that reflects systemic inflammation and regulates the immune response to disease. However, there is a scarcity of data on fibrinogen in recurrent aphthous stomatitis (RAS). We aimed to test the hypothesis that fibrinogen is involved in the aetiology of RAS. Between November 2016 and November 2018, we included 109 minor RAS patients and 29 age- and sex-matched controls in a single-center, observational study. Their clinical history and ulcer manifestations led to the diagnosis of minor RAS. The ulcer severity score (USS) was used to assess disease severity, and fibrinogen was also collected. We conducted three analyses: Analysis 1 (comparison of fibrinogen levels between patients and controls), Analysis 2 (comparison of fibrinogen levels between high and low USS patients) and Analysis 3 (comparison of fibrinogen levels between before and after anti-inflammatory treatment in patients). The fibrinogen levels in the 109 minor RAS patients were statistically higher than in the 29 controls (mean [SD], 2.6 [0.5] vs. 2.3 [0.3]; Student's t-test, p < 0.001). However, there were no significant differences in fibrinogen levels among the 43 patients with high USS and the 39 patients with low USS (mean [SD], 2.7 [0.5] vs. 2.6 [0.4]; Student's t-test, p = 0.278). Furthermore, fibrinogen levels were significantly higher before anti-inflammatory treatment in comparison to those after anti-inflammatory treatment in the 35 paired patients (mean [SD], 2.6 [0.4] vs. 2.5 [0.4]; Student's t-test, p = 0.026). Interestingly, fibrinogen levels were significantly higher in the 35 paired patients after anti-inflammatory treatment compared to the 29 control subjects (mean [SD], 2.5 [0.4] vs. 2.3 [0.3]; Student's t-test, p = 0.026]. Fibrinogen may play a role in the aetiology of RAS and may be a drug target for RAS treatment. Clinicians should be alert that high serum fibrinogen levels might be associated with the risk of RAS.

The effect of vitamin D supplementation on attacks in PFAPA syndrome patients with low vitamin D levels.

BACKGROUND-AIM: To evaluate the effect of vitamin D supplementation on the frequency and duration of attacks in patients of PFAPA syndrome with low vitamin D levels. METHODS: This retrospective study comprised PFAPA patients with vitamin D deficiency/insufficiency between 2018 and 2023. The frequency and duration of PFAPA attacks before and after vitamin D supplementation were noted. RESULTS: Seventy-one patients were included. Of the 71 patients, 24 (33.8%) had vitamin D insufficiency, and 47 (66.2%) had vitamin D deficiency. In patients with vitamin D insufficiency, mean attack frequency and mean attack duration before vitamin D supplementation were 4.3 ± 1.9/year and 2.2 ± 1.6 days, respectively, while mean attack frequency and mean attack duration after vitamin D supplementation were 3.5 ± 2.7/year per year and 1.3 ± 0.9 days respectively (p = 0.2, p = 0.2, respectively). In patients with vitamin D deficiency, mean attack frequency and mean attack duration before vitamin D supplementation were 7.4 ± 2.1/year and 2.2 ± 1.6 days, respectively, while mean attack frequency and mean attack duration after vitamin D supplementation were 3.3 ± 2.4/year and 1.3 ± 0.9 days respectively (p < 0.01, p = 0.04, respectively). When the vitamin D level and the frequency of attacks were compared, the cut-off value of vitamin D was found to be 29.7 nmol/L. CONCLUSIONS: In PFAPA patients with low vitamin D levels, the frequency and duration of PFAPA attacks were reduced with vitamin D supplementation. Especially at vitamin D level cut-off > 29.7 nmol/L, the frequency of attacks reduced significantly.

Cardiovascular diseases, risk factors, and ulcer relapse in older adults with aphthous stomatitis.

OBJECTIVES: To test the hypothesis that cardiovascular diseases and risk factors are associated with ulcer relapse in after-retirement patients with recurrent aphthous stomatitis. SUBJECTS AND METHODS: This retrospective cohort study analyzed the data of 40 minor recurrent aphthous stomatitis patients aged 55-75 years, admitted to Oral Medicine Clinic at one university hospital in China between 2016 and 2018. The diagnosis of minor recurrent aphthous stomatitis was made based on the history and manifestation of oral ulcers. The ulcer relapse was evaluated after a 5-week anti-inflammatory treatment, and the history of systemic diseases was collected. cardiovascular disease/metabolic risk referred to the presence of any cardiovascular diseases and metabolic cardiovascular disease risks. Associations among cardiovascular diseases, risk factors, and ulcer relapse were evaluated. RESULTS: The mean age of 40 patients with minor recurrent aphthous stomatitis was 62.4 years (SD 5.1), and 60% were women. The ulcer relapse rate was 37.5% (95% CI, 0.242-0.530). The proportion of cardiovascular disease/metabolic risk was higher in the relapse group than in the no-relapse group after 5-week anti-inflammatory treatment (Fisher's exact test, p = 0.041). CONCLUSIONS: According to this single-center experience, older patients with cardiovascular disease/metabolic risk may be more prone to oral ulcer recurrence. Nevertheless, larger prospective studies are needed to confirm our findings.

The use of ketotifen as long-term anti-inflammatory prophylaxis in children with PFAPA syndrome.

Introduction: Periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome (PFAPA) is the most frequent periodic fever syndrome in children. Its pathogenesis is still unknown, but some disease-modifying factors were observed. Several medications were tested for the long-term prophylaxis of inflammatory flares; however, none are standardly used. Methods: This prospective clinical trial enrolled 142 children (71 girls, 50%) meeting diagnostic criteria for PFAPA syndrome. We analysed selected clinical characteristics and compared laboratory parameters during the flare and attack-free period (at least two weeks after the attack). Moreover, we assessed the possible therapeutic effect of ketotifen on the duration of attack free-periods and clinical picture. Results: The mean age of patients was 6.81 ± 3.03 years and the mean age of onset of symptoms was 2.31 ± 2.02 years. No significant differences were observed between genders.We recorded a positive family history for PFAPA in 31.69% of patients. Attacks lasted for 2.8 ± 1.2 days, with intervals between attacks of 4 ± 1 weeks. We administered ketotifen in 111 (77.8%) patients, and a positive effect was observed in 86 (77.5%) of patients. We observed prolonged attack-free intervals in patients treated with ketotifen (14.7 ± 8.9 days in comparison with 4.4 ± 1.9 days before the treatment; p<0.001). The used dose of ketotifen was 0.08 ± 0.01 mg/kg/day. Mild side effects were observed in four patients (restlessness, irritability, agitation and constipation). Discussion: Our data supports the use of ketotifen for long-term prophylaxis in children with PFAPA syndrome with positive effects on the attenuation of disease activity and the prolongation of attack-free periods. Further well-designed studies should confirm the preliminary data.

Effect of lactobacillus reuteri-derived probiotic nano-formulation on recurrent aphthous stomatitis: a double-blinded randomized clinical trial.

OBJECTIVES: We aimed to assess the therapeutic effects of a topical probiotic nano-formulation derived from Lactobacillus reuteri on treating recurrent aphthous stomatitis. MATERIALS AND METHODS: 60 participants were randomly allocated into two groups (control and probiotic). Probiotic group administered topical probiotic nano-formulation three times a day for seven days. The control group administered a standard analgesic oral rinse. The size of ulcer(s) and pain severity were recorded on days 0, 3, 5, and 7 after intervention. RESULTS: Before the intervention, the groups had no significant differences in terms of pain severity (P-value = 0.28) and lesion size (P-value = 0.24). Both groups exhibited significant reductions in pain severity and lesion size over the course of the intervention. After one week, the probiotic group had a notably larger lesion size reduction than the control group (P-value = 0.01). The probiotic group also showed a significantly greater reduction in pain severity than the control group (P-value = 0.04). CONCLUSIONS: Applying topical probiotic nano-formulation derived from Lactobacillus reuteri three times a day decreased lesion size and pain severity in RAS patients faster than the local analgesic oral rinse. CLINICAL RELEVANCE: Lactobacillus reuteri-derived probiotic nano-formulation might be a promising treatment option for RAS.

COMPARATIVE EFFICACY OF THERAPEUTIC INTERVENTIONS FOR THE MANAGEMENT OF RECURRENT APHTHOUS ULCERS: A SYSTEMATIC REVIEW AND NETWORK META-ANALYSIS.

BACKGROUND: Recurrent aphthous ulceration (RAU) is an oral condition cavity affecting 2.5 billion people worldwide. We aimed to assess the comparative efficacy and safety of available interventions in the management of RAU. MATERIALS AND METHODS: An electronic search of 3 databases (Medline, CENTRAL, Scopus) was performed to identify randomized control trials evaluating the efficacy of RAU interventions published until December 2022. A network meta-analysis (NMA) was conducted on 4 outcomes: reduction in pain, duration of ulceration, the diameter of ulceration, and area of ulceration. The interventions are then arranged using the surface area under cumulative ranking (SUCRA). RESULTS: A total of 38 trials involving 2773 patients were included were included in quantitative synthesis by NMA. Our analysis showed that Diode laser [MD, -4.865 ± 1.951 (95%CI = (-8.690, -1.041)] was the most effective in reducing the pain score followed by Amlexanox [MD, -2.673 ± 1.075 (95%CI = -4.779, -0.566)]. Iralvex performed the best in reducing the duration of ulceration [MD, -6.481 ± 1.841 (95%CI = -10.090, -2.872)]. Diode laser, acacia nilotica with licorice formulation, and amlexanox were the most effective interventions for reduction of ulcer diameter. Majority of the trials reported absence of any adverse effects and those reported were mild. CONCLUSION: Our NMA has identified several interventions to be more effective than a placebo. Laser therapy may be an option for promoting pain management, however, most have only been tested in 1 or 2 trials. Further studies with rigorous methodology on larger samples are recommended to strengthen the current evidence.

Topical betamethasone and systemic colchicine for treatment of recurrent aphthous stomatitis: a randomised clinical trial.

BACKGROUND: Recurrent Aphthous Stomatitis (RAS) is painful oral ulceration frequently treated with topical steroids. There is limited published evidence for the efficacy of any treatment for RAS and there remains a need for longitudinal randomised clinical trials to evaluate and compare the effectiveness of different therapies in the management of RAS. The aim of the current project was to assess the efficacy of betamethasone mouthwash and colchicine tablets, individually and combined, for the treatment of RAS, and to establish the optimum treatment period necessary for a significant reduction in the disease severity. METHODOLOGY: A randomised, prospective, parallel-group clinical trial was conducted over one year, to compare the efficacy of three therapies in RAS. One hundred and six patients were randomized into three groups; 35 received betamethasone mouthwash, 35 had colchicine tablets and 36 received both therapies. The response was evaluated quantitatively every 3 months for 1 year, using the Ulcer Severity Score (USS). RESULTS: For all three treatment regimes, the mean USS decreased by about 30% in the first 3 months (p < 0.001). Further improvement was noted for up to 9 months. At the end of the study, the mean USS had improved by 50% from 34.9 ± 7.2 before treatment to 17.5 ± 8.9 after treatment (p < 0.001). Of included participants, 86% showed significant clinical improvement by the end of the study. There were no significant differences in outcomes between the three regimes (p < 0.05). CONCLUSIONS: This clinical trial has provided evidence for the efficacy of betamethasone mouthwash and for colchicine tablets in the treatment of RAS and has shown that at least six months of treatment may be required for optimum effect. CLINICAL TRIAL REGISTRATION NUMBER: ISRCTN3267716. Date of clinical trial registration: 15/04/2018.

Topical Licorice for Aphthous: A Systematic Review of Clinical Trials.

Background: Recurrent aphthous stomatitis (RAS) is the most common ulcerative disease that affects oral mucosa. The coating agents, topical analgesics, and topical steroids are usually used as treatment methods. Glycyrrhiza glabra has been used for RAS treatment based on its anti-inflammatory, antioxidant, and immunomodulatory properties. In this study, a systemic review on the therapeutic effect of topical licorice on RAS management was performed. Methods: Science Direct, Scopus, Cochrane databases, PubMed Google Scholar, and ResearchGate were searched up to September 2021 to find all English randomized clinical trials studying the effect of G. glabra, or its compositions on RAS. Meta-analysis was not conducted because of data heterogeneity. Articles were reviewed qualitatively, and only those with a Jadad score ≥3 were included. Animal studies, in vitro, review papers, non-English papers, and case reports were excluded. Results: Six studies with 314 subjects were included after screening. The result showed licorice has significant effects on RAS pain reduction, ulcer size, and healing time. Its effectiveness is related to its dose-dependent anti-inflammatory and antioxidant effects through several mechanisms. It also has antibacterial effects against Streptococci mutans and Porphyromonas gingivalis as another mechanism of action in RAS treatment. In addition, licorice can elevate the epidermal growth factor (EGF) level compared to the control group, which has an essential role in oral mucosal tissue integrity. Conclusion: Licorice extract has been used in different dosage forms, including paste, patch, and mouthwash with concentrations of 1% or 5%. The healing time after licorice therapy is expected to be within 4-8 days. Licorice did not show any adverse effect in the intervention groups, indicating its effectiveness and safety in RAS treatment.

Effectiveness of Zhibai Dihuang pill (Chinese herbal formula) in combination with western drugs in the treatment of recurrent aphthous stomatitis: A systematic review and meta-analysis.

BACKGROUND: The pain caused by recurrent aphthous stomatitis (RAS) and the recurrent nature of RAS lead to diminished quality of life for RAS patients. An alternative treatment for RAS is the oral administration of the Chinese herbal medicine Zhibai Dihuang pill (ZBDHP). Our study aims to investigate the clinical efficacy of ZBDHP when used in combination with Western medicine (WM) for the treatment of RAS and its effectiveness in preventing the recurrence of RAS. METHODS: Following the PRISMA 2020 guidelines, we conducted a literature search on 7 electronic databases according to predefined criteria. The methodological quality of randomized controlled trials (RCTs) was evaluated based on the Cochrane Handbook, and data analysis was performed using RevMan 5.3 software. RESULTS: A meta-analysis which included 7 studies and 669 participants in total was carried out in this study. The quantitative analysis revealed that the combined treatment of ZBDHP and WM has witnessed significantly improved overall clinical efficacy (RR = 1.20, 95% CI [1.12, 1.28], P < .05), reduced recurrence rate (RR = 0.24, 95% CI [0.13, 0.45], P < .05), decreased ulcer area (MD = -0.75, 95% CI [-0.91, -0.59], P < .05), and reduced pain visual simulation score (MD = -0.42, 95% CI [-0.52, -0.33], P < .05). No significant heterogeneity was observed among the studies. Qualitative analysis showed that the combination therapy significantly reduced serum levels of tumor necrosis factor-α (TNF-α), interleukin-6 and interleukin-10, shortened ulcer healing time and pain disappearance time, with no adverse effects observed. CONCLUSION: It was found that the combination of ZBDHP and WM is more effective in treating RAS than the use of WM alone, which thus provides clinicians with a more optimal treatment option. However, due to limitations in the methodological quality of the included original studies and the small sample size, we hold the opinion that more rigorous and scientific clinical trials are needed to further evaluate the efficacy of ZBDHP in treating RAS.

Topical medications for the treatment of recurrent aphthous stomatitis: A network meta-analysis.

BACKGROUND: The present network meta-analysis aims to answer the question "what is the best topical intervention for the treatment of recurrent aphthous stomatitis that can provide an acceptable pain relief and promote wound healing?" METHODS: From inception to October 2022, PubMed, Embase, Scopus, Cochrane Library, and China National Knowledge Infrastructure were searched to identify all potentially eligible randomized controlled trials. The primary outcomes were pain scores and/or healing time, while the secondary outcomes were the associated side effects. The Bayesian network meta-analysis accompanied by a random effect model and 95% credible intervals were calculated. RESULTS: Forty-three randomized controlled trials with a total of 3067 participants, comparing 20 different topical medications, were included. Concerning pain reduction, the network meta-analysis failed to show any statistically significant differences when different topical treatments were compared together or even with a placebo at different time intervals. Except for doxycycline, which showed a statistically significant difference in terms of accelerating healing time, other topical interventions showed no statistically significant differences when compared with placebo or with each other. CONCLUSION: Within the limitations of the current network meta-analysis, it seems that: A low to moderate quality of evidence showed no superiority of any topical treatment over others concerning pain reduction, although rank probability tests revealed sucralfate, doxycycline, hyaluronic acid, and chamomile as the most efficacious treatment options at different evaluation times. Hence, further well-designed clinical trials with larger sample sizes are warranted. Topical doxycycline was shown to be the most efficacious intervention in promoting healing of recurrent aphthous stomatitis.

Systemic and topical treatment methods of recurrent aphthous stomatitis: A systematic review.

AIM: To analyze the latest systemic and topical recurrent aphthous stomatitis (RAS) treatment methods that could help patients in their daily lives. MATERIAL AND METHODS: A systematic literature review was performed of randomized control trials in English identified in MEDLINE (PubMed), Cochrane Central Register of Controlled Trials (Cochrane Library), Researchgate, published between 2018 and 2023. Studies had to be performed in vivo. RESULTS: 34 randomized clinical trials matched all criterias and were included in systematic literature review. A wide variety of topical and systemic agents are suggested for the treatment of RAS. CONCLUSION: Topical medications can promote the healing time of ulcers and relieve the pain, but most of the time can not decrease the frequency of RAS relapse. However, for continuous RAS, treatment with systemic medication should be considered.

Triamcinolone acetonide release modelling from novel bilayer mucoadhesive films: an in vitro study.

OBJECTIVES: Recurrent aphthous stomatitis (RAS) is a painful disorder that commonly appears as ulcers on the oral mucosa, lasting ∼two weeks (minor) to months (major and herpetiform). Current treatment often necessitates the use of topical steroids in the form of pastes, mouthwashes, or gels, but these forms are often ineffective due to inadequate drug contact time with the ulcers. In this study, the performance of novel bilayer mucoadhesive buccal films loaded with triamcinolone acetonide (TA) has been evaluated for targeted drug delivery. METHODS: Experimental mucoadhesive films of hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), and polyvinyl pyrrolidone (PVP) were prepared by the solvent casting method, and ethyl cellulose (EC) was applied as the backing layer. The films were characterized for their physical properties, including swelling index (SI), folding endurance, adhesion force with porcine buccal mucosa, residence time and in-vitro drug release. RESULTS: The data showed that the films were flexible with folding endurance> 300 times. With porcine buccal mucosa i) suitable adhesion forces were obtained (between 2.72 and 4.03 N), ii) residence times of> 24 h, and iii) surface pH between 6.8 and 7.1 indicating they would be non-irritant. All films released 100% TA over 6 h, but with varying profiles. The release of TA (over 6 h) from PVP-free films followed Fickian diffusion kinetics (diffusion-controlled release of drug), whereas the mechanism of release from PVP-containing films was found to be a superposition of diffusion-controlled and erosion-controlled release (anomalous). SIGNIFICANCE: The developed films hold great promise for potentially treating RAS and other oral conditions.

Antibacterial, anti-inflammatory and wet-adhesive poly(ionic liquid)-based oral patch for the treatment of oral ulcers with bacterial infection.

Oral aphthous ulcers are a common inflammatory efflorescence of oral mucosa, presenting as inflammation and oral mucosal damage and manifesting as pain. The moist and highly dynamic environment of the oral cavity makes the local treatment of oral aphthous ulcers challenging. Herein, a poly(ionic liquid)-based diclofenac sodium (DS)-loaded (PIL-DS) buccal tissue adhesive patch fabricated with intrinsically antimicrobial, highly wet environment adhesive properties and anti-inflammatory activities to treat oral aphthous ulcers was developed. The PIL-DS patch was prepared via polymerization of a catechol-containing ionic liquid, acrylic acid, and butyl acrylate, followed by anion exchange with DS-. The PIL-DS can adhere to wet tissues, including mucosa muscles and organs, and efficiently deliver the carried DS- at wound sites, exerting remarkable synergistic antimicrobial (bacteria and fungi) properties. Accordingly, the PIL-DS elicited dual therapeutic effects on oral aphthous ulcers with Staphylococcus aureus infection through antibacterial and anti-inflammatory activities, significantly accelerating oral aphthous ulcer healing as an oral mucosa patch. The results indicated that the PIL-DS patch, with inherently antimicrobial and wet adhesion properties, is promising for treating oral aphthous ulcers in clinical practice. STATEMENT OF SIGNIFICANCE: Oral aphthous ulcers are a common oral mucosal disease, which could lead to bacterial infection and inflammation in severe cases, especially for people with large ulcers or low immunity. However, moist oral mucosa and highly dynamic oral environment make it challenging to maintain therapeutic agents and physical barriers at the wound surface. Therefore, an innovative drug carrier with wet adhesion is urgently needed. Herein, a poly(ionic liquid)-based diclofenac sodium (DS)-loaded (PIL-DS) buccal tissue adhesive patch was developed to treat oral aphthous ulcers showing intrinsically antimicrobial and highly wet environment adhesive properties due to the presence of catechol-containing ionic liquid monomer. Additionally, the PIL-DS showed significantly therapeutic effects on oral aphthous ulcers with S. aureus infection through antibacterial and anti-inflammatory activities. We expect that our work can provide inspiration for the development of treatment for microbially infected oral ulcers.