[Summary and evaluation of randomized controlled trial on Chinese patent medicine in treatment of diabetic foot ulcer].

This study systematically collected, analyzed, and evaluated randomized controlled trial(RCT) in the treatment of diabetic foot ulcer(DFU). The aim as provide references for future studies and to enhance the application of clinical evidence. The RCT of DFU treated with Chinese Patent Medicine was obtained and analyzed using the AI-Clinical Evidence Database of Chinese Patent Medicine(AICED-CPM). The analysis was supplemented with data from CNKI, Wanfang, VIP, SinoMed, PubMed, EMbase, Cochrane Library, and Web of Science. A total of 275 RCTs meeting the requirements were retrieved, with only 7 of them having a sample size of 200 or more. These trials involved 66 different Chinese patent medicine including 25 oral medications, 24 Chinese herbal injections, and 17 external drugs. Among the 33 different intervention/control designs identified, the most common design was Chinese patent medicine + conventional treatment vs conventional treatment(86 cases, 31.27%). Out of the 275 articles included in the literature, 50 did not provide information on the specific course of treatment(18.18%). A total of 10 counting indicators(with a frequency of 426) and 36 measuring indicators(with a frequency of 962) were utilized. The methodological quality of the RCT for the treatment of DFU with Chinese patent medicine was found to be low, with deficiencies in blind methods, other bias factors, study registration, and sample size estimation. There were noticeable shortcomings in the reporting of allocation hiding and implementation bias(blind method application). More studies should prioritize trial registration, program design, and strict quality control during implementation to provide valuable data for clinical practice and serve as a reference for future investigations.

Topical pravibismane as adjunctive therapy for moderate or severe diabetic foot infections: A phase 1b randomized, multicenter, double-blind, placebo-controlled trial.

This Phase 1b study was designed to evaluate the safety and efficacy of pravibismane, a novel broad-spectrum topical anti-infective, in managing moderate or severe chronic diabetic foot ulcer (DFU) infections. This randomized, double-blind, placebo-controlled, multicenter study consisted of 39 individuals undergoing pravibismane treatment and 13 individuals in the placebo group. Assessment of safety parameters included clinical observations of tolerability and pharmacokinetics from whole blood samples. Pravibismane was well-tolerated and exhibited minimal systemic absorption, as confirmed by blood concentrations that were below the lower limit of quantitation (0.5 ng/mL) or in the low nanomolar range, which is orders of magnitude below the threshold of pharmacological relevance for pravibismane. Pravibismane treated subjects showed approximately 3-fold decrease in ulcer size compared to the placebo group (85% vs. 30%, p = 0.27). Furthermore, the incidence of ulcer-related lower limb amputations was approximately 6-fold lower (2.6%) in the pooled pravibismane group versus 15.4% in the placebo group (p = 0.15). There were no treatment emergent or serious adverse events related to study drug. The initial findings indicate that topical pravibismane was safe and potentially effective treatment for improving recovery from infected chronic ulcers by reducing ulcer size and facilitating wound healing in infected DFUs (ClinicalTrials.gov Identifier NCT02723539).

Advanced multifunctional hydrogels for diabetic foot ulcer healing: Active substances and biological functions.

AIM: Hydrogels with excellent biocompatibility and biodegradability can be used as the desirable dressings for the therapy of diabetic foot ulcer (DFU). This review aimed to summarize the biological functions of hydrogels, combining with the pathogenesis of DFU. METHODS: The studies in the last 10 years were searched and summarized from the online database PubMed using a combination of keywords such as hydrogel and diabetes. The biological functions of hydrogels and their healing mechanism on DFU were elaborated. RESULTS: In this review, hydrogels were classified by their active substances such as drugs, cytokines, photosensitizers, and biomimetic peptide. Based on this, the biological functions of hydrogels were summarized by associating the pathogenesis of DFU, including oxidative stress, chronic inflammation, cell phenotype change, vasculopathy, and infection. This review also pointed out some of the shortcomings of hydrogels in present researches. CONCLUSIONS: Hydrogels were classified into carrier hydrogels and self-functioning hydrogels in this review. Besides, the functions and components of existing hydrogels were clarified to provide assistance for future researches and clinical applications.

Developing an interprofessional decision support tool for diabetic foot ulcers management in primary care within the family medicine group model: a Delphi study in Canada.

BACKGROUND: Primary care professionals encounter difficulties coordinating the continuum of care between primary care providers and second-line specialists and adhere to practice guidelines pertaining to diabetic foot ulcers management. Family medicine groups are providing primary care services aimed to improve access, interdisciplinary care, coordination and quality of health services, and reduce emergency department visits. Most professionals working in family medicine groups are primary care physicians and registered nurses. The aim of this study was to develop and validate an interprofessional decision support tool to guide the management of diabetic foot ulcers for primary care professionals working within the family medicine group model. METHODS: A one-page decision tool developed by the research team was validated by an expert panel using a three-round Delphi protocol held between December 2019 and August 2021. The tool includes 43 individual actions and a care pathway from initial presentation to secondary prevention. Data collection was realized with both paper and electronic questionnaires, and answers were compiled in an electronic spreadsheet. Data was analyzed with use of descriptive statistics, and consensus for each item was defined as ≥ 80% agreement. RESULTS: Experts from 12 pre-identified professions of the diabetic foot ulcer interdisciplinary care team were included, 39 participants out of the 59 invited to first round (66.1%), 34 out of 39 for second (87.2%) and 22 out of 34 for third (64.7%) rounds. All items included in the final version of the decision support tool reached consensus and were deemed clear, relevant and feasible. One or more professionals were identified to be responsible for every action to be taken. CONCLUSIONS: This study provided a comprehensive decision support tool to guide primary care professionals in the management of diabetic foot ulcers. Implementation and evaluation in the clinical setting will need to be undertaken in the future.

Microbiological Distribution, Antimicrobial Susceptibility and Risk Factors of Polymicrobial Infections in Diabetic Foot.

BACKGROUND: Diabetic foot infection (DFI) leads to poor prognosis and polymicrobial infections are usually the main cause. The study is to explore the microbiological distribution, antimicrobial drug susceptibility, and risk factors of polymicrobial infections in hospitalized patients with DFI. METHODS: This retrospective study included 160 patients with DFI in Wagner's grades 2, 3, and 4. Deep necrotic tissue was used to acquire specimens for microbiological culture. VITEK-2 system and MALDI-TOF mass spectrometry were used to identify the bacterial isolates. The Kirby Bauer method was used for drug susceptibility tests. RESULTS: A total of 202 pathogens were isolated. The proportion of gram-negative bacilli (GNB, 62.4%, 126 of 202) was higher than that of gram-positive cocci (GPC, 37.6%, 76 of 202). The most prevalent GPC was Staphylococcus aureus in every Wagner grade, while the most common GNB varied in different Wagner grades. Linezolid was the most effective antibiotic for GPC in different Wagner grades. Imipenem was the most effective antibiotic for GNB in Wagner grade 2. Amikacin was the most effective antibiotic for GNB in Wagner grades 3 and 4. Polymicrobial infections existed only in Wagner grades 3 and 4 and increased the risk of amputation (p < 0.01). History of antibiotics, duration of diabetic foot, CRP, and lower extremity arterial disease were the independent risk factors of polymicrobial infections (p < 0.05). CONCLUSIONS: Clinicians should adjust the antibiotic as needed based on the results of drug susceptibility and clinical treatment effect among different Wagner grades. Particular attention should be given to the treatment of polymicrobial infections.

Timolol in the treatment of hard-to-heal wounds: a comprehensive review.

OBJECTIVE: The aims of this study were to ascertain the effectiveness and safety of the off-label use of topical timolol as an adjunct treatment for hard-to-heal (chronic) wounds. Furthermore, to review and analyse the existing literature regarding the use of topical timolol on wounds of varying aetiologies. METHOD: A systematic review of literature in the English language published between May 1961-May 2021 on the application of topical timolol for hard-to-heal wounds in adults was performed. Each research study was evaluated by two reviewers independently. Studies eligible for inclusion in the review were randomised controlled trials (RCTs), clinical trials, observational studies of at least 4 weeks' duration, case series and case studies. Search strategies were performed according to PRISMA guidelines and included MeSH terms and keyword searches. RESULTS: An initial 878 articles were identified from a search of PubMed, Ovid Medline, Embase, Cochrane, and SCOPUS. Of these, 699 were reviewed for eligibility, 19 were read in full-text, and 12 were selected for inclusion in the review. In total, two RCTs and 10 observational studies, including five case studies, were analysed. All studies demonstrated efficacy and safety of topical timolol; however, statistical analysis remained limited by lack of blinding and small sample sizes. CONCLUSION: This review concludes with all currently available evidence that topical timolol may be considered as an effective and safe adjunct treatment for refractory wounds, primarily venous leg ulcers and diabetic foot ulcers. Given the overall safety, low cost and ease of application of topical timolol, this review provides evidence in favour of off-label use and should prompt further, more rigorous studies.

Effect of denosumab on inflammation and bone health in active Charcot foot: A phase II randomised controlled trial.

AIMS: We aimed to investigate the effect of denosumab on pedal bone health and clinical resolution in active Charcot foot (CN). METHODS: This multicentre open-label phase 2 randomised controlled trial recruited adults with diabetes mellitus and active CN within 3 months of onset. Participants were randomised to standard care alone, or with denosumab 60 mg subcutaneously. Denosumab was administered at baseline and again at 6 months, unless foot temperature had normalised (i.e. <2 °C compared to contralateral foot). Co-primary outcomes were change in calcaneal Stiffness Index and foot temperature normalisation over 18 months. RESULTS: Twelve participants per group were analysed; mean age 58 ± 11 years, 83 % male and 92 % had type 2 diabetes. Active CN duration was median 8 (IQR 7-12) weeks. Ninety-two percent were Eichenholtz stage 1 and 96 % involved the midfoot. After 1-month, median decline in Stiffness Index was less in the denosumab verses standard care group (0.5 [IQR -1.0 to 3.9] vs -2.8 [-8.5 to -1.0], p = 0.008). At 18-months, 92 % of the denosumab group attained foot temperature normalisation versus 67 % of the standard care group (p = 0.13). CONCLUSIONS: Denosumab ameliorated the early decline in calcaneal Stiffness Index associated with active CN. However, no difference in normalisation of foot temperature was observed.

Discussion on the mechanism of Danggui Sini decoction in treating diabetic foot based on network pharmacology and molecular docking and verification of the curative effect by meta-analysis.

Objective: The main active components and mechanism of Danggui Sini decoction (DSD) in treating diabetic foot (DF) were studied and verified by network pharmacology and molecular docking. Evidence-based medicine was used to prove its efficacy. Methods: The TCMSP systematic pharmacology platform screened out DSD's practical components and targets-screening disease targets in GeneCards database, using Cytoscape 3.7.2 to draw DSD-active ingredient-target network diagram, and drawing the protein interaction network diagram through STRING database. The Metascape platform was used to analyze the GO function enrichment and KEGG signal pathway. The molecular docking experiment was carried out by using Auto Dock vina 4.2. The related literature on DSD in treating DF in China Zhiwang, Wanfang, Weipu, and China Biomedical Literature Database was searched. The literature was screened, data was extracted, and quality was evaluated according to the inclusion and exclusion criteria. Then, a meta-analysis was performed using RevMan 5.3 software. Results: A total of 256 targets of all effective components of DSD were obtained. Among 1,272 disease targets, there are 113 common targets. The GO analysis received 6,179 entries, and the KEGG pathway enrichment analysis found 251 related pathways. The molecular docking results of the main targets of diabetic foot and the active substances of DSD all showed a high docking activity. The meta-analysis included six literature, all of which were randomized controlled experiments. The quality grade of the literature was C, and the results showed that the total effective rate of clinical efficacy in the experimental group was significantly higher than that in the control group. Conclusions: DSD may treat DF by participating in biological processes such as cell proliferation regulation, inflammatory reaction, oxidative stress reaction, and promotion of angiogenesis. DSD treats DF through AKT1, TP53, IL6, TNF, VEGFA, and other targets. DSD plays a role in treating DF mainly through the AGE-RAGE signaling pathway and PI3K-AKT signaling pathway. The molecular docking results of AKT1, TP53, IL-6, TNF, and VEGFA with the active substances of DSD show that they all have a high docking activity; among them, VEGFA has a higher docking activity. Compared with conventional treatment, DSD has a high effective rate, short wound healing time, large wound healing area, and high ABI index.

Extended-Spectrum Beta-Lactamase Escherichia coli Diabetic Foot Osteomyelitis Causing Sausage Toe Deformity: Successful Therapy with Ertapenem in the Outpatient Setting.

BACKGROUND Diabetic foot osteomyelitis is a high-morbidity and debilitating complication of diabetic foot ulcers that contributes to significantly worse quality of life in the affected population and higher cost of healthcare services. One of the clinical presentations of diabetic foot osteomyelitis is the 'sausage' toe deformity, which affects the phalanges (local soft tissue infection and underlying bony changes). This deformity is highly suggestive of the presence of osteomyelitis. Unfortunately, during recent years, the emergence of antibiotic-resistant bacteria have created great difficulties in choosing appropriate empirical antibiotics for the treatment of diabetic foot infections. Multidrug-resistant pathogens have been strongly related to higher morbidity and mortality compared with infections caused by their antibiotic-susceptible counterparts. CASE REPORT We describe a case of a 74-year-old woman with long-standing insulin-treated type 2 diabetes, who experienced extended-spectrum beta-lactamase-producing Escherichia coli infection that caused diabetic foot osteomyelitis with 'sausage' deformity in her second right toe. She was successfully treated with surgical debridement combined with the administration of ertapenem in the outpatient setting, completing, in total, a 6-week course of antibiotic therapy. CONCLUSIONS 'Sausage' toe deformity is one of the clinical presentations of diabetic foot osteomyelitis, and should be an alarming sign in everyday clinical practice. Ertapenem is an excellent option for the treatment of diabetic foot infections caused by extended-spectrum beta-lactamase E. coli in the outpatient setting. Early diagnosis and proper therapeutic approach are of great importance to reduce the risk of amputations, overall mortality, total cost, and the surge of antimicrobial resistance in the community.

The effect of traditional Chinese medicine soaking method on the healing of diabetic foot ulcers: A meta-analysis.

Foot infections, sores or deep tissue damage from diabetes can be a serious psychological and physical injury. This paper aims at making meta-analyses on the therapeutic effects of traditional Chinese medicine (TCM) on diabetic foot ulcers. The Chinese National Knowledge Infrastructure, VIP Database, Wanfang Database and so on, has conducted a randomized controlled trial to evaluate the clinical effect of TCM soaking method for diabetes patients with diabetes. Literature has been determined to be included by computer search and by hand rough checks. The search period was from the creation of the database to October 2023. Review Manager 5.3 was used to analyse the meta data and evaluate it systematically. Altogether, 479 research was conducted in China's data base and 20 of them were eventually collected for the final statistical analysis. In all, 1361 patients were enrolled in the trials. The results indicated that TCM immersion in diabetic foot resulted in significantly improved obvious wound healing (OR, 3.2; 95% CI, 2.5, 4.09, p < 0.0001); results showed that TCM immersion therapy significantly increased the efficiency of effective wound healing (OR, 4.55; 95% CI, 3.25, 6.37, p < 0.001). Statistical significance was found. Using Egger's approach to detect publishing bias suggests that there is no risk of publishing bias in terms of marked wound healing and effective healing. Traditional Chinese drug immersion can increase obviously the recovery ratio and the effective recovery ratio of diabetic foot.

Successful topical treatment of human biofilms using multiple antibiotic elution from a collagen-rich hydrogel.

Chronic non-healing wounds significantly strain modern healthcare systems, affecting 1-2% of the population in developed countries with costs ranging between $28.1 and $96.8 billion annually. Additionally, it has been established that chronic wounds resulting from comorbidities, such as peripheral vascular disease and diabetes mellitus, tend to be polymicrobial in nature. Treatment of polymicrobial chronic wounds with oral and IV antibiotics can result in antimicrobial resistance, leading to more difficult-to-treat wounds. Ideally, chronic ulcers would be topically treated with antibiotic combinations tailored to the microbiome of a patient's wound. We have previously shown that a topical collagen-rich hydrogel (cHG) can elute single antibiotics to inhibit bacterial growth in a manner that is nontoxic to mammalian cells. Here, we analyzed the microbiology of cultures taken from human patients diagnosed with diabetes mellitus suffering from chronic wounds present for more than 6 weeks. Additionally, we examined the safety of the elution of multiple antibiotics from collagen-rich hydrogel in mammalian cells in vivo. Finally, we aimed to create tailored combinations of antibiotics impregnated into cHG to successfully target and treat infections and eradicate biofilms cultured from human chronic diabetic wound tissue. We found that the majority of human chronic wounds in our study were polymicrobial in nature. The elution of multiple antibiotics from cHG was well-tolerated in mammalian cells, making it a potential topical treatment of the polymicrobial chronic wound. Finally, combinations of antibiotics tailored to each patient's microbiome eluted from a collagen-rich hydrogel successfully treated bacterial cultures isolated from patient samples via an in vitro assay.

Use of amniotic membrane in hard-to-heal wounds: a multicentre retrospective study.

OBJECTIVE: Hard-to-heal (chronic) wounds negatively impact patients and are a source of significant strain on the healthcare system and economy. These wounds are often resistant to standard of care (SoC) wound healing approaches due to a diversity of underlying pathologies. Cellular, acellular, and matrix-like products, such as amniotic membranes (AM), are a potential solution to these challenges. A growing body of evidence suggests that AM may be useful for treatment-resistant wounds; however, limited information is available regarding the efficacy of dehydrated amniotic membrane (DHAM) on multi-aetiology, hard-to-heal wounds. Therefore, we analysed the efficacy of DHAM treatment in reducing the size of hard-to-heal diabetic and venous leg ulcers (VLUs) that had failed to improve after SoC-based treatments. METHOD: In this multicentre retrospective study, we analysed wound size during clinic visits for patients being treated for either diabetic or VLUs. During each visit, the treatment consisted of debridement followed by application of DHAM. Each wound was measured after debridement and prior to DHAM application, and wound volumes over time or number of DHAM applications were compared. RESULTS: A total of 18 wounds in 11 patients were analysed as part of this study. Wounds showed a significant reduction in volume after a single DHAM application, and a 50% reduction in wound size was observed after approximately two DHAM applications. These findings are consistent with reports investigating DHAM treatment of diabetic ulcers that were not necessarily resistant to treatment. CONCLUSION: To our knowledge, this study is the first to directly compare the efficacy of standalone DHAM application to hard-to-heal diabetic and venous leg ulcers, and our findings indicate that DHAM is an effective intervention for resolving these types of wounds. This suggests that implementing this approach could lead to fewer clinic visits, cost savings and improved patient quality of life. DECLARATION OF INTEREST: This research was supported in part by Merakris Therapeutics, US, and facilitated access to deidentified patient datasets, which may represent a perceived conflict of interest; however, the primary data analysis was performed by FSB who is unaffiliated with Merakris Therapeutics. TCB is a founder, employee of and shareholder in Merakris Therapeutics; WSF is a co-founder of, consultant for, and shareholder in Merakris Therapeutics, and was also supported by the National Institutes of Health National Center for Advancing Translational Sciences Clinical and Translational Science Awards Grant KL2 Scholars Program (KL2TR001441). The research was also supported through endowments to WSF from the University of Texas Medical Branch Mimmie and Hallie Smith Endowed Chair of Transplant Research and the John L Hern University Chair in Transplant Surgery.

A model for diabetic foot ulcer clinical trials on advanced therapies.

DECLARATION OF INTEREST: TS is a consultant for Inotec AMD Ltd., UK. The authors have no other conflicts of interest to declare.

L-arginine supplementation abrogates hypoxia-induced virulence of Staphylococcus aureus in a murine diabetic pressure wound model.

Diabetic foot ulcers (DFUs) are the most common complications of diabetes resulting from hyperglycemia leading to ischemic hypoxic tissue and nerve damage. Staphylococcus aureus is the most frequently isolated bacteria from DFUs and causes severe necrotic infections leading to amputations with a poor 5-year survival rate. However, very little is known about the mechanisms by which S. aureus dominantly colonizes and causes severe disease in DFUs. Herein, we utilized a pressure wound model in diabetic TALLYHO/JngJ mice to reproduce ischemic hypoxic tissue damage seen in DFUs and demonstrated that anaerobic fermentative growth of S. aureus significantly increased the virulence and the severity of disease by activating two-component regulatory systems leading to expression of virulence factors. Our in vitro studies showed that supplementation of nitrate as a terminal electron acceptor promotes anaerobic respiration and suppresses the expression of S. aureus virulence factors through inactivation of two-component regulatory systems, suggesting potential therapeutic benefits by promoting anaerobic nitrate respiration. Our in vivo studies revealed that dietary supplementation of L-arginine (L-Arg) significantly attenuated the severity of disease caused by S. aureus in the pressure wound model by providing nitrate. Collectively, these findings highlight the importance of anaerobic fermentative growth in S. aureus pathogenesis and the potential of dietary L-Arg supplementation as a therapeutic to prevent severe S. aureus infection in DFUs.IMPORTANCES. aureus is the most common cause of infection in DFUs, often resulting in lower-extremity amputation with a distressingly poor 5-year survival rate. Treatment for S. aureus infections has largely remained unchanged for decades and involves tissue debridement with antibiotic therapy. With high levels of conservative treatment failure, recurrence of ulcers, and antibiotic resistance, a new approach is necessary to prevent lower-extremity amputations. Nutritional aspects of DFU treatment have largely been overlooked as there has been contradictory clinical trial evidence, but very few in vitro and in vivo modelings of nutritional treatment studies have been performed. Here we demonstrate that dietary supplementation of L-Arg in a diabetic mouse model significantly reduced duration and severity of disease caused by S. aureus. These findings suggest that L-Arg supplementation could be useful as a potential preventive measure against severe S. aureus infections in DFUs.

Effect of Chinese herbal compound dressings in treating patients with diabetic foot ulcers: A meta-analysis.

This meta-analysis aims to systematically investigate the clinical efficacy of Chinese herbal compound dressings in treating patients with diabetic foot ulcers (DFUs). A comprehensive computerised search was conducted in databases including PubMed, Embase, Google Scholar, Cochrane Library, China National Knowledge Infrastructure, and Wanfang databases, from database inception to November 2023, to identify randomised controlled trials (RCTs) concerning the use of Chinese herbal compound dressings in patients with DFU. Two researchers independently screened the literature, extracted data, and assessed the quality based on inclusion and exclusion criteria. Data analysis was performed using Stata 17.0 software. Overall, 18 RCTs involving 1405 DFU patients were included. The analysis indicated that compared to the control group, the group treated with Chinese herbal compound dressings had significantly shorter ulcer healing time (standardised mean difference [SMD] = -2.49, 95% confidence interval [CI]: -3.53 to -1.46, p < 0.001), reduced ulcer surface area (SMD = -3.38, 95% CI: -4.67 to -2.09, p < 0.001), and higher healing rates (odds ratio [OR] = 2.24, 95% CI: 1.72-2.92, p < 0.001) as well as overall effectiveness rates (OR = 4.56, 95% CI: 3.10-6.71, p < 0.001). This study demonstrates that the external application of Chinese herbal compound dressings in patients with DFU can significantly shorten the ulcer healing time and improve wound healing rates.

Association between antidepressants and the risk of diabetic foot ulcers and amputation in antidepressant-naïve type 2 diabetes mellitus patients: A nested case-control study.

AIMS: Antidepressants are widely used by individuals with type 2 diabetes mellitus (T2DM). This study aimed to explore the correlation between antidepressant use, considering specific antidepressant subclasses or cumulative doses, and diabetic foot ulcer (DFU) risk. METHODS: This nested case-control study was conducted using a representative population-based Korean cohort database from 2002 to 2019. Participants with DFUs were matched with participants without DFUs based on age, sex, date of T2DM diagnosis, and follow-up duration. In total, 791 DFUs and 3900 controls were included. The association between antidepressant use or cumulative dose of each antidepressant subclass, DFU risk and amputation risk was examined using a conditional logistic regression model. RESULTS: Antidepressant ever-use was associated with an increased incidence of DFUs compared with non-use. Furthermore, an increase in DFU risk was evident with increasing cumulative antidepressant dosage, particularly among tricyclic antidepressant (TCA) ever-users and selective serotonin reuptake inhibitors (SSRIs) ever-users. Additionally, antidepressant ever-users displayed a higher risk of DFUs requiring amputation, which was consistently observed when the cumulative dosages of overall antidepressants and TCAs were considered. CONCLUSION: Caution is advised when administering TCAs and SSRIs in antidepressant-naïve T2DM patients to reduce DFU and the consequent amputation risk.

Healing of diabetic foot ulcer with topical and oral administrations of herbal products: A systematic review and meta-analysis of randomized controlled trials.

This systematic review aimed to qualitatively synthesize recent randomized controlled trials (RCTs) regarding the effect of topical application and oral intake of herbal products on the healing of diabetic foot ulcer (DFU). Also, we sought to pool the obtained findings in a meta-analysis using a random-effects model, if RCTs were relatively comparable and homogenous. A comprehensive search was performed on five electronic data sources from their inception through 23 January 2024. The RCTs, without restriction on the country of origin, were included if they compared the effect of administering standard treatments and/or placebo (i.e. control condition) to applying standard treatments and/or herbal products in topical or oral routes (i.e. experimental condition). Out of 1166 retrieved records, 28 RCTs were included. Studies used different poly and single herbal formulations. Based on the meta-analysis, administration of standard care plus daily dressing of the ulcer site with olive oil for 28 days significantly increased the total ulcer healing score (3 RCTs; weighted mean difference [WMD] = 89.30; p < 0.001), raised frequency of complete ulcer healing (2 RCTs; risk ratio [RR] = 12.44; p = 0.039) and declined ulcer degree (3 RCTs; WMD = -22.28; p = 0.002). Also, daily use of the bitter melon leaf extract in oral form for 28 days significantly increased the total ulcer healing score (2 RCTs; WMD = 0.40; p = 0.001). Additionally, based on qualitative synthesis, the adjuvant use of herbal agents seems an intriguing choice to manage DFU. Nonetheless, considering the undesirable methodological quality of most studies and the high heterogeneity in administered herbal formulations, more robust trials are required to build a solid conclusion regarding the use of herbal products for healing DFU.

Effectiveness of Ya-Samarn-Phlae in diabetic wound healing: Evidence from in vitro studies and a multicenter randomized controlled clinical trial.

ETHNOPHARMACOLOGICAL RELEVANCE: Ya-Samarn-Phlae (YaSP) has traditionally been widely used in southern Thailand for treating chronic and infected wounds, including diabetic foot ulcers. However, there are only a limited number of clinical studies supporting the use of this polyherbal formulation. Therefore, the present work aims to provide clinical evidence to support the application of YaSP, prepared according to a standardized traditional procedure (T-YaSP). Additionally, its potential chemical markers and wound healing-related biological activities were examined. MATERIALS AND METHODS: The in vitro wound healing-related biological activities of YaSP ethanol extract and T-YaSP, including antibacterial activity against Staphylococcus epidermidis, inhibition and eradication of staphylococcal biofilm, anti-inflammatory effects, and enhancement of human dermal fibroblast migration in scratch wounds, were examined using well-established protocols. The chemical profiles of the ethanol extract of YaSP and T-YaSP were compared, and with promising chemical markers, arecoline, alpha-mangostin, and curcumin were selected and quantified using the HPLC method. A prospective, multicenter, randomized, controlled, parallel-group study was conducted over 12 weeks to evaluate the efficacy of the YaSP solution as an adjunct therapy, combined with standard wound care, for diabetic ulcers compared to standard treatment. RESULTS: The YaSP extract reduces NO production and can scavenge NO radicals in LPS-induced RAW 264.7 macrophage cells. Additionally, in a scratch assay, this extract and one of its herbal components, Curcuma longa, enhance the migration of human dermal fibroblasts. T-YaSP, containing 2.412 ± 0.002 mg/g of arecoline, 2.399 ± 0.005 mg/g of curcumin, and 0.017 ± 0.000 mg/g of α-mangostin, has shown the ability to inhibit the development and eradicate the mature biofilm of S. epidermidis. The use of T-YaSP as an adjunct therapy led to a significantly higher proportion of patients achieving healing within six weeks compared to the standard treatment group (36%/9 patients vs. 4%/1 patient; p = 0.013). After 12 weeks, 19 out of 25 patients in the T-YaSP group experienced complete healing, whereas only four patients in the standard treatment group achieved complete wound healing (76% in the T-YaSP group vs. 16% in the control group; p < 0.001). CONCLUSION: The results presented here represent the first randomized controlled trial to demonstrate the effectiveness of the traditional polyherbal solution, T-YaSP, which exhibits a wide range of wound healing-related activities. Utilizing T-YaSP as an adjunctive treatment resulted in a significant improvement in the number of type 2 diabetic patients achieving complete healing. However, to explore and utilize YaSP further, conducting a double-blind, randomized controlled trial with a larger population is necessary.

Efficacy of acellular fish skin graft in the management of chronic ulcer: a systematic review and meta-analysis.

BACKGROUND: The wounds failing to heal through a timely and orderly standard of care (SOC) treatment are considered as chronic wounds, which add significant burden to healthcare systems around the world. SOC treatment has been commonly applied for management of chronic wounds, but SOC alone may not be adequate to heal all ulcers effectively. Fish skin graft (FSG) is a xenogenic skin substitute which could be used for accelerating skin healing. The current study was performed with the view of evaluating the effectiveness of FSG as an adjuvant treatment of SOC for chronic ulcer treatment. METHODS: Two authors independently searched the following electronic databases: PubMed, Embase, and CENTRAL, using keywords including "diabetic foot ulcer," "fish skin graft," and "wound healing." Clinical studies that evaluated the clinical outcomes of FSG in treatment of chronic ulcers were included in this meta-analysis. Random- or fixed-effect modeled meta-analyses were performed according to the heterogeneity test result (i.e., I2), to analyze the clinical outcome of FSG. RESULTS: A total of 8 studies were included in qualitative synthesis and meta-analysis, with 145 patients treated by SOC and 245 patients treated by SOC plus FSG. There was no significant difference between two groups for time to healing (MD = 1.99, 95% CI: -3.70~7.67, p = 0.493). The complete healing rate was significantly higher in FSG group compared with SOC alone (OR = 3.44, 95% CI: 2.03~5.82, p < 0.001***). Mean percentage area reduction (PAR) was reported in six studies, with a range of 71.6~97.3%. However, many of these studies did not report the value of standard deviation (SD), so we could not pool the data. No significantly different ulcer recurrence rate (RR = 0.60, 95% CI: 0.07~5.27, p = 0.645) and severe adverse events (SAEs) risk (RR = 1.67, 95% CI: 0.42~6.61, p = 0.467) were found between two groups. CONCLUSIONS: The application of FSG treatment for patients with chronic ulcers that do not respond well to SOC management could significantly increase the complete healing rate compared with SOC alone, without increased recurrence rate and SAEs risk.

Treatment of clinically uninfected diabetic foot ulcers, with and without antibiotics.

OBJECTIVE: Current guidelines do not recommend the use of antibiotics to treat clinically uninfected ulcers. However, physicians continue to prescribe antibiotics for clinically uninfected ulcers with the rationale 'better to be safe than sorry'. Yet, antibiotic resistance is increasing, side-effects are common and treatment costs are rising. Evidence is needed to identify whether antibiotic treatment for clinically uninfected ulcers can be justified or we should stop prescribing them. The aim of this study was to evaluate whether antibiotic treatment in cases of clinically uninfected ulcers improved ulcer healing compared to treatment without antibiotics. METHOD: Consecutive patients treated in the outpatient clinic for clinically uninfected diabetic foot ulcer both in 2015 and in 2017 were retrospectively analysed. Primary outcome was ulcer healing at one year. Secondary outcomes were limb salvage, freedom from any amputation, amputation-free survival (AFS) and survival. RESULTS: A total of 102 ulcers of 91 patients were included for final analyses. The non-antibiotics and antibiotics groups both consisted of 51 ulcers. Ulcer healing at one year was 77.3% in the non-antibiotics group and 74.7% in the antibiotics group (p=0.158). No difference was found for limb salvage (93.8% versus 95.9%, respectively; p=0.661), freedom from any amputation (85.6% versus 85.6%, respectively; p=1.000), AFS (85.4% versus 79.1%, respectively; p=0.460) or survival (89.6% versus 83.7%, respectively; p=0.426). CONCLUSION: In this study, no benefits of antibiotic treatment over non-antibiotic treatment for clinically uninfected ulcers were identified. The findings of this study emphasise the recommendation of current guidelines to not treat clinically uninfected ulcer with antibiotics.