Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism.

The biguanide drug metformin is widely prescribed to treat type 2 diabetes and metabolic syndrome, but its mode of action remains uncertain. Metformin also increases lifespan in Caenorhabditis elegans cocultured with Escherichia coli. This bacterium exerts complex nutritional and pathogenic effects on its nematode predator/host that impact health and aging. We report that metformin increases lifespan by altering microbial folate and methionine metabolism. Alterations in metformin-induced longevity by mutation of worm methionine synthase (metr-1) and S-adenosylmethionine synthase (sams-1) imply metformin-induced methionine restriction in the host, consistent with action of this drug as a dietary restriction mimetic. Metformin increases or decreases worm lifespan, depending on E. coli strain metformin sensitivity and glucose concentration. In mammals, the intestinal microbiome influences host metabolism, including development of metabolic disease. Thus, metformin-induced alteration of microbial metabolism could contribute to therapeutic efficacy-and also to its side effects, which include folate deficiency and gastrointestinal upset.

Biguanide-Vancomycin Conjugates are Effective Broad-Spectrum Antibiotics against Actively Growing and Biofilm-Associated Gram-Positive and Gram-Negative ESKAPE Pathogens and Mycobacteria.

Strategies to increase the efficacy and/or expand the spectrum of activity of existing antibiotics provide a potentially fast path to clinically address the growing crisis of antibiotic-resistant infections. Here, we report the synthesis, antibacterial efficacy, and mechanistic activity of an unprecedented class of biguanide-antibiotic conjugates. Our lead biguanide-vancomycin conjugate, V-C6-Bg-PhCl (5e), induces highly effective cell killing with up to a 2 orders-of-magnitude improvement over its parent compound, vancomycin (V), against vancomycin-resistant enterococcus. V-C6-Bg-PhCl (5e) also exhibits improved activity against mycobacteria and each of the ESKAPE pathogens, including the Gram-negative organisms. Furthermore, we uncover broad-spectrum killing activity against biofilm-associated Gram-positive and Gram-negative bacteria as well as mycobacteria not observed for clinically used antibiotics such as oritavancin. Mode-of-action studies reveal that vancomycin-like cell wall synthesis inhibition with improved efficacy attributed to enhanced engagement at vancomycin binding sites through biguanide association with relevant cell-surface anions for Gram-positive and Gram-negative bacteria. Due to its potency, remarkably broad activity, and lack of acute mammalian cell toxicity, V-C6-Bg-PhCl (5e) is a promising candidate for treating antibiotic-resistant infections and notoriously difficult-to-treat slowly growing and antibiotic-tolerant bacteria associated with chronic and often incurable infections. More generally, this study offers a new strategy (biguanidinylation) to enhance antibiotic activity and facilitate clinical entry.

Polyhexanide based contact lens storage fluids frequently exhibit insufficient antifungal activity against Fusarium species.

PURPOSE: Fusarium keratitis is a severe infection of the anterior eye, frequently leading to keratoplasty or surgical removal of the affected eye. A major risk factor for infection is the use of contact lenses. Inadequate hygiene precautions and mold-growth permissive storage fluids are important risk factors for fungal keratitis. The aim of this study was to comparatively analyze contact lens storage fluids disinfection efficacy against Fusarium species. METHODS: Eleven commercially available storage fluids were tested. The storage fluids were classified according to their active ingredients myristamidopropyldimethylamine (Aldox), polyhexanide and hydrogen peroxide. Efficacy was tested against isolates belonging to the Fusarium solani and Fusarium oxysporum species complexes as the most common agents of mould keratitis. Tests were carried out based on DIN EN ISO 14729. RESULTS: All Aldox and hydrogen peroxide (H2O2) based fluids were effective against Fusarium spp., while the majority of polyhexanide based storage fluids showed only limited or no antifungal effects. Efficacy of polyhexanide could be restored by the addition of the pH-regulating agent tromethamine - an additive component in one commercially available product. CONCLUSIONS: In summary, the use of Aldox- or hydrogen peroxide-based storage fluids may reduce the risk of Fusarium keratitis, while polyhexanide-based agents largely lack efficacy against Fusarium.

The Orphan Drug for Acanthamoeba Keratitis (ODAK) Trial: PHMB 0.08% (Polihexanide) and Placebo versus PHMB 0.02% and Propamidine 0.1.

PURPOSE: To compare topical PHMB (polihexanide) 0.02% (0.2 mg/ml)+ propamidine 0.1% (1 mg/ml) with PHMB 0.08% (0.8 mg/ml)+ placebo (PHMB 0.08%) for Acanthamoeba keratitis (AK) treatment. DESIGN: Prospective, randomized, double-masked, active-controlled, multicenter phase 3 study (ClinicalTrials.gov identifier, NCT03274895). PARTICIPANTS: One hundred thirty-five patients treated at 6 European centers. METHODS: Principal inclusion criteria were 12 years of age or older and in vivo confocal microscopy with clinical findings consistent with AK. Also included were participants with concurrent bacterial keratitis who were using topical steroids and antiviral and antifungal drugs before randomization. Principal exclusion criteria were concurrent herpes or fungal keratitis and use of antiamebic therapy (AAT). Patients were randomized 1:1 using a computer-generated block size of 4. This was a superiority trial having a predefined noninferiority margin. The sample size of 130 participants gave approximately 80% power to detect 20-percentage point superiority for PHMB 0.08% for the primary outcome of the medical cure rate (MCR; without surgery or change of AAT) within 12 months, cure defined by clinical criteria 90 days after discontinuing anti-inflammatory agents and AAT. A prespecified multivariable analysis adjusted for baseline imbalances in risk factors affecting outcomes. MAIN OUTCOME MEASURES: The main outcome measure was MCR within 12 months, with secondary outcomes including best-corrected visual acuity and treatment failure rates. Safety outcomes included adverse event rates. RESULTS: One hundred thirty-five participants were randomized, providing 127 in the full-analysis subset (61 receiving PHMB 0.02%+ propamidine and 66 receiving PHMB 0.08%) and 134 in the safety analysis subset. The adjusted MCR within 12 months was 86.6% (unadjusted, 88.5%) for PHMB 0.02%+ propamidine and 86.7% (unadjusted, 84.9%) for PHMB 0.08%; the noninferiority requirement for PHMB 0.08% was met (adjusted difference, 0.1 percentage points; lower one-sided 95% confidence limit, -8.3 percentage points). Secondary outcomes were similar for both treatments and were not analyzed statistically: median best-corrected visual acuity of 20/20 and an overall treatment failure rate of 17 of 127 patients (13.4%), of whom 8 of 127 patients (6.3%) required therapeutic keratoplasty. No serious drug-related adverse events occurred. CONCLUSIONS: PHMB 0.08% monotherapy may be as effective (or at worse only 8 percentage points less effective) as dual therapy with PHMB 0.02%+ propamidine (a widely used therapy) with medical cure rates of more than 86%, when used with the trial treatment delivery protocol in populations with AK with similar disease severity. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Mechanistic insights into antifungal potential of Alexidine dihydrochloride and hexachlorophene in Candida albicans: a drug repurposing approach.

Candida albicans has been listed in the critical priority group by the WHO in 2022 depending upon its contribution in invasive candidiasis and increased resistance to conventional drugs. Drug repurposing offers an efficient, rapid, and cost-effective solution to develop alternative therapeutics against pathogenic microbes. Alexidine dihydrochloride (AXD) and hexachlorophene (HCP) are FDA approved anti-cancer and anti-septic drugs, respectively. In this study, we have shown antifungal properties of AXD and HCP against the wild type (reference strain) and clinical isolates of C. albicans. The minimum inhibitory concentrations (MIC50) of AXD and HCP against C. albicans ranged between 0.34 and 0.69 µM and 19.66-24.58 µM, respectively. The biofilm inhibitory and eradication concentration of AXD was reported comparatively lower than that of HCP for the strains used in the study. Further investigations were performed to understand the antifungal mode of action of AXD and HCP by studying virulence features like cell surface hydrophobicity, adhesion, and yeast to hyphae transition, were also reduced upon exposure to both the drugs. Ergosterol content in cell membrane of the wild type strain was upregulated on exposure to AXD and HCP both. Biochemical analyses of the exposed biofilm indicated reduced contents of carbohydrate, protein, and e-DNA in the extracellular matrix of the biofilm when compared to the untreated control biofilm. AXD exposure downregulated activity of tissue invading enzyme, phospholipase in the reference strain. In wild type strain, ROS level, and activities of antioxidant enzymes were found elevated upon exposure to both drugs. FESEM analysis of the drug treated biofilms revealed degraded biofilm. This study has indicated mode of action of antifungal potential of alexidine dihydrochloride and hexachlorophene in C. albicans.

Time trends and regional variation in utilization of antidiabetic medicines in China, 2015-2022.

AIM: To assess the use of non-insulin antidiabetic medicines in China. MATERIALS AND METHODS: We analysed the national procurement data for 29 non-insulin antidiabetic medicines from nine subgroups in China from 2015 to 2022. We estimated the number of defined daily doses (DDDs) procured per year in seven regions of China for nine subgroups and adjusted the data by the number of patients with diabetes. For each subgroup, the regional ratio was calculated by comparing the procurement per patient in each region with the procurement nationwide. The regional disparity was the difference between the highest and lowest regional ratios. We compared the medication patterns across regions. RESULTS: Nationally, between 2015 and 2022, the number of DDDs per patient increased from 14.45 to 47.37. The two most commonly used categories were sulphonylurea and biguanides, which increased from 7.04 to 15.39 (119%) and 3.28 to 11.11 (239%) DDDs per patient, respectively. The procurement of new drugs (dipeptidyl peptidase-4 inhibitors, sodium-glucose cotransporter type 2 inhibitors and glucagon-like peptide-1 receptor agonists) increased quickly and had >5000% relative changes. Particularly for sodium-glucose cotransporter type 2 inhibitors, it increased from 0.08 to 5.03 DDDs (6662%). The southwest region had the highest relative change (319%), while the southern region had the lowest (118%). Biguanide and thiazolidinediones had the lowest (1.19) and highest level (2.21) of regional disparity in 2022, respectively. CONCLUSION: The procurement of non-insulin antidiabetic medicines in China has increased a lot from 2015 to 2022. In terms of DDDs per patient, sulphonylurea ranked first, followed by metformin. The procurement of new drugs increased greatly. A large regional disparity existed in medicine usage and patterns.

Novel Effective Medical Therapy for Acanthamoeba Keratitis.

PURPOSE: To report first clinical use of novel medical treatment for Acanthamoeba keratitis. METHODS: Interventional observational case series. Two patients with Acanthamoeba keratitis were unsuccessfully treated with polihexanide (PHMB) 0.02% and propamidine 0.1% for 6 weeks, then all were shifted in a compassionate use of PHMB 0.08% with novel standardized protocol. The postinterventional follow-up of patients was at least 7 months. RESULTS: PHMB 0.08% eyedrops in a novel standardized protocol improved infection resolution and led to complete healing of the lesion after 4 weeks in the two cases. Corneal opacities and neovascularization decreased slowly, best-corrected visual acuity slightly improved and progressively increased in the further 7 months, and no infection recurrence occurred. CONCLUSIONS: This preliminary report of two cases shows promising response to polihexanide 0.08% lowering drastically the illness duration, with reduced chance of recurrence, and mostly improving patients' quality of life.

Safety and effectiveness of an antiseptic wound cleansing and irrigation solution containing polyhexamethylene biguanide.

OBJECTIVE: There is currently a wide range of cleansing and irrigation solutions available for wounds, many of which contain antimicrobial agents. The aim of this study was to assess the safety of HydroClean Solution (HARTMANN, Germany), a polyhexamethylene biguanide (PHMB)-containing irrigation solution, in a standard cytotoxicity assay, and to assess its effect in a three-dimensional (3D) full-thickness model of human skin. METHOD: A number of commercially available wound cleansing and irrigation solutions, including the PHMB-containing irrigation solution, were tested in a cytotoxicity assay using L929 mouse fibroblasts (ISO 10993-5:2009). The PHMB-containing irrigation solution was then assessed in an in vitro human keratinocyte-fibroblast 3D full-thickness wounded skin model to determine its effect on wound healing over six days. The effect of the PHMB-containing irrigation solution on tissue viability was measured using a lactate dehydrogenase (LDH) assay, and proinflammatory effects were measured using an interleukin-6 (IL-6) production assay. RESULTS: The PHMB-containing irrigation solution was shown to be equivalent to other commercially available cleansing and irrigation solutions when tested in the L929 fibroblast cytotoxicity assay. When assessed in the in vitro 3D human full-thickness wound healing model, the PHMB-containing irrigation solution treatment resulted in no difference in levels of LDH or IL-6 when compared with levels produced in control Dulbecco's phosphate-buffered saline cultures. There was, however, a pronounced tissue thickening of the skin model in the periwound region. CONCLUSION: The experimental data presented in this study support the conclusion that the PHMB-containing irrigation solution has a safety profile similar to other commercially available cleansing and irrigation solutions. Evidence also suggests that the PHMB-containing irrigation solution does not affect tissue viability or proinflammatory cytokine production, as evidenced by LDH levels or the production of IL-6 in a 3D human full-thickness wound healing model. The PHMB-containing irrigation solution stimulated new tissue growth in the periwound region of the skin model.

Clinical use of 0.1% polyhexanide and propylbetaine on acute and hard-to-heal wounds: a literature review.

OBJECTIVE: To summarise the findings on the effect of the clinical use of 0.1% polyhexanide-propylbetaine (PHMB/betaine) solution/gel on acute and hard-to-heal (chronic) wound healing. METHOD: A literature search was conducted in MEDLINE, CINAHL, Embase, Scopus and the CENTRAL Trials Registry of the Cochrane Collaboration. Paired reviewers conducted title and abstract screening and full-text screening to identify experimental, quasi-experimental and observational studies. Study quality and risk of bias were not formally evaluated. RESULTS: A total of 17 studies met the eligibility criteria. The findings from 12 studies indicated that the use of 0.1% PHMB/betaine solution/gel had: a low risk of contact sensitivity; could help debridement during wound cleansing; aided effective wound bed preparation; reduced wound size, odour and exudate; improved pain control; reduced microbial load; and enhanced wound healing. The results of three studies indicated that both 0.1% PHMB and saline solution were effective in reducing bacterial load, while another showed that adding 0.1% PHMB to tie-over dressings had no effect on reducing bacterial loads in wounds. Another study concluded that disinfection and granulation of pressure ulcers with hydrobalance dressing with 0.3% PHMB was faster and more effective than using 0.1% PHMB/betaine. CONCLUSION: The findings of this literature review showed that 0.1% PHMB/betaine solution/gel appeared to be useful and safe for wound cleansing, was effective in removing soft debris and slough from the wound bed, and created a wound environment optimal for healing. Although these actions cannot be attributed solely to this treatment modality, these results do highlight the unique action of this combined product. However, more robust studies are needed to confirm these results.

Assessing antibacterial efficacy of a polyhexanide hydrogel versus alginate-based wound dressing in burns.

OBJECTIVE: Burn injuries pose a heightened risk of infection, which is primarily responsible for increased morbidity and mortality. Factors such as extensive skin damage and compromised immunity exacerbate this vulnerability. Pseudomonas aeruginosa and Staphylococcus aureus are frequently identified in burns, with Gram-negative Pseudomonas aeruginosa often resistant to antibacterial agents. While Flaminal, an alginate-based wound dressing (Flen Health, Belgium), aids wound healing, its antibacterial effects are limited compared with 1% silver sulfadiazine (1% SSD). In contrast, Prontosan Wound Gel X, a betaine and polyhexanide-based hydrogel (B. Braun Medical AG, Switzerland), has been shown to effectively combat various microbes and promotes wound healing. METHOD: In this study, two research cohorts were retrospectively established (control group: patients receiving standard of care with the alginate-based wound dressing; intervention group: patients receiving the polyhexanide hydrogel wound dressing), comprising patients admitted to a burn centre between 2019 and 2022. Patients were eligible when continuous wound treatment with either of the two wound dressings was performed. Laser Doppler imaging (LDI) scans were conducted. Regions of interest (ROIs) were selected based on LDI scans and divided into healing time categories. Wound swabs were collected and the presence of Pseudomonas aeruginosa and Staphylococcus aureus was documented. Bacterial load was evaluated using a semiquantitative scale. Wound healing was recorded. RESULTS: The control group consisted of 31 patients with 93 ROIs, while the intervention group had 67 ROIs involving 29 patients. Both groups exhibited similar proportions of healing time categories (p>0.05). The polyhexanide hydrogel dressing outperformed the alginate-based dressing in antiseptic efficacy by significantly reducing the incidence of Pseudomonas aeruginosa- and Staphylococcus aureus-positive cultures in patients' wounds. Wound healing time for conservative treatment was comparable between groups. CONCLUSION: In this study, the polyhexanide hydrogel dressing minimised Pseudomonas aeruginosa and Staphylococcus aureus colonisation in burn wounds, demonstrating strong antibacterial properties, emphasising its potential to minimise infections in burn injuries.

Gaining Insight into Mitochondrial Targeting: AUTAC-Biguanide as an Anticancer Agent.

AUTAC-Biguanide is a hybrid compound designed to target mitochondria, inducing their degradation by mitophagy. This study unveils the potential of biguanides as cancer cell-targeting agents, emphasizing AUTAC-Biguanide's superior antiproliferative properties compared to metformin and its selectivity for cancer cells. The mechanism behind this heightened effect includes the ability of AUTAC-Biguanide to trigger mitophagy. By providing a comprehensive analysis of these findings, this study adds valuable insights to the field of mitochondrial-targeting anticancer agents.

Evaluation of the Smear Layer Removal Ability of Various Rotary Files with/without Chemical Agents on Primary Teeth: An In Vitro Study.

AIM: The aim of the current study was to assess the cleaning and smear layer removal efficacy of two different rotary files with or without chemical agents on primary teeth. MATERIALS AND METHODS: For the study, 90 extracted primary maxillary incisors without internal or external resorption and with at least two-thirds of complete roots were chosen. Then, based on the kind of instruments used to clean and shape the canals, they were randomly assigned to three experimental groups, each consisting of 30 teeth. Group-I: The canal was instrumented manually with K-files, Group-II: The canal was instrumented with Kedo-S files, Group-III: The canal was instrumented with Kedo-SG Blue files. After the canals were finally instrumented, 2 mL of QMixTM solution was used to irrigate 15 samples from each group. The samples were subsequently allowed to remain in the canals for 90 seconds in order to eliminate the smear layer. After that a stereomicroscope was used to assess the cleaning effectiveness. RESULTS: With irrigant solution, the highest mean value was found in manual K-files (2.86 ± 0.34), followed by Kedo-S files group (1.34 ± 0.26) and Kedo-SG Blue files (1.28 ± 0.18). Without irrigant solution, the highest mean value was found in manual K-files (2.92 ± 0.22) followed by Kedo-S files group (1.44 ± 0.18) and Kedo-SG Blue files (1.36 ± 0.14). There was a statistically significant difference found at all the three levels. CONCLUSION: On conclusion, the current study's findings demonstrated that irrigation solution was significantly more effective in cleaning and removing smear layers from pediatric rotary files than manual K-files. CLINICAL SIGNIFICANCE: The effectiveness of endodontic therapy depends on a successful chemomechanical preparation. The canals are instrumented using either hand files or rotary instruments; there are several irrigation and instrumentation techniques. In order to completely sterilize the canals, chemical agents are utilized for irrigation during instrumentation. Due to their numerous biological, antibacterial, anti-inflammatory, and antioxidant qualities, many natural compounds are also utilized as irrigants. How to cite this article: Abushanan A. Evaluation of the Smear Layer Removal Ability of Various Rotary Files with/without Chemical Agents on Primary Teeth: An In Vitro Study. J Contemp Dent Pract 2024;25(4):354-357.

Quality of life case series review: wound bed preparation from a UK perspective.

Previous studies have reported that polyhexamethylene biguanide (PHMB) and betaine solution and gels remove biofilm, improve wound healing and reduce infection rates. Quality of life (QoL) outcomes are not commonly reported on when it comes to wound care. This review aims to summarise QoL data from a cohort of case studies previously published on chronic lower limb ulcers using PHMB products (Prontosan® Solution, Prontosan® Wound Gel X and Prontosan® Debridement Pad). Here, we report on and review a total of 38 case studies describing 56 wounds. From these 38 case studies, 36 reported that all the wounds involved had either healed or improved by the end of their respective study period. QoL themes explore malodour, slough, and exudate, pain, mobility, hair growth, antibiotic intake, return to work, social life and mood. This case series demonstrates that treatment with Prontosan® products improves many QoL outcomes for patients with non-healing wounds.

Hip and vertebral fracture risk after initiating antidiabetic drugs in Japanese elderly: a nationwide study.

INTRODUCTION: We aimed to clarify the risks of initiating antidiabetic drugs for fractures using a nationwide health insurance claims database (NDBJ). MATERIALS AND METHODS: Patients aged ≥ 65 years initiating antidiabetic drugs at the outpatient department were enrolled after a 180-day period without prescribed antidiabetic drugs and followed with during 2012-2018 using NDBJ. The adjusted hazard risks (HRs) of each antidiabetic drug (thiazolidine, alpha-glucosidase inhibitor, dipeptidyl peptidase-4 [DPP-4] inhibitor, sulfonylurea, glinide, and insulin) for fractures compared with biguanide were obtained adjusting for age, gender, polypharmacy, dementia, and the other antidiabetic drugs. RESULTS: The DPP-4 inhibitor was the most often prescribed antidiabetic drug followed by biguanide with prescribed proportions of 71.7% and 12.9%. A total of 4,304 hip fractures and 9,388 vertebral fractures were identified among the 966,700 outpatient participants. Compared with biguanide, insulin, alpha-glucosidase inhibitor, and DPP-4 inhibitor were related to increased hip fracture risks. Vertebral fracture risk was higher in outpatients prescribed with insulin, thiazolidine, and DPP-4 inhibitor compared with biguanide. Patients prescribed insulin for hip and vertebral fractures' adjusted HRs were 2.17 (95% CI 1.77-2.66) and 1.45 (95% CI 1.24-1.70), respectively. Those prescribed DPP-4 inhibitor for hip and vertebral fractures' adjusted HRs were 1.27 (95% CI 1.15-1.40) and 1.20 (95% CI 1.12-1.28), respectively. CONCLUSIONS: Initiating insulin increased the risk of not only hip fractures but also vertebral fractures. Patients initiating antidiabetic drugs had increased risks of hip and vertebral fractures compared with those initiating biguanide independently for age, gender, polypharmacy, and dementia in the Japanese elderly.

Modulating the therapeutic response of tumours to dietary serine and glycine starvation.

The non-essential amino acids serine and glycine are used in multiple anabolic processes that support cancer cell growth and proliferation (reviewed in ref. 1). While some cancer cells upregulate de novo serine synthesis, many others rely on exogenous serine for optimal growth. Restriction of dietary serine and glycine can reduce tumour growth in xenograft and allograft models. Here we show that this observation translates into more clinically relevant autochthonous tumours in genetically engineered mouse models of intestinal cancer (driven by Apc inactivation) or lymphoma (driven by Myc activation). The increased survival following dietary restriction of serine and glycine in these models was further improved by antagonizing the anti-oxidant response. Disruption of mitochondrial oxidative phosphorylation (using biguanides) led to a complex response that could improve or impede the anti-tumour effect of serine and glycine starvation. Notably, Kras-driven mouse models of pancreatic and intestinal cancers were less responsive to depletion of serine and glycine, reflecting an ability of activated Kras to increase the expression of enzymes that are part of the serine synthesis pathway and thus promote de novo serine synthesis.

Prescription Trends for the Antidiabetic Agents Used to Treat Type 2 Diabetes Mellitus in Japan from 2012-2020: a Time-Series Analysis.

In April 2014, sodium-glucose cotransporter 2 inhibitor (SGLT-2i) was introduced in Japan. In May 2015, the prescription limitation for SGLT-2i was lifted. Subsequently, SGLT-2i was shown to reduce cardiovascular events in patients with type 2 diabetes mellitus (T2DM). SGLT-2i prescription is expected to increase and consequently affect the prescription trends for other antidiabetic agents. Therefore, we evaluated the trends for antidiabetic agent prescriptions in Japan from April 2012 to March 2020. In this study, a dynamic cohort consisting of patients with T2DM derived from the Japan Medical Data Center health insurance database and with at least one antidiabetic agent prescription was investigated. The prescription rates were calculated monthly (/1000 person-months) for each class of antidiabetic agent. The eligible cohort comprised 34333 patients. The prescription rate for dipeptidyl peptidase-4 inhibitor increased from 424.0 in April 2012 to 656.3 in May 2015, and slightly decreased to 635.4 in March 2020. The prescription rate for biguanide consistently increased from 347.2 in April 2012 to 500.1 in March 2020. The prescription rate for sulfonylurea consistently decreased from 393.8 in April 2012 to 172.5 in March 2020. The prescription rate for SGLT-2i consistently increased from 4.1 in April 2014 to 363.1 in March 2020. SGLT-2i prescription increased and may affect the prescription trends for dipeptidyl peptidase-4 inhibitor and sulfonylurea after May 2015, when the prescription limitation for SGLT-2i was lifted. Biguanide prescriptions increased regardless of the introduction of SGLT-2i. The treatment of T2DM in Japan is clearly changing, with a focus on SGLT-2i and biguanide.

Ex vivo wound model on porcine skin for the evaluation of the antibiofilm activity of polyhexamethylene biguanide and ciprofloxacin.

This study aimed to standardize the use of an ex vivo wound model for the evaluation of compounds with antibiofilm activity. The in vitro susceptibility of Staphylococcus aureus ATCC 29213 and Pseudomonas aeruginosa ATCC 27853 to ciprofloxacin and polyhexamethylene biguanide (PHMB) was evaluated in planktonic and biofilm growth. The effects of ciprofloxacin and PHMB on biofilms grown on porcine skin explants were evaluated by colony-forming unit (CFU) counting and confocal microscopy. Minimum inhibitory concentrations (MICs) against S. aureus and P. aeruginosa were, respectively, 0.5 and 0.25 µg mL-1 for ciprofloxacin, and 0.78 and 6.25 µg mL-1 for PHMB. Minimum biofilm eradication concentrations (MBECs) against S. aureus and P. aeruginosa were, respectively, 2 and 8 µg mL-1 for ciprofloxacin, and 12.5 and >25 µg mL-1 for PHMB. Ciprofloxacin reduced (P < 0.05) log CFU counts of the biofilms grown ex vivo by 3 and 0.96 for S. aureus and P. aeruginosa, respectively, at MBEC, and by 0.58 and 8.12 against S. aureus and P. aeruginosa, respectively, at 2xMBEC. PHMB (100 µg/mL) reduced (P < 0.05) log CFU counts by 0.52 for S. aureus and 0.68 log for P. aeruginosa, leading to an overall decrease (P < 0.05) in biofilm biomass. The proposed methodology to evaluate the susceptibility of biofilms grown ex vivo led to reproducible and reliable results.

Comparison of decision tree with common machine learning models for prediction of biguanide and sulfonylurea poisoning in the United States: an analysis of the National Poison Data System.

BACKGROUND: Biguanides and sulfonylurea are two classes of anti-diabetic medications that have commonly been prescribed all around the world. Diagnosis of biguanide and sulfonylurea exposures is based on history taking and physical examination; thus, physicians might misdiagnose these two different clinical settings. We aimed to conduct a study to develop a model based on decision tree analysis to help physicians better diagnose these poisoning cases. METHODS: The National Poison Data System was used for this six-year retrospective cohort study.The decision tree model, common machine learning models multi layers perceptron, stochastic gradient descent (SGD), Adaboosting classiefier, linear support vector machine and ensembling methods including bagging, voting and stacking methods were used. The confusion matrix, precision, recall, specificity, f1-score, and accuracy were reported to evaluate the model's performance. RESULTS: Of 6183 participants, 3336 patients (54.0%) were identified as biguanides exposures, and the remaining were those with sulfonylureas exposures. The decision tree model showed that the most important clinical findings defining biguanide and sulfonylurea exposures were hypoglycemia, abdominal pain, acidosis, diaphoresis, tremor, vomiting, diarrhea, age, and reasons for exposure. The specificity, precision, recall, f1-score, and accuracy of all models were greater than 86%, 89%, 88%, and 88%, respectively. The lowest values belong to SGD model. The decision tree model has a sensitivity (recall) of 93.3%, specificity of 92.8%, precision of 93.4%, f1_score of 93.3%, and accuracy of 93.3%. CONCLUSION: Our results indicated that machine learning methods including decision tree and ensembling methods provide a precise prediction model to diagnose biguanides and sulfonylureas exposure.

Polyhexamethylene biguanide and its antimicrobial role in wound healing: a narrative review.

A wound offers an ideal environment for the growth and proliferation of a variety of microorganisms which, in some cases, may lead to localised or even systemic infections that can be catastrophic for the patient; the development of biofilms exacerbates these infections. Over the past few decades, there has been a progressive development of antimicrobial resistance (AMR) in microorganisms across the board in healthcare sectors. Such resistant microorganisms have arisen primarily due to the misuse and overuse of antimicrobial treatments, and the subsequent ability of microorganisms to rapidly change and mutate as a defence mechanism against treatment (e.g., antibiotics). These resistant microorganisms are now at such a level that they are of grave concern to the World Health Organization (WHO), and are one of the leading causes of illness and mortality in the 21st century. Treatment of such infections becomes imperative but presents a significant challenge for the clinician in that treatment must be effective but not add to the development of new microbes with AMR. The strategy of antimicrobial stewardship (AMS) has stemmed from the need to counteract these resistant microorganisms and requires that current antimicrobial treatments be used wisely to prevent amplification of AMR. It also requires new, improved or alternative methods of treatment that will not worsen the situation. Thus, any antimicrobial treatment should be effective while not causing further development of resistance. Some antiseptics fall into this category and, in particular, polyhexamethylene hydrochloride biguanide (PHMB) has certain characteristics that make it an ideal solution to this problem of AMR, specifically within wound care applications. PHMB is a broad-spectrum antimicrobial that kills bacteria, fungi, parasites and certain viruses with a high therapeutic index, and is widely used in clinics, homes and industry. It has been used for many years and has not been shown to cause development of resistance; it is safe (non-cytotoxic), not causing damage to newly growing wound tissue. Importantly there is substantial evidence for its effective use in wound care applications, providing a sound basis for evidence-based practice. This review presents the evidence for the use of PHMB treatments in wound care and its alignment with AMS for the prevention and treatment of wound infection.

Metformin May Alter the Metabolic Reprogramming in Cancer Cells by Disrupting the L-Arginine Metabolism: A Preliminary Computational Study.

Metabolic reprogramming in cancer is considered to be one of the most important hallmarks to drive proliferation, angiogenesis, and invasion. AMP-activated protein kinase activation is one of the established mechanisms for metformin's anti-cancer actions. However, it has been suggested that metformin may exert antitumoral effects by the modulation of other master regulators of cellular energy. Here, based on structural and physicochemical criteria, we tested the hypothesis that metformin may act as an antagonist of L-arginine metabolism and other related metabolic pathways. First, we created a database containing different L-arginine-related metabolites and biguanides. After that, comparisons of structural and physicochemical properties were performed employing different cheminformatic tools. Finally, we performed molecular docking simulations using AutoDock 4.2 to compare the affinities and binding modes of biguanides and L-arginine-related metabolites against their corresponding targets. Our results showed that biguanides, especially metformin and buformin, exhibited a moderate-to-high similarity to the metabolites belonging to the urea cycle, polyamine metabolism, and creatine biosynthesis. The predicted affinities and binding modes for biguanides displayed good concordance with those obtained for some L-arginine-related metabolites, including L-arginine and creatine. In conclusion, metabolic reprogramming in cancer cells by metformin and biguanides may be also driven by metabolic disruption of L-arginine and structurally related compounds.