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Bacterial cellulose wound dressings containing silk sericin and PHMB (BCSP) were developed in our previous studies. It had good physical properties, efficacy, and safety. For further use as a medical material, this dressing was investigated for its efficacy and safety in split-thickness skin graft (STSG) donor-site wound treatment compared to Bactigras® (control). Moreover, the inflammatory responses to both dressings were also deeply investigated. For in vivo study, expressions of anti-inflammatory cytokines were intensely considered in the tissue interfacing area. The result showed that IL-4 and TGF-β from BCSP-treated tissue had advantages over Bactigras®-treated tissue at 14 and 21 days post-implantation. For clinical study, a single-blinded, randomized controlled study was generated. The half of STSG donor site wound was randomly assigned to cover with BCSP or Bactigras®. Twenty-one patients with 32 STSG donor site wounds were enrolled. The results showed that wound-healing time was not significantly different in both dressings. However, wound quality of BCSP was better than Bactigras® at healing time and after 1 month (p < 0.05). The pain scores of BCSP-treated wound were statistically significant lower than Bactigras®-treated wound (p < 0.05). No sign of infection or adverse event was observed after treatment with both dressings. In conclusion, the inflammation responses of the dressing were clearly clarified. The advantages of BCSP were wound-quality improvement, pain reduction, and infection protection without adverse events. It was fit to be used as the alternative treatment of STSG donor site wound.

IntroductionThe prevalence of surgical site infection (SSI) remains higher in gastrointestinal surgery than in other surgeries. Although several guidelines have indicated the efficacy of chlorhexidine and povidone-iodine in reducing the SSI rate, the optimal recommendation has still not been established. Therefore, it is necessary to determine the more effective antiseptic for surgical site preparation. Olanexidine (1.5% olanedine, Otsuka Pharmaceutical Factory, Tokushima, Japan), which is a new antiseptic in Japan, has antimicrobial activity against a wide range of bacteria, including Gram-positive and Gram-negative bacteria. Our study will contribute to determining a new antiseptic for use in gastrointestinal and other surgeries.Methods and analysisWe propose a multicentre, randomised controlled clinical trial for comparing two treatments, that is, 1.5% olanexidine or 10% povidone-iodine, for surgical skin preparation to prevent SSI in clean-contaminated gastrointestinal surgeries with surgical wounds. Patients aged ≥20 years at the time of consent will be included. The primary outcome measure is the 30-day postoperative SSI rate. For the primary analysis, which is aimed at comparing the treatment effects, the adjusted risk ratio and its 95% CI will be estimated using the Mantel-Haenszel method.Ethics and disseminationThe protocol was first approved by the Institutional Review Board of Keio University School of Medicine, followed by the institutional review board of each participating site. Participant recruitment began in June 2018. The final results will be published in international peer-reviewed medical journals.Trial registration numberUMIN 000031560; Pre-results.

Wound cleansing represents a fundamental step in chronic wound management. Several investigations in recent years have led to a refinement of the wound cleansing protocol in order to obtain a better control of the bacterial burden during wound bed preparation and to avoid further cell and tissue damage. The aim of the present randomized controlled trial was to investigate the effects of a wound cleansing solution containing polihexanide and betaine in venous leg ulcers by means of clinical and instrumental assessment. A portable device was used on the wound bed to assess surface pH, which has been shown to be one of the most useful non-invasive biophysical parameters in order to correlate the level of bacterial burden in different types of chronic wounds. Baseline pH on the wound surface (median range) was initially 8.9, and after 4 weeks of cleansing treatment and moist wound dressing was reduced and stable at 7.0 in the group treated with active cleanser. The pH value was significantly lower (p < 0.05) in this group compared to the control group at the end of the study. The treatment with the solution containing polihexanide and betaine was well tolerated by the patients and was found useful in the absorption of wound odours.

Metformin is a widely-used drug that results in clear benefits in relation to glucose metabolism and diabetes-related complications. The mechanisms underlying these benefits are complex and still not fully understood. Physiologically, metformin has been shown to reduce hepatic glucose production, yet not all of its effects can be explained by this mechanism and there is increasing evidence of a key role for the gut. At the molecular level the findings vary depending on the doses of metformin used and duration of treatment, with clear differences between acute and chronic administration. Metformin has been shown to act via both AMP-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms; by inhibition of mitochondrial respiration but also perhaps by inhibition of mitochondrial glycerophosphate dehydrogenase, and a mechanism involving the lysosome. In the last 10 years, we have moved from a simple picture, that metformin improves glycaemia by acting on the liver via AMPK activation, to a much more complex picture reflecting its multiple modes of action. More work is required to truly understand how this drug works in its target population: individuals with type 2 diabetes.

Background To determine whether 12 months of intensive medical therapy (IMT) improves HDL functionality parameters in subjects with type II diabetes (T2D). Methods Retrospective, randomized, and controlled 12-month IMT intervention trial that enrolled 13-subjects with T2D (age 51- years, fasting glucose 147 mg/dL, body mass index [BMI] 36.5 kg/m 2 ) and nine healthy control (46-years, fasting glucose 90 mg/dL, BMI 26.5 kg/m2). Subjects with T2D underwent IMT and HDL functionality measures (pro-inflammatory index of high-density lipoprotein (pHDL)), paraoxonase one (PON1), ceruloplasmin (Cp), and myeloperoxidase (MPO) activity were performed on samples at baseline and at 12-months following IMT. Results At baseline, pHDL index was significantly higher in subjects with T2D ( p  < 0.001) and apolipoprotein A-1 levels were significantly lower ( p  = 0.013) vs. controls. After 12-months, there was a trend for improved pHDL activity ( p  = 0.083), as indicated by intent-to-treat analysis, but when the non-adherent subject was omitted (per-protocol), significant attenuations in pHDL activity ( p  = 0.040) were noted; Δ pHDL activity at 12-months was associated with Δ weight ( r  = 0.62, p  = 0.032) and Δ fasting glucose ( r  = 0.65, p  = 0.022). Moreover, PON1 activity significantly improved ( p  < 0.001). The aforementioned occurred in association with improvements in inflammatory markers (i.e., C-reactive protein & tumor necrosis factor), hemoglobin A1C, fasting glucose, triglycerides, high-density lipoprotein levels and adipokines. Conclusion IMT ameliorates pHDL index and significantly improves anti-oxidative function, as measured by PON1. Improvements in weight and fasting glucose mediated the decrease in pHDL index. Pharmacological aids and lifestyle modification are required to improve cardiovascular risk factors, subsequent mortality risk, and promote T2D remission. Application of either form of therapy alone may only have relatively miniscule effects on the aforementioned factors, in relation to the aggregate.

Key Points Greater understanding of the complex and multifactorial pathogenesis of type 2 diabetes mellitus (T2DM) has informed the development of several new classes of glucose-lowering therapies Metformin remains the first-line pharmacotherapy for patients with T2DM, whereas the use of other well-established agents, such as sulfonylureas, meglitinides, pioglitazone and α-glucosidase inhibitors, varies in different regions Agents that enhance incretin activity (DPP-4 inhibitors), supplement endogenous GLP-1 (GLP-1 receptor agonists) or increase urinary glucose elimination (SGLT2 inhibitors) have low risk of hypoglycaemia and can assist weight control Treatment with two or three agents with different modes of action can be required as T2DM advances, and insulin therapy is required if other agents are unable to maintain adequate glycaemic control Glycaemic targets and the choice of glucose-lowering agents should be customized to meet the needs and circumstances of individual patients, which could be facilitated by future developments in pharmacogenomics Although the balance of benefits and risks for different agents varies between individual patients, early, effective and sustained glycaemic control delays the onset and reduces the severity of hyperglycaemia-related complications Several classes of glucose-lowering therapies are now available for treatment of type 2 diabetes mellitus. In this Review, the current knowledge relating to mechanisms of action, pharmacokinetics, pharmacodynamics and safety profiles is presented for members of each of these drug classes. Type 2 diabetes mellitus (T2DM) is a global epidemic that poses a major challenge to health-care systems. Improving metabolic control to approach normal glycaemia (where practical) greatly benefits long-term prognoses and justifies early, effective, sustained and safety-conscious intervention. Improvements in the understanding of the complex pathogenesis of T2DM have underpinned the development of glucose-lowering therapies with complementary mechanisms of action, which have expanded treatment options and facilitated individualized management strategies. Over the past decade, several new classes of glucose-lowering agents have been licensed, including glucagon-like peptide 1 receptor (GLP-1R) agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors and sodium/glucose cotransporter 2 (SGLT2) inhibitors. These agents can be used individually or in combination with well-established treatments such as biguanides, sulfonylureas and thiazolidinediones. Although novel agents have potential advantages including low risk of hypoglycaemia and help with weight control, long-term safety has yet to be established. In this Review, we assess the pharmacokinetics, pharmacodynamics and safety profiles, including cardiovascular safety, of currently available therapies for management of hyperglycaemia in patients with T2DM within the context of disease pathogenesis and natural history. In addition, we briefly describe treatment algorithms for patients with T2DM and lessons from present therapies to inform the development of future therapies.

Metformin is widely prescribed for the treatment of type II diabetes. Recently, it has been proposed that this compound or related biguanides may have antineoplastic activity. Biguanides may exploit specific metabolic vulnerabilities of transformed cells by acting on them directly, or may act by indirect mechanisms that involve alterations of the host environment. Preclinical data suggest that drug exposure levels are a key determinant of proposed direct actions. With respect to indirect mechanisms, it will be important to determine whether recently demonstrated metformin-induced changes in levels of candidate systemic mediators such as insulin or inflammatory cytokines are of sufficient magnitude to achieve therapeutic benefit. Results of the first generation of clinical trials now in progress are eagerly anticipated. Ongoing investigations may justify a second generation of trials that explore pharmacokinetic optimization, rational drug combinations, synthetic lethality strategies, novel biguanides, and the use of predictive biomarkers.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are increasingly recommended as first-line treatment for type 2 diabetes mellitus (T2DM), but head-to-head data comparing them with metformin, the canonical biguanide, remain sparse in Japan. To compare the long-term effectiveness and cost of initiating treatment with a biguanide versus an SGLT2 inhibitor, excluding the alternative class for 12 months but permitting other antidiabetic drugs, on a composite of major cardio-cerebrovascular events and all-cause death, and a composite of diabetic complications. We emulated a new-user cohort trial using the Shizuoka Kokuho Database (2014-2021). Patients initiating treatment with either a biguanide or an SGLT2 inhibitor, while avoiding the alternative class during the first 12 months but allowing other glucose-lowering agents, were included. Follow-up began at treatment initiation; those who received the comparator drug within 12 months were excluded. After 1:1 propensity-score matching on demographic, clinical, laboratory, and lifestyle variables, cause-specific Cox models estimated hazard ratios (HRs). Daily medication costs were compared. After matching, 1,246 patients (623 per group) were followed for a median of 2.9 years (maximum 7.2 years). Cardio-cerebrovascular composite: 44/623 biguanide users (7.1%) and 35/623 SGLT2 inhibitor users (5.6%) experienced a first event (HR 0.80, 95% CI 0.51-1.24). Diabetic complications: 86/623 (13.8%) vs. 78/623 (12.5%) (HR 0.88, 95% CI 0.70-1.13). Median daily drug cost was 124.7 JPY for biguanides and 184.0 JPY for SGLT2 inhibitors (P < 0.001). Using a large-scale regional database from Japan, we found that among adults with type 2 diabetes without prior major cardiac or renal disease, first-line treatment with an SGLT2 inhibitor did not reduce risks of cardio-cerebrovascular events, mortality, or complications compared with metformin, and cost about 50% more.

The similarities between fungal and mammalian cells pose inherent challenges for the development of treatments for fungal infections, due to drug crossover recognition of host drug targets by antifungal agents. Thus, there are a limited number of drug classes available for treatment. Treatment is further limited by the acquisition and dissemination of antifungal resistance which contributes to the urgent need of new therapies. Polyhexamethylene biguanide (PHMB) is a cationic antimicrobial polymer with bactericidal, parasiticidal and fungicidal activities. The antifungal mechanism of action appears to involve preferential mechanical disruption of microbial cell structures, offering an alternative to conventional antifungals. However, the antifungal mechanisms have been little studied. The aim of this study was to characterise PHMB’s activities on selected yeast ( Saccharomyces cerevisiae, Candida albicans ) and filamentous fungal species ( Fusarium oxysporum, Penicillium glabrum ). Fungal membrane disruption, cell entry and intracellular localisation activities of PHMB were evaluated using viability probe entry and polymer localisation studies. We observed that PHMB initially permeabilises fungal cell membranes and then accumulates within the cytosol. Once in the cytosol, it disrupts the nuclear membrane, leading to DNA binding and fragmentation. The electrostatic interaction of PHMB with membranes suggests other intracellular organelles could be potential targets of its action. Overall, the results indicate multiple antifungal mechanisms, which may help to explain its broad-spectrum efficacy. A better understanding of PHMB’s mechanism(s) of action may aid the development of improved antifungal treatment strategies.

Preclinical models suggest anticancer activity of IM156, a novel biguanide mitochondrial protein complex 1 inhibitor of oxidative phosphorylation (OXPHOS). This first-in-human dose-escalation study enrolled patients with refractory advanced solid tumors to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Eligible patients received oral IM156 every other day (QOD) or daily (QD) and were assessed for safety, dose-limiting toxicities (DLTs), pharmacokinetics, and preliminary signals of efficacy. 22 patients with advanced cancers (gastric, n = 8; colorectal, n = 3; ovarian, n = 3; other, n = 8) received IM156 100 to 1,200 mg either QOD or QD. There were no DLTs. However, 1,200 mg QD was not well tolerated due to nausea; 800 mg QD was determined as the RP2D. The most frequent treatment-related AEs (TRAEs) were nausea (n = 15; 68%), diarrhea (n = 10; 46%), emesis (n = 9; 41%), fatigue (n = 4; 18%) and abdominal pain, constipation, and blood lactate increased (n = 2 each; 9%). Grade 3 nausea (n = 3; 14%) was the only grade ≥ 3 TRAE. Plasma exposures increased dose proportionally; mean Day 27 area under the curve (AUC0-24) values were higher following QD administration compared to the respective QOD regimen. Stable disease (SD), observed in 7 (32%) patients (confirmed in 2 [9%]), was the best response. To our knowledge, this is the first phase 1 study of an OXPHOS inhibitor that established a RP2D for further clinical development in cancer. Observed AEs of IM156 were manageable and SD was the best response.