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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.

Bacterial nanocellulose (BNC) is chemically identical with plant cellulose but free of byproducts like lignin, pectin, and hemicelluloses, featuring a unique reticulate network of fine fibers. BNC sheets are mostly obtained by static cultivation. Now, a Horizontal Lift Reactor may provide a cost efficient method for mass production. This is of particular interest as BNC features several properties of an ideal wound dressing although it exhibits no bactericidal activity. Therefore, BNC was functionalized with the antiseptics povidone-iodine (PI) and polihexanide (PHMB). Drug loading and release, mechanical characteristics, biocompatibility, and antimicrobial efficacy were investigated. Antiseptics release was based on diffusion and swelling according to Ritger–Peppas equation. PI-loaded BNC demonstrated a delayed release compared to PHMB due to a high molar drug mass and structural changes induced by PI insertion into BNC that also increased the compressive strength of BNC samples. Biological assays demonstrated high biocompatibility of PI-loaded BNC in human keratinocytes but a distinctly lower antimicrobial activity against Staphylococcus aureus compared to PHMB-loaded BNC. Overall, BNC loaded with PHMB demonstrated a better therapeutic window. Moreover, compressive and tensile strength were not changed by incorporation of PHMB into BNC, and solidity during loading and release could be confirmed.

Platelet rich fibrin (PRF) is an autologous fibrin glue, produced from patients' blood, which, besides intraoperative use, has applications in the treatment of infected wounds. The combination with antimicrobial agents results in a prolonged antibacterial effect allowing for wound dressing change intervals of seven days even in infected wounds. The aim of this study was to evaluate release kinetics of amikacin, teicoplanin or polyhexanide from a PRF-layer. PRF mixed with teicoplanin, amikacin or polyhexanide was sprayed on a silicon gauze patch and put on a colombia agar with bacteria with known minimal inhibitory concentration (MIC) and incubated for 24 hours and afterwards transferred to another agar with the same bacterial strain. Inhibition zones were measured every 24 hours. This was repeated on 7 consecutive days. Antibiotic concentrations were calculated by interpolation. More than 1000 mg/L teicoplanin were released within the first 24 hours and 28.22 mg/L after 168 hours. Amikacin release was above 10,000 mg/L within the first 24 hours and still 120.8 mg/L after 120 hours. A release of polyhexanide could be verified for the first 24 hours only. Consequently teicoplanin and amikacin released from PRF showed antimicrobial in-vitro effects for almost a week, whereas an antimicrobial effect of polyhexanide could only be verified for the first 24 hours. Our Results show that a weekly dressing regimen may be justified in wounds treated with PRF plus amikacin or teicoplanin, since bacteria will be eradicated over a considerable period of time after a single application of PRF.

Type 2 diabetes mellitus (T2DM) is an increasingly prevalent disease. Several classes of drugs are currently available to treat T2DM patients; however, clinical response to these drugs often exhibits significant variation among individuals. For the oral antidiabetic drug classes of sulfonylureas, nonsulfonylurea insulin secretagogs, biguanides and thiazolidinediones, pharmacogenomic evidence has accumulated demonstrating an association between specific gene polymorphisms and interindividual variability in their therapeutic and adverse reaction effects. These polymorphisms are in genes of molecules involved in metabolism, transport and therapeutic mechanisms of the aforementioned drugs. Overall, it appears that pharmacogenomics has the potential to improve the management of T2DM and help clinicians in the effective prescribing of oral antidiabetic medications. Although pharmacogenomics can explain some of the heterogeneity in dose requirements, response and incidence of adverse effects of drugs between individuals, it is now clearly understood that much of the diversity in drug effects cannot be solely explained by studying the genomic diversity. Epigenomics, the field that focuses on nongenomic modifications that influence gene expression, may expand the scope of pharmacogenomics towards optimization of drug therapy. Therefore, pharmacoepigenomics, the combined analysis of genetic variations and epigenetic modifications, holds promise for the realization of personalized medicine. Although pharmacoepigenomics has so far been evaluated mainly in cancer pharmacotherapy, studies on epigenomic modifications during T2DM development provide useful data on the potential of pharmacoepigenomics to elucidate the mechanisms underlying interindividual response to oral antidiabetic treatment. In summary, the present article focuses on available data from pharmacogenomic studies of oral antidiabetic drugs and also provides an overview of T2DM epigenomic research, which has the potential to boost the development of pharmacoepigenomics in antidiabetic treatment.

From 2004 through 2006, fusarium keratitis associated with contact lens use was recognized. In this letter, a potential mechanism for this event is identified. To the Editor: Between 2004 and 2006, fusarium keratitis developed in hundreds of patients in Hong Kong, Singapore, the United States, and the French West Indies. The infections were traced to a specific multipurpose contact lens solution that was manufactured at one facility. This solution contained the antimicrobial agent alexidine dihydrochloride (0.00045%), an ingredient that was new to the contact lens–solution market at that time. The manufacturer was subsequently cited by the Food and Drug Administration (FDA) for inadequate temperature control of their products, and the contact lens solution, ReNu with MoistureLoc (Bausch & Lomb), was ultimately withdrawn from the . . .

Type 2 diabetes mellitus is an increasingly prevalent disorder associated with multiple metabolic derangements. Insulin resistance is the most prominent feature common in both type 2 diabetes and its associated metabolic abnormalities. Until 1995, the only therapeutic interventions available in the United States were the insulin secretagogues sulfonylureas and insulin. With the introduction of metformin in the United States in the mid-1990s and the subsequent advent of thiazolidinediones, an opportunity exists to address and directly reverse, at least in part, the defects in insulin action seen in individuals with type 2 diabetes. Evidence shows that insulin sensitizers not only have beneficial effects on glycemic control but also have multiple effects on lipid metabolism and atherosclerotic vascular processes that could prove to be beneficial. We discuss safety issues of these agents, their potential use in preventing onset and progression of diabetes, and their use in other related metabolic conditions such as polycystic ovary syndrome.

Biguanides, particularly the widely prescribed drug metformin, have been marketed for many decades and have well-established absorption profiles. They are commonly administered via the oral route and, despite variation in oral uptake, remain commonly prescribed for diabetes mellitus, typically type 2. Studies over the last decade have focused on the design and development of advanced oral delivery dosage forms using bio nano technologies and novel drug carrier systems. Such studies have demonstrated significantly enhanced delivery and safety of biguanides using nanocapsules. Enhanced delivery and safety have widened the potential applications of biguanides not only in diabetes but also in other disorders. Hence, this review aimed to explore biguanides’ pharmacokinetics, pharmacodynamics, and pharmaceutical applications in diabetes, as well as in other disorders.

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.

Background/Objectives: In the context of diabetes, a multifactorial metabolic disorder with significant clinical implications, the present study investigates the hypoglycemic effects of a synthetic sulfonamide (S) administered individually and in combination with Salvia officinalis extract, compared to metformin as a standard therapeutic agent. Methods: An in vivo model of experimentally induced diabetes using alloxan was applied to Wistar female rats, divided into six experimental groups, including a healthy control group and a diabetes-induced, untreated group. Plasma concentrations of metformin and sulfonamide were quantified by high-performance liquid chromatography. The plasma steady-state concentrations of the pharmaceutical agents and their correlation with hypoglycemic effect were evaluated. Results: The combination of the synthetic sulfonamide (S) with Salvia officinalis extract resulted in the greatest reduction in blood glucose level (average value of 50.2%) compared to S (40.6%) or metformin (36.4%). All treatments demonstrated statistically significant differences in blood glucose levels compared to the diabetes-induced untreated group (p < 0.05). Pharmacokinetic analysis revealed a larger volume of distribution for the synthetic sulfonamide S (23.92 ± 8.40 L) compared to metformin (16.07 ± 5.60 L), consistent with its physicochemical properties. No significant correlation was found between plasma drug levels and glycemic response (p > 0.05). Conclusions: Our findings support the potential of combining standard therapeutic agents with natural alternatives such as Salvia officinalis to achieve improved glycemic control through complementary mechanisms. To the best of our knowledge, this is the first in vivo study to evaluate the combined effects of a sulfonylurea-type compound and Salvia officinalis extract in a diabetic animal model.