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Benzydamine hydrochloride (BZD) having analgesic, anesthetic, and anti-inflammatory effects is used orally or topically in the treatment of disorders such as joint inflammation and muscle pain. Within the scope of this study, sprayable thermosensitive BZD hydrogels were developed using thermoresponsive poloxamers to avoid systemic side effects and to provide better compliance for topical administration. Also, hydroxypropyl methyl cellulose (HPMC) was employed to improve the mechanical strength and bioadhesive properties of the hydrogel. The addition of BZD generally decreased the viscosity of the formulations (p < 0.05), while increasing the gelation temperature (p < 0.05). The formulations that did not have any clogs or leaks in the nozzle of the bottle during the spraying process were considered lead formulations. To spray the formulations easily, it was found that the viscosity at RT should be less than 200 mPa·s, and their gelation temperature should be between 26 and 34°C. Increasing HPMC and poloxamer improved bioadhesion. The amount of HPMC and poloxamers did not cause a significant change in the release characteristics of the formulations (p > 0.05); the release profiles of BZD from the formulations were similar according to model-independent kinetic (f2 > 50). HPMC and poloxamers had important roles in the accumulation of BZD in the skin. In vitro biological activity studies demonstrated that the formulations presented their anti-inflammatory activity with TNF-α inhibition but did not have any effect on the inhibition of COX enzymes as expected. As a result, thermosensitive hydrogels containing BZD might be an appropriate alternative, providing an advantage in terms of easier application compared to conventional gels. [ABSTRACT FROM AUTHOR]

Previous research has demonstrated a link between the administration of analgesic drugs and the reduction of empathy levels in humans. This apparent blunting effect of pain medication has been explained through shared neural mechanisms for the first-hand and the empathic experience of pain (simulation theory). Considering that analgesics are among the most consumed drugs in the world and the ability to empathize with others is fundamental to human social interactions, the aim of the present study was to investigate whether the typical day-to-day analgesic consumption rate in Austria and Germany is associated with a reduction in empathy and prosocial behavior. We therefore collected self-reports of analgesic consumption behavior as well as empathy for pain and prosocial behavior measures in an online survey (n = 940). Analyses revealed no significant association between the analgesic intake frequency and measures of empathy or prosocial behavior. However, liberal intake of analgesics (i.e. mind-set of "a pill is a quick solution") was linked to lower empathic concern and helping behavior, which may hint towards a negative effect in people who take pain medication for non-pain related issues or episodes of low pain. Nevertheless, further research is needed to investigate the effects of analgesic drugs in high frequency users. [ABSTRACT FROM AUTHOR]

Background: Serum retinol (SR) and retinol-binding protein (RBP) are commonly used indicators, but they are affected by infections and inflammation. This study aimed to assess the sensitivity and specificity of VA indicators to detect vitamin A deficiency (VAD) in 36–59-month-old children living in a rural area in Burkina Faso. Methods: In a community-based study, two cross-sectional surveys were carried out from November 2016 to September 2017 in the health district of Dandé in Burkina Faso. The surveys included 115 children 36–59 months old. Indicators of VA and inflammation assessed in all children included SR, RBP and total liver VA reserves (TLR) estimated by retinol isotope dilution, and inflammation markers (C-reactive protein (CRP) and alpha 1-acid glycoprotein (AGP)). We calculated the sensitivity, specificity, positive and negative predictive values. In addition, the effects of inflammation, helminth infection, and season on sensitivity and specificity were assessed. Results: The prevalence of VAD assessed by SR (< 0.7 µmol/L), RBP (< 0.7 µmol/L), and TLR (< 0.1 µmol/g liver) were, respectively, 30.9%, 33.3%, and 0%. Compared to TLR, the specificity, positive predictive value, and negative predictive value of SR were 71.1%, 0%, and 100%, and of RBP, were 68.9%, 0%, and 100%, respectively. The sensitivity was indeterminable for SR and RBP. The specificity of SR and RBP was lower during the dry season. Elevated CRP (> 5.0 mg/L) and AGP (> 1.0 g/L) were detected in 1.9% and 28.6% of children, respectively. The adjustment of VA indicators for inflammation improved SR's specificity to 75.9% and decreased RBP's specificity to 67.8%. Conclusion: No cases of VAD were identified by TLR. However, (inflammation-adjusted) SR and RBP had varying accuracy in the estimation of VAD. Trial registration: The study was registered, retrospectively, on 22 March 2018 as a clinical trial with the Pan African Clinical Trials Registry under the number Cochrane South Africa; PACTR201803002999356. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) remains a significant global health challenge, necessitating innovative approaches for effective treatment. Conventional TB therapy encounters several limitations, including extended treatment duration, drug resistance, patient noncompliance, poor bioavailability, and suboptimal targeting. Advanced drug delivery strategies have emerged as a promising approach to address these challenges. They have the potential to enhance therapeutic outcomes and improve TB patient compliance by providing benefits such as multiple drug encapsulation, sustained release, targeted delivery, reduced dosing frequency, and minimal side effects. This review examines the current landscape of drug delivery strategies for effective TB management, specifically highlighting lipid nanoparticles, polymer nanoparticles, inorganic nanoparticles, emulsion-based systems, carbon nanotubes, graphene, and hydrogels as promising approaches. Furthermore, emerging therapeutic strategies like targeted therapy, long-acting therapeutics, extrapulmonary therapy, phototherapy, and immunotherapy are emphasized. The review also discusses the future trajectory and challenges of developing drug delivery systems for TB. In conclusion, nanomedicine has made substantial progress in addressing the challenges posed by conventional TB drugs. Moreover, by harnessing the unique targeting abilities, extended duration of action, and specificity of advanced therapeutics, innovative solutions are offered that have the potential to revolutionize TB therapy, thereby enhancing treatment outcomes and patient compliance. [ABSTRACT FROM AUTHOR]

Lipid metabolism reprogramming is one of the most prominent metabolic anomalies in cancer, wherein cancer cells undergo dysregulation of lipid metabolism to acquire adequate energy, cell membrane building blocks, as well as signaling molecules essential for cell proliferation, survival, invasion, and metastasis. These adaptations enable cancer cells to effectively respond to challenges posed by the tumor microenvironment, leading to cancer therapy resistance and poor cancer prognosis. Head and neck cancer, ranking as the seventh most prevalent cancer, exhibits numerous abnormalities in lipid metabolism. Nevertheless, the precise role of lipid metabolic rewiring in head and neck cancer remains unclear. In line with the LIPID MAPS Lipid Classification System and cancer risk factors, the present review delves into the dysregulated molecules and pathways participating in the process of lipid uptake, biosynthesis, transportation, and catabolism. We also present an overview of the latest advancements in understanding alterations in lipid metabolism and how they intersect with the carcinogenesis, development, treatment, and prognosis of head and neck cancer. By shedding light on the significance of metabolic therapy, we aspire to improve the overall prognosis and treatment outcomes of head and neck cancer patients. [ABSTRACT FROM AUTHOR]

To increase the performance of indomethacin (IND) by enhancing its water solubility and promoting its therapeutic efficiency, a ternary physically stable co-amorphous system of this poorly soluble drug with paracetamol and polyvinylpyrrolidone (PVP K30) was prepared. The effect of PVP on molecular interactions was also evaluated. Binary solid dispersions (IND:paracetamol) were prepared by a kneading method. Then, the PVP as a third component was added at different weight ratios (w/w). The generated systems were characterized by x-ray diffraction, Fourier transform infrared (FTIR) spectroscopy, scanning electronic microscopy, and 13C NMR spectroscopy. As evidenced by FTIR spectroscopy and 13C NMR investigations, the PVP interacted with paracetamol and IND through hydrogen bonds. A physical stability study under high stress conditions at relative humidity = 75% and T = 40°C for 3 months showed the ability of PVP to stabilize amorphous drug molecules. This has significantly improved the water solubility of IND at T = 37°C and pH = 7.0 in comparison with the binary solid dispersion (IND:paracetamol) or the pure state of the drug. The synergistic effect that PVP provides to the binary mixture of IND and paracetamol was the driving force behind forming a robust co-amorphous system with enhanced physical stability and water solubility. [ABSTRACT FROM AUTHOR]

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for treating pain and inflammation. Spontaneous adverse drug reaction (ADR) reports represent a rich data source for the detection of unknown and rare ADRs. This cross-sectional study aimed to analyze the characteristics of ADRs due to NSAIDs in Thailand. All ADR reports of NSAIDs for systemic use from 2015 to 2019 were extracted from the national database in Thailand. Patient characteristics, drug use information, adverse event information, and source of senders in 32,857 reports were analyzed. The annual number of ADR reports due to NSAIDs decreased from 7,008 in 2015 to 5,922 in 2019. The most frequently reported drug was ibuprofen (n=12,645, 38.5%) followed by diclofenac (n=7,795, 23.7%), most patients were 40–59 years old, and the major adverse reaction was angioedema (n=7,513, 22.9%). Serious reactions were recorded in 20.7% (n=6,801) of the total ADRs. Most patients (n=20,593, 62.7%) recovered without sequelae, but there were 5,420 patients (16.5%) who could not recover and 3,109 patients (9.5%) who were recovering. Eight patients (0.02%) died of Stevens-Johnson syndrome (n=3), toxic epidermal necrolysis (n=4), and anaphylactic shock (n=1), which were possibly related to ADRs. The number of ADR reports due to NSAIDs decreased from 2015 to 2019 in Thailand. Serious ADRs and death cases accounted for 20.7% and 0.02%, respectively. Most fatal cases exhibited severe drug-induced skin reactions. [ABSTRACT FROM AUTHOR]

With the increased disability associated with osteoarthritis (OA) progression, and the significant socioeconomic burden of joint replacement surgeries, there is a need for more reliable conservative treatments for patients presenting with hip OA. Most studies of OA treatments involve the knee. We conducted a literature search and reviewed non-operative hip OA treatment recommendations by the Osteoarthritis Research Society International, the American College of Rheumatology, American Academy of Orthopedic Surgeons, and European Alliance of Associations for Rheumatology, as well as Cochrane Reviews. Non-steroidal anti-inflammatory drugs and corticosteroid injections are the most supported and recommended options for hip OA; other medications with potential benefits for short-term pain relief include acetaminophen and tramadol. Most societies recommend against the use of glucosamine, typical opioids, and viscosupplementation injections. Platelet-rich plasma has potential benefits, but evidence of its effectiveness is incomplete. Further research is needed to better inform and guide clinicians who create treatment plans for patients with symptomatic hip OA. [ABSTRACT FROM AUTHOR]

Oral squamous cell carcinoma (OSCC) is one of the most common malignancies and has a high mortality, posing a great threat to both human physical and mental health. With the advancement of scientific research, a variety of cancer therapies have been used for OSCC treatment. However, the prognosis of OSCC shows no significant improvement. Metformin has been recognized as the first-line drug for the treatment of diabetes, and recent studies have shown that metformin has a remarkable suppressive effect on tumor progression. Metformin can not only affect the energy metabolism of tumor cells but also play an antitumor role by modulating the tumor microenvironment and cancer stem cells. In this review, the molecular mechanism of metformin and its anticancer mechanism in OSCC are summarized. In addition, this article summarizes the side effects of metformin and the future prospects of its application in the treatment of OSCC. [ABSTRACT FROM AUTHOR]

In this study, we aimed to evaluate limited sampling strategies for achieving the therapeutic ranges of the area under the concentration‐time curve (AUC) of vancomycin on the first and second day (AUC0–24, AUC24–48, respectively) of therapy. A virtual population of 1000 individuals was created using a population pharmacokinetic (PopPK) model, which was validated and incorporated into our model‐informed precision dosing tool. The results were evaluated using six additional PopPK models selected based on a study design of prospective or retrospective data collection with sufficient concentrations. Bayesian forecasting was performed to evaluate the probability of achieving the therapeutic range of AUC, defined as a ratio of estimated/reference AUC within 0.8–1.2. The Bayesian posterior probability of achieving the AUC24–48 range increased from 51.3% (a priori probability) to 77.5% after using two‐point sampling at the trough and peak on the first day. Sampling on the first day also yielded a higher Bayesian posterior probability (86.1%) of achieving the AUC0–24 range compared to the a priori probability of 60.1%. The Bayesian posterior probability of achieving the AUC at steady‐state (AUCSS) range by sampling on the first or second day decreased with decreased kidney function. We demonstrated that second‐day trough and peak sampling provided accurate AUC24–48, and first‐day sampling may assist in rapidly achieving therapeutic AUC24–48, although the AUCSS should be re‐estimated in patients with reduced kidney function owing to its unreliable predictive performance. [ABSTRACT FROM AUTHOR]

Allopurinol (ALP) is a successful drug used in the treatment of gout. However, this drug has been implicated in hypersensitivity reactions that can cause severe to life‐threatening reactions such as Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Individuals who carry the human leukocyte antigen (HLA)‐B*58:01 allotype are at higher risk of experiencing a hypersensitivity reaction (odds ratios ranging from 5.62 to 580.3 for mild to severe reactions, respectively). In addition to the parent drug, the metabolite oxypurinol (OXP) is implicated in triggering T cell‐mediated immunopathology via a labile interaction with HLA‐B*58:01. To date, there has been limited information regarding the T‐cell receptor (TCR) repertoire usage of reactive T cells in patients with ALP‐induced SJS or TEN and, in particular, there are no reports examining paired αβTCRs. Here, using in vitro drug‐treated PBMCs isolated from both resolved ALP‐induced SJS/TEN cases and drug‐naïve healthy donors, we show that OXP is the driver of CD8+ T cell‐mediated responses and that drug‐exposed memory T cells can exhibit a proinflammatory immunophenotype similar to T cells described during active disease. Furthermore, this response supported the pharmacological interaction with immune receptors (p‐i) concept by showcasing (i) the labile metabolite interaction with peptide/HLA complexes, (ii) immunogenic complex formation at the cell surface, and (iii) lack of requirement for antigen processing to elicit drug‐induced T cell responsiveness. Examination of paired OXP‐induced αβTCR repertoires highlighted an oligoclonal and private clonotypic profile in both resolved ALP‐induced SJS/TEN cases and drug‐naïve healthy donors. [ABSTRACT FROM AUTHOR]

Background: Post-translational modifications (PTMs) are considered to be an important factor in the pathogenesis of Systemic lupus erythematosus (SLE). Lysine 2-hydroxyisobutyryl (Khib), as an emerging post-translational modification of proteins, is involved in some important biological metabolic activities. However, there are poor studies on its correlation with diseases, especially SLE. Objective: We performed quantitative, comparative, and bioinformatic analysis of Khib proteins in Peripheral blood mononuclear cells (PBMCs) of SLE patients and PBMCs of healthy controls. Searching for pathways related to SLE disease progression and exploring the role of Khib in SLE. Methods: Khib levels in SLE patients and healthy controls were compared based on liquid chromatography tandem mass spectrometry, then proteomic analysis was conducted. Results: Compared with healthy controls, Khib in SLE patients was up-regulated at 865 sites of 416 proteins and down-regulated at 630 sites of 349 proteins. The site abundance, distribution and function of Khib protein were investigated further. Bioinformatics analysis showed that Complement and coagulation cascades and Platelet activation in immune-related pathways were significantly enriched, suggesting that differentially modified proteins among them may affect SLE. Conclusion: Khib in PBMCs of SLE patients was significantly up- or down-regulated compared with healthy controls. Khib modification of key proteins in the Complement and coagulation cascades and Platelet activation pathways affects platelet activation and aggregation, coagulation functions in SLE patients. This result provides a new direction for the possible significance of Khib in the pathogenesis of SLE patients. [ABSTRACT FROM AUTHOR]

For all other aspects concerning the management of patients with diabetes, we refer to the recommendations from diabetes associations, e.g. the European Association for the Study of Diabetes (EASD) or the American Diabetes Association (ADA).[1] These Guidelines offer evidence-based recommendations to manage CV risk in patients with diabetes and provide guidance for the treatment of atherosclerotic cardiovascular disease (ASCVD) in patients with diabetes. The impact of diabetes on peripheral atherosclerosis Diabetes is one of the most important risk factors for the development and progression of atherosclerosis.[[749], [751], [753]] The number of patients with atherosclerosis associated with diabetes is steadily increasing alongside the increasing number of patients with diabetes worldwide. There has not been a specific trial on revascularization strategies in patients with diabetes; however, a review of 56 studies including patients with diabetes suggested higher limb-salvage rates after revascularization (78-85% at 1 year) compared with conservative management.[770] Due to disease progression, long-term follow-up is very important in patients with diabetes and LEAD.[771] 10.1.2. [Extracted from the article]

Layered double hydroxide nanocarriers are capable of intercalating hydrophobic NSAIDs, such as mefenamic acid, which improves their pharmacokinetics and bioavailability. [ABSTRACT FROM AUTHOR]

Background and Aims: The study aimed to evaluate the pharmacological properties of methanolic extracts of leaves and barks of Woodfordia fruticosa (L.) Kurz (family: Lythraceae) focusing on antioxidant, thrombolytic, anti‐inflammatory, antibacterial, analgesic, and antidiarrheal effects. Methods: 1,1‐Diphenyl‐2‐picrylhydrazyl (DPPH) free radical scavenging assay, clot lysis, disc diffusion, and membrane stabilizing methods were employed to assess in vitro antioxidant, thrombolytic, antibacterial, and anti‐inflammatory properties of the leaf and bark methanolic extracts (ME) of W. fruticosa and different organic solvents, that is, petroleum ether (PE), dichloromethane (DCM), chloroform (CL), and aqueous (AQ) fractions. In addition, in vivo central and peripheral analgesic and antidiarrheal activities of both crude extracts were evaluated at two doses (200 and 400 mg/kg of body weight [bw]). Results: All the extracts and fractions showed promising antioxidant properties by scavenging DDPH free radicals with IC50 of 6.11–20.79 μg/mL. AQ fraction (41.24%) of leaves and ME (44.90%) of bark exerted notable in vitro thrombolytic activity. The CL fraction of leaves and AQ fraction of the bark showed 43.16% and 45.37% inhibition of RBC hemolysis, respectively, compared to the inhibition of RBC hemolysis by aspirin in a hypotonic‐induced membrane stabilizing assay. Besides, both extracts were observed to provide significant (p < 0.001) central and peripheral analgesic responses at both doses of 200 and 400 mg/kg bw. Furthermore, both doses of bark extract (p < 0.001) and the 400 mg/kg bw of leaf extract (p < 0.05) were observed to possess statistically significant antidiarrheal activity. Additionally, in an in vivo acute toxicity investigation, both extracts had a median lethal dose (LD50) greater than 5000 mg/kg bw, indicating their safety level. Conclusion: The current study proves the ethnomedicinal uses of W. fruticosa; however, further studies are required for phytochemical screening to isolate the responsible bioactive compounds and discover the lead molecules from the plant species. [ABSTRACT FROM AUTHOR]

Complex regional pain syndrome (CRPS) is a chronic disease that affects a limb following an injury or trauma. The CRPS associated with symptoms, including severe pain, swelling, as well as changes in skin color and temperature. Treatment of CRPS requires a multidisciplinary approach, with a focus on personalized treatment plans and addressing psychological factors. This review provides an overview of updates in the diagnosis and treatment of CRPS. There are clinical criteria for diagnosing CRPS, including persistent pain and swelling. The CRPS can also be diagnosed with imaging and laboratory tests. Novel insights into treatment approaches for CRPS have been gained from advances in understanding its pathophysiology. Treatment of CRPS includes both pharmacological and non-pharmacological interventions. The latest guidelines for CRPS treatment emphasize the importance of early diagnosis and intervention, personalized treatment plans, and addressing psychological factors in managing CRPS. [ABSTRACT FROM AUTHOR]

The potential interaction between metformin and exercise on glucose-lowering effects remains controversial. We studied the separated and combined effects of metformin and/or exercise on fasting and postprandial insulin sensitivity in individuals with pre-diabetes and type 2 diabetes (T2D). Eight T2D adults (60 ± 4 yr) with overweight/obesity (32 ± 4 kg·m-2) under chronic metformin treatment (9 ± 6 yr; 1281 ± 524 mg·day-1) underwent four trials; 1) taking their habitual metformin treatment (MET), 2) substituting during 96 h their metformin medication by placebo (PLAC), 3) placebo combined with 50 min bout of high-intensity interval exercise (PLAC þ EX), and 4) metformin combined with exercise (MET þ EX). Plasma glucose kinetics using stable isotopes (6,6-2H2 and [U-13C] glucose), and glucose oxidation by indirect calorimetry, were assessed at rest, during exercise, and in a subsequent oral glucose tolerance test (OGTT). Postprandial glucose and insulin concentrations were analyzed as mean and incremental area under the curve (iAUC), and insulin sensitivity was calculated (i.e., MATSUDAindex and OGISindex). During OGTT, metformin reduced glucose iAUC (i.e., MET and MET þ EX lower than PLAC and PLAC þ EX, respectively; P = 0.023). MET þ EX increased MATSUDAindex above PLAC (4.8 ± 1.4 vs. 3.3 ± 1.0, respectively; P = 0.018) and OGISindex above PLAC (358 ± 52 vs. 306 ± 46 mL·min-1·m-2, respectively; P = 0.006). Metformin decreased the plasma appearance of the ingested glucose (Ra OGTT; MET vs. PLAC, -3.5; 95% CI -0.1 to -6.8 lmol·kg-1·min-1; P = 0.043). Metformin combined with exercise potentiates insulin sensitivity during an OGTT in individuals with pre-diabetes and type 2 diabetes. Metformin's blood glucose-lowering effect seems mediated by decreased oral glucose entering the circulation (gut-liver effect) an effect partially blunted after exercise. [ABSTRACT FROM AUTHOR]

Background: A proper diet plan is one of the necessary conditions for maintaining the children's health. The aim of this study was to evaluate the effect of consumption of pasteurized cow's milk fortified with albumin protein in primary-school children, in Yasuj, Iran. Materials and Methods: In this double-blind randomized clinical trial with 12 weeks of duration, 60 children aged 7-13 years, mild to moderate underweight (-1≥ weight-for-age z-score ≥-3), were randomly assigned to control and albumin groups. The albumin group and the control group received 200 cc of milk with 10 g of albumin powder and 200 cc of milk with 10 g of cornstarch powder, respectively. At the beginning and end of the study, food intake and anthropometric indices were measured. Results: After 12 weeks of intervention, none of the anthropometric indices (weight, weight-for-age z-score, body mass index (BMI), BMI-for-age z-score, and waist circumference) showed significant changes as compared to baseline in the control group, but weight-for-age z-score and BMI-for-age z-score showed significant increase as compared to baseline in the albumin group (before: -2.25 ± 0.40, after: -1.98 ± 0.35, P = 0.001 and before: -3.48 ± 0.86, after: -3.06 ± 0.71, P = 0.009, respectively). The comparison of the mean changes between the two groups showed significant difference regarding weight-for-age z-score (control group: -1.70 ± 0.31 in comparison with albumin group: -1.98 ± 0.35, P = 0.002), BMI (control group: 12.08 ± 1.96 in comparison with albumin group: 12.13 ± 1.49, P = 0.03), and BMI-for-age z-score (control group: -3.11 ± 0.91 in comparison with albumin group: -3.06 ± 0.71, P = 0.02). Conclusion: The consumption of albumin powder with milk can improve weight-for-age z-score and BMI-for-age z-score indices in children with mild-to-moderate underweight. Larger controlled interventional studies with longer duration are recommended. [ABSTRACT FROM AUTHOR]

Purpose: Dietary fibers and hypoglycemic drugs can be used concomitantly in the treatment of diabetes mellitus. We aimed to perform this review in order to evaluate whether scientific evidence is available regarding the interaction between these components and whether these interactions alter drug absorption. Methods: We conducted a search of the literature for controlled clinical trials that evaluated the occurrence and clinical relevance of interactions between dietary fibers and hypoglycemic drugs. Six databases were searched from inception to April 20, 2020 and trials were eligible for inclusion if they measured changes in drug absorption parameters. Results: In three studies, there were interactions between dietary fibers and hypoglycemic drugs, causing alterations in drug absorption. The other two studies had no significant changes in absorption pharmacokinetic parameters. Conclusions: The physicochemical characteristics of the dietary fiber used, the chemical structure of the drug, and the pharmaceutical form administered are determining factors for the occurrence of alterations in drug absorption. [ABSTRACT FROM AUTHOR]

This study aimed to assess the general population's knowledge, attitudes, and practices regarding the use of over-the-counter analgesics.Methods: This cross-sectional study took place in Indonesia from December 2019 to June 2020. A validated questionnaire was used to survey a total of 582 respondents. A comparative analysis examined the variations in mean scores for respondents' characteristics concerning their knowledge, attitude, and practice. A regression analysis was also employed to explore the factors associated with adopting good analgesia practices.Results: The findings of the study revealed significant differences in average knowledge scores related to gender, educational attainment, and employment status for the use of both paracetamol and NSAIDs. Regarding knowledge, the respondents demonstrated a higher average score for analgesics (4.56 ± 1.84) than NSAIDs (2.881 ± 2.40), out of a maximum score of 6 points. The results indicate that the respondents obtained a low score for attitude (6.80 ± 3.74) out of 16 points and a positive score for practice (2.71 ± 0.48) out of 3 points regarding using analgesics. Moreover, the regression analysis revealed that gender, residing near primary health care facilities, and having sound knowledge of NSAID use were significant predictors of good analgesic practice (p < 0.05).Conclusion: The respondents demonstrated a greater understanding of analgesics compared with NSAIDs. However, despite this higher knowledge level, they had relatively low attitude scores but positive practice scores, indicating a discrepancy between attitudes and actual behavior in using analgesics. [ABSTRACT FROM AUTHOR]

Acetaminophen (APAP) is a widely used drug known for its analgesic and antipyretic properties. However, its exact mechanism of action is still unclear and has been primarily associated with its effects on COX enzymes and serotonergic pathways. Till date, the immunological mechanisms affected by APAP has gained only inadequate attention. A distinct group of immune cells called Group 2 Innate Lymphoid Cells (ILC2s) are known to play an important role in type 2 cytokine-mediated immunity and their regulatory dysfunction is associated with numerous type 2 pathologies, such as allergy. Conversely, another class of recently characterized Innate Lymphoid Cells called Innate Regulatory Cells (ILCregs) suppress the activation of ILC2s. Maintaining a balance between ILC2s and ILCregs is vital for achieving a well-controlled immune response and tissue homeostasis. Recent studies have highlighted the critical role of prostaglandin D2 (PGD2) in the maturation and development of ILC2 functions. Since APAP also suppresses PGD2 synthesis, it was speculated that APAP treatment could reduce the number of ILC2s while potentially increasing the number of ILCregs. To investigate this hypothesis, here, we administered therapeutic doses of APAP to OVA-sensitized mice, a well-established model of type 2 pathological inflammation. The mice received oral doses of 200 mg/kg body wt. of APAP twice weekly, along with weekly OVA sensitizations for six weeks. The mice were sacrificed at different time points (days 14, 28 and 42) to assess the kinetics of ILC2s, ILCregs and immunoglobulins (IgE and IgG1). The results demonstrated that APAP treatment effectively suppressed OVA-induced ILC2s while significantly increasing the number of IL-10+ ILCregs. APAP exposure also led to decreased levels of serum PGD2, OVA-specific IgE and IgG1, and enhanced the level of IL-10 in OVA sensitized mice. Moreover, OVA sensitized mice treated with APAP did not develop pathological changes in spleen, when compared to OVA sensitized mice. Additionally, APAP treatment did not cause any adverse effects on mice liver in treatment groups. These preliminary findings suggest that APAP exhibits the capacity to modulate type 2 immune responses by suppressing ILC2s and inducing the expansion of IL-10+ ILCregs. [ABSTRACT FROM AUTHOR]

The antidiabetic drug metformin (MF) exhibits redox-modulating effects in various pathologies associated with oxidative stress and mitigates ionizing radiation-induced toxicity, but the underlying mechanisms remain to be elucidated. Thus, we studied some radiomitigatory effects of MF and explored the possible mechanisms behind them. Highly sensitive luminescence methods and non-competitive enzyme-linked immunosorbent assay (ELISA) were used in in vitro studies, and in vivo the damage to bone marrow cells and its repair were assessed by the micronucleus test. In a solution, MF at concentrations exceeding 0.1 µM effectively intercepts •OH upon X-ray-irradiation, but does not react directly with H2O2. MF accelerates the decomposition of H2O2 catalyzed by copper ions. MF does not affect the radiation-induced formation of H2O2 in the solution of bovine gamma-globulin (BGG), but has a modulating effect on the generation of H2O2 in the solution of bovine serum albumin (BSA). MF at 0.05–1 mM decreases the radiation-induced formation of 8-oxoguanine in a DNA solution depending on the concentration of MF with a maximum at 0.25 mM. MF at doses of 3 mg/kg body weight (bw) and 30 mg/kg bw administered to mice after irradiation, but not before irradiation, reduces the frequency of micronucleus formation in polychromatophilic erythrocytes of mouse red bone marrow. Our work has shown that the radiomitigatory properties of MF are mediated by antioxidant mechanisms of action, possibly including its ability to chelate polyvalent metal ions. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study was to quantify identifiable sources of variability, including key pharmacogenetic variants in oxypurinol pharmacokinetics and their pharmacodynamic effect on serum urate (SU). Methods: Hmong participants (n = 34) received 100 mg allopurinol twice daily for 7 days followed by 150 mg allopurinol twice daily for 7 days. A sequential population pharmacokinetic pharmacodynamics (PKPD) analysis with non‐linear mixed effects modelling was performed. Allopurinol maintenance dose to achieve target SU was simulated based on the final PKPD model. Results: A one‐compartment model with first‐order absorption and elimination best described the oxypurinol concentration–time data. Inhibition of SU by oxypurinol was described with a direct inhibitory Emax model using steady‐state oxypurinol concentrations. Fat‐free body mass, estimated creatinine clearance and SLC22A12 rs505802 genotype (0.32 per T allele, 95% CI 0.13, 0.55) were found to predict differences in oxypurinol clearance. Oxypurinol concentration required to inhibit 50% of xanthine dehydrogenase activity was affected by PDZK1 rs12129861 genotype (−0.27 per A allele, 95% CI −0.38, −0.13). Most individuals with both PDZK1 rs12129861 AA and SLC22A12 rs505802 CC genotypes achieve target SU (with at least 75% success rate) with allopurinol below the maximum dose, regardless of renal function and body mass. In contrast, individuals with both PDZK1 rs12129861 GG and SLC22A12 rs505802 TT genotypes would require more than the maximum dose, thus requiring selection of alternative medications. Conclusions: The proposed allopurinol dosing guide uses individuals' fat‐free mass, renal function and SLC22A12 rs505802 and PDZK1 rs12129861 genotypes to achieve target SU. [ABSTRACT FROM AUTHOR]

Acquired von Willebrand syndrome (AVWS) is a relatively infrequent but often overlooked finding when testing for von Willebrand factor (VWF) levels in a patient with mucocutaneous bleeding. Known causes include cardiovascular disorders, hematologic and solid tumors, autoimmune disorders, hypothyroidism, and drugs. An incoercible oral bleeding after a two-teeth removal in a patient with a mechanical aortic valve eventually raised suspicion about an AVWS that was confirmed through laboratory testing. Substitution therapy with an exogenous VWF factor was required to control the bleeding. Known causes of AVWS, including Heyde's syndrome, were ruled out. VWF levels finally normalized two days after suspension of allopurinol, which the patient received for symptomatic hyperuricemia, leading to his complete recovery and early discharge without any other complications. AVWS is an underdiagnosed entity due to a lack of testing. Allopurinol has never been postured before as a possible etiology and should be evaluated when reaching a diagnosis. [ABSTRACT FROM AUTHOR]

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Purpose: Allopurinol is a potent inhibitor of the enzyme xanthine oxidase used primarily in the treatment of hyperuricemia and gout. The aim of this study was to compare the analgesic efficacy of preanesthetic allopurinol versus placebo on postoperative pain and anxiety in patients undergoing abdominal hysterectomy., Methods: This is a prospective, double-blinded, placebo-controlled, randomized clinical trial. We investigated 54 patients scheduled to undergo elective abdominal hysterectomy. Patients were randomly assigned to receive either oral allopurinol 300 mg (n = 27) or placebo (n = 27) the night before and 1 h before surgery. Patients were submitted to evaluation of pain and anxiety before the treatment, for 24 h postoperatively, 30 and 90 days after surgery. Cerebrospinal fluid was collected at the time of the spinal anesthesia to perform the measurement of the central levels of purines., Results: Preoperative administration of allopurinol was effective in reducing postoperative pain 2 h after surgery. Allopurinol caused a reduction of approximately 40% in pain scores measured by the visual analogue pain scale after surgery (p < 0.05). No differences were found between groups in anxiety scores after surgery. There was a significant change in the cerebrospinal fluid concentrations of xanthine and uric acid before surgery (p < 0.01)., Conclusion: This study showed a short-term benefit of the use of allopurinol as a preanesthetic medication since it was related to a reduction on pain scores 2 h after surgery. The purinergic system is a potential target for new analgesic drugs. New studies investigating more selective purine derivatives in the management of pain should be performed., Trial Number Registration: Brazilian Registry of Clinical Trials-ReBEC #RBR-9pw58p., (© 2021. Japanese Society of Anesthesiologists.)

Background and Purpose: Measurement of gastro-intestinal motility is increasingly performed under general anesthesia during endoscopic or surgical procedures. The aim of the present study was to review the impact of different anesthetic agents on digestive motility measurements in humans., Methods: This systematic review was performed using the Medline-Pubmed and Web of Science databases. All articles published until October 2023 were screened by identification of key words. Studies were reviewed if patients had an assessment of digestive motility using conventional perfused manometry, high-resolution manometry, electronic barostat or functional lumen impedance planimetry with the use of inhaled or intravenous anesthetic anesthetic agents (propofol, ketamine, halogens, nitrous oxide, opioids, and neuromuscular blockades)., Results: Four hundred and eighty-eight unique citations were identified, of which 42 studies met the inclusion criteria and were included in the present review. The impact of anesthetics was mostly studied in patients who underwent esophageal manometry. There was a heterogeneity in both the dose and timing of administration of anesthetics among the studies. Remifentanil analgesia was the most studied anesthetic drug in the literature, showing a decrease in both distal latency and lower esophageal sphincter pressure after its administration, but the impact on Chicago classification was not studied. Inhaled anesthetics administration elicited a decrease in lower esophageal sphincter pressure, but contradictory findings were shown on esophageal motility following propofol or neuromuscular blocking agents administration., Conclusion: Studies of the impact of anesthetics on digestive motility remain scarce in the literature, although some agents have been reported to profoundly affect gastro-intestinal motility., (© 2024 The Author(s). Neurogastroenterology & Motility published by John Wiley & Sons Ltd.)

Fenamates as classical nonsteroidal anti-inflammatory agents are widely used for relieving pain. Preclinical studies and epidemiological data highlight their chemo-preventive and chemotherapeutic potential for cancer. However, comprehensive reviews of fenamates in cancer are limited. To accelerate the repurposing of fenamates, this review summarizes the results of fenamates alone or in combination with existing chemotherapeutic agents. This paper also explores targets of fenamates in cancer therapy, including COX, AKR family, AR, gap junction, FTO, TEAD, DHODH, TAS2R14, ion channels, and DNA. Besides, this paper discusses other mechanisms, such as regulating Wnt/β-catenin, TGF-β, p38 MAPK, and NF-κB pathway, and the regulation of the expressions of Sp, EGR-1, NAG-1, ATF-3, ErbB2, AR, as well as the modulation of the tumor immune microenvironment. Furthermore, this paper outlined the structural modifications of fenamates, highlighting their potential as promising leads for anticancer drugs., (© 2024 Wiley Periodicals LLC.)

Chronic kidney disease (CKD) is a complication of diabetes that affects circulating drug concentrations and elimination of drugs from the body. Multiple drugs may be prescribed for treatment of diabetes and co-morbidities, and CKD complicates the pharmacotherapy selection and dosing regimen. Characterizing variations in renal drug clearance using models requires large clinical datasets that are costly and time-consuming to collect. We propose a flexible approach to incorporate impaired renal clearance in pharmacokinetic (PK) models using descriptive statistics and secondary data with mechanistic models and PK first principles. Probability density functions were generated for various drug clearance mechanisms based on the degree of renal impairment and used to estimate the total clearance starting from glomerular filtration for metformin (MET) and dapagliflozin (DAPA). These estimates were integrated with PK models of MET and DAPA for simulations. MET renal clearance decreased proportionally with a reduction in estimated glomerular filtration rate (eGFR) and estimated net tubular transport rates. DAPA total clearance varied little with renal impairment and decreased proportionally to reported non-renal clearance rates. Net tubular transport rates were negative to partially account for low renal clearance compared with eGFR. The estimated clearance values and trends were consistent with MET and DAPA PK characteristics in the literature. Dose adjustment based on reduced clearance levels estimated correspondingly lower doses for MET and DAPA while maintaining desired dose exposure. Estimation of drug clearance rates using descriptive statistics and secondary data with mechanistic models and PK first principles improves modeling of CKD in diabetes and can guide treatment selection., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Metformin (dimethyl-biguanide) can claim its origins in the use of Galega officinalis as a plant treatment for symptoms ascribed to diabetes. Since the first clinical use of metformin as a glucose-lowering agent in 1957, this medicine has emerged as a first-line pharmacological option to support lifestyle interventions in the management of type 2 diabetes (T2D). It acts through multiple cellular pathways, principally in the gut, liver and muscle, to counter insulin resistance and lower blood glucose without weight gain or risk of overt hypoglycaemia. Other effects include improvements in lipid metabolism, decreased inflammation and lower long-term cardiovascular risk. Metformin is conveniently combined with other diabetes medications, can be prescribed in prediabetes to reduce the risk of progression to T2D, and is used in some regions to assist glycaemic control in pregnancy. Consistent with its diversity of actions, established safety profile and cost-effectiveness, metformin is being assessed for further possible clinical applications. The use of metformin requires adequate renal function for drug elimination, and may cause initial gastrointestinal side effects, which can be moderated by taking with meals or using an extended-release formulation. Thus, metformin serves as a valuable therapeutic resource for use throughout the natural history of T2D., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Metformin is the first-line medication for type 2 diabetes. It is effective and safe, provided some caution is taken in specific populations. In patients with chronic kidney disease, metformin may provide long-term benefits, and it is a first-line therapy for diabetes, but the estimated glomerular filtration rate (eGFR) must be assessed regularly, to minimize the risk for metformin accumulation. When eGFR is 30-60 mL/min/1.73m 2 , the dose should be reconsidered, and sick-days education provided. Metformin should be discontinued when eGFR falls below 30 mL/min/1.73m 2 . Metformin accumulation may increase the risk for lactic acidosis if concomitant risk factors for hyperlactataemia (liver or respiratory insufficiency, sepsis, acute heart failure) are present; in these conditions, metformin is contraindicated, even although the available evidence is reassuring. Patients on metformin often complain of gastrointestinal side effects (mainly diarrhoea and nausea) during therapy initiation, but they may sometimes occur after years of stable therapy. These usually resolve if the dose is carefully titrated, or by switching to the extended-release formulation. Patients with obesity may benefit from the significant, although modest, metformin-associated weight loss and appetite reduction. During pregnancy, metformin is associated with a reduction of pregnancy complications, especially in obese women, but some concern remains, because metformin crosses the placenta, and it is associated with a significantly lower mean birth weight than insulin. In the elderly, gastrointestinal tolerability and renal function must be reassessed more often. Vitamin B-12 should be screened regularly in long-time metformin users because metformin may induce clinical vitamin B-12 deficiency., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Gout affects 15%-30% of individuals with advanced kidney disease. Allopurinol which is rapidly and extensively metabolised to an active metabolite, oxypurinol, is the most commonly prescribed urate-lowering therapy. Oxypurinol is almost entirely eliminated by the kidneys (>95%) and has an elimination half-life of 18-30 h in those with normal kidney function. However, oxypurinol pharmacokinetics are poorly understood in individuals with kidney failure on peritoneal dialysis. This study characterised the elimination of oxypurinol and urate in people with gout receiving peritoneal dialysis. Oxypurinol steady-state oral clearance (CL/F), elimination half-life as well as kidney (CL k ) and peritoneal (CL pd ) clearances for oxypurinol and urate were calculated from the plasma, urine and dialysate concentration data for each individual. Our results demonstrate that oxypurinol and urate are removed by peritoneal dialysis, accounting for more than 50% of oxypurinol and urate clearances. An allopurinol dose about 50%-60% lower than the usual dose used for a patient with normal kidney function will provide adequate urate-lowering therapy., (© 2024 The Authors. Nephrology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Nephrology.)

Listeria monocytogenes is a notable food-borne pathogen that has the ability to create biofilms on different food processing surfaces, making it more resilient to disinfectants and posing a greater risk to human health. This study assessed melittin peptide's anti-biofilm and anti-pathogenicity effects on L. monocytogenes ATCC 19115. Melittin showed minimum inhibitory concenteration (MIC) of 100 μg/mL against this strain and scanning electron microscopy images confirmed its antimicrobial efficacy. The OD measurement demonstrated that melittin exhibited a strong proficiency in inhibiting biofilms and disrupting pre-formed biofilms at concentrations ranging from 1/8MIC to 2MIC and this amount was 92.59 ± 1.01% to 7.17 ± 0.31% and 100% to 11.50 ± 0.53%, respectively. Peptide also reduced hydrophobicity and self-aggregation of L. monocytogenes by 35.25% and 14.38% at MIC. Melittin also significantly reduced adhesion to HT-29 and Caco-2 cells by 61.33% and 59%, and inhibited invasion of HT-29 and Caco-2 cells by 49.33% and 40.66% for L. monocytogenes at the MIC value. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) revealed melittin's impact on gene expression, notably decreasing inlB (44%) and agrA (45%) gene expression in L. monocytogenes. flaA and hly genes also exhibited reduced expression. Also, significant changes were observed in sigB and prfA gene expression. These results underscore melittin's potential in combating bacterial infections and biofilm-related challenges in the food industry., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Pharmaceuticals are significant environmental stressors, since they are utilized around the world; they are usually released in to the aquatic system without adequate treatment and several non-target species can be harmed because of their intrinsic properties. Paracetamol is one of the most widely prescribed analgesics in human medical care. Consequently, this compound is systematically reported to occur in the wild, where it may exert toxic effects on non-target species, which are mostly uncharacterized so far. The objective of the present work was to assess the acute (control, 5, 25, 125, 625 and 3125 μg/L) and chronic (control, 5, 10, 20, 40 and 80 μg/L) effects of paracetamol on behavioural endpoints, as well as on selected oxidative stress biomarkers [superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GRed)] and the anti-inflammatory activity biomarker cyclooxygenase (COX), in the polychaete Hediste diversicolor (Annelida: Polychaeta). Exposure to paracetamol caused effects on behavioural traits, with increased burrowing time (96 h) and hypoactivity (28 days). In addition, exposure to paracetamol resulted also in significant increases of SOD activity, but only for intermediate levels of exposure, but for both acute and chronic exposures. Both forms of GPx had their activities significantly increased, especially after chronic exposure. Acutely exposed organisms had their GRed significantly decreased, while chronically exposed worms had their GRed activity augmented only for the lowest tested concentrations. Effects were also observed in terms of COX activity, showing that paracetamol absorption occurred and caused an inhibition of COX activity in both exposure regimes. It is possible to conclude that the exposure to concentrations of paracetamol close to the ones in the environment may be deleterious to marine ecosystems, endangering marine life by changing their overall redox balance, and the biochemical control of inflammatory intermediaries. Behaviour was also modified and the burrowing capacity was adversely affected. This set of effects clearly demonstrate that paracetamol exposure, under realistic conditions, it not exempt of adverse effects on marine invertebrates, such as polychaetes.

Abstracts only were excluded. We extracted information from the studies to answer the research question, ie, study design, publication year, population, sample size, patient characterization, duration, Jadad score, and liver function outcomes.Results: We screened 512 publications from the databases and identified 11 studies that met the inclusion criteria. Ten out of 11 included studies were double-blind RCTs. In the majority of the included studies, no statistically significant differences were observed in terms of hepatic safety data between febuxostat and allopurinol. However, in studies where allopurinol titration was used, it posed a challenge to maintain blinding. Notably, consistent adverse events related to liver function findings were observed across all reviewed RCTs. These abnormal liver function test results sometimes led to study withdrawal based on the investigators' assessment. Nevertheless, the investigators classified most liver function test elevations as mild to moderate in severity.Conclusion: Our analysis concluded that adult gout patients enrolled in the included RCTs exhibited similar hepatic safety profiles for both febuxostat and allopurinol treatment. Liver function abnormalities were identified in all RCTs included in this systematic review. Consequently, it is important for the product labeling information of both allopurinol and febuxostat to present and describe the current safety data to guide healthcare practitioners when prescribing these medications to patients. Pharmacovigilance and post-marketing pharmacoepidemiology data are essential in establishing the comprehensive safety profile. [ABSTRACT FROM AUTHOR]

Copyright of Equine Veterinary Journal is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Acetaminophen (paracetamol) is increasingly used to treat painful conditions in horses but its ocular penetration has not been studied. Objectives: To determine whether orally administered acetaminophen penetrates the aqueous humour of the normal equine eye and report an aqueous humour:serum acetaminophen concentration ratio in horses. Study design: In vivo experiment. Methods: Six privately owned horses with normal ophthalmic examinations weighing 568 ± 65 kg (mean ± standard deviation) and aged 11 ± 4 years were given 20 mg/kg acetaminophen orally every 12 h for a total of six doses. Physical exam parameters were recorded prior to, during, and after the dosing period. One hour after the final dose, horses were sedated and simultaneous aqueous humour and serum samples were collected and analysed for acetaminophen concentrations and selected eicosanoids. An aqueous humour:serum acetaminophen concentration ratio was calculated. A second aqueous humour sample was taken and analysed for eicosanoid concentrations 3 months after acetaminophen dosing. Physical exam data were compared between time points using a mixed model analysis (significance p < 0.05). Results: Acetaminophen was detected in both serum and aqueous humour of all horses and mean ± standard deviation aqueous humour:serum acetaminophen concentration ratio was 44.9 ± 15.9%. No significant changes in physical exam parameters occurred during or after dosing. Eicosanoids were not detected in aqueous humour at any sampling point. Main limitations: Presence of acetaminophen in the aqueous humour may not relate to clinical effect. A therapeutic level of acetaminophen has not been determined in horses, and the absence of ocular inflammation does not reflect conditions in which acetaminophen may be used. Conclusions: Acetaminophen readily penetrates the aqueous humour of the normal equine eye after consecutive oral dosing. Further study is required to determine whether acetaminophen is useful in the treatment of ocular pain and inflammation. [ABSTRACT FROM AUTHOR]

Frailty is an emerging and newly recognized complication of diabetes in older people. However, frailty is not thoroughly investigated in diabetes outcome studies. This manuscript reviews the effect of glycemic control and hypoglycemic therapy on the incidence of frailty in older people with diabetes. Current studies show that both low glycemia and high glycemia are associated with frailty. However, most of the studies, especially low glycemia studies, are cross-sectional or retrospective, suggesting association, rather than causation, of frailty. In addition, frail patients in the low glycemia studies are characterized by lower body weight or lower body mass index (BMI), contrary to those in the high glycemia studies, who are either overweight or obese. This may suggest that frailty has a heterogeneous metabolic spectrum, starting with an anorexic malnourished (AM) phenotype at one end, which is associated with low glycemia and a sarcopenic obese (SO) phenotype on the other end, which is associated with high glycemia. The current little evidence suggests that poor glycemic control increases the risk of frailty, but there is a paucity of evidence to suggest that tight glycemic control would reduce the risk of incident frailty. Metformin is the only well-studied hypoglycemic agent, so far, to have a protective effect against frailty independent of glycemic control in the non-frail older people with diabetes. However, once frailty is developed, the choice of the best hypoglycemic agent for these patients will be affected by the metabolic phenotype of frailty. For example, sodium glucose transporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RA) are appropriate in the SO phenotype due to their weight losing properties, while insulin therapy may be considered early in the AM phenotype due to its anabolic and weight gaining benefits. Future studies are still required to further investigate the metabolic effects of frailty on older people with diabetes, determine the most appropriate HbA1c target, and explore the most suitable hypoglycemic agent in each metabolic phenotype of frailty. [ABSTRACT FROM AUTHOR]

Metformin is used by women during pregnancy to manage diabetes and crosses the placenta, yet its effects on the fetus are unclear. We show that the liver is a site of metformin action in fetal sheep and macaques, given relatively abundant OCT1 transporter expression and hepatic uptake following metformin infusion into fetal sheep. To determine the effects of metformin action, we performed studies in primary hepatocytes from fetal sheep, fetal macaques, and juvenile macaques. Metformin increases AMP-activated protein kinase (AMPK) signaling, decreases mammalian target of rapamycin (mTOR) signaling, and decreases glucose production in fetal and juvenile hepatocytes. Metformin also decreases oxygen consumption in fetal hepatocytes. Unique to fetal hepatocytes, metformin activates stress pathways (e.g., increased PGC1A gene expression, NRF-2 protein abundance, and phosphorylation of eIF2α and CREB proteins) alongside perturbations in hepatokine expression (e.g., increased growth/differentiation factor 15 [GDF15] and fibroblast growth factor 21 [FGF21] expression and decreased insulin-like growth factor 2 [IGF2] expression). Similarly, in liver tissue from sheep fetuses infused with metformin in vivo, AMPK phosphorylation, NRF-2 protein, and PGC1A expression are increased. These results demonstrate disruption of signaling and metabolism, induction of stress, and alterations in hepatokine expression in association with metformin exposure in fetal hepatocytes. [ABSTRACT FROM AUTHOR]

Introduction: Metformin intoxication causes lactic acidosis by inhibiting Krebs' cycle and oxidative phosphorylation. Continuous renal replacement therapy (CRRT) is recommended for metformin removal in critically ill patients. According to current guidelines, regional citrate anticoagulation (RCA) is the first-line strategy. However, since metformin also inhibits citrate metabolism, a risk of citrate accumulation could be hypothesized. In the present study, we monitored the potential citrate accumulation in metformin-associated lactic acidosis (MALA) patients treated with CRRT and RCA using the physical-chemical approach to acid-base interpretation. Methods: We collected a case series of 3 patients with MALA. Patients were treated with continuous venovenous hemofiltration (CVVH), and RCA was performed with diluted citrate solution. Citrate accumulation was monitored through two methods: the ratio between total and ionized plasma calcium concentrations (T/I calcium ratio) above 2.5 and the strong ion gap (SIG) to identify an increased concentration of unmeasured anions. Lastly, a mathematical model was developed to estimate the expected citrate accumulation during CVVH and RCA. Results: All 3 patients showed a resolution of MALA after the treatment with CVVH. The T/I calcium ratio was consistently below 2.5, and SIG decreased, reaching values lower than 6 mEq/L after 48 h of CVVH treatment. According to the mathematical model, the estimated SIG without citrate metabolism should have been around 21 mEq/L due to citrate accumulation. Conclusions: In our clinical management, no signs of citrate accumulation were recorded in MALA patients during treatment with CVVH and RCA. Our data support the safe use of diluted citrate to perform RCA during metformin intoxication. [ABSTRACT FROM AUTHOR]

Background: Cuproptosis is a novel form of programmed cell death that differs from other types such as pyroptosis, ferroptosis, and autophagy. It is a promising new target for cancer therapy. Additionally, immune-related genes play a crucial role in cancer progression and patient prognosis. Therefore, our study aimed to create a survival prediction model for lung adenocarcinoma patients based on cuproptosis and immune-related genes. This model can be utilized to enhance personalized treatment for patients. Methods: RNA sequencing (RNA-seq) data of lung adenocarcinoma (LUAD) patients were collected from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The levels of immune cell infiltration in the GSE68465 cohort were determined using gene set variation analysis (GSVA), and immune-related genes (IRGs) were identified using weighted gene coexpression network analysis (WGCNA). Additionally, cuproptosis-related genes (CRGs) were identified using unsupervised clustering. Univariate COX regression analysis and least absolute shrinkage selection operator (LASSO) regression analysis were performed to develop a risk prognostic model for cuproptosis and immune-related genes (CIRGs), which was subsequently validated. Various algorithms were utilized to explore the relationship between risk scores and immune infiltration levels, and model genes were analyzed based on single-cell sequencing. Finally, the expression of signature genes was confirmed through quantitative real-time PCR (qRT-PCR), immunohistochemistry (IHC), and Western blotting (WB). Results: We have identified 5 Oncogenic Driver Genes namely CD79B, PEBP1, PTK2B, STXBP1, and ZNF671, and developed proportional hazards regression models. The results of the study indicate significantly reduced survival rates in both the training and validation sets among the high-risk group. Additionally, the high-risk group displayed lower levels of immune cell infiltration and expression of immune checkpoint compared to the low-risk group. [ABSTRACT FROM AUTHOR]

Gout is one of the most common noncommunicable diseases in Hong Kong. Although effective treatment options are readily available, the management of gout in Hong Kong remains suboptimal. Like other countries, the treatment goal in Hong Kong usually focuses on relieving symptoms of gout but not treating the serum urate level to target. As a result, patients with gout continue to suffer from the debilitating arthritis, as well as the renal, metabolic, and cardiovascular complications associated with gout. The Hong Kong Society of Rheumatology spearheaded the development of these consensus recommendations through a Delphi exercise that involved rheumatologists, primary care physicians, and other specialists in Hong Kong. Recommendations on acute gout management, gout prophylaxis, treatment of hyperuricemia and its precautions, co-administration of non-gout medications with urate-lowering therapy, and lifestyle advice have been included. This paper serves as a reference guide to all healthcare providers who see patients who are at risk and are known to have this chronic but treatable condition. [ABSTRACT FROM AUTHOR]

Metformin (1,1‐dimethylbiguanidine hydrochloride) (MF) is a drug that has long been in use for the treatment of type 2 diabetes mellitus and recently is coming into use in the radiation therapy of cancer and other conditions. Exposure to ionizing radiation disturbs the redox homeostasis of cells and causes damage to proteins, membranes, and mitochondria, destroying a number of biological processes. After irradiation, MF activates cellular antioxidant and repair systems by signaling to eliminate the harmful consequences of disruption of redox homeostasis. The use of MF in the treatment of the negative effects of irradiation has great potential in medical patients after radiotherapy and in victims of nuclear accidents or radiologic terrorism. [ABSTRACT FROM AUTHOR]

Aims: This study investigated the safe use of metformin in patients with (1) type 2 diabetes mellitus (T2DM) and heart failure on metformin, and (2) heart failure without T2DM and metformin naïve. Methods: Two prospective studies on heart failure patients were undertaken. The first was a cross‐sectional study with two patient cohorts, one with T2DM on metformin (n = 44) and one without T2DM metformin naive (n = 47). The second was a 12‐week interventional study of patients without T2DM (n = 27) where metformin (500 mg immediate release, twice daily) was prescribed. Plasma metformin and lactate concentrations were monitored. Individual pharmacokinetics were compared between cohorts. Univariable and multivariable analysis analysed the effects of variables on plasma lactate concentrations. Results: Plasma metformin and lactate concentrations mostly (99.9%) remained below safety thresholds (5 mg/L and 5 mmol/L, respectively). Metformin concentration had no significant relationship with lactic acidosis safety markers. In the interventional study, New York Heart Association (NYHA) II (P <.03) and III (P <.001) grading was associated with higher plasma lactate concentrations, whereas male sex was associated with 47% higher plasma lactate concentrations (P <.05). The pharmacokinetics of heart failure patients with and without T2DM were similar. Conclusions: We observed no unsafe plasma lactate concentrations in patients with heart failure treated with metformin. Metformin exposure did not influence plasma lactate concentrations, but NYHA class and sex did. The pharmacokinetics of metformin in heart failure patients are similar irrespective of T2DM. These findings may support the safe use of metformin in heart failure patients with and without T2DM. [ABSTRACT FROM AUTHOR]

Metformin is used worldwide in the treatment of type 2 diabetes and has been used in the treatment of diabetes in pregnancy since the 1970s. It is highly acceptable to patients due to its ease of administration, cost and adverse effect profile. It is effective in reducing macrosomia, large-for-gestational-age infants and reduces maternal weight gain. Despite its many advantages, metformin has been associated with reductions in foetal size and has been associated with an increase in infants born small-for-gestational-age in certain cohorts. In this article, we review its efficacy, adverse effects and long-term follow-up before, during and after pregnancy for both mother and infant. We also evaluate the other forms of treatment for gestational diabetes, including oral therapies, insulin therapy and emerging treatments. [ABSTRACT FROM AUTHOR]