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An appreciation of the contribution of Professor Gary Graham to anti-inflammatory and antirheumatic pharmacology and clinical pharmacology. [ABSTRACT FROM AUTHOR]

Benzbromarone, a potent uricosuric drug, was introduced in the 1970s and was viewed as having few associated serious adverse reactions. It was registered in about 20 countries throughout Asia, South America and Europe. In 2003, the drug was withdrawn by Sanofi-Synthélabo, after reports of serious hepatotoxicity, although it is still marketed in several countries by other drug companies. The withdrawal has greatly limited its availability around the world, and increased difficulty in accessing it in other countries where it has never been available.The overall aim of this paper is to determine if the withdrawal of benzbromarone was in the best interests of gouty patients and to present a benefit-risk assessment of benzbromarone. To determine this, we examined (i) the clinical benefits associated with benzbromarone treatment and compared them with the success of alternative therapies such as allopurinol and probenecid, particularly in patients with renal impairment; (ii) the attribution of the reported cases of hepatotoxicity to treatment with benzbromarone; (iii) the incidence of hepatotoxicity possibly due to benzbromarone; (iv) adverse reactions to allopurinol and probenecid. From these analyses, we present recommendations on the use of benzbromarone.Large reductions in plasma urate concentrations in patients with hyperuricaemia are achieved with benzbromarone and most patients normalize their plasma urate. The half-life of benzbromarone is generally short (about 3 hours); however, a uricosuric metabolite, 6-hydroxybenzbromarone, has a much longer half-life (up to 30 hours) and is the major species responsible for the uricosuric activity of benzbromarone, although its metabolism by cytochrome P450 (CYP) 2C9 in the liver may vary between patients as a result of polymorphisms in this enzyme. It is effective in patients with moderate renal impairment. Standard dosages of benzbromarone (100 mg/day) tend to produce greater hypouricaemic effects than standard doses of allopourinol (300 mg/day) or probenecid (1000 mg/day).Adverse effects associated with benzbromarone are relatively infrequent, but potentially severe. Four cases of benzbromarone-induced hepatotoxicity were identified from the literature. Eleven cases have been reported by Sanofi-Synthélabo, but details are not available in the public domain. Only one of the four published cases demonstrated a clear relationship between the drug and liver injury as demonstrated by rechallenge. The other three cases lacked incontrovertible evidence to support a diagnosis of benzbromarone-induced hepatotoxicity. If all the reported cases are assumed to be due to benzbromarone, the estimated risk of hepatotoxicity in Europe was approximately 1 in 17 000 patients but may be higher in Japan.Benzbromarone is also an inhibitor of CYP2C9 and so may be involved in drug interactions with drugs dependent on this enzyme for clearance, such as warfarin. Alternative drugs to benzbromarone have significant adverse reactions. Allopurinol is associated with rare life-threatening hypersensitivity syndromes; the risk of these reactions is approximately 1 in 56 000. Rash occurs in approximately 2% of patients taking allopurinol and usually leads to cessation of prescription of the drug. Probenecid has also been associated with life-threatening reactions in a very small number of case reports, but it frequently interacts with many renally excreted drugs. Febuxostat is a new xanthine oxidoreductase inhibitor, which is still in clinical trials, but abnormal liver function is the most commonly reported adverse reaction.Even assuming a causal relationship between benzbromarone and hepatotoxicity in the identified cases, benefit-risk assessment based on total exposure to the drug does not support the decision by the drug company to withdraw benzbromarone from the market given the paucity of alternative options. It is likely that the risks of hepatotoxicity could be ameliorated by employing a graded dosage increase, together with regular monitoring of liver function. Determination of CYP2C9 status and consideration of potential interactions through inhibition of this enzyme should be considered. The case for wider and easier availability of benzbromarone for treating selected cases of gout is compelling, particularly for patients in whom allopurinol produces insufficient response or toxicity.We conclude that the withdrawal of benzbromarone was not in the best interest of patients with gout. [ABSTRACT FROM AUTHOR]

Uric acid (UA) levels in blood serum have been associated with hypertension, indicating a potential causal relationship between high serum UA levels and the progression of hypertension. Therefore, the reduction of serum UA level is considered a potential strategy for lowering and mitigating blood pressure. If an individual is at risk of developing or already manifesting elevated blood pressure, this intervention could be an integral part of a comprehensive treatment plan. By addressing hyperuricaemia, practitioners may subsidize the optimization of blood pressure regulation, which illustrates the importance of addressing UA levels as a valuable strategy within the broader context of hypertension management. In this analysis, we outlined the operational principles of effective xanthine oxidase inhibitors for the treatment of hyperuricaemia and hypertension, along with an exploration of the contribution of nanotechnology to this field. [ABSTRACT FROM AUTHOR]

Diabetic peripheral neuropathy (DPN) affects ∼50% of the 500 million people with type 2 diabetes worldwide and is considered disabling and irreversible. The current study was undertaken to assess the effect of metformin on peripheral neuropathy outcomes in type 2 diabetes. Participants with type 2 diabetes (n = 69) receiving metformin were recruited and underwent clinical assessment, peripheral nerve ultrasonography, nerve conduction studies, and axonal excitability studies. Also concurrently screened were 318 participants who were not on metformin, and 69 were selected as disease control subjects and matched to the metformin participants for age, sex, diabetes duration, BMI, HbA1c, and use of other diabetes therapies. Medical record data over the previous 20 years were analyzed for previous metformin use. Mean tibial nerve cross-sectional area was lower in the metformin group (metformin 14.1 ± 0.7 mm2, nonmetformin 16.2 ± 0.9 mm2, P = 0.038), accompanied by reduction in neuropathy symptom severity (P = 0.021). Axonal excitability studies demonstrated superior axonal function in the metformin group, and mathematical modeling demonstrated that these improvements were mediated by changes in nodal Na+and K+conductances. Metformin treatment is associated with superior nerve structure and clinical and neurophysiological measures. Treatment with metformin may be neuroprotective in DPN. Article Highlights: We aimed to assess whether peripheral neuropathy outcomes for patients with type 2 diabetes were better on metformin treatment. Metformin and nonmetformin groups with type 2 diabetes were matched for demographic and metabolic factors. Clinical neuropathy scores, peripheral nerve ultrasonography, nerve conduction studies, axonal excitability, and mathematical modeling findings were all superior in the metformin group. Mathematical modeling suggested this was due to superior nodal Na+and K+conductances. Treatment with metformin may be neuroprotective in diabetic peripheral neuropathy. [ABSTRACT FROM AUTHOR]

This study investigated the efficacy of utilizing eggshells and their pyrolyzed derivatives, within the temperature range of 400–800 °C, as adsorbents for ciprofloxacin (CIP) removal. Experimental data were analyzed using various machine learning (ML) algorithms, viz. linear regression, random forest, support vector machines, decision trees, and k-nearest neighbor to predict performance. Results demonstrated that pyrolyzed eggshells at 600 °C (PES-600) exhibited the highest CIP removal rate (86.06 ± 2.25%). Optimal performance was consistently observed at an initial CIP concentration of 125 mg/L, with the order of PES-600 > PES-500 > PES-400 > PES-700 > eggshells > PES-800. Adsorption capacity peaked at pH 5 (5.84 ± 0.1 mg/g), attributed to interactions including hydrogen bonding, π–π interaction, and ion exchange. Scanning electron microscope images revealed that PES-600 had the highest number of pores, resulting in a smoother surface post-adsorption. Langmuir isotherm model fitting was best for ES, PES-700, and PES-800, while Freundlich isotherm was suitable for PES-400, PES-500, and PES-600. PES-600 showed the best fit with the pseudo-second-order kinetic model. Characterization analysis highlighted the significance of functional groups like C = O, C = C, and –CH groups in aromatic rings. ML algorithms demonstrated remarkable performance with an accuracy level of 90.28%. In conclusion, pyrolyzed eggshells can effectively remove ciprofloxacin (CIP) from wastewater, with optimal performance predicted by the random forest machine learning algorithm when considering real environmental factors. [ABSTRACT FROM AUTHOR]

Background: The long-term disease trajectory of people living with multiple sclerosis (MS) can be improved by initiating efficacious treatment early. More quantitative evidence is needed on factors that affect a patient's risk of disability worsening or possibility of improvement to inform timely treatment decisions. Methods: We developed a multistate model to quantify the influence of demographic, clinical, and imaging factors on disability worsening and disability improvement simultaneously across the disability spectrum as measured by the Expanded Disability Status Scale (EDSS). We used clinical trial data from the Novartis–Oxford MS database including ~130,000 EDSS assessments from ~8000 patients, spanning all MS phenotypes. Results: Higher brain volume was positively associated with disability improvement at all disability levels (hazard ratio (HR) = 1.09–1.19; 95% credible interval (CI) = 1.02–1.27). Higher T2 lesion volume was negatively associated with disability improvement up to EDSS 6 (HR = 0.80–0.89; 95% CI = 0.75–0.94). Older age, time since first symptoms, and the number of relapses in the past year were confirmed as predictors of future disability worsening. Conclusions: Brain damage was identified as the most consistent factor limiting the patient's probability for improvements from the earliest stages and across the whole course of MS. Protecting brain integrity early in MS should have greater weight in clinical decision-making. [ABSTRACT FROM AUTHOR]

Six healthy lactating mothers who gave birth to preterm infants at a median post conceptional age of 29.5 (range 26-30) weeks were given 2.5 mg phylloquinone (vitamin K1) orally daily for 2 weeks beginning at a median postconceptional age of 31.5 (range 28-32) weeks. Phylloquinone was measured in the breastmilk daily for 14 d. Trough plasma phylloquinone concentrations were also determined on four occasions. Phylloquinone levels in the breastmilk increased from a baseline of 3 +/- 2.3 ng ml(-1) to 22.6 +/- 16.3 ng ml(-1) (mean +/- SD) after the first dose (p < 0.05); a gradual increase was noted until phylloquinone levels reached a plateau of 64.2 +/- 31.4 ng ml(-1) after the sixth daily dose. [ABSTRACT FROM AUTHOR]

1. Ototoxicity is a common and troublesome side-effect of high-dose aspirin treatment but there has been little previous study of the relationships between the degree of ototoxicity and the plasma concentrations of salicylate. 2. In order to investigate the relationships between aspirin dose, total and unbound plasma salicylate concentrations and ototoxicity, eight normal volunteers were dosed with aspirin 1.95, 3.25, 4.55 and 5.85 g day-1 for 1 week at each dose level, the doses being administered in random order and double-blind, 2 weeks apart. 3. Ototoxic effects measured were hearing loss in decibels (dB) over six frequencies and tinnitus intensity, estimated both by electronic matching and a fixed interval scale (FIS). Measurements were taken after steady-state concentrations of salicylate had been achieved. 4. Total and unbound plasma salicylate concentrations increased disproportionately with increasing daily doses of aspirin. The increase in the unbound salicylate was relatively greater since the percentage of salicylate unbound in plasma increased over the dose range investigated from a mean of 3.9% to 10.4%. 5. Hearing loss and tinnitus intensity increased progressively with the aspirin dosage and increasing concentrations of total and unbound plasma salicylate concentrations. These ototoxic symptoms were observed at lower concentrations of total salicylate than previously reported. 6. There was a linear relationship between hearing loss and unbound salicylate concentrations. 7. Further work is required to test the hypothesis that unbound plasma salicylate concentration is a better predictor of salicylate-induced ototoxicity than total plasma salicylate concentration. [ABSTRACT FROM AUTHOR]

1. 1-methyl xanthine (1-MX) is metabolized exclusively to 1-methyl uric acid (1-MU) by the enzyme xanthine oxidase. 2. The ratio of 1-MU to 1- MX in the urine, following a dose of 50 mg of 1-MX infused intravenously over 20 min, was used to measure the inhibition of xanthine oxidase induced by different doses of allopurinol. 3. Normal volunteers (n = 8) were given allopurinol 50, 100, 300 and 600 mg daily for 1 week each, in random order and 1 week separated each treatment. Inhibition of xanthine oxidase was assessed twice, on the last 2 days of each treatment week. 4. Steady-state oxipurinol concentrations increased linearly with increasing dose of allopurinol. 5. There was a hyperbolic relationship between the 1-MU/1-MX ratio and plasma oxipurinol concentrations, with an initial steep decline in the ratio which plateaued when plasma oxipurinol was around 4-6 mg l-1. This reduction in the ratio was quickly reversible upon cessation of allopurinol. 6. The 50% and 90% effective inhibitory oxipurinol concentrations, in relation to the 1-MU-/1-MX ratio were 1.4 +/- 0.46 and 4.08 +/- 2.03 mg l-1 respectively. 7. The concentration of oxipurinol required for almost complete inhibition of the enzyme was substantially less than those often observed in clinical practice. [ABSTRACT FROM AUTHOR]

Corticosteroids have been reported to decrease the plasma concentrations of salicylate when salicylates have been administered chronically at high doses. In the present study, two single, oral doses of sodium salicylate, 10 mg kg-1 were administered to six adult subjects with a variety of inflammatory conditions both before and during treatment with daily oral doses of prednisone (12-60 mg). Concomitant prednisone therapy did not increase the whole body clearance of single doses of salicylate in these subjects (0.0275 +/- 0.08 l kg-1 h-1 before prednisone; 0.0247 +/- 0.03 l kg-1 h-1 during prednisone therapy; P greater than 0.05). These results indicate that corticosteroids do not alter the clearance of single doses of salicylate in man. [ABSTRACT FROM AUTHOR]

Introduction: Nonsteroidal anti-inflammatory drugs (NSAIDs) may potentially delay or cause non-union of fractures by inhibiting prostaglandin synthesis. However, studies have shown conflicting results. This systematic review and meta-analysis aim to synthesize current evidence on the potential influence of NSAIDs on bone healing. Methods: We conducted a comprehensive search of PubMed, Embase, and Cochrane CENTRAL databases for studies published up to 25 July 2023. Specific keywords included "NSAID," "nonsteroidal anti-inflammatory drug," "cyclooxygenase-2 inhibitor," "bone healing," "non-union," "pseudoarthrosis," "delayed union," and "atrophic bone." Eligible studies included prospective, retrospective, and case-controlled studies assessing the correlation between NSAID use and bone healing outcomes. The leave-one-out approach was used to test the robustness of the meta-analysis results. Results: A total of 20 studies with 523,240 patients were included in the analysis. The mean patient age ranged from 6.7 to 77.0 years, with follow-up durations from 3 to 67 months. The meta-analysis revealed no significant difference in non-union or delayed union between NSAID users and non-users [pooled adjusted odds ratio (OR) = 1.11; 95% confidence interval (CI): 0.99-1.23]. Initial analysis identified a significant association between NSAID usage and an increased risk of reoperation, but this association became insignificant upon sensitivity analysis (crude OR = 1.42; 95% CI: 0.88-2.28). Discussion: NSAIDs may have a minimal impact on non-union or delayed union risks. However, caution is advised due to the limited number of studies and the absence of a specific focus on NSAID types and dosages. Further research is necessary to better understand the implications of NSAID use on bone healing. [ABSTRACT FROM AUTHOR]

The anti-diabetic drug metformin is one of the most widely prescribed medicines in the world. Together with its degradation product guanylurea, it is a major pharmaceutical pollutant in wastewater treatment plants and surface waters. An operon comprising two genes of the ureohydrolase family in Pseudomonas and Aminobacter species has recently been implicated in metformin degradation. However, the corresponding proteins have not been characterized. Here we show that these genes encode a Ni2+-dependent enzyme that efficiently and specifically hydrolyzes metformin to guanylurea and dimethylamine. The active enzyme is a heteromeric complex of α- and β- subunits in which only the α-subunits contain the conserved His and Asp residues for the coordination of two Ni2+ ions in the active site. A crystal structure of metformin hydrolase reveals an α2β4 stoichiometry of the hexameric complex, which is unprecedented in the ureohydrolase family. By studying a closely related but more widely distributed enzyme, we find that the putative predecessor specifically hydrolyzes dimethylguanidine instead of metformin. Our findings establish the molecular basis for metformin hydrolysis to guanylurea as the primary pathway for metformin biodegradation and provide insight into the recent evolution of ureohydrolase family proteins in response to an anthropogenic compound. The diabetes drug metformin and its degradation product guanylurea are major pharmaceutical contaminants in waste and surface water. Here, a Ni2+-dependent enzyme that hydrolysed metformin to guanylurea and its evolutionary predecessor are presented. [ABSTRACT FROM AUTHOR]

Background: Headache disorders, particularly primary headaches like migraine and tension-type headache, still remain underdiagnosed and undertreated despite their high prevalence and significant impact on quality of life. In recent years, several specific medications targeting key pathways in the pathophysiology of migraine have been developed. Despite this advancement, numerous studies indicate that non-steroidal anti-inflammatory drugs (NSAIDs) and analgesics remain the most commonly used drugs. This study focused on the use of NSAIDs and simple analgesics as acute treatments for migraine among patients at a tertiary headache center. Methods: A retrospective observational study was conducted at the Fondazione Policlinico Universitario Campus Bio-Medico throughout 2022. Data were collected on the type and frequency of headaches, the usage and dosage of NSAIDs and other medications, and changes in their use at follow-up visits. Statistical analyses were performed to evaluate the efficacy and determinants of NSAID consumption and headache frequency changes. Results: Two hundred and eightythree patients diagnosed with migraine undergoing their first examination at our center were enrolled. Initially, 58.7% of patients used NSAIDs or simple analgesics, which decreased to 46.6% 3 months after, while triptan use increased from 65.1 to 72.8%. Changes in prophylactic therapies were significantly associated with a decrease in NSAID intake (W = 834.000, p = 0.004) and in headache frequency (W = 5960.5, p = 0.003). Specifically, the addition of topiramate or amitriptyline was associated with a reduction in NSAID use and headache frequency. Even pain freedom after the intake of NSAIDs improved from 55.2 to 79.4% of cases at follow-up. Conclusion: The study highlights the importance of appropriate diagnosis and tailored treatment strategies in the management of primary headaches. It underscores the need for specialized care to enhance treatment efficacy and patient outcomes, demonstrating that adjustments in prophylactic therapy can significantly reduce NSAID intake and improve headache care. This reinforces the role of tertiary headache centers in providing specialized care that can adapt treatments to individual patient needs and improve overall headache management. [ABSTRACT FROM AUTHOR]

Febuxostat is commonly used in clinic for the treatment of hyperuricemia. Multiple-peak phenomenon has been observed in human plasma concentration-time profiles of febuxostat, but has not been paid enough attention in previous research. This study takes a pivotal step forward by conducting a comprehensive population pharmacokinetic (PopPK) analysis of febuxostat in a healthy Chinese cohort, with a central focus on delineating its absorption profile under contrasting fasting and fed conditions, while concurrently assessing the influence of food alongside other potential covariates on febuxostat's PK profile. The plasma concentration data used for modeling was obtained from two bioequivalence (BE) studies. Subjects were administered febuxostat 20 mg or 80 mg under fasting or fed condition. Goodness-of-fit plots, visual predict check (VPC), and normalized prediction distribution error (NPDE) were used for model evaluation. Based on the established model, PK profiles in healthy Caucasian subjects were simulated with parameter adjustment for race difference on clearance and bioavailability. Data from 128 subjects were used in the PopPK analysis. Febuxostat concentration-time curves were described by a two-compartment model with two deposit absorption compartments and lag times (Tlag). Prandial states (Food) showed significant impact on absorption rate ka1 and ka2, as well as Tlag1, and body weight was identified as a significant covariate on the apparent distribution volume. The PopPK analysis of febuxostat in healthy Chinese volunteers, under both fasted and fed conditions, successfully characterized its PK profile and underscored the significant influence of food on absorption. The potential difference of absorption between Chinese population and Caucasian population indicated from the simulations needs further investigation. [ABSTRACT FROM AUTHOR]

Objective: To scope how the Australian Bureau of Statistics Socio-Economic Indexes for Areas (SEIFA) has been applied to measure socio-economic status (SES) in peer-reviewed cardiovascular disease (CVD) research. Methods: The Joanna Briggs Institute's scoping review methodology was used. Results: The search retrieved 2788 unique citations, and 49 studies were included. Studies were heterogeneous in their approach to analysis using SEIFA. Not all studies provided information as to what version was used and how SEIFA was applied in analysis. Spatial unit of analysis varied between studies, with participant postcode most frequently applied. Study quality varied. Conclusions: The use of SEIFA in Australian CVD peer-reviewed research is widespread, with variations in the application of SEIFA to measure SES as an exposure. There is a need to improve the reporting of how SEIFA is applied in the methods sections of research papers for greater transparency and to ensure accurate interpretation of CVD research. What is known about the topic? A socio-economic status (SES) gradient is well established for cardiovascular disease (CVD). Research has generally applied two approaches to classifying SES: at an individual level using income, education or occupation data, and at an area level using a range of existing socio-economic information, including the Australian Bureau of Statistics (ABS) Socio-Economic Indexes for Areas (SEIFA). What does this paper add? This review examined how SEIFA has been applied to measure SES in Australian peer-reviewed CVD research and to identify any variations in research practice. What are the implications for practitioners? It is recommended that researchers provide a clear explanation in the methods section of research papers as to which SEIFA version and index was applied, how it was applied, at what spatial unit, and whether the spatial unit was an ABS or non-ABS unit. [ABSTRACT FROM AUTHOR]

Background: Atherosclerosis (AS) is a progressive disease that interferes with blood flow, leading to cardiovascular complications such as hypertension, ischemic heart disease, ischemic stroke, and vascular ischemia. The progression of AS is correlated with inflammation, oxidative stress, and endothelial dysfunction. Various signaling pathways, like nuclear erythroid‐related factor 2 (Nrf2) and Kruppel‐like factor 2 (KLF2), are involved in the pathogenesis of AS. Nrf2 and KLF2 have anti‐inflammatory and antioxidant properties. Thus, activation of these pathways may reduce the development of AS. Metformin, an insulin‐sensitizing drug used in the management of type 2 diabetes mellitus (T2DM), increases the expression of Nrf2 and KLF2. AS is a common long‐term macrovascular complication of T2DM. Thus, metformin, through its pleiotropic anti‐inflammatory effect, may attenuate the development and progression of AS. Aims: Therefore, this review aims to investigate the possible role of metformin in AS concerning its effect on Nrf2 and KLF2 and inhibition of reactive oxygen species (ROS) formation. In addition to its antidiabetic effect, metformin can reduce cardiovascular morbidities and mortalities compared to other antidiabetic agents, even with similar blood glucose control by the Nrf2/KLF2 pathway activation. Conclusion: In conclusion, metformin is an effective therapeutic strategy against the development and progression of AS, mainly through activation of the KLF2/Nrf2 axis. [ABSTRACT FROM AUTHOR]

This work presents highly porous magnetic activated carbon nanoparticles (MPFRC-A) derived from pine fruit residue. The MPFRC-A were produced through a three-step process: physical activation (carbonization temperature: 110–550 °C), chemical activation (H2SO4 (0.1 N, 96%)), and co-precipitation. These nanoparticles were then used to remove tetracycline (TC) and paracetamol (PC) from water. Functionalization with Fe3O4 nanoparticles on the surface of the pine fruit residue-derived activated carbon (PFRC-A) resulted in high saturation magnetization, allowing for separation from aqueous solution using an external magnet. The MPFRC-A adsorbent was characterized by Brunauer–Emmett–Teller (BET) analysis, Fourier-transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), X-ray diffraction (XRD), and Energy-dispersive X-ray spectroscopy (EDX) analyses, In the experimental section, the effects of various factors on the adsorption process were investigated, including pH, contact time, initial pollutant concentrations, adsorbent dosage, and temperature. Based on these investigations, adsorption isotherm models and kinetics were studied and determined. The results showed that MPFRC-A exhibited a large specific surface area (182.5 m2/g) and a high total pore volume (0.33 cm3/g). The maximum adsorption capacity was achieved at pH 6 and 5 for PC and TC drugs with an adsorbent dose of 400 mg and an initial concentration of 20 mg/L at 25 °C. The study revealed that the experimental data were well-fitted by the Langmuir isotherm model (R2 > 0.98), with maximum uptake capacities of 43.75 mg/g for TC and 41.7 mg/g for PC. Outcomes of the adsorption thermodynamics shows non-spontaneity of the reaction and the adsorption process by all adsorbents was endothermic. [ABSTRACT FROM AUTHOR]

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Copyright of Chinese Journal of Diabetes Mellitus is the property of Chinese Journal of Diabetes Mellitus 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: Gout is a chronic disease caused by the accumulation of uric acid crystals in joints, resulting in sudden pain, stiffness, and swelling. Febuxostat (FBX), a xanthine oxidase inhibitor, is commonly used to treat gout but has poor solubility, which affects its bioavailability. Materials and Methods: To address this issue, a skin-permeating emulgel was developed using Cinnamon (CN) oil as an oil solvent, cremophor RH 40 (Cr. RH 40) as a co-surfactant/solubilizer, and Poloxamer 407 as an emulsifier. A solubility study was performed followed by optimization by 32 factorial designs. The formulation was further evaluated for viscosity, globule size, drug release, and stability studies. Results: Solubility of FBX was found 1 in 10 parts in selected oil. The optimized emulgel containing 10% Cremophor RH 40 and 20% Poloxamer 407 shown improved drug release compared to the pure drug. All other parameters were found satisfactory. Conclusion: The formulated emulgel designed to penetrate the skin shown a good potential for topical formulations enhancing the effectiveness of drug. Moreover, creating a skin-permeating emulsion-based gel in a cost-effective and industrially viable manner could enhance drug penetration and absorption through the skin thereby faster cure of gout compared to the conventional product. [ABSTRACT FROM AUTHOR]

Metal ions play an essential role in regulating the functions of immune cells by transmitting intracellular and extracellular signals in tumor microenvironment (TME). Among these immune cells, we focused on the impact of metal ions on T cells because they can recognize and kill cancer cells and play an important role in immune-based cancer treatment. Metal ions are often used in nanomedicines for tumor immunotherapy. In this review, we discuss seven metal ions related to anti-tumor immunity, elucidate their roles in immunotherapy, and provide novel insights into tumor immunotherapy and clinical applications. [ABSTRACT FROM AUTHOR]

Copper, a trace element and vital cofactor, plays a crucial role in the maintenance of biological functions. Recent evidence has established significant correlations between copper levels, cancer development and metastasis. The strong redox‐active properties of copper offer both benefits and disadvantages to cancer cells. The intestinal tract, which is primarily responsible for copper uptake and regulation, may suffer from an imbalance in copper homeostasis. Colorectal cancer (CRC) is the most prevalent primary cancer of the intestinal tract and is an aggressive malignant disease with limited therapeutic options. Current research is primarily focused on the relationship between copper and CRC. Innovative concepts, such as cuproplasia and cuproptosis, are being explored to understand copper‐related cellular proliferation and death. Cuproplasia is the regulation of cell proliferation that is mediated by both enzymatic and nonenzymatic copper‐modulated activities. Whereas, cuproptosis refers to cell death induced by excess copper via promoting the abnormal oligomerisation of lipoylated proteins within the tricarboxylic acid cycle, as well as by diminishing the levels of iron‐sulphur cluster proteins. A comprehensive understanding of copper‐related cellular proliferation and death mechanisms offers new avenues for CRC treatment. In this review, we summarise the evolving molecular mechanisms, ranging from abnormal intracellular copper concentrations to the copper‐related proteins that are being discovered, and discuss the role of copper in the pathogenesis, progression and potential therapies for CRC. Understanding the relationship between copper and CRC will help provide a comprehensive theoretical foundation for innovative treatment strategies in CRC management. [ABSTRACT FROM AUTHOR]

Metformin is an orally effective anti-hyperglycemic drug that despite being introduced over 60 years ago is still utilized by an estimated 120 to 150 million people worldwide for the treatment of type 2 diabetes (T2D). Metformin is used off-label for the treatment of polycystic ovary syndrome (PCOS) and for pre-diabetes and weight loss. Metformin is a safe, inexpensive drug with side effects mostly limited to gastrointestinal issues. Prospective clinical data from the United Kingdom Prospective Diabetes Study (UKPDS), completed in 1998, demonstrated that metformin not only has excellent therapeutic efficacy as an anti-diabetes drug but also that good glycemic control reduced the risk of micro- and macro-vascular complications, especially in obese patients and thereby reduced the risk of diabetes-associated cardiovascular disease (CVD). Based on a long history of clinical use and an excellent safety record metformin has been investigated to be repurposed for numerous other diseases including as an anti-aging agent, Alzheimer's disease and other dementias, cancer, COVID-19 and also atrial fibrillation (AF). AF is the most frequently diagnosed cardiac arrhythmia and its prevalence is increasing globally as the population ages. The argument for repurposing metformin for AF is based on a combination of retrospective clinical data and in vivo and in vitro pre-clinical laboratory studies. In this review, we critically evaluate the evidence that metformin has cardioprotective actions and assess whether the clinical and pre-clinical evidence support the use of metformin to reduce the risk and treat AF. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is a complicated condition involving multiple metabolic and immunologic pathophysiological processes that can occur with the hallmark pathologies of amyloid-β, tau, and neurodegeneration. Metformin, an anti-diabetes drug, targets several of these disease processes in in vitro and animal studies. However, the effects of metformin on human cerebrospinal fluid (CSF) and plasma proteins as potential biomarkers of treatment remain unexplored. Objective: Using proteomics data from a metformin clinical trial, identify the impact of metformin on plasma and CSF proteins. Methods: We analyzed plasma and CSF proteomics data collected previously (ClinicalTrials.gov identifier: NCT01965756, conducted between 2013 and 2015), and conduced bioinformatics analyses to compare the plasma and CSF protein levels after 8 weeks of metformin or placebo use to their baseline levels in 20 non-diabetic patients with mild cognitive impairment (MCI) and positive AD biomarkers participants. Results: 50 proteins were significantly (unadjusted p < 0.05) altered in plasma and 26 in CSF after 8 weeks of metformin use, with 7 proteins in common (AZU1, CASP-3, CCL11, CCL20, IL32, PRTN3, and REG1A). The correlation between changes in plasma and CSF levels of these 7 proteins after metformin use relative to baseline levels was high (r = 0.98). The proteins also demonstrated temporal stability. Conclusions: Our pilot study is the first to investigate the effect of metformin on plasma and CSF proteins in non-diabetic patients with MCI and positive AD biomarkers and identifies several candidate plasma biomarkers for future clinical trials after confirmatory studies. [ABSTRACT FROM AUTHOR]

Background: Vancomycin Bayesian modeling provides 24-hour area under the curve (AUC24) estimations. However, the agreement between two-concentration and one-concentration Bayesian estimates in patients with obesity is unknown. Objective: The purpose of this study was to determine the agreement between two-concentration and one-concentration Bayesian AUC24 estimates in patients with obesity receiving vancomycin. Methods: This retrospective within-subjects cohort study included patients with obesity and two vancomycin concentrations. The first concentration was hidden from dosing software to record the one-concentration AUC24. AUC24 estimates were categorized into 1 of 3 groups: <400, 400 to 600, or >600 mg*h/L. Patients were excluded for vancomycin duration less than 48 hours or renal dysfunction. The primary outcome was AUC24 agreement with two versus one concentration. Secondary outcomes included the AUC24 category, matching of AUC24 categorization, and correlation between two-concentration versus one-concentration AUC24. AUC24 estimate agreement was assessed by Bland Altman plot and bias via linear regression. Statistical analyses were performed using SPSS (version 20.0). Results: A total of 31 patients were included. The mean difference in AUC24 between two versus one concentration was 11.4 mg*h/L (95% limits of agreement = −72 to 95 mg*h/L). Linear regression indicated the presence of proportional bias at higher AUC24 values (β = 0.16; P = 0.015). Matching of AUC24 categorization with two versus one concentration was 87% (27/31 patients). Conclusion and Relevance: This study demonstrated overall agreement between AUC24 estimates when using two versus one vancomycin concentration in patients with obesity, though proportional bias was detected at higher AUC24. Future studies with larger sample sizes are needed to confirm these results. [ABSTRACT FROM AUTHOR]

The association of type 2 diabetes with certain cancer risk has been of great interest for years. However, the effect of diabetic medications on cancer development is not fully understood. Prospective clinical trials have not elucidated the long‐term influence of hypoglycemic drugs on cancer incidence and the safety for cancer‐bearing patients with diabetes, whereas numerous preclinical studies have shown that antidiabetic drugs could have an impact on carcinogenesis processes beyond the glycemic control effect. Because there is no evidence of the safety profile of antidiabetic agents on cancer biology, careful consideration would be required when prescribing any medicines to patients with diabetes and existing tumor. In this review, we discuss the potential influence of each diabetes therapy in cancer 'initiation', 'promotion' and 'progression'. [ABSTRACT FROM AUTHOR]

Background and Objective: The prediction of pharmacokinetic parameters for drugs metabolised by cytochrome P450 enzymes has been the subject of active research for many years, while the application of in vitro–in vivo extrapolation (IVIVE) techniques for non-cytochrome P450 enzymes has not been thoroughly evaluated. There is still no established quantitative method for predicting hepatic clearance of drugs metabolised by uridine 5′-diphospho-glucuronosyltransferases (UGTs), not to mention those which undergo hepatic uptake. The objective of the study was to predict the human hepatic clearance for telmisartan based on in vitro metabolic stability and hepatic uptake results. Methods: Telmisartan was examined in liver systems, allowing to estimate intrinsic clearance (CLint, in vitro) based on the substrate disappearance rate with the use of liquid chromatography tandem mass spectrometry (LC-MS/MS) technique. Obtained CLint, in vitro values were corrected for corresponding unbound fractions. Prediction of human hepatic clearance was made from scaled unbound CLint, in vitro data with the use of the well-stirred model, and finally referenced to the literature value of observed clearance in humans, allowing determination of the essential scaling factors. Results: The in vitro scaled CLint, in vitro by UGT1A3 was assessed using three systems, human hepatocytes, liver microsomes, and recombinant enzymes. Obtained values were scaled and hepatic metabolism clearance was predicted, resulting in significant clearance underprediction. Utilization of the extended clearance concept (ECC) and hepatic uptake improved prediction of hepatic metabolism clearance. The scaling factors for hepatocytes, assessing the in vitro–in vivo difference, changed from sixfold difference to only twofold difference with the application of the ECC. Conclusions: The study showed that taking into consideration hepatic uptake of a drug allows us to obtain satisfactory scaling factors, hence enabling the prediction of in vivo hepatic glucuronidation from in vitro data. [ABSTRACT FROM AUTHOR]

Background and objective: Pharmacokinetic studies encompass the examination of the absorption, distribution, metabolism, and excretion of bioactive compounds. The pharmacokinetics of drugs exert a substantial influence on their efficacy and safety. Consequently, the investigation of pharmacokinetics holds great importance. However, laboratory-based assessment necessitates the use of numerous animals, various materials, and significant time. To mitigate these challenges, alternative methods such as artificial intelligence have emerged as a promising approach. This systematic review aims to review existing studies, focusing on the application of artificial intelligence tools in predicting the pharmacokinetics of drugs. Methods: A pre-prepared search strategy based on related keywords was used to search different databases (PubMed, Scopus, Web of Science). The process involved combining articles, eliminating duplicates, and screening articles based on their titles, abstracts, and full text. Articles were selected based on inclusion and exclusion criteria. Then, the quality of the included articles was assessed using an appraisal tool. Results: Ultimately, 23 relevant articles were included in this study. The clearance parameter received the highest level of investigation, followed by the area under the concentration-time curve (AUC) parameter, in pharmacokinetic studies. Among the various models employed in the articles, Random Forest and eXtreme Gradient Boosting (XGBoost) emerged as the most commonly utilized ones. Generalized Linear Models and Elastic Nets (GLMnet) and Random Forest models showed the most performance in predicting clearance. Conclusion: Overall, artificial intelligence tools offer a robust, rapid, and precise means of predicting various pharmacokinetic parameters based on a dataset containing information of patients or drugs. [ABSTRACT FROM AUTHOR]

The pharmacokinetic profile of paracetamol in koalas is described when administered orally at 15 mg/kg; followed by the same dose, administered every 12 hours (hrs), repeated five times. After the initial oral administration, the median (range) maximal plasma concentration (Cmax), the time Cmax was reached (Tmax) and elimination half-life (t1/2) were 16.93 μg/mL (13.66 to 20.25 μg/mL); 4 hrs (4 to 8 hrs) and 5.54 hrs (4.66 to 7.67 hrs), respectively. When paracetamol was administered orally at 15 mg/mL every 12 hrs, the trough total plasma concentration range remained comparable to the therapeutic range in humans i.e. 4 to 20 μg/mL that is known to provide some analgesia. However, there is a smaller proportion of free drug (i.e. not bound to plasma proteins; and the active form) available in koala plasma (approximately 40% unbound) compared to human plasma (approximately 80% unbound). Consequently, even when there are similar total drug plasma concentrations in both koala and human plasma, the therapeutic efficacy may be reduced in koalas compared to humans. The initial oral dose and subsequent twice daily doses resulted in no obvious adverse effects in any koala. Haematology, plasma electrolyte and biochemical analyte values remained within their reference ranges eight hrs after the last dose but there was a significant change in alanine transaminase (ALT) levels (an increase), and in total protein (a decrease) (both p = 0.03). A dose of 15 mg/kg was also administered as a subcutaneous injection, diluted 50:50 with saline, to two koalas. As the oral formulation and the subcutaneous administration resulted in comparable absorption, the study focused on the oral profile. Based on these results there is an argument to recommend a slight increase in the oral paracetamol dose for the koala, however further investigation is required to confirm whether repeated administration of a slightly higher dose may be associated with more severe or additional significant changes in haematology, electrolytes or biochemical analytes. However, a preferable recommendation would be to administer this dosage of paracetamol in combination with another analgesic such as tramadol, as a subcutaneous injection, to improve efficacy. [ABSTRACT FROM AUTHOR]

Maternal diet influences breast milk nutritional profile; however, it is unclear which nutrients and contaminants are particularly responsive to short- and long-term changes in maternal intake, and the impact of specific exclusion diets, such as vegan or vegetarian. This study systematically reviewed the literature on the effects of maternal nutrient intake, including exclusion diets, on both the nutrient and contaminant content of breast milk. The electronic databases, PubMed, CENTRAL, Web of Science and CINALH were systematically searched until 4 June 2023, with additionally searches of reference lists (PROSPERO, CRD42020221577). The quality of the studies was examined using Cochrane Risk of Bias tool and Newcastle–Ottawa scale. Eighty-eight studies (n 6577) met the search criteria. Due to high heterogeneity, meta-analysis was not possible. There was strong evidence of response to maternal intakes for DHA and EPA, vitamins A, E and K, iodine and Se in breast milk composition, some evidence of response for α -linolenic acid, B vitamins, vitamin C and D, ovalbumin, tyrosine and contaminants, and insufficient evidence to identify the effects arachidonic acid, Cu, Fe, Zn and choline. The paucity of evidence and high heterogeneity among studies reflects the need for more high-quality trials. However, this review identified the importance of maternal intake in the nutritional content of breast milk for a wide range of nutrients and supports the recommendation for supplementation of DHA and vitamin B12 for those on restrictive diets. [ABSTRACT FROM AUTHOR]

This study aimed to understand predictors of inadequate response (IR) to low-dose febuxostat treatment based on clinical variables. Methods: We pooled data from 340 patients of an observational cohort and two clinical trials who received febuxostat 20 mg/day for at least 3 months. IR was defined as failure to reach the target serum urate level (sUA< 6 mg/dL) at any time point during 3 months treatment. The potential predictors associated with short- or mid-term febuxostat IR after pooling the three cohorts were explored using mixed-effect logistic analysis. Machine learning models were performed to evaluate the predictors for IR using the pooled data as the discovery set and validated in an external test set. Results: Of the 340 patients, 68.9% and 51.8% were non-responders to low-dose febuxostat during short- and mid-term follow-up, respectively. Serum urate and triglyceride (TG) levels were significantly associated with febuxostat IR, but were also selected as significant features by LASSO analysis combined with age, BMI, and C-reactive protein (CRP). These five features in combination, using the best-performing stochastic gradient descent classifier, achieved an area under the receiver operating characteristic curve of 0.873 (95% CI [0.763, 0.942]) and 0.706 (95% CI [0.636, 0.727]) in the internal and external test sets, respectively, to predict febuxostat IR. Conclusion: Response to low-dose febuxostat is associated with early sUA improvement in individual patients, as well as patient age, BMI, and levels of TG and CRP. [ABSTRACT FROM AUTHOR]

The article focuses on the application of homeopathic medicines during symptom-free periods influenced by artificial morbific agents. Topics include doctor Stuart Close's scientific perspective on vital force and its role in health, the philosophical and ethical foundations of homeopathy, and the challenges of integrating homeopathic treatments in a modern medical context.

In the current report, we introduce a simple, mild efficient and green protocol for N-formylation and N-acetylation of anilines using formamide, formic acid, and acetic acid as inexpensive, nontoxic, and easily available starting materials just with heating along stirring in [ChCl][ZnCl2]2 as a durable, reusable deep eutectic solvent (DES), which acts as a dual catalyst and solvent system to produce a wide range of formanilides and acetanilides. Also, a variety of unsymmetrical urea derivatives were synthesized by the reaction of phenyl isocyanate with a range of amine compounds using this benign DES in high to excellent yields. [ChCl][ZnCl2]2 showed good recycling and reusability up to four runs without considerable loss of its catalytic activity. [ABSTRACT FROM AUTHOR]

This scoping review identifies the mechanistic pathways of metformin when used to treat head and neck cancer cells, in the pre-clinical setting. Understanding the underlying mechanisms will inform future experimental designs exploring metformin as a potential adjuvant for head and neck cancer. This scoping review was conducted according to the Joanna-Briggs Institute framework. A structured search identified 1288 studies, of which 52 studies fulfilled the eligibility screen. The studies are presented in themes addressing hallmarks of cancer. Most of the studies demonstrated encouraging anti-proliferative effects in vitro and reduced tumor weight and volume in animal models. However, a few studies have cautioned the use of metformin which supported cancer cell growth under certain conditions. [ABSTRACT FROM AUTHOR]

Metformin is a widely prescribed oral antihyperglycemic agent and currently a first-line medication in the treatment of human type 2 diabetes, with a total of 92 million US prescriptions in 2022. The daily dose per human can be as much as 2.5 grams/day which is excreted largely unchanged into the environment. Metformin is chemically stable and a widely distributed environmental substance. Metformin therefore has the potential to be identified at trace levels in equine blood and urine samples as a result of random exposure to environmental metformin. Given these circumstances we have reviewed the scientific literature and calculated an irrelevant blood/plasma/serum concentration of metformin of 5 nanograms/ml. We now therefore propose this plasma concentration of metformin as an interim Screening Limit of Detection (SLOD) for metformin, below which concentration a blood/plasma/serum identification of metformin should not be considered appropriate for regulatory action. [ABSTRACT FROM AUTHOR]