Improving the aqueous solubility of moderately soluble drugs using safe and sustainable solvent systems remains an important challenge in pharmaceutical formulation. In this study, a series of aqueous natural deep eutectic solvents (NADESs) were systematically designed and evaluated to enhance the solubility, stability, and biocompatibility of acetaminophen (ACP). The effects of hydrogen bond donor type, hydrogen bond acceptor type, molar ratio, and NADES concentration were investigated to identify the optimal formulation. Among the tested systems, the aqueous betaine chloride-acetic acid NADES (BeCl-Ace) at a molar ratio of 1 : 4 and a concentration of 70% exhibited the highest solubilization capacity, increasing ACP solubility by 25.28 and 22.14-fold at 25 and 37 °C, respectively, compared with water. Computational analyses based on electrostatic potential mapping, binding energy calculations, and interaction region indicator analysis revealed that the enhanced solubility originates from cooperative hydrogen bonding, electrostatic attraction, and van der Waals interactions between ACP and the BeCl-Ace components, particularly BeCl. In addition, the selected NADES formulation significantly improved ACP stability under thermal stress, retaining 89.13% of the initial drug content after 30 days at 37 °C, compared with 70.20% in water. Cytotoxicity evaluation on HEK-293A cells further confirmed good biocompatibility, with cell viability remaining above 92% across the tested concentration range. These findings indicate that aqueous BeCl-Ace NADESs represent a promising and sustainable solvent system for improving ACP formulation performance.

Plant extract-based formulations may influence behavior and gut microbiota, but their effects following acute paracetamol (PAR) exposure remain unclear. This preliminary study evaluated the behavioral effects of two formulations, coded MOD and TEL, and explored TEL-associated microbiota changes in adult zebrafish. Sixty fish were randomized to six groups (10/group). PAR exposure (5 mM for 24 h) was followed by formulation treatment (500 mg/L for five days), alongside untreated, PAR-only, and formulation-only controls. Behavior was assessed using the novel tank test (NTT) and social behavior test. Full-length 16S ribosomal ribonucleic acid (rRNA) gene sequencing was performed in untreated, PAR-only, and PAR-plus-TEL groups (three fish/group). Compared with PAR alone, MOD increased swimming distance and velocity during social testing (p = 0.028 and p = 0.003, respectively), whereas TEL reduced vertical crossings in the NTT (p = 0.035) and time spent near social stimuli (p = 0.0033). Reductions in freezing duration with both formulations were not statistically significant compared with PAR alone. No significant differences in alpha or beta diversity were detected, and no genus-level differences remained significant after multiple-testing correction. These exploratory findings suggest formulation- and test-dependent behavioral responses without statistically supported microbiota changes. Larger studies with replicated tanks and deeper sequencing are needed to clarify these associations.

Liver metabolic zonation enables hepatocytes to carry out diverse, spatially organized functions essential for liver homeostasis and metabolism. However, in vitro recapitulation of zone-specific diversity, particularly in human pluripotent stem cell (PSC)-derived hepatocyte-like cells (HLCs), remains challenging, as these cells typically exhibit an immature phenotype. Here, we report a scalable differentiation protocol for generating 3D organoids from PSCs with defined zone 1 (z1-HLCs) or zone 3 (z3-HLCs) identities. When benchmarked against primary human hepatocytes (PHHs), these HLCs exhibit zone-specific enhanced postnatal metabolic functions. z1-HLCs reveal high albumin and urea production, whereas z3-HLCs show elevated glutamine secretion and cytochrome P450 (CYP) enzyme activity, including CYP3A4, CYP1A2, and CYP2C9. Hallmarks of functional zonation were further confirmed via proteomics, transcriptomics, metabolic assays, and oxygen consumption. z3-HLCs show increased sensitivity to acetaminophen-induced cytotoxicity and distinct immune interactions with primary monocytes. Collectively, the zonated liver organoids provide a promising platform for studying zone-specific liver metabolism, drug metabolism, toxicology, and liver disease, including liver injury.

Citrin deficiency is a rare autosomal recessive metabolic disorder caused by pathogenic variants in the SLC25A13 gene. Pregnancy in affected women is uncommon and presents unique challenges because conventional obstetric management may conflict with metabolic requirements. The coexistence of gestational diabetes mellitus (GDM) introduces additional complexity. A 25-year-old, gravida 2 para 0+1 woman with genetically confirmed citrin deficiency (homozygous SLC25A13 c.1763G>A mutation) was managed jointly by obstetric and inherited metabolic disease (IMD) teams. Her pregnancy was complicated by severe nausea and vomiting during the first trimester and subsequent GDM diagnosed using capillary glucose monitoring rather than an oral glucose tolerance test. Representative fasting glucose values were 6.3-6.8 mmol/L, with postprandial values up to 10.7 mmol/L. Specialist dietary modification and insulin therapy were instituted following multidisciplinary review. A personalised metabolic plan emphasised avoidance of prolonged fasting, restriction of excessive carbohydrate intake, maintenance of adequate energy intake, and avoidance of routine glucose-containing intravenous fluids. At 38+5 weeks' gestation, she underwent emergency caesarean section for failure to progress in labour under spinal anaesthesia. A healthy infant weighing 3074 g was delivered with Apgar scores of 9, 10 and 10 at 1, 5 and 10 minutes, respectively. Postoperative pain management was challenging because the specialist metabolic plan advised caution with paracetamol. Following inadequate analgesia with ibuprofen and dihydrocodeine, paracetamol was cautiously introduced at reduced doses and subsequently increased to 500 mg four times daily, with additional opioid analgesia as required. Daily plasma ammonia and liver function monitoring was undertaken during the five-day postoperative admission; ammonia values remained within the laboratory reference range, with no hyperammonaemia (range <10-32 µmol/L) or significant hepatic biochemical deterioration. This case highlights the complexity of managing pregnancy in women with citrin deficiency, particularly when complicated by GDM. It also demonstrates a practical approach to postoperative analgesia following caesarean delivery using cautious dose escalation and biochemical surveillance.

Percutaneous nephrolithotomy (PCNL) is the gold standard for large renal calculi, yet postoperative pain from tract dilation, capsule injury, and inflammation often delays recovery, prolongs hospital stays, and reduces patient satisfaction. Amid the opioid crisis, reliance on opioids for pain control raises concerns over adverse effects like respiratory depression, nausea, and dependence. This has spurred interest in opioid-sparing multimodal strategies, with recent studies suggesting feasibility of opioid-free discharge and comparable relief from NSAIDs with fewer side effects. However, robust comparative evidence remains scarce. This systematic review and network meta-analysis (NMA) evaluates and ranks postoperative analgesic strategies in PCNL, aiming to highlight approaches that may reduce opioid use while improving clinical outcomes in endourology. We searched PubMed, Embase, Web of Science, and Cochrane Library up to March 11, 2025 for RCTs assessing VAS pain in adults undergoing PCNL. Interventions grouped: local anesthesia/nerve blocks, intravenous analgesics, local instillation, intrathecal anesthesia, aromatherapy. Bayesian NMA used ADDIS v1.16.8/R v4.0.5, with MCMC simulations, node-splitting for consistency, SMAA for benefit-risk of VAS (<24h, ≥24h) and complications. 45 RCTs (2,626 patients) formed consistent network without significant inconsistency/heterogeneity. Levobupivacaine outperformed bupivacaine/ropivacaine in VAS reduction (<24h, ≥24h) via erector spinae plane block/local infiltration. Non-opioid analgesics (NSAIDs/paracetamol) showed superior efficacy; opioids excelled short-term but not long-term. IV paracetamol plus LI-levobupivacaine ranked highest in the multicriteria analysis, although the benefit-risk ranking should be interpreted cautiously because the safety component was based on sparse and imprecise data. Limitations: RCT protocol variability (e.g., pain assessment), moderate bias in 21 studies, limited data for high-risk subgroups (e.g., renal impairment, obesity). Comparative safety could not be established because complication data were sparse and estimates were highly imprecise. This NMA supports levobupivacaine and NSAID-based IV analgesics for PCNL pain management, positioning IV-Paracetamol+LI-Levobupivacaine as a leading opioid-sparing multimodal option to address complex pain profiles. These findings encourage safer practices amid opioid concerns, potentially accelerating recovery, shortening stays, and enhancing endourology patient outcomes.Trial registration: PROSPERO CRD42024600872.

Alcohol-induced dose dumping is a significant concern for modified-release oral dosage forms, as it can compromise the intended release behaviour. For enteric-coated formulations, alcohol exposure may lead to loss of enteric functionality and unintended premature drug release in the stomach. Although previous studies have mainly assessed the loss of enteric performance in delayed-release dosage forms, the mechanisms underlying alcohol-induced changes remain poorly understood. In this study, the behaviour of isolated hydroxypropyl methylcellulose phthalate (HPMC-P) films was investigated in aqueous ethanolic media containing 0-40% v/v ethanol. Film permeability was evaluated using paracetamol, nicotinamide and tritiated water as model permeants. No significant change in permeability was observed at ethanol concentrations up to 20% v/v. However, exposure to 40% v/v ethanol significantly increased permeability. Under these conditions, permeability differences between paracetamol (4.4 ± 0.6 E-05 cm/s) and nicotinamide (2.4 ± 0.3 E-05 cm/s) were observed and were initially attributed to differences in drug solubility in hydroalcoholic medium. However, studies with tritiated water eliminated solubility-related effects and provided direct evidence of ethanol-induced changes in film permeability. Microscopic imaging revealed ethanol concentration dependent pore formation within the films. Mass loss study showed negligible film erosion even at 40% v/v ethanol, despite the substantial increase in permeability. These findings demonstrate that increased film permeability originates primarily from ethanol-induced microstructural changes rather than polymer erosion. Overall, this work provides mechanistic insights into the effects of ethanol exposure on HPMC-P films and improves understanding of alcohol-induced alterations in enteric-coated formulations.