To evaluate the bioequivalence and safety of a generic ibuprofen arginine formulation (T) compared to Sibide (R) in healthy Chinese subjects under fed conditions, a randomized, open-label, single-dose, two-period, two-sequence crossover study was conducted. Twenty-eight eligible healthy subjects received a single 400 mg dose of either the T or R formulation following a standardized high-fat meal, with a 3-day washout period between doses. Plasma ibuprofen concentrations were quantified using a validated LC-MS/MS method. Pharmacokinetic parameters, including Cmax, AUC0-t, and AUC0-∞, were calculated using non-compartmental analysis. Bioequivalence was assessed based on the geometric mean ratios (GMRs) and 90% confidence intervals (CIs) derived from ANOVA. All 28 enrolled subjects completed the study. The GMRs (90% CIs) for Cmax, AUC0-t, and AUC0-∞ were 107.03% (100.02%-114.52%), 100.99% (98.46%-103.58%), and 100.95% (98.24%-103.74%), respectively. All 90% CIs fell entirely within the regulatory bioequivalence acceptance range of 0.80-1.25. Both formulations were well tolerated; adverse events were mild to moderate, and no serious adverse events were reported. Thus, the T formulation of ibuprofen arginine demonstrated bioequivalence to the R formulation in healthy Chinese subjects under fed conditions.

Medication non-adherence is recognized as a critical determinant of therapeutic efficacy and safety. However, its specific impact on the concentration fluctuations of chiral drugs remains poorly understood. By incorporating dual stochasticity in dosing intervals and dosages, we developed a stochastic pharmacokinetic model for chiral drugs comprising bio-active and bio-inactive enantiomers under multiple intravenous bolus administrations. Utilizing characteristic functions and second-type Volterra integral equations, we derived explicit expressions for the expectation and variance of both the active moiety and total measured concentrations, as well as their discrepancy. Moreover, leveraging Kesten theorem and ergodic theory, the existence and the geometric ergodicity of the stationary probability distribution were mathematically demonstrated. Taking ibuprofen as a case study, we simulated various medication non-adherence scenarios to quantify the enantiomeric randomness. The results demonstrated that stochastic concentrations not only cause significant deviation from the ideal levels under perfect adherence, but also induce non-negligible discrepancy between the effective and total measured concentrations. These findings of the work provide a rigorous theoretical guidance for the characterization of two enantiomers variability of chiral drugs induced by medication non-adherence, offering new insights for enhancing therapeutic efficacy and safety.

Background: Acute pain in children is frequently under-recognized and undertreated despite validated assessment tools and effective therapies. This systematic review aimed to synthesize recent evidence on assessment and management of acute pediatric pain. Methods: The review followed PRISMA 2020 guidelines. Clinical questions were developed using the PICO framework, and evidence certainty was assessed with GRADE. PubMed and Embase were searched for studies published from 2016 to 2025. Italian pediatric scientific societies and specialists involved in acute pediatric care contributed to the process. Results: A total of 13 studies were included. Validated pain scales showed high reliability and were associated with reduced pain scores after analgesic administration. Paracetamol and ibuprofen showed comparable efficacy for mild-to-moderate pain; evidence suggesting a modest late advantage of ibuprofen was inconsistent. Combination therapy reduced rescue analgesia in individual studies. Non-pharmacological interventions, including virtual reality, distraction, and hospital play, reduced anxiety and procedural distress, although certainty of evidence was low. Evidence on opioids was limited and did not show clear superiority over non-opioid strategies. Intranasal fentanyl appeared comparable to intravenous morphine and more feasible in emergency settings. Overall, evidence for several clinical questions remains limited, and GRADE recommendations were only possible for selected PICOs. Conclusions: Acute pediatric pain management should rely on structured assessment and multimodal strategies. Validated pain scales should be used routinely. Paracetamol and ibuprofen remain first-line treatments for mild-to-moderate pain, with possible context-specific benefits of ibuprofen or combination therapy. Non-pharmacological interventions may be useful adjuncts, especially for anxiety and procedural distress. Further high-quality studies are needed on opioids, intranasal administration, alternating regimens, and inhaled versus topical analgesia.

Marrubium vulgare L. aerial parts are a rich source of polyphenols with recognized antioxidant and anti-inflammatory properties; however, their therapeutic potential is limited due to poor stability and bioavailability. To enhance its pharmacological efficacy, a liposomal formulation of M. vulgare polyphenolic extract (MV-Lipos) was developed in this study by employing the thin-film hydration method. Before encapsulating, the free-extract (MV-Ext) was analyzed using LC-MS, and the resultant nanoliposomes were tested for physicochemical qualities, biological activity, and safety. MV-Lipos exhibited particle sizes ranging from 127 to 200 nm, an 84% encapsulation efficiency, and high colloidal stability (zeta potential -29.58 ± 0.40 mV). In vitro evaluations revealed anti-inflammatory and antioxidant activities without cytotoxic effects. In vivo, MV-Lipos significantly improved analgesic and anti-inflammatory responses. Specifically, a dose of 100 mg/kg lowered acetic acid induced writhing by up to 75.9% and carrageenan induced paw edema by 72%, with efficacy comparable to ibuprofen. A 28-day subacute toxicity assessment found no treatment-related adverse effects. Furthermore, molecular docking analyses validated the experimental results by revealing possible interactions with inflammation-related targets. Overall, liposomal encapsulation improved the biological efficacy and safety profile of M. vulgare polyphenols, highlighting their potential as natural agents for the management of pain and inflammatory conditions.

Protein-bound uremic toxins (PBUTs) such as 4-ethylphenyl sulfate (4-EPS) challenge kidney failure management due to strong binding to human serum albumin (HSA), thus limiting dialysis clearance. This study examined 4-EPS-HSA interactions using saturation transfer difference nuclear magnetic resonance spectroscopy (STD-NMR), isothermal titration calorimetry (ITC), in silico analysis via molecular docking, molecular dynamics (MD), and molecular mechanics Generalized Born surface area (MM/GBSA) simulations. STD-NMR qualitatively showed competitive binding with the site-specific ligands, warfarin and ibuprofen, indicating interaction with both Sudlow Sites I and II; competitive ITC results also showed competition between these molecules. ITC analysis using a two-component model indicated two distinct binding interactions with association constants Ka1 = 6.62 × 10[5] M[-1] (entropically unfavorable) and Ka2 = 2.71 × 10[4] M[-1] (enthalpically favorable), respectively. Docking models were used to analyze representative binding poses at Sudlow Sites I and II, while MD revealed hydrophobic stabilization at Site I and polar interactions at Site II. MM/GBSA per-residue decomposition identified key stabilizing residues. Circular dichroism measurements showed that the observed binding effects are not accompanied by gross protein unfolding. Comparisons with other PBUTs, including indoxyl sulfate and p-cresyl sulfate, indicated the role of electrostatic and hydrophobic forces involved in binding. These findings advance understanding of PBUT-HSA interactions and inform strategies for improved toxin removal in kidney failure treatments.

Robust chronic ecotoxicological data are essential for EU pharmaceutical regulation, yet many ibuprofen studies in the public domain fail to meet quality criteria, creating uncertainty in its chronic aquatic toxicity profile. Additionally, due to the cost and complexity of full life-cycle fish tests, most studies focus on early/specific life stages rather than reproductive outcomes, limiting insights into population-level effects. The authors used a collaborative approach that included consultation with leading academic experts and regulatory authorities to develop a full life cycle test suitable for investigating the toxicological effects of ibuprofen to fish (Pimephales promelas). Fish were continuously exposed from F0 embryos (<24-hours old) through all growth and reproduction stages to the production and growth of free feeding F1 juveniles. The nominal test concentrations (0.01, 0.032, 0.10, 0.32, and 1.0 mg/L) were selected based on scientific literature and the findings of OECD 236 Fish Embryo Toxicity Tests (FET) and a larval growth test that were used as range finding tests. Ecotoxicology endpoints (NOEC, LOEC, EC10) of relevance were determined and no statistically significant effects were identified at the highest test concentration (1.0 mg/L) for all endpoints except F0 survival and F1 hatching success. These endpoints were considered to represent the most sensitive NOEC (0.32 mg/L) based on statistical significance (p < 0.05) but following additional statistics that identified an outlier the NOEC of ≥ 1.0 mg/L based on biological significance was concluded.

Emerging contaminants, such as antibiotics, antidepressants, non-steroidal anti-inflammatory drugs, analgesics, hormones, pesticides, and microplastics, pose a growing threat to aquatic ecosystems, primarily affecting macroinvertebrates, which are crucial as bioindicators of water quality. This study aims to evaluate the effects of these contaminants on the physiological and bioindicator responses of macroinvertebrates through a systematic review following the PRISMA methodology and a principal component analysis of standardised, categorised data to identify patterns in sublethal effects. It was found that anti-inflammatories, such as ketoprofen, and antidepressants, such as fluoxetine, alter the reproduction of Daphnia magna, reducing the number of offspring and affecting community structure. Non-steroidal anti-inflammatory drugs, such as ibuprofen, affect the locomotion of Gammarus pulex, reducing their speed and mobility, thereby disrupting their feeding and refuge-seeking behaviour. Analgesics, such as diclofenac, reduce the reproduction and abundance of aquatic species, including Neocaridina denticulata, thereby impacting biodiversity. Hormones, such as 17α-ethinylestradiol, interfere with the endocrine system of Mytilus galloprovincialis, thus altering reproduction. Pesticides, such as imidacloprid, favour tolerant species, including Asellus aquaticus, thereby affecting the structure of aquatic communities. Microplastics also alter the locomotion of Gammarus pulex, disrupting their ecological functions. In conclusion, emerging contaminants alter macroinvertebrate communities and compromise traditional water quality indices (BMWP, ASPT, EPT, SPEAR, and AMBI). It is necessary to adapt these indices by incorporating sensitivity weights and a functional approach to achieve more accurate assessments of water quality.