Pharmaceuticals serve as indispensable allies in human and veterinary medication. Acetaminophen (APAP) is extensively consumed as an analgesic and antipyretic medication. The indiscriminate usage of APAP has led to widespread consequences, transforming it into a formidable contaminant of emerging concern, posing severe and underestimated threats. Therefore, to eliminate APAP from the environment, the development of sustainable and efficient methods is compelling. In the present study, Paracoccus sp. APAP_BH8 was utilized for the biodegradation of APAP in a laboratory-scale bioreactor packed with wood charcoal. The response surface methodology was employed for the optimization of distinct degradation parameters, revealing pH of 7.0, inoculum size of 0.3, co-substrate concentration of 15 mg L-1, and APAP concentration of 350 mg L-1 as most favorable. The bioreactor was intended for the removal of APAP at higher concentrations from wastewater. The bioreactor exhibited 90.58% degradation in batch mode studies, and the kinetic parameters Ks, Vmax, and Vmax/Ks were 322.58 mg L-1, 53.52 mg L-1 day-1, and 0.1659 day-1, respectively. For the degradation in continuous mode, the bioreactor was operated at different flow rates and APAP concentrations. The removal efficiency observed in the range of 48.08%-89.35%, and the maximum elimination capacity was 721.19 mg L-1 h-1 at an inlet concentration of 450 mg L-1. Overall, the findings highlighted that Paracoccus sp. APAP_BH8 is a reliable, promising, and sustainable candidate for bioremediation of APAP and similar contaminants from pharmaceutical wastewater within wood charcoal packed-bed bioreactor.

Developing directly-compressed formulations remains a resource-intensive task, requiring substantial experimental effort to characterise the compressibility and compactability of a formulation space. This study extends a global optimisation of mixture rules to a ternary formulation space (API-brittle filler-elastic filler) and investigates the potential for reducing experimental burden whilst maintaining the predictive accuracy of empirical compression and compaction models. Three grades each of paracetamol and ibuprofen, combined with a consistent placebo base, were used to evaluate the approach. The global optimisation outperformed the traditional line of best fit approach, achieving strong predictive performance for the Kawakita model (R2>0.94; RMSE<0.01) and more variable fits for the Ryshkewitch-Duckworth model (R2 = 0.93 - 0.95 and RMSE = 0.23 - 0.39 MPa for paracetamol; R2 = 0.70 - 0.83 and RMSE = 0.31 - 0.37 MPa for ibuprofen). The optimisations performance was found to improve when the training dataset considered only drug-loaded blends. The exploration of reducing experimental burden considered a Model-Based Design of Experiments (MBDoE) which was benchmarked against random experiment selection. Integrating MBDoE with optimised mixture rules reduced API consumption by over 30% across all formulations, with median savings of 75%-95% under Acceptable and Good performance thresholds. Savings decreased with increasing threshold stringency, with the greatest variability observed in ibuprofen formulations. The Kawakita model supported reductions across all threshold levels, whilst the Ryshkewitch-Duckworth model showed limited capacity beyond the Acceptable threshold. tThe MBDoE did not outperform the random selection of experiments, however the optimisation framework for populating empirical compression and compaction models offers a resource-efficient approach to predicting tablet porosity and tensile strength of ternary API loaded blends.

Pharmaceutical contamination in aquatic ecosystems is a growing concern for marine biodiversity and human health. We have detected six different non-steroideal anti-inflamatory drugs (carprofen, ibuprofen, ketoprofen, phenylbutazone, diclofenac and flunixin), five antibiotics (florfenicol, enrofloxacin, ciprofloxacin, oxytetracycline and trimethoprim), acetaminophen and caffeine in liver samples from 13 bottlenose dolphins (Tursiops truncattus) and 14 striped dolphins (Stenella coeruleoalba) inhabiting the western Mediterranean Sea and stranded in the coast of Valencian Community (Spain) between 2010 and 2024. To our knowledge, this study is the first documentation of some of these pharmaceuticals in wild marine-mammal tissues. Our results confirm the presence of these contaminants in the Mediterranean marine ecosystem and their incorporation into the top predator level, likely mainly through the food chain. These pollutants could cause physiological alterations in exposed individuals and may represent a potential risk for population health and resilience under chronic exposure scenarios. Potential sources of such contamination include domestic wastewater and discharges from large cruise ships, as well as open aquaculture plants, highlighting the need for enhanced monitoring and awareness to mitigate the impact of pharmaceutical contamination in marine mammals and advocate for effectively protecting marine biodiversity and human health.

Basal fatty tubular vacuolisation (BFTV) of the kidneys has mostly been associated with ketoacidosis. Its occurrence in paracetamol intoxication has not been described. Paracetamol in overdose is hepatotoxic and nephrotoxic but does not cause ketoacidosis. This study aimed at investigating whether BFTV occurs in paracetamol intoxication. The Swedish National Board of Forensic Medicine database was searched for the Uppsala area for 2016-2024 for paracetamol intoxication cases with kidney samples taken. Two equally-sized control groups, matched for age, sex and post-mortem interval, were selected from the same period: other intoxications and hangings. The kidney slides were evaluated by both authors for BFTV according to the scale "none-possible-scant-easily identifiable". The kidney slides were also marked with ten fields and evaluated for the number of fields with BFTV and for the number of fields with formalin pigment deposition. A Kruskal-Wallis test was used to calculate significant differences between the groups. Spearman's rho was used to evaluate associations and a p-value < 0.05 was considered statistically significant. The database search yielded 24 cases. Paracetamol intoxications showed a higher degree of BFTV and more BFTV-positive fields than both control groups (p < 0.05). The number of BFTV-fields correlated with the degree of BFTV and the number of fields with formalin pigment deposition (Spearman's rho 0.691 and 0.544, respectively, p < 0.001). The correlation between the authors' assessments was moderate. Thus, the present study found an association between paracetamol intoxication and BFTV. This likely represents a renal stress reaction due to paracetamol toxicity and not ketoacidosis.

Acute liver failure (ALF), characterized by severe hepatocyte necrosis with a high mortality rate, remains a major global health challenge. However, there are currently no effective drug options for the clinical treatment of ALF. Herein, inspired by the new concept of a full-API nanodrug (FAND), we have rationally developed a quadruplex bioactive FAND (termed FAND[HP@FuEVs]) composed entirely of active pharmaceutical ingredients (APIs). This FAND[HP@FuEVs] is constructed from fusion extracellular vesicles (FuEVs), which hybridize M2 macrophage-derived EVs (M2-EVs) with mesenchymal stem cell-derived EVs (MSC-EVs) and is subsequently engineered with two clinically therapeutic biomacromolecules: hepatocyte growth factor (HGF) and polyene phosphatidylcholine (PPC). Notably, FAND[HP@FuEVs] efficiently targets the damaged liver, benefiting from the dual inherent inflammation-tropism of the FuEVs. Moreover, FAND[HP@FuEVs] harnesses quadruplex biological activities by leveraging four natural bioactive components-M2-EVs, MSC-EVs, HGF, and PPC-to deliver pleiotropic therapies, including antioxidant, anti-inflammatory, pro-regenerative, and macrophage repolarization effects. These therapies are effective in treating ALF induced by both acetaminophen and hepatectomy, demonstrating significant clinical relevance based on data from patients with liver disease. Overall, the utilization of naturally derived or clinically approved APIs to construct full-bioactive nanodrugs creates opportunities for clinical translation as a safe, versatile, and multifaceted treatment for ALF.

Reactive infectious mucocutaneous eruption (RIME) is an infection-associated mucositis syndrome previously described under terms including incomplete Stevens-Johnson syndrome (SJS), Fuchs syndrome, and Mycoplasma pneumoniae-induced rash and mucositis (MIRM). It is characterised by an infectious prodrome, prominent mucosal involvement, and sparse or absent cutaneous disease. Severe ocular involvement may clinically mimic atypical Stevens-Johnson syndrome. We report the case of a previously healthy woman in her 20s who developed coryzal symptoms and self-treated with ibuprofen, paracetamol, and pseudoephedrine before presenting with worsening cough, pyrexia, odynophagia, and bilateral conjunctival discharge. She received doxycycline and topical chloramphenicol but re-presented overnight with rapidly progressive lip swelling, dysphagia, oral mucosal ulceration, and severe bilateral ocular inflammation without cutaneous lesions. Recent exposure to non-steroidal anti-inflammatory medication and doxycycline created initial diagnostic uncertainty, while the preceding respiratory prodrome and skin-sparing mucositis supported infection-associated RIME. Ophthalmological assessment demonstrated severe ocular surface inflammation with pseudomembrane formation, early symblepharon, and progressive corneal involvement, requiring tertiary transfer and amniotic membrane grafting. Initial chest radiography and respiratory multiplex polymerase chain reaction (PCR) testing were negative, including for Mycoplasma pneumoniae; however, subsequent serology returned positive for Mycoplasma pneumoniae IgM. Later drug challenge testing demonstrated tolerance to suspected medications, supporting an infection-associated rather than drug-induced aetiology. This case highlights that Mycoplasma pneumoniae-associated RIME may mimic atypical Stevens-Johnson syndrome, particularly when severe ocular and oral mucositis occurs after recent medication exposure. Early dermatology and ophthalmology involvement, combined molecular and serological testing, and prompt ocular treatment are essential to reduce long-term ocular morbidity.