paracetamol (Kid Relief / Tachipirina)

The interaction between paracetamol and ethanol during the early development of zebrafish.

Małkowska Anna A, Wieczorek Karolina K, Pawlak Kacper K, Bonder Julia Elżbieta JE

The issue of drug-alcohol interactions is a major concern in drug therapy and can endanger patient safety. Paracetamol is one of the most widely used analgetic drugs, while ethanol is commonly consumed addictive substance. This study investigated the toxic effects of paracetamol, ethanol, and their mixture at different concentrations on the embryonic development of zebrafish (Danio rerio, D. rerio). Zebrafish embryos (20 embryos per group, 3 biological replicates for each concentration or combination of concentrations) were exposed for 72 h post-fertilization to paracetamol (0.5, 1.0, 2.0, 3.0, 5.0, and 10.0 mM), ethanol (85.5, 171.0, 256.5, 342.0, 513.0, 855.0) or their combinations. Additionally, combinations of paracetamol and ethanol were examined to assess the type of interaction (0.5:85.5; 1.0:171.0; 1.5:256.5; 2.0:342.0; 3.0:513.0; and 5.0: 855.0 mM). The combination of the drug and alcohol resulted in a higher incidence of developmental defects compared to the effects of either substance used alone. The most frequently observed changes included decreased larval pigmentation, pericardial and sac edema or increased larval mortality compared to control (e.g., 2-4 fold increase over control). Notably, there was a statistically significant reduction in both eye size and body length of the larvae. Furthermore, the severity of the defects increased proportionally with dose. Additionally, analysis using the Chou-Talalay method revealed the synergism in this interaction, with a combination index below 1. These findings demonstrate that exposure to paracetamol and ethanol exerts a synergistic toxic effect on early zebrafish development, emphasising the potential risks associated with drug-alcohol co-exposure.

Fetal exposure to paracetamol is associated with altered markers of ovarian development and reduced uterine volume in girls: the COPANA study.

Fischer Margit B MB, Mola Gylli G, Sundberg Karin K, Scheel Lone L et al.

Is fetal exposure to paracetamol associated with markers of ovarian function in infancy? Mild to moderate doses of prenatal paracetamol exposure, assessed by detailed maternal reports and urinary measurements, are associated with ovarian morphology and activity as well as reduced size of estrogen-responsive tissues in infant girls. Maternal use of paracetamol is widespread. Across multiple independent animal studies, fetal exposure consistently impairs the formation of primordial ovarian follicles, causing subfertility and premature estropause in female offspring. The Copenhagen Analgesic study (COPANA) is a single-center, prospective, observational cohort study conducted at a university hospital (March 2020 to November 2022). From 3425 eligible participants, 685 healthy singleton pregnant women of Caucasian origin, were enrolled in the first trimester of pregnancy, and 302 infant daughters were examined at follow-up. Exclusion criteria included maternal diabetes or thyroid disease, pre- or post-term delivery, or severe infant illness. Pregnant women reported paracetamol use biweekly and provided first-trimester urinary samples which were analyzed for paracetamol levels (LC-MS/MS) and adjusted for urinary osmolarity (n = 299). Girls were classified by timing of initial exposure: early fetal life (<17 weeks, n = 92), mid-late fetal life (≥17 weeks, n = 67), or unexposed controls (n = 143). Of the 92 girls initially exposed in early fetal life, a subgroup was exposed exclusively in early fetal life (n = 22).In an independent confirmatory cohort, 1210 girls were followed from infancy to adolescence. Their exposure was maternal self-reported (any) use of paracetamol during pregnancy and reported early in the third trimester (yes/no). Early fetal exposure was associated with reduced ovarian volume (-0.11 cm3, 95% CI -0.19 to -0.03) and reduced uterine volume (-0.18 cm3, -0.35 to -0.01), whereas mid-late fetal exposure was associated with fewer ovarian follicles (-1.05 follicles, -1.71 to -0.39) compared to unexposed girls. AMH levels were lower in girls exposed exclusively in early fetal life (-0.45 SDS, -0.87 to -0.03) compared to unexposed girls. Maternal urinary paracetamol concentrations were inversely associated with ovarian and uterine volume as well as breast tissue diameter. In the independent confirmatory cohort, fetal paracetamol exposure was associated with reduced uterine volume at puberty (-4.11 cm3, -7.29 to -0.92) and smaller ovarian volume during adolescence (-2.76 cm3, -4.82 to -0.70). The observational design of the study allows evaluation of exposure outcome associations, while the causality interpretation is supported by consistency with experimental models demonstrating comparable effects. Residual confounding by indication for paracetamol use cannot be completely excluded, although the results were robust after accounting for fever and other maternal factors. The analytic design of the current study limited our ability to evaluate whether frequency or patterns of paracetamol use influenced the observed associations. In this prospective cohort study of infant girls, prenatal exposure to paracetamol was associated with differences in several markers of ovarian development, including ovarian volume, follicle number, and circulating AMH, as well as uterine volume and breast tissue diameter. The associations with reduced ovarian and uterine size were also observed in a confirmatory cohort followed to adolescence. Whether these early-life differences have long-term clinical relevance, including effects on reproductive lifespan, remains uncertain and requires analyses in studies with extended follow-up. This research was supported by Rigshospitalets Research Council under grant (E-22717-21), Læge Sofus Carl Emil Friis og hustru Doris Friis'Legat (F-23936-01), Aase og Ejnar Danielsens Foundation (20-10-0367), Helsefonden (20-B-0388), Axel Muusfeldt Foundation (2020-0385), and The Danish Centre for Endocrine Disrupting Substances (CeHoS) (2022-23219). The funders had no role in considering the study design or in the collection, analysis, interpretation of data, writing of the report, or decision to submit the article for publication. The publication was completed as part of the MERLON project under grant agreement No. 101137411. The MERLON project is funded by the European Union. Views and opinions expressed are, however, those of the authors only and do not necessarily reflect those of the European Union or the European Health and Digital Executive Agency (HADEA). Neither the European Union nor HADEA can be held responsible for them. All authors declare no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years, and no other relationships or activities that could appear to have influenced the submitted work. One author (MA) is a government official. ClinicalTrials.gov ID: NCT0436922.

Connecting prenatal exposure to paracetamol with postnatal reproductive development: a first of its kind study in reproductive toxicology.

De Geyter Christian C

Hand-Held Raman Spectroscopy for Paracetamol Assay in Solution for Infusion: Expanding the Capabilities of Process Analytical Technologies.

Henriques João J, De Beer Thomas T, Cardoso Catarina C, Moura Vera V et al.

Currently, the manufacture of injectable drug products relies on a quality-by-test approach, where product quality is evaluated at fixed manufacturing steps. The introduction of the quality-by-design approach, supported on process analytical technologies (PAT) is changing this paradigm. The US Food and Drug Administration established the foundations for the application of PAT in real-time control of the drug manufacturing process. One of the most versatile PAT tools is the Raman spectroscopy. Nevertheless, the application of this technique to injectables is still underexplored. This work intends to expand the use of Raman spectroscopy as a PAT tool for injectable drug products. A Raman spectroscopy method was developed for the assay of paracetamol in paracetamol infusion solutions, using a PLS (partial least squares) algorithm. The method is specific, with a root mean square error of calibration (RMSEC), cross-validation (RMSECV) and prediction (RMSEP) of 1.067%, 2.591%, and 2.601%, respectively, with R2 of 0.999 and Q2 of 0.992. The method was developed with a hand-held Raman spectrometer and was tested as an at-line PAT tool, rendering similar error levels to the ones found for the validation, with results readily available in ca. 1 min. This work presents a further extension of PAT applied to injectable drug products, specifically with the development of an at-line paracetamol assay method. This approach enables flexible sampling in several manufacturing steps with a single instrument and without adaptation of the manufacturing line. This work marks a significant step towards a comprehensive monitorization and control of the injectable manufacturing process.