ChatGPT: First Glance from a Perspective of Clinical PharmacologyAuthors: Julie Rudbech Krumborg1,2, Nicolaj Mikkelsen1,2, Per Damkier1,2, Zandra Nymand Ennis1,2, Daniel Pilsgaard Henriksen1,2, Mads Lillevang-Johansen1,2, Sidsel Arnspang Pedersen1,2, Troels K Bergmann1,31. Department of Clinical Pharmacology, Odense University Hospital, Denmark2. Department of Clinical Research, Faculty of Health Science, University of Southern Denmark, Denmark3. Department of Regional Health Research, University of Southern Denmark, Esbjerg, DenmarkCorresponding author: Julie Rudbech Krumborg: [email protected] : Artificial intelligence, Clinical Pharmacology, Drug Information Services, evidence-based medicine, Medical WritingConflict of interest statement: The authors state no conflicts of interest

The present study evaluates the influence of type 2 diabetes (T2D) on important CYP450 isoforms and P-glycoprotein (P-gp) transporter activities before and 3 months after intensifying treatment regimen of 40 patients. Results have been compared with 21 non-T2D healthy participants (control group). CYPs and P-gp activities were assessed after administration of Geneva cocktail. Mean metabolic ratios (MR) for CYP2B6 (1.81±0.93 vs. 2.68±0.87), CYP2C19 (0.420 ± 0.360 vs. 0.687 ± 0.558), and CYP3A4/5 (0.487 ± 0.226 vs. 0.633 ± 0.254) significantly decreased in T2D subjects compared to control group (p<0.05). CYP2C9 (0.089±0.037 vs. 0.069±0.017) activities slightly increased in diabetic subjects and no difference was observed for CYP1A2 (0.154±0.085 vs. 0.136±0.065), CYP2D6 (1.17 ± 0.56 vs. 1.24 ± 0.83) and P-gp activities in comparison with control group. Three months after intensifying treatment regimen, MRs of CYP2C9 (0.080 ± 0.030) and CYP3A4/5 (0.592 ± 0.268) have shown a significant improvement and were not statistically different compared to control group (P>0.05). Several covariables such as inflammatory markers (IL-1β and IL-6), genotypes, diabetes- and demographic-related factors were considered in our analyses. Our results indicate that low chronic inflammatory status associated with T2D modulates CYP450 activities in an isoform specific manner.

4-Methylbenzylidene camphor (4-MBC) is a photo-absorbing UV filter, which can be absorbed into the circulation and cause systemic effects. 4-MBC is found extensively in the environment and measurements suggest bioaccumulation in human tissues. 4-MBC is continued to be released in the environment despite the growing knowledge about its potential endocrine and reproductive disrupting effects. 4-MBC interfers with various processes, such as placental development, spermatogenesis, and inflammatory cascades. Previous reviews mention 4-MBC as one of the several UV filters but here we focus on 4-MBC only. We cover the potential effects on human health regarding systemic and molecular effects, with the focus on reproduction. We also cover the potential bioaccumulation and interactions with receptor systems, such as the estrogen receptors β and α, and progesterone receptor, and analyze 4-MBC´s effects on mRNA expression and protein expression. Furthermore, 4-MBC is reported to act with inflammatory pathways by activating p38 MAPK and NF-κB, leading to the production of inflammatory TNF-α and IL-6. In conclusion, 4-MBC has wide ranging effects in different models while there is more research warranted to detail the mechanism of action, long-term effects at low doses and the potential interaction with many pathways and other pollutants.

Objective: Combining different drugs increases the potential for drug-drug interactions en-hancing the risk of adverse drug reactions. We aimed to unravel potential pharma-cokinetic interactions between aripiprazole and duloxetine. Methods: Plasma concentrations of aripiprazole of two groups of 78 patients each, receiving aripiprazole as a monotherapy, or combined with duloxetine, were compared. A po-tential impact of duloxetine on the metabolism of aripiprazole was expected in high-er plasma concentrations of aripiprazole and higher dose-adjusted plasma concen-trations. Results: Patients co-medicated with duloxetine showed significantly higher plasma concen-trations of aripiprazole (p=0.019) by 54.2%. Dose-adjusted plasma concentrations were 45.6% higher (p=0.001). 65.4 % of these patients exhibited aripiprazole plasma concentrations above the upper limit of the therapeutic reference range, in the con-trol group this was only the case for 43.6% of the patients (p=0.006). A positive rela-tionship was found between the daily dose of duloxetine and dose-adjusted plasma concentrations of aripiprazole (p=0.034). Conclusions: Combining duloxetine and aripiprazole leads to significantly higher drug concentra-tions of aripiprazole, most likely via an inhibition of cytochrome P450 CYP2D6 and to a lesser extent of CYP3A4 by duloxetine. Clinicians have to consider increasing aripiprazole concentrations when adding duloxetine to a treatment regimen with ari-piprazole.

Background: Deprescribing is a complex process requiring a patient-centred approach. One frequently expressed deprescribing barrier is patients’ attitudes and beliefs toward reducing or stopping a medication. This study aims to identify the willingness to deprescribe predictors in a sample of Portuguese older patients. Methods: Cross-sectional study with community-dwelling patients aged ≥ 65 and taking at least one regular medication. Data collection included patients’ demographic and clinical characteristics and the Portuguese Revised Patients’ Attitudes Towards Deprescribing (rPATD) Questionnaire. Descriptive statistics were used to present patients’ characteristics and attitudes towards deprescribing. A multiple binary logistic regression analysis was performed to identify willingness to desprescribe predictors. Results: 192 participants (median age 72 years; 65.6% female) were included. A large majority (83.33%) were willing to deprescribe if recommended by their doctor. The willingness to desprescribe predictors were age (adjusted odds ratio (aOR)= 1.136), female sex (aOR= 3.036), and the rPATD concerns about stopping (aOR= 0.391). Conclusions: Most patients were willing to deprescribe if recommended by their doctor. Older age and female sex increase the odds of willingness to deprescribe; conversely, higher concerns about stopping medications decrease the odds. These findings suggest that addressing patients’ concerns about stopping their medicines may contribute to deprescribing success.