Basic & Clinical Pharmacology & Toxicology最新文献

The COVID-19 pandemic may have increased anticoagulant initiation due to the thrombogenic nature of the disease or decreased due to the societal impact of the pandemic. We aimed to study the effect of the COVID-19 pandemic on initiation of anticoagulants in Sweden. We conducted a single interrupted time series analysis on the monthly cumulative incidence of nonvitamin K antagonist oral anticoagulants (NOAC), warfarin, or heparins, before and after March 2020, using SCIFI-PEARL dataset. For anticoagulants in total, there were no statistically significant changes or differences in the trends of initiation after the start of the pandemic. There was a slight numerical decrease in initiation after the onset of the pandemic, particularly for NOACs. For individuals aged ≥ 65 years, however, the immediate decrease in initiation was considerable for NOACs. The prepandemic declining trend of warfarin initiation seemed to attenuate, that is, became less negative, after March 2020. We did not find any profound effect of the COVID-19 pandemic on the initiation of anticoagulants in total. However, among individuals aged ≥ 65 years, a notable immediate decrease in initiation of NOACs was observed. Furthermore, the onset of the pandemic may have attenuated the downward temporal trend in initiation of warfarin use.

We examined the number of patients tested for serum ethanol concentration (SEC) at admission to a large Emergency Department (ED) and the relationship of SEC with sex and age. SEC was analysed by enzymatic method. We retrieved SEC in patient samples from the ED during 2015–2020 from the laboratory information system. Altogether, 174 378 patients were admitted, and 7.3% were tested for SEC. Of these, 35.3% had a positive test. The percentage of patients tested increased from 4.8% in 2015 to 14.4% in 2020. A total of 416 patients had more than one positive SEC. For individual data, we included the first positive test per patient, n = 3607. Of these, 73% were men and 27% were women. The median SEC for both men and women was 1.9 g/L. About 4.4% had a SEC ≥ 3.5 g/L. The median SEC in patients aged 30–59 years was 0.2 g/L higher than the 12–29 and ≥ 60 age groups. In conclusion, the increase in the percentage of patients tested did not lead to a corresponding increase in ethanol-positive tests. There was a large predominance of men, the median SEC was the same for men and women and highest in the 30–59 age group.

Quercetin is known to reduce blood pressure (BP); however, its acute effects are unclear. We investigated the acute effects of quercetin on BP, aortic mechanical properties and vascular reactivity in female Sprague–Dawley (SD) rats. Hypertension was induced using L-NAME (40 mg/kg/day). Quercetin (4.5 mg/kg) was administered intravenously. Mechanical properties of the aortae were measured by echo-tracking in normotensive and hypertensive rats. L-NAME and quercetin quantities in the aorta were determined using AP-MALDI-MSI. Vascular reactivity was performed in mesenteric and renal arteries. L-NAME increased BP and PWVβ while decreasing strain. Quercetin decreased BP and ameliorated PWVβ in L-NAME-induced hypertensive rats. Ex vivo, the acetylcholine (ACh)-induced increase in tension at 100 μM was reduced in renal arteries when exposed to quercetin while phenylephrine (Phe)-induced contractile response was augmented. In quiescent rings of renal arteries incubated with L-NAME (10 μM) and TRAM-34 (1 μM), the ACh-induced vasoconstrictions were inhibited by quercetin. Quercetin resulted in concentration-dependent vasodilation in mesenteric arteries and increased its sensitivity to ACh-induced relaxations. Quercetin lowered BP in L-NAME-induced hypertensive rats, likely due to changes in aortic mechanical properties and relaxation of resistance arteries. Further research is warranted to clarify the acute effects of quercetin on renal arteries in this hypertensive model.

Raloxifene has low bioavailability due to extensive glucuronidation in the intestine and the liver, and its pharmacokinetics is associated with high intra- and interindividual variability. Some of this variability could be explained by the enterohepatic recycling of raloxifene, which is driven by transporter-mediated uptake and efflux and gut microbial deglucuronidation of raloxifene glucuronides. These individual processes involved in raloxifene disposition, however, have not been characterized in full detail. In this study, we evaluated the interactions of raloxifene and its three glucuronide metabolites (raloxifene 4′-glucuronide, raloxifene 6-glucuronide and raloxifene 4′,6-diglucuronide) with drug transporters using Sf9 membrane vesicles and HEK293 cells. Additionally, we measured the deglucuronidation of raloxifene glucuronides in human faecal extracts. All raloxifene glucuronides were transported by MRP2 and MRP3, whereas raloxifene monoglucuronides were identified as substrates of OATP1B1, OATP1B3 and OATP2B1. All three raloxifene glucuronides were readily deglucuronidated in the presence of faecal extracts, although with high between-subject variability. The results of this study provide further understanding of the disposition of raloxifene, which can help understand the sources behind the interindividual variability in raloxifene pharmacokinetics.

In a 2022 consultation, the UK public highlighted the need to disseminate trial results to participants. We assess whether the information provided to trial participants in publicly available participant information sheets (PISs) of trials conducted in the UK is helpful for future trials. This cross-sectional study is based on a search conducted on 18 August 2023 on ClinicalTrials.gov looking for UK completed or terminated phase 2–4 medicine trials. The posted PIS (or the protocol, if the PIS was unavailable) were reviewed checking the text used to inform participants on how results will be disseminated to participants. Of the 48 records retrieved, 32 were included: 23 and 9 had the PIS or the protocol posted, respectively. Seven (22%) did not mention dissemination of results to participants. Thirteen (41%) used the same short “common, standard text” of four sentences to inform participants. This text mentioned ClinicalTrials.gov as the source for further information and US Law as the reason for it. Twelve (38%) used different texts with different scopes and lengths. These results showed that publicly available PISs of medicinal product trials conducted in the UK are very limited and of scarce utility for investigators aiming to start a new trial.