ABSTRACT We synthesised a series of N 2 , N 4 ‐diaminoquinazoline derivatives, among which 3‐[[4‐(benzylamino)quinazolin‐2‐yl]amino]benzenesulfonamide (compound 5 ) exhibited potent phosphodiesterase type 5 (PDE5) inhibitory activity. Increasing evidence suggests that PDE5 inhibition is a promising therapeutic strategy for peripheral vascular disease. This study aimed to investigate vasorelaxant effects of 5 and its underlying mechanisms in rat mesenteric arteries. Compound 5 was synthesised and purified, and evaluated its vascular activity using organ bath assay. Molecular docking was performed to identify its potential molecular targets. Compound 5 (0.0001–30 μM) induced relaxation of phenylephrine (PE)‐precontracted mesenteric arteries (EC 50 = 0.76 ± 0.29 μM; E max = 95.6% ± 1.1%). This effect was attenuated by endothelium removal (EC 50 = 5.24 ± 0.98 μM) and by L‐NAME (eNOS inhibitor). Compound 5 enhanced sodium nitroprusside–induced relaxation, supporting modulation of the NO–sGC–cGMP axis via PDE5 inhibition. Iberiotoxin (BK Ca blocker) reduced relaxation, whereas 4‐aminopyridine (K V blocker) and glibenclamide (K ATP blocker) had no effect. Compound 5 inhibited vasoconstriction mediated by extracellular Ca 2+ influx via receptor‐operated Ca 2+ channels (ROCCs) and α 1 ‐adrenergic receptor activation. Molecular docking provided qualitative support for PDE5A, BK Ca channels and α 1 ‐adrenergic receptor as potential targets. In conclusion, 5 induces potent vasorelaxation in resistance arteries through eNOS/NO/cGMP signalling, BK Ca channel activation and inhibition of ROCCs and α 1 ‐adrenergic receptors, supporting its potential as a therapeutic candidate for peripheral vascular disorders.
ABSTRACT We previously proposed stereoselective 5‐hydroxy‐omeprazole/omeprazole cut‐offs for R‐ and S‐omeprazole to differentiate between rapid, normal, and poor CYP2C19 metabolisers. However, the performance of these stereoselective CYP2C19 phenotyping approaches has never been compared with conventional racemic omeprazole phenotyping. Therefore, dried blood spots from healthy, genetically predicted rapid ( n = 15), normal ( n = 15), and intermediate ( n = 14) CYP2C19 metabolisers were stereoselectively reanalysed after administration of omeprazole alone (10 mg) and following CYP2C19 inhibition with voriconazole (400 mg administered prior to omeprazole). Using stereoselective R‐, S‐, and racemic 5‐hydroxy‐omeprazole/omeprazole ratios, CYP2C19 phenotyping performance was assessed by genotype–phenotype concordance and phenoconversion patterns relative to prior reports. An adaptive phenotyping strategy using the 3‐h metabolic ratio in individuals with delayed absorption and retaining the 2‐h ratio otherwise improved agreement with AUC‐based CYP2C19 activity measures (Spearman ρ = 0.99 vs. 0.93 and 0.88 for fixed 2‐ and 3‐h ratios, respectively). Across methods, the racemic approach demonstrated the most favourable overall performance, closely followed by the S‐enantiomer–based strategy. In conclusion, while racemic omeprazole phenotyping modestly remains the most accurate strategy for assessing CYP2C19 activity, stereoselective assessment of the S‐enantiomer provides an alternative that enables CYP2C19 phenotyping in patients treated with esomeprazole without treatment interruption or substitution with omeprazole.
ABSTRACT We investigated the effects of angiotensin II receptor blockers (ARBs) on the progression of Alzheimer's disease (AD). This retrospective cohort study used data from the Korean nationwide claims data to identify patients with AD aged 60–79 years in 2010. ARB users and nonusers were 1:1 propensity score matched. Cox proportional hazards regression evaluated AD progression, defined as memantine initiation and mortality. Active‐comparator and dose–response analyses were conducted. ARB use was associated with lower risks of memantine initiation (hazard ratio [HR] = 0.79; 95% confidence interval [CI] = 0.70–0.89) and mortality (HR = 0.83; 95% CI = 0.76–0.89). Cumulative exposure analyses showed stronger associations in the highest exposure categories, including 2–3 years of ARB use and ≥ 2 DDD‐years, whereas associations in the lower exposure categories were not statistically significant. In active‐comparator analyses, ARBs were associated with lower mortality risk than ACE inhibitors and beta‐blockers, but not with dihydropyridine calcium channel blockers (CCBs). ARB use may be a reasonable antihypertensive choice in patients with AD, although the comparable outcomes between ARBs and CCBs suggest that these associations may not be unique to ARBs and may instead reflect shared blood pressure–lowering and vascular effects. Further prospective research is warranted to optimize antihypertensive selection in patients with AD.
ABSTRACT The telepharmacological outpatient clinic (TPOC) is a hospital service in which clinical pharmacologists and clinical pharmacists review a patient's full medication regimen and hospital record, then discuss it with the referring general practitioner (GP) by video conference. Seven GPs in the Region of Southern Denmark who had used or been introduced to the service were interviewed to explore how it was used and what prevented wider use. Interviews were semi‐structured and analysed thematically. GPs described practices organised around single diagnoses, with no separate pathway for patients who are difficult because they are complex. This was the setting the service entered. Four themes were identified. Whether the service was used depended on integration into existing clinical software. Its value reached past the referred patient, as GPs applied what they had learned to patients never referred. GPs described a coordination gap for patients attending several outpatient clinics, where no clinician held an overview of the whole treatment. They wanted the intensity of the service matched to the complexity of the case. GPs who wanted to refer more often pointed to awareness and time pressure, not to doubts about the service. Uptake appears to depend on workflow integration.
ABSTRACT Chemotherapy‐induced peripheral neuropathy (CIPN) adversely affects treatment efficacy and quality of life. Despite studies on glutathione (GSH) or GSH boosters' antioxidative effects for prevention, optimal management remains uncertain. We conducted a systematic review and network meta‐analysis of randomized controlled trials to consolidate and critically appraise the current evidence and to compare the efficacy of GSH and GSH boosters for the prevention of CIPN. The MEDLINE, Embase and CENTRAL databases were searched through March 2025. Twenty‐five RCTs involving 1625 patients were included. No intervention significantly reduced all‐grade CIPN compared with placebo. N ‐acetylcysteine (odds ratio [OR] 0.19, 95% credible intervals [CrI] 0.05–0.63), GSH (OR 0.34, 95% CrI 0.13–0.79) and vitamin E (OR 0.33, 95% CrI 0.11–0.91) were associated with a reduced incidence of grade 3/4 CIPN compared with placebo. N ‐acetylcysteine ranked highest for both all‐grade and grade 3/4 CIPN prevention. These findings remained consistent in sensitivity analyses excluding patients with pre‐existing neuropathy but were not retained in analyses restricted to double‐blind studies. Overall, N ‐acetylcysteine, GSH, and vitamin E were associated with potential reductions in severe CIPN, with N ‐acetylcysteine consistently ranking highest, although these associations should be regarded as preliminary. Further rigorously conducted and adequately powered trials are warranted to confirm these findings and evaluate agents demonstrating potential benefits.
