Patient perspectives are highly important to ensure optimal patient care in hospitals or primary care settings. Clinical pharmacy services, in which clinical pharmacists provide direct patient care, are a relatively recent addition to healthcare and are increasing in scope and availability. In this focused narrative review, relevant qualitative studies describing patients' perspectives after the integration of clinical pharmacists into healthcare services were included. Patients described predominantly positive feedback, presented as facilitators. The facilitators described in studies were that patients felt safe, experienced clear communication and collaboration with pharmacists, increased their knowledge of medications, and appreciated pharmacists' time and availability. Occasionally, patients described challenges with the pharmacist or service, presented as barriers. The barriers were that patients were unfamiliar with the clinical pharmacists' role and services, lacked trust or experienced conflicting information, experienced a lack of patient-centredness, and some disagreed or had challenges with elements of the intervention. In conclusion, most perspectives represented positive facilitators that should be kept and protected in the future, with some barriers that can be overcome in the future for optimal patient care and development of clinical pharmacy services.

We previously developed nanobodies acting as positive allosteric modulators (PAMs) of the calcium-sensing receptor (CaSR). Here, we sought to develop more potent CaSR modulators by creating bivalent nanobody constructs using 'tail-to-head' peptide-linker conjugation. The constructs were functionally characterized at CaSR in HEK293 cells in a Ca[2+] mobilization assay. Homobivalent Nb4-Nb4 and Nb10-Nb10 constructs with linkers comprising 3, 5, 6 or 9 GGGG(S/T) repeats all displayed CaSR PAM potencies comparable with those exhibited by their monovalent counterparts. Likewise, five heterobivalent nanobodies combining Nb4, Nb10, Nb11, Nb36 or Nb37 through [GGGG(S/T)]9 linkers exhibited PAM potencies similar to that of the monovalent version of the first (N-terminal) nanobody in the respective constructs. This prompted us to examine the functional properties of [GGGG(S/T)]9-linked constructs combining Nb4 and the mGluR5-selective nanobody PAM Nb43[mGlu5]. Nb4-L9-Nb43[mGlu5] displayed slightly increased CaSR PAM potency relative to Nb4, whereas Nb43[mGlu5]-L9-Nb4 exhibited ~40- and ~10-fold reduced potency compared with Nb4-L9-Nb43[mGlu5] and Nb4, respectively. The findings indicate that 'tail-to-head' conjugation markedly reduces CaSR binding affinity of the second (C-terminal) nanobody and likely explains the lack of synergistic enhancement of PAM potency in the bivalent constructs. Thus, the suitability of tail-to-head linker conjugation of nanobodies is context dependent, governed by how the nanobody engages its target and by whether the linker perturbs these interactions.

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 (EC50 = 0.76 ± 0.29 μM; Emax = 95.6% ± 1.1%). This effect was attenuated by endothelium removal (EC50 = 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 (BKCa blocker) reduced relaxation, whereas 4-aminopyridine (KV blocker) and glibenclamide (KATP blocker) had no effect. Compound 5 inhibited vasoconstriction mediated by extracellular Ca[2+] influx via receptor-operated Ca[2+] channels (ROCCs) and α1-adrenergic receptor activation. Molecular docking provided qualitative support for PDE5A, BKCa channels and α1-adrenergic receptor as potential targets. In conclusion, 5 induces potent vasorelaxation in resistance arteries through eNOS/NO/cGMP signalling, BKCa channel activation and inhibition of ROCCs and α1-adrenergic receptors, supporting its potential as a therapeutic candidate for peripheral vascular disorders.

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.

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.

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.

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.

Migraine is a common disabling disorder, and optimising affordable preventive treatments remains highly relevant. Candesartan is an effective and well-tolerated preventive treatment, but little is known about its dose-concentration-response relationships. We explored these relationships using data from the MigriNor study, a prospective observational cohort of adults with episodic or chronic migraine initiating oral preventive treatment. A total of 166 participants using candesartan were included (median age 35 years; 89% female). Participants completed a daily electronic headache diary during a 4-week baseline and 12-week follow-up period with accompanying blood sampling. Dosing regimen was flexible. No differences in adverse drug reactions (ADRs) or treatment acceptability were observed between participants starting 4 versus 8 mg. Substantial interindividual variability in serum concentrations was observed. Higher serum concentrations were associated with lower odds of headache attacks (OR = 0.97, 95% CI = 0.96-0.98, p < 0.001) and migraine attacks (OR = 0.98, 95% CI = 0.97-0.99, p = 0.005). Interquartile ranges of serum concentrations among ≥ 30% and ≥ 50% responders were 62.9-141.2 and 62.3-129.3 nmol/L, respectively, suggesting preliminary therapeutic reference ranges. Serum concentration was not associated with ADRs or treatment acceptability. Interpretation is limited by the flexible dosing design, and studies with fixed dosing regimens are warranted.

Chemokines orchestrate immune cell trafficking through receptor-mediated signalling and are implicated in inflammatory, autoimmune and neuropathic disorders. The XCL1-XCR1 axis is of particular interest because XCR1 is selectively expressed on mature conventional type 1 dendritic cells (cDC1s), where it supports communication with activated CD8[+] T cells and NK cells and promotes antigen cross-presentation. This selectivity has made XCR1 an attractive target for dendritic cell-based cancer vaccines, while emerging evidence also links XCL1-XCR1 signalling to neuroinflammation and pain. Despite its therapeutic potential, the mechanisms governing XCR1 activation and trafficking remain understudied. Here, we characterize XCR1 expression, membrane trafficking, and basal internalization to define mechanisms that may influence therapeutic targeting. We show that XCR1 undergoes constitutive internalization through a β-arrestin-independent but adaptor protein 2 (AP2)-dependent pathway, distinguishing it from other chemokine receptors with constitutive endocytosis. Furthermore, we identify specific sequence motifs critical for its subcellular localization and intracellular trafficking. These findings provide new mechanistic insights into XCR1 regulation and may inform the development of targeted therapeutics and antigen-delivery strategies in cancer and inflammation.

Vitamin D is a nutrient and prohormone obtained from diet and supplements and synthesized in the skin. It is essential for calcium and phosphate homeostasis and skeletal health and influences multiple extra-skeletal processes, yet deficiency remains common worldwide. This narrative review summarizes vitamin D sources, physiology, metabolism, pharmacokinetics, clinical relevance and safety and outlines the distinct pharmacokinetic profiles and clinical roles of vitamin D, calcidiol and calcitriol and its analogues. Evidence consistently supports vitamin D, combined with calcium, for preventing and treating deficiency-related skeletal disorders in high-risk populations, and in specific conditions such as malabsorption, chronic kidney disease, hypoparathyroidism and frailty. In vitamin D-replete populations, large trials show limited extra-skeletal benefits, apart from modest effects on cancer mortality and progression from prediabetes to Type 2 diabetes. Untargeted screening is not recommended. Future research should prioritize targeted supplementation, standardized assays and identification of populations most likely to benefit from supplementation.

N-acetyl-p-aminophenol (APAP), or acetaminophen, is the most prescribed analgesic and antipyretic, even used in association with other drugs. Because it is easily bought in drugstores, much evidence about its toxic effects is known due to high doses or continuous use, which can lead to death in cases of intoxication. The present study aimed demonstrate the ability of APAP to change the brain and heart electrical activities, as early as significant increase in liver enzymes. Thus, a toxic dose of 1 g/kg was administered orally, and the animals were assessed every 3 h until 12 h for electroencephalography, electrocardiography and liver function data. The results showed that a toxic dose of APAP was capable of reducing brain electrical activity for the delta, theta, beta and gamma waves; however, the alpha wave activity was increased. In the heart, a reduced electrical activity was observed synchronously with the electroencephalogram. During the 12-h follow-up period, a significant increase in liver enzymes was observed. Taken together, we conclude that high doses of APAP can alter frequency brain oscillations and promote cardiac changes independently of liver damage in the first 12 h.

The prevalence of ADHD is increasing rapidly, and lisdexamfetamine is increasingly popular, but few studies investigate its safety. We performed a sequence symmetry analysis (SSA) using Danish register data to identify potential ADRs associated with lisdexamfetamine in 2013-2023. Outcomes were incident prescriptions or incident discharge diagnoses. We calculated trend-adjusted sequence ratios (SR) with 95% confidence intervals (CI). We additionally performed two comparator SSAs for the same outcomes following incident use of stimulants (methylphenidate and dexamfetamine) or non-stimulants (guanfacine and atomoxetine). This study is reported according to RECORD-PE guidelines. We included 48 740 incident lisdexamfetamine users with a median age of 24 years (IQR 16-35). SRs were calculated for 1426 exposure-diagnosis and 1337 exposure-prescription pairs. The 50 highest SRs from each category were evaluated. Among these, 28 exposure-outcome combinations had a 95% CI lower bound above 1. Of the 100 outcomes, 33 were considered known ADRs, while 60 were previously unknown. Two outcomes indicating increased urinary symptoms were identified ('hematuria', SR: 1.88 [95% CI: 1.25; 2.85] and 'other urinary symptoms', SR: 1.63 [1.20; 2.23]). We also identified serious gastrointestinal outcomes as a potential safety alert. Further investigation into these symptoms as potential ADRs is warranted.

Cystitis is common during pregnancy and requires effective antibiotic treatment to prevent complications. Gastric bypass surgery alters gastrointestinal anatomy and may impair oral drug absorption, raising concerns about antibiotic effectiveness. We therefore aimed to examine antibiotic use for cystitis and the risk of treatment failure in pregnant women with prior gastric bypass. In this nationwide Danish register-based study, we compared 1985 pregnancies among women with prior gastric bypass with 1 400 174 pregnancies among women without bariatric surgery. We assessed redeemed prescriptions for cystitis-related antibiotics and potential treatment failure defined as repeated antibiotic prescriptions within 14 days, hospital-recorded cystitis or severe urinary tract complications (pyelonephritis or urosepsis). Pregnant women with prior gastric bypass more frequently redeemed cystitis-related antibiotics than those without bariatric surgery (22.6% vs. 12.7%). Among antibiotic-exposed pregnancies, prior gastric bypass was associated with an increased risk of potential treatment failure, including repeated antibiotic prescriptions (adjusted odds ratio [aOR] 1.69, 95% confidence interval [CI] 1.22-2.30) and hospital-recorded cystitis (aOR 2.22, 95% CI 1.24-3.67), while severe complications were rare. These findings suggest that antibiotic treatment may be less effective or that the clinical course is more complicated in this group, highlighting a need for closer monitoring and tailored treatment strategies.