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.

Renal tubulointerstitial fibrosis is a final common pathway of chronic kidney disease (CKD), but the metabolic mechanisms linking mitochondrial dysfunction to ferroptotic tubular injury remain incompletely defined. We found that a SIRT3-GLS1-glutamate-p53/SLC7A11 pathway links mitochondrial deacetylation to ferroptosis and renal fibrosis. SIRT3 expression was reduced in human CKD kidneys and UUO-induced fibrotic mouse kidneys and correlated positively with eGFR and negatively with albuminuria. Sirt3 deletion aggravated renal dysfunction, mitochondrial injury, lipid peroxidation and fibrotic remodeling, whereas AAV-mediated Sirt3 restoration was protective. In HK-2 cells, SIRT3 loss increased susceptibility to TGF-β1-induced ferroptosis. Transcriptomic and functional analyses identified GLS1-dependent glutamate accumulation as a major downstream consequence of SIRT3 loss. LC-MS/MS confirmed dynamic acetylation of GLS1 at K311, while mutagenesis, cycloheximide-chase and ubiquitination assays showed that K311 status regulated GLS1 ubiquitination and protein stability. Pharmacological GLS1 inhibition attenuated glutamate accumulation and ferroptotic injury. Glutamate activated p53 signaling, reduced SLC7A11/GPX4, and increased lipid peroxidation; p53 inhibition and ChIP-qPCR supported p53-dependent repression of SLC7A11. SLC7A11 restoration rescued SIRT3-deficiency-induced ferroptosis in vitro and in vivo. Finally, candesartan preferentially bound SIRT3 over comparator ARBs and suppressed ferroptosis in a SIRT3-dependent manner. SIRT3-dependent regulation of GLS1 therefore links glutamate stress to ferroptosis during renal fibrosis.

Evidence remains limited on whether telmisartan with partial peroxisome proliferator-activated receptor-gamma (PPAR-γ) activity lowers new-onset diabetes mellitus (NODM) risk compared with non-PPAR-γ-active angiotensin II receptor blocker (ARB). We therefore evaluated the NODM risk of telmisartan compared with losartan, valsartan, and candesartan using real-world clinical data. We conducted a multicenter, retrospective, treatment-control cohort study using clinical data from 17 institutions between 2005 and 2023, covering 19 283 922 patients converted to a common data model. Adults newly prescribed telmisartan or other ARBs (losartan, valsartan, or candesartan) and taking the medication for ≥6 months were included, while patients with pre-existing diabetes were excluded. Propensity score matching (PSM) was performed, and hazard ratios (HR) were estimated using a Cox proportional hazards model. The primary outcome was incident NODM, defined by a diagnosis of diabetes (ICD-10), initiation of glucose-lowering medications, or HbA1c ≥ 6.5%. A total of 6 868 patients of new-users of telmisartan and 22 500 patients of other ARBs were included. In the overall population, telmisartan was associated with lower NODM risk (HR 0.87, 95% CI 0.80-0.94). After 1:2 PSM, there was no significant difference in the risk of NODM between telmisartan and other ARBs (10.61% [39.50/1 000 person-years] vs. 11.02% [40.42/1 000 person-years]; HR 0.97, 95% CI 0.88-1.08). Secondary analyses were also not significantly different. Overall, this study did not detect sufficient evidence that telmisartan reduces NODM risk compared with losartan, valsartan, or candesartan.

Background/Objectives: The global rise in obesity-related hypertension, metabolic syndrome, and chronic inflammation calls for a precise characterization of the safety profiles of first-line therapies. While amlodipine is considered metabolically neutral, its real-world impact on dysglycemia and inflammatory biomarkers remains incompletely defined. This study aims to characterize the metabolic and inflammatory adverse drug reaction profile of amlodipine, using the EudraVigilance database. Methods: Descriptive and disproportionality analyses were performed on 41,872 Individual Case Safety Reports recorded prior to 17 May 2026. Amlodipine was compared against major antihypertensive classes (beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, sartans, and diuretics), calculating reporting odds ratios (ROR) and 95% confidence intervals. Results: "Hyperglycaemia" could be considered a safety signal for amlodipine, compared to beta-blockers (e.g., bisoprolol-ROR: 2.56), ACE inhibitors (e.g., ramipril-ROR: 2.82), and sartans (e.g., candesartan-ROR: 3.85). "Metabolic syndrome" was reported for amlodipine with a lower probability than for hydrochlorothiazide (ROR: 0.35). Inflammatory signals (e.g., increased C-reactive protein) appeared less frequently for amlodipine than for certain renin-angiotensin-aldosterone system inhibitors (e.g., perindopril-ROR: 0.53). Conclusions: The disproportionality analysis identified relatively lower reporting frequencies for several metabolic and inflammatory adverse drug reactions, compared with selected antihypertensive agents. These findings represent pharmacovigilance signals that warrant further investigation in analytical epidemiological and clinical studies. Although hyperglycemia was reported disproportionally relative to several comparator drugs, reports of T2DM were less frequently reported for amlodipine. However, these observations should not be interpreted as evidence of differences in clinical risk, because disproportionality analyses cannot establish incidence or causality. Reports of inflammation likely reflect patient comorbidities rather than a direct drug effect. These findings demonstrate that post-marketing surveillance remains essential, even when accounting for the methodological limitations of spontaneous reporting.

Codeine is a prodrug opioid whose analgesic efficacy depends on its bioactivation into morphine via cytochrome P450 2D6. Its use in migraine is discouraged because of limited efficacy, tolerance, and the risk of medication-overuse headache. Drug-drug interactions affecting its metabolism may further compromise pain control. We report the case of a 72-year-old man with chronic migraine and daily codeine use. A pharmacist-led medication review identified a potential pharmacokinetic interaction between codeine and extended-release nicardipine. Plasma concentrations of codeine and its metabolites were measured before and after codeine intake under nicardipine treatment and three months after substitution with candesartan. The fold increase in morphine-glucuronide concentration between baseline and peak rose from 1.6 with nicardipine to 3.5 after discontinuation, consistent with restored codeine bioactivation. This case highlights a clinically relevant interaction between nicardipine and codeine leading to reduced opioid efficacy. Beyond tolerance and medication-overuse headache, pharmacokinetic interactions should be systematically considered in patients with refractory pain.

Cardiovascular risk factors are often undertreated in patients with dementia. Renin-angiotensin system inhibitors (RASI) are first-line treatments for hypertension. We examined the association between RASI and all-cause mortality in hypertensive patients with and without dementia, comparing angiotensin-converting enzyme inhibitors (ACEI) to angiotensin receptor blockers (ARB); and selected individual agents. This nationwide register-based cohort study included data from Swedish national registries 2007-2018. The study included 158 176 hypertensive patients with exposure to RASI medications (21 152 RASI users and 137,024 non-users), after excluding prevalent users. Propensity score matching was used to balance measured confounders. Cox regressions compared mortality risk among RASI users versus non-users, ACEI users versus ARB users, and users of enalapril, ramipril, losartan, and candesartan versus other RASI users. RASI use was associated with lower all-cause mortality (hazard ratio[HR] 0.93, 95% confidence interval[CI] 0.91-0.95, p< 0.001) in the full cohort, and among patients with dementia (HR 0.88, 95% CI 0.85-0.92). Compared to ACEI, ARB were associated with lower mortality in the full cohort (HR 0.90, 95% CI 0.85-0.96), but results were not significant in patients with dementia. The comparison of the individual drugs were consistent with class-level findings. RASI use was associated with lower all-cause mortality among older hypertensive patients, including those with dementia. These observational findings support continued attention to evidence-based hypertension treatment in patients with dementia.

Hypertension (HTN) is a major global health burden and a leading risk factor for cardiovascular morbidity and mortality. Although numerous studies have explored host genetic factors and molecular mechanisms underlying HTN, increasing evidence indicates that gut microbiota dysbiosis also contributes to disease development. However, the specific microbial genes involved in HTN pathogenesis and their potential therapeutic targeting remain largely unexplored. This study aimed to identify HTN-associated differentially abundant bacterial genes (DAGs), prioritize bacterial key genes (bKGs) from among them, and repurpose potential therapeutic agents targeting these bKGs using an integrated bioinformatics framework. A total of 167 stool (fecal) microbiome samples, comprising 72 samples from HTN patients and 95 samples from HCs, were analyzed using publicly available 16 S rRNA sequencing data. After quality processing and clustering at 97% similarity, 95,361 representative operational taxonomic units were obtained. Microbial diversity analysis revealed significant alterations in community composition between HTN and HC groups. Differential abundance analysis identified 24 significantly altered bacterial genera associated with HTN. Functional prediction analysis further revealed 28 differentially abundant metabolic pathways and 631 differentially abundant bacterial genes (DAGs) potentially involved in HTN pathogenesis. From these DAGs, protein-protein interaction network analysis prioritized ten hub genes as bKGs (alsB, ampC, gsiB, araC, coaA, dnaB, fruA, ssuA, minE and tsx) representing potential microbial therapeutic targets. Structure-based molecular docking identified five approved drugs, namely Azilsartan, Eplerenone, Candesartan, Conivaptan, and Telmisartan, as top-ranked compounds exhibiting strong binding affinities toward the proposed targets. ADMET evaluation suggested favorable pharmacokinetic and safety profiles for Azilsartan, Eplerenone, and Candesartan. Furthermore, molecular dynamics simulation analyses confirmed that Eplerenone and Candesartan exhibited greater structural stability and sustained binding interactions, suggesting their potential as promising therapeutic candidates for HTN management. Therefore, this study identifies microbial gene signatures potentially involved in HTN and proposes a microbiome-guided drug repurposing strategy targeting bacterial functional pathways. These findings provide novel insights into microbiota-host interactions in HTN and highlight promising therapeutic candidates that warrant further experimental and clinical validation.