olmesartan + amlodipine (Sevikar / Normetec / Konverge)

Design-Assisted Chemometric UV Spectrophotometric Determination of Candesartan Cilexetil, Chlorthalidone and Amlodipine Using Principal Component Regression, Partial Least Squares and Genetic Algorithm-Partial Least Squares Models.

Amin Khanda F M KFM, Elagamy Samar H SH, Obaydo Reem H RH, Lotfy Hayam M HM

This study presents a sustainable chemometric-assisted UV spectrophotometric strategy for the simultaneous determination of candesartan cilexetil (CAN), chlorthalidone (CTL) and amlodipine (AML) in laboratory-prepared mixtures and commercial pharmaceutical formulations. Owing to the extensive spectral overlap of the three drugs in the UV region, conventional spectrophotometric methods are inadequate for their direct simultaneous analysis. To address this challenge, multivariate calibration models based on principal component regression (PCR), partial least squares (PLS) and genetic algorithm-optimized partial least squares (GA-PLS) were developed, enabling accurate quantification without prior separation or complex sample preparation. A design of experiments (DoE) approach was employed to construct the calibration set, while an independent validation set was generated using orthogonal array-based Latin hypercube sampling (OALHS) to ensure robust external validation across the concentration domain. The GA-PLS model enhanced predictive performance through effective wavelength selection, reducing spectral redundancy and improving model robustness. Furthermore, variable importance in projection (VIP) analysis was employed to identify the most influential spectral variables and provide insight into the spectral regions contributing to analyte quantification. The developed models exhibited excellent analytical performance, characterized by low calibration errors (root mean square error of calibration [RMSEC] < 0.30), strong predictive ability and satisfactory external validation results (RMSEP = 0.2278-0.4419; RRMSEP = 0.1558-0.3978), with recoveries ranging from 99.0% to 100.0%. The sustainability of the proposed methodology was assessed using the multi-colour assessment (MA) tool according to white analytical chemistry principles, yielding a high whiteness score and demonstrating superior environmental performance compared with conventional chromatographic methods. In addition, the graphical layout tool for analytical chemistry evaluation (GLANCE) visualization framework provided a comprehensive graphical assessment of analytical performance and sustainability metrics. The proposed chemometric strategy offers a rapid, reliable, cost-effective and environmentally friendly alternative for routine quality control of multicomponent pharmaceutical formulations.

Clinical Presentation and Treatment Response in Women With Acetylcholine-Confirmed Coronary Spasm: A Single-Center Observational Study.

Sikulu Josephine J, Kubini Ralf R, Turkman Muath M, Immohr Moritz Benjamin MB et al.

Coronary vasomotor disorders are frequently underdiagnosed in women with angina and non-obstructive coronary arteries. We investigated clinical presentation, diagnostic delay, spasm subtype, and patient-reported treatment response in women with acetylcholine-confirmed coronary spasm. This single-center observational study included women with a positive intracoronary acetylcholine provocation test who completed a locally developed questionnaire on symptoms, triggers, comorbidities, medication tolerance, and treatment response. Epicardial spasm was defined as ≥ 90% epicardial diameter reduction with symptom reproduction and ischemic ECG changes; microvascular spasm as symptoms and ischemic ECG changes with < 90% epicardial vasoconstriction. Diltiazem was initiated as first-line therapy, with amlodipine as an alternative. Regression analyses exploring therapeutic failure were considered exploratory because of the low event count. A total of 194 women were included (median age 60 years [IQR 52-67]). Chest pain/tightness was reported by 163/190 (85.8%), dyspnea by 70/135 (51.9%), and palpitations by 74/136 (54.1%). Epicardial/microvascular spasm was present in 110/187 (58.8%) and 77/187 (41.2%). Median symptom-to-diagnosis time was 24 months [IQR 8-90]. Diltiazem was prescribed in 162/194 (83.5%). Among respondents with follow-up data, symptom frequency decreased in 103/128 (80.5%), episode duration decreased in 91/118 (77.1%), and pain intensity decreased/resolved in 92/115 (80.0%). Therapeutic failure occurred in 8/106 (7.5%). Residual symptom burden remained common, with CCS class > II at follow-up in 65/124 (52.4%) and persistent complaints in 53/107 (49.5%). In women with acetylcholine-confirmed coronary spasm, symptom burden and diagnostic delay were substantial. Calcium-channel blocker therapy was associated with patient-reported symptom improvement among respondents with available follow-up data.

Nebivolol treatment improves hypertension-induced endothelial cell dysfunction by reducing TGF-β1-dependent senescence and normalizing mitochondrial indices.

Uruski Paweł P, Mikuła-Pietrasik Justyna J, Tykarski Andrzej A, Książek Krzysztof K

Serum from patients with hypertension (HT) causes endothelial cell (EC) damage, leading to senescence and dysfunctional phenotype. This study investigated whether serum from patients treated with the antihypertensive drugs could normalize EC activity. This study involved 71 patients with newly diagnosed HT, who were randomly assigned to one of three groups based on the antihypertensive treatment: amlodipine, nebivolol, or perindopril. Serum samples collected before and 6 weeks after treatment were applied to ECs in vitro to assess their angiogenic activity, cellular senescence, mitochondrial metabolism, and oxidative stress. Results showed that exposure of ECs to serum from patients treated for 6 weeks significantly altered EC function, with varying effects among the drugs. Serum from nebivolol-treated patients produced the most consistent benefits, reducing EC proliferation and HIF-1α expression, likely due to lower levels of angiogenic factors such as angiopoietin-1, basic fibroblast growth factor (bFGF), insulin-like growth factor 1 (IGF-1), and vascular endothelial growth factor (VEGF). Additionally, this serum contained reduced levels of pro-inflammatory cytokines (E-selectin, P-selectin, monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor α (TNFα)) and lower TGF-β1, which are linked to HT-related EC senescence. Nebivolol treatment decreased senescence biomarkers such as SA-β-Gal, 53BP1, and p16, with SA-β-Gal reduction comparable to that of TGF-β1 neutralizing antibodies. Oxidative stress was reduced, indicated by lower oxidized DNA product levels. Nebivolol was the most effective at reducing the factors, associated with HT induced cellular senescence of endothelium, through reducing TGF-β1.

Publisher Correction: Randomized-controlled trial of sacubitril/valsartan and amlodipine combination in Japanese uncontrolled hypertensive patients (J-SAMIT).

Kario Kazuomi K, Rakugi Hiromi H, Ito Chiyo C, Sayyed Sarfaraz S et al.