Coronavirus disease (COVID-19) remains a global health concern due to its high mortality and morbidity. In this study, we combined ligand-based pharmacophore modeling (LBPM) with structure-based virtual screening (SBVS) to identify novel inhibitors targeting the SARS-CoV-2 spike protein. Ligands from the MolPort database were screened via docking and molecular dynamics simulations at the receptor-binding domain (RBD). Four compounds showed promising docking scores (-8.7 to -6.4 kcal/mol) and dynamic stability (root mean square deviation < 5 Å). In vitro assays confirmed that compounds C3 (IC50 = 0.03 µM) and C4 (IC50 = 10.4 µM) effectively inhibited spike-ACE2 binding with low cytotoxicity (CC50 > 100 µM). These findings show the efficacy of the LBPM technique and highlight 1H-pyrazol-5-ol derivatives as potential building blocks for developing new antiviral agents against SARS-CoV-2.

Elderly people with chronic diseases are at risk for having severe COVID-19 disease. We were interested whether the drugs prescribed for the chronic diseases are associated with lower mortality in COVID-19 patients.We used Finnish national registry data for analysis of potential associations of 73 prescription drugs to mortality among 6082 adult COVID-19 patients between 1.1.2020 and 30.6.2020, before COVID-19 vaccinations were available. Adjusted odds ratios (aORs) with 95 percent confidence intervals (95% CIs) for different medications are presented.The use of three cardiovascular drugs was associated with lower 30 days all-cause mortality rate: candesartan (aOR 0.34, 95% CI 0.16-0.72, p=0.005), metoprolol (aOR 0.37, 95% CI 0.16-0.88, p=0.024) and rosuvastatin (aOR 0.44, 95% CI 0.21-0.94, p=0.034).In conclusion, COVID-19 patients who used cardiovascular drugs candesartan, metoprolol or rosuvastatin have lower 30 days all-cause mortality than other COVID-19 patients.

IgA nephropathy (IgAN) is the most common primary glomerulonephritis globally, exhibiting marked diversity in clinical presentation, risk of progression, and response to therapy. Despite advances in understanding its pathophysiology, including the pivotal role of galactose-deficient IgA1 (Gd-IgA1), anti-Gd-IgA1 autoantibodies, and dysregulated mucosal and systemic immune responses, therapeutic options remain limited. This review provides a comprehensive overview of the current therapeutic landscape in IgAN, which is stratified into conservative care with renin-angiotensin-aldosterone system (RAAS) inhibitors, sodium-glucose cotransporter-2 (SGLT2) inhibitors, and corticosteroids, and newer advances like the endothelin receptor antagonists, immunosuppressive agents, and targeted therapeutics. Through synthesizing evidence from recent clinical trials and ongoing studies, we aim to provide clinicians and researchers with a current and forward-looking perspective on therapeutic strategies in IgAN, emphasizing the shift from conservative therapy to targeted, individualized interventions.

Hypertension is one of the most important comorbidities of diabetes, significantly contributing to increased mortality and leading to macrovascular and microvascular complications. When assessing the medical priorities for patients with diabetes, treating hypertension should be a primary consideration. In the present review practical approaches to hypertension in diabetes, including individualized targets for preventing specific complications are discussed according to the current evidence and guidelines. Blood pressure values of 120-129/70-79 mm Hg are associated with the best outcome; most importantly, at least blood pressure values < 140/90 mm Hg should be achieved in most patients. Most patients with diabetes require combination therapy to achieve blood pressure goals; agents with clear evidence of cardiovascular risk reduction should be used (including, besides angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, dihydropyridine calcium channel antagonists and thiazide diuretics), preferable in single pill combinations. Once the target is achieved, antihypertensive drugs should be continued. The use of SGLT‑2 inhibitors and GLP‑1 receptor agonists contribute to blood pressure lowering in diabetes. This also holds true für the newly available combined GLP-1/GIP receptor agonist tirzepatide. Since the last release of these guidelines evidence from clinical trials has become available that supports more stringent blood pressure control in diabetes, which is reflected in international guidelines and has also been adopted in these recommendations. The individualization of blood pressure management, however, remains a core recommendation of the Austrian Diabetes Association.

The renin-angiotensin-aldosterone system regulates blood pressure and is influenced by antihypertensive therapy. We examined plasma aldosterone concentration (PAC), plasma renin activity (PRA), and clinical characteristics in untreated hypertensive patients without primary aldosteronism, followed for 3 years. Among 456 newly diagnosed patients, 397 (219 males, 178 females) were analyzed after excluding those with low blood pressure, suspected primary aldosteronism, or renovascular hypertension. PAC and PRA were measured at baseline, and clinic blood pressure was monitored at 3 months, 1 year, and 3 years. A high PAC/PRA ratio (>200) was found in 19.6% of patients and was significantly associated with female sex (p < 0.0001) and higher serum sodium (p = 0.0004). PAC did not differ between groups, but PRA was markedly lower in the high PAC/PRA group (p < 0.0001). Multivariate analysis identified female sex as the only independent predictor (p < 0.0001), with prevalence rates of 29.8% in females and 11.4% in males. In females, PAC/PRA correlated positively with sodium, while PRA correlated negatively, relationships not observed in males. Mineralocorticoid receptor antagonists (MRAs) were used as first-line therapy in patients with high PAC/PRA. Their blood pressure declined from 159/95 mmHg at baseline to 137/80, 135/78, and 133/77 mmHg at 3 months, 1 year, and 3 years, respectively. In the normal group, values were 159/96, 142/81, 138/77, and 136/77 mmHg, with greater systolic reduction at 3 months in the high PAC/PRA group (p = 0.03). We identified gender differences in the renin-aldosterone-sodium system. MRAs effectively reduced blood pressure in patients with relatively low PRA levels.

BackgroundThe comparative effectiveness of angiotensin-converting enzyme inhibitors (ACEis) versus angiotensin receptor blockers (ARBs) in heart failure with nonreduced ejection fraction (HFnon-rEF) remains uncertain. We evaluated long-term outcomes of these therapies in a real-world cohort following hospitalization for acute heart failure.MethodsThis retrospective multicenter study (2005-2019) included 5837 patients with HFnon-rEF (left ventricular ejection fraction ≥ 40%). Patients were categorized by discharge prescription into ACEi, ARB, or non-renin-angiotensin system inhibitor (RASi) groups. A 14-day landmark approach ensured pharmacological stabilization and reduced time-related bias. Inverse probability of treatment weighting was used to balance covariates (SMD < 0.1). The primary outcome was a composite of cardiovascular (CV) death or heart failure rehospitalization at 1 year.ResultsThe primary composite outcome was similar between ARB and ACEi users (adjusted hazard ratio [HR], 0.94; 95% confidence interval [CI], 0.75-1.17; P = .556). However, ARB therapy was associated with lower all-cause mortality compared with ACEi (adjusted HR, 0.74; 95% CI, 0.55-0.99; P = .041) and non-RASi (adjusted HR, 0.80; 95% CI, 0.67-0.94; P = .008). Subgroup analyses showed generally consistent directional associations between ARB use and lower mortality, although these findings were exploratory.ConclusionsIn this real-world cohort of patients with HFnon-rEF, ARB use was associated with lower all-cause mortality compared with ACEi, despite similar CV outcomes. These findings do not establish superiority and should be interpreted as hypothesis-generating.

Mild obstructive sleep apnea (OSA) is often underdiagnosed but contributes to treatment-resistant hypertension through oxygen deprivation and activation of the renin-angiotensin-aldosterone system. Spironolactone, an aldosterone antagonist, may help manage both hypertension and OSA-related symptoms. This study aims to evaluate the effectiveness and safety of spironolactone in patients with mild OSA and resistant hypertension. This retrospective observational cohort study included 96 patients diagnosed with mild OSA and resistant hypertension between December 2022 and October 2023. Patients were grouped according to whether they received spironolactone (20 mg/day) in addition to conventional antihypertensive treatment. Outcomes included blood pressure (office, ambulatory, and daytime), apnea-hypopnea index (AHI), lowest oxygen saturation (SaO2), and biochemical parameters (blood urea nitrogen [BUN], potassium, sodium, and creatinine). Missing data were handled using multiple imputation. After 12 weeks, the spironolactone group showed greater reductions in blood pressure compared with the control group: office systolic blood pressure (OSBP) decreased by 5.75 mm Hg (95% CI: -8.84 to -2.66) and office diastolic blood pressure (ODBP) decreased by 3.67 mm Hg (95% CI: -6.46 to -0.88). The AHI improved by 1.85 events/hour (95% CI: -3.23 to -0.47), and SaO2 increased by 3.33% (95% CI: 0.93-5.73). No cases of hyperkalemia or clinically significant kidney dysfunction were observed, and the treatment was well tolerated. Spironolactone was associated with improved blood pressure control and modest improvements in sleep-related parameters in patients with mild OSA and resistant hypertension, with a favorable short-term safety profile. The small sample size and relatively young cohort limit the generalizability of the findings.

This observational matched cohort study evaluated the combined use of angiotensin receptor blockers (ARBs) and calcium channel blockers (CCBs) in high-risk hypertensive patients to optimize treatment strategies. A total of 330 high-risk hypertensive patients treated between 2018 and 2024 were identified from the cardiovascular department database. Propensity score matching was applied to balance baseline characteristics, yielding three matched groups (n = 110 each): ARB monotherapy (valsartan 80 mg once daily), CCB monotherapy (amlodipine 5 mg once daily), and combination therapy (valsartan/amlodipine 80/5 mg once daily). Data were collected through medical record review, ambulatory blood pressure monitoring, vascular and cardiac ultrasound, electrocardiography, pulse wave velocity measurement, and SF-36 questionnaires. Primary outcomes were cardiovascular and cerebrovascular events and blood pressure control; secondary outcomes included vascular function, cardiac performance, arterial elasticity, and quality of life. All procedures followed standardized protocols, and adverse events were systematically recorded. The findings suggest that the combination therapy was associated with advantages in blood pressure control and vascular outcomes, though further prospective studies are warranted to confirm these observations.

Diabetic kidney disease (DKD) affects 40% of individuals with diabetes and is the leading cause of chronic kidney disease worldwide. While the KDIGO guidelines have established quadruple therapy comprising renin-angiotensin system inhibitors, SGLT2 inhibitors, GLP-1 receptor agonists, and mineralocorticoid receptor antagonists as the cornerstone of DKD management, substantial phenotypic and molecular heterogeneity among patients limits the efficacy of standardized protocols. Emerging evidence highlights distinct DKD subtypes defined by inflammatory, metabolic, fibrotic, and vascular pathobiological pathways, which may warrant tailored therapeutic strategies. Novel biomarkers, including tubular injury markers, inflammatory mediators, and genetic variants such as APOL1, offer opportunities for phenotype-driven treatment. Multi-omic integration, encompassing genomics, transcriptomics, proteomics, and metabolomics, combined with machine learning algorithms, enables the identification of treatment-responsive phenotypes and supports clinical decision-making. Emerging therapeutic targets, including complement system inhibitors, ketone metabolism modulators, and JAK-STAT pathway inhibitors, have further expanded the precision medicine landscape in DKD management. Implementation challenges include biomarker standardization, healthcare infrastructure requirements, cost-effectiveness, regulatory validation, and equitable access to diverse populations. Addressing these barriers through multidisciplinary collaboration, point-of-care diagnostics, and inclusive clinical trials is essential for personalized DKD management. Goal-directed personalized DKD management represents a transformative paradigm with the potential to optimize outcomes, minimize adverse effects, and reduce long-term healthcare costs.

The expanding therapeutic armamentarium for IgA nephropathy (IgAN) has brought to the forefront a key strategic dilemma: whether to intervene simultaneously on IgAN-specific pathogenic mechanisms and the downstream, non-specific consequences of nephron loss, or to follow a sequential, stepwise approach in which therapies are added only as residual risk becomes evident. This debate article contrasts these philosophies. Proponents of early, combined treatment, in line with KDIGO 2025 guidance, argue that the traditional paradigm of first maximizing 'supportive' care-renin-angiotensin system blockade, strict blood pressure and sodium control, and more recently SGLT2 inhibitors and mineralocorticoid receptor antagonists-before initiating immunosuppressive or other disease-directed agents embeds harmful delay. They emphasize that IgAN is driven by continuous immune activity, with ongoing production of pathogenic IgA, immune complex formation, complement activation, and glomerular injury that proceeds even when proteinuria is hemodynamically reduced. Once a critical threshold of nephron loss is crossed, self-perpetuating hyperfiltration, fibrosis, and microvascular rarefaction limit reversibility. Advocates of a more sequential strategy highlight heterogeneity in disease course, the risks and costs of polypharmacy, and the need for individualized escalation based on dynamic risk assessment. Together, the opposing yet complementary viewpoints underscore that future algorithms will likely integrate baseline risk stratification, evolving biomarkers of immune activity and chronic damage, and patient preferences to balance early, comprehensive disease control against overtreatment and toxicity in IgAN.

Doxorubicin-induced cardiotoxicity remains a leading cause of mortality among cancer patients, with oxidative stress serving as a central pathogenic mechanism. This study investigated whether combination therapy with sacubitril valsartan and bisoprolol attenuates doxorubicin-induced cardiotoxicity through modulation of oxidative stress pathways. Sixty male Sprague-Dawley rats were randomized into five groups: control, doxorubicin (DOX), bisoprolol (1.0 mg/kg/d), sacubitril valsartan (30 mg/kg/d), and combination therapy. All groups except control received intraperitoneal DOX (2.5 mg/kg weekly for 5 weeks). Cardiac function was assessed by echocardiography, myocardial injury by histopathology and enzyme levels (CK-MB, cTnI, BNP), and oxidative stress by ROS fluorescence, MDA, and SOD. Protein expression of Nrf2, HO-1, and Keap1 was analyzed by Western blot. DOX administration significantly impaired cardiac function, induced myocardial structural damage, elevated cardiac enzymes and oxidative stress markers, and downregulated Nrf2 pathway proteins compared to controls (all P < 0.05). All treatment groups significantly attenuated these abnormalities versus DOX (all P < 0.05), with combination therapy demonstrating superior cardioprotection evidenced by greatest improvement in LVEF (68.74 ± 6.87% vs. 50.26 ± 6.11%, P < 0.05), lowest cardiac enzyme levels, and most robust restoration of Nrf2 pathway expression. These findings demonstrate that sacubitril valsartan combined with bisoprolol effectively reduces doxorubicin-induced cardiotoxicity in rats by activating Nrf2-mediated antioxidant responses, providing experimental evidence for a potentially synergistic prophylactic strategy.

Low-dose single-pill combinations (SPCs) are gaining recognition as an efficient therapeutic strategy for mild hypertension. However, evidence from randomized controlled trials regarding the efficacy and safety of half-dose telmisartan/amlodipine SPCs remains limited. In this randomized, double-blind, active-controlled phase III trial, patients with essential hypertension [mean sitting systolic blood pressure (MSSBP) ≥ 140 and < 180 mmHg] were allocated to four treatment arms to receive either telmisartan/amlodipine 20/2.5 mg SPC (TEL/AML 20/2.5), or monotherapy with telmisartan 20 mg (TEL 20), amlodipine 2.5 mg (AML 2.5), or telmisartan 40 mg (TEL 40) once daily for 8 weeks. The primary endpoint was the change in MSSBP from baseline to week 8. A gatekeeping approach was used to test the superiority of TEL/AML 20/2.5 over TEL 20 and AML 2.5, followed by non-inferiority versus TEL 40. At week 8, TEL/AML 20/2.5 showed significantly greater MSSBP reductions compared with TEL 20 [least squares mean (LSM) differences: -5.79 mmHg; p = 0.0003] and AML 2.5 (-8.57 mmHg; p < 0.0001). Non-inferiority to TEL 40 was established, with an LSM difference of -3.88 mmHg (95% Confidence Interval: -6.67 to -1.09), which met the pre-specified 3 mmHg margin. The overall incidence of adverse events was 8.05%, with no statistically significant differences between groups. Overall, TEL/AML 20/2.5 SPC provided superior BP-lowering efficacy compared with TEL 20 and AML 2.5 monotherapies and was non-inferior to TEL 40. With a comparable safety profile across treatment groups, these findings suggest that TEL/AML 20/2.5 is a practical and effective option for hypertension management. Trial Registration: ClinicalTrials.gov, NCT06052748.