Search Results (178)

Cardiovascular disease (CVD) is the leading cause of death worldwide, with pathophysiological mechanisms often involving platelet activation and chronic inflammation. While antiplatelet agents targeting adenosine diphosphate (ADP)-mediated pathways are well established in CVD management, less is known about drug interactions with the platelet-activating factor (PAF) pathway, a key mediator of inflammation. This study aimed to evaluate the effects of several commonly used cardiovascular and anti-inflammatory drug classes—including clopidogrel, non-steroidal anti-inflammatory drugs (NSAIDs), angiotensin II receptor blockers (ARBs), β-blockers, and analgesics—on platelet function via both the ADP and PAF pathways. Using human platelet-rich plasma (hPRP) from healthy donors, we assessed platelet aggregation in response to these two agonists in the absence and presence of graded concentrations of each of these drugs or of their usually prescribed combinations. The study identified differential drug effects on platelet aggregation, with some agents showing pathway-specific activity. Clopidogrel and NSAIDs demonstrated expected antiplatelet effects, while some (not all) antihypertensives exhibited additional anti-inflammatory potential. These findings highlight the relevance of evaluating pharmacological activity beyond traditional targets, particularly in relation to PAF-mediated inflammation and thrombosis. This dual-pathway analysis may contribute to a broader understanding of drug mechanisms and inform the development of more comprehensive therapeutic strategies for the prevention and treatment of cardiovascular, hypertension, and inflammation-driven diseases. Full article

Diabetic nephropathy affects approximately 30–40% of individuals with diabetes mellitus (DM) and is a major contributor to end-stage renal disease (ESRD). While angiotensin II receptor blockers (ARBs) have long served as a standard treatment, sodium-glucose cotransporter-2 inhibitors (SGLT2i) have recently gained attention for their renal and cardiovascular benefits. However, comparative real-world data on their long-term renal effectiveness remain limited. We conducted a retrospective, longitudinal study over a 2-year period to compare the impact of ARB monotherapy versus SGLT2i and angiotensin-converting enzyme inhibitor (ACEi) combination therapy on the progression of chronic kidney disease (CKD) in patients with DM. A total of 126 patients were included and grouped based on treatment regimen. Renal biomarkers were analyzed using t-tests and ANOVA (p < 0.01). Albuminuria was qualitatively classified via urinalysis as negative, level 1 (+1), level 2 (+2), or level 3 (+3). The ARB group demonstrated higher estimated glomerular filtration rate (eGFR) and lower serum creatinine (sCr) levels than the combination therapy group, with glycated hemoglobin (HbA1c), potassium (K⁺), and blood pressure remaining within normal limits in both cohorts. Albuminuria remained stable over time, with 60.8% of ARB users and 73.1% of combination therapy users exhibiting persistently or on-average negative results. Despite the expected additive benefits of SGLT2i/ACEi therapy, ARB monotherapy was associated with slightly more favorable renal function markers and a lower incidence of severe albuminuria. These findings suggest a need for further controlled studies to clarify the comparative long-term renal effects of these treatment regimens. Full article

The renin–angiotensin–aldosterone system (RAAS) plays a central role in cardiovascular and renal homeostasis and is increasingly recognized for its broad immunomodulatory effects. Pharmacological RAAS inhibition, primarily via angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), has demonstrated therapeutic value beyond its use in hypertension and heart failure, extending to autoimmune, infectious, oncologic, and neurodegenerative conditions. ACEIs and ARBs modulate both innate and adaptive immune responses through Ang II-dependent and -independent mechanisms, influencing macrophage polarization, T-cell differentiation, cytokine expression, and antigen presentation. Notably, ACEIs exhibit Ang II-independent effects by enhancing antigen processing and regulating amyloid-β metabolism, offering potential neuroprotective benefits in Alzheimer’s disease. ARBs, particularly telmisartan and candesartan, provide additional anti-inflammatory effects via PPARγ activation. In cancer, RAAS inhibition affects tumor growth, angiogenesis, and immune surveillance, with ACEIs and ARBs showing distinct yet complementary impacts on tumor microenvironment modulation and chemotherapy cardioprotection. Moreover, ACEIs have shown promise in autoimmune myocarditis, colitis, and diabetic nephropathy by attenuating inflammatory cytokines. While clinical evidence supports the use of centrally acting ACEIs to treat early cognitive decline, further investigation is warranted to determine the long-term outcomes across disease contexts. These findings highlight the evolving role of RAAS inhibitors as immunomodulatory agents with promising implications across multiple systemic pathologies. Full article

Background/Objectives: Hypertension is a pathological condition characterized by elevated systolic and/or diastolic blood pressure. A range of pharmacotherapeutic agents are available to treat this condition and prevent complications, including the angiotensin II AT1-receptor blocker losartan. Following oral administration, losartan is exposed to a variety of enzymes that facilitate its metabolism or transportation. The structural characteristics of the genes that encode the enzymes may potentially impact the pharmacokinetics and pharmacodynamics of losartan, thereby modulating its effects on the treatment process. Methods: In this study, a computational model of losartan pharmacokinetics was developed, taking into account the influence of different alleles of the CYP2C9 gene, which plays a pivotal role in losartan metabolism, and the ABCB1 gene, which is responsible for losartan transport. Results: Alterations in the modeled activities of the enzymes encoded by CYP2C9 and ABCB1 result in changes in the losartan and its metabolite profiles that are consistent with known experimental data in real patients with different CYP2C9 and ABCB1 genotypes. Conclusions: The findings of the modeling can potentially be used to personalize drug therapy for arterial hypertension. Full article

Background: Olmesartan-induced enteropathy is a rare complication of a widely used angiotensin II receptor blocker. Patients usually present with chronic diarrhea and weight loss. Histologically, villous atrophy and intraepithelial lymphocyte infiltrates within the duodenum confirm the diagnosis. The prognosis is usually good after withdrawal of the offending drug. Case presentation: Here, we report the case of a 76-year-old woman who developed a severe form of Olmesartan-induced enteropathy complicated by acute kidney injury and acute recurrence after drug rechallenge. After definite cessation of the drug, the patient did not experience any gastrointestinal (GI) symptom recurrence after 6 months of follow-up. However, she experienced chronic kidney disease stage G3b. Histological analysis did not show any villous atrophy or intraepithelial lymphocyte infiltrates within the duodenum or the colon biopsy. Discussion and conclusion: This case highlights the broad spectrum of clinical manifestations and histological findings in Olmesartan-induced enteropathy. It also highlights the importance of rapid diagnosis in order to limit organ damage such as chronic kidney disease. Full article

Background/Objectives: The use of angiotensin II (AT2S) as a vasopressor in patients receiving angiotensin receptor blockers (ARBs) prior to kidney transplant (KT) raises theoretical concerns. At our center, AT2S is the first-line vasopressor during KT. This study evaluated the hemodynamic and clinical effects of pre-transplant ARBs on AT2S use in KT. Methods: This single-center, retrospective cohort trial included patients with hypertension ≥ 18 years old on antihypertensive therapy who received AT2S as the first-line vasopressor peri-transplant. Patients were divided into ARB and non-ARB cohorts. Primary outcomes included total AT2S duration, time with SBP < 120 mmHg, and need for additional vasopressor support. Results: A total of 65 patients were analyzed: 22 in the ARB group and 43 in the non-ARB group. There were no significant differences in the frequency or duration of SBP < 120 mmHg or additional vasopressor requirements between groups (p > 0.05). Hospital and ICU stay length, safety, and adverse drug events were also similar. Conclusions: Contrary to theoretical concerns and observations in other distributive shock populations, no significant hemodynamic or clinical differences were observed in the response to AT2S in patients with pre-transplant ARB use. Full article

Recent bioassay studies have unexpectedly supported the high (computationally predicted) binding affinities of angiotensin receptor blockers (ARBs) at α-adrenergic receptors (αARs) in isolated smooth muscle. Computational predictions from ligand docking studies are consistent with very low concentrations of ARBs (e.g., sartans or bisartans) that partially reduce (20–50%) the contractile response to phenylephrine, suggesting that some ARBs may function as partial inverse agonists at αARs. Virtual ligand screening (docking) and molecular dynamics (MD) simulations were carried out to explore the binding affinities and stabilities of selected non-peptide ligands (e.g., ARBs and small-molecule opioids) for several G-protein coupled receptor (GPCR) types, including angiotensin II (AngII) type 1 receptor (AT₁R), α1AR, α2AR, and μ-(µOR) and ժ-opioid receptors (ժOR). Results: All ligands docked preferentially to the binding pocket on the cell surface domain of the GPCR types investigated. Drug binding was characterized by weak interactions (hydrophobic, hydrogen bonding, pi-pi) and stronger ionic and salt-bridge interactions (cation-pi and cation-anion interactions). Ligands specific to each GPCR category showed considerable cross-binding with alternative GPCRs, with small-molecule medications appearing less selective than their peptide or ARB functional equivalents. ARBs that exhibit higher affinities for AT₁R also demonstrate higher affinities for µORs and ժORs than opiate ligands, such as fentanyl and naltrexone. Moreover, ARBs had a higher affinity for αARs than either alpha agonists (epinephrine and phenylephrine) or inhibitors (prazosin and doxazosin). MD simulations of membrane-embedded ARB-GPCR complexes proved stable over nanosecond time scales and suggested that some ARBs may behave as agonists or antagonists depending on the GPCR type. Based on the results presented in this and related investigations, we propose that agonists bind to the resting A-site of GPCRs, while inverse agonists occupy the desensitizing D-site, which partial agonists like morphine and fentanyl share, contributing to addiction. ARBs block both AngII and alpha receptors, suggesting that they are more potent antihypertensive drugs than ACE inhibitors. ARBs have the potential to inhibit morphine tolerance and appear to disrupt receptor desensitization processes, potentially by competing at the D-site. Our results suggest the possible therapeutic potential of ARBs in treating methamphetamine and opiate addictions. Full article

Background/Objectives: Horseshoe kidney is a congenital anomaly characterized by the fusion of the kidneys at the lower pole. Polycystic kidney disease with horseshoe kidney is called polycystic horseshoe kidney. Genetic testing is essential for the diagnosis of polycystic horseshoe kidney disease because it can result from a number of genetic disorders. Fewer than 20 cases of polycystic horseshoe kidney have been reported to date. However, polycystic horseshoe kidney disease was mostly diagnosed via autopsy or radiologic imaging techniques including computed tomography, magnetic resonance imaging, and angiography. Because polycystic kidney disease has various causes, genetic testing is essential for the diagnosis of autosomal dominant polycystic kidney disease (ADPKD) in patients with polycystic horseshoe kidney disease. At present, the diagnosis of ADPKD is made using genetic approaches, including next-generation sequencing. We reported a potentially pathogenic polycystin 1 (PKD1) gene in a patient with ADPKD and horseshoe kidney. Methods: We performed the sequencing of the PKD1 gene and radiological examinations (computed abdominal tomography). Results: Computed abdominal tomography revealed enlarged kidneys with multiple cysts fused at the lower poles, indicating polycystic HSK. The sequencing of the PKD1 gene revealed a heterozygous pathogenic variant c.165_171del (p.Leu56ArgfsTer15), which genetically confirmed the diagnosis of ADPKD. The patient was treated with an angiotensin II receptor blocker. Conclusions: In this case report, we suggest that genetic testing becomes the key approach to the diagnosis of ADPKD with horseshoe kidney. Additionally, this approach offers the benefit of avoiding the possibility of the condition being mistakenly diagnosed or diagnosed late due to its uncommon occurrence and nonspecific symptoms. Full article

For the interaction of angiotensin II (AngII) with AngII type 1 receptors (AT₁R), two potential proton hopping pathways have been identified, each associated with distinct physiological outcomes. The octapeptide AngII (Asp¹-Arg²-Val³-Tyr⁴-Ile⁵-His⁶-Pro⁷-Phe⁸) appears to form a charge relay system (CRS) in solution in which the C-terminal carboxylate abstracts a proton from the His⁶ imidazole group, which, in turn, abstracts a proton from the Tyr⁴ hydroxyl (OH) group, creating a tyrosinate anion. When AngII binds to the AT₁R, the CRS can be reconstituted with D281 of the receptor taking up the role of the Phe⁸ carboxylate in the tripartite interaction, whilst the Phe⁸ carboxylate forms a salt bridge with K199 of the receptor. As a consequence, the Tyr⁴ OH of AngII is positioned with accessibility to either the Phe⁸ carboxylate (bound to K199) or the His⁶ imidazole (activated by D281), thereby creating a potential gating mechanism for AT₁R receptor signaling. This study summarizes evidence based on structure activity data for various analogs wherein Tyr⁴ OH interaction with His⁶ imidazole (CRS formation) leads to G protein sequestration and vasoconstriction, whereas Tyr⁴ OH interaction with Phe⁸ carboxylate (bound to K199) engenders arrestin-mediated vasodilation and receptor desensitization. These findings, combined with quantum mechanical (semiempirical) calculations of CRS proton transfer presented herein, provide insights for the therapeutic targeting of angiotensin receptor blockers (sartans) and the development of second-generation drugs (bisartans). Full article

Angiotensin II receptor blockers (ARBs), a critical class of second-generation antihypertensive drugs, require azide intermediates for constructing their biphenyl tetrazole pharmacophore. This synthetic reaction introduces hypertoxicity risks, as residual azides can induce fatal damage even at trace concentrations. The pharmacopoeias of most countries have highlighted the urgency for improved detection paradigms of the control of azides in ARBs. Current ion chromatography (IC) methods face analytical challenges due to matrix interference from organic solvents and incompatibility with hydrophobic ARB ingredients. Herein, an in situ matrix elimination ion chromatography methodology was established for the sensitive detection of trace azides in angiotensin II receptor blocker pharmaceuticals. The switching strategy used in the proposed methodology eliminates organic interference and avoids the incompatibility issue with ARB ingredients. Under the optimal conditions, the proposed method exhibited satisfactory linearity in the range of 2.0–200.0 ng/mL, with a correlation coefficient of 0.9996. Validation studies demonstrated a detection limit (LOD, S/N = 3) of 0.57 ng/mL and a quantification limit (LOQ, S/N = 10) of 1.89 ng/mL, surpassing the sensitivity requirements in pharmacopeias. Method robustness was confirmed, with recovery rates from 92.8 to 108.7% using spiked ARBs real samples, and the intra-day and inter-day RSDs were less than 9.7%. The proposed approach establishes a reliable, precise, and sensitive alternative for monitoring azide impurities in ARBs, and such a framework can overcome limitations such as solubility issues, contributing to a universal applicability to diverse hydrophobic drugs. Full article

Background: Heart failure (HF) is a leading cause of hospital admissions and in-hospital mortality among the elderly. This study aims to characterize HF patients admitted to Virgen de la Victoria University Hospital (HUVV), identify factors associated with in-hospital mortality and analyze the impact of added morbidity on healthcare costs. Methods: A cross-sectional study was conducted using data from the Minimum Basic Data Set (MBDS) at HUVV. We included all discharges with a primary diagnosis of HF in 2021. Logistic regression analysis was employed to identify factors associated with mortality, and cost analysis was performed to assess the economic impact of added morbidity. Results: A total of 731 hospital discharges for HF were analyzed, with a mortality rate of 14.77%. Mortality was significantly associated with age ≥ 75 years (OR = 4.12; p < 0.001), high or extreme severity (OR = 2.26 and 8.10, respectively; p < 0.001), and more than 10 diagnoses at discharge (OR = 2.95; p < 0.01). Treatment with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) was associated with a reduced risk of death (OR = 0.29; p < 0.001). Hospital-acquired morbidity occurred in 27.22% of patients, resulting in an additional cost of EUR 152,780.61, representing a 3.8% increase over the total hospitalization costs. Conclusions: In-hospital mortality in HF patients at HUVV is strongly associated with advanced age, disease severity, and multiple comorbidities. Treatment with ACEIs or ARBs was associated with a lower likelihood of in-hospital mortality. Preventable added morbidity was associated with increased healthcare costs, highlighting the importance of infection control measures and multidisciplinary management to potentially improve outcomes and reduce costs. Full article

Secreted protein acidic rich in cysteine (SPARC), one of the extracellular matrix proteins, is highly induced during inflammation. We investigated the pathophysiological regulation and role of SPARC in vascular inflammation in a rat model of hypertension created using deoxycorticosterone acetate (DOCA, 40 mg/kg/week, s.c.) and salt (1% in drinking water). DOCA–salt administration time-dependently increased systolic blood pressure during the 3-week treatment period, blunted endothelium-dependent vasodilation, and increased monocyte chemoattractant protein-1 (MCP-1) and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) expression in the aorta. SPARC expression transiently increased until week 2 in the DOCA–salt rat aorta. Interestingly, aortic SPARC levels correlated with blood pressure and the levels of MCP-1 and LOX-1 during 0–2 weeks. The AT₁ receptor blocker, losartan, suppressed the overexpression of SPARC, and in vitro treatment with angiotensin II enhanced the production of SPARC in rat aortic endothelial cells. Exposure to recombinant SPARC protein induced overexpression of MCP-1 and LOX-1 mRNA in endothelial cells. Bioactive forms of a disintegrin and metalloproteinase with thrombospondin type 1 motif (ADAMTS1), excessive activation of which contributes to pathological states and overexpression of which is reported to be induced by SPARC, were increased in the DOCA–salt rat aorta. These results suggest that SPARC is induced by the vascular renin–angiotensin system and causes inflammation in the early stages of hypertensive vascular injury, and that activation of ADAMTS1 might be related to the proinflammatory effects of SPARC. Full article

Background/Objectives: Heart transplantation (HTX) is the definitive treatment for advanced heart failure (AdHF). The angiotensin receptor neprilysin inhibitor (ARNI) sacubitril/valsartan (S/V) has been shown to reduce heart failure (HF) hospitalizations and mortality when compared to conventionally administered HF medications (i.e. angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs)). Nevertheless, limited data are available on the hemodynamic (HD) effects of ARNI in patients with AdHF. Therefore, the aim of the present study was to compare echocardiographic, laboratory, and HD parameters relevant to HF before and after switching to ARNI in patients with AdHF awaiting HTX. Methods: A retrospective analysis was conducted utilizing available data on HD parameters, N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, data on kidney function, HF therapy, and comorbidities. The study cohort comprised 13 AdHF patients (3 women, 10 men; mean age 56.4 ± 9 years) of whom 53.8% presented with non-ischemic and 46.2% with ischemic etiology. All patients were awaiting heart transplantation (HTX) and were transitioned to ARNI therapy between 2018 and 2021. Results: After switching to ARNI, we observed significant improvements: in left ventricular ejection fraction (LVEF: 27.27 ± 1.04% vs. 23.65 ± 1.02%, p = 0.03; data are given as mean ± SEM after vs. before ARNI therapy, respectively), cardiac output (CO: 4.90 ± 0.35 L/min vs. 3.83 ± 0.24 L/min, p = 0.013), and stroke volume (SV: 70.9 ± 5.9 mL vs. 55.5 ± 4.12 mL, p = 0.013). Significant reductions in systemic vascular resistance (SVR: 1188 ± 79.8 vs. 1600 ± 100 DS/cm⁵, p = 0.004) and pulmonary vascular resistance (PVR: 232.5 ± 34.8 vs. 278.9 ± 31.7 DS/cm⁵, p = 0.04) were also noted. Central venous pressure (CVP), pulmonary arterial systolic and diastolic pressures (PAPs and PAPd), pulmonary capillary wedge pressure (PCWP), and NT-proBNP levels did not exhibit significant changes upon ARNI administration. Conclusions: Early transition to ARNI therapy offers significant benefits for invasively measured hemodynamic parameters in patients with AdHF, potentially aiding in the stabilization and improvement of this vulnerable patient population. Full article

Despite extensive research, the exact cause of oral lichenoid lesions remains unknown. The chronic inflammatory tissue reaction mediated by T cells is the basis of the etiological process. However, oral lichenoid lesions often occur in the presence of certain drugs. Our aim was to conduct a preliminary retrospective study to assess the correlation between the administration of statins or HMG-inhibitor CoA reductase, which are commonly used for treating hypercholesterolemia, and the sartans or blockers of the angiotensin II receptor, which are used for treating hypertension, in relation to the occurrence of oral lichenoid lesions. This preliminary retrospective study included 2158 patients who attended the Oral Medicine and Maxillofacial Surgery (Mo-Max) Department of Oral Science and Maxillofacial Surgery, Sapienza University of Rome, from 2019 to 2022. A significant association was found between the presence of oral lichenoid lesions and the simultaneous administration of sartans and statins (χ² = 46.49; p < 0.001). Of the 2158 patients, 118 (5.5%) were diagnosed with oral lichenoid lesions. In the analysis of standardized residues, we found that pathology developed in 16.3% of patients taking statins and 15.9% of those taking sartans. Oral lichenoid lesions only developed in 4.4% of those not taking these drugs. Full article

Background: Chronic Kidney Disease (CKD) affects 8–16% of the population worldwide and is characterized by an estimated Glomerular Filtration Rate (eGFR) of less than 60 mL/min/1.73 m² for more than 3 months. The main purpose of the study is to record the treatment algorithms and disease management of patients presenting for the first time to hospital-based nephrologists with a reduced eGFR and CKD diagnosis, under real-world clinical practice in Greece. Methods: This is the 6-month interim analysis of an ongoing, multicenter, observational, prospective, national study, which included 178 patients, with an eGFR between <60 and 15 mL/min/1.73 m², presenting for the first time to nephrologists at 15 public hospital units. Results: The median age of the patients was 71 years old, with 39.6% of them categorized as CKD stage G3b. Of these patients, 71.6% and 33.7% suffered from arterial hypertension and type 2 diabetes mellitus, respectively; 78.7% of patients received antihypertensive and 38.5% antidiabetic medications. Calcium channel blocker usage increased with disease progression (from 52.2% at G3a, to 67.9% and 67.6% at G3b and G4, respectively), while that of angiotensin II receptor antagonists decreased (from 78.3% at G3a, to 41.5% and 17.6% at G3b and G4, respectively). A decrease in metformin usage and an increase in Dipeptidyl peptidase-4 inhibitor (DPP4i) usage was also observed upon disease progression. Furthermore, 18.5%, 32.0% and 7.7% of patients received Sodium-glucose cotransporter-2 inhibitors (SGLT2i) at the G3a, G3b and G4 stages, respectively. Conclusions: The interim analysis results contributed to the collection of real-world data for the therapeutic patterns and the management of CKD in Greece. Full article