Endothelin Receptor Research Articles

Abstract 34: Elevation of Plasma anti-Endothelin A Receptor Autoantibodies in Lupus Subjects Correlates with Plasma Vascular Adhesion Molecule-1 Independent of Blood Pressure

Systemic Lupus Erythematosus (SLE) is an autoimmune disease that is characterized by deposition of autoantibodies and their immune complexes, resulting in inflammation, and end-organ damage to the kidney and vasculature. SLE disproportionally affects women to men (9:1 ratio), with a high prevalence in African American women and patients often have cardiovascular complications including hypertension (HTN). The activation of the endothelin (ET) system has been implicated in numerous pathological disease states including HTN, SLE, and diabetes. Recently, dual ET receptor antagonism was approved for treatment of patients with uncontrolled hypertension. Studies have demonstrated the presence of biologically active endothelin A receptor autoantibodies (ETAR-AAs) in systemic sclerosis and cystic fibrosis patients. Few studies have investigated the role of the synergistic interplay of SLE and HTN on ETAR-AAs. We hypothesized that women with SLE and HTN would have elevated plasma ETAR-AAs compared to control or SLE only subjects. To investigate this, we recruited non-SLE non-HTN controls (n=10), non-SLE HTN (n=10), SLE non-HTN (n=8), and SLE-HTN (n=10) female human subjects and analyzed clinical characteristics, plasma ETAR-AAs, soluble vascular adhesion molecule-1 (sVCAM-1) and soluble intracellular adhesion molecule-1 (sICAM-1). Plasma ETAR-AAs did not significantly correlate with either age (r=-0.1375; p=0.4453) or body mass index (r=-0.3149; p=0.0743). When subjects were categorized by SLE or HTN diagnosis, we found that subjects with SLE had a profound increase in ETAR-AAs compared to non-SLE controls (p<0.0001) while the levels were similar between HTN and non-HTN controls (p=0.7626). Next, we stratified subjects by blood pressure status and found a significant elevation in plasma ETAR-AAs in SLE non-HTN over non-SLE HTN subjects (p=0.0121), while SLE-HTN subjects had significant elevations in ETAR-AAs compared to both non-SLE non-HTN (p=0.0183) and non-SLE HTN (p=0.0014) subjects. We correlated plasma levels of ETAR-AA with sVCAM-1 and sICAM-1 and found that plasma ETAR-AAs were positively associated with plasma sVCAM-1 (r=0.4288; p=0.0114) and sICAM-1 (r=0.3812; p=0.0286). These data indicate that irrespective of blood pressure status, elevated plasma ETAR-AAs are associated with markers of vascular dysfunction in SLE subjects. Further investigation of cell-specific ETAR-AA and ETAR signaling should be performed in murine models and human subjects with SLE.

Abstract 19: Effect of the endothelin receptor antagonist aprocitentan on plasma endothelin, renin and aldosterone concentrations in patients with resistant hypertension. A biomarker analysis of the PRECISION study.

Hypothesis: Dual endothelin (ET) ET A /ET B receptor antagonist aprocitentan significantly reduced blood pressure in patients with resistant hypertension, who were still hypertensive despite standard background anti-hypertensive drugs including a diuretic, an ARB and a CCB (PRECISION trial, NCT03541174). The effect of aprocitentan in this population, characterized with low renin and elevated aldosterone levels, was assessed on a panel of plasma biomarkers: ET-1, CT-proET-1 (a stable peptide and biomarker for ET-1 production), renin, aldosterone. Methods: From the 730 randomized patients in PRECISION, ET-1 (n=700), CT-proET-1 (n=100, randomly selected), immunoreactive renin (n=679) and aldosterone (n=703) were measured in plasma samples collected at randomization (baseline) and after 4 weeks for either placebo, aprocitentan 12.5 or 25 mg. Results: Four-week placebo treatment had no effect on the studied biomarkers compared to baseline. Treatment with aprocitentan 12.5 and 25 mg increased plasma ET-1 by +34% and +53% and CT-proET-1 by +38% and +47% vs. baseline respectively. Aprocitentan had no effect on renin levels (p>0.05) while decreasing plasma aldosterone by -17% and -24% at the 12.5 and 25 mg dose respectively. Importantly, the reduction in aldosterone did not result in a change in kalemia (see Table ). Conclusions: Aprocitentan caused reactive dose-dependent increases in plasma CT-proET-1 and ET-1, resulting from effective ET receptor blockade. The increase in CT-proET-1 may indicate a compensatory increase in ET-1 de novo synthesis, while the increase in ET-1 may reflect a reduced clearance due to blockade of ET B and increased production. The decrease of aldosterone by aprocitentan confirms the secretagogue role of ET-1 on aldosterone production by adrenal cortical cells via both ET A and ET B receptors This decrease of aldosterone was observed on top of the known decrease induced by an ARB but did not induce hyperkalemia nor aggravation of renal function.

Pulmonary vasodilators in patients with advanced chronic kidney disease and pre‐capillary pulmonary hypertension—A case series

AbstractPulmonary hypertension (PH) is a prevalent complication among patients with chronic kidney disease (CKD). In these patients, pulmonary vasodilators may be useful but are underused. We describe a group of patients with precapillary PH and advanced CKD treated with pulmonary vasodilators. This was a case series of patients with CKD stage 4 and 5 and precapillary PH (isolated or combined) based on right heart catheterization (RHC) treated with pulmonary vasodilators from 2018 to 2023. Of 263 patients with isolated precapillary or combined PH and advanced CKD, only 17 (6%) were treated with pulmonary vasodilators; 53% (n = 9) with precapillary PH and 47% (n = 8) with combined PH. Most patients (94%, n = 16) received phosphodiesterase‐5 antagonists, while 12% (n = 2) received endothelin receptor antagonists. Adverse clinical outcomes were seen in 35% of patients within a year. The use of pulmonary vasodilator did not prevent adverse outcomes in patients with precapillary PH and advanced CKD.

Current Pharmaceutical Strategies in the Management of Persistent Pulmonary Hypertension of the Newborn (PPHN): A Comprehensive Review of Therapeutic Agents.

Persistent Pulmonary Hypertension of the Newborn (PPHN) is a life-threatening condition characterized by the failure of normal circulatory transition after birth, leading to sustained pulmonary hypertension and severe hypoxemia. Despite advancements in neonatal care, PPHN remains a significant cause of morbidity and mortality among newborns, particularly in full-term and near-term infants. This review provides a comprehensive overview of current pharmaceutical strategies for managing PPHN, focusing on various therapeutic agents' mechanisms, efficacy, and safety. Key interventions include inhaled nitric oxide, which has become the standard treatment for reducing pulmonary vascular resistance, alongside prostacyclin analogs, phosphodiesterase inhibitors, and endothelin receptor antagonists. Additionally, extracorporeal membrane oxygenation (ECMO) is highlighted as a critical intervention for severe, refractory cases. The review also discusses emerging therapies and the potential role of personalized medicine in improving treatment outcomes. Despite the progress made, challenges remain, including the timely diagnosis of PPHN and the need for accessible treatments in resource-limited settings. As research continues to uncover the underlying pathophysiology of PPHN, it is crucial to develop more targeted and effective pharmaceutical strategies. This review aims to inform clinicians and researchers of the current state of PPHN management and the ongoing advancements that may shape future therapeutic approaches.

B cell targeting in IgA nephropathy.

The "multi-hit theory/4-hit theory" pathogenesis hypothesis is widely accepted and IgA nephropathy (IgAN) is understood to be a disease originating from Hit 1, galactose deficient IgA1 (GdIgA1). The chronic repetitive activation of the complement pathway (alternative and lectin pathways) and the subsequent inflammation results in progressive glomerular damage that spills over into increased intraglomerular pressure and other hemodynamic changes, increased urinary protein, glomerulosclerosis, and tubulointerstitial fibrosis. The basic pathophysiology of this disease is the progression of a mixture of such acute and chronic pathologies. Currently, a number of new drugs has emerged as promising agents, such as complement regulators, endothelin receptor antagonists, and SGLT2 inhibitors, which are associated with each pathological step after glomerular deposition of GdIgA1/immune complexes. On the other hand, the molecular mechanisms of GdIgA1 production are gradually being elucidated, and the development of several novel therapeutic agents targeting the responsible B cells and their international clinical trials are progressing. These agents that inhibit or control the production of the Hit1, GdIgA1, are highly expected as essential therapies for this disease. The large body of clinical and basic research findings to date strongly suggest that nephritogenic GdIgA1 is a polymeric IgA1 of mucosal origin. In addition, the B cells involved in its nephritogenic GdIgA1 production are mainly differentiated mature B cells such as plasma cells, which may migrate to the bone marrow as well as the mucosa. The innate immune system in the mucosa, especially Toll-like receptors (TLRs), is thought to be involved in their production. Among TLRs, TLT9 and TLR7, which recognize bacterial and viral unmethylated DNA and RNA, have been reported to be involved. The mucosal activation of these TLRs is associated with the production of APRIL (A Proliferation Inducing Ligand) and BAFF (B cell activating factor), which are TNF superfamily cytokines involved in B cell maturation, survival, and IgA class switching, and may also be involved in the production of nephritogenic GdIgA1. It is still inconclusive whether APRIL or BAFF is more closely involved in the production of nephritogenic GdIgA1. Phenotypes in transgenic animal models suggest BAFF involvement, however, a genome wide association study (GWAS) analysis of human IgAN has identified APRIL, not BAFF, as a candidate gene. Based on the above background, several international clinical trials are underway for drugs such as TLR regulators (hydroxychloroquine), anti-APRIL drugs, anti-BAFF drugs, APRIL/BAFF receptor (TACI) binding inhibitors, and cytoreductive drugs (proteasome inhibitors, anti-CD38 antibodies) to inhibit nephritogenic GdIgA1 production in responsible B cells. This session will provide an overview of the responsible B cells, their GdIgA1 production mechanism, and ongoing drugs.

Postoperative Management of Aneurysmal Subarachnoid Hemorrhage

Delayed cerebral ischemia(DCI) is one of the most significant complications of subarachnoid hemorrhage. Despite significant evolution in understanding DCI pathophysiology, vasospasm affecting cerebral vessels of large and moderate diameters remain the only clinically measurable component of DCI and is therefore the primary target for intervention in the postoperative management of subarachnoid hemorrhage. In Japan, fasudil hydrochloride and ozagrel sodium are widely used to prevent vasospasms; however, their effects are sometimes insufficient. Clazosentan, a selective endothelin receptor subtype A antagonist, reduces vasospasm-related morbidity and all-cause mortality following aneurysmal subarachnoid hemorrhage. This was demonstrated in a recent randomized phase 3 trial, leading to the approval of clazosentan by the Pharmaceuticals and Medical Devices Agency in Japan. Recent advances in our understanding of subarachnoid hemorrhage will facilitate improved management to reduce the incidence of DCI.

Zibotentan in Microvascular Angina: A Randomized, Placebo-Controlled, Crossover Trial.

Background: Microvascular angina is associated with dysregulation of the endothelin system and impairments in myocardial blood flow, exercise capacity, and health-related quality of life. The G allele of the noncoding single nucleotide polymorphism RS9349379 enhances expression of the endothelin-1 gene (EDN1) in human vascular cells, potentially increasing circulating concentrations of Endothelin-1 (ET-1). Whether zibotentan, an oral ET-A receptor selective antagonist, is efficacious and safe for the treatment of microvascular angina is unknown. Methods: Patients with microvascular angina were enrolled in this double-blind, placebo-controlled, sequential crossover trial of zibotentan (10 mg daily for 12 weeks). The trial population was enriched to ensure a G allele frequency of 50% for the RS9349379 single nucleotide polymorphism. Participants and investigators were blinded to genotype. The primary outcome was treadmill exercise duration (seconds) using the Bruce protocol. The primary analysis estimated the mean within-participant difference in exercise duration after treatment with zibotentan versus placebo. Results: A total of 118 participants (mean ±SD; years of age 63.5 [9.2 ]; 71 [60.2% ] females; 25 [21.2% ] with diabetes) were randomized. Among 103 participants with complete data, the mean exercise duration with zibotentan treatment compared with placebo was not different (between-treatment difference, -4.26 seconds [95 ] CI, -19.60 to 11.06] P=0.5871). Secondary outcomes showed no improvement with zibotentan. Zibotentan reduced blood pressure and increased plasma concentrations of ET-1. Adverse events were more common with zibotentan (60.2%) compared with placebo (14.4%; P<0.001). Conclusions: Among patients with microvascular angina, short-term treatment with a relatively high dose (10 mg daily) of zibotentan was not beneficial. Target-related adverse effects were common.

Abstract P178: Sex Differences in the Role of the Immune ET-1/ET A Axis in Controlling Blood Pressure during a Hypertension Challenge

Immune cells like dendritic cells (DCs) and T cells are essential for the development of hypertension. Upregulation of the vasoactive peptide endothelin-1 (ET-1) is key in the progression of hypertension. ET-1 acting via its ET A receptor raises blood pressure and promotes end-organ damage and inflammation. DCs and T cells express ET-1 receptors and respond to changing levels of ET-1. However, it is unknown whether activation of the ET-1/ET A receptor axis on DCs or T cells is critical in driving hypertension, or if a differential activation of this axis in immune cells leads to the sex differences that exist in the pathophysiology of this disease. We hypothesized that activation of the ET-1/ ET A axis on immune cells is crucial in the development of hypertension, with a more prominent role in males than females. Male and female mice lacking ET A receptor on DCs (DC ET A KO) or on T cells (T cell ET A KO) and floxed ET A control mice were given the nitric oxide synthase inhibitor L-NAME (0.5 mg/mL) in drinking water for 3 wks to induce hypertension. Systolic blood pressure (SBP) was measured 3 times/wk via tail cuff plethysmography. Glomerular filtration rate (GFR) was evaluated at baseline and after L-NAME treatment via the transcutaneous FITC-sinistrin clearance method. Absence of ET A receptor on DCs resulted in a ~10 mmHg decrease in SBP at baseline in both sexes, and this difference increased throughout the protocol in males (Floxed ET A vs. DC ET A KO: L-NAME: 150.8±6.7 vs. 130.8±2.6 mmHg, n=4/group, p=0.002), but not in females (137.4±5.7 vs. 137.2±2.4 mmHg, n=3/group). Lack of the ET A receptor on T cells led to a similar decrease of ~10 mmHg in SBP at baseline. However, the difference in SBP widened when males were challenged with L-NAME (Floxed ET A vs. T cell ET A KO: 135.2±2.0 vs. 118.0±4.1, n=11/group, p=0.003), whereas the group difference in SBP disappeared in females (131.5±4.0 vs. 132.4±4.7, n=8-9/group). Following L-NAME, GFR trended to decline in control male mice, while it increased in T cell ET A KO males. Our data suggest that activation of ET A receptors on DCs and T cells modulates SBP in response to a hypertensive insult in males, but not in females. Additionally, absence of ET-1/ ET A axis activation on T cells suggests improved renal function during hypertension. Our results suggest that the use of ET A antagonism in the clinic may be more protective during hypertension in males than females.

Mechanism of Mongolian mind-body interactive therapy in regulating essential hypertension through HTR2B: A metabolome- and transcriptome-based study

Essential hypertension is a psychosomatic disease associated with emotions and behaviors. Although Mongolian mind–body interactive therapy can help patients with essential hypertension reduce their systolic blood pressure (SBP), the mechanism is unclear. We assigned patients who underwent Mongolian mind–body interactive therapy to groups that were treated with (DT) or without (NDT) antihypertensive drugs (Clinical registration no: ChiCTR2000034918). We screened differentially expressed genes (DEGs) using targeted metabolic and transcriptomic analyses of blood samples before and after intervention. Sequenced data were analyzed using quantitative polymerase chain reaction (qPCR) and validated using enzyme-linked immunosorbent assays (ELISAs). Small interfering (Si)-RNA interference on key DEGs in human umbilical vein endothelial cells (HUVECs) was experimentally verified. Omics analysis identified 187 DEGS, including human 5-hydroxytryptamine (5-HT) receptor 2B (5-HTR2B), human endothelin receptor type B (EDNRB), and the metabolite N-acetylserotonin. The qPCR and transcriptome sequencing results were consistent. Post-intervention ELISA assays revealed significantly elevated 5-HT in the NDT group after intervention (P < 0.05). Interactions between 5-HTR2B and N-acetylserotonin differed between the groups. The cellular findings showed significantly reduced G protein-coupled receptor 82 (GPR82) and phospholipid phosphatase-related protein type 4 (PLPPR4), and significantly increased S100A2 protein expression in the Si-HTR2B group, compared with the controls (P < 0.05). The biochemical results uncovered significantly decreased nitric oxide (NO) and significantly increased malondialdehyde and NO synthetase concentrations compared with the models (P < 0.05). Mongolian mind–body interactive therapy might affect SBP in patients with essential hypertension by combining 5-HT with 5-HTR2B to mediate NO relaxation.

Sunitinib-induced endocapillary proliferative glomerulonephritis with IgA2 deposit in addition to thrombotic microangiopathy: a case report

BackgroundSunitinib, a multi-targeted tyrosine kinase inhibitor, is used as a second-line therapy for gastrointestinal stromal tumors (GIST) resistant to imatinib. However, its impact on the vascular endothelial growth factor (VEGF) pathway can lead to significant toxicities, including hypertension and thrombotic microangiopathy (TMA).Case presentationThis case report describes a unique instance of a patient with metastatic GIST who developed endocapillary proliferative glomerulonephritis (EPGN) with IgA2 deposits and TMA following sunitinib treatment. The patient presented with severe hypertension, nephrotic syndrome, and acute kidney injury. Renal biopsy confirmed the diagnosis, revealing IgA2 deposits, which are not commonly associated with TMA. Discontinuation of sunitinib led to a rapid improvement in renal function and proteinuria. The potential mechanisms underlying sunitinib-induced glomerular injury may involve the blockade of VEGFR-1, affecting immune cell recruitment and function, and the disruption of the nitric oxide and endothelin systems, leading to endothelial damage and immune dysregulation. Management of these toxicities requires a personalized approach, with options ranging from symptomatic relief to drug discontinuation. The use of endothelin receptor antagonists and other therapeutic alternatives for GIST management is discussed.ConclusionsThis case highlights the complex interplay between the therapeutic effects of sunitinib and its potential renal and cardiovascular toxicities, emphasizing the need for close monitoring and effective management strategies to optimize patient outcomes.

Updates in Management of Pulmonary Hypertension in Pediatrics: A Systematic Review

Objectives: To provide an updated synthesis of the evidence on the management of pulmonary hypertension (PH) in pediatric patients. Methods: We performed a thorough search of electronic databases such as PubMed, Science Direct, Cochrane Library, and Scopus. Two independent reviewers evaluated and retrieved information from qualifying papers. Results: Our data consists of eight studies with 2003 children, 930 (46.3%) of whom were female. Prostacyclin agonists were found to significantly improve hemodynamic parameters and reduced BNP levels, which implies that they have promising clinical efficacy and a good tolerance profile. No major side effects were noted except for headaches and gastrointestinal symptoms. Systemic glucocorticoids, inhaled NO, endothelin receptor antagonists, and PDE showed tolerability and clinical improvements in pediatric PH. Side effects such as acute kidney damage, renal failure, and methemoglobinemia were noted with the inhaled NO. Conclusion: Pediatric PH is still a difficult condition with high morbidity and mortality. All of the reported pharmacological interventions demonstrated good clinical outcomes and almost no adverse effects. Healthcare practitioners can improve the care of children with PH and eventually improve their quality of life and long-term survival by incorporating new research into clinical practice.

Endothelin 3/EDNRB signaling induces thermogenic differentiation of white adipose tissue

Thermogenic adipose tissue, consisting of brown and beige fat, regulates nutrient utilization and energy metabolism. Human brown fat is relatively scarce and decreases with obesity and aging. Hence, inducing thermogenic differentiation of white fat offers an attractive way to enhance whole-body metabolic capacity. Here, we show the role of endothelin 3 (EDN3) and endothelin receptor type B (EDNRB) in promoting the browning of white adipose tissue (WAT). EDNRB overexpression stimulates thermogenic differentiation of human white preadipocytes through cAMP-EPAC1-ERK activation. In mice, cold induces the expression of EDN3 and EDNRB in WAT. Deletion of EDNRB in adipose progenitor cells impairs cold-induced beige adipocyte formation in WAT, leading to excessive weight gain, glucose intolerance, and insulin resistance upon high-fat feeding. Injection of EDN3 into WAT promotes browning and improved whole-body glucose metabolism. The findings shed light on the mechanism of WAT browning and offer potential therapeutics for obesity and metabolic disorders.

Efficacy of Vitamin B12 and Adenosine Triphosphate in Enhancing Skin Radiance: Unveiled with a Drug-Target Interaction Deep Learning-Based Model.

Skin radiance is crucial for enhancing facial attractiveness and is negatively affected by factors like hyperpigmentation and aging-related changes. Current treatments often lack comprehensive solutions for improving skin radiance. This study aimed to develop a cosmetic formula that enhances skin radiance by reducing hyperpigmentation and improving skin regeneration by targeting specific receptors-the endothelin receptor type B (EDNRB) for hyperpigmentation and the adiponectin receptor 1 (ADIPOR1) for sagging and wrinkles. To achieve this, we used artificial intelligence technologies to screen and select ingredients with an affinity for EDNRB and ADIPOR1. Vitamin B12 (VitB12) was identified as a molecule that targets EDNRB, which is involved in melanogenesis. Adenosine triphosphate (ATP) targets ADIPOR1, which is associated with skin regeneration. VitB12 successfully inhibited intracellular calcium elevation and melanogenesis induced by endothelin-1. In contrast, ATP increased the mRNA expression of collagen and elastin and promoted wound healing. Moreover, the VitB12 and ATP complex significantly increased the expression of hyaluronan synthases, which are crucial for skin hydration. Furthermore, in human participants, the application of the VitB12 and ATP complex to one-half of the face significantly improved skin radiance, elasticity, and texture. Our findings provide valuable insights for the development of skincare formulations.

The role of venous capacity in fluid retention with endothelin A antagonism: Mathematical modelling of the RADAR trial.

Endothelin-1 (ET-1) receptor A (ETA) antagonists reduce proteinuria and prevent renal outcomes in chronic kidney disease (CKD) patients, but their utility has been limited because of associated fluid retention, resulting in increased heart failure risk. Understanding the mechanisms responsible for fluid retention could result in solutions that preserve renoprotective effects while mitigating fluid retention, but the complexity of the endothelin system has made identification of the underlying mechanisms challenging. We utilized a previously developed mathematical model of ET-1 kinetics, ETA receptor antagonism, kidney function, haemodynamics, and sodium and water homeostasis to evaluate hypotheses for mechanisms of fluid retention with ETA antagonism. To do this, we simulated the RADAR clinical trial of atrasentan in patients with type 2 diabetes and CKD and evaluated the ability of the model to predict the observed decreases in haematocrit, urine albumin creatinine ratio (UACR), mean arterial pressure (MAP), and estimated glomerular filtration rate (eGFR). An effect of ETA antagonism on venodilation and increased venous capacitance was found to be the critical mechanism necessary to reproduce the simultaneous decrease in both MAP and haematocrit observed in RADAR. These findings indicate that fluid retention with ETA antagonism may not be caused by a direct antidiuretic effect within the kidney but is instead be an adaptive response to venodilation and increased venous capacity, which acutely tends to reduce cardiac filling pressure and cardiac output, and that fluid retention occurs in an attempt to maintain cardiac filling and cardiac output.

Endothelin-1 (ET-1) contributes to senescence and phenotypic changes in brain pericytes in diabetes-mimicking conditions.

Diabetes mediates endothelial dysfunction and increases the risk of Alzheimer's disease and related dementias. Diabetes also dysregulates the ET system. ET-1-mediated constriction of brain microvascular pericytes (BMVPCs) has been shown to contribute to brain hypoperfusion. Cellular senescence, a process that arrests the proliferation of harmful cells and instigates phenotypical changes and proinflammatory responses in endothelial cells that impact their survival and function. Thus, we hypothesized that ET-1 mediates BMVPC senescence and phenotypical changes in diabetes-like conditions. Human BMVPCs were incubated in diabetes-like conditions with or without ET-1 (1 µmol/L) for 3 and 7 days. Hydrogen peroxide (100 µmol/L H2O2) was used as a positive control for senescence and to mimic ischemic conditions. Cells were stained for senescence-associated β-galactosidase or processed for immunoblotting and quantitative real-time PCR analyses. In additional experiments, cells were stimulated with ET-1 in the presence or absence of ETA receptor antagonist BQ-123 (20 μmol/L) or ETB receptor antagonist BQ-788 (20 μmol/L). ET-1 stimulation increased β-galactosidase accumulation which was prevented by BQ-123. ET-1 also increased traditional senescence marker p16 protein and pericyte-specific senescence markers, TGFB1i1, PP1CA, and IGFBP7. Furthermore, ET-1 stimulated contractile protein α-SMA and microglial marker ostepontin in high glucose suggesting a shift toward an ensheathing or microglia-like phenotype. In conclusion, ET-1 triggers senescence, alters ETA and ETB receptors, and causes phenotypical changes in BMVPCs under diabetes-like conditions. These in vitro findings need to be further studied in vivo to establish the role of ETA receptors in the progression of pericyte senescence and phenotypical changes in VCID.

Development of ocular delivery systems for macitentan and ex vivo study of intraocular permeation

Macitentan is a drug that acts as a non-selective antagonist of endothelin receptors. It has been officially approved for the treatment of cases of pulmonary arterial hypertension. There are studies in animal models that indicate a therapeutic potential for this drug in the treatment of glaucoma, a degenerative eye disease marked by a progressive reduction in the visual field that can progress to irreversible blindness. In the present work, ophthalmic formulations of macitentan were developed with the aim of evaluating their potential to deliver the active ingredient to therapeutically relevant sites. An HPLC-DAD method was adapted from the literature and validated to quantify macitentan in each step. Physicochemical characterization studies of the formulations were performed, and a Franz vertical diffusion cell was used in an analysis of the in vitro/ex vivo permeation using cornea and sclera of porcine eyes to represent biological membranes. The developed formulations presented different permeation profiles according to the presence or absence of water in the base formulation and the type of viscosity promoting agent used. The formulations that showed the highest percentage of permeation were evaluated for mucus adhesiveness and the most promising were further analyzed for stability that included measuring drug content, pH, and viscosity. One formulation was developed for the ocular release of macitentan with a high percentage of drug permeation, adequate viscosity and stability that could represent an advancement in the treatment of glaucoma with a high potential for patient adherence.

Risk evaluation and mitigation strategy compliance for pulmonary hypertension medications after policy implementation with computerized provider order entry support.

In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. Treatment for pulmonary hypertension includes medications with risk evaluation and mitigation strategy (REMS) programs. Health-system inpatient pharmacies dispensing these agents must comply with inpatient REMS dispensing criteria. Implementing a health-system policy with computerized provider order entry (CPOE) decision support may improve REMS compliance. This was a retrospective, quasi-experimental study comparing REMS compliance before and after development of a policy with CPOE decision support that was implemented in August 2019. Patients 18 years of age or older with a diagnosis of pulmonary hypertension were included if they received at least one dose of an endothelin receptor antagonist or riociguat while hospitalized. Patients were included in the preintervention group if they were hospitalized between August 1, 2017, and August 31, 2019, and in the postintervention group if they were hospitalized between September 1, 2019, and August 31, 2021. The primary outcome was the REMS compliance rate. Secondary endpoints included the time to REMS compliance and independent factors associated with failed or delayed REMS compliance. A total of 150 patients were included, with 75 patients in both the pre- and postintervention groups. Compliance increased significantly from the preintervention (50%) to postintervention (92%) group (P < 0.001). Time to compliance was also significantly reduced from 770 minutes in the preintervention group to 140 minutes in the postintervention group (P = 0.031). Factors independently associated with REMS compliance were being in the postintervention group (odds ratio, 16.9; 95% confidence interval, 5.8-49.2) and being admitted to a pulmonary hypertension center for comprehensive care. (odds ratio, 7.8; 95% confidence interval, 2.9-21.2). A health-system policy with CPOE decision support improved both the rate of and time to compliance with inpatient REMS dispensing procedures.

Efficacy and safety of macitentan in Fontan-palliated patients: 52-week randomized, placebo-controlled RUBATO Phase 3 trial and open-label extension

ObjectivesThe efficacy and safety of macitentan, an endothelin receptor antagonist, were assessed in a 52-week, prospective, multicenter, double-blind, randomized, placebo-controlled, parallel-group study assessing the efficacy and safety of macitentan in Fontan-palliated adult and adolescent patients (RUBATO-DB) and an open-label extension trial (RUBATO-OL). MethodsPatients aged 12 years and older with New York Heart Association functional class II or III underwent total cavopulmonary connection more than 1 year before screening and showed no signs of Fontan failure/clinical deterioration. In RUBATO-DB, the primary efficacy end point was change in peak oxygen consumption from baseline to week 16; secondary end points were change from baseline over 52 weeks in peak oxygen consumption and change in mean count/minute of daily physical activity via accelerometer from baseline to week 16. Safety was assessed throughout both studies. ResultsIn RUBATO-DB, 137 patients were randomized to macitentan 10 mg (n = 68) or placebo (n = 69); 92.7% completed 52-week double-blind treatment. At week 16, mean ± SD change in peak oxygen consumption was −0.16 ± 2.86 versus −0.67 ± 2.66 mL/kg/minute with macitentan versus placebo (median unbiased treatment difference estimate, 0.62 mL/kg/minute [99% repeated CI, −0.62 to 1.85]; P = .19). No treatment effect was observed in either of the secondary end points. During RUBATO-DB, most common adverse events with macitentan were headache, nasopharyngitis, and pyrexia. Across RUBATO-DB and RUBATO-OL, most common adverse events were COVID-19, headache, and fatigue. RUBATO-OL was prematurely discontinued because RUBATO-DB did not meet its primary or secondary end point. ConclusionsThe primary end point of RUBATO-DB was not met; macitentan did not improve exercise capacity versus placebo in patients with Fontan palliation. Macitentan was generally well tolerated over long-term treatment.

REACT: a randomized trial to assess the efficacy and safety of clazosentan for preventing clinical deterioration due to delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage.

Ischemic complications account for significant patient morbidity following aneurysmal subarachnoid hemorrhage (aSAH). The Prevention and Treatment of Vasospasm with Clazosentan (REACT) study was designed to assess the safety and efficacy of clazosentan, an endothelin receptor antagonist, in preventing clinical deterioration due to delayed cerebral ischemia (DCI) in patients with aSAH. REACT was a prospective, multicenter, randomized, double-blind, phase 3 study. Eligible patients had aSAH secured by surgical clipping or endovascular coiling, and had presented with thick and diffuse clot on admission CT scan. Patients were randomized (1:1 ratio) to 15 mg/hour intravenous clazosentan or placebo within 96 hours of the aSAH for up to 14 days, in addition to standard of care treatment including oral or intravenous nimodipine. The primary efficacy endpoint was the occurrence of clinical deterioration due to DCI up to 14 days after initiation of the study drug. The main secondary endpoint was the occurrence of clinically relevant cerebral infarction at day 16 after study drug initiation. Other secondary endpoints included clinical outcome assessed on the modified Rankin Scale (mRS) and the Glasgow Outcome Scale-Extended (GOSE) at week 12 post-aSAH. Imaging and clinical endpoints were centrally adjudicated. A total of 409 patients were randomized between February 2019 and May 2022 across 74 international sites. Three patients did not start study treatment and were not included in the analysis set. The occurrence of clinical deterioration due to DCI was 15.8% (32/202 patients) in the clazosentan group and 17.2% (35/204 patients) in the placebo group, and the difference was not statistically significant (relative risk reduction [RRR] 7.2%, 95% CI -42.6% to 39.6%, p = 0.734). A nonsignificant RRR of 34.1% (95% CI -21.3% to 64.2%, p = 0.177) was observed in clinically relevant cerebral infarcts treated with clazosentan (7.4%, 15/202) versus placebo (11.3%, 23/204). Rescue therapy was less frequently needed for patients treated with clazosentan compared to placebo (10.4%, 21/202 vs 18.1%, 37/204; RRR 42.6%, 95% CI 5.4%-65.2%). A nonsignificant relative risk increase of 25.4% (95% CI -10.7% to 76.0%, p = 0.198) was reported in the risk of poor GOSE and mRS scores with clazosentan (24.8%, 50/202) versus placebo (20.1%, 41/204) at week 12 post-aSAH. Treatment-emergent adverse events were similar to those reported previously. Clazosentan administered for up to 14 days at 15 mg/hour had no significant effect on the occurrence of clinical deterioration due to DCI. Clinical trial registration no.: NCT03585270 (ClinicalTrials.gov) EU clinical trial registration no.: 2018-000241-39 (clinicaltrialsregister.eu).

New and Emerging Therapeutic Drugs for the Treatment of Pulmonary Arterial Hypertension: A Systematic Review.

Pulmonary arterial hypertension (PAH) is a serious, progressive, and potentially fatal lung disease characterized by a gradual increase in mean pulmonary arterial pressure to over 20 mmHg at rest. The pathogenesis of PAH is multifactorial. It involves dynamic obstruction of the pulmonary vasculature through vasoconstriction, structural obstruction due to adverse vascular remodeling, and pathological obstruction caused by vascular fibrosis and stiffening, which reduces compliance. PAH often presents with vague initial symptoms and is frequently diagnosed at an advanced stage. The increased pulmonary arterial pressure leads to vascular remodeling, eventually resulting in right ventricular hypertrophy and failure. PAH is a rare condition with a median life expectancy of three years, underscoring the need for effective treatment alternatives. Several FDA-approved therapeutic options are available, including prostacyclin analogs (epoprostenol, iloprost, and treprostinil), the non-prostanoid IP receptor agonist selexipag, selective endothelin receptor antagonists (ERA) (ambrisentan, bosentan, and macitentan), phosphodiesterase 5 inhibitors (sildenafil and tadalafil), and the soluble guanylate cyclase (sGC) stimulator riociguat. Despite these advancements, current medications do not provide a permanent cure. This study presents an overview of current and emerging PAH therapies through a systematic literature review. It involved an analysis of nine studies and a review of 800 papers from reputable journals published between 2013 and June 2023. The research focused on drug effects on the six-minute walk distance (6-MWD) and associated side effects in randomized controlled trials. The review found that while udenafil, imatinib, racecadotril, sotatercept, anastrozole, riociguat, tacrolimus, and ralinepag were evaluated, imatinib was notably associated with adverse side effects. Conversely, udenafil, racecadotril, sotatercept, anastrozole, riociguat, tacrolimus, and ralinepag were found to be safe, well-tolerated, and effective in improving hemodynamic measures and 6-MWDs. This study aims to summarize the developing treatment options currently under clinical trials, highlighting the need for further trials before their application in clinical practice.