The Anti-Atherosclerotic Effects of Endothelin Receptor Antagonist, Bosentan, in Combination with Atorvastatin-An Experimental Study.

Bosentan, an endothelin receptor antagonist (ERA), has potential anti-atherosclerotic properties. We investigated the complementary effects of bosentan and atorvastatin on the progression and composition of the atherosclerotic lesions in diabetic mice. Forty-eight male ApoE-/- mice were fed high-fat diet (HFD) for 14 weeks. At week 8, diabetes was induced with streptozotocin, and mice were randomized into four groups: (1) control/COG: no intervention; (2) ΒOG: bosentan 100 mg/kg/day per os; (3) ATG: atorvastatin 20 mg/kg/day per os; and (4) BO + ATG: combined administration of bosentan and atorvastatin. The intra-plaque contents of collagen, elastin, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-a (TNF-a), matrix metalloproteinases (MMP-2, -3, -9), and TIMP-1 were determined. The percentage of lumen stenosis was significantly lower across all treated groups: BOG: 19.5 ± 2.2%, ATG: 12.8 ± 4.8%, and BO + ATG: 9.1 ± 2.7% compared to controls (24.6 ± 4.8%, p < 0.001). The administration of both atorvastatin and bosentan resulted in significantly higher collagen content and thicker fibrous cap versus COG (p < 0.01). All intervention groups showed lower relative intra-plaque concentrations of MCP-1, MMP-3, and MMP-9 and a higher TIMP-1concentration compared to COG (p < 0.001). Importantly, latter parameters presented lower levels when bosentan was combined with atorvastatin compared to COG (p < 0.05). Bosentan treatment in diabetic, atherosclerotic ApoE-/- mice delayed the atherosclerosis progression and enhanced plaques' stability, showing modest but additive effects with atorvastatin, which are promising in atherosclerotic cardiovascular diseases.

Targeting the endothelium by combining endothelin-1 antagonism and SGLT-2 inhibition: better together?

Endothelin A and B receptors, together with sodium-glucose cotransporter-2 (SGLT-2) channels are important targets in improving endothelial function and intervention with inhibitors has been the subject of multiple mechanistic and clinical outcome trials over recent years. Notable successes include the treatment of pulmonary hypertension with endothelin receptor antagonists, and the treatment of heart failure and chronic kidney disease with SGLT-2 inhibitors. With distinct and complementary mechanisms, in this review, we explore the logic of combination therapy for a number of diseases which have endothelial dysfunction at their heart.

Is endothelin targeting finally ready for prime time?

The endothelin family of peptides has long been recognized as a physiological regulator of diverse biological functions and mechanistically involved in various disease states, encompassing, among others, the cardiovascular system, the kidney, and the nervous system. Pharmacological blockade of the endothelin system, however, has encountered strong obstacles in its entry into the clinical mainstream, having obtained only a few proven indications until recently. This translational gap has been attributable predominantly to the relevant side effects associated with endothelin receptor antagonism (ERA), particularly fluid retention. Of recent, however, an expanding understanding of the pathophysiological processes involving endothelin, in conjunction with the development of new antagonists of endothelin receptors or adjustment of their doses, has driven a flourish of new clinical trials. The favorable results of some of them have extended the proven indications for ET targeting to a variety of clinical conditions, including resistant arterial hypertension and glomerulopathies. In addition, on the ground of strong preclinical evidence, other studies are ongoing to test the potential benefits of ERA in combination with other treatments, such as sodium-glucose co-transporter 2 inhibition in fluid retentive states or anti-cancer therapies in solid tumors. Furthermore, antibodies providing long-term blockade of endothelin receptors are under testing to overcome the short half-life of most small molecule endothelin antagonists. These efforts may yet bring new life to the translation of endothelin targeting strategies in clinical practice.

Fixed-dose combination therapy in pulmonary arterial hypertension: Pros & cons.

Quality of life of patients suffering from chronic diseases is inevitably conditioned by the number of pills taken during the day. To improve patients' tolerability, compliance and quality of life and reduce healthcare costs, pharmaceutical companies are focusing on the commercialization of fixed-dose combination (FDC) therapies. The last ESC/ERS guidelines for the treatment of pulmonary arterial hypertension (PAH) recommend initial dual combination therapy for newly diagnosed patients at low or intermediate mortality risk. In this regard, polypills including an endothelin receptor antagonist (ERA) and a phosphodiesterase 5 inhibitor (PDE5-i) could represent an useful therapeutic strategy, although with some limitations. To date, evidence about the use of FDCs in PAH is limited but future studies evaluating their safety and efficacy are welcome.

Combination therapy for kidney disease in people with diabetes mellitus.

Diabetic kidney disease (DKD), defined as co-existing diabetes and chronic kidney disease in the absence of other clear causes of kidney injury, occurs in approximately 20-40% of patients with diabetes mellitus. As the global prevalence of diabetes has increased, DKD has become highly prevalent and a leading cause of kidney failure, accelerated cardiovascular disease, premature mortality and global health care expenditure. Multiple pathophysiological mechanisms contribute to DKD, and single lifestyle or pharmacological interventions have shown limited efficacy at preserving kidney function. For nearly two decades, renin-angiotensin system inhibitors were the only available kidney-protective drugs. However, several new drug classes, including sodium glucose cotransporter-2 inhibitors, a non-steroidal mineralocorticoid antagonist and a selective endothelin receptor antagonist, have now been demonstrated to improve kidney outcomes in people with type 2 diabetes mellitus. In addition, emerging preclinical and clinical evidence of the kidney-protective effects of glucagon-like-peptide-1 receptor agonists has led to the prospective testing of these agents for DKD. Research and clinical efforts are geared towards using therapies with potentially complementary efficacy in combination to safely halt kidney disease progression. As more kidney-protective drugs become available, the outlook for people living with DKD should improve in the next few decades.

Maximizing the Therapeutic Effect of Endothelin Receptor Antagonists in Pulmonary Fibrosis: A Paradigm for Treating the Disease.

Using a lipopolysaccharide model of acute lung injury, we previously showed that endothelin-1 (ET-1), a potent mediator of vasoconstriction, may act as a "gatekeeper" for the influx of inflammatory cells into the lung. These studies provided a rationale for testing the effect of HJP272, an endothelin receptor antagonist (ERA), in hamster models of pulmonary fibrosis induced by intratracheal instillation of either bleomycin (BLM) or amiodarone (AM). To determine the temporal effects of blocking ET-1 activity, animals were given HJP272 either 1 h before initiation of lung injury or 24 h afterward. The results indicated that pretreatment with this agent caused significant reductions in various inflammatory parameters, whereas post-treatment was ineffective. This finding suggests that ERAs are only effective at a very early stage of pulmonary fibrosis and explains their lack of success in clinical trials involving patients with this disease. Nevertheless, ERAs could serve as prophylactic agents when combined with drugs that may induce pulmonary fibrosis. Furthermore, developing a biomarker for the initial changes in the lung extracellular matrix could increase the efficacy of ERAs and other therapeutic agents in preventing the progression of the disease. While no such biomarker currently exists, we propose the ratio of free to peptide-bound desmosine, a unique crosslink of elastin, as a potential candidate for detecting the earliest modifications in lung microarchitecture associated with pulmonary fibrosis.

Tonic action of endothelin type B and dopamine D3 receptors in spontaneously hypertensive and deoxycorticosterone acetate-salt hypertensive rats: effects of intrarenally applied selective antagonists.

Endothelins and renal dopamine contribute to control of renal function and arterial pressure in health and various forms of experimental hypertension, the action is mediated by tonic activity of specific receptors. We determined the action mediated by endothelin type B and by dopamine D3 receptors (ETB-R, D3-R) in anaesthetized spontaneously hypertensive (SHR) and in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. In rats of both hypertension models infused during 60 min into the interstitium of in situ kidney were either ETB-R antagonist, BQ788 (0.67 mg kg-1 BW h-1) or D3-R antagonist, GR103691 (0.2 mg kg-1 BW h-1). Arterial pressure (MAP), renal artery blood flow (RBF, transonic probe) and renal medullary blood flow (MBF, laser-Doppler) were measured along with sodium, water and total solute excretion (UNaV, V, UosmV). Experiments with ETB-R blockade confirmed their tonic vasodilator action in the whole kidney (RBF) and medulla (MBF) in both hypertension models. In SHR only, the first evidence was provided that ETB-R specifically increases transtubular backflux of non-electrolyte solutes. In DOCA-salt rats ETB-R blockade caused an early decrease in water and salt transport whereas an increase was often reported from many previous studies. The most striking effect of D3-R blockade in SHR was a selective increase in MBF, which strongly suggested tonic vasoconstrictor action of these receptors in the renal medulla; this speaks against prevailing opinion that D3 receptors are virtually inactive in SHR. In our model variant of DOCA-salt rats of D3-R blockade clearly caused a rapid major increase in MAP in parallel with depression of renal haemodynamics.

Comparative adherence of macitentan versus ambrisentan and bosentan in Australian patients with pulmonary arterial hypertension: a retrospective real-world database study.

AIM: Bosentan, ambrisentan, and macitentan are endothelin receptor antagonists (ERAs), currently available in Australia for treatment of pulmonary arterial hypertension (PAH). This study assessed the comparative adherence of these ERAs for PAH in Australian patients. METHODS: This retrospective, observational study used data for adults with PAH from the Services Australia 10% Pharmaceuticals Benefits Scheme (PBS) dataset (01/2006-10/2020). The primary outcome was treatment adherence (i.e. receiving ≥80% of ERA doses over 12 months). Secondary outcomes were time to treatment change (add-on or switch) and overall survival. RESULTS: The study included 436 patients who took bosentan (n = 200), ambrisentan (n = 69), or macitentan (n = 167). Treatment adherence was significantly greater in patients who received macitentan (65.3%) versus ambrisentan (56.5%) and bosentan (58.0%), with odds ratios (ORs; 95% CI) of 0.51 (0.30-0.88; p = 0.016) for bosentan versus macitentan and 0.48 (0.24-0.96; p = 0.037) for ambrisentan versus macitentan. The median time to treatment change was 47.2 and 43.4 months for bosentan and ambrisentan, respectively (not calculated for macitentan because of insufficient duration of data). LIMITATIONS AND CONCLUSIONS: Real-world data for Australian patients with PAH showed that treatment adherence for ERAs was suboptimal. Adherence was higher for macitentan compared with ambrisentan and bosentan.

Population pharmacokinetics of the dual endothelin receptor antagonist aprocitentan in subjects with or without essential or resistant hypertension.

Aprocitentan is a novel, potent, dual endothelin receptor antagonist that recently demonstrated efficacy in the treatment of difficult-to-treat (resistant) hypertension. The aim of this study was to develop a population pharmacokinetic (PK) model describing aprocitentan plasma concentration over time, to investigate relationships between subject-specific factors (covariates) and model parameters, and to quantify the influence of the identified covariates on the exposure to aprocitentan via model-based simulations, enabling judgment about the clinical relevance of the covariates.PK data from 902 subjects in ten Phase 1, one Phase 2, and one Phase 3 study were pooled to develop a joint population PK model. The concentration-time course of aprocitentan was described by a two-compartment model with absorption lag time, first-order absorption and elimination, and reduced relative bioavailability following very high doses of 300 and 600 mg.The population PK model described the observed data well. Volume and clearance parameters were associated with body weight. Renal function as reflected by estimated glomerular filtration rate (eGFR), hepatic impairment, and sex were identified as relevant covariates on clearance.The subject-specific characteristics of body weight, eGFR, hepatic impairment, and sex were shown to influence exposure parameters area under the concentration-time curve and maximum concentration in steady state to a limited extent, i.e., not more than 25% different from a reference subject, and therefore do not warrant dose adjustments.

Clinical course of COPD patients with exercise-induced elevation of pulmonary artery pressure or less severe pulmonary hypertension presenting with respiratory symptoms and the impact of bosentan intervention-prospective, single-center, randomized, parallel-group study.

BACKGROUND: The data on bosentan were lacking for the treatment of exercise-induced elevation of pulmonary artery pressure (eePAP) or less severe PH in COPD. This study was conducted to investigate long-term efficacy and safety of bosentan for the treatment of eePAP or less severe PH in COPD. METHODS: COPD patients diagnosed at this hospital as having COPD (WHO functional class II, III or IV) with eePAP or less severe PH whose respiratory symptoms were stable but remained and gradually progressed even after COPD therapy were randomly assigned in a 1:1 ratio to receive either bosentan or no PH treatment for two years and assessed at baseline and every 6 months for respiratory failure, activities of daily living (ADL), lung and heart functions by right heart catheterization (RHC), and other parameters. RESULTS: A total of 29 patients who underwent RHC for detail examination were enrolled in the current study between August 2010 and October 2018.No death occurred in drug-treated group (n = 14) for 2 years; 5 patients died in untreated group (n = 15). Significant differences were noted between the 2 group in hospital-free survival (686.00 ± 55.87 days vs. 499.94 ± 53.27 days; hazard ratio [HR], 0.18; P = 0.026) and overall survival (727 days vs. 516.36 ± 55.38 days; HR, 0.095; P = 0.030) in all causes of death analysis, but not in overall survival in analysis of respiratory-related death. Bosentan was not associated with increased adverse events including requiring O2 inhalation. CONCLUSIONS: This study suggested that the prognosis for COPD patients with eePAP or less severe PH presenting with respiratory symptoms was very poor and that bosentan tended to improve their prognosis and suppress ADL deterioration without worsening respiratory failure. TRIAL REGISTRATION: This study was registered with UMIN-CTR Clinical Trial as UMIN000004749 . First trial registration at 18/12/2010.

Sparsentan: the first and only non-immunosuppressive therapy for the reduction of proteinuria in IgA nephropathy.

INTRODUCTION: IgA nephropathy is one of the most common forms of glomerular disease. Patients with persistent proteinuria are at increased risk of progression to kidney failure. There is a significant need for safe and effective therapies to lower proteinuria in these patients. Sparsentan is a non-immunosuppressive agent that acts as a dual angiotensin and endothelin receptor antagonist. It lowers proteinuria in experimental models of glomerular disease and in affected patients. AREAS COVERED: This review covers the immunological and non-immunological actions of sparsentan in glomerular disease. It reviews the clinical trials that evaluated the impact of the drug in pediatric and adult patients with IgA nephropathy. It places the use of sparsentan in an overall treatment paradigm for the full spectrum of patients with IgA nephropathy including nonspecific renoprotective agents such as inhibitors of the renin-angiotensin-aldosterone axis and SGLT2 transporter and immunosuppressive drugs. The review represents a search of the current literature about the effect of the drug on normal physiology and the pathogenesis of IgA nephropathy. EXPERT OPINION: The safety, tolerability, and therapeutic efficacy of sparsentan have been demonstrated in long-term studies of patients with primary glomerular diseases extending over 5 years. The evidence in support of a beneficial treatment effect of sparsentan is stronger in IgAN than in FSGS. It is anticipated that sparsentan will supplant the use of ACEI or ARB as the first-line therapy to reduce proteinuria prior to the implementation of immunosuppressive agents in patients with IgA nephropathy. It may be combined with other renoprotective drugs like SGLT2 inhibitors. Practice guidelines are needed to promote safe and effective use of this new drug by nephrologists caring for patients with IgAN in all clinical settings.

Impact of rapid sequential combination therapy on distinct haemodynamic measures in newly diagnosed pulmonary arterial hypertension.

AIMS: In pulmonary arterial hypertension (PAH), upfront combination therapy with ERA and PDE5i is associated with a reduction in morbidity and mortality events and improves standard haemodynamics, but data remain limited. Aims of this study were (i) to capture detailed haemodynamic effects of rapid sequential dual combination therapy in patients with newly diagnosed PAH; (ii) to monitor the impact of treatment initiation on clinical variables and patients' risk status, and (iii) to compare the treatment effect in patients with 'classical PAH' and 'PAH with co-morbidities'. METHODS: Fifty patients (median age 57 [42-71] years, 66% female) with newly diagnosed PAH (76% idiopathic) were treated with a PD5i/sGC-S or ERA, followed by addition of the respective other drug class within 4 weeks. All patients underwent repeat right heart catheterization (RHC) during early follow-up. RESULTS: At early repeat RHC (7 ± 2 months), there were substantial reductions in mean pulmonary artery pressure (mPAP: 52.2 ± 13.5 to 39.0 ± 10.6 mmHg; -25.3%), and pulmonary vascular resistance (PVR: 12.1 ± 5.7 to 5.8 ± 3.1 WU; -52.1%), and an increase in cardiac index (2.1 ± 0.4 to 2.7 ± 0.7 mL/min/m2; +32.2%) (all P < 0.05). Haemodynamic improvements correlated with improved clinical parameters including 6-min walking distance (336 ± 315 to 389 ± 120 m), NTproBNP levels (1.712 ± 2.024 to 506 ± 550 ng/L, both P < 0.05) and WHO-FC at 12 months, resulting in improved risk status, and were found in patients with few (n = 37) or multiple cardiovascular co-morbidities (BMI > 30 kg/m2, hypertension, diabetes, coronary artery disease [≥3]; n = 13), albeit baseline PVR in PAH patients with multiple co-morbidities was lower (9.3 ± 4.4 vs. 13.1 ± 5.9 WU) and PVR reduction less pronounced compared with those with few co-morbidities (-42.7% vs. -54.7%). However, comprehensive haemodynamic assessment considering further variables of prognostic relevance such as stroke volume index and pulmonary artery compliance showed similar improvements among the two groups (SVI: +50.0% vs. +49.2%; PAC: 91.7% vs. 100.0%). Finally, the 4-strata risk assessment approach was better able to capture treatment response as compared with other approaches, particularly in patients with co-morbidities. CONCLUSIONS: Rapid sequential combination therapy with PDE5i/sGC-S and ERA substantially ameliorates cardiopulmonary haemodynamics at early follow-up in patients without, and to a lesser extent, with cardiovascular co-morbidities. This occurs in line with improvements of clinical parameters and risk status.

Randomized Trial of Macitentan/Tadalafil Single-Tablet Combination Therapy for Pulmonary Arterial Hypertension.

BACKGROUND: Endothelin receptor antagonist (ERA) and phosphodiesterase 5 inhibitor (PDE5i) combination therapy is recommended for low-/intermediate-risk pulmonary arterial hypertension (PAH) patients. A fixed-dose combination of the ERA macitentan and PDE5i tadalafil (M/T FDC) in a once-daily, single tablet would simplify treatment. OBJECTIVES: The multicenter, double-blind, adaptive phase 3 A DUE study investigated the efficacy and safety of M/T FDC vs macitentan 10 mg and vs tadalafil 40 mg monotherapies in PAH patients, including treatment-naïve and prior ERA or PDE5i monotherapy-treated patients. METHODS: World Health Organization functional class II-III patients were randomized to M/T FDC, macitentan, or tadalafil depending on their PAH treatment (treatment-naïve, ERA, or PDE5i monotherapy) at baseline. The primary endpoint was change in pulmonary vascular resistance (PVR) at week 16. RESULTS: In total, 187 patients were randomized to single-tablet M/T FDC (n = 108), macitentan (n = 35), or tadalafil (n = 44). PVR reduction with M/T FDC was significantly greater vs macitentan (29%; geometric mean ratio 0.71; 95% CL: 0.61-0.82; P < 0.0001) and vs tadalafil (28%; geometric mean ratio 0.72; 95% CL: 0.64-0.80; P < 0.0001). Three patients died in the M/T FDC arm (judged unrelated to treatment). Adverse events (AEs) leading to discontinuation, serious AEs, and those of special interest (anemia, hypotension, and edema) were more frequent with M/T FDC. CONCLUSIONS: Macitentan and tadalafil FDC significantly improved PVR vs monotherapies in PAH patients, with a safety and tolerability profile consistent with the individual components. The A DUE study supports M/T FDC as a once-daily, single-tablet combination for initial therapy and escalation to double combination therapy in patients with PAH. (Clinical Study to Compare the Efficacy and Safety of Macitentan and Tadalafil Monotherapies With the Corresponding Fixed-dose Combination Therapy in Subjects With Pulmonary Arterial Hypertension [PAH]) [A DUE]; NCT03904693).

Liver injury due to endothelin receptor antagonists: a real-world study based on post-marketing drug monitoring data.

BACKGROUND: Liver injury is the hallmark adverse reaction of endothelin receptor antagonist (ERA). Since the first drug, bosentan has been widely used in clinical practice, hepatotoxicity has been accompanied by the history of ERA. The new ERA has been proven to have a lower liver risk but the current research findings are inconsistent. ERA-based targeted drug combinations are commonly used in the treatment of pulmonary arterial hypertension, where the risk of liver injury is difficult to estimate. OBJECTIVES: This study aimed to compare the correlation between ERA and different ERA combination regimens with liver injury in the real world. DESIGN: This is a retrospective study using data from the Adverse Event Reporting System (Food and Drug Administration AERS, FAERS). METHODS: The study used proportional imbalance and Bayesian analysis to mine FAERS data from January 2004 to December 2022 to determine the association of three ERAs with liver injury and to further mine the risk of liver injury due to the combination of ERAs with other targeted drugs. In addition, we analyzed the onset time, mortality, and hospitalization rate of liver injury caused by different ERA combination regimens. RESULTS: We screened out 3581 ERA-related liver injury events, of which bosentan (59.82%) had the largest number of cases. The patients with liver injury were mainly female (60.63%), and the age was concentrated between 61 and 75 years (26.75%). According to different signal mining methods, reporting odds ratio (ROR; 3.38, 95% confidence interval = 3.23-3.53), proportional reporting ratio (PRR; 3.22, χ2 = 37.84), Bayesian confidence propagation neural network (BCPNN; 1.68, 95% confidence interval = 1.61), multi-item gamma Poisson shrinker (MGPS; 3.21, 95% confidence interval = 3.09), bosentan had the strongest association with liver injury compared to ambrisentan and macitentan. Furthermore, bosentan + sildenafil [ROR (2.52, 95% confidence interval = 2.23-2.84), PRR (2.44, χ2 = 15.92), BCPNN (1.29, 95% confidence interval = 1.14), MGPS (2.44, 95% confidence interval = 2.21)], bosentan + epoprostenol [ROR (5.39, 95% confidence interval = 4.29-6.77), PRR (4.94, χ2 = 65.18), BCPNN (2.30, 95% confidence interval = 1.83), MGPS (4.94, 95% confidence interval = 4.08)], bosentan + iloprost [ROR (2.70, 95% confidence interval = 2.11-3.45), PRR (2.61, χ2 = 31.03), BCPNN (1.38, 95% confidence interval = 1.08), MGPS (2.61, 95% confidence interval = 2.12)] had a higher risk of liver injury caused by the three ERA combination regimens. The median time to onset of hepatotoxicity associated with all ERA combination regimens was 259 days (interquartile range: 58-716.5 days). Finally, the hospitalization rate for patients experiencing hepatotoxicity with ERA combination regimens was 47.86% and the mortality rate was 12.67%. CONCLUSION: By mining the FAERS, we analyzed and compared the risk of liver injury related to different ERA and ERA combination regimens, and the onset time and adverse reaction outcomes of all ERA combination regimens. According to the results of the study, bosentan had the highest risk of liver injury and the combination regimens bosentan + sildenafil, bosentan + epoprostenol, and bosentan + iloprost had a stronger risk of liver injury. From the early stages of treatment, we need to regularly monitor the liver function of patients, especially for females and the elderly, and discontinue the suspected drug as soon as the liver injury occurs.

Long-term efficacies of selective vasodilators in pulmonary arterial hypertension: a comprehensive comparison using a spontaneous reporting database.

There is no clinical evidence of differences in drugs associated with long-term survival in patients with pulmonary arterial hypertension (PAH) due to the small population and lack of information on death in Japanese medical database systems. This study evaluated whether patient data from a spontaneous reporting database could be used for comparing the effects of pulmonary vasodilators on long-term survival in PAH patients. PAH patient data reported in the Japanese Adverse Drug Event Report (JADER) database from April 2004 to July 2022 were extracted. Kaplan-Meier curves were used to compare survival times. Adjusted hazard ratios (aHRs) for all-cause mortality were determined using Cox proportional hazards models. Of 1969 PAH patients reported in the JADER database, 1208 were included in the survival analyses. The patient demographics were similar to those of the PAH population reported in the Japan Pulmonary Hypertension Registry. Among drugs targeting the prostacyclin pathway, epoprostenol was most associated with long-term survival (aHR, 0.38; 95% confidence interval (CI), 0.23-0.64). The PAH patients treated with endothelin receptor antagonists had improved survival, especially among the macitentan users (aHR, 0.30; 95% CI, 0.22-0.42). Sildenafil was associated with a poor prognosis in the PAH patients (aHR, 1.56; 95% CI, 1.19-2.04). Although our results must be interpreted with caution due to several limitations inherent to spontaneous reporting databases, our approach using the JADER database for survival analysis may provide useful information in limited situations such as the treatment of rare diseases including PAH.

Screening and evaluation of the hit compound from a DNA-encoded library derived from natural products based on immobilized endothelin receptor A.

The enormous growing demand for drug candidates binding to endothelin receptor A (ETA) has made it necessary to continuously pursue new strategies for ligand screening and early evaluation. This work achieved the one-step immobilization of ETA based on the bioorthogonal chemistry between the epidermal growth factor receptor tag (EGFR-tag) and ibrutinib. Comprehensive characterizations including Western blot analysis are performed to realize the morphology, antibody/ligand recognition activity, and specificity of the immobilized ETA. Taking macitentan, ambrisentan, and bosentan as an example, we utilized the immobilized ETA to construct a thermodynamic model for the evaluation of the specific ligands binding to ETA. Using this model, we screened the potential compound NP845 from a DNA-encoded library with 10,686 members derived from natural products and calculated the association constant as (2.24 ± 0.15) × 105 M-1 at 37 °C, thereby demonstrating the good pharmacological activity of NP845. The entropy change (∆Sθ), enthalpy change (∆Hθ), and Gibbs free energy (∆Gθ) were 1.75 J/mol·K, -31.1 kJ/mol, and -31.6 kJ/mol at 37 °C, whereby we recognized the electrostatic force was the driving force of the interaction between NP845 and ETA. In vitro cell tests proved that NP845 can downregulate the expression level of PKA, B-Raf, MEK, and ERK1 in VSMC. Our results indicated that NP845 was a potential lead compound for fighting the ailments mediated by ETA.

Endothelin System in Hypertension and Chronic Kidney Disease.

ET (endothelin) is a powerful vasoconstrictor 21-amino acid peptide present in many tissues, which exerts many physiological functions across the body and participates as a mediator in many pathological conditions. ETs exert their effects through ETA and ETB receptors, which can be blocked by selective receptor antagonists. ETs were shown to play important roles among others, in systemic hypertension, particularly when resistant or difficult to control, and in pulmonary hypertension, atherosclerosis, cardiac hypertrophy, subarachnoid hemorrhage, chronic kidney disease, diabetic cardiovascular disease, scleroderma, some cancers, etc. To date, ET antagonists are only approved for the treatment of primary pulmonary hypertension and recently for IgA nephropathy and used in the treatment of digital ulcers in scleroderma. However, they may soon be approved for the treatment of patients with resistant hypertension and different types of nephropathy. Here, the role of ETs is reviewed with a special emphasis on participation in and treatment of hypertension and chronic kidney disease.

[Pulmonary hypertension - The new ESC guideline]. / Pulmonale Hypertonie ­ Die neue ESC-Leitlinie.

The current guidelines on the diagnosis and treatment of pulmonary hypertension (PH) contain several important new aspects. The definition of PH is changed to a mean pulmonary arterial pressure (mPAP) of >20mmHg in combination with PVR threshold value of >2 Wood units to a define a precapillary component. The clinical classification of PH still distinguishes 5 main groups. The diagnostic algorithm begins with the evaluation of dyspnea in primary care and early referral of patients with suspected PAH (group I), CTEPH (group IV) or severe PH of other groups.Initial treatment planning in PAH is guided by complex risk assessment in 3 risk levels, follow-up assessment is performed using 3 parameters (WHO-FC, NT-proBNP, and 6MWD) with 4 risk levels or individually in patients with comorbidities.For low or intermediate risk patients, initial combination therapy with a phosphodiesterase type 5 inhibitor and an endothelin receptor antagonist is recommended. In high-risk patients, initial triple combination therapy with additional prostacyclin analogues should be considered.Diagnosis and treatment of CTEPH including pulmonary endarterectomy, medical therapy and pulmonary balloon angioplasty should be carried out in CTEPH centers.Patients with severe PH (PVR >5WE) due to PH group II, III or V should be referred to the PH center for study inclusion or individual therapy.