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Background The mechanism leading to the development of immunoglobulin A nephropathy (IgAN) remains to be completely understood. Endothelin-1 (ET-1) as well as angiotensin II (AngII) promote glomerular injury, tubulointerstitial inflammation and fibrosis leading to chronic kidney disease. Sparsentan, a dual endothelin angiotensin receptor antagonist, recently received accelerated approval in the USA for the reduction of proteinuria in adults with IgAN at high risk of disease progression. To elucidate the mechanisms by which sparsentan is efficacious in IgAN, we examined the effect of treatment in gddY mice, a spontaneous IgAN mouse model, versus the monoselective angiotensin II type 1 receptor (AT1R) antagonist, losartan, on the development of renal injury at doses resulting in similar blood pressure lowering. Methods Four-week-old gddY mice were given control chow, chow containing sparsentan or drinking water containing losartan until 12 or 20 weeks old. Results Remarkably, the albumin:creatine ratio (ACR) was attenuated more rapidly and to a greater extent in mice treated with sparsentan than those treated with losartan. The decrease in ACR from baseline after 4 weeks of treatment correlated with beneficial effects of sparsentan on glomerulosclerosis and protection of podocytes and glycocalyx after 16 weeks of treatment across treatment groups; thus, sparsentan treatment delayed development of renal injury to a greater extent than losartan. Expression of mRNA for ET-1, endothelin type A receptor and AT1R and proinflammatory genes was upregulated in 12-week-old gddY mice and was prevented by sparsentan and losartan to a comparable extent. Conclusions The results of this study, and in light of the results of the phase 3 PROTECT trial, provide a novel perspective and understanding of the mechanisms by which sparsentan has a beneficial renoprotective effect against IgAN compared with AT1R antagonism alone. [ABSTRACT FROM AUTHOR]

Abstract 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 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.

Objective: To retrospectively evaluate the incidence rate (IR) of elevated echocardiographic estimated systolic pulmonary artery pressure (sPAP), suspected for pulmonary hypertension (PH), in systemic sclerosis (SSc) patients after the introduction of a combination therapy with bosentan and sildenafil for treatment or prevention of digital ulcers. Methods: Patients attending the Scleroderma Unit of the Universital Hospital of Careggi from July 2010 to July 2023 were enrolled. Patients older than 18 years old with a history of digital ulcers, treated with bosentan and sildenafil in combination for at least 12 months, were included. Patients with a diagnosis of PH preceding the introduction of the therapy were excluded. Demographical data, disease duration, laboratoristic, and instrumental data (pulmonary function tests, echocardiographic estimation of sPAP, and ultrasonographic value of renal resistive index) were collected. The IR of echocardiographic signs suspected of pulmonary hypertension and their 95% confidence interval were calculated in events/1000 patients-years. Results: Thirty-five patients were enrolled; the mean disease duration was 12.82 years (SD 5.92). The mean duration of the combination treatment was 81.03 (SD 43.1.3) months, and the total at-risk time was 2674 months. Two patients (5.7%) presented echocardiographic signs of PH (sPAP 50 mmHg and 40 mmHg); the IR was calculated to be 9/1000 patients-years (95% CI 7.95–10.12). In one of the two patients, right heart catheterism (RHC) excluded PAH, while the other patient refused to undergo RHC, and PAH could not be confirmed/excluded. The stability of PFTs and echocardiographic sPAP was observed during the observation time. Conclusions: The results of this retrospective study suggest that combination therapy with endothelin receptor antagonists and phosphodiesterase-5 (PDE5) inhibitors could help in preventing PAH in SSc; prospective case–control studies on a larger population are needed to improve knowledge in this field. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

This open-label, extension study assessed long-term safety, tolerability, and efficacy of ambrisentan in a pediatric population (age 8– < 18 years) with pulmonary arterial hypertension (PAH). Following completion of a 6-month, randomized study, participants entered the long-term extension at individualized ambrisentan dosages (2.5/5/7.5 or 10 mg/day). Safety assessments included adverse events (AEs), AEs of special interest, and serious AEs (SAEs); efficacy outcomes included 6-min walking distance (6MWD) and World Health Organization functional class (WHO FC). Thirty-eight of 41 (93%) randomized study participants entered the extension; 21 (55%) completed (reaching age 18 years). Most participants received concomitant phosphodiesterase-5 inhibitors (n = 25/38, 66%). Median ambrisentan exposure was 3.5 years. Most participants experienced ≥ 1 AE (n = 34/38, 89%), and 21 (55%) experienced SAEs, most commonly worsening PAH (n = 3/38, 8%), acute cardiac failure, pneumonia, or anemia (n = 2/38; 5% each); none considered ambrisentan-related. Seven participants (18%) died, with recorded reasons (MedDRA preferred term): cardiac failure (n = 2), PAH (n = 2), COVID-19 (n = 1), acute right ventricular failure (n = 1), and failure to thrive (n = 1); median time to death: 5.2 years. Anemia and hepatotoxicity AEs were generally mild to moderate and did not require ambrisentan dose adjustment. Assessed at study end in 29 participants (76%), mean 6MWD improved by 17% (standard deviation: 34.3%), and all (29/29, 100%) had improved or unchanged WHO FC. Conclusion: Long-term weight-based ambrisentan dosing, alone or combined with other PAH therapies in children with PAH aged 8– < 18 years, exhibited tolerability and clinical improvements consistent with prior randomized study results. Trial registration: NCT01342952, April 27, 2011. What is Known: •The endothelin receptor antagonist, ambrisentan, is indicated for treatment of pulmonary arterial hypertension (PAH). Previous studies have shown similar efficacy and tolerability in pediatric patients as in adults. What is New: • This open-label extension study assessed the long-term use of ambrisentan in pediatric patients (8–<18 years) with PAH, most of whom were also receiving recommended background PAH treatment. • Weight-based dosing of ambrisentan, given alone or in combination with other PAH therapies, was well tolerated with clinical improvements consistent with prior randomized study results. [ABSTRACT FROM AUTHOR]

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, χ 2 = 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, χ 2 = 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, χ 2 = 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, χ 2 = 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. [ABSTRACT FROM AUTHOR]

Purpose of Review: To provide an update and review approaches to the treatment of resistant hypertension (RH) with a focus on emerging potential therapies. Recent Findings: Resistant hypertension is defined as a blood pressure that remains elevated above a patient's individualized target despite the concurrent use of 3 antihypertensive agents of different classes including a diuretic or use of 4 or more antihypertensive agents. Patients with RH have an increased risk of adverse cardiovascular and renal outcomes. Most RH is attributed to apparent RH and is not true RH. True RH is a diagnosis of exclusion after apparent RH has been excluded. Treatment of RH is challenging, and blood pressure goal is often difficult to achieve. Currently several new therapies have emerged with forthcoming data that provide promise for improved blood pressure control in those with resistant hypertension. Summary: Once RH has been diagnosed, patients should be on standardized therapy that includes agents from three different classes including a diuretic with addition in most cases of a mineralocorticoid as a fourth line agent. There are newer agents in development currently being studied in clinical trials including dual endothelin receptor antagonists and aldosterone synthase inhibitors that appear to be efficacious. Other approved medications including SGLT2 inhibitors and non-steroidal mineralocorticoids such as finerenone also need to be incorporated into treatment paradigms. Renal denervation with catheter based devices is another potential promising treatment option in this population. [ABSTRACT FROM AUTHOR]

Abstract Background Insulin resistance (IR) is a pathophysiologic hallmark of type 2 diabetes and associated with the presence of chronic kidney disease (CKD). Experimental studies suggest that endothelin-1 increases IR. We assessed the association between IR and cardio-renal outcomes and the effect of the selective endothelin receptor antagonist atrasentan on IR in patients with type 2 diabetes and CKD. Methods We used data from the RADAR and SONAR trials that recruited participants with type 2 diabetes and CKD [eGFR 25–75 mL/min/1.73 m², urine albumin-to-creatinine ratio of 300–5000 mg/g]. IR was calculated using the homeostatic model assessment (HOMA-IR). The association between HOMA-IR and the pre-specified cardio-renal outcomes was assessed using multivariable Cox proportional hazards regression, and effects of atrasentan on HOMA-IR by a linear mixed effect model. Results In the SONAR trial, each log-unit increase in HOMA-IR was associated with an increased risk of the composite cardio-renal outcome [hazard ratio 1.32 (95%CI 1.09,1.60; p = 0.004)], kidney outcome [hazard ratio 1.30 (95%CI 1.00,1.68; p-value = 0.048)], and the kidney or all-cause mortality outcome [hazard ratio 1.25 (95%CI 1.01,1.55; p-value = 0.037)]. After 12 weeks treatment in the RADAR trial (N = 123), atrasentan 0.75 mg/day and 1.25 mg/day compared to placebo reduced HOMA-IR by 19.1 (95%CI -17.4, 44.3) and 26.7% (95%CI -6.4, 49.5), respectively. In the SONAR trial (N = 1914), atrasentan 0.75 mg/day compared to placebo reduced HOMA-IR by 9.6% (95%CI 0.6, 17.9). Conclusions More severe IR is associated with increased risk of cardio-renal outcomes. The endothelin receptor antagonist atrasentan reduced IR. Trial registration RADAR trial (Reducing Residual Albuminuria in Subjects With Diabetes and Nephropathy With AtRasentan): NCT01356849. SONAR trial (The Study Of Diabetic Nephropathy With AtRasentan) NCT01858532.

Objective: To retrospectively evaluate the incidence rate (IR) of elevated echocardiographic estimated systolic pulmonary artery pressure (sPAP), suspected for pulmonary hypertension (PH), in systemic sclerosis (SSc) patients after the introduction of a combination therapy with bosentan and sildenafil for treatment or prevention of digital ulcers. Methods: Patients attending the Scleroderma Unit of the Universital Hospital of Careggi from July 2010 to July 2023 were enrolled. Patients older than 18 years old with a history of digital ulcers, treated with bosentan and sildenafil in combination for at least 12 months, were included. Patients with a diagnosis of PH preceding the introduction of the therapy were excluded. Demographical data, disease duration, laboratoristic, and instrumental data (pulmonary function tests, echocardiographic estimation of sPAP, and ultrasonographic value of renal resistive index) were collected. The IR of echocardiographic signs suspected of pulmonary hypertension and their 95% confidence interval were calculated in events/1000 patients-years. Results: Thirty-five patients were enrolled; the mean disease duration was 12.82 years (SD 5.92). The mean duration of the combination treatment was 81.03 (SD 43.1.3) months, and the total at-risk time was 2674 months. Two patients (5.7%) presented echocardiographic signs of PH (sPAP 50 mmHg and 40 mmHg); the IR was calculated to be 9/1000 patients-years (95% CI 7.95–10.12). In one of the two patients, right heart catheterism (RHC) excluded PAH, while the other patient refused to undergo RHC, and PAH could not be confirmed/excluded. The stability of PFTs and echocardiographic sPAP was observed during the observation time. Conclusions: The results of this retrospective study suggest that combination therapy with endothelin receptor antagonists and phosphodiesterase-5 (PDE5) inhibitors could help in preventing PAH in SSc; prospective case–control studies on a larger population are needed to improve knowledge in this field.

A 69-year-old woman was diagnosed with idiopathic interstitial pneumonia (IIP). The patient underwent a combination therapy of steroid therapy and intravenous cyclophosphamide, long-term oxygen therapy, and the initiation of Nintedanib. However, there was no improvement in IIP, and as a result, the activities of daily living also declined. As one of the various examinations conducted, the results of the right heart catheterization diagnosed the patient with mild pulmonary hypertension, and Macitentan therapy was initiated. The subsequent clinical course appeared to show an improvement in Idiopathic Interstitial Pneumonia (IIP) by adding Macitentan therapy to Nintedanib therapy.

Purpose of Review: Resistant hypertension (RH) defined as uncontrolled blood pressure despite the use of a combination of a renin-angiotensin system blocker, a calcium channel blocker, and a diuretic at maximally tolerated doses is associated with a substantially increased risk of cardiovascular and renal events. Despite targeting relevant pathophysiological pathways contributing to elevated blood pressure, approximately 10–15% of hypertensive patients remain above recommended blood pressure targets. Further optimization of blood pressure control is particularly challenging in patient populations who frequently present with RH such as elderly and patients with chronic kidney disease, due to the unfavorable safety profile of the recommended fourth-line therapy with mineralocorticoid receptor antagonists. This review explores the potential role of endothelin antagonists as an alternative fourth-line therapy. Recent Findings: Despite the well-described role of the endothelin pathway in the pathogenesis of hypertension, it is currently not targeted therapeutically. Recently however, main outcome data from the PRECISION study, a randomized placebo-controlled phase 3 trial, in patients with RH on guideline-recommended standardized single-pill background therapy convincingly demonstrated the safety and blood pressure-lowering efficacy of the dual endothelin antagonist Aprocitentan. Summary: Findings from the phase 3 PRECISION study could signify a turning point in the utilization of endothelin receptor antagonists as a standard treatment for patients with RH. [ABSTRACT FROM AUTHOR]

Background: Insulin resistance (IR) is a pathophysiologic hallmark of type 2 diabetes and associated with the presence of chronic kidney disease (CKD). Experimental studies suggest that endothelin-1 increases IR. We assessed the association between IR and cardio-renal outcomes and the effect of the selective endothelin receptor antagonist atrasentan on IR in patients with type 2 diabetes and CKD. Methods: We used data from the RADAR and SONAR trials that recruited participants with type 2 diabetes and CKD [eGFR 25–75 mL/min/1.73 m², urine albumin-to-creatinine ratio of 300–5000 mg/g]. IR was calculated using the homeostatic model assessment (HOMA-IR). The association between HOMA-IR and the pre-specified cardio-renal outcomes was assessed using multivariable Cox proportional hazards regression, and effects of atrasentan on HOMA-IR by a linear mixed effect model. Results: In the SONAR trial, each log-unit increase in HOMA-IR was associated with an increased risk of the composite cardio-renal outcome [hazard ratio 1.32 (95%CI 1.09,1.60; p = 0.004)], kidney outcome [hazard ratio 1.30 (95%CI 1.00,1.68; p-value = 0.048)], and the kidney or all-cause mortality outcome [hazard ratio 1.25 (95%CI 1.01,1.55; p-value = 0.037)]. After 12 weeks treatment in the RADAR trial (N = 123), atrasentan 0.75 mg/day and 1.25 mg/day compared to placebo reduced HOMA-IR by 19.1 (95%CI -17.4, 44.3) and 26.7% (95%CI -6.4, 49.5), respectively. In the SONAR trial (N = 1914), atrasentan 0.75 mg/day compared to placebo reduced HOMA-IR by 9.6% (95%CI 0.6, 17.9). Conclusions: More severe IR is associated with increased risk of cardio-renal outcomes. The endothelin receptor antagonist atrasentan reduced IR. Trial registration: RADAR trial (Reducing Residual Albuminuria in Subjects With Diabetes and Nephropathy With AtRasentan): NCT01356849. SONAR trial (The Study Of Diabetic Nephropathy With AtRasentan) NCT01858532. [ABSTRACT FROM AUTHOR]

However, after accounting for differences in patient characteristics between patients using loop and thiazide diuretics, we did not observe a significant difference in fluid retention biomarkers between patients stably using these two classes of diuretic agents. Of those, 1514 patients used a loop diuretic, 1303 used a thiazide diuretic, and 93 used a combination of both a loop and a thiazide diuretic in a stable dose throughout the enrichment phase. Loop and thiazide diuretics are frequently used in patients with CKD, with loop diuretics recommended in patients with more advanced kidney disease. [Extracted from the article]

BACKGROUND & OBJECTIVE: We aimed to evaluate the effect of sitaxentan on renal microvascular perfusion via application of ultrasound microbubble contrast. METHODS: Male beagles were randomly divided into: Sham, cardiopulmonary bypass (CPB) and sitaxentan-infused (Sit) groups (n = 6). The ascending slope rate (ASR), area under the curve (AUC), derived peak intensity, and time to peak (TTP) were obtained via ultrasound microbubble contrast before CPB (T1), after 1 h CPB (T2), at end of CPB (T3), and 2 h after CPB (T4). RESULTS: Compared with the Sham group, the CPB group had lower ASR of the renal cortex and medulla at T2 - 4, higher AUC and TTP at T3 - 4, and lower derived peak intensity at T4. The ASR at T2 - 4 in the Sit group was lower, TTP was higher at T2 - 4, and AUC was higher at T3 - 4 (P < 0.05). Compared with the CPB group, the Sit group had higher ASR of the renal cortex and medulla at T3 - 4 and AUC and TTP at T3 - 4 (P < 0.05). Compared with that at T1, the ASR of the renal cortex and medulla at T2 - 4 in the CPB group was lower, and AUC and TTP were higher at T3 - 4. The ASR of the renal cortex and medulla at T2 - 4 in the Sit group was lower, TTP was higher at T2 - 4, and AUC was higher at T4 (P < 0.05). CONCLUSIONS: Ultrasound microbubble contrast could be effectively used to evaluate renal microvascular perfusion peri-CPB in beagles, which was prone to decrease and could be improved via pretreatment with sitaxentan. [ABSTRACT FROM AUTHOR]

Abstract The design and baseline data of the PRECISION study, which evaluates the effect of the dual endothelin receptor antagonist aprocitentan on blood pressure (BP) in patients with resistant hypertension (RHT) are presented. The study is a blinded, randomized, parallel‐group Phase 3 study and its three‐part design assesses the short‐term and sustained long‐term effects of aprocitentan on BP. Results are expected in 2022. Patients with uncontrolled BP (measured as unattended automated office BP) despite the use of three or more antihypertensive medications for at least 1 year were screened. They were switched to a single‐tablet triple fixed combination antihypertensive therapy for at least 4 weeks before entering a single‐blind placebo run‐in period. The 4‐week placebo run‐in period further excluded placebo responders. The randomization period consisted of three sequential parts: (1) a 4‐week double‐blind part with aprocitentan 12.5 mg, 25 mg, or placebo (1:1:1 ratio); (2) a 32‐week single‐blind part with aprocitentan 25 mg; and (3) a 12‐week randomized withdrawal part with aprocitentan 25 mg or placebo (1:1 ratio). The purpose was to demonstrate the BP lowering effect of aprocitentan in RHT (Part 1) and the persistence of this effect (Parts 2 and 3). Out of 1965 screened patients, 730 were randomized resulting in an overall inclusion failure rate of 62.8%. The most common reason for exclusion (44.4% of all screened patients) was failure to meet the BP inclusion criteria. These results underline the high proportion of pseudoresistant hypertension among patients referred for RHT.

Portopulmonary hypertension (PoPH) is a rare subtype of Group 1 pulmonary arterial hypertension (PAH) with a poor prognosis. According to the most up-to-date definition, PoPH is characterized by a mean pulmonary arterial pressure (PAP) of >20 mmHg at rest, a pulmonary artery wedge pressure of ≤15 mmHg, and a pulmonary vascular resistance (PVR) of >2 Wood units with portal hypertension. Like PAH, PoPH is underpinned by an imbalance in vasoactive substances. Therefore, current guidelines recommend PAH-specific therapies for PoPH treatment; however, descriptions of the actual treatment approaches are inconsistent. Given the small patient population, PoPH is often studied in combination with idiopathic PAH; however, recent evidence suggests important differences between PoPH and idiopathic PAH in terms of hemodynamic parameters, treatment approaches, survival, socioeconomic status, and healthcare utilization. Therefore, large, multi-center registry studies are needed to examine PoPH in isolation while obtaining statistically meaningful results. PoPH has conventionally been excluded from clinical drug trials because of concerns over hepatotoxicity. Nevertheless, newer-generation endothelin receptor antagonists have shown great promise in the treatment of PoPH, reducing PVR, PAP, and World Health Organization functional class without causing hepatotoxicity. The role of liver transplantation as a treatment option for PoPH has also been controversial; however, recent evidence shows that this procedure may be beneficial in this patient population. In the future, given the shortage of liver donors, predictors of a favorable response to liver transplantation should be determined to select the most eligible patients. Collectively, advances in these three areas could help to standardize PoPH treatment in the clinic.

Abstract Pulmonary arterial hypertension (PAH) is the second most common lung complication in antiphospholipid syndrome (APS) patients. However, the concurrent development of APS-related nonthrombotic PAH is rarely reported. Lack of awareness for group 1 PAH in APS patient may contribute to underdiagnosis of this condition. Herein, we reviewed the case of a 56-year-old female who was diagnosed with PAH related to APS that mimicked chronic thromboembolic pulmonary hypertension (CTEPH). It is crucial to be aware of the possibility of a group 1 PAH diagnosis, even though patients have already been diagnosed with CTEPH. Furthermore, a multidisciplinary approach and serial follow-up right heart catheterization with echocardiography are important to make a timely diagnosis and provide optimal treatment for APS-related PAH in patients with CTEPH-like clinical features.

Objective: This article reviews the published data including the pharmacology, efficacy, and safety of aprocitentan, a novel endothelin receptor antagonist developed to treat hypertension in conjunction with additional agents., Data Sources: A literature search was conducted from drug discovery until May 2024 through PubMed, MEDLINE, and National Institutes of Health Clinical Trials Registry utilizing the following search terms: Tryvio, aprocitentan, hypertension, resistant hypertension, endothelin receptor antagonist, and ACT-132577., Study Selection and Data Extraction: All relevant English-language studies, or studies that could be appropriately translated into English, containing the pharmacology, pharmacokinetics, safety, and efficacy of aprocitentan, were selected for review., Data Synthesis: In the setting of resistant hypertension, aprocitentan has shown significant reductions in blood pressure in both medical office and 24-hour ambulatory settings at 4 weeks with a sustained effect at 40 weeks. Studies evaluating cardiovascular risk reduction have not been conducted at this time. Fluid retention and edema were the most frequent adverse events reported in clinical studies with aprocitentan. As a class, endothelin receptor antagonists may cause fetal harm; aprocitentan should be used with caution to avoid embryo-fetal toxicity., Relevance to Patient Care and Clinical Practice in Comparison to Existing Drugs: Owing to the existent barriers for the treatment of resistant hypertension, aprocitentan presents itself as an effective option when added to traditional antihypertensives. This single-strength, once-daily regimen may serve as an appealing option to both patients and prescribers., Conclusion: Aprocitentan is a safe and effective medication for the treatment of hypertension when added to other pharmacological therapies., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: The 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)., Methods: Patients 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., Results: In 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., Conclusions: The 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., Competing Interests: Conflict of Interest Statement Ms Efficace and Drs Freiberg and Haberle are employees and shareholders of Johnson & Johnson. Ms Walter is a contractor of Johnson & Johnson. Drs Clift, Berger, Sondergaard, and d’Udekem received consulting fees from Johnson & Johnson. Dr Sondergaard is currently chief medical officer and divisional vice president at Abbott Structural Heart. Dr Nicolarsen received consulting fees from Medtronic, accommodation support for attending meetings from the Adult Congenital Heart Association, and served as a board member for Adult Congenital Heart Association and Alliance for Adult Research in Congenital Cardiology. All other authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The design and baseline data of the PRECISION study, which evaluates the effect of the dual endothelin receptor antagonist aprocitentan on blood pressure (BP) in patients with resistant hypertension (RHT) are presented. The study is a blinded, randomized, parallel‐group Phase 3 study and its three‐part design assesses the short‐term and sustained long‐term effects of aprocitentan on BP. Results are expected in 2022. Patients with uncontrolled BP (measured as unattended automated office BP) despite the use of three or more antihypertensive medications for at least 1 year were screened. They were switched to a single‐tablet triple fixed combination antihypertensive therapy for at least 4 weeks before entering a single‐blind placebo run‐in period. The 4‐week placebo run‐in period further excluded placebo responders. The randomization period consisted of three sequential parts: (1) a 4‐week double‐blind part with aprocitentan 12.5 mg, 25 mg, or placebo (1:1:1 ratio); (2) a 32‐week single‐blind part with aprocitentan 25 mg; and (3) a 12‐week randomized withdrawal part with aprocitentan 25 mg or placebo (1:1 ratio). The purpose was to demonstrate the BP lowering effect of aprocitentan in RHT (Part 1) and the persistence of this effect (Parts 2 and 3). Out of 1965 screened patients, 730 were randomized resulting in an overall inclusion failure rate of 62.8%. The most common reason for exclusion (44.4% of all screened patients) was failure to meet the BP inclusion criteria. These results underline the high proportion of pseudoresistant hypertension among patients referred for RHT. [ABSTRACT FROM AUTHOR]

Background: Although major advances have been made in the pathogenesis and management of pulmonary arterial hypertension (PAH), the endothelin system is still considered to play a vital role in the pathology of PAH due to its vasoconstrictive action. Endothelin receptor antagonists (ERAs), either as monotherapy or in combination with other drugs, have attracted much attention in the treatment of this lethal disease, and research is continuing. Methods: A novel ERA, pipersentan 5-(1,3-Benzodioxol-5-yl)-6-[2-(5-bromopyrimidin-2-yl)oxyethoxy]-N-(2-methoxyethylsulfamoyl)pyrimidin-4-amine, was recently synthesized and the physicochemical characterizations and the pharmacology both in vitro and in vivo were studied. Results: This orally administered ERA can both competitively and selectively inhibit the binding of endothelin-1 (ET-1) to its receptors with good physicochemical characteristics. Pipersentan efficaciously antagonized the effects of ET-1 on pulmonary artery smooth muscle cell proliferation, migration and calcium mobilization and effectively improved right ventricular hypertrophy and pulmonary arterial pressure in both monocrotaline- and hypoxia-induced pulmonary hypertension (PH) rat models. Conclusions: This profile identifies pipersentan as a new agent for treating ET-1 system activation-related PH. [ABSTRACT FROM AUTHOR]

Simple Summary: In this review, we describe the basic functions of endothelin and related molecules, including their receptors and enzymes. Furthermore, we discuss the important role of endothelin in several cardiovascular diseases, the relevant clinical evidence for targeting the endothelin pathway, and the scope of endothelin-targeting treatments in the future. We highlight the present uses of endothelin receptor antagonists and the advancements in the development of future treatment options, thereby providing an overview of endothelin research over the years and its future scope. Endothelin was first discovered more than 30 years ago as a potent vasoconstrictor. In subsequent years, three isoforms, two canonical receptors, and two converting enzymes were identified, and their basic functions were elucidated by numerous preclinical and clinical studies. Over the years, the endothelin system has been found to be critical in the pathogenesis of several cardiovascular diseases, including hypertension, pulmonary arterial hypertension, heart failure, and coronary artery disease. In this review, we summarize the current knowledge on endothelin and its role in cardiovascular diseases. Furthermore, we discuss how endothelin-targeting therapies, such as endothelin receptor antagonists, have been employed to treat cardiovascular diseases with varying degrees of success. Lastly, we provide a glimpse of what could be in store for endothelin-targeting treatment options for cardiovascular diseases in the future. [ABSTRACT FROM AUTHOR]

In patients treated with macitentan (Opsumit®, Actelion Pharmaceuticals Ltd., Basel, Switzerland) for pulmonary arterial hypertension (PAH), prevention and/or effective management of treatment-related adverse events may improve adherence. However, management of these adverse events can be challenging and the base of evidence and clinical experience for macitentan is limited. In the absence of evidence, consensus recommendations from physicians experienced in using macitentan to treat PAH may benefit patients and physicians who are using macitentan. Consensus recommendations were developed by a panel of physicians experienced with macitentan and PAH using a modified Delphi process. Over three iterations, panelists developed and refined a series of statements on the use of macitentan in PAH and rated their agreement with each statement on a Likert scale. The panel of 18 physicians participated and developed a total of 118 statements on special populations, add-on therapy, drug-drug interactions, warnings and precautions, hospitalization and functional class, and adverse event management. The resulting consensus recommendations are intended to provide practical guidance on real-world issues in using macitentan to treat patients with PAH.

Background: Although major advances have been made in the pathogenesis and management of pulmonary arterial hypertension (PAH), the endothelin system is still considered to play a vital role in the pathology of PAH due to its vasoconstrictive action. Endothelin receptor antagonists (ERAs), either as monotherapy or in combination with other drugs, have attracted much attention in the treatment of this lethal disease, and research is continuing.Methods: A novel ERA, pipersentan 5-(1,3-Benzodioxol-5-yl)-6-[2-(5-bromopyrimidin-2-yl)oxyethoxy]-N-(2-methoxyethylsulfamoyl)pyrimidin-4-amine, was recently synthesized and the physicochemical characterizations and the pharmacology both in vitro and in vivo were studied.Results: This orally administered ERA can both competitively and selectively inhibit the binding of endothelin-1 (ET-1) to its receptors with good physicochemical characteristics. Pipersentan efficaciously antagonized the effects of ET-1 on pulmonary artery smooth muscle cell proliferation, migration and calcium mobilization and effectively improved right ventricular hypertrophy and pulmonary arterial pressure in both monocrotaline- and hypoxia-induced pulmonary hypertension (PH) rat models.Conclusions: This profile identifies pipersentan as a new agent for treating ET-1 system activation-related PH.

A 69-year-old woman was diagnosed with idiopathic interstitial pneumonia (IIP). The patient underwent a combination therapy of steroid therapy and intravenous cyclophosphamide, long-term oxygen therapy, and the initiation of Nintedanib. However, there was no improvement in IIP, and as a result, the activities of daily living also declined. As one of the various examinations conducted, the results of the right heart catheterization diagnosed the patient with mild pulmonary hypertension, and Macitentan therapy was initiated. The subsequent clinical course appeared to show an improvement in Idiopathic Interstitial Pneumonia (IIP) by adding Macitentan therapy to Nintedanib therapy. [ABSTRACT FROM AUTHOR]

Sickle cell disease (SCD), a haemoglobinopathy characterized by chronic haemolysis with acute exacerbations and vascular occlusion episodes, may be complicated by pulmonary hypertension. The latter may be caused by chronic thromboembolic disease of pulmonary artery branches and its management is not well-defined. Herein, we present a case of SCD complicated by chronic thromboembolic pulmonary hypertension of subsegmental pulmonary artery branches successfully treated with endothelin receptor antagonists, orally administered prostacyclin analogs and balloon pulmonary angioplasty. This challenging case highlights the need for clinical awareness of chronic thromboembolic pulmonary hypertension as a specific and potentially curable form of pulmonary hypertension complicating SCD course that may necessitate combined pharmacologic and interventional management. [ABSTRACT FROM AUTHOR]

Ambrisentan is a selective type A endothelin receptor antagonist used to treat primary pulmonary arterial hypertension (PAH). A 52-year-old female was admitted to the emergency department with presenting symptoms of submandibular swelling and worsening dyspnea. The patient has a history of PAH on treatment. She was previously on sildenafil. All her blood parameters except renal function tests (blood urea, creatinine, potassium, and sodium) were normal during hospitalization for the management of PAH. Some months after treatment with sildenafil, she was switched to Ambrisentan by her consultant. ECG showed severe PAH (80 mmHg), mild right ventricle dysfunction, no regional wall motion abnormalities, and good left ventricle systolic function. She was diagnosed as cor pulmonale. She was dehydrated with reduced skin turgor. USG abdomen revealed bilateral renal parenchymal disease. She also complained of a puffy reddish discoloration of the skin along with angioedema. After ruling out the possibility of other factors contributing to angioedema, Ambrisentan was most likely related and was not excluded. Ambrisentan was, therefore, discontinued and replaced with tadalafil. She was seen on an outpatient basis and was symptomatically better. Health education was provided on the safe use of drugs. Through this report, we bring your attention to the possibility of such events with Ambrisentan, and cannot be neglected. [ABSTRACT FROM AUTHOR]

Background: In a long-term event-driven trial, macitentan has demonstrated beneficial time to clinical worsening in patients with pulmonary arterial hypertension (PAH) and reduced PAH-related hospitalization rates compared with placebo. Macitentan is the most recently approved endothelin receptor antagonist (ERA) and is the first ERA that has shown efficacy for morbidity and mortality in PAH patients; therefore, patients and physicians may consider converting treatment from ambrisentan to macitentan. Our study evaluated the safety, efficacy, and quality of life in PAH patients transitioning from ambrisentan to macitentan. Methods: This was a real-world, prospective study with a 12-month follow-up. PAH patients who had received stable doses of ambrisentan for over 3 months, were within the World Health Organization Functional Class II/III, and 6-min walk distance ≥ of 250 m were enrolled. The study included a screening period, followed by a transition phase, after which patients entered the long-term follow-up. Clinical data and treatment satisfaction outcomes were collected to assess and monitor the safety and efficacy of the transition. The trial was registered at the Chinese Clinical Trial Registry (www.chictr.org.cn; No. ChiCTR2000034898). Results: One hundred and fifty-seven enrolled PAH patients completed the transition. All criteria for continuous treatment transition were met by 145 patients (92.4%). Results showed improvements in exercise capacity, cardiac function, and hemodynamics compared with baseline. During the process, 4 patients discontinued macitentan due to adverse events. There was no statistical difference in the overall incidence of adverse events before and after the transition. Conclusion: Transition to macitentan from ambrisentan was successful and well-tolerated by PAH patients, and was associated with greater efficacy and satisfaction. [ABSTRACT FROM AUTHOR]

This paper summarizes a personal perspective on key learnings from projects the author was involved in over the last 20 years. For example, the discovery of macitentan, the most successful molecule to date from this personal collection, marketed by J&J for the treatment of pulmonary arterial hypertension (PAH). [1] Then the discovery of ACT-462206, a dual orexin receptor antagonist for the treatment of insomnia disorder with a serendipitously short story from the screening hit to the drug [2] followed by the identification of daridorexant, another dual orexin receptor antagonist. Daridorexant successfully passed first pivotal phase 3 clinical trial in April 2020 for the treatment of insomnia disorder [3] ("Good things come to those who wait"). Finally, ACT-451840, an antimalarial drug with a novel mechanism of action, identified in the perfect collaboration between academia and industry. The compound is in phase 2 clinical development. [4] In addition, the importance of the screening compound collection is briefly discussed, as a key asset for drug discovery. The measures Idorsia implemented to obtain valuable hits from high-throughput screening (HTS) campaigns are elaborated. [5] Drug discovery is a multi-disciplinary business with unlimited exciting challenges asking for excessive optimism when tackling them in a playful manner.

Introduction: Endothelin receptor antagonists (ERAs) are widely accepted as a specific treatment for pulmonary arterial hypertension. Unfortunately, consensus and recommendations are lacking for the treatment of patients who suffer from pulmonary arterial hypertension and congenital heart disease, including Eisenmenger syndrome. Objective: This meta-analysis aimed to compare the effect of ERA on patients with Eisenmenger syndrome. Methods: Electronic search on PubMed (MEDLINE), EBSCO, EuropePMC, Clinicaltrials.gov, and Google Scholar was done. Studies involving the use of ERAs on Eisenmenger syndrome patients were included. There were 18 studies included. The primary outcome of interest was the 6-min walking test distance before and after exposure to ERA. Results: There were 517 patients with Eisenmenger syndrome. The subjects had Eisenmenger syndrome secondary to congenital heart disorders, with WHO functional Class ranging from Class I–IV. The follow-up ranges from a mean of 4–60 months. Seventeen studies reported a statistically significant difference between pretreatment and the posttreatment result of 6-min walking test distance. Pooled mean difference comparing pre and posttreatment values yielded an increase of 55.24 m (42.15, 68.33) P < 0.001; moderate heterogeneity I2 51% P = 0.008. Pooled mean pulmonary vascular resistance index difference comparing pre and posttreatment values yielded a decrease of 4.76 woods unit (-6.86, -2.66), P < 0.001 favoring posttreatment; low heterogeneity I2 0%, P = 0.82. Pooled mean mean pulmonary arterial pressure difference comparing pre and posttreatment values yielded a decrease of 5.40 mmHg (-7.53, -3.28), P < 0.001 favoring posttreatment, low heterogeneity I2 0%, P = 0.65. Conclusion: Implementation of ERA in Eisenmenger improves 6-min walking distance and pulmonary vascular pressure indices. Earlier administration of ERA might be beneficial, further studies are needed to assess mortality benefit of this agent.

Background: In a long-term event-driven trial, macitentan has demonstrated beneficial time to clinical worsening in patients with pulmonary arterial hypertension (PAH) and reduced PAH-related hospitalization rates compared with placebo. Macitentan is the most recently approved endothelin receptor antagonist (ERA) and is the first ERA that has shown efficacy for morbidity and mortality in PAH patients; therefore, patients and physicians may consider converting treatment from ambrisentan to macitentan. Our study evaluated the safety, efficacy, and quality of life in PAH patients transitioning from ambrisentan to macitentan.Methods: This was a real-world, prospective study with a 12-month follow-up. PAH patients who had received stable doses of ambrisentan for over 3 months, were within the World Health Organization Functional Class II/III, and 6-min walk distance ≥ of 250 m were enrolled. The study included a screening period, followed by a transition phase, after which patients entered the long-term follow-up. Clinical data and treatment satisfaction outcomes were collected to assess and monitor the safety and efficacy of the transition. The trial was registered at the Chinese Clinical Trial Registry (www.chictr.org.cn; No. ChiCTR2000034898).Results: One hundred and fifty-seven enrolled PAH patients completed the transition. All criteria for continuous treatment transition were met by 145 patients (92.4%). Results showed improvements in exercise capacity, cardiac function, and hemodynamics compared with baseline. During the process, 4 patients discontinued macitentan due to adverse events. There was no statistical difference in the overall incidence of adverse events before and after the transition.Conclusion: Transition to macitentan from ambrisentan was successful and well-tolerated by PAH patients, and was associated with greater efficacy and satisfaction.

Retinitis pigmentosa (RP) and macular dystrophy (MD) are characterized by gradual photoreceptor death in the retina and are often associated with genetic mutations, including those in the prominin-1 (Prom1) gene. Prom1-knockout (KO) mice recapitulate key features of these diseases including light-dependent retinal degeneration and constriction of retinal blood vessels. The mechanisms underlying such degeneration have remained unclear, however. We here analysed early events associated with retinal degeneration in Prom1-KO mice. We found that photoreceptor cell death and glial cell activation occur between 2 and 3 weeks after birth. Whereas gene expression was not affected at 2 weeks, the expression of several genes was altered at 3 weeks in the Prom1-KO retina, with the expression of that for endothelin-2 (Edn2) being markedly upregulated. Expression of Edn2 was also induced by light stimulation in Prom1-KO mice reared in the dark. Treatment with endothelin receptor antagonists attenuated photoreceptor cell death, gliosis and retinal vessel stenosis in Prom1-KO mice. Our findings thus reveal early manifestations of retinal degeneration in a model of RP/MD and suggest potential therapeutic agents for these diseases. This article has an associated First Person interview with the first author of the paper.

Aprocitentan is an orally active dual endothelin receptor antagonist currently in development for treatment of difficult‐to‐control (resistant) hypertension. In phase 1 and 2 studies, aprocitentan has been characterized predominantly in Caucasian subjects. In this bridging, double‐blind study, 20 healthy Japanese and Caucasian male and female subjects received 25 mg of aprocitentan or placebo once daily for 10 days and were monitored until 216 hours after the last dosing. The pharmacokinetics of aprocitentan were similar between ethnicities. At steady state, maximum plasma concentration was reached at 4 and 3 hours, and elimination half‐life was 49.1 and 48.8 hours for Japanese and Caucasian subjects, respectively. The accumulation index was around 3 for both populations. Geometric means ratios for maximum plasma concentration and area under the plasma concentration–time curve during 1 dosing interval were around 1, with 90% confidence interval ranging from 0.87 to 1.30. Aprocitentan was safe and well tolerated in both groups. As no clinically relevant differences were found between Japanese and Caucasian subjects, it is unlikely that the pharmacokinetics of aprocitentan would differ significantly between Caucasian subjects and other ethnicities. Aprocitentan can therefore be administered at a dose level of up to 25 mg in any ethnicity without dose adjustment. [ABSTRACT FROM AUTHOR]

Background: Pulmonary hypertension patients experienced a high financial burden due to the high cost of drug therapy, high incidence of comorbidities and hospitalizations. Endothelin receptor antagonists (ERAs) in PAH treatment showed a high cost. While ambrisentan has been covered by medical insurance of a local government of China, there has been a drug transition from bosentan to ambrisentan in treating PAH patients. We evaluated the safety, efficacy and tolerability of ambrisentan after drug transition. Methods: Liver and renal functions were inspected at baseline, month 1, 3 and 6. NT-proBNP, echocardiographic variables, WHO functional class (WHO-FC), 6-minute walking distance (6MWD) were measured in the baseline and month 6 to evaluate the safety and efficacy. Quality of life (QOL) scale was used in the baseline and month 6 to investigate the tolerability and quality of life of PAH patients. Results: Among 224 PAH patients, 49 stable PAH patients meet the inclusion criteria were enrolled, among which three patients discontinued during the study. Our results showed no difference in 6-minute walking distance (6MWD) of PAH patients from baseline and month 6. The liver and renal function, N-terminal pro-brain natriuretic peptide (NT-proBNP), WHO functional class (WHO-FC) showed no difference either. For echocardiography parameters, the left ventricular end-diastolic dimension (LVEDD) of month 6 decreased. Other parameters were no significant difference from the baseline. There was no difference in the QOL scale between baseline and month 6. Conclusion: Our results suggested that it is safe and tolerable for stable PAH patients to transition from bosentan to ambrisentan without influencing hematologic parameters or heart function. [ABSTRACT FROM AUTHOR]

Patricia N Sidharta,1 Meggane Melchior,1 Martin K Kankam,2 Jasper Dingemanse1 1Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil CH-4123, Switzerland; 2Vince and Associates Clinical Research, Overland Park, KS 66211, USA Background: Aprocitentan is an orally active, dual endothelin (ET) receptor antagonist developed for the treatment of hypertension in which, despite available treatments, a medical need exists for drugs with a new mechanism of action. Subjects and methods: In this study, the single- and multiple-dose tolerability, safety, pharmacokinetics (PK), and pharmacodynamics of up to 600 mg (single doses) and 100 mg once a day (qd; multiple doses) of aprocitentan were investigated in healthy male and female subjects. The effect of age on the tolerability and PK parameters was investigated at a dose of 100 mg qd.Results: Aprocitentan was well tolerated across all doses. No serious adverse events (AEs) occurred. The most frequently reported AE was headache. Small increases in body weight were recorded in subjects receiving 100 mg qd. Plasma concentration–time profiles of aprocitentan were similar after single- and multiple-dose administration, and support a qd dosing regimen based on a half-life of 44 hours. After multiple doses, PK was dose proportional. Accumulation at steady state, reached by Day 8, was 3-fold. Only minor differences in exposure between healthy females and males, healthy elderly and adult subjects, and fed and fasted conditions were observed. Plasma ET-1 concentrations, reflecting ETB receptor antagonism, significantly increased with doses ≥25 mg. Time-matched analysis of electrocardiogram (ECG) parameters did not suggest drug-induced ECG effects. Exposure–response analysis indicated no QTc prolongations at plasma levels up to 10 µg/mL. Conclusion: Aprocitentan was well tolerated in healthy subjects with a PK profile favorable for qd dosing. Keywords: first-in-human study, endothelin, endothelin receptor antagonist, aprocitentan, pharmacokinetics, pharmacodynamics

Endothelin was first discovered more than 30 years ago as a potent vasoconstrictor. In subsequent years, three isoforms, two canonical receptors, and two converting enzymes were identified, and their basic functions were elucidated by numerous preclinical and clinical studies. Over the years, the endothelin system has been found to be critical in the pathogenesis of several cardiovascular diseases, including hypertension, pulmonary arterial hypertension, heart failure, and coronary artery disease. In this review, we summarize the current knowledge on endothelin and its role in cardiovascular diseases. Furthermore, we discuss how endothelin-targeting therapies, such as endothelin receptor antagonists, have been employed to treat cardiovascular diseases with varying degrees of success. Lastly, we provide a glimpse of what could be in store for endothelin-targeting treatment options for cardiovascular diseases in the future.

Chronic kidney disease (CKD) is the main cause of end-stage renal disease worldwide arising as a frequent complication of diabetes, obesity, and hypertension. Current therapeutic options, mainly based of inhibition of the renin-angiotensin system (RAS), provide imperfect renoprotection if started at an advanced phase of the disease, and treatments that show or even reverse the progression of CKD are needed. The endothelin (ET) system contributes to the normal renal physiology; however, robust evidence suggests a key role of ET-1 and its cognate receptors, in the progression of CKD. The effectiveness of ET receptor antagonists in ameliorating renal hemodynamics and fibrosis has been largely demonstrated in different experimental models. A significant antiproteinuric effect of ET receptor antagonists has been found in diabetic and non-diabetic CKD patients even on top of RAS blockade, and emerging evidence from ongoing clinical trials highlights their beneficial effects on a wide range of kidney disorders. [ABSTRACT FROM AUTHOR]

Heart failure (HF) and pulmonary hypertension (PH) are increasingly prevalent comorbidities in patients presenting for noncardiac surgery. The unique pathophysiology and pharmacotherapies associated with these syndromes have important perioperative implications. As new medications for HF and PH emerge, it is imperative that anesthesiologists and other perioperative providers understand their mechanisms of action, pharmacokinetics, and potential adverse effects. We present an overview of the novel HF and PH pharmacotherapies and strategies for their perioperative management., Competing Interests: Disclosure The authors have no conflicts of interest to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aprocitentan is an investigational, orally active, dual, endothelin receptor antagonist that targets a novel pathway in the treatment of difficult‐to‐control (resistant) hypertension. The drug‐drug interaction potential of aprocitentan on the breast cancer resistance protein (BCRP) transporter substrate rosuvastatin was investigated in this single‐center, open‐label, single‐sequence study. Twenty healthy male subjects received a single dose of 10‐mg rosuvastatin on days 1 and 13 followed by pharmacokinetic and tolerability assessments for up to 120 hours. From day 5 to day 17, subjects received 25 mg of aprocitentan once daily. Seventeen of 20 enrolled subjects completed the treatment. At steady state, aprocitentan did not affect the pharmacokinetics of rosuvastatin in a clinically relevant way. The maximum plasma concentration was increased by 40% with a 90% confidence interval of 1.19 to 1.65. However, the ratio of the geometric means for both area under the plasma concentration–time curve from time 0 to time t and area under the plasma concentration–time curve from time 0 to infinity was close to 1 with the 90% confidence interval within a reference interval of 0.80 to 1.25. Adverse events leading to study discontinuation were reported in 2 subjects. Overall, the combination of rosuvastatin and aprocitentan was well tolerated. Based on these data, aprocitentan does not affect BCRP and can be administered concomitantly with drugs dependent on BCRP transport. [ABSTRACT FROM AUTHOR]

Abstract The dual endothelin receptor antagonist macitentan was approved in 2013 for the treatment of pulmonary arterial hypertension. Macitentan is an inducer of cytochrome P450 expression in vivo in animal species but not in man. In rat and dog, changes in P450 expression manifest as autoinduction upon repeat dosing. The induction pattern, however, significantly differed between both species, and between male and female rats. While macitentan exposure steadily declined with dose in the dog, P450 induction was saturable in the rat reaching levels of 40%‐60% and 60%‐80% at steady‐state in male and female animals, respectively. The nature and number of P450 enzymes involved in macitentan clearance were identified as a major reason for the observed species differences. In the dog, macitentan was metabolized by a single P450 enzyme, that is, Cyp3a12, whereas several members of the Cyp2c and Cyp3a families were involved in the rat. Macitentan selectively upregulated Cyp3a expression in rat, whereas the expression of the Cyp2c enzymes involved in macitentan metabolism remained mostly unchanged, eventually leading to a higher contribution of Cyp3a upon induction. Macitentan also induced CYP3A4 expression in human hepatocytes via initial activation of the human pregnane X receptor. No such induction was evident in humans at the therapeutic macitentan dose of 10 mg as shown in a clinical drug‐drug interaction study with the CYP3A4 substrate sildenafil.

Objective: To assess the safety and efficacy of the endothelin receptor antagonist ambrisentan in pediatric pulmonary arterial hypertension (PAH). Study design: In this open-label, phase IIb study, patients with PAH aged 8 to

At the present time evidential base on bosentan use comprises more randomized control trials results compared with other Lag-specific medications. Bosentan can be successfully used as monotherapy of in combination with medications of other groups in patients with idiopathic pulmonary hypertension (PH), pulmonary arterial hypertension (PAH) comorbid with connective tissue disease (PAH-CTD), HIV (PAH-HIV), congenital heart disorders (systemic-to-pulmonary shunts) - PAH-CHD, and also in PH treatment and for disease progression delay in patients with unimpaired functional class. It is the only Lag-specific medication approved for use in children and the only medication of this group included in the list of essential medicines. The articles presents literature review of clinical trials on bosentan and discusses indications, contradictions and side effects of its use.

At the present time evidential base on bosentan use comprises more randomized control trials results compared with other Lag-specific medications. Bosentan can be successfully used as monotherapy of in combination with medications of other groups in patients with idiopathic pulmonary hypertension (PH), pulmonary arterial hypertension (PAH) comorbid with connective tissue disease (PAH-CTD), HIV (PAH-HIV), congenital heart disorders (systemic-to-pulmonary shunts) – PAHCHD, and also in PH treatment and for disease progression delay in patients with unimpaired functional class. It is the only Lag-specific medication approved for use in children and the only medication of this group included in the list of essential medicines. The articles presents literature review of clinical trials on bosentan and discusses indications, contradictions and side effects of its use.