Oral Endothelin Receptor Antagonist Research Articles

Bosentan in the treatment of persistent pulmonary hypertension in newborns: a systematic review and meta-analysis.

Persistent pulmonary hypertension of the newborn is a life-threatening condition that affects about 1-2 per 1,000 live births worldwide. Bosentan is an oral dual endothelin receptor antagonist that may have a beneficial effect on persistent pulmonary hypertension of the newborn by reducing pulmonary vascular resistance and improving oxygenation. However, its role in persistent pulmonary hypertension of the newborn remains unclear. To systematically evaluate the efficacy and safety of bosentan as an adjuvant therapy for persistent pulmonary hypertension of the newborn in newborns. We searched six English and two Chinese databases from their inception to 1 January 2023 following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We included randomised controlled trials and retrospective studies that compared bosentan with placebo or other drugs for persistent pulmonary hypertension of the newborn in newborns. We performed a meta-analysis using random-effects models and assessed the risk of bias and heterogeneity in the included studies. We included 10 studies with a total of 550 participants. Bosentan significantly reduced the treatment failure rate (relative risk = 0.25, P < 0.001), pulmonary artery pressure (mean difference = -11.79, P < 0.001), and length of hospital stay (mean difference = -1.04, P = 0.003), and increased the partial pressure of oxygen (mean difference = 10.02, P < 0.001) and blood oxygen saturation (SpO2) (mean difference = 8.24, P < 0.001) compared with a placebo or other drugs. The occurrence of adverse reactions was not significantly different between bosentan and a placebo or other drugs. Bosentan is effective in the treatment of persistent pulmonary hypertension of the newborn but adverse reactions such as abnormal liver function should be observed when using it.

Treatment of nonarteritic anterior ischemic optic neuropathy with an endothelin antagonist: ENDOTHELION (ENDOTHELin antagonist receptor in Ischemic Optic Neuropathy)—a multicentre randomised controlled trial protocol

BackgroundNonarteritic anterior ischemic optic neuropathy (NAAION) is a major cause of blindness in individuals over 50 years of age, with no available effective treatment. The oral dual endothelin receptor antagonist, bosentan, increases retinal optic nerve head blood flow in healthy humans and glaucoma patients. The objective of this trial is to assess the efficacy of bosentan administered at the acute stage in improving outcomes in NAAION patients.MethodsENDOTHELION (ENDOTHELin antagonist receptor in Ischemic Optic Neuropathy) is a phase III, interventional, prospective, multicentre, placebo-controlled randomised double-blind clinical trial. The primary outcome is change in the visual field mean deviation (MD) at 3 months (Humphrey 30-2 SITA standard programme). Secondary outcomes include MD and visual acuity changes up to 24 months, changes in peripapillary retinal nerve fibre and macular ganglion cell layer thickness in the affected eye, as measured by optical coherence tomography, rate of NAAION bilateralisation at 2 years, and quality-of-life. Patients over 50 years of age presenting with typical NAAION of recent onset (less than 21 days) are randomly assigned to either 125 mg oral bosentan or placebo, twice a day, during 8 weeks. Besides visits during the treatment phase, patients attend follow-up visits at 2, 3, 6, 12 and 24 months. The inclusion of patients began in August 2015 at five French University hospital ophthalmology departments and two specialised ophthalmology centres. It is planned to include 86 patients in this trial. To date we have included 72 patients and 49 have completed the full follow-up process.DiscussionAn endothelin receptor antagonist is a potential approach to improving the anatomical and functional prognosis of patients with NAAION. This multicentre double-blind randomised controlled trial is an opportunity to assess (1) the effect of bosentan on the structure and function of the optic nerve in NAAION, at 3 months, (2) the effect of bosentan on the bilateralisation rate at 24 months and (3) the tolerance profile of bosentan in this population.Trial registrationClinicalTrials.gov NCT02377271. Registered on March 3, 2015.

Safety of macitentan for the treatment of pulmonary hypertension: Real-world experience from the OPsumit® USers Registry (OPUS) and OPsumit® Historical USers cohort (OrPHeUS).

Macitentan is an oral endothelin receptor antagonist for the management of pulmonary arterial hypertension (PAH). The OPsumit® USers Registry (OPUS) and the OPsumit® Historical USers cohort (OrPHeUS) medical chart review provide real-world data for patients newly initiating macitentan. This study aims to describe the characteristics, safety profile, and clinical outcomes of PAH patients newly treated with macitentan in the combined OPUS/OrPHeUS data set. OPUS was a prospective, multicenter, long-term, observational drug registry from April 2014 to June 2020. OrPHeUS was a retrospective, US, multicenter chart review: observation period October 2013 to March 2017. All analyses were descriptive. At registry closure in June 2020, the combined population consisted of 5654 patients, of whom 81.9% were diagnosed with PAH. For these 4626 patients, median duration of macitentan exposure observed was 14.5 (Q1 = 5.2, Q3 = 29.0) months; idiopathic PAH (54.8%) was the most common form of PAH; macitentan was initiated as monotherapy (37.9%), or as part of double (48.0%) or triple therapy (14.1%); discontinuation due to nonhepatic/hepatic adverse events occurred in 17.1%/0.3% of patients; 9.9% of patients experienced ≥1 hepatic adverse events; Kaplan-Meier estimates showed that at 1 year 59.9% (95% confidence interval: 58.3, 61.5) of patients were free from hospitalization and survival was 90.4% (89.3, 91.3). This analysis of real-world data from the combined OPUS and OrPHeUS populations demonstrated that macitentan is well tolerated in a large, diverse population of PAH patients, with overall and hepatic safety profiles consistent with previous macitentan clinical trials.

Evaluation of herb-drug interaction of ambrisentan with shikonin based on UPLC-MS/MS

Context Ambrisentan is an oral endothelin-receptor antagonist (ERA). However, there is no report on the interaction between ambrisentan and shikonin. Objective To investigate the effect of shikonin on ambrisentan metabolism in vivo and in vitro. Materials and methods This study developed an ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for simultaneous determination of ambrisentan and (S)-4-hydroxymethyl ambrisentan in rat plasma. Twelve male Sprague-Dawley (SD) rats were divided into two groups (n = 6): the control group and shikonin (20 mg/kg) group. The pharmacokinetics of ambrisentan (2.5 mg/kg) were investigated after 30 min. Additionally, human and rat liver microsomes were used to investigate the herb-drug interaction. Results The UPLC-MS/MS method was shown to be accurate, precise and reliable, and was successfully applied to the herb-drug interaction study of ambrisentan with shikonin. When co-administrated with 20 mg/kg shikonin, the C max and AUC(0–∞) of ambrisentan were significantly increased by 44.96 and 16.65%, respectively (p < 0.05). In addition, there were modest decreases in (S)-4-hydroxymethyl ambrisentan Cmax and AUC(0–∞) in the presence of shikonin (p < 0.05), which indicated that these results were in accordance with the inhibition of shikonin on ambrisentan metabolism. Moreover, enzyme kinetic study indicated that shikonin had an inhibitory effect on human and rat microsomes where the IC50 values of shikonin were 5.865 and 6.358 μM, respectively. Conclusions Our study indicated that shikonin could inhibit ambrisentan metabolism. Further studies need to be carried out to verify whether similar interaction truly apply in humans and whether this interaction has clinical significance.

Results of a phase I trial to assess the safety of macitentan in combination with temozolomide for the treatment of recurrent glioblastoma.

BackgroundThere is an urgent need for additional therapies to treat recurrent glioblastoma (GBM). Preclinical studies suggest that high dose macitentan, an oral dual endothelin receptor antagonist, enhances the cytotoxic effects of temozolomide (TMZ) in GBM, improving survival. This phase I trial investigated the maximum tolerated dose of macitentan combined with TMZ in patients with recurrent GBM and assessed the safety and tolerability of high dose macitentan in these patients (NCT01499251).MethodsAdults with recurrent GBM received ascending doses of macitentan from 30 mg once daily concomitantly with TMZ. Safety and tolerability were assessed in addition to exploratory efficacy and pharmacokinetic endpoints. An ancillary study examined biomarker expression following macitentan treatment prior to surgical resection of recurrent GBM.ResultsThirty-eight patients with recurrent GBM were administered macitentan doses up to 300 mg once daily; no dose-limiting toxicities were observed, and a maximum tolerated dose was not determined. All patients experienced at least one treatment-emergent adverse event (TEAE), the majority associated with GBM or TMZ treatment. TEAEs related to macitentan and TMZ were reported for 16 (42.1%) and 26 (68.4%) patients, respectively, with no serious macitentan-related TEAEs. Macitentan concentrations increased with dose, with no plateau in exposure. Substantial heterogeneity was observed in the expression of efficacy biomarkers within tumors. The Kaplan-Meier estimate of median overall survival across all dose groups was 9.4 (95% CI 8.5, 13.4) months.ConclusionHigh-dose macitentan was well tolerated in recurrent GBM patients concomitantly receiving TMZ. TEAEs were consistent with those seen in patients receiving either drug individually.

ACUTE HEMODYNAMIC IMPROVEMENT IN CHRONIC PULMONARY ARTERIAL HYPERTENSION ON DUAL THERAPY FOLLOWING RT234 INHALATION

SESSION TITLE: Advances in the Diagnosis and Management of Pulmonary Hypertension SESSION TYPE: Original Investigations PRESENTED ON: October 18-21, 2020 PURPOSE: RT234 is an inhaled formulation of the phosphodiesterase type-5 inhibitor (PDE5i) vardenafil, and is being developed for ‘as-needed’ use for episodic symptoms of pulmonary arterial hypertension (PAH). This study assessed the hemodynamic (HD) response to RT234. METHODS: A multicentre, open label, Phase 2a escalating dose ongoing clinical trial to evaluate acute changes in pulmonary vascular resistance (PVR) and other HD parameters in PAH patients on stable maintenance dual therapy. Three cohorts of 5 subjects each were to receive 0.2, 0.6, 1.2 mg RT234 during right heart catheterization. HD parameters were recorded at 5, 15, 30, 45, and 60-min post-inhalation. RESULTS: Of the 14 subjects enrolled, mean age was 54±14 years (79% females). 57% of subjects were functional class (FC) II, 36% FC III, and 7% FC IV. All subjects took a long-term oral endothelin receptor antagonist combined with oral PDE5i. Mean baseline PVR was 635±344, 469±431, 579±337 dyn/sec/cm-5 for the 0.2 mg, 0.6 mg and 1.2 mg cohorts respectively. RT234 administration at 0.2 mg, 0.6 mg and 1.2 mg dosages reduced PVR by -6.6% (-22.2 to 2.7), -23.7% (-44.7 to -18.6), and -16.0% (-22.7 to -10.5), respectively. With the 0.6 and 1.2 mg doses, PVR fell by >10% at 5 min, and the reduced PVR was sustained at least 60 mins. PVR/SVR ratio changed by -8.0% (-27.1 to 14.1), -18.4% (-37.8 to 0.9) and -11.9% (-23.9 to -0.3) for the 0.2, 0.6 and 1.2 mg doses respectively, indicating that the 0.6 mg dose may offer the greatest pulmonary selectivity. No clinically significant changes in systemic blood pressure or heart rate were observed. The change in PaO2 was +1.8% (-13.5 to 27.4), +8.1% (-13.5 to 22.6) and +4.3% (-1.4 to 9.9) for the three dose levels. Improvements in pulmonary HD with 0.6mg inhaled RT234 were on par with 20mg oral vardenafil, but with less systemic hypotension and higher oxygenation. The only treatment related adverse events (AE) observed were a mild headache and mild throat irritation, each in a single subject. No respiratory AEs (cough, dyspnoea, wheezing, bronchospasm) occurred. CONCLUSIONS: RT234 inhalation resulted in rapid reduction in PVR that was sustained for at least 60 min post-administration and was well tolerated. The optimally effective dose of RT234 appears to be 0.6 mg. RT234 is well-suited for further clinical development as an “as-needed” or even pre-emptive therapy in PAH. CLINICAL IMPLICATIONS: The observed acute improvements in HD should enable PAH patients to perform more of their activities of daily living, resulting in an improved quality of life. DISCLOSURES: Advisory Committee Member relationship with Actelion Please note: $1001 - $5000 Added 03/22/2020 by Nathan Dwyer, source=Web Response, value=Consulting fee Advisory Committee Member relationship with GSK Please note: $1001 - $5000 Added 03/22/2020 by Nathan Dwyer, source=Web Response, value=Consulting fee Advisory Committee Member relationship with Bayer Please note: $1001 - $5000 Added 03/22/2020 by Nathan Dwyer, source=Web Response, value=Consulting fee Institutional Funding to Conduct Study relationship with Respira Therapeutics Please note: $20001 - $100000 Added 03/22/2020 by Nathan Dwyer, source=Web Response, value=Grant/Research Support No relevant relationships by David Kaye, source=Admin input No relevant relationships by Anne Keogh, source=Web Response No relevant relationships by Eugene Kotlyar, source=Web Response Employee relationship with Respira Therapeutics, Inc. Please note: >$100000 Added 03/23/2020 by Mari Maurer, source=Web Response, value=Salary Consultant relationship with Respira Therapeutics Please note: $20001 - $100000 Added 03/26/2020 by Ed Parsley, source=Web Response, value=Consulting fee Employee relationship with Respira Therapeutics Please note: >$100000 Added 03/22/2020 by Jeffry Weers, source=Web Response, value=Salary

Macitentan in Pulmonary Arterial Hypertension: A Focus on Combination Therapy in the SERAPHIN Trial.

SERAPHIN was a double-blind, placebo-controlled, event-driven phase III trial that evaluated the effects of long-term treatment with macitentan, an oral endothelin receptor antagonist, in patients with pulmonary arterial hypertension (PAH). The majority of patients were receiving PAH therapy at enrollment, providing the opportunity to evaluate the efficacy and safety of macitentan in combination with other PAH therapies (predominantly phosphodiesterase type 5 inhibitors [PDE-5i]). In patients receiving background therapy, macitentan reduced the risk of morbidity/mortality by 38% compared with placebo (hazard ratio [HR] 0.62; 95% confidence level [CL] 0.43–0.89; p = 0.009). Furthermore, patients receiving macitentan and background therapy had a 37% reduction in the risk of being hospitalized for PAH (HR 0.63; 95% CL 0.41–0.96) compared with patients receiving background therapy only (placebo arm). Macitentan treatment in combination with background therapy was also associated with improvements in exercise capacity, functional class, cardiopulmonary hemodynamics, and health-related quality of life compared with background therapy alone. The safety profile of macitentan as part of a combination therapy regimen was consistent with that of macitentan in the overall SERAPHIN population. The SERAPHIN study has provided evidence that combination therapy with macitentan and a PDE-5i is effective and well tolerated in the management of PAH. Based on these data, and those from subsequent long-term trials, combination therapy is increasingly recognized as an important treatment option for improving long-term outcomes in PAH.Clinical trial registration number: NCT00660179

Isolated unilateral absence of pulmonary artery in adulthood: a clinical analysis of 65 cases from a case series and systematic review.

Isolated unilateral absence of pulmonary artery (UAPA) in adulthood is a rare congenital anomaly. Although some case reports exist, the clinical symptomatology, lung parenchymal features, collateral circulation and therapeutic approaches in adult patients with isolated UAPA remain unknown. The objectives of this study are to investigate the clinical characteristics, elucidate the correlation between clinical symptomatology and radiology, and summarize treatment of adult patients with isolated UAPA. Cases of adult patients with isolated UAPA who had been diagnosed at our hospital and identified from PubMed, EMBASE and Web of Science from 1990 to 2016 were analyzed. Hemoptysis was present in 41.5% of patients, exertional dyspnea in 41.5%, and recurrent respiratory infection in 35.4%. Lung parenchymal abnormalities were found on chest computed tomography (CT) scan, including bronchiectasis, which occurred in 30.2% of the patients, interstitial changes in 14.0%, and multiple bullae in 14.0% of the patients. Exertional dyspnea was more frequent in patients with pulmonary hypertension than in those without pulmonary hypertension (P<0.001). Recurrent respiratory infection were more frequent in patients with bronchiectasis than in those without bronchiectasis (P<0.001). Hypertrophic bronchial, phrenic, internal thoracic and intercostal arteries were found in 71.9%, 46.9%, 43.8%, and 43.8% of the patients, respectively. Pneumonectomy reduced hemoptysis in seven cases. Oral phosphodiesterase inhibitors or endothelin receptor antagonist improved exertional dyspnea in three cases with pulmonary hypertension. Clinicians should be aware of undiagnosed cases of isolated UAPA in adults with unexplained hemoptysis or exertional dyspnea. Early recognition and management of isolated UAPA in adult patients are crucial to avoid the devastating effect of massive hemoptysis or severe pulmonary hypertension (PHT) in the long term.

Association of oral endothelin receptor antagonists with risks of cardiovascular events and mortality: meta-analysis of randomized controlled trials.

Endothelin receptor antagonists (ERAs) are widely used in a variety of disorders, including pulmonary artery hypertension, systemic sclerosis, diabetic and kidney diseases, and several tumors. However, reported adverse events, especially increased risks of cardiovascular disease (CVD) morbidity and mortality, have cast doubt on their potential clinical application. Therefore, we conducted this meta-analysis to confirm whether ERAs increased CVD risk and mortality. We systematically searched PubMed (1966-2015), EMBASE (1974-2015), ClinicalTrials.gov, and the Cochrane Controlled Clinical Trials Register Database for randomized controlled trials published between Jan 1, 1990 and Mar 18, 2015. Inclusion criteria included a study duration of more than 3weeks, the use of a randomized control group receiving an oral ERA or placebo, and the availability of outcome data for cardiovascular events and all-cause death. A total of 33 trials met the inclusion criteria. There were 8098 cases in the ERA group and 5074 cases in the placebo group. Compared with the control group, the risk ratio (RR) for all-cause death in the ERA group was 0.983 [95% confidence interval (CI), 0.883 to 1.094, P = 0.754]. The summary RR for cardiovascular events was 1.651 in the ERA group (95% CI, 1.164 to 2.34, P = 0.005). The pooled results showed that ERAs treatment could lead to more edema, anemia, and abnormal transaminase levels. Also, there was an increased proportion of discontinued therapy in the ERA treatment because of side effects (RR = 1.322, 95% CI, 1.036 to 1.686, P = 0.025). There were no significant differences in the experienced episodes of headache and dyspnea between the active therapy and control groups. ERAs therapy is not significantly associated with increased all-cause death, but there are more cardiovascular events and edema or fluid retention, anemia, and liver enzymes disorder. Large clinical randomized controlled studies are needed to further confirm the safety of the clinical application of ERAs.

Macitentan therapy for bosentan hepatic intolerance in Eisenmenger’s syndrome patient. (RCD code: II-1A.4d)

Pulmonary arterial hypertension associated with congenital heart disease is included in clinical group 1 pulmonary arterial hypertension. Eisenmenger’s syndrome develops over time as a result of large intra- and extra-cardiac arterial and venous blood communication. The pulmonary vascular resistance (PVR) increases and thus the systemic-to pulmonary blood flow reverses direction, producing a pulmonary-to-systemic shunt (Eisenmenger’s syndrome). Bosentan, an oral endothelin receptor antagonist A and B, is recommended in monotherapy and drug combination therapy in this group of patients. Liver toxic reactions occur in about 10% of treated patients but severe hepatotoxicity is rare. We present a clinical case of a patient with Eisenmenger’s syndrome due to large ventricular septal defect. The patient was for many years successfully treated with bosentan and subsequently developed drug-induced hepatitis. JRCD 2016; 2 (8): 259–262

Targeted Treatments for Pulmonary Arterial Hypertension: Interpreting Outcomes by Network Meta-analysis

No meta-analysis for indirect comparisons has been conducted to study the effectiveness of treatments for pulmonary arterial hypertension (PAH). Our search covered the literature up to December 2014. The following five classes of agents indicated for PAH were evaluated: 1) oral endothelin receptor antagonists (ERAs); 2) oral phosphodiesterase type 5 inhibitors (PDE-5Is); 3) prostanoids administered by oral, intravenous, subcutaneous or inhalatory route; 4) selective non-prostanoid prostacyclin receptor (IP receptor) agonists (sPRAs); 5) soluble guanylate cyclase stimulators (sGCSs). Our methodology was based on standard models of Bayesian network meta-analysis. The end-point of our analysis was clinical worsening. Odds ratio was the outcome measure along with 95% credible intervals. Our search identified 17 randomised controlled trials (4,465 patients). There were 15 head-to-head comparisons (five direct, 10 indirect). As expected, nearly all values of odds ratio estimated for the direct comparisons versus placebo favoured the treatment arm at levels of statistical significance. More interestingly, none of the 10 head-to-head indirect comparisons between active agents showed any statistically significant difference. Our results indicate that these five classes of agents for PAH are more effective than placebo and show no significant difference in effectiveness from one another. In this context, choosing the treatment for an individual patient is a quite difficult task.

Clinical utility of treprostinil in the treatment of pulmonary arterial hypertension: an evidence-based review.

Pulmonary arterial hypertension (PAH) remains a progressive disease without a cure, despite the development of several treatment options over the past several decades. Its management strategy consists of the endothelin receptor antagonists (ambrisentan, bosentan, macitentan), phosphodiesterase-5 inhibitors (sildenafil, tadalafil, vardenafil), and prostacyclin analogs (epoprostenol, treprostinil, iloprost). Treprostinil, a stable prostacyclin analog, displays vasodilatory effects in the pulmonary vasculature, as well as antiplatelet aggregation properties. Clinical practice guidelines recommend oral endothelin receptor antagonist or phosphodiesterase inhibitor therapy in mild to moderate PAH. Epoprostenol is specifically suggested as first-line therapy in moderate to severe PAH patients (ie, World Health Organization/New York Heart Association functional class III–IV). However, treprostinil may be an alternative option in these severe PAH patients. The longer half-life and stability at room temperature with treprostinil may be associated with lower risk of pulmonary hemodynamic worsening as a result of abrupt infusion discontinuation and less frequent drug preparation. These characteristics make treprostinil an attractive alternative to continuous infusion of epoprostenol, due to convenience and patient safety. The purpose of this review is to evaluate the safety and efficacy of continuous infusion of treprostinil as well as the inhaled and oral routes of administration in PAH.

Ambrisentan therapy in pulmonary hypertension: clinical use and tolerability in a referral centre.

Ambrisentan is an oral selective endothelin receptor antagonist licensed for use in pulmonary arterial hypertension (PAH). There are few data on clinical use and long-term tolerability in a wider range of patients with pulmonary hypertension (PH). All patients treated with ambrisentan over a 4-year period were identified. Baseline characteristics, liver function test (LFT) results and World Health Organization (WHO) functional class were retrieved from hospital databases. 272 patients received ambrisentan between March 2009 and June 2013 (32% idiopathic PAH, 36% connective tissue disease PAH, 11% congenital heart disease PAH, 6% portopulmonary hypertension, 1% HIV PAH, 4% PH in association with lung disease, 8% chronic thromboembolic PH and 2% PH in association with sarcoidosis). 33.5% of patients received ambrisentan as monotherapy and 12% received ambrisentan as their initial PH therapy. 18% stopped treatment due to side effects and 12% stopped due to lack of efficacy. Oedema was the most common side effect leading to cessation of therapy, which occurred in 7% of patients. 57% of patients who discontinued ambrisentan due to side effects also discontinued other PAH therapies due to side effects previously or subsequently. Ambrisentan was discontinued in two (<1%) patients due to abnormal LFTs. The 3-year survival in congenital heart disease PAH, idiopathic PAH and systemic sclerosis-associated PAH was 80%, 62%, and 38%, respectively (p = 0.003). Survival was superior in patients in whom WHO functional class improved in response to therapy. Ambrisentan is used as an initial therapy and as monotherapy in a minority of patients in a large UK PH referral centre. Discontinuation due to side effects, and especially oedema, was higher than reported in previous studies while discontinuation due to abnormal LFTs was very uncommon. A majority of patients who discontinued therapy due to side effects also previously or subsequently discontinued other PAH therapies. Improvement in WHO functional class was associated with superior survival.

Sustained effect of macitentan, a novel oral endothelin receptor antagonist, on exercise capacity and the association of its measure with long-term outcomes in pulmonary arterial hypertension

Purpose: In SERAPHIN ([NCT00660179][1]), a Phase III trial in pulmonary arterial hypertension (PAH), macitentan reduced the risk of morbidity and mortality (primary outcome) and risk of PAH-related death or hospitalisation (PAHDH; secondary outcome). The effect of macitentan on 6-minute walk distance (6MWD) and the association between 6MWD and PAHDH were explored. Methods: 742 PAH patients were randomised to placebo, 3 or 10mg macitentan, once daily. Treatment-by-visit interaction and placebo-corrected treatment effects were calculated using repeated measures analysis on 6MWD change from baseline at Months 3, 6, 12 in the all-randomised set. Hazard ratios were calculated to measure the association between interquartile ranges of baseline 6MWD, 6MWD changes, or values at Month 6 (± adjustment for significant covariates) and PAHDH. This was performed independently of treatment in patients with available data for 6MWD at Month 6 and from Month 6 up to end of treatment for PAHDH Results: Baseline mean±SD 6MWD for placebo (n=249), 3mg (n=248) and 10mg macitentan (n=242) was 352±111m, 364±96m and 363±93m, respectively. No significant treatment-by-visit interaction (p=0.47) suggested that beneficial effects of macitentan on 6MWD (3mg: 21.5m [10.0–33.0]; p=0.0003 and 10mg: 25.4m [13.8–37.0]; p<0.0001 vs placebo) were maintained over 12 months. There were 125 PAHDH events in 595 patients with 6MWD data available. Lower 6MWD at baseline and Month 6 were strongly associated with a risk of PAHDH (Table). Absolute 6MWD at Month 6 lost its association when adjusted for baseline 6MWD and sex. Neither adjusted nor non-adjusted changes in 6MWD from baseline to Month 6 were significantly associated with the risk of PAHDH. View this table: Table 1. Association of 6MWD with risk of PAHDH Conclusions: Macitentan provided sustained improvements in 6MWD over 12 months. No association between 6MWD changes and long-term clinical outcome was demonstrated. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00660179&atom=%2Fehj%2F34%2Fsuppl_1%2F1061.atom

AB1189 Bosentan treatment of digital ulcers in paediatric patients with scleroderma

BackgroundScleroderma is a connective tissue disorder that is associated with changes in the skin and sometimes in internal organs. Digital ulcers in these patients can be difficult to treat and...

Circulation: Clinical Summaries

<i>Circulation:</i> Clinical Summaries

Successful Treatment with Bosentan of Lower Extremity Ulcers in a Scleroderma Patient

Digital ulcers are a well-known problem in patients with systemic sclerosis. Lower extremity ulcers are less prevalent but are also a challenging and underestimated complication of the disease causing important pain and morbidity. Bosentan, an oral dual endothelin receptor antagonist, has been shown to be effective in preventing digital ulcers in patients with systemic sclerosis. A few recent observations showed the efficacy of bosentan for accelerating the healing of nondigital ulcers in scleroderma patients. This report deals with a 48-year-old patient with systemic sclerosis who developed painful ulcers on the left ankle and hallux. The ulcers were refractory to a combination of vasodilator therapy with a calcium antagonist and several courses of intravenous prostanoids, low molecular weight heparin, aspirin, simvastatin, and intensive local treatment. Bosentan treatment showed spectacular healing of the ulcers already after 4 months of therapy. This case supports the previous few observations of accelerating wound healing of lower extremity ulcers in systemic sclerosis patients with bosentan treatment.

Device Closure of a Large Atrial Septal Defect in a Patient with Severe Pulmonary Arterial Hypertension after 1 Year Use of an Oral Endothelin Receptor Antagonist

The presence of severe pulmonary arterial hypertension (PAH) in patients with atrial septal defect (ASD) is still thought to preclude shunt closure, although there are several reports of good clinical outcomes after vasodilator therapy. We report the case of a young woman with ASD and severe PAH who was able to successfully undergo percutaneous shunt closure following 1 year use of the oral endothelin receptor antagonist, bosentan.

Safety and efficacy evaluation of ambrisentan in pulmonary hypertension

Introduction: Pulmonary arterial hypertension (PAH) is characterized by an increase in pulmonary vascular resistance, which can lead to right heart failure and death. Endothelin-1 binding ETA and ETB receptors seem to play a critical role in the pathogenesis and progression of the disease, and oral endothelin receptor antagonists (ERAs) have been shown to be an effective treatment. Bosentan and ETA-selective ambrisentan are the ERAs currently available for PAH treatment.Areas covered: On the basis of the analysis of the literature, this paper addresses the efficacy and safety of ambrisentan in the treatment for PAH.Expert opinion: Ambrisentan has shown an efficacy comparable with other ERAs. Compared with bosentan, ambrisentan seems to have a better safety profile with regards to hepatic safety and drug–drug interactions. On the other hand, ambrisentan shows a higher rate of other adverse events, such as nasal congestion and peripheral edema. Ambrisentan is a viable option for PAH treatment. However, there is still a need for more robust data about long-term mortality, treatment in non-PAH pulmonary hypertension (PH) (such as PH due to left heart disease and PH due to chronic hypoxic lung diseases) and combination therapy.

Iontophoresis of Endothelin Receptor Antagonists in Rats and Men

IntroductionThe treatment of scleroderma-related digital ulcers is challenging. The oral endothelin receptor antagonist (ERA) bosentan has been approved but it may induce liver toxicity. The objective of this study was to test whether ERAs bosentan and sitaxentan could be locally delivered using iontophoresis.MethodsCathodal and anodal iontophoresis of bosentan and sitaxentan were performed on anaesthetized rat hindquarters without and during endothelin-1 infusion. Skin blood flow was quantified using laser-Doppler imaging and cutaneous tolerability was assessed. Iontophoresis of sitaxentan (20 min, 20 or 100 µA) was subsequently performed on the forearm skin of healthy men (n = 5).ResultsIn rats neither bosentan nor sitaxentan increased skin blood flux compared to NaCl. When simultaneously infusing endothelin-1, cathodal iontophoresis of sitaxentan increased skin blood flux compared to NaCl (AUC0–20 were 44032.2±12277 and 14957.5±23818.8 %BL.s, respectively; P = 0.01). In humans, sitaxentan did not significantly increase skin blood flux as compared to NaCl. Iontophoresis of ERAs was well tolerated both in animals and humans.ConclusionsThis study shows that cathodal iontophoresis of sitaxentan but not bosentan partially reverses endothelin-induced skin vasoconstriction in rats, suggesting that sitaxentan diffuses into the dermis. However, sitaxentan does not influence basal skin microvascular tone in rats or in humans.