Endothelin Receptor-A Inhibition Decreases Ductular Reaction, Liver Fibrosis, and Angiogenesis in a Model of Cholangitis.

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) leads to ductular reaction and fibrosis and is complicated by vascular dysfunction. Cholangiocyte and endothelial cell crosstalk modulates their proliferation in cholestatic models. Endothelin (ET)-1 and ET-2 bind to their receptor, ET-A, and cholangiocytes are a key source of ET-1 after bile duct ligation. We aimed to evaluate the therapeutic potential of ET-A inhibition in PSC and biliary-endothelial crosstalk mediated by this pathway. METHODS: Wild-type and multidrug resistance 2 knockout (Mdr2-/-) mice at 12 weeks of age were treated with vehicle or Ambrisentan (ET-A antagonist) for 1 week by daily intraperitoneal injections. Human control and PSC samples were used. RESULTS: Mdr2-/- mice at 4, 8, and 12 weeks displayed angiogenesis that peaked at 12 weeks. Mdr2-/- mice at 12 weeks had enhanced biliary ET-1/ET-2/ET-A expression and secretion, whereas human PSC had enhanced ET-1/ET-A expression and secretion. Ambrisentan reduced biliary damage, immune cell infiltration, and fibrosis in Mdr2-/- mice. Mdr2-/- mice had squamous cholangiocytes with blunted microvilli and dilated arterioles lacking cilia; however, Ambrisentan reversed these alterations. Ambrisentan decreased cholangiocyte expression of pro-angiogenic factors, specifically midkine, through the regulation of cFOS. In vitro, ET-1/ET-A caused cholangiocyte senescence, endothelial cell angiogenesis, and macrophage inflammation. In vitro, human PSC cholangiocyte supernatants increased endothelial cell migration, which was blocked with Ambrisentan treatment. CONCLUSIONS: ET-A inhibition reduced biliary and liver damage in Mdr2-/- mice. ET-A promotes biliary angiocrine signaling that may, in turn, enhance angiogenesis. Targeting ET-A may prove therapeutic for PSC, specifically patients displaying vascular dysfunction.

Sitaxsentan-induced acute severe hepatitis treated with glucocorticoid therapy.

Endothelin receptor antagonists are commonly used in the treatment of pulmonary hypertension. Sitaxsentan, a selective endothelin A receptor blocker, induces a mild transaminitis in approximately 3% to 5% of patients, but rarely an acute severe hepatitis. A case involving a 61-year-old female with sitaxsentan-induced acute severe liver failure is presented. Depite withdrawal of therapy, her liver tests failed to improve. After six weeks of monitoring, the patient was administered high-dose corticosteroids, with a good clinical and biochemical response. While endothelin receptor antagonists are postulated to cause hepatitis by inhibition of a bile salt transporter pump, an immune-mediated or idiosyncratic mechanism should be considered.

Tratamiento específico de la hipertensión arterial pulmonar. Experiencia de la policlínica de hipertensión pulmonardel Hospital Maciel, período 2009-2011 / Specific treatment of pulmonary arterial hypertension. Experience of the pulmonary hypertension clinic at the polyclinic Hospital Maciel, period 2009-2011

Introducción:la hipertensión pulmonar (HP) es una condición hemodinámica definida por un aumento de la presiónarterial pulmonar media (PmAP) 25 mmHg en reposo estimada mediante el cateterismo cardíaco derecho (CCD). Secomunica la experiencia adquirida en el diagnóstico, seguimiento y tratamiento de la hipertensión arterial pulmonar(HAP) y de la HP tromboembólica crónica (HPTEC) de la policlínica de HP del Hospital Maciel. Métodos: se analiza una cohorte de 15 pacientes (2009-2011). Se estimaron la clase funcional (CF), la prueba de caminata de 6 minutos (P6M), la excursión sistólica del plano del anillo tricuspídeo (ESPAT) y la velocidad sistólica pico(Sm). La severidad hemodinámica fue estimada por CCD. Se definió respuesta vasorreactiva aguda (RVA) positiva porel descenso de la PmAP 10 mmHg, alcanzando un valor absoluto 40 mmHg sin cambios o aumento del índice cardíaco (IC). Los datos se expresaron como media ± DS. Se empleó el test de t student pareado para comparar el efecto deltratamiento específico y el test de Kruskal-Wallis para comparaciones entre los grupos, con una p<0,05.Resultados:la edad promedio fue de 43 ± 12 años, 12 (80%) mujeres. Diez (67%) del grupo 1 y 5 (33%) del grupo 4. El20% se presentó en CF I-II y 80% en CF III-IV. El tiempo de seguimiento fue de 19 ± 11 meses. La ESPAT y la Sm basales fueron de 17 ± 7 mm y 11 ± 2 cm/s, respectivamente. La PmAP fue de 54 ± 15 mmHg, la presión auricular derecha 11± 6 mmHg, IC 2,1 ± 0,7 l/min/m2, resistencia vascular pulmonar 1.087 ± 625 dinas.s.cm-5, capacitancia pulmonar 1,3 ±0,6 ml/mmHg. Un paciente presentó RVA positiva. Se empleó sildenafil (100%), bosentan (50%) e iloprost (43%); en71% el tratamiento fue combinado. No se registró hepatotoxicidad por bosentan durante el período de seguimiento. Unpaciente murió por rechazo a recibir tratamiento específico. Los 14 pacientes restantes presentaron una mejoría de laCF (3,0 ± 0,8 versus 2,1 ± 0,8, p<0,05), así como de la P6M ...

[Pulmonary arterial hypertension in childhood]. / Pulmonale arteriële hypertensie bij kinderen in Nederland.

Progressive pulmonary arterial hypertension (PAH) is a rare condition with high morbidity and mortality. Paediatric PAH distinguishes itself from PAH in adults, but is still poorly characterized. Paediatric PAH presents itself with non-specific symptoms which often results in later diagnosis. Determination of the correct underlying diagnosis in paediatric PAH is complex, and must therefore take place at specialized centres. Paediatric progressive PAH is usually either idiopathic or associated with congenital heart disease. Pediatric PAH frequently co-occurs with dysmorphic abnormalities, which may point towards aetiological mechanisms. Recent reports suggest an improved survival and exercise tolerance due to treatment with new second-generation drugs for paediatric PAH. In the Netherlands, the care for children with PAH is centralised to guarantee the optimization of diagnosis and treatment in accordance with the most recent scientific insights.

Benefícios e limitações do tratamento atual da hipertensao arterial pulmonar / Benefits and limitations about today's treatment of pulmonary arterial hypertension

Hipertensão arterial pulmonar (HAP) é uma doença rara causada pela proliferação vascular e remodelamento, resultando no aumento progressivo da resistência vascular pulmonar e disfunção ventricular direita. Apesar de recentes avanços terapêuticos, essa doença é ainda grave e rapidamente progressiva. Existem, atualmente, três classes principais de drogas que podem ser utilizadas para o tratamento da HAP: prostanoides, antagonistas dos receptores de endotelina e inibidores da fosfodiesterase-5. Nessa revisão, discutiremos o tratamento de suporte nessa população de doentes, assim como as drogas específicas atualmente disponíveis.

Outcome of pediatric patients with pulmonary arterial hypertension in the era of new medical therapies.

Little is known about the effects of "second-generation drugs" (prostanoids, endothelin receptor antagonists, 5-phosphodiesterase inhibitors) in children with pulmonary arterial hypertension (PAH). This study describes the outcome of a national cohort of children with PAH in an era when these drugs became available. From 1993 to 2008, 52 consecutive children with idiopathic PAH (n = 29) or systemic-to-pulmonary shunt-associated PAH (n = 23) underwent baseline and follow-up assessments. Treatment was initiated depending on functional class, acute pulmonary vasoreactivity response, and drug availability. Observed survival was evaluated depending on time of diagnosis in relation to second-generation drug availability and subsequently compared to calculated predicted survival. Children for whom second-generation drugs were available had improved survival compared to their predicted survival (1-, 3-, and 5-year survival rates 93%, 83%, and 66% vs 79%, 61%, and 50%, respectively). However, this improved survival was observed only in patients for whom second-generation drugs became available during their disease course. No improved survival was observed in patients for whom drugs were available already at diagnosis. Baseline variables associated with decreased survival included higher functional class, higher pulmonary-to-systemic arterial pressure ratio, lower cardiac index, and higher serum levels of N-terminal pro-brain natriuretic peptide and uric acid. After start of second-generation drugs, functional class, 6-minute walking distance, and N-terminal pro-brain natriuretic peptide improved but gradually decreased after longer follow-up. In conclusion, survival of pediatric PAH seemed improved since the introduction of second-generation drugs only in selected patients for whom these drugs became available during their disease course. Start of second-generation drugs initially induced clinical improvements, but these effects decreased after longer follow-up.

Effect of bosentan on skin fibrosis in patients with systemic sclerosis: a prospective, open-label, non-comparative trial.

OBJECTIVES: To assess the effect of the ET-receptor antagonist bosentan on skin fibrosis and functionality in patients with SSc. METHODS: In this prospective, open-label, non-comparative trial, a total of 10 patients with SSc received 62.5 mg of bosentan twice daily for 4 weeks and then 125 mg twice daily for 20 weeks. The primary endpoint was skin thickening as measured by the modified Rodnan skin score (mRSS). Further assessments included 20 MHz ultrasound, examination of digital ulcers (DUs) and evaluation of hand function by examining patients' fist closure. Furthermore, patients with SSc used the UK SSc Functional Score (UKFS), the modified scleroderma HAQ (SHAQ) and its visual analogue scale (VAS) to rate their disability related to specific organ systems. RESULTS: The mean change from baseline mRSS (the primary endpoint) was 6.4 at Week 24 of bosentan treatment, which was statistically significant (P < 0.001). Patients with both diffuse and limited SSc exhibited a statistically significant mean difference in the mRSS. Moreover, there was a significant healing of DUs noted between baseline and at Week 24 of bosentan treatment (P < 0.001); however, the 20 MHz ultrasound and the fist closure evaluation revealed no significant differences. There were also no statistically significant changes between baseline and Week 24 in the UKFS, the modified SHAQ and its VAS. CONCLUSION: In addition to the well-known effect of bosentan in prevention of DUs, the results of this study demonstrate that bosentan may also be effective at reducing skin fibrosis in patients with SSc.

Pulmonary veno-occlusive disease: diagnostic and therapeutic alternatives.

Pulmonary veno-occlusive disease (PVOD) is a rare cause of pulmonary hypertension. Surgical biopsy was usually required for diagnostic confirmation. However, the morbidity, mortality and limited benefit of this procedure have generated discussion regarding noninvasive diagnostic techniques. We present the case of a female patient with progressive dyspnea, hypoxemia and pulmonary hypertension, the last diagnosed via catheterization. Computed tomography revealed septal thickening and diffuse micronodules. Bronchoalveolar lavage revealed occult alveolar hemorrhage. Treatment with an endothelin antagonist was started, resulting in symptomatic and functional improvement. Occult alveolar hemorrhage differentiates PVOD from idiopathic pulmonary hypertension. We believe that this finding, in combination with characteristic tomographic findings, is sufficient to establish a diagnosis of PVOD.

HIV-related pulmonary arterial hypertension: clinical presentation and management.

Pulmonary arterial hypertension (PAH) is a progressive albeit rare long-term complication of HIV infection, which has gained importance following the improved survival of HIV-infected patients with the use of HAART. The clinical and pathological findings in PAH associated with HIV infection (HIV-PAH) share many features with the idiopathic form of the disease. HIV-PAH is associated with a particularly poor prognosis and decreased survival compared with HIV-infected patients without this complication, and patients with HIV-PAH tend to die from the effects of PAH rather than as a result of their HIV infection. Prompt diagnosis and effective treatment of PAH in HIV-infected patients is therefore essential. There are currently only limited data regarding the efficacy of PAH therapies in HIV-PAH. Treatment with epoprostenol has been reported to provide benefit in some cases, but is associated with a range of problems linked to the need for continuous intravenous infusion. The dual endothelin receptor antagonist bosentan has proved to be effective in HIV-PAH without affecting the control of HIV infection, and has the benefit of oral administration. Other PAH therapies including prostacyclin analogs, phosphodiesterase type 5 inhibitors and selective endothelin receptor antagonists have yet to be trialed in this setting. Taking into account currently available data and clinical experience, a treatment algorithm for HIV-PAH based on that defined in treatment guidelines for other forms of PAH is suggested.

Doença veno-oclusiva pulmonar: alternativas diagnósticas e terapêuticas / Pulmonary veno-occlusive disease: diagnostic and therapeutic alternatives

A doença veno-oclusiva pulmonar (DVOP) é uma causa rara de hipertensão pulmonar. A biópsia cirúrgica era usualmente necessária para seu diagnóstico; entretanto, sua morbidade, mortalidade e seu impacto limitado levantou a discussão sobre o diagnóstico não-invasivo. Apresentamos um caso de uma paciente com dispnéia progressiva, hipoxemia e hipertensão pulmonar no cateterismo. A tomografia computadorizada revelou espessamento septal e micronódulos difusos. O lavado broncoalveolar revelou hemorragia alveolar oculta. Iniciou-se tratamento com antagonista da endotelina, que resultou em melhora clínica e funcional. A hemorragia alveolar oculta é uma característica da DVOP capaz de diferenciá-la da hipertensão pulmonar idiopática. Acreditamos que sua presença, associada à tomografia característica, seja suficiente para o diagnóstico de DVOP.

Pulmonary veno-occlusive disease (PVOD) is a rare cause of pulmonary hypertension. Surgical biopsy was usually required for diagnostic confirmation. However, the morbidity, mortality and limited benefit of this procedure have generated discussion regarding noninvasive diagnostic techniques. We present the case of a female patient with progressive dyspnea, hypoxemia and pulmonary hypertension, the last diagnosed via catheterization. Computed tomography revealed septal thickening and diffuse micronodules. Bronchoalveolar lavage revealed occult alveolar hemorrhage. Treatment with an endothelin antagonist was started, resulting in symptomatic and functional improvement. Occult alveolar hemorrhage differentiates PVOD from idiopathic pulmonary hypertension. We believe that this finding, in combination with characteristic tomographic findings, is sufficient to establish a diagnosis of PVOD.

Endothelin receptor antagonists in pulmonary arterial hypertension.

The endothelin (ET) system, especially ET-1 and the ET(A) and ET(B) receptors, has been implicated in the pathogenesis of pulmonary arterial hypertension (PAH). Together with prostanoids and phosphodiesterase 5 inhibitors, ET receptor antagonists have become mainstays in the current treatment of PAH. Three substances are currently available for the treatment of PAH. One of these substances, bosentan, blocks both ET(A) and ET(B) receptors, whereas the two other compounds, sitaxsentan and ambrisentan, are more selective blockers of the ET(A) receptor. There is ongoing debate as to whether selective or nonselective ET receptor blockade is advantageous in the setting of PAH, although there is no clear evidence that receptor selectivity is relevant with regard to the clinical effects of these drugs. For the time being, other features, such as safety profiles and the potential for pharmacokinetic interactions with other drugs used in the treatment of PAH, may be more important than selectivity or nonselectivity when selecting treatments for individual patients.

Treatment of pulmonary arterial hypertension.

OBJECTIVE: To perform a review of the diagnostic and therapeutic management of pulmonary hypertension in the pediatric population, with emphasis on pharmacological factors. SOURCES: Electronic search of publications on the MEDLINE/PubMed, LILACS and Cochrane Collaboration databases. The search strategy adopted gave priority to the identification of clinical trials (controlled or uncontrolled), systematic reviews and directives published during the last 10 years. SUMMARY OF THE FINDINGS: Many advances have been incorporated into our understanding of pulmonary hypertension during recent years. Issues related to differences in the pathophysiological mechanism of the disease between different age groups have altered both the treatment and prognosis of patients. The combined effect of more selective vasodilatory properties and antiproliferative action and the employment of new drugs are the basic principles of new treatment proposals. In order to be able to gauge the benefits associated with the use of these new therapies, it is of fundamental importance that all patients have their disease correctly diagnosed, the degree of functional compromise classified and their vascular reactivity capacity established, which is more difficult with pediatric patients. CONCLUSIONS: To date there is no treatment that can be considered ideal for the management of pulmonary hypertension. With reference to the possibility of employing new drugs, the majority of studies that have been published were undertaken with adult populations. Few data are available on children, and the majority of studies are uncontrolled trials or case series. Taking into account differences that have already been established between different age groups in terms of disease mechanisms and prognostic aspects, it is difficult to claim that these drugs can be incorporated into the treatment of childhood pulmonary hypertension with the same indications and results.

Treatment of pulmonary arterial hypertension

OBJETIVO: Estabelecer uma revisão acerca do manejo diagnóstico e terapêutico da hipertensão pulmonar na população pediátrica, com ênfase nos aspectos farmacológicos. FONTES DOS DADOS: Busca eletrônica de publicações nas bases de dados MEDLINE/PubMed, LILACS e Cochrane Collaboration. Estabeleceu-se uma estratégia de busca priorizando a identificação de ensaios clínicos (controlados ou não controlados), revisões sistemáticas e diretrizes publicados nos últimos 10 anos. SíNTESE DOS DADOS: Muitos avanços têm sido incorporados ao conhecimento da hipertensão pulmonar nos últimos anos. Aspectos relativos a diferenças nos mecanismos fisiopatológicos da doença entre as diferentes faixas etárias têm modificado o tratamento e o prognóstico dos pacientes. Uma ação combinada de propriedades vasodilatadoras mais seletivas e ação antiproliferativa e o emprego de novas drogas representam princípios fundamentais das novas propostas terapêuticas. Para considerar benefícios associados à utilização dessas novas terapêuticas, é fundamental que cada paciente tenha a sua doença adequadamente diagnosticada, classificado o grau de comprometimento da doença e a sua capacidade de reatividade vascular estabelecida, o que é mais difícil na população pediátrica. CONCLUSÃO: Até o momento, não existe um tratamento que possa ser considerado ideal para o manejo da hipertensão pulmonar. Considerando a possibilidade do emprego de novas drogas, a maioria dos estudos existentes foi conduzida em populações adultas. Poucos dados são disponíveis para crianças, sendo a maioria ensaios clínicos não controlados e séries de casos. Considerando diferenças já estabelecidas entre os mecanismos da doença e aspectos prognósticos entre as diferentes faixas etárias, é difícil afirmar que tais drogas possam ser incorporadas, com as mesmas indicações e os mesmos resultados, ao tratamento da hipertensão pulmonar infantil.

OBJECTIVE: To perform a review of the diagnostic and therapeutic management of pulmonary hypertension in the pediatric population, with emphasis on pharmacological factors. SOURCES: Electronic search of publications on the MEDLINE/PubMed, LILACS and Cochrane Collaboration databases. The search strategy adopted gave priority to the identification of clinical trials (controlled or uncontrolled), systematic reviews and directives published during the last 10 years. SUMMARY OF THE FINDINGS: Many advances have been incorporated into our understanding of pulmonary hypertension during recent years. Issues related to differences in the pathophysiological mechanism of the disease between different age groups have altered both the treatment and prognosis of patients. The combined effect of more selective vasodilatory properties and antiproliferative action and the employment of new drugs are the basic principles of new treatment proposals. In order to be able to gauge the benefits associated with the use of these new therapies, it is of fundamental importance that all patients have their disease correctly diagnosed, the degree of functional compromise classified and their vascular reactivity capacity established, which is more difficult with pediatric patients. CONCLUSIONS: To date there is no treatment that can be considered ideal for the management of pulmonary hypertension. With reference to the possibility of employing new drugs, the majority of studies that have been published were undertaken with adult populations. Few data are available on children, and the majority of studies are uncontrolled trials or case series. Taking into account differences that have already been established between different age groups in terms of disease mechanisms and prognostic aspects, it is difficult to claim that these drugs can be incorporated into the treatment of childhood pulmonary hypertension with the same indications and results.

Bosentan: a review of its use in pulmonary arterial hypertension and systemic sclerosis.

Bosentan (Tracleer), an orally administered dual endothelin (ET)(A) and ET(B) receptor antagonist, is indicated in the treatment of pulmonary arterial hypertension (PAH). The efficacy of oral bosentan 125 mg twice daily in improving exercise capacity has been demonstrated in well designed trials in adult patients with idiopathic PAH or PAH associated with connective tissue disease or congenital systemic-to-pulmonary shunts, and in other trials in patients with idiopathic PAH or PAH associated with congenital heart disease or HIV infection. The beneficial effects of first-line bosentan treatment may be maintained for up to 1 year in patients with idiopathic PAH or PAH associated with connective tissue disease. Despite the potential for treatment-related teratogenicity and hepatotoxicity, long-term data indicate that bosentan is generally well tolerated at the approved dosages. Although well designed trials are required to establish the efficacy of bosentan versus or in combination with other specific PAH therapies, especially sildenafil, the convenient oral administration and lack of serious injection-related adverse effects may render bosentan preferable to other PAH therapies. Preliminary data indicate that bosentan may be effective in pediatric PAH patients, although randomized trials are required. Furthermore, bosentan may be a useful option for the prevention of digital ulcer development in patients with systemic sclerosis. Thus, in accordance with current clinical guidelines, bosentan is a convenient, effective, and generally well tolerated agent for use in the first-line treatment of class III PAH or second-line treatment of class IV PAH.

Treatment of pulmonary hypertension with selective pulmonary vasodilators.

PURPOSE OF REVIEW: Pulmonary vasodilators are important in the management of pulmonary hypertension. Although systemic vasodilators may be effective in lowering pulmonary artery pressure, systemic vasodilation is the main limitation to dose titration. This review summarizes the latest research and developments in pulmonary vasodilators in the management of acute and chronic pulmonary hypertension. RECENT FINDINGS: Nitric oxide, the prototype of selective pulmonary vasodilators, remains an effective option in the management of pulmonary hypertension; however, cost and complexity of administration have led to consideration of other pulmonary vasodilators. Animal research suggests that nitric oxide may have an important role in the prevention of pulmonary hypertension after cardiopulmonary bypass. Experience with phosphodiesterase inhibitors, as monotherapy or as part of combination therapy, suggests that these agents improve cardiopulmonary hemodynamics and can be considered as alternatives and/or adjuncts to nitric oxide. Prostacyclins are a versatile class of pulmonary vasodilator as they have been shown to improve pulmonary hemodynamics administered intravenously or via inhalation. Endothelin receptor antagonists have been shown to be effective for long-term management of pulmonary hypertension. Several gene therapy strategies are currently undergoing evaluation. SUMMARY: Selective pulmonary vasodilation can be achieved through delivery of vasodilators directly to the lungs or targeting pulmonary specific processes. Several therapeutic options are available that demonstrate selectivity for the pulmonary vasculature. These agents can facilitate optimization of cardiopulmonary hemodynamics.

Treatments for pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a devastating disease that leads to right heart failure and premature death. Historically, we are restricted by limited options for drug treatment. Over the past decade, with advances in our understanding of pathophysiological and molecular mechanisms, many new therapeutic strategies (synthetic prostacyclin and prostacyclin analogues, endothelin receptor antagonists and sildenafil) have been developed for the treatment of PAH, and the clinical efficacy has been tested in many randomized-controlled trials (RCTs). In this overview, we review the evidence for the use of historical and new treatments that arises from the Cochrane Collaboration of Systematic Reviews and from recent RCTs.

Treatment of congestive heart failure: present and future.

The treatment of patients with congestive heart failure has markedly improved over the past 25 years. The most successful therapy has been attenuation of neurohumoral overactivation with antagonists of the renin-angiotensin-aldosterone system, as well as beta-adrenergic blockade. Cardiac surgical interventions, which include not only aortocoronary artery bypass surgery but also interventions that remodel the heart and repair the mitral valve, have also been advocated. However, randomized clinical trials to prove their benefit and to identify which patients could derive the most benefit from these interventions are lacking. Cardiac devices, such as biventricular pacemakers (for cardiac resynchronization) and implantable cardiac defibrillators, have proved useful in improving survival and quality of life. The treatment of sleep apnea with continuous positive airway pressure has shown some promise, as has immune modulation therapy, but more research to conclusively prove their efficacy is necessary. Cell therapy with skeletal myoblasts or pluripotential stem cells is an interesting and emerging area of research that shows enormous promise. However, fundamental questions regarding the optimal use of this therapy remain unanswered. Finally, although exciting, these developments, along with the changing demographics of the Canadian population, will require a change in the way we provide care for patients with congestive heart failure. These changes will require greater involvement of health care professionals other than physicians, and greater emphasis on outpatient care, early detection and prevention, and evidence-based practice.