Novel therapeutics for the treatment of paediatric pulmonary arterial hypertension

The treatment of paediatric pulmonary arterial hypertension is challenging due to the serious nature of the disease, its rapid progression and the limited treatment options available. However, recent advances in the treatment of pulmonary arterial hypertension may offer significant improvements for patients suffering from this condition. Novel treatment options include prostacyclin analogues and endothelin receptor antagonists. A comprehensive review of the newer agents, with an emphasis on the pathobiology/pathophysiology of pulmonary arterial hypertension provides insight into future management of paediatric pulmonary arterial hypertension.     

治疗肺动脉高压新药-Selexipag研究进展

肺动脉高压是以血管收缩、血管重构、平滑肌细胞增殖和原位血栓形成等为主要特征的肺小动脉异常疾病。Selexipag是一种新型口服前列环素受体激动剂,已被证明可改善Ⅱ期临床试验的血液动力学,并可减少Ⅲ期临床试验中肺动脉高压患者的疾病恶化情况。本文对其作用机制、药动学、药效学、临床试验、不良反应等方面做一综述。     

Iloprost inhalation solution for the treatment of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a condition that is characterised by increased pulmonary arterial pressure and vascular resistance that can lead to right ventricular failure and death. A variety of disturbances in pulmonary vascular endothelial and smooth muscle function are present in PAH, including reduced production of vasodilator and antiproliferative substances, such as nitric oxide and prostacyclin, and an overproduction of mitogens, such as endothelin. As a result of these observations, therapies have been developed for PAH that specifically target these pathogenic processes, including prostacyclin analogues and endothelin receptor antagonists. This article reviews iloprost inhalation solution, the most recently approved form of prostacyclin therapy that is delivered directly to the lungs by inhalation.     

Treatment of pulmonary hypertension with riociguat: a review of current evidence and future perspectives

ABSTRACT

Introduction

Pulmonary arterial hypertension (PAH) is still a chronic disorder characterized by high morbidity and mortality. Chronic thromboembolic pulmonary hypertension (CTEPH) is another form of pulmonary hypertension (PH) for which pulmonary endarterectomy (PEA) is the treatment of choice. However, not all patients are operable, while PH is often recurrent or persistent. Thus, for both disorders novel treatment options are urgently needed.     

Inhaled Iloprost for Chronic Thromboembolic Pulmonary Hypertension (CTEPH) During Pregnancy: A Case Report

Chronic thromboembolic pulmonary hypertension (CTEPH) is a subset of pulmonary hypertension caused by acute and recurrent pulmonary emboli. Pulmonary thromboendarterectomy is the treatment of choice, but 10–50% of patients are ineligible for this procedure. We describe the case of a 25‐year‐old, morbidly obese (228‐kg, body mass index 83.5 kg/m²) pregnant woman (G₃P₂) who presented at 24 weeks’ gestation; bilateral pulmonary angiography revealed filling defects and confirmed the diagnosis of CTEPH. The patient was evaluated and deemed to present too high of a risk for pulmonary thromboendarterectomy, so a multidisciplinary team initiated medical therapy. Sildenafil 20 mg orally 3 times/day was started at week 24 of gestation, and inhaled iloprost was added at 26 weeks and titrated to 5 µg inhaled every 2 hrs in order to optimize hemodynamic status prior to a cesarean section delivery scheduled to be performed 6 weeks later. At 32 weeks of gestation, the patient's pulmonary arterial systolic pressure was 77 mm Hg, right atrial pressure was 15 mm Hg, and pulmonary capillary wedge pressure of 16 mm Hg, and a healthy 1741‐g male infant was delivered by cesarean section. The patient was transferred back to the medical intensive care unit in stable condition and discharged home 9 days following the procedure. Pharmacotherapeutic strategies for patients with CTEPH who become pregnant are limited to phosphodiesterase type 5 inhibitors and prostacyclin analog therapies due to the teratogenicity of the other drug classes used to treat the disorder (endothelin receptor antagonists and soluble guanylate cyclase stimulators). To our knowledge, this is the first case report of inhaled iloprost use in addition to oral sildenafil to improve patient symptomatology and hemodynamics during the peripartum period of a young pregnant patient with inoperable CTEPH. This drug therapy was used safely, with no noted adverse effects to the newborn or to the patient.     

肺动脉高压药物治疗进展

肺动脉高压分为原发性和继发性肺动脉高压。肺动脉高压具有药物治疗效果和预后差的特点。血管内皮功能减退与肺动脉高压的发生发展具有极其密切的关系。前列环素类似物、内皮素受体拮抗药等是新开发的有效治疗肺动脉高压的药物。     

Leads for the treatment of pulmonary hypertension

Background: Knowledge of the causative reasons for pulmonary arterial hypertension, a major category of pulmonary hypertension, has expanded dramatically over the past 10 years. This has led to heightened research across a range of potential new mechanistic approaches and resulted in the identification of further treatment options, together with several promising leads and prototypes. Objective: This review aims to summarise and assess the most relevant research fields, covering key publications and recent patent literature. Methods: Searching revealed in excess of 700 patents claiming uses that relate to pulmonary hypertension. These patents were filtered into key therapeutic approaches based on pharmacological reviews of the pulmonary arterial hypertension field. Results/conclusions: Endothelin antagonists and phosphodiesterase 5 inhibitors have emerged as recently approved treatment options and are proving extremely beneficial. Further new mechanistic approaches have yielded promising leads, some of which have the potential to be disease modifying; notably, tyrosine kinase inhibitors, soluble guanylate cyclase agonists, Rho-kinase inhibitors, vasoactive intestinal peptide analogues and 5-HT antagonists.     

Treprostinil for the treatment of pulmonary hypertension

Background: Pulmonary hypertension (PH) is a severely disabling disorder characterized by sustained elevations of pulmonary arterial pressure, ultimately leading to right-heart failure and death. Pulmonary arterial hypertension (PAH) usually occurs in the absence of an evident cause (idiopathic PAH) or may be associated with connective tissue disease, HIV infection, congenital heart disease, chronic liver disease or result from the use of toxic agents and anorexigens. Objective/method: Intravenous epoprostenol has been widely used in patients with PAH, leading to long-term clinical benefits and improved survival. Epoprostenol has to be delivered through a permanently implanted Intravenous catheter. This may expose patients to potentially life-threatening complications. Thus, more stable compounds and alternative modes of prostacyclin delivery have been sought. Conclusion: Treprostinil sodium is a stable prostacyclin analogue, sharing pharmacologic actions similar to epoprostenol with comparable haemodynamic effects. Treprostinil is chemically stable at room temperature and has a long half-life (2 – 4 h), making this drug suitable for subcutaneous administration, with practical benefits in avoiding the risk of line infection and thrombosis, and cardiovascular reactions due to abrupt drug discontinuation.     

An evaluation of selexipag for the treatment of pulmonary hypertension

ABSTRACT

Introduction

Selexipag is a first-in-class, oral, long-acting, selective, non-prostanoid agonist of the prostacyclin receptor (IP receptor), indicated for the treatment of symptomatic adult pulmonary arterial hypertension (PAH). It was designed with the objective to surpass the inconveniences associated with standard prostanoid therapy, presenting fewer adverse effects and comparable hemodynamic benefits.     

Riociguat for pulmonary hypertension

Pulmonary hypertension, an elevation of the mean pulmonary artery pressure ≥25 mmHg, ultimately leads to premature death due to right ventricular dysfunction. Ten treatments from three classes of drugs are licensed for the management of pulmonary arterial hypertension. These treatments have improved exercise capacity but median survival is still poor. Additionally there are no licensed therapies for the other groups of pulmonary hypertension. Riociguat is a novel drug that stimulates soluble guanylate cyclase independently of nitric oxide and in synergy with nitric oxide. This review summarises the available evidence for riociguat in the treatment across all groups of pulmonary hypertension with a focus on pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.     

基于Markov模型的肺动脉高压靶向治疗药物的成本-效果分析

目的：评价中国医疗环境下肺动脉高压一线靶向治疗药物的成本-效果。方法：从支付者角度,根据肺动脉高压的自然转归和现有的医疗成本构建Markov模型。结果指标包括人均总成本、总质量调整生命年和增量成本-效果比,应用一元敏感度和概率敏感度分析验证模型稳定性。结果：基线分析结果显示：在整个生命周期的模拟过程中安立生坦、马昔腾坦、波生坦、他达拉非、西地那非和姑息治疗的人均医疗成本分别为363 406.14,481 387.69,323 264.71,167 531.23,41 700.08和24 507.12元,人均可获得5.61,6.14,5.23,5.88,4.64和2.33个质量调整生命年,姑息治疗作为对照组的增量成本-效果比分别为103 410.74,120 034.97,103 079.80,40 351.36和7 438.14元/质量调整生命年,小于预设的意愿支付阈值,敏感度分析显示结果稳定。结论：在中国肺动脉高压患者使用安立生坦、马昔腾坦、波生坦、他达拉非和西地那非具有成本-效果性。     

Treprostinil therapy for pulmonary artery hypertension

Pulmonary artery hypertension is a life-threatening disease characterised by a pulmonary vasculopathy and progressive right ventricular failure. Major advances were made with the development of continuous intravenous epoprostenol (Flolan?) as a treatment modality. Nevertheless, it is far from ideal as treatment for this disease. Subcutaneous treprostinil has been FDA approved for the treatment of New York Heart Association Functional Class II – IV pulmonary artery hypertension. It is a longer acting subcutaneous prostacyclin analogue that offers an additional mode of therapy for this disease. A discussion of the pharmacology of this prostacyclin analogue as compared to its related compounds, the clinical studies which led to its approval, a review of some additional basic studies and the practical use of this drug in the treatment modalities for precapillary pulmonary artery hypertension in 2002 in light of other available therapies is discussed.     

Therapeutic options in pulmonary hepatic vascular diseases

Pulmonary-hepatic vascular disorders are frequent complications in patients with portal hypertension and cirrhosis. Both hepatopulmonary syndrome (HPS) and portopulmonary hypertension (POPH) are associated with increased morbidity and mortality. The diagnosis of HPS should be confirmed early by arterial blood gas analysis and contrast enhanced echocardiography whereas POPH is finally diagnosed by presence of pulmonary arterial hypertension evaluated via right heart catheterization and presence of portal hypertension. Therapeutic options are initiation of long term oxygen therapy and liver transplantation in patients with severe HPS. Patients with POPH should receive targeted medical therapies with endothelin receptor antagonists, phosphodiesterase-5 inhibitors and/or prostanoids. In contrast, β-blockers should be avoided. It is unclear whether liver transplantation cures POPH or not. This review summarizes current knowledge of underlying conditions and focuses on therapeutic options in patients with pulmonary-hepatic vascular disorders.     

简介欧盟医药管理局的肺动脉高压医药产品临床研究指导原则

欧盟医药管理局的人用医药产品委员会(CHMP)于2008年12月18日,在伦敦发布了作为征求意见草案的CHMP关于治疗肺动脉高压医药产品的临床研究指导原则,旨在为评价新的用于联合治疗肺动脉高压的医疗产品或药物提供指南.本文旨在介绍该指南,为相关药物的临床试验设计和评价提供参考.     

Clinical pharmacology and efficacy of inhaled iloprost for the treatment of pulmonary arterial hypertension

Similar to other prostanoids, iloprost is a potent vasodilator with considerable antiproliferative and anti-thrombotic properties, although the relevance of its ability to affect platelet aggregation in this subset of patients is unrecognized. The pathogenesis of pulmonary arterial hypertension (PAH) is a multifactorial and complex process secondary to an innate deficiency of substances that induce vasodilation and an overproduction of substances producing vasoconstriction. The production of endothelial vasoactive mediators such as nitric oxide, prostacyclin, endothelin-1, thromboxane and serotonin affect the growth of smooth muscle cells, which facilitate the development of structural remodeling changes that are characteristic of PAH. There have been remarkable advances in understanding the pathologic processes that are responsible for increasing pulmonary vascular resistance and that result in elevated pulmonary artery pressures in order to reverse and prevent progression of the disease process. The goals of treatment in these patients are to alleviate the patients’ symptoms, to improve functional capacity and to prevent the progression of the disease. The prostacyclin analogs, such as iloprost, have given hope to these patients who struggle under the burdens of this complex disease.     

Overview of treprostinil sodium for the treatment of pulmonary arterial hypertension

Pulmonary arterial hypertension is a life-threatening disorder that refers to a group of diseases characterized by an abnormal elevation of the blood pressure within the pulmonary circulation due to a vasculopathy of the pulmonary microcirculation (1). If left untreated, the overall prognosis of pulmonary arterial hypertension is poor, with a 5-year survival rate of 34%. The most common cause of death is progressive right-sided heart failure (2). There is no pharmacologic cure for pulmonary arterial hypertension, and a team approach is required for the proper care of these patients (3). Treatment is directed at improving clinical symptoms, increasing exercise tolerance and extending survival. Until just a few years ago, standard treatment options for the treatment of pulmonary arterial hypertension were limited and included coumarin derivatives, calcium channel blockers, diuretics, digoxin and oxygen supplementation (4). In the last decade, the therapeutic options for pulmonary arterial hypertension have made considerable advances. In at least three major randomized controlled trials, the continuous intravenous infusion of epoprostenol, a synthetic salt of prostacyclin with potent vasodilatory ability, has been shown to improve exercise tolerance, hemodynamics, survival and quality of life in patients with New York Heart Association (NYHA) functional classes III and IV with either primary pulmonary hypertension or pulmonary arterial hypertension associated with scleroderma (5-9). Epoprostenol has now become a mainstay therapy in the long-term treatment of primary pulmonary hypertension or pulmonary arterial hypertension associated with scleroderma. Nevertheless, epoprostenol is far from an ideal form of therapy. Issues such as the short half-life of the drug, need for continuous central intravenous access and significant side effects have led to the development of more stable prostacyclin analogues as alternative therapies for primary pulmonary hypertension. These alternative therapies include iloprost (inhaled delivery) and treprostinil (subcutaneous delivery). As a result, the Food and Drug Administration (FDA) recently approved treprostinil for the treatment of pulmonary arterial hypertension in patients with NYHA classes II-IV. This review will offer a discussion of the basic pharmacology of treprostinil, its similarities to and differences from epoprostenol, the animal studies as well as the initial investigational studies leading to its FDA approval, and clinical uses of the drug alone or in combination with newer therapies directed at pulmonary arterial hypertension developed over the last decade.     

Role of the serotonin transporter in pulmonary arterial hypertension

Pulmonary arterial hypertension is a disease in which pulmonary arterial pressure is raised, leading to right heart failure. Survival is poor despite current therapeutic strategies. The ‘serotonin hypothesis of pulmonary arterial hypertension’ arose in the 1960s following an ‘epidemic’ of pulmonary arterial hypertension in women taking the indirect serotinergic agonist aminorex as an anorexigen. In the 1980s, the hypothesis was revisited following the occurrence of pulmonary arterial hypertension associated with the use of fenfluramines as anorexigens; these are also indirect serotinergic agents. Research has identified changes in serotonin synthesis, serotonin receptor activation and serotonin uptake via the serotonin transporter in experimental and clinical pulmonary arterial hypertension. This review will discuss our current understanding of this serotonin hypothesis with particular reference to the role of the serotonin transporter.     

辛伐他汀治疗慢性阻塞性肺疾病合并肺动脉高压疗效观察

目的探讨辛伐他汀在治疗慢性阻塞性肺疾病合并肺动脉高压患者肺功能、血浆内皮素等变化的疗效。方法临床统计38例慢性阻塞性肺疾病合并肺动脉高压患者,随机分为辛伐他汀治疗组和氨氯地平对照组各19例,治疗组每晚口服辛伐他汀20mg一次,对照组每日口服苯磺酸氨氯地平5mg。结果治疗组中总治疗有效率为66.67%,对照组中总治疗有效率为52.94%。治疗组与对照组相比,其呼吸困难改善更为明显,肺功能改善也更为明显。结论辛伐他汀治疗慢性阻塞性肺疾病合并肺动脉高压,能提高疗效,改善肺功能。     

Emerging drugs for pulmonary hypertension

Importance of the field: Pulmonary arterial hypertension (PAH) is a clinical syndrome characterized by structural narrowing of the small pulmonary arteries that often culminates in fatal right heart failure.

Areas covered in this review: PubMed was searched for PAH and treatment. Data from scientific meetings and pharmaceutical websites are also included. There are currently eight FDA approved drugs for PAH that fall into one of three classes: prostacyclins, endothelin-receptor antagonists and PDE-5 inhibitors. All have important limitations and morbidity and mortality remain high. Several new agents with similar mechanisms of action are in clinical development. Multiple novel therapeutic targets are being explored. New applications for PAH therapies, such as pulmonary hypertension due to left heart and lung disease, are also being investigated.

What the reader will gain: An understanding of currently available drugs and those in clinical development for pulmonary hypertension.

Take home message: Drugs targeting the pulmonary vasculature have been an extremely active area of basic and clinical research for the past 20 years and will continue to be so for the foreseeable future. Considerable progress has been made, and yet there continues to be a great unmet medical need for developing more efficacious therapies.     

Notch信号通路在肺动脉高压肺血管重构中的研究进展

肺动脉高压是一种以肺动脉压力和肺血管阻力持续升高为特征,引起肺血管重构发生的心血管性疾病。Notch信号通路是一种高度保守的信号路径,主要通过调控细胞的增殖、分化及凋亡等过程,参与心血管、神经、肿瘤等疾病的发生、发展。该文主要对Notch信号通路参与肺血管重构发生的分子机制进行综述,以期为肺动脉高压的治疗提供新的策略。