Riociguat for the treatment of pulmonary hypertension

Introduction: Pulmonary arterial hypertension (PAH) is still an incurable disease with high mortality despite recent treatment advances. Chronic thromboembolic pulmonary hypertension (CTEPH) is a specific form of pulmonary hypertension due to thromboembolic occlusion of pulmonary arteries. Although 50 – 60% of the CTEPH patients can be cured via pulmonary endarterectomy (PEA), a significant portion is inoperable. For both diseases, therefore, new treatments are urgently needed.

Areas covered: The review will explain the mechanism of action of the soluble guanylate cyclase stimulator riociguat (BAY 63-2521) and will give an overview regarding the current scientific and clinical data of riociguat in both indications PAH and CTEPH. The most relevant publications up to date were used as sources for this review.

Expert opinion: Riociguat is a novel treatment option in PAH class 1, which, in contrast to phosphodiesterase-5 inhibitors, acts independently of endogenous nitric oxide and has shown efficacy in combination therapy with endothelin-1 receptor antagonists. Riociguat is the first approved drug for non-operable CTEPH and sustained CTEPH after PEA, thus introducing a proven pharmacologic treatment option for this group of patients. Long-term results in the real-life setting are still lacking and are needed to provide evidence for the true amount of progress riociguat adds to the field.     

New pharmacotherapy options for pulmonary arterial hypertension

Introduction: Epoprostenol was the first targeted therapy available for the treatment of pulmonary arterial hypertension (PAH). Since then great advances in our knowledge of the disease have been made and the spectrum of therapeutic options for PAH has expanded. After an overview of current available treatments, this article describes the new pharmacotherapy options and their place in the management of PAH.

Areas covered: This paper is based on a literature search and the review of studies published on PAH pharmacotherapy using the MEDLINE database.

Expert opinion: The last decade has been particularly important in PAH management with the emergence of six new molecules, the development of novel routes of administration and improvement of pharmacokinetics. Moreover, pediatric formulations have been developed. However, further research is required to inform clinicians regarding optimal choices of combination therapies (progressive add-on therapy or upfront combination therapy, selection of associated molecules regarding the patient’s profile...), to continue to improve the quality of life of patients with new drugs and to reach the ultimate goal of curing the disease.     

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.     

The prostacyclin analogue treprostinil in the treatment of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a rare but life‐threatening disease that progresses rapidly and is currently without a cure. Pharmacological treatments aim to slow down disease progression and to reduce symptoms by targeting the prostacyclin, the endothelin or the nitric oxide pathway. Drugs targeting the prostacyclin pathway have been shown to be favourable for PAH patients by causing vasodilatative, anti‐proliferative as well as anti‐inflammatory effects, but tend to be underused, partially due to adverse effects and difficulties associated with their intravenous administration. Treprostinil, a stable prostacyclin analogue, was FDA‐approved in 2002 to improve exercise capacity in PAH patients and is available in intravenous, subcutaneous, inhaled and oral form. The four different possible ways of administration, a long half‐life and its stability at room temperature give treprostinil an advantage over epoprostenol, iloprost and selexipag, the three other FDA‐approved drugs targeting the prostacyclin pathway. In clinical trials, treprostinil improved exercise capacity, quality of life (QOL), functional class and clinical status. While the different forms of treprostinil lead to specific complications, its general adverse effects are dizziness, nausea, pain in the jaw and extremities, diarrhoea, flushing and headache. This MiniReview will assess the benefits and drawbacks of treprostinil in the treatment of PAH by examining its specific mechanism of action and pharmacological properties, such as pharmacokinetics, pharmacodynamics, adverse effects and interactions. In addition, we will analyse and discuss results from different clinical trials, comparing treprostinil's four different forms to each other as well as to other drugs targeting the prostacyclin pathway.     

Guanylate cyclase regulates ileal longitudinal muscle contractions induced by neurogenic nitrergic activity in the rat

1. Nitrergic neurons regulate gastrointestinal (GI) activity and their dysfunction has been associated with various GI diseases. Nitric oxide (NO) typically relaxes GI smooth muscle, but nitrergic contractions also occur. Although guanylate cyclase is well established as mediating nitrergic GI relaxation, its role in contraction remains uncertain. 2. We used electrical field stimulation (EFS; 0.3 msec pulses, three trains of 1.2 s width, 2 Hz, at 30 s intervals) to evoke biphasic contraction–relaxation responses in rat ileum strips (longitudinal muscle–myenteric plexus preparations), mediated by the endogenous nitrergic transmitter, under non‐adrenergic, non‐cholinergic (NANC) conditions (1 μmol/L atropine and 4 μmol/L guanethidine). 3. All EFS responses were abolished by tetrodotoxin (1 μmol/L). Inhibition of NO synthase with N^ω‐nitro‐l ‐arginine‐methyl‐ester (l ‐NAME; 100 and 300 μmol/L) prevented both EFS‐evoked contractions and relaxations. l ‐Arginine (3 mmol/L) reversed l ‐NAME inhibition, primarily restoring contractions and suggesting that these require lower nitrergic transmitter levels than relaxations. 4. Pretreatment of preparations with subrelaxant concentrations of sodium nitroprusside (1 μmol/L) selectively desensitized EFS‐evoked contractions without affecting relaxations, suggesting different downstream mechanisms. Nevertheless, the selective guanylate cyclase inhibitor 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one (3 and 10 μmol/L) inhibited both nitrergic contractions and relaxations, indicating that guanylate cyclase activation is required for both responses. 5. The results of the present study support the hypothesis that the endogenous nitrergic transmitter differentially regulates guanylate cyclase, leading to either contractions or relaxations depending on its concentrations, thus providing additional insight into the regulation of ileum contractility by nitrergic activity.     

Nebivolol in the treatment of arterial hypertension

This MiniReview reports the current knowledge about the treatment of arterial hypertension with the third‐generation beta‐adrenoceptor antagonist (BAA) nebivolol. Furthermore, it reviews the advantages of nebivolol compared to the earlier generation of BAAs with respect to their different pharmacological properties. Beta‐adrenoceptor antagonists are a class of drugs applied for several different conditions, including hypertension and heart failure. They differ significantly in their pharmacological properties, including varying β₁/β₂‐selectivity and/or exertion of additive effects on the heart and circulation. Although these drugs have been a part of hypertensive therapy for about 40 years, the outcome of large clinical trials has put the role of BAAs into question. However, most of these results were based on first‐ and second‐generation BAAs and cannot be translated directly into third‐generation drugs. The third‐generation BAA nebivolol has the highest β₁‐selectivity seen so far, together with additional vasodilating and anti‐oxidative properties. It is currently applied in the treatment of hypertension and congestive heart failure. Nebivolol has a unique pharmacological profile, despite showing similar blood pressure‐lowering effects, and has certain advantages in the treatment of hypertension compared to the previous generations of BAAs. This includes significant improvements in endothelial dysfunction, central haemodynamics and the degree of erectile dysfunction in men, a neutral/beneficial metabolic profile and lastly a more favourable side effect profile. It is widely beneficial for, for example, sexually active men and patients with comorbidities such as type II diabetes mellitus, metabolic syndrome and chronic obstructive lung disorders. Whether the advantages translate to an improved long‐term clinical outcome remains to be clarified, and ongoing prospective studies will show this in the future.     

Riociguat for the treatment of pulmonary hypertension

Introduction: Pulmonary hypertension (PH) is a severe condition with a poor prognosis despite recent treatment advances. Therapies with new mechanisms of action are needed.

Areas covered: This review will help readers understand the mechanism of action of the soluble guanylate cyclase (sGC) stimulator riociguat (BAY 63-2521) and will provide a comprehensive summary regarding efficacy and safety of this drug in the management of PH. The most relevant publications up to December 2010 were used as sources for this review.

Expert opinion: Cyclic guanosine monophosphate (cGMP) is an important mediator of the preferential perfusion of well-ventilated regions throughout the lung. Drugs that increase cGMP levels could promote pulmonary vasorelaxation while maintaining optimal gas exchange. cGMP is generated by sGC, which can be stimulated by nitric oxide (NO). Riociguat stimulates sGC independently of NO and increases the sensitivity of sGC to NO, resulting in increased cGMP levels. Results to date suggest rapid, potent and prolonged efficacy and good tolerability in different types of PH. Phase III clinical trials are evaluating the long-term safety and clinical effectiveness of riociguat in pulmonary arterial hypertension (PAH) and chronic thromboembolic PH. Riociguat has the potential to become an important drug for the treatment of patients with PH.     

肺动脉高压治疗药riociguat的合成

目的 合成肺动脉高压治疗药物riociguat.方法 以2-氟溴苄为起始原料合成2-氟苄肼(2);以草酸二乙酯为起始原料合成氰基丙酮酸乙酯的钠盐(3);2和3关环后再经过5步反应合成1-(2-氟苄基)-1H-吡唑并[3,4-b]吡啶-3-甲脒盐酸盐(9);以苯胺和丙二腈为起始原料合成苯偶氮丙二腈(10);9和10关环后...     

阿托伐他汀对低氧性肺动脉压的影响

目的研究他汀类药物治疗慢性阻塞性肺疾病（chronic obstructive pulmonary disease,COPD）合并肺动脉高压（pulmonary hypertension,PH）的疗效和机制。方法选择2007年1月至2010年5月在我院诊治的COPD合并PH 100例,随机分为治疗组和对照组各50例。对照组给予常规治疗;治疗组在常规治疗基础上加用阿托伐他汀,首剂10～20 mg/d,若无不良反应,则维持剂量10 mg/d,疗程6个月,观察一氧化氮（nitric oxide,NO）、内皮素（endotheli,ET）、肺动脉收缩压（pulmonary artery systolicpressure,PAP）、6分钟步行距离（6-minute walking distance6,MWD）的变化。结果治疗后,两组6MWD、NO较治疗前升高,PAP、ET降低,差异有统计学意义（P〈0.01）,但治疗组较对照组更明显,差异有统计学意义（P〈0.01）。Spearman相关分析：ET与PAP呈正相关（r=0.452）,NO数值与PAP呈负相关（r=-0.557）。结论阿托伐他汀能降低COPD合并PH患者肺动脉压,改善患者心肺功能及运动耐量。其机制可能与阿托伐他汀能增加NO含量,降低ET的分泌,改善内皮功能有关。     

鸟苷对大鼠胸主动脉血管环的舒张作用及机制

目的研究鸟苷对大鼠离体血管环的影响,并探讨其可能的作用机制。方法分离SD大鼠胸主血管环,分成去内皮组和内皮完整组,采用离体血管环实验方法,经生物信号采集与分析系统测定血管环张力的变化,观察鸟苷的舒血管作用并探讨不同抑制剂对鸟苷舒张大鼠离体血管环作用的影响。结果鸟苷(10-9～10-5 mol.L-1)对基础状态下或KCl预收缩血管环的张力无影响;对PE预收缩的血管环有内皮依赖性舒张作用;环氧合酶抑制剂吲哚美辛孵育对鸟苷的舒张作用无明显影响;一氧化氮合酶抑制剂L-NAME或鸟苷酸环化酶抑制剂亚甲蓝可阻断鸟苷的血管舒张作用。结论鸟苷对大鼠离体胸主动脉有浓度依赖性舒张作用,其舒张作用可能与NO-GC-cGMP途径相关。     

New perspectives for the treatment of pulmonary hypertension

Pulmonary hypertension (PH) is a debilitating disease with a poor prognosis. Therapeutic options remain limited despite the introduction of prostacyclin analogues, endothelin receptor antagonists and phosphodiesterase 5 inhibitors within the last 15 years; these interventions address predominantly the endothelial and vascular dysfunctionS associated with the condition, but simply delay progression of the disease rather than offer a cure. In an attempt to improve efficacy, emerging approaches have focused on targeting the pro-proliferative phenotype that underpins the pulmonary vascular remodelling in the lung and contributes to the impaired circulation and right heart failure. Many novel targets have been investigated and validated in animal models of PH, including modulation of guanylate cyclases, phosphodiesterases, tyrosine kinases, Rho kinase, bone morphogenetic proteins signalling, 5-HT, peroxisome proliferator activator receptors and ion channels. In addition, there is hope that combinations of such treatments, harnessing and optimizing vasodilator and anti-proliferative properties, will provide a further, possibly synergistic, increase in efficacy; therapies directed at the right heart may also offer an additional benefit. This overview highlights current therapeutic options, promising new therapies, and provides the rationale for a combination approach to treat the disease.     

内皮素受体拮抗剂用于肺动脉高压的治疗进展

肺动脉高压（PAH）是一类以肺血管阻力进行性升高为主要特征的心肺血管疾病,最终可导致右心衰竭甚至死亡。早期发现PAH患者中内皮素明显高于正常,可引起肺血管的持续收缩及重构。内皮素受体拮抗剂可阻断该通路进而起到降低肺高压的作用。但目前国内临床上对于该类药物了解甚少。本文参考国内外文献对内皮素受体拮抗剂在PAH中的作用机制及临床应用作简要综述,旨在指导临床用药,使更多患者获益。     

Endothelium-independent relaxation of aortic rings by the nitric oxide synthase inhibitor diphenyleneiodonium

1. The flavoprotein binder diphenyleneiodonium (DPI) is a potent, irreversible inhibitor of nitric oxide synthase (NOS), but produces only a transient pressor response following systemic administration to animals, despite evidence of persistent NOS inhibition. To characterize further the effects of DPI on vascular tone, isometric tension was recorded from rat isolated aortic rings mounted between steel wires in an organ bath.
2. The NOS inhibitor N^G-nitro-L-arginine methyl ester (L-NAME, 1 mM) initiated an additional contraction of prostaglandin F_2α-preconstricted rings with endothelium which was sustained throughout the period of L-NAME exposure (+234±39% at 15 min). In contrast, addition of DPI (5 μM) to rings with endothelium produced a transient initial contraction (+111±27% at 2 min) followed by a more sustained relaxation (−27±19% at 15 min, P<0.001 vs L-NAME).
3. The contraction to DPI was also observed in rings without endothelium, was abolished by L-NAME pretreatment, and was unaffected by the α-adrenoreceptor inhibitor prazosin. Relaxation in response to DPI was not inhibited by endothelium removal or by pretreatment with either L-NAME or with the ATP-sensitive potassium channel blocker glibenclamide.
4. The endothelium-independent relaxation to DPI was inhibited at 23°C and its time course was delayed by pretreatment with the guanylate cyclase inhibitor methylene blue.
5. Thus, in addition to a transient initial contraction due to NOS inhibition, DPI produces an endothelium-independent, temperature-dependent relaxation which appears in part due to activation of guanylate cyclase. This relaxant effect of DPI may explain the transient nature of its pressor effect in vivo despite sustained NOS inhibition.

     

法舒地尔治疗肺动脉高压疗效的Meta分析

目的运用Meta分析方法评价法舒地尔治疗肺动脉高压的疗效。方法计算机检索中国期刊全文数据库(CNKI)、中文科技期刊全文数据库(VIP)、万方数字化期刊全文库、Pubmed和Cochrane library,对纳入的随机对照试验文献进行质量评价,并采用Rev Man 5.3软件进行Meta分析。结局指标为总有效率、6分钟步行试验(6MWT)、肺动脉收缩压(s PAP)、血氧饱和度(Sa O2)。结果共纳入13篇随机对照试验,共933例患者。Meta分析结果显示,法舒地尔加用常规治疗可有效提高肺动脉高压患者的临床疗效[RR=1.27,95%CI(1.15,1.40),P0.01]和6MWT[WMD=51.82,95%CI(40.66,62.97),P0.01],降低s PAP[WMD=-6.91,95%CI(-8.11,-5.71),P0.01]。Sa O2亚组分析,法舒地尔加用常规治疗可有效提高肺动脉高压患者的Sa O2(P0.01),慢性肺源性心脏病组:WMD=7.85,95%CI(5.68,10.01)、多种原发病组:WMD=3.18,95%CI(1.35,5.01)。结论法舒地尔治疗肺动脉高压具有较好的疗效,但仍需开展高质量的药物临床试验。     

Prevalence of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension in the United States

Abstract

Background:

The prevalence of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) in the US is largely unknown. Prior research has estimated PAH prevalence in Europe at ～15–52 per million.     

遗传性高血压大鼠和L-NAME性高血压大鼠的血压波动性升高(英文)

目的:观察自发性高血压大鼠(SHR)和L-NAME性高血压大鼠(NHR)的血压波动性(BPV)。方法:清醒自由活动大鼠连续血压监测技术测定BPV。尾套法观察L-NAME引起的升压过程,硝酸还原酶法测定NO浓度。结果:两种高血压大鼠的收缩压波动性(SBPV)和舒张压波动性(DBPV)均升高。在SHR,DBPV升高较多。而在NHR,SBPV升高较多。而且,NHR的SBPV升高(102％)明显高于SHR(28％)。饮用水中加L-NAME 1g/L使大鼠血压进行性升高,4周时100％造成高血压。NHR的血浆NO水平下降。结论:BPV升高是高血压的普遍现象。NO参与BPV的调控。     

The importance of the nitric oxide‐cGMP pathway in age‐related cardiovascular disease: Focus on phosphodiesterase‐1 and soluble guanylate cyclase

Among ageing‐related illnesses, cardiovascular disease (CVD) remains the leading cause of morbidity and mortality causing one‐third of all deaths worldwide. Ageing evokes a number of functional, pharmacological and morphological changes in the vasculature, accompanied by a progressive failure of protective and homeostatic mechanisms, resulting in target organ damage. Impaired vasomotor, proliferation, migration, antithrombotic and anti‐inflammatory function in both the endothelial and vascular smooth muscle cells are parts of the vascular ageing phenotype. The endothelium regulates these functions by the release of a wide variety of active molecules including endothelium‐derived relaxing factors such as nitric oxide, prostacyclin (PGI₂) and endothelium‐derived hyperpolarization (EDH). During ageing, a functional decay of the nitric oxide pathway takes place. Nitric oxide signals to VSMC and other important cell types for vascular homeostasis through the second messenger cyclic guanosine monophosphate (cGMP). Maintenance of proper cGMP levels is an important goal in sustainment of proper vascular function during ageing. For this purpose, different components can be targeted in this signalling system, and among them, phosphodiesterase‐1 (PDE1) and soluble guanylate cyclase (sGC) are crucial. This review focuses on the role of PDE1 and sGC in conditions that are relevant for vascular ageing.     

Caffeine inhibits the viability and osteogenic differentiation of rat bone marrow-derived mesenchymal stromal cells

Background and purpose:

Soluble guanylate cyclase (sGC) is the signal transduction enzyme most responsible for mediating the effects of nitric oxide (NO). Recently, NO-independent small molecule activators of sGC have been developed that have promising clinical activities. We have shown that the secreted matrix protein thrombospondin-1 (TSP-1) binds to CD47 and potently inhibits NO stimulation of sGC in endothelial and vascular smooth muscle cells (VSMCs) and platelets. Here we show that TSP-1 signalling via CD47 inhibits sGC activation by NO-independent sGC activating small molecules.

Experimental approach:

Vascular smooth muscle cells and washed human platelets were pretreated with TSP-1 (2.2 nM) in the presence of haeme-dependent sGC activators (YC-1, BAY 41-2272), and a haeme-independent activator (meso-porphyrin IX), and cGMP levels were measured. The effect of sGC activators on platelet aggregation and contraction of VSMC embedded in collagen gels was also assayed in the presence and absence of TSP-1.

Key results:

Thrombospondin-1 inhibited sGC activator-dependent increase in cGMP in VSMC and platelets. TSP-1 pretreatment also inhibited the ability of these agents to delay thrombin-induced platelet aggregation. TSP-1 pretreatment reduced the ability of sGC activating agents to abrogate VSMC contraction in vitro.

Conclusions and implications:

This work demonstrates that TSP-1 is a universal inhibitor of sGC, blocking both haeme-dependent and haeme-independent activation. These data coupled with the reported increases in TSP-1 with age, diabetes, ischaemia/reperfusion, and atherosclerosis implies that the therapeutic potential of all drugs that activate sGC could be compromised in disease states where TSP-1/CD47 signalling is elevated.