Riociguat: Stimulation der löslichen Guanylatzyklase

H. H. Leuchte; J. Behr; R. Ewert; H. A. Ghofrani; E. Grünig; M. Halank; M. Held; H. Klose; S. Rosenkranz; R. T. Schermuly; H. Wilkens; M. M. Hoeper

doi:10.1055/s-0034-1391435

Pneumologie 2015; 69(03): 135-143
DOI: 10.1055/s-0034-1391435

Übersicht

Riociguat: Stimulation der löslichen Guanylatzyklase

Neuer Wirkmechanismus zur Behandlung der pulmonal-arteriellen und der nicht operablen chronisch thromboembolischen pulmonalen HypertonieRiociguat: Stimulator of Soluble Guanylate-cyclaseNew Mode of Action for the Treatment of Pulmonary Arterial and Non Operable Chronic Thromboembolic Pulmonary Hypertension

H. H. Leuchte

¹Innere Medizin II, KH Neuwittelsbach, Akademisches Lehrkrankenhaus LMU, München

,

J. Behr

²Medizinische Klinik und Polklinik V, Klinikum der Universität München und Asklepios Fachkliniken München-Gauting, Comprehensive Pneumology Center, Mitglied des Deutschen Zentrums für Lungenforschung

,

R. Ewert

³Bereich Pneumologie/Infektiologie und Weaningzentrum Klinik und Poliklinik für Innere Medizin B Universitätsmedizin Greifswald

,

H. A. Ghofrani

⁴Medizinische Klinik II, Universitätsklinikum Gießen Marburg, Deutsches Zentrum für Lungenforschung. Kerckhoff Klinik Bad Nauheim

,

E. Grünig

⁵Zentrum Pulmonale Hypertonie der Thoraxklinik Heidelberg am Universitätsklinikum Heidelberg. Mitglied Deutsches Zentrum für Lungenforschung

,

M. Halank

⁶Medizinische Klinik und Poliklinik I; Universitätsklinikum Carl Gustav Carus an der TU Dresden, Dresden

,

M. Held

⁷Innere Medizin. Missionsärztliche Klinik Würzburg

,

H. Klose

⁸Sektion Pneumologie Onkologisches Zentrum, Universitätsklinikum Hamburg-Eppendorf, Hamburg

,

S. Rosenkranz

⁹Herzzentrum der Uniklinik Köln

,

R. T. Schermuly

¹⁰Pulmonale Pharmakotherapie Justus Liebig Universität Gießen

,

H. Wilkens

¹¹Innere Medizin V – Pneumologie, Allergologie, Beatmungs- und Umweltmedizin Universitätsklinikum des Saarlandes, Homburg Saar

,

M. M. Hoeper

¹²Klinik für Pneumologie, Medizinische Hochschule Hannover und Deutsches Zentrum für Lungenforschung (DZL)

› Author Affiliations

Abstract

Zusammenfassung

Riociguat ist der erste klinisch verfügbare Vertreter der Stimulatoren der löslichen Guanylatzyklase (sGC), einer neuartigen Substanzgruppe. Die primäre Zulassungsindikation erhielt Riociguat für die pulmonal-arterielle Hypertonie (PAH) und für die Behandlung der nicht operablen bzw. postoperativ wiederkehrenden/persistierenden chronisch thomboembolischen pulmonalen Hypertonie (CTEPH). Darüber hinaus besteht ein Studienprogramm in weiteren Indikationsgebieten.

Der nachfolgende Artikel beschreibt den Wirkmechanismus und die bisher verfügbaren klinischen Daten von Riociguat. Zudem ziehen die Autoren aus den vorliegenden Daten, der Zulassungs- und der Kostensituation ein Fazit für die Integration von Riociguat in den bisherigen Therapiealgorithmus der PAH und CTEPH.

Full Text

References

Literatur
1 Hoeper MM, Bogaard HJ, Condliffe R et al. Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol 2013; 62: D42-50
2 Simonneau G, Gatzoulis MA, Adatia I et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2013; 62: D34-41
3 DʼAlonzo GE, Barst RJ, Ayres SM et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med 1991; 115: 343-349
4 Vachiery JL, Adir Y, Barbera JA et al. Pulmonary hypertension due to left heart diseases. J Am Coll Cardiol 2013; 62: D100-108
5 Wagenvoort CA. Pathology of pulmonary thromboembolism. Chest 1995; 107: 10S-17S
6 Wilkens H, Lang I, Behr J et al. Chronic thromboembolic pulmonary hypertension (CTEPH): updated Recommendations of the Cologne Consensus Conference 2011. Int J Cardiol 2011; 154 (Suppl. 01) 54-60
7 Hoeper MM, Markevych I, Spiekerkoetter E et al. Goal-oriented treatment and combination therapy for pulmonary arterial hypertension. Eur Respir J 2005; 26: 858-863
8 Hoeper MM, Huscher D, Ghofrani HA et al. Elderly patients diagnosed with idiopathic pulmonary arterial hypertension: results from the COMPERA registry. Int J Cardiol 2013; 168: 871-880
9 Arcangeli C, Squillantini G, Santoro G et al. [Association of pulmonary and portal hypertension]. Minerva Cardioangiol 1996; 44: 343-352
10 Held M, Walthelm J, Baron S et al. Functional impact of pulmonary hypertension due to hypoventilation and changes under noninvasive ventilation. Eur Respir J 2014; 43: 156-165
11 Friebe A, Koesling D. Regulation of nitric oxide-sensitive guanylyl cyclase. Circ Res 2003; 93: 96-105
12 Follmann M, Griebenow N, Hahn MG et al. The chemistry and biology of soluble guanylate cyclase stimulators and activators. Angewandte Chemie 2013; 52: 9442-9462
13 Ghofrani HA, Pepke-Zaba J, Barbera JA et al. Nitric oxide pathway and phosphodiesterase inhibitors in pulmonary arterial hypertension. J Am Coll Cardiol 2004; 43: 68S-72S
14 Takimoto E. Cyclic GMP-dependent signaling in cardiac myocytes. Circ J 2012; 76: 1819-1825
15 Girgis RE, Champion HC, Diette GB et al. Decreased exhaled nitric oxide in pulmonary arterial hypertension: response to bosentan therapy. Am J Respir Crit Care Med 2005; 172: 352-357
16 Malerba M, Radaeli A, Ragnoli B et al. Exhaled nitric oxide levels in systemic sclerosis with and without pulmonary involvement. Chest 2007; 132: 575-580
17 Giaid A, Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med 1995; 333: 214-221
18 Kielstein JT, Bode-Boger SM, Hesse G et al. Asymmetrical dimethylarginine in idiopathic pulmonary arterial hypertension. Arterioscler Thromb Vasc Biol 2005; 25: 1414-1418
19 Pullamsetti S, Kiss L, Ghofrani HA et al. Increased levels and reduced catabolism of asymmetric and symmetric dimethylarginines in pulmonary hypertension. FASEB J 2005; 19: 1175-1177
20 Skoro-Sajer N, Mittermayer F, Panzenboeck A et al. Asymmetric dimethylarginine is increased in chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med 2007; 176: 1154-1160
21 Xu W, Kaneko FT, Zheng S et al. Increased arginase II and decreased NO synthesis in endothelial cells of patients with pulmonary arterial hypertension. FASEB J 2004; 18: 1746-1748
22 Bowers R, Cool C, Murphy RC et al. Oxidative stress in severe pulmonary hypertension. Am J Respir Crit Care Med 2004; 169: 764-769
23 Cracowski JL, Degano B, Chabot F et al. Independent association of urinary F2-isoprostanes with survival in pulmonary arterial hypertension. Chest 2012; 142: 869-876
24 Developing new guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 2009; 30: 2416-2418
25 Black SM, Sanchez LS, Mata-Greenwood E et al. sGC and PDE5 are elevated in lambs with increased pulmonary blood flow and pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2001; 281: L1051-1057
26 Maclean MR, Johnston ED, McCulloch KM et al. Phosphodiesterase isoforms in the pulmonary arterial circulation of the rat: changes in pulmonary hypertension. J Pharmacol Exp Ther 1997; 283: 619-624
27 Farrow KN, Lee KJ, Perez M et al. Brief hyperoxia increases mitochondrial oxidation and increases phosphodiesterase 5 activity in fetal pulmonary artery smooth muscle cells. Antioxid Redox Signal 2012; 17: 460-470
28 Farrow KN, Wedgwood S, Lee KJ et al. Mitochondrial oxidant stress increases PDE5 activity in persistent pulmonary hypertension of the newborn. Respir Physiol Neurobiol 2010;
29 Galie N, Ghofrani HA, Torbicki A et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005; 353: 2148-2157
30 Galie N, Brundage BH, Ghofrani HA et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation 2009; 119: 2894-2903
31 Schermuly RT, Stasch JP, Pullamsetti SS et al. Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension. Eur Respir J 2008; 32: 881-891
32 Stasch JP, Evgenov OV. Soluble guanylate cyclase stimulators in pulmonary hypertension. Handb Exp Pharmacol 2013; 218: 279-313
33 Frey R, Muck W, Unger S et al. Pharmacokinetics, pharmacodynamics, tolerability, and safety of the soluble guanylate cyclase activator cinaciguat (BAY 58-2667) in healthy male volunteers. J Clin Pharmacol 2008; 48: 1400-1410
34 Frey R, Muck W, Unger S et al. Single-dose pharmacokinetics, pharmacodynamics, tolerability, and safety of the soluble guanylate cyclase stimulator BAY 63-2521: an ascending-dose study in healthy male volunteers. J Clin Pharmacol 2008; 48: 926-934
35 Grimminger F, Weimann G, Frey R et al. First acute haemodynamic study of soluble guanylate cyclase stimulator riociguat in pulmonary hypertension. Eur Respir J 2009; 33: 785-792
36 Ghofrani HA, Voswinckel R, Gall H et al. Riociguat for pulmonary hypertension. Future Cardiol 2010; 6: 155-166
37 Ghofrani HA, Galie N, Grimminger F et al. Riociguat for the treatment of pulmonary arterial hypertension. NEJM 2013; 369: 330-340
38 Galie N, Neusser D, Muller K et al. A Placebo-Controlled, Double-Blind Phase II Interaction Study To Evaluate Blood Pressure Following Addition Of Riociguat To Patients With Symptomatic Pulmonary Arterial Hypertension (pah) Receiving Sildenafil (PATENT plus). ATS: Am J Respir Crit Care Medicine 2013; p. A 3530
39 Ghofrani HA, DʼArmini AM, Grimminger F et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. NEJM 2013; 369: 319-329
40 Lettieri CJ, Nathan SD, Barnett SD et al. Prevalence and outcomes of pulmonary arterial hypertension in advanced idiopathic pulmonary fibrosis. Chest 2006; 129: 746-752
41 Hoeper MM, Halank M, Wilkens H et al. Riociguat for interstitial lung disease and pulmonary hypertension: a pilot trial. Eur Respir J 2013; 41: 853-860
42 Guazzi M, Galie N. Pulmonary hypertension in left heart disease. Eur Respir Rev 2012; 21: 338-346
43 Bonderman D, Ghio S, Felix SB et al. Riociguat for patients with pulmonary hypertension caused by systolic left ventricular dysfunction: a phase IIb double-blind, randomized, placebo-controlled, dose-ranging hemodynamic study. Circulation 2013; 128: 502-511
44 Pulido T, Adzerikho I, Channick RN et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med 2013; 369: 809-818
45 Galie N, Hoeper MM, Humbert M et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J 2009; 34: 1219-1263