Pharmacokinetic evaluation of sildenafil as a pulmonary hypertension treatment

Expert Opinion on Drug Metabolism and Toxicology

Volumn 9, Issue 9, 2013, Pages 1193-1205

  Chaumais, Marie Camille ^a,b,c   Perrin, Swanny ^a,c,d   Sitbon, Olivier ^a,c,d   Simonneau, Gérald ^a,c,d   Humbert, Marc ^a,c,d   Montani, David ^a,c,d  

^a UNIVERSITÉ PARIS SACLAY   (France)

^b HÔPITAL ANTOINE BÉCLÈRE   (France)

^c CENTRE CHIRURGICAL MARIE LANNELONGUE   (France)

^d BICÊTRE HOSPITAL   (France)

Author keywords

Pharmacokinetics; Phosphodiesterase type 5 inhibitor; Pulmonary arterial hypertension; Sildenafil citrate

Indexed keywords

AMBRISENTAN; BOSENTAN; CIMETIDINE; CIPROFLOXACIN; CLARITHROMYCIN; DARUNAVIR; ERYTHROMYCIN; INDINAVIR; KETOCONAZOLE; PROSTANOID; RITONAVIR; SILDENAFIL; TADALAFIL;

AREA UNDER THE CURVE; ARTICLE; DIZZINESS; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG DISTRIBUTION; DRUG EFFICACY; DRUG HALF LIFE; DRUG MEGADOSE; DRUG METABOLISM; DRUG SAFETY; DRUG TOLERABILITY; DYSPEPSIA; EPISTAXIS; ERECTILE DYSFUNCTION; FLUSHING; HEADACHE; HUMAN; LOW DRUG DOSE; MAXIMUM PLASMA CONCENTRATION; MYALGIA; NAUSEA; NOSE OBSTRUCTION; PULMONARY HYPERTENSION; SIDE EFFECT;

ADULT; ANIMALS; CARBOLINES; CHILD; DISEASE MODELS, ANIMAL; DRUG EVALUATION, PRECLINICAL; HUMANS; HYPERTENSION, PULMONARY; PHOSPHODIESTERASE 5 INHIBITORS; PIPERAZINES; PURINES; RANDOMIZED CONTROLLED TRIALS AS TOPIC; SULFONES;

EID: 84882295721     PISSN: 17425255     EISSN: 17447607     Source Type: Journal    
DOI: 10.1517/17425255.2013.804063     Document Type: Article

References (120)

1. Farber HW, Loscalzo J. Pulmonary arterial hypertension. N Engl J Med 2004;351:1655-65
2. Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med 2004;351:1425-36
3. Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J 2009;34:1219-63
4. Ghofrani HA, Osterloh IH, Grimminger F. Sildenafil: from angina to erectile dysfunction to pulmonary hypertension and beyond. Nat Rev Drug Discov 2006;5:689-702
5. Wright PJ. Comparison of phosphodiesterase type 5 (PDE5) inhibitors. Int J Clin Pract 2006;60:967-75
6. SILDENAFIL-National Library of Medicine HSDB Database. Available from: http://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?./temp/~bKQtUS:1:sol
7. Shin HS, Bae SK, Lee MG. Pharmacokinetics of sildenafil after intravenous and oral administration in rats: hepatic and intestinal first-pass effects. Int J Pharm 2006;320:64-70
8. Friebe A, Koesling D. Regulation of nitric oxide-sensitive guanylyl cyclase. Circ Res 2003;93:96-105
9. Mayer B, Hemmens B. Biosynthesis and action of nitric oxide in mammalian cells. Trends Biochem Sci 1997;22:477-81
10. Lincoln TM, Dey NB, Boerth NJ, et al. Nitric oxide-cyclic GMP pathway regulates vascular smooth muscle cell phenotypic modulation: implications in vascular diseases. Acta Physiol Scand 1998;164:507-15
11. Giaid A. Nitric oxide and endothelin-1 in pulmonary hypertension. Chest 1998;114(3 Suppl):208S-12S
12. Giaid A, Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med 1995;333:214-21
13. Steinhorn RH. Nitric oxide and beyond: new insights and therapies for pulmonary hypertension. J Perinatol 2008;28(Suppl 3):S67-71
14. Zuckerbraun BS, George P, Gladwin MT. Nitrite in pulmonary arterial hypertension: therapeutic avenues in the setting of dysregulated arginine/nitric oxide synthase signalling. Cardiovasc Res 2011;89:542-52
15. Sarkar R, Meinberg EG, Stanley JC, et al. Nitric oxide reversibly inhibits the migration of cultured vascular smooth muscle cells. Circ Res 1996;78:225-30
16. Zuckerbraun BS, Stoyanovsky DA, Sengupta R, et al. Nitric oxide-induced inhibition of smooth muscle cell proliferation involves S-nitrosation and inactivation of RhoA. Am J Physiol Cell Physiol 2007;292:C824-31
17. Tsihlis ND, Oustwani CS, Vavra AK, et al. Nitric oxide inhibits vascular smooth muscle cell proliferation and neointimal hyperplasia by increasing the ubiquitination and degradation of UbcH10. Cell Biochem Biophys 2011; 60:89-97
18. Rybalkin SD, Yan C, Bornfeldt KE, Beavo JA. Cyclic GMP phosphodiesterases and regulation of smooth muscle function. Circ Res 2003;93:280-91
19. Corbin JD, Beasley A, Blount MA, Francis SH. High lung PDE5: a strong basis for treating pulmonary hypertension with PDE5 inhibitors. Biochem Biophys Res Commun 2005;334:930-8
20. Rabe KF, Tenor H, Dent G, et al. Identification of PDE isozymes in human pulmonary artery and effect of selective PDE inhibitors. Am J Physiol 1994;266(5 Pt 1):L536-43
21. Schermuly RT, Kreisselmeier KP, Ghofrani HA, et al. Chronic sildenafil treatment inhibits monocrotaline-induced pulmonary hypertension in rats. Am J Respir Crit Care Med 2004;169:39-45
22. Liu H, Liu Z, Guan Q. Oral sildenafil prevents and reverses the development of pulmonary hypertension in monocrotaline-treated rats. Interact Cardiovasc Thorac Surg 2007;6:608-13
23. Yen C-H, Leu S, Lin Y-C, et al. Sildenafil limits monocrotaline-induced pulmonary hypertension in rats through suppression of pulmonary vascular remodeling. J Cardiovasc Pharmacol 2010;55:574-84
24. Zeng Z, Li Y, Jiang Z, et al. The extracellular signal-regulated kinase is involved in the effects of sildenafil on pulmonary vascular remodeling. Cardiovasc Ther 2010;28:23-9
25. Tantini B, Manes A, Fiumana E, et al. Antiproliferative effect of sildenafil on human pulmonary artery smooth muscle cells. Basic Res Cardiol 2005;100:131-8
26. Wharton J, Strange JW, Moller GMO, et al. Antiproliferative effects of phosphodiesterase type 5 inhibition in human pulmonary artery cells. Am J Respir Crit Care Med 2005;172:105-13
27. Yang J, Li X, Al-Lamki RS, et al. Sildenafil potentiates bone morphogenetic protein signaling in pulmonary arterial smooth muscle cells and in experimental pulmonary hypertension. Arterioscler Thromb Vasc Biol 2013;33:34-4
28. Kuang T, Wang J, Zeifman A, et al. Combination use of sildenafil and simvastatin increases BMPR-II signal transduction in rats with monocrotaline-mediated pulmonary hypertension. Pulm Circ 2011;1:111-14
29. Luo L, Dai D-Z, Cheng Y-S, et al. Sildenafil improves diabetic vascular activity through suppressing endothelin receptor A, iNOS and NADPH oxidase which is comparable with the endothelin receptor antagonist CPU0213 in STZ-injected rats. J Pharm Pharmacol 2011;63:943-51
30. Cadirci E, Halici Z, Odabasoglu F, et al. Sildenafil treatment attenuates lung and kidney injury due to overproduction of oxidant activity in a rat model of sepsis: a biochemical and histopathological study. Clin Exp Immunol 2011;166:374-84
31. Iseri SO, Ersoy Y, Ercan F, et al. The effect of sildenafil, a phosphodiesterase-5 inhibitor, on acetic acid-induced colonic inflammation in the rat. J Gastroenterol Hepatol 2009;24:1142-8
32. Wang T, Liu Y, Chen L, et al. Effect of sildenafil on acrolein-induced airway inflammation and mucus production in rats. Eur Respir J 2009;33:1122-32
33. Toward TJ, Smith N, Broadley KJ. Effect of phosphodiesterase-5 inhibitor, sildenafil (Viagra), in animal models of airways disease. Am J Respir Crit Care Med 2004;169:227-34
34. Balarini CM, Leal MA, Gomes IBS, et al. Sildenafil restores endothelial function in the apolipoprotein E knockout mouse. J Transl Med 2013;11:3
35. Burnett AL, Strong TD, Trock BJ, et al. Serum biomarker measurements of endothelial function and oxidative stress after daily dosing of sildenafil in type 2 diabetic men with erectile dysfunction. J Urol 2009;181:245-51
36. De Visser YP, Walther FJ, Laghmani EH, et al. Sildenafil attenuates pulmonary inflammation and fibrin deposition, mortality and right ventricular hypertrophy in neonatal hyperoxic lung injury. Respir Res 2009;10:30
37. Percival JM, Whitehead NP, Adams ME, et al. Sildenafil reduces respiratory muscle weakness and fibrosis in the mdx mouse model of Duchenne muscular dystrophy. J Pathol 2012;228:77-87
38. Xie Y-P, Chen B, Sanders P, et al. Sildenafil prevents and reverses transverse-tubule remodeling and Ca(2+) handling dysfunction in right ventricle failure induced by pulmonary artery hypertension. Hypertension 2012;59:355-62 Beneficial cardiac effect of sildenafil.
39. Takimoto E, Champion HC, Li M, et al. Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat Med 2005;11:214-22
40. Nagayama T, Hsu S, Zhang M, et al. Sildenafil stops progressive chamber, cellular, and molecular remodeling and improves calcium handling and function in hearts with pre-existing advanced hypertrophy caused by pressure overload. J Am Coll Cardiol 2009;53:207-15
41. Chau VQ, Salloum FN, Hoke NN, et al. Mitigation of the progression of heart failure with sildenafil involves inhibition of RhoA/Rho-kinase pathway. Am J Physiol Heart Circ Physiol 2011;300:H2272-9
42. Nagendran J, Archer SL, Soliman D, et al. Phosphodiesterase type 5 is highly expressed in the hypertrophied human right ventricle, and acute inhibition of phosphodiesterase type 5 improves contractility. Circulation 2007;116:238-48
43. Schwartz BG, Levine LA, Comstock G, et al. Cardiac uses of phosphodiesterase-5 inhibitors. J Am Coll Cardiol 2012;59:9-15
44. Redfield MM, Chen HH, Borlaug BA, et al. Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA 2013;309(12):1268-77; 1-10
45. Chaumais M-C, Jobard M, Huertas A, et al. Pharmacokinetic evaluation of continuous intravenous epoprostenol. Expert Opin Drug Metab Toxicol 2010;6:1587-98
46. Revatio, INN-sildenafil citrate-WC500055835.pdf
47. Rezvanfar MA, Rahimi HR, Abdollahi M. ADMET considerations for phosphodiesterase-5 inhibitors. Expert Opin Drug Metab Toxicol 2012;8:1231-45
48. Nichols DJ, Muirhead GJ, Harness JA. Pharmacokinetics of sildenafil after single oral doses in healthy male subjects: absolute bioavailability, food effects and dose proportionality. Br J Clin Pharmacol 2002;53(Suppl 1):5S-12S
49. Rosen RC, Kostis JB. Overview of phosphodiesterase 5 inhibition in erectile dysfunction. Am J Cardiol 2003;92:9M-18M
50. Ghofrani HA, Voswinckel R, Reichenberger F, et al. Differences in hemodynamic and oxygenation responses to three different phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension: a randomized prospective study. J Am Coll Cardiol 2004;44:1488-96
51. Available from: http://www.ema.europa. eu/docs/en-GB/document-library/ EPAR-Product-Information/human/000638/WC500055840.pdf
52. Bailey DG, Dresser GK. Interactions between grapefruit juice and cardiovascular drugs. Am J Cardiovasc Drugs 2004;4:281-97
53. Al-Ghazawi MA, Tutunji MS, AbuRuz SM. The effects of pummelo juice on pharmacokinetics of sildenafil in healthy adult male Jordanian volunteers. Eur J Clin Pharmacol 2010;66:159-63
54. Choi M-K, Song I-S. Characterization of efflux transport of the PDE5 inhibitors, vardenafil and sildenafil. J Pharm Pharmacol 2012;64:1074-83
55. Guimaraes AC, Malachias MV, Coelho OR, et al. Use of sildenafil in patients with cardiovascular disease. Arq Bras Cardiol 1999;73:515-26
56. Mukherjee A, Dombi T, Wittke B, Lalonde R. Population pharmacokinetics of sildenafil in term neonates: evidence of rapid maturation of metabolic clearance in the early postnatal period. Clin Pharmacol Ther 2008;85:56-63
57. Hyland R, Roe EG, Jones BC, Smith DA. Identification of the cytochrome P450 enzymes involved in the N-demethylation of sildenafil. Br J Clin Pharmacol 2001;51:239-48
58. Walker DK, Ackland MJ, James GC, et al. Pharmacokinetics and metabolism of sildenafil in mouse, rat, rabbit, dog and man. Xenobiotica 1999;29:297-310
59. Muirhead GJ, Rance DJ, Walker DK, Wastall P. Comparative human pharmacokinetics and metabolism of single-dose oral and intravenous sildenafil. Br J Clin Pharmacol 2002;53:13S-20S
60. Montani D, Chaumais M-C, Savale L, et al. Phosphodiesterase type 5 inhibitors in pulmonary arterial hypertension. Adv Ther 2009;26:813-25
61. Chinello P, Cicalini S, Pichini S, et al. Sildenafil plasma concentrations in two HIV patients with pulmonary hypertension treated with ritonavir-boosted protease inhibitors. Curr HIV Res 2012;10:162-4
62. Sekar V, Lefebvre E, De Marez T, et al. Effect of repeated doses of darunavir plus low-dose ritonavir on the pharmacokinetics of sildenafil in healthy male subjects: phase I randomized, open-label, two-way crossover study. Clin Drug Investig 2008;28:479-85
63. Muirhead GJ, Wulff MB, Fielding A, et al. Pharmacokinetic interactions between sildenafil and saquinavir/ritonavir. Br J Clin Pharmacol 2000;50:99-107
64. Muirhead GJ, Faulkner S, Harness JA, Taubel J. The effects of steady-state erythromycin and azithromycin on the pharmacokinetics of sildenafil in healthy volunteers. Br J Clin Pharmacol 2002;53:37S-43S
65. Wilner K, Laboy L, LeBel M. The effects of cimetidine and antacid on the pharmacokinetic profile of sildenafil citrate in healthy male volunteers. Br J Clin Pharmacol 2002;53(Suppl 1):31S-6S
66. Merry C, Barry MG, Ryan M, et al. Interaction of sildenafil and indinavir when co-administered to HIV-positive patients. AIDS 1999;13:F101-7
67. Simonsen U. Interactions between drugs for erectile dysfunction and drugs for cardiovascular disease. Int J Impot Res 2002;14:178-88
68. Dresser GK, Spence JD, Bailey DG. Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Clin Pharmacokinet 2000;38:41-57
69. Hedaya MA, El-Afify DR, El-Maghraby GM. The effect of ciprofloxacin and clarithromycin on sildenafil oral bioavailability in human volunteers. Biopharm Drug Dispos 2006;27:103-10
70. Sitbon O, Lascoux-Combe C, Delfraissy J-F, et al. Prevalence of HIV-related pulmonary arterial hypertension in the current antiretroviral therapy era. Am J Respir Crit Care Med 2008;177:108-13
71. Sitbon O. HIV-related pulmonary arterial hypertension: clinical presentation and management. AIDS 2008;22(Suppl 3):S55-62
72. Sitbon O, Gressin V, Speich R, et al. Bosentan for the treatment of human immunodeficiency virus-associated pulmonary arterial hypertension. Am J Respir Crit Care Med 2004;170:1212-17
73. Hardy H, Backman ES, Farber HW. Successful bosentan and nonnucleoside reverse transcriptase inhibitor-based therapy in a patient with acquired immunodeficiency syndrome and pulmonary arterial hypertension. Pharmacotherapy 2010;30:139e-44e
74. Savale L, Lador F, Jais X, et al. HIV-related pulmonary arterial hypertension. Rev Mal Respir 2012;29:491-500
75. Humbert M, Segal ES, Kiely DG, et al. Results of European post-marketing surveillance of bosentan in pulmonary hypertension. Eur Respir J 2007;30:338-44
76. Spence R, Mandagere A, Dufton C, Venitz J. Pharmacokinetics and safety of ambrisentan in combination with sildenafil in healthy volunteers. J Clin Pharmacol 2008;48:1451-9
77. Muirhead GJ, Wilner K, Colburn W, et al. The effects of age and renal and hepatic impairment on the pharmacokinetics of sildenafil. Br J Clin Pharmacol 2002;53(Suppl 1):21S-30S
78. Sharma RK, Prasad N, Gupta A, Kapoor R. Treatment of erectile dysfunction with sildenafil citrate in renal allograft recipients: a randomized, double-blind, placebo-controlled, crossover trial. Am J Kidney Dis 2006;48:128-33
79. Bhatia S, Frantz RP, Severson CJ, et al. Immediate and long-term hemodynamic and clinical effects of sildenafil in patients with pulmonary arterial hypertension receiving vasodilator therapy. Mayo Clin Proc 2003;78:1207-13
80. Michelakis ED, Tymchak W, Noga M, et al. Long-term treatment with oral sildenafil is safe and improves functional capacity and hemodynamics in patients with pulmonary arterial hypertension. Circulation 2003;108:2066-9
81. Ghofrani HA, Schermuly RT, Rose F, et al. Sildenafil for long-term treatment of nonoperable chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med 2003;167:1139-41
82. Sastry BKS, Narasimhan C, Reddy NK, Raju BS. Clinical efficacy of sildenafil in primary pulmonary hypertension: a randomized, placebo-controlled, double-blind, crossover study. J Am Coll Cardiol 2004;43:1149-53
83. Singh TP, Rohit M, Grover A, et al. A randomized, placebo-controlled, double-blind, crossover study to evaluate the efficacy of oral sildenafil therapy in severe pulmonary artery hypertension. Am Heart J 2006;151:851.e1-5
84. Galie N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005;353:2148-57
85. Badesch DB, Hill NS, Burgess G, et al. Sildenafil for pulmonary arterial hypertension associated with connective tissue disease. J Rheumatol 2007;34:2417-22
86. Rubin LJ, Badesch DB, Fleming TR, et al. Long-term treatment with sildenafil citrate in pulmonary arterial hypertension: the SUPER-2 study. Chest 2011;140:1274-83
87. Wilkins MR, Paul GA, Strange JW, et al. Sildenafil versus Endothelin Receptor Antagonist for Pulmonary Hypertension (SERAPH) study. Am J Respir Crit Care Med 2005;171:1292-7
88. Hoeper MM, Faulenbach C, Golpon H, et al. Combination therapy with bosentan and sildenafil in idiopathic pulmonary arterial hypertension. Eur Respir J 2004;24:1007-10
89. Simonneau G, Rubin LJ, Galie N, et al. Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: a randomized trial. Ann Intern Med 2008;149:521-30
90. Barst RJ, Ivy DD, Gaitan G, et al. A randomized, double-blind, placebo-controlled, dose-ranging study of oral sildenafil citrate in treatment-naive children with pulmonary arterial hypertension. Circulation 2012;125:324-34
91. Drug Safety and Availability. FDA Drug Safety Communication: FDA recommends against use of Revatio (sildenafil) in children with pulmonary hypertension. Available from: http://www.fda.gov/Drugs/DrugSafety/ucm317123.htm
92. Revatio, INN. sildenafil-WC500107804.pdf.
93. Abman SH, Kinsella JP, Rosenzweig EB, et al. Implications of the FDA warning against the use of sildenafil for the treatment of pediatric pulmonary hypertension. Am J Respir Crit Care Med 2013;187(6):572-5
94. Bischoff E. Potency, selectivity, and consequences of nonselectivity of PDE inhibition. Int J Impot Res 2004;16(Suppl 1):S11-14
95. Foresta C, Caretta N, Zuccarello D, et al. Expression of the PDE5 enzyme on human retinal tissue: new aspects of PDE5 inhibitors ocular side effects. Eye (Lond) 2008;22:144-9
96. Azzouni F, Abu samra K. Are phosphodiesterase type 5 inhibitors associated with vision-threatening adverse events? A critical analysis and review of the literature. J Sex Med 2011;8:2894-903
97. Wirostko BM, Tressler C, Hwang L-J, et al. Ocular safety of sildenafil citrate when administered chronically for pulmonary arterial hypertension: results from phase III, randomised, double masked, placebo controlled trial and open label extension. BMJ 2012;344:e554
98. Laties A, Sharlip I. Ocular safety in patients using sildenafil citrate therapy for erectile dysfunction. J Sex Med 2006;3:12-27
99. Boshier A, Pambakian N, Shakir SAW. A case of nonarteritic ischemic optic neuropathy (NAION) in a male patient taking sildenafil. Int J Clin Pharmacol Ther 2002;40:422-3
100. Sowka JW, Neiberg MN, Vollmer LA. Optic atrophy after sildenafil use. Optometry 2007;78:122-8
101. Calvet C, Martin K, Robert G, et al. Treatment of erectile dysfunction by phosphodiesterase-5 inhibitors and nonarteritic anterior ischemic optic neuropathy (NOIAN). Prog Urol 2007;17:920-7
102. Kerr NM, Danesh-Meyer HV. Phosphodiesterase inhibitors and the eye. Clin Experiment Ophthalmol 2009;37:514-23
103. Laties AM. Vision disorders and phosphodiesterase type 5 inhibitors: a review of the evidence to date. Drug Saf 2009;32:1-18
104. FDA Announces Revisions to Labels for Cialis, Levitra and Viagra. 2007.Available from: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ 2007/ucm109012. htm
105. McGwin G Jr. Phosphodiesterase type 5 inhibitor use and hearing impairment. Arch Otolaryngol Head Neck Surg 2010;136:488-92
106. Maddox PT, Saunders J, Chandrasekhar SS. Sudden hearing loss from PDE-5 inhibitors: a possible cellular stress etiology. Laryngoscope 2009;119:1586-9
107. Khan AS, Sheikh Z, Khan S, et al. Viagra deafness-sensorineural hearing loss and phosphodiesterase-5 inhibitors. Laryngoscope 2011;121:1049-54
108. Arif SA, Poon H. Tadalafil: a long-acting phosphodiesterase-5 inhibitor for the treatment of pulmonary arterial hypertension. Clin Ther 2011;33:993-1004
109. Schermuly RT, Pullamsetti SS, Kwapiszewska G, et al. Phosphodiesterase 1 upregulation in pulmonary arterial hypertension: target for reverse-remodeling therapy. Circulation 2007;115:2331-9
110. Ghofrani HA, Voswinckel R, Reichenberger F, et al. Differences in hemodynamic and oxygenation responses to three different phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension: a randomized prospective study. J Am Coll Cardiol 2004;44:1488-96
111. Burgess G, Hoogkamer H, Collings L, Dingemanse J. Mutual pharmacokinetic interactions between steady-state bosentan and sildenafil. Eur J Clin Pharmacol 2008;64:43-50
112. Tay EL-W, Geok-Mui MK, Poh-Hoon MC, Yip J. Sustained benefit of tadalafil in patients with pulmonary arterial hypertension with prior response to sildenafil: a case series of 12 patients. Int J Cardiol 2008;125:416-17
113. Sildenafil to Tadalafil in Pulmonary Arterial Hypertension (SITAR)-Full Text View-ClinicalTrials.gov. Available from: http://clinicaltrials.gov/show/ NCT01043627
114. Galie N, Manes A, Negro L, et al. A meta-analysis of randomized controlled trials in pulmonary arterial hypertension. Eur Heart J 2009;30:394-403
115. Ghofrani HA, Distler O, Gerhardt F, et al. Treatment of pulmonary arterial hypertension (PAH): updated Recommendations of the Cologne Consensus Conference 2011. Int J Cardiol 2011;154(Suppl 1):S20-33
116. Kass DA, Takimoto E, Nagayama T, Champion HC. Phosphodiesterase regulation of nitric oxide signaling. Cardiovasc Res 2007;75:303-14
117. 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;33:785-92
118. Ghofrani H, Galie N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled study (PATENT-1). Chest 2012;142:1027A
119. Ghofrani HA, Hoeper MM, Halank M, et al. Riociguat for chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension: a phase II study. Eur Respir J 2010;36:792-9
120. Humbert M, McLaughlin VV. The 4th World Symposium on Pulmonary