Pharmacologic Treatments for Pulmonary Hypertension: Exploring Pharmacogenomics

• Thenappan T , ShahSJ, RichS, Gomberg-MaitlandM. A USA-based registry for pulmonary arterial hypertension: 1982–2006. Eur. Respir. J., 30(6), 1103–1110 (2007).
   PubMed Web of Science ®Google Scholar
• Benza RL , MillerDP, BarstRJ, BadeschDB, FrostAE, McGgoonMD. An evaluation of long-term survival from time of diagnosis in pulmonary arterial hypertension from the REVEAL Registry. Chest, 142(2), 448–456 (2012).
   PubMed Web of Science ®Google Scholar
• Simonneau G , RobbinsIM, BeghettiMet al. Updated clinical classification of pulmonary hypertension. J. Am. Coll. Cardiol. , 54(Suppl. 1), S43–S54 (2009).
   PubMed Web of Science ®Google Scholar
• Humbert M , SitbonO, ChaouatAet al. Pulmonary arterial hypertension in France: results from a national registry. Am. J. Respir. Crit. Care Med. , 173(9), 1023–1030 (2006).
   PubMed Web of Science ®Google Scholar
• Peacock AJ , MurphyNF, McMurrayJJ, CaballeroL, StewartS. An epidemiological study of pulmonary arterial hypertension. Eur. Respir. J., 30(1), 104–109 (2007).
   PubMed Web of Science ®Google Scholar
• Machado RD , AldredMA, JamesVet al. Mutations of the TGF-beta type II receptor BMPR2 in pulmonary arterial hypertension. Hum. Mutat. , 27(2), 121–132 (2006).
   PubMed Web of Science ®Google Scholar
• Archer SL , MichelakisED. Phosphodiesterase type 5 inhibitors for pulmonary arterial hypertension. N. Engl. J. Med., 361(19), 1864–1871 (2009).
   PubMed Web of Science ®Google Scholar
• Cogan J , AustinE, HedgesLet al. Role of BMPR2 alternative splicing in heritable pulmonary arterial hypertension penetrance. Circulation , 126(15), 1907–1916 (2012).
   PubMed Web of Science ®Google Scholar
• Trembath RC , ThomsonJR, MachadoRDet al. Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N. Engl. J. Med. , 345(5), 325–334 (2001).
   PubMed Web of Science ®Google Scholar
• Giaid A , SalehD. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N. Engl. J. Med., 333(4), 214–221 (1995).
   PubMed Web of Science ®Google Scholar
• Rubens C , EwertR, HalankMet al. Big endothelin-1 and endothelin-1 plasma levels are correlated with the severity of primary pulmonary hypertension. Chest , 120(5), 1562–1569 (2001).
   PubMed Web of Science ®Google Scholar
• Schwartzenberg S , RedfieldMM, FromAM, SorajjaP, NishimuraRA, BorlaugBA. Effects of vasodilation in heart failure with preserved or reduced ejection fraction implications of distinct pathophysiologies on response to therapy. J. Am. Coll. Cardiol., 59(5), 442–451 (2012).
   PubMed Web of Science ®Google Scholar
• Ghio S , GavazziA, CampanaCet al. Independent and additive prognostic value of right ventricular systolic function and pulmonary artery pressure in patients with chronic heart failure. J. Am. Coll. Cardiol. , 37(1), 183–188 (2001).
   PubMed Web of Science ®Google Scholar
• Willens HJ , KesslerKM. Severe pulmonary hypertension associated with diastolic left ventricular dysfunction. Chest, 103(6), 1877–1883 (1993).
   PubMed Web of Science ®Google Scholar
• Lam CS , RogerVL, RodehefferRJ, BorlaugBA, EndersFT, RedfieldMM. Pulmonary hypertension in heart failure with preserved ejection fraction: a community-based study. J. Am. Coll. Cardiol., 53(13), 1119–1126 (2009).
   PubMed Web of Science ®Google Scholar
• Bursi F , McnallanSM, RedfieldMMet al. Pulmonary pressures and death in heart failure: a community study. J. Am. Coll. Cardiol. , 59(3), 222–231 (2012).
   PubMed Web of Science ®Google Scholar
• Oswald-Mammosser M , WeitzenblumE, QuoixEet al. Prognostic factors in COPD patients receiving long-term oxygen therapy. Importance of pulmonary artery pressure. Chest , 107(5), 1193–1198 (1995).
   PubMed Web of Science ®Google Scholar
• Lettieri CJ , NathanSD, BarnettSD, AhmadS, ShorrAF. Prevalence and outcomes of pulmonary arterial hypertension in advanced idiopathic pulmonary fibrosis. Chest, 129(3), 746–752 (2006).
   PubMed Web of Science ®Google Scholar
• Hoeper MM , BarberaJA, ChannickRNet al. Diagnosis, assessment, and treatment of non-pulmonary arterial hypertension pulmonary hypertension. J. Am. Coll. Cardiol. , 54(Suppl. 1), S85–S96 (2009).
   PubMed Web of Science ®Google Scholar
• Pengo V , LensingAW, PrinsMHet al. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N. Engl. J. Med. , 350(22), 2257–2264 (2004).
   PubMed Web of Science ®Google Scholar
• Condliffe R , KielyDG, GibbsJSet al. Improved outcomes in medically and surgically treated chronic thromboembolic pulmonary hypertension. Am. J. Respir. Crit. Care Med. , 177(10), 1122–1127 (2008).
   PubMed Web of Science ®Google Scholar
• Shigemitsu H , NagaiS, SharmaOP. Pulmonary hypertension and granulomatous vasculitis in sarcoidosis. Curr. Opin. Pulm. Med., 13(5), 434–438 (2007).
   PubMed Web of Science ®Google Scholar
• Baughman RP , CulverDA, JudsonMA. A concise review of pulmonary sarcoidosis. Am. J. Respir. Crit. Care Med., 183(5), 573–581 (2011).
   PubMed Web of Science ®Google Scholar
• Fisher KA , SerlinDM, WilsonKC, WalterRE, BermanJS, FarberHW. Sarcoidosis-associated pulmonary hypertension: outcome with long-term epoprostenol treatment. Chest, 130(5), 1481–1488 (2006).
   PubMed Web of Science ®Google Scholar
• Barnett CF , BonuraEJ, NathanSDet al. Treatment of sarcoidosis-associated pulmonary hypertension. A two-center experience. Chest , 135(6), 1455–1461 (2009).
   PubMed Web of Science ®Google Scholar
• Macchia A , MarchioliR, TognoniGet al. Systematic review of trials using vasodilators in pulmonary arterial hypertension: why a new approach is needed. Am. Heart J. , 159(2), 245–257 (2010).
   PubMed Web of Science ®Google Scholar
• Savarese G , PaolilloS, CostanzoPet al. Do changes of 6-minute walk distance predict clinical events in patients with pulmonary arterial hypertension? A meta-analysis of 22 randomized trials. J. Am. Coll. Cardiol. , 60(13), 1192–1201 (2012).
   PubMed Web of Science ®Google Scholar
• Rubin LJ . The 6-minute walk test in pulmonary arterial hypertension: how far is enough? Am. J. Respir. Crit. Care Med., 186(5), 396–397 (2012).
   PubMed Web of Science ®Google Scholar
• Rich S . The 6-minute walk test as a primary endpoint in clinical trials for pulmonary hypertension. J. Am. Coll. Cardiol., 60(13), 1202–1203 (2012).
   PubMed Web of Science ®Google Scholar
• Said SI , HamidiSA. Pharmacogenomics in pulmonary arterial hypertension: toward a mechanistic, target-based approach to therapy. Pulm. Circ., 1(3), 383–388 (2011).
   PubMedGoogle Scholar
• Geraci MW , GaoB, ShepherdDCet al. Pulmonary prostacyclin synthase overexpression in transgenic mice protects against development of hypoxic pulmonary hypertension. J. Clin. Invest. , 103(11), 1509–1515 (1999).
   PubMed Web of Science ®Google Scholar
• Tahara N , KaiH, NiiyamaHet al. Repeated gene transfer of naked prostacyclin synthase plasmid into skeletal muscles attenuates monocrotaline-induced pulmonary hypertension and prolongs survival in rats. Hum. Gene Ther. , 15(12), 1270–1278 (2004).
   PubMed Web of Science ®Google Scholar
• Tuder RM , CoolCD, GeraciMWet al. Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am. J. Respir. Crit. Care Med. , 159(6), 1925–1932 (1999).
   PubMed Web of Science ®Google Scholar
• Bihari D , SmithiesM, GimsonA, TinkerJ. The effects of vasodilation with prostacyclin on oxygen delivery and uptake in critically ill patients. N. Engl. J. Med., 317(7), 397–403 (1987).
   PubMed Web of Science ®Google Scholar
• Kiernan FJ , KlugerJ, RegnierJC, RutkowskiM, FieldmanA. Epoprostenol sodium (prostacyclin) infusion in acute myocardial infarction. Br. Heart J., 56(5), 428–432 (1986).
   PubMedGoogle Scholar
• Ashby B . Comparison of Iloprost, Cicaprost and prostacyclin effects on cyclic AMP metabolism in intact platelets. Prostaglandins, 43(3), 255–261 (1992).
   PubMedGoogle Scholar
• Moncada S , GryglewskiR, BuntingS, VaneJR. An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation. Nature, 263(5579), 663–665 (1976).
   PubMed Web of Science ®Google Scholar
• Moncada S , VaneJR. Prostacyclin and blood coagulation. Drugs, 21(6), 430–437 (1981).
   PubMed Web of Science ®Google Scholar
• Flolan, package insert. GlaxoSmithKline, NC, USA.
   Google Scholar
• Kingman MS , TankersleyMA, LombardiSet al. Prostacyclin administration errors in pulmonary arterial hypertension patients admitted to hospitals in the United States: a national survey. J. Heart Lung Transplant. , 29(8), 841–846 (2010).
   PubMed Web of Science ®Google Scholar
• Kallen AJ , LedermanE, BalajiAet al. Bloodstream infections in patients given treatment with intravenous prostanoids. Infect. Control Hosp. Epidemiol. , 29(4), 342–349 (2008).
   PubMed Web of Science ®Google Scholar
• Veletri®, package insert. Actelion Pharmaceuticals US Inc., CA, USA.
   Google Scholar
• Tyvaso®, package insert. United Therapeutics Corp., NC, USA.
   Google Scholar
• Remodulin®, package insert. United Therapeutics Corp., NC, USA.
   Google Scholar
• Tapson VF , MclaughlinVV, Gomberg-MaitlandMet al. Delivery of intravenous treprostinil at low infusion rates using a miniaturized infusion pump in patients with pulmonary arterial hypertension. J. Vasc. Access , 7(3), 112–117 (2006).
   PubMedGoogle Scholar
• Laliberte K , ArnesonC, JeffsR, HuntT, WadeM. Pharmacokinetics and steady-state bioequivalence of treprostinil sodium (Remodulin) administered by the intravenous and subcutaneous route to normal volunteers. J. Cardiovasc. Pharmacol., 44(2), 209–214 (2004).
   PubMed Web of Science ®Google Scholar
• Ventavis®, package insert. Actelion Pharmaceuticals US Inc., CA, USA.
   Google Scholar
• Barst RJ , RubinLJ, LongWAet al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N. Engl. J. Med. , 334(5), 296–301 (1996).
   PubMed Web of Science ®Google Scholar
• Badesch DB , TapsonVF, McgoonMDet al. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial. Ann. Intern. Med. , 132(6), 425–434 (2000).
   PubMed Web of Science ®Google Scholar
• Simonneau G , BarstRJ, GalieNet al. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial. Am. J. Respir. Crit. Care Med. , 165(6), 800–804 (2002).
   PubMed Web of Science ®Google Scholar
• Hiremath J , ThanikachalamS, ParikhKet al. Exercise improvement and plasma biomarker changes with intravenous treprostinil therapy for pulmonary arterial hypertension: a placebo-controlled trial. J. Heart Lung Transplant. , 29(2), 137–149 (2010).
   PubMed Web of Science ®Google Scholar
• Mclaughlin VV , BenzaRL, RubinLJet al. Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trial. J. Am. Coll. Cardiol. , 55(18), 1915–1922 (2010).
   PubMed Web of Science ®Google Scholar
• Olschewski H , SimonneauG, GalieNet al. Inhaled iloprost for severe pulmonary hypertension. N. Engl. J. Med. , 347(5), 322–329 (2002).
   PubMed Web of Science ®Google Scholar
• Mclaughlin VV , OudizRJ, FrostAet al. Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. , 174(11), 1257–1263 (2006).
   PubMed Web of Science ®Google Scholar
• Califf RM , AdamsKF, MckennaWJet al. A randomized controlled trial of epoprostenol therapy for severe congestive heart failure: the Flolan International Randomized Survival Trial (FIRST). Am. Heart J. , 134(1), 44–54 (1997).
   PubMed Web of Science ®Google Scholar
• Archer SL , MikeD, CrowJ, LongW, WeirEK. A placebo-controlled trial of prostacyclin in acute respiratory failure in COPD. Chest, 109(3), 750–755 (1996).
   PubMed Web of Science ®Google Scholar
• Dernaika TA , BeavinM, KinasewitzGT. Iloprost improves gas exchange and exercise tolerance in patients with pulmonary hypertension and chronic obstructive pulmonary disease. Respiration, 79(5), 377–382 (2010).
   PubMed Web of Science ®Google Scholar
• Minai OA , SahooD, ChapmanJT, MehtaAC. Vaso-active therapy can improve 6-min walk distance in patients with pulmonary hypertension and fibrotic interstitial lung disease. Resp. Med., 102(7), 1015–1020 (2008).
   PubMed Web of Science ®Google Scholar
• Cabrol S , SouzaR, JaisXet al. Intravenous epoprostenol in inoperable chronic thromboembolic pulmonary hypertension. J. Heart Lung Transplant. , 26(4), 357–362 (2007).
   PubMed Web of Science ®Google Scholar
• Skoro-Sajer N , BondermanD, WiesbauerFet al. Treprostinil for severe inoperable chronic thromboembolic pulmonary hypertension. J. Thromb. Haemost. , 5(3), 483–489 (2007).
   PubMed Web of Science ®Google Scholar
• Stitham J , StojanovicA, HwaJ. Impaired receptor binding and activation associated with a human prostacyclin receptor polymorphism. J. Biol. Chem., 277(18), 15439–15444 (2002).
   PubMed Web of Science ®Google Scholar
• Fetalvero KM , ShyuM, NomikosAPet al. The prostacyclin receptor induces human vascular smooth muscle cell differentiation via the protein kinase A pathway. Am. J. Physiol. , 290(4), H1337–H1346 (2006).
   Google Scholar
• Arehart E , StithamJ, AsselbergsFWet al. Acceleration of cardiovascular disease by a dysfunctional prostacyclin receptor mutation: potential implications for cyclooxygenase-2 inhibition. Circ. Res. , 102(8), 986–993 (2008).
   PubMed Web of Science ®Google Scholar
• Mohite A , ChillarA, SoSP, CervantesV, RuanKH. Novel mechanism of the vascular protector prostacyclin: regulating microRNA expression. Biochemistry, 50(10), 1691–1699 (2011).
   PubMed Web of Science ®Google Scholar
• Yanagisawa M , KuriharaH, KimuraSet al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature , 332(6163), 411–415 (1988).
   PubMed Web of Science ®Google Scholar
• Penna C , RastaldoR, MancardiDet al. Effect of endothelins on the cardiovascular system. J. Cardiovasc. Med. , 7(9), 645–652 (2006).
   Google Scholar
• Khalil RA . Modulators of the vascular endothelin receptor in blood pressure regulation and hypertension. Curr. Mol. Pharmacol., 4(3), 176–186 (2011).
   PubMedGoogle Scholar
• Galie N , ManesA, BranziA. The endothelin system in pulmonary arterial hypertension. Cardiovasc. Res., 61(2), 227–237 (2004).
   PubMed Web of Science ®Google Scholar
• Humbert M , MorrellNW, ArcherSLet al. Cellular and molecular pathobiology of pulmonary arterial hypertension. J. Am. Coll. Cardiol. , 43(Suppl. 12), S13–S24 (2004).
   PubMed Web of Science ®Google Scholar
• Dingemanse J , van Giersbergen PL. Clinical pharmacology of bosentan, a dual endothelin receptor antagonist. Clin. Pharmacokinet., 43(15), 1089–1115 (2004).
   PubMed Web of Science ®Google Scholar
• van Giersbergen PL , HalabiA, DingemanseJ. Single- and multiple-dose pharmacokinetics of bosentan and its interaction with ketoconazole. Br. J. Clin. Pharmacol., 53(6), 589–595 (2002).
   PubMed Web of Science ®Google Scholar
• van Giersbergen PL , TreiberA, SchneiterR, DietrichH, DingemanseJ. Inhibitory and inductive effects of rifampin on the pharmacokinetics of bosentan in healthy subjects. Clin. Pharmacol. Therapeut., 81(3), 414–419 (2007).
   PubMed Web of Science ®Google Scholar
• Dingemanse J , SchaarschmidtD, van Giersbergen PL. Investigation of the mutual pharmacokinetic interactions between bosentan, a dual endothelin receptor antagonist, and simvastatin. Clin. Pharmacokinet., 42(3), 293–301 (2003).
   PubMed Web of Science ®Google Scholar
• Weber C , SchmittR, BirnboeckHet al. Multiple-dose pharmacokinetics, safety, and tolerability of bosentan, an endothelin receptor antagonist, in healthy male volunteers. J. Clin. Pharmacol. , 39(7), 703–714 (1999).
   PubMed Web of Science ®Google Scholar
• Tracleer (bosentan) Risk Evaluation Mitigation Strategy (REMS). Actelion Pharmaceuticals US, Inc., CA, USA (2010).
   Google Scholar
• Treiber A , SchneiterR, HauslerS, StiegerB. Bosentan is a substrate of human OATP1B1 and OATP1B3: inhibition of hepatic uptake as the common mechanism of its interactions with cyclosporin A, rifampicin, and sildenafil. Drug Metab. Disposit., 35(8), 1400–1407 (2007).
   PubMed Web of Science ®Google Scholar
• Letairis®, package insert. Gilead Sciences, Inc., CA, USA.
   Google Scholar
• Rubin LJ , BadeschDB, BarstRJet al. Bosentan therapy for pulmonary arterial hypertension. N. Engl. J. Med. , 346(12), 896–903 (2002).
   PubMed Web of Science ®Google Scholar
• Galie N , RubinL, HoeperMet al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet , 371(9630), 2093–2100 (2008).
   PubMed Web of Science ®Google Scholar
• Galie N , OlschewskiH, OudizRJet al. Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2. Circulation , 117(23), 3010–3019 (2008).
   PubMed Web of Science ®Google Scholar
• Mcmurray JJ , TeerlinkJR, CotterGet al. Effects of tezosentan on symptoms and clinical outcomes in patients with acute heart failure: the VERITAS randomized controlled trials. JAMA , 298(17), 2009–2019 (2007).
   PubMed Web of Science ®Google Scholar
• Packer M , McmurrayJ, MassieBMet al. Clinical effects of endothelin receptor antagonism with bosentan in patients with severe chronic heart failure: results of a pilot study. J. Cardiac Fail. , 11(1), 12–20 (2005).
   PubMed Web of Science ®Google Scholar
• Hefke T , ZittermannA, FuchsU, Schulte-EistrupS, GummertJF, SchulzU. Bosentan effects on hemodynamics and clinical outcome in heart failure patients with pulmonary hypertension awaiting cardiac transplantation. Thorac. Cardiovasc. Surg., 60(1), 26–34 (2012).
   PubMed Web of Science ®Google Scholar
• Stolz D , RaschH, LinkaAet al. A randomised, controlled trial of bosentan in severe COPD. Eur. Respir. J. , 32(3), 619–628 (2008).
   PubMed Web of Science ®Google Scholar
• Gunther A , EnkeB, MarkartPet al. Safety and tolerability of bosentan in idiopathic pulmonary fibrosis: an open label study. Eur. Respir. J. , 29(4), 713–719 (2007).
   PubMed Web of Science ®Google Scholar
• Badesch DB , FeldmanJ, KeoghAet al. ARIES-3: ambrisentan therapy in a diverse population of patients with pulmonary hypertension. Cardiovasc. Therapeut. , 30(2), 93–99 (2012).
   PubMed Web of Science ®Google Scholar
• Jais X , D‘ArminiAM, JansaPet al. Bosentan for treatment of inoperable chronic thromboembolic pulmonary hypertension: BENEFiT (Bosentan Effects in Inoperable Forms of Chronic Thromboembolic Pulmonary Hypertension), a randomized, placebo-controlled trial. J. Am. Coll. Cardiol. , 52(25), 2127–2134 (2008).
   PubMed Web of Science ®Google Scholar
• Judson MA , HighlandKB, KwonSet al. Ambrisentan for sarcoidosis associated pulmonary hypertension. Sarcoidosis Vasc. Diffuse Lung Dis. , 28(2), 139–145 (2011).
   PubMed Web of Science ®Google Scholar
• Letairis® (ambrisentan) Risk Evaluation and Mitigation Strategy (REMS). Gilead Sciences, Inc., CA, USA (2012).
   Google Scholar
• Gabler NB , FrenchB, StromBLet al. Race and sex differences in response to endothelin receptor antagonists for pulmonary arterial hypertension. Chest , 141(1), 20–26 (2012).
   PubMed Web of Science ®Google Scholar
• Calabro P , LimongelliG, MaddaloniVet al. Analysis of endothelin-1 and endothelin-1 receptor A gene polymorphisms in patients with pulmonary arterial hypertension. Intern. Emerg. Med. , 7(5), 425–430 (2012).
   PubMed Web of Science ®Google Scholar
• Weiss J , HerzogM, HaefeliWE. Differential modulation of the expression of important drug metabolising enzymes and transporters by endothelin-1 receptor antagonists ambrisentan and bosentan in vitro.Eur. J. Pharmacol., 660(2–3), 298–304 (2011).
   PubMed Web of Science ®Google Scholar
• Wharton J , StrangeJW, MollerGMet al. Antiproliferative effects of phosphodiesterase type 5 inhibition in human pulmonary artery cells. Am. J. Respir. Crit. Care Med. , 172(1), 105–113 (2005).
   PubMed Web of Science ®Google Scholar
• Gupta M , KovarA, MeibohmB. The clinical pharmacokinetics of phosphodiesterase-5 inhibitors for erectile dysfunction. J. Clin. Pharmacol., 45(9), 987–1003 (2005).
   PubMed Web of Science ®Google Scholar
• Schermuly RT , PullamsettiSS, KwapiszewskaGet al. Phosphodiesterase 1 upregulation in pulmonary arterial hypertension: target for reverse-remodeling therapy. Circulation , 115(17), 2331–2339 (2007).
   PubMed Web of Science ®Google Scholar
• Nichols DJ , MuirheadGJ, HarnessJA. Pharmacokinetics of sildenafil after single oral doses in healthy male subjects: absolute bioavailability, food effects and dose proportionality. Br. J. Clin. Pharmacol., 53(Suppl. 1), S5–S12 (2002).
   PubMed Web of Science ®Google Scholar
• Muirhead GJ , RanceDJ, WalkerDK, WastallP. Comparative human pharmacokinetics and metabolism of single-dose oral and intravenous sildenafil. Br. J. Clin. Pharmacol., 53(Suppl. 1), S13–S20 (2002).
   PubMed Web of Science ®Google Scholar
• Muirhead GJ , WulffMB, FieldingA, KleinermansD, BussN. Pharmacokinetic interactions between sildenafil and saquinavir/ritonavir. Br. J. Clin. Pharmacol., 50(2), 99–107 (2000).
   PubMed Web of Science ®Google Scholar
• Muirhead GJ , FaulknerS, HarnessJA, TaubelJ. The effects of steady-state erythromycin and azithromycin on the pharmacokinetics of sildenafil in healthy volunteers. Br. J. Clin. Pharmacol., 53(Suppl. 1), S37–S43 (2002).
   PubMed Web of Science ®Google Scholar
• Paul GA , GibbsJS, BoobisAR, AbbasA, WilkinsMR. Bosentan decreases the plasma concentration of sildenafil when coprescribed in pulmonary hypertension. Br. J. Clin. Pharmacol., 60(1), 107–112 (2005).
   PubMed Web of Science ®Google Scholar
• Adcirca, package insert. Eli Lilly and Company, IN, USA.
   Google Scholar
• Galie N , GhofraniHA, TorbickiAet al. Sildenafil citrate therapy for pulmonary arterial hypertension. N. Engl. J. Med. , 353(20), 2148–2157 (2005).
   PubMed Web of Science ®Google Scholar
• Simonneau G , RubinLJ, GalieNet al. Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: a randomized trial. Ann. Int. Med. , 149(8), 521–530 (2008).
   PubMed Web of Science ®Google Scholar
• Machado RF , BarstRJ, YovetichNAet al. Hospitalization for pain in patients with sickle cell disease treated with sildenafil for elevated TRV and low exercise capacity. Blood , 118(4), 855–864 (2011).
   PubMed Web of Science ®Google Scholar
• Galie N , BrundageBH, GhofraniHAet al. Tadalafil therapy for pulmonary arterial hypertension. Circulation , 119(22), 2894–2903 (2009).
   PubMed Web of Science ®Google Scholar
• Guazzi M , VicenziM, ArenaR, GuazziMD. Pulmonary hypertension in heart failure with preserved ejection fraction: a target of phosphodiesterase-5 inhibition in a 1-year study. Circulation, 124(2), 164–174 (2011).
   PubMed Web of Science ®Google Scholar
• Reichenbach A , Al-HitiH, MalekIet al. The effects of phosphodiesterase 5 inhibition on hemodynamics, functional status and survival in advanced heart failure and pulmonary hypertension: a case-control study. Int. J. Cardiol. pii: S0167-5273(12)01180-1 (2012).
   PubMed Web of Science ®Google Scholar
• Cooper TJ , GuazziM, Al-MohammadAet al. Sildenafil in Heart Failure (SILHF). An investigator-initiated multinational randomized controlled clinical trial: rationale and design. Eur. J. Heart Fail. , 15(1), 119–122 (2012).
   PubMed Web of Science ®Google Scholar
• Blanco I , GimenoE, MunozPAet al. Hemodynamic and gas exchange effects of sildenafil in patients with chronic obstructive pulmonary disease and pulmonary hypertension. Am. J. Respir. Crit. Care Med. , 181(3), 270–278 (2010).
   PubMed Web of Science ®Google Scholar
• Lederer DJ , BartelsMN, SchlugerNWet al. Sildenafil for chronic obstructive pulmonary disease: a randomized crossover trial. COPD , 9(3), 268–275 (2012).
   PubMedGoogle Scholar
• Rietema H , HolverdaS, BogaardHJet al. Sildenafil treatment in COPD does not affect stroke volume or exercise capacity. Eur. Respir. J. , 31(4), 759–764 (2008).
   PubMed Web of Science ®Google Scholar
• Holverda S , RietemaH, BogaardHJet al. Acute effects of sildenafil on exercise pulmonary hemodynamics and capacity in patients with COPD. Pulm. Pharmacol. Ther. , 21(3), 558–564 (2008).
   PubMed Web of Science ®Google Scholar
• Collard HR , AnstromKJ, SchwarzMI, ZismanDA. Sildenafil improves walk distance in idiopathic pulmonary fibrosis. Chest, 131(3), 897–899 (2007).
   PubMed Web of Science ®Google Scholar
• Ghofrani HA , WiedemannR, RoseFet al. Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial. Lancet , 360(9337), 895–900 (2002).
   PubMed Web of Science ®Google Scholar
• Reichenberger F , VoswinckelR, EnkeBet al. Long-term treatment with sildenafil in chronic thromboembolic pulmonary hypertension. Eur. Respir. J. , 30(5), 922–927 (2007).
   PubMed Web of Science ®Google Scholar
• Milman N , BurtonCM, IversenM, VidebaekR, JensenCV, CarlsenJ. Pulmonary hypertension in end-stage pulmonary sarcoidosis: therapeutic effect of sildenafil? J. Heart Lung Transplant., 27(3), 329–334 (2008).
   PubMed Web of Science ®Google Scholar
• Revatio, package insert. Pfizer Labs, NY, USA.
   Google Scholar
• Hazell L , CorneliusV, WiltonLV, ShakirSA. The safety profile of tadalafil as prescribed in general practice in England: results from a prescription-event monitoring study involving 16 129 patients. BJU Int., 103(4), 506–514 (2009).
   PubMed Web of Science ®Google Scholar
• Margo CE , FrenchDD. Ischemic optic neuropathy in male veterans prescribed phosphodiesterase-5 inhibitors. Am. J. Ophthalmol., 143(3), 538–539 (2007).
   PubMed Web of Science ®Google Scholar
• Salvi F , SarzaniR, GiorgiRet al. Cardiovascular effects of sildenafil in hypertensive men with erectile dysfunction and different alleles of the type 5 cGMP-specific phosphodiesterase (PDE5). Int. J. Impot. Res. , 16(5), 412–417 (2004).
   PubMed Web of Science ®Google Scholar
• Peskircioglu L , AtacFB, ErdemSR, DeveciS, VerdiH, OzkardesH. The association between intron 4 VNTR, E298A and IVF 23+10 G/T polymorphisms of ecNOS gene and sildenafil responsiveness in patients with erectile dysfunction. Int. J. Impot. Res., 19(2), 149–153 (2007).
   PubMed Web of Science ®Google Scholar
• Muniz JJ , LacchiniR, RinaldiTOet al. Endothelial nitric oxide synthase genotypes and haplotypes modify the responses to sildenafil in patients with erectile dysfunction. Pharmacogenomics J. , 13(2), 189–196 (2011).
   PubMed Web of Science ®Google Scholar
• Sperling H , EisenhardtA, VirchowSet al. Sildenafil response is influenced by the G protein beta 3 subunit GNB3 C825T polymorphism: a pilot study. J. Urol. , 169(3), 1048–1051 (2003).
   PubMed Web of Science ®Google Scholar
• Jetter A , LazarA, SchomigE, FuhrU, Kinzig-SchippersM, SorgelF. The CYP2C9 genotype does not influence sildenafil pharmacokinetics in healthy volunteers. Clin. Pharmacol. Therapeutics, 78(4), 441–443 (2005).
   PubMed Web of Science ®Google Scholar
• Rich S , KaufmannE, LevyPS. The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N. Engl. J. Med., 327(2), 76–81 (1992).
   PubMed Web of Science ®Google Scholar
• Mclaughlin VV , ArcherSL, BadeschDBet al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J. Am. Coll. Cardiol. , 53(17), 1573–1619 (2009).
   PubMed Web of Science ®Google Scholar
• Sitbon O , HumbertM, JaisXet al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation , 111(23), 3105–3111 (2005).
   PubMed Web of Science ®Google Scholar
• Carlin CM , CelnikDF, PakO, WadsworthR, PeacockAJ, WelshDJ. Low-dose fluvastatin reverses the hypoxic pulmonary adventitial fibroblast phenotype in experimental pulmonary hypertension. Am. J. Resp. Cell Mol. Biol., 47(2), 140–148 (2012).
   PubMed Web of Science ®Google Scholar
• Ali OF , GrowcottEJ, ButrousGS, WhartonJ. Pleiotropic effects of statins in distal human pulmonary artery smooth muscle cells. Resp. Res., 12, 137 (2011).
   PubMedGoogle Scholar
• Kawut SM , BagiellaE, LedererDJet al. Randomized clinical trial of aspirin and simvastatin for pulmonary arterial hypertension: ASA-STAT. Circulation , 123(25), 2985–2993 (2011).
   PubMed Web of Science ®Google Scholar
• Cavasin MA , Demos-DaviesK, HornTRet al. Selective class I histone deacetylase inhibition suppresses hypoxia-induced cardiopulmonary remodeling through an antiproliferative mechanism. Circ. Res. , 110(5), 739–748 (2012).
   PubMed Web of Science ®Google Scholar
• Zhao L , ChenCN, HajjiNet al. Histone deacetylation inhibition in pulmonary hypertension: therapeutic potential of valproic acid and suberoylanilide hydroxamic acid. Circulation , 126(4), 455–467 (2012).
   PubMed Web of Science ®Google Scholar
• Bogaard HJ , MizunoS, HussainiAAet al. Suppression of histone deacetylases worsens right ventricular dysfunction after pulmonary artery banding in rats. Am. J. Respir. Crit. Care Med. , 183(10), 1402–1410 (2011).
   PubMed Web of Science ®Google Scholar
• Hatano M , YaoA, ShigaT, KinugawaK, HirataY, NagaiR. Imatinib mesylate has the potential to exert its efficacy by down-regulating the plasma concentration of platelet-derived growth factor in patients with pulmonary arterial hypertension. Int. Heart J., 51(4), 272–276 (2010).
   PubMed Web of Science ®Google Scholar
• Duggan N , BonneauO, HusseyMet al. Comparison of effects of imatinib and nilotinib in a rodent model of pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. , 181, A6304 (2010).
   Web of Science ®Google Scholar
• Voelkel NF , CoolC, LeeSD, WrightL, GeraciMW, TuderRM. Primary pulmonary hypertension between inflammation and cancer. Chest, 114(Suppl. 3), S225–S230 (1998).
   Google Scholar
• Gomberg-Maitland M , MaitlandML, BarstRJet al. A dosing/cross-development study of the multikinase inhibitor sorafenib in patients with pulmonary arterial hypertension. Clin. Pharmacol. Therapeut. , 87(3), 303–310 (2010).
   PubMed Web of Science ®Google Scholar
• Ghofrani HA , SeegerW, GrimmingerF. Imatinib for the treatment of pulmonary arterial hypertension. N. Engl. J. Med., 353(13), 1412–1413 (2005).
   PubMed Web of Science ®Google Scholar
• Ghofrani HA , MorrellNW, HoeperMMet al. Imatinib in pulmonary arterial hypertension patients with inadequate response to established therapy. Am. J. Respir. Crit. Care Med. , 182(9), 1171–1177 (2010).
   PubMed Web of Science ®Google Scholar
• Patterson KC , WeissmannA, AhmadiT, FarberHW. Imatinib mesylate in the treatment of refractory idiopathic pulmonary arterial hypertension. Ann. Intern. Med., 145(2), 152–153 (2006).
   PubMedGoogle Scholar
• Hoeper M , BarstR, GaliéNet al. Imatinib in pulmonary arterial hypertension, a randomized, efficacy study (IMPRES). Presented at: European Repiratory Soceity Amsterdam 2011 Annual Congress. Amsterdam, The Netherlands, 24–28 September 2011 (Abstract 413).
   Google Scholar
• Ghofrani et al. Kawut SM, Horn EM, Berekashvili KK Selective serotonin reuptake inhibitor use and outcomes in pulmonary arterial hypertension. Pulm. Pharmacol. Therapeut., 19(5), 370–374 (2006).
   PubMed Web of Science ®Google Scholar
• Shah SJ , Gomberg-MaitlandM, ThenappanT, RichS. Selective serotonin reuptake inhibitors and the incidence and outcome of pulmonary hypertension. Chest, 136(3), 694–700 (2009).
   PubMed Web of Science ®Google Scholar
• de Man FS , TuL, HandokoMLet al. Dysregulated renin–angiotensin–aldosterone system contributes to pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. , 186(8), 780–789 (2012).
   PubMed Web of Science ®Google Scholar
• Rubin L , PulidoT, ChannickRet al. Effect of macitentan on morbidity and mortality in pulmonary arterial hypertension (PAH): results from the SERAPHIN Trial. Chest , 142, A1026–A1026 (2012).
   Google Scholar
• Tapson VF , TorresF, KermeenFet al. Oral treprostinil for the treatment of pulmonary arterial hypertension in patients on background endothelin receptor antagonist and/or phosphodiesterase type 5 inhibitor therapy (the FREEDOM-C study): a randomized controlled trial. Chest , 142(6), 1383–1390 (2012).
   PubMed Web of Science ®Google Scholar
• Simonneau G , LangI, TorbickiAet al. Efficacy, safety and tolerability of ACT-293987, a novel oral, non-prostanoid, prostaglandin I2 (IP) receptor agonist: results from a Phase IIa study in pulmonary arterial hypertension (PAH). Am. J. Respir. Crit. Care Med. , 181, A2515 (2010).
   Web of Science ®Google Scholar
• Hoeper MM , HalankM, WilkensHet al. Riociguat for interstitial lung disease and pulmonary hypertension: a pilot trial. Eur. Respir. J. , 41(4), 853–860 (2013).
   PubMed Web of Science ®Google Scholar
• Ghofrani HA , HoeperMM, HalankMet al. Riociguat for chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension: a Phase II study. Eur. Respir. J. , 36(4), 792–799 (2010).
   PubMed Web of Science ®Google Scholar
• Kojonazarov B , MyrzaakhmatovaA, SooronbaevT, IshizakiT, AldashevA. Effects of fasudil in patients with high-altitude pulmonary hypertension. Eur. Respir. J., 39(2), 496–498 (2012).
   PubMed Web of Science ®Google Scholar
• Fujita H , FukumotoY, SajiKet al. Acute vasodilator effects of inhaled fasudil, a specific Rho-kinase inhibitor, in patients with pulmonary arterial hypertension. Heart Vessels , 25(2), 144–149 (2010).
   PubMed Web of Science ®Google Scholar
• Robbins IM , HemnesAR, GibbsJSet al. Safety of sapropterin dihydrochloride (6r-bh4) in patients with pulmonary hypertension. Exp. Lung Res. , 37(1), 26–34 (2011).
   PubMed Web of Science ®Google Scholar
• Dumitrascu R , KulckeC, KonigshoffMet al. Terguride ameliorates monocrotaline-induced pulmonary hypertension in rats. Eur. Respir. J. , 37(5), 1104–1118 (2011).
   PubMed Web of Science ®Google Scholar
• Dromparis P , PaulinR, StensonTH, HaromyA, SutendraG, MichelakisED. Attenuating endoplasmic reticulum stress as a novel therapeutic strategy in pulmonary hypertension. Circulation, 127(1), 115–125 (2013).
   PubMed Web of Science ®Google Scholar
• Li J , LongC, CuiW, WangH. Iptakalim ameliorates monocrotaline-induced pulmonary arterial hypertension in rats. J. Cardiovasc. Pharmacol. Therapeut., 18(1), 60–69 (2013).
   PubMed Web of Science ®Google Scholar
• Perez-Vizcaino F , CogolludoA, MorenoL. Reactive oxygen species signaling in pulmonary vascular smooth muscle. Resp. Physiol. Neurobiol., 174(3), 212–220 (2010).
   PubMed Web of Science ®Google Scholar
• Ward JP , McmurtryIF. Mechanisms of hypoxic pulmonary vasoconstriction and their roles in pulmonary hypertension: new findings for an old problem. Curr. Opin. Pharmacol., 9(3), 287–296 (2009).
   PubMed Web of Science ®Google Scholar
• Kanki-Horimoto S , HorimotoH, MienoSet al. Implantation of mesenchymal stem cells overexpressing endothelial nitric oxide synthase improves right ventricular impairments caused by pulmonary hypertension. Circulation , 114(Suppl. 1), I181–I185 (2006).
   PubMed Web of Science ®Google Scholar
• Reynolds AM , HolmesMD, DanilovSM, ReynoldsPN. Targeted gene delivery of BMPR2 attenuates pulmonary hypertension. Eur. Respir. J., 39(2), 329–343 (2012).
   PubMed Web of Science ®Google Scholar
• Kataoka M , KawakamiT, TamuraYet al. Gene transfer therapy by either type 1 or type 2 adeno-associated virus expressing human prostaglandin i2 synthase gene is effective for treatment of pulmonary arterial hypertension. J. Cardiovasc. Pharmacol. Therapeut. , 18(1), 54–59 (2013).
   PubMed Web of Science ®Google Scholar
• Morecroft I , WhiteK, CarusoPet al. Gene therapy by targeted adenovirus-mediated knockdown of pulmonary endothelial Tph1 attenuates hypoxia-induced pulmonary hypertension. Mol. Ther. , 20(8), 1516–1528 (2012).
   PubMed Web of Science ®Google Scholar
• D‘Alonzo GE , BarstRJ, AyresSMet al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann. Intern. Med. , 115(5), 343–349 (1991).
   PubMed Web of Science ®Google Scholar

Websites

• Efficacy, safety, tolerability and pharmacokinetics (PK) of nilotinib (AMN107) in pulmonary arterial hypertension (PAH). http://clinicaltrials.gov/ct2/show/NCT01179737
   Google Scholar
• United Therapeutics Corportation. UT-15C treprostinil diethanolamine sustained release tablets (oral treprostinil). www.unither.com/oral-treprostinil-for-pah
   Google Scholar
• A multi-center, open-label, multiple dose, dose finding study exploring the safety and tolerability of beraprost sodium modified release in PAH patients. http://clinicaltrials.gov/ct2/show/NCT00781885
   Google Scholar
• United Therapeutics Corportation. BPS for PAH. www.unither.com/bps-for-pah
   Google Scholar
• ACT-293987 in pulmonary arterial hypertension. http://clinicaltrials.gov/ct2/show/NCT01106014
   Google Scholar
• 6R-BH4 pulmonary arterial hypertension study. www.clinicaltrials.gov/ct2/show/NCT00435331
   Google Scholar