Abstract
The treatment of pediatric pulmonary arterial hypertension (PAH) is challenging due to the serious nature of the disease, its rapid progression, and the limited treatment options available. While oral calcium channel antagonists and continuous intravenous epoprostenol have been used successfully for over a decade, novel treatment options — including prostacyclin analogs, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors — may change the course of this disease for many children in the future.
Prostacyclin analogs offer the benefit over continuous intravenous epoprostenol of an alternative delivery system. However, the efficacy of these medications compared with intravenous epoprostenol and the risk/benefits of each analog need to be weighed in future trials, which need to include larger numbers of pediatric patients to optimize therapy and outcome for individual children with PAH.
For patients who do not have an acute response to vasodilator testing or have failed treatment with oral calcium channel antagonists, endothelin receptor antagonists may offer a viable treatment option. Furthermore, in the future, the addition of endothelin receptor antagonists to long-term therapy with calcium channel antagonists or to epoprostenol or a prostacyclin analog may increase the overall efficacy of treatment of PAH. Large multi-institutional randomized trials to determine whether sildenafil is effective and safe for the long-term treatment of PAH in children are in progress.
A comprehensive review of these newer agents with an emphasis on the pathobiology/pathophysiology of PAH provides insight into the future management of pediatric PAH patients.
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References
D’Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension: results from a national prospective registry. Ann Intern Med 1991 Sep 1; 115(5): 343–9
Yamaki S, Wagenvoort CA. Comparison of primary plexogenic arteriopathy in adults and children: a morphometric study in 40 patients. Br Heart 1985; 54: 423–34
Long WA. Persistent pulmonary hypertension of the newborn syndrome. In: Long WA, editor. Fetal and neonatal cardiology. Philadelphia (PA): WB Saunders, 1989: 627–655
Wagenvoort CA, Wagenvoort N. Primary pulmonary hypertension. New York: Wiley & Sons, 1977
Barst RJ. Medical therapy of pulmonary hypertension: an overview of treatment and goals. In: Rich S, McLaughlin VV, editors. Clinics in chest medicine. Philadelphia (PA): WB Saunders Co, 2001: 509–15
Deng Z, Morse JH, Singer SL, et al. Familial primary pulmonary hypertension (gene PPH 1) is caused by mutations in the bone morphogenetic proteinreceptor-II gene. Am J Hum Genet 2000; 67: 737–44
Lane KB, Machado RD, Pauciulo MW, et al. Heterozygous germline mutations in BMPR2, encoding a TGF-β receptor, causes familial primary pulmonary hypertension. Nat Genet 2000 Sep; 26(1): 81–4
Christman BW, McPherson CD, Newman JH, et al. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med 1992; 327: 70–5
Stewart DJ, Levy RD, Cernacek P, et al. Increased plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease? Ann Intern Med 1991; 114: 467–9
Giaid A, Yanagisa WAM, Langleben D, et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med 1993; 328: 1732–9
Wagenvoort CA, Wagenvoort N. Pathology of the Eisenmenger syndrome and primary pulmonary hypertension. Adv Cardiol 1974; 11: 123–30
Galie N, Manes A, Branzi A. Emerging medical therapies for pulmonary arterial hypertension. Prog Cardiovasc Dis 2002 Nov–Dec; 45(3): 213–24
Rich S, Kaufmann E, Levy PS. The effect of high doses of calcium channel blockers on survival in primary pulmonary hypertension. N Engl J Med 1992; 327: 76–81
Fuster V, Steele PM, Edwards WD, et al. Primary pulmonary hypertension: natural history and the importance of thrombosis. Circulation 1984; 70: 580–7
Wagenvoort CA, Wagenvoort N. Primary pulmonary hypertension: a pathologic study of the lung vessels in 156 clinically diagnosed cases. Circulation 1970; 42: 1163–84
Barst RJ, Maislin G, Fishman AP. Vasodilator therapy in primary pulmonary hypertension in children. Circulation 1999; 99: 1197–204
Barst RJ. Pulmonary arterial hypertension. Cecil textbook of medicine. 22nd ed. Philadelphia (PA): Saunders, Elsevier Science, 2003
Rubin LJ, Mendoza J, Hood M, et al. Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin: results of randomized trial. Annals Int Med 1991; 115: 343–9
Barst RJ, Rubin LJ, McGoon MD, et al. Survival in primary pulmonary hypertension with long-term continuous prostacyclin. Ann Intern Med 1994; 121: 409–15
Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med 1996; 334: 296–301
McLaughlin VV, Genthner DE, Panella MM, et al. Reduction in pulmonary vascular resistance with long-term epoprostenol (prostacyclin) therapy in primary pulmonary hypertension. N Engl J Med 1998; 338: 273–7
Berman-Rosenzweig E, Kerstein D, Barst RJ. Chronic prostacyclin therapy for pulmonary hypertension with associated congenital heart defects. Circulation 1999; 99: 1858–65
Badesch DB, Tapson VF, McGoon MD, et al. A comparison of continuous intravenous epoprostenol with conventional therapy for pulmonary hypertension secondary to the scleroderma spectrum of disease. Ann Intern Med 2000; 132: 425–34
Olschewski H, Ghofrani HA, Schmehl T, et al. Inhaled iloprost to treat severe pulmonary hypertension: an uncontrolled trial. German PPH Study Group. Ann Intern Med 2000; 132(6): 435–43
Hoeper MM, Schwarze M, Ehlerding S, et al. Long-term treatment of primary pulmonary hypertension with aerosolized iloprost, a prostacyclin analog. N Engl J Med 2000; 342: 1866–70
Nagaya N, Uematsu M, Okano Y, et al. Effect of orally active prostacyclin analog on survival of outpatients with primary pulmonary hypertension. J Am Coll Cardiol 1999; 34: 1188–92
Barst RJ, Simonneau G, Rich S, et al. for the Uniprost PAH Study Group. Efficacy and safety of chronic subcutaneous infusion of UT-15 (Uniprost) in pulmonary arterial hypertension (PAH). Circulation 2000; 102(18): II–100–1
McLaughlin VV, Genthner DE, Panella MM, et al. Compassionate use of continuous prostacyclin in the management of secondary pulmonary hypertension: a case series. Ann Intern Med 1999; 130: 740–3
Steffen RP, De La Mata M. The Effects of 15AU81, a chemically stable prostacyclin analog, on the cardiovascular and renin-angiotensin systems of anesthetized dogs. Prostaglandins Leukot Essent Fatty Acids 1991; 43: 277–86
Barst RJ, Horn EM, Widlitz AC, et al. Efficacy of long-term subcutaneous infusion of UT-15 in patients with primary pulmonary hypertension. Eur Heart J 2000; 21(S): 315
Patterson JH, Adams KF, Gheorghiade M, et al. Acute hemodynamic effects of the prostacyclin analog 15AU81 in severe congestive heart failure. Am J Cardiol 1995; 75(3): 26A-33A
Vachiéry JL, Hill N, Zwicke D, et al. Transitioning from IV epoprostenol to subcutaneous treprostinil in pulmonary arterial hypertension. Chest 2002; 121: 1561–5
Kaukinen S, Ylitalo P, Pessi T, et al. Hemodynamic effects of iloprost, a prostacyclin analog. Clin Pharmacol Ther 1984; 36: 464–9
Schror K, Darius H, Matzky R, et al. The anti-platelet and cardiovascular actions of a new carbacyclin derivative (ZK36374): equipotent to PGI2 in vitro. Arch Pharmacol 1981; 316: 252–5
Bugiardini R, Galvani M, Ferrini D, et al. Effects of Iloprost, a stable prostacyclin analog, on exercise capacity and platelet aggregation in stable angina pectoris. Am J Cardiol 1986; 58: 453–9
Skuballa W, Raduchel B, Vorbruggen H. Chemistry of stable prostacyclin analogs; synthesis of iloprost. In: Gryglewski RS, Stock G, editors. Prostacyclin and its stable analog iloprost. Berlin: Springer, 1987: 17–24
Hoeper MM, Oschewski H, Ghofrani HA, et al. A comparison of the acute hemodynamic effects of inhaled nitric oxide and aerosolized iloprost in primary pulmonary hypertension. J Am Coll Cardiol 2000; 35: 176–82
Wensel R, Opitz CF, Ewer R, et al. Effects of iloprost inhalation on exercise capacity and ventilatory efficiency in patients with primary pulmonary hypertension. Circulation 2000; 101(20): 2388–92
Olschewski H, Simonneau G, Galie N, et al. Inhaled iloprost for severe pulmonary hypertension: Aerosolized Iloprost Randomized Study Group. N Engl J Med 2002; 347(5): 322–9
Toda N. Beraprost sodium. Cardiovasc Drug Rev 1988; 6: 222–38
Mortia A, Kamoshita K, Ito T, et al. Beneficial effect of sodium salt of 17(R)-methyl-20-iso-propylidenecarbacyclin on experimentally-induced ischemic hind limb lesions and blood viscosity. Arzneimittel-Forschung 1986; 36: 680–3
Akiba T, Miyazaki M, Toda N. Vasodilator actions of TRK-100, a new prostaglandinI2 analog. Br J Pharmacol 1986; 89: 703–11
Umetsu T, Murata T, Nishio S. Studies on the antiplatelet effect of the stable epoprostenol analog beraprost sodium and its mechanism of action in rats. Arzneimittel-Forschung 1989; 39: 68–73
Sim AK, McCraw AP, Cleland ME, et al. Effect of a stable prostacyclin analog on platelet function and experimentally-induced thrombosis in the microcirculation. Arzneimittel-Forschung 1985; 35: 1816–8
Nishio S, Matsura H, Kanai N, et al. The in vitro and ex vivo antiplatelet effect of TRK-100, a stable prostacyclin analog, in several species. Jpn J Pharmacol 1988; 47: 1–10
Saji T, Ozawa Y, Ishikita T, et al. Short-term hemodynamic effect of a new oral prostacyclin analog, beraprost in primary and secondary pulmonary hypertension. Am J Cardiol 1996; 78(2): 244–7
Kuneida T, et al. Clinical trials of TRK-100 in Primary and Collagen Pulmonary Hypertension. Jpn J Clin Exp Med 1997; 74: 10
Okano Y, Yoshioka T, Shimouchi A, et al. Orally active prostacyclin analog in primary pulmonary hypertension. Lancet 1997; 349: 1365
Galie N, Humbert M, Vachiery JL, et al. Effects of beraprost sodium, an oralprostacyclin analog, in patients with pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled trial. Arterial Pulmonary Hypertension and Beraprost European (ALPHABET) Study Group. J Am Coll Cardiol 2002; 39(9): 496–502
Barst RJ, McGoon M, McLaughlin V, et al. for the Beraprost Study Group. Beraprost therapy for pulmonary arterial hypertension. J Am Coll Cardiol 2003; 41: 2119–25
Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1998; 332: 411–5
Galie N, Grigoni F, Bacchi-Reggiani L, et al. Relation of endothelin-1 to survival in patients with primary pulmonary hypertension. Eur J Clin Invest 1996; 26 Suppl. 1: 273
Yoshibayashi M, Nishioka K, Nakao K, et al. Plasma endothelin concentrations in patients with pulmonary hypertension associated with congenital heart defects: evidence for increased production of endothelin in pulmonary circulation. Circulation 1991; 84(6): 2280–5
Ohlstein EH, Douglas SA. Endothelin-1 modulates vascular smooth muscle structure and vasomotion: implications in cardiovascular pathology. Drug Dev Res 1993; 29: 108–28
Fukuroda T, Fujikawa T, Ozaki S, et al. Clearance of circulating endothelin-1 by ETinB receptors in rats. Biochem Biophys Res Commun 1994; 199: 1461–5
Ozaki S, Ohwaki K, Ihara M, et al. ETB-mediated regulation of extracellular levels of endothelin-1 in cultured endothelial cells. Biochem Biophys Res Commun 1995; 209: 483–9
Channick RN, Rubin LJ, Simonneau G, et al. Bosentan, a dual endothelin receptor antagonist improves exercise capacity and hemodynamics in patients with pulmonary arterial hypertension: results of a double-blind, randomized, placebo-controlled trial. Lancet 2001; 358: 1119–23
Barst RJ, Rich S, Horn EM, et al. Efficacy and safety with chronic treatment with selective endothelin-A receptor blockade in pulmonary arterial hypertension (PAH). Circulation 2000; 102(18): 11–427
Roux S, Breu V, Ertel S, et al. Endothelin antagonism with bosentan: a review of potential applications. J Mol Med 1999; 77: 364–76
Chen SJ, Chen YF, Meng QC, et al. Endothelin-receptor antagonist prevents and reverses chronic hypoxia-induced hypertension in rats. J Appl Physiol 1995; 9: 2122–31
Di Carlo VS, Chen SJ, Meng QC, et al. ETA-receptor antagonist prevents and reverses chronic hypoxia-induced pulmonary hypertension in rat. Am J Physiol 1995; 69: L690–7
Prie S, Stewart DJ, Dupuis J. Endothelin A receptor blockade improves nitric oxide-mediated vasodilation in monocrotaline-induced pulmonary hypertension. Circulation 1998; 97: 169–74
Underwood DC, Bochonowicz S, Osborn RR, et al. Effect of SB217242 on hypoxia-induced cardiopulmonary changes in the high-altitude sensitive rat. Pulm Pharmacol Ther 1999; 12: 13–26
Rondelet B, Kerbaul F, Motte S, et al. Bosentan for the prevention of overcirculation-induced experimental pulmonary arterial hypertension. Circulation 2003; 107: 1329–35
Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002; 346(12): 896–903
Barst RJ, Ivy D, Dingemanse J, et al. Pharmacokinetics, safety, and efficacy of bosentan in pediatric patients with pulmonary arterial hypertension. ClinPharmacol Ther 2003 Apr; 73(4): 37–82
Rosenzweig EB, Ivy DD, Widlitz A, et al. Effects of long-term bosentan in children with pulmonary arterial hypertension. J Am Coll Cardiol 2005 Aug 16; 46(4): 697–704
Barst RJ, Rich S, Widlitz A, et al. Clinical efficacy of sitaxsentan, an endothelin a receptor antagonist, in patients with pulmonary arterial hypertension: open label pilot study. Chest 2002; 121: 1860–8
Barst RJ, Langleben D, Frost A, et al. for the STRIDE Study Group. Sitaxsentantherapy for pulmonary arterial hypertension. Am J Respir Crit Care Med 2004; 169: 441–7
Michelakis E, Tymchak W, Lien D, et al. Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension. Circulation 2002; 105: 2398–403
Abrams D, Schulze-Neick I, Magee AG. Sildenafil as a selective pulmonary vasodilator in childhood primary pulmonary hypertension. Heart 2000 Aug; 84(2): E4
Murad F. Cyclic guanosine monophosphate as a mediator of vasodilatation. J Clin Invest 1986; 78: 1–5
Galie N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005 Nov 17; 353(20): 2148–57
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Dr Rosenzweig is on speakers bureau for Actelion and Pfizer, but the authors have no conflicts of interest directly related to the content or preparation of this article.
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Rosenzweig, E.B., Barst, R.J. Pulmonary Arterial Hypertension. Treat Respir Med 5, 117–127 (2006). https://doi.org/10.2165/00151829-200605020-00005
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DOI: https://doi.org/10.2165/00151829-200605020-00005