Inhalational therapy for pulmonary arterial hypertension: Current status and future prospects

Critical Reviews in Therapeutic Drug Carrier Systems

Volumn 27, Issue 4, 2010, Pages 313-370

  Gupta, Vivek ^a   Ahsan, Fakhrul ^a  

^a TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER   (United States)

Author keywords

Inhalational therapy; Mean pulmonary arterial pressure; Prostacyclin analogues; Pulmonary arterial hypertension; Rho kinase inhibitors

Indexed keywords

ACT 29387; AMBRISENTAN; ANGIOPEPTIN; ANTIHYPERTENSIVE AGENT; BERAPROST; BONE MORPHOGENETIC PROTEIN RECEPTOR 2; BOSENTAN; CYCLOSPORIN; DECAPEPTIL; ENANTONE DEPOT; ENDOTHELIN; ENDOTHELIN A RECEPTOR ANTAGONIST; ENDOTHELIN RECEPTOR ANTAGONIST; FASUDIL; ILOPROST; INTERLEUKIN 1; INTERLEUKIN 6; KETOCONAZOLE; LEUPRORELIN; MACITENTAN; MRE 269; NEUTROPIN DEPOT; NITRATE; NITRIC OXIDE; NS 304; PHOSPHODIESTERASE V INHIBITOR; PROSTACYCLIN; PROSTACYCLIN DERIVATIVE; PROSTAGLANDIN RECEPTOR STIMULATING AGENT; SILDENAFIL; SITAXSENTAN; TRIPTORELIN; UNCLASSIFIED DRUG; UNINDEXED DRUG; UNIPROST; VASOACTIVE INTESTINAL POLYPEPTIDE; WARFARIN;

ADJUVANT THERAPY; ALANINE AMINOTRANSFERASE BLOOD LEVEL; ANTIINFLAMMATORY ACTIVITY; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; ASPARTATE AMINOTRANSFERASE BLOOD LEVEL; BLUD LAVENDER VISION; CATHETER INFECTION; CATHETER THROMBOSIS; CELL PROLIFERATION; CLINICAL ASSESSMENT; CLINICAL FEATURE; CLINICAL TRIAL; COMPUTER ASSISTED TOMOGRAPHY; CONTINUOUS INFUSION; COST EFFECTIVENESS ANALYSIS; DIARRHEA; DISEASE CLASSIFICATION; DIZZINESS; DRUG COST; DRUG DELIVERY SYSTEM; DRUG DOSE INCREASE; DRUG EFFICACY; DRUG FORMULATION; DRUG HALF LIFE; DRUG HYDROLYSIS; DRUG INDUCED HEADACHE; DRUG METABOLISM; DRUG RELEASE; DRUG SAFETY; DRUG WITHDRAWAL; DYSPNEA; ELECTROCARDIOGRAPHY; ENDOTHELIAL PROGENITOR CELL; ENDOTHELIUM CELL; ERECTILE DYSFUNCTION; EXERCISE TEST; FAMILIAL DISEASE; FIBROBLAST; FOOD AND DRUG ADMINISTRATION; GASTROINTESTINAL SYMPTOM; GENETIC ANALYSIS; HEART CATHETERIZATION; HEART RIGHT VENTRICLE HYPERTROPHY; HEMATOPOIETIC STEM CELL; HEMOGLOBIN BLOOD LEVEL; HERITABILITY; HIGH RESOLUTION COMPUTER TOMOGRAPHY; HOT FLUSH; HUMAN; HYPERTHYROIDISM; HYPOTENSION; INFLAMMATORY CELL; INFUSION SITE PAIN; INFUSION SITE REACTION; JAW PAIN; LEG EDEMA; LIPOSOMAL DELIVERY; LIVER INJURY; LONG TERM CARE; LUNG ARTERY PRESSURE; LUNG BLOOD VESSEL; LUNG CIRCULATION; LUNG FUNCTION TEST; MEAN ARTERIAL PRESSURE; MORBIDITY; MUSCLE HYPERTROPHY; MUSCULOSKELETAL PAIN; NAUSEA; NONHUMAN; NOSE CONGESTION; PATHOGENESIS; PATHOPHYSIOLOGY; PHYSICAL EXAMINATION; PROGNOSIS; PULMONARY ARTERY; PULMONARY HYPERTENSION; QUALITY OF LIFE; REBOUND SYNDROME; REVIEW; RISK FACTOR; SEROLOGY; SHOCK; SIDE EFFECT; SIGNAL TRANSDUCTION; SIX MINUTE WALK TEST; SMOOTH MUSCLE FIBER; STEM CELL; SURVIVAL RATE; SYMPTOM; SYNCOPE; THORAX RADIOGRAPHY; THROMBOCYTE; TRANSTHORACIC ECHOCARDIOGRAPHY; UNITED STATES; VASCULAR ENDOTHELIUM; VASOCONSTRICTION; VASODILATATION; WORLD HEALTH ORGANIZATION;

EID: 78650071304     PISSN: 07434863     EISSN: None     Source Type: Journal    
DOI: 10.1615/CritRevTherDrugCarrierSyst.v27.i4.20     Document Type: Review

References (205)

1. Humbert M, McLaughlin VV. The 4th World Symposium on Pulmonary Hypertension. Introduction. J Am Coll Cardiol. 2009;54:S1-2.
2. Gaine SP, Rubin LJ. Primary pulmonary hypertension. Lancet. 1998;352:719-25.
3. Rubin LJ. Primary pulmonary hypertension. Chest. 1993;104:236-50.
4. Traiger GL. Pulmonary arterial hypertension. Crit Care Nurs Q. 2007;30:20-43.
5. Rich S, Dantzker DR, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Goldring RM, Groves BM, Koerner SK, et al. Primary pulmonary hypertension. A national prospective study. Ann Intern Med. 1987;107:216-23.
6. Simonneau G, Galie N, Rubin LJ, Langleben D, Seeger W, Domenighetti G, Gibbs S, Lebrec D, Speich R, Beghetti M, Rich S, Fishman A. Clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2004;43:5S-12S.
7. Simonneau G, Robbins IM, Beghetti M, Channick RN, Delcroix M, Denton CP, Elliott CG, Gaine SP, Gladwin MT, Jing ZC, Krowka MJ, Langleben D, Nakanishi N, Souza R. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54:S43-54.
8. Pietra GG, Capron F, Stewart S, Leone O, Humbert M, Robbins IM, Reid LM, Tuder RM. Pathologic assessment of vasculopathies in pulmonary hypertension. J Am Coll Cardiol. 2004;43:25S-32S.
9. Stewart S, Rassl D. Advances in the understanding and classification of pulmonary hypertension. Histopathology. 2009;54:104-16.
10. Rich S. Primary pulmonary hypertension: executive summary from the World Symposium on Primary Pulmonary Hypertension. Evian, France: World Health Organization; 1998.
11. Martin KB, Klinger JR, Rounds SI. Pulmonary arterial hypertension: new insights and new hope. Respirology. 2006;11:6-17.
12. What is PAH? Available from: http://www.pah-info.com/What-is-PAH [cited 22 Mar 2010].
13. Morse JH, Jones AC, Barst RJ, Hodge SE, Wilhelmsen KC, Nygaard TG. Mapping of familial primary pulmonary hypertension locus (PPH1) to chromosome 2q31-q32. Circulation. 1997;95:2603-6.
14. Deng Z, Morse JH, Slager SL, Cuervo N, Moore KJ, Venetos G, Kalachikov S, Cayanis E, Fischer SG, Barst RJ, Hodge SE, Knowles JA. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet. 2000;67:737-44.
15. Newman JH, Trembath RC, Morse JA, Grunig E, Loyd JE, Adnot S, Coccolo F, Ventura C, Phillips JA, 3rd, Knowles JA, Janssen B, Eickelberg O, Eddahibi S, Herve P, Nichols WC, Elliott G. Genetic basis of pulmonary arterial hypertension: current understanding and future directions. J Am Coll Cardiol. 2004;43:33S-39S.
16. Yeager ME, Halley GR, Golpon HA, Voelkel NF, Tuder RM. Microsatellite instability of endothelial cell growth and apoptosis genes within plexiform lesions in primary pulmonary hypertension. Circ Res. 2001;88:E2-E11.
17. Junbao D, Hui Y, Bing W, Jian L, Jianguang Q, Chaoshu T. Effect of L-arginine on collagen of high flow-induced pulmonary arterial remodeling. Circ J. 2005;69:603-8.
18. Stenmark KR, Davie N, Frid M, Gerasimovskaya E, Das M. Role of the adventitia in pulmonary vascular remodeling. Physiology (Bethesda). 2006;21:134-45.
19. Newman JH, Fanburg BL, Archer SL, Badesch DB, Barst RJ, Garcia JG, Kao PN, Knowles JA, Loyd JE, McGoon MD, Morse JH, Nichols WC, Rabinovitch M, Rodman DM, Stevens T, Tuder RM, Voelkel NF, Gail DB. Pulmonary arterial hypertension: future directions: report of a National Heart, Lung and Blood Institute/Office of Rare Diseases workshop. Circulation. 2004;109:2947-52.
20. Allegra A, Coppolino G, Bolignano D, Giacobbe MS, Alonci A, D'Angelo A, Bellomo G, Teti D, Loddo S, Musolino C, Buemi M. Endothelial progenitor cells: pathogenetic role and therapeutic perspectives. J Nephrol. 2009;22:463-75.
21. Sueblinvong V, Weiss DJ. Cell therapy approaches for lung diseases: current status. Curr Opin Pharmacol. 2009;9:268-73.
22. Ward MR, Stewart DJ, Kutryk MJ. Endothelial progenitor cell therapy for the treatment of coronary disease, acute MI, and pulmonary arterial hypertension: current perspectives. Catheter Cardiovasc Interv. 2007;70:983-98.
23. Zhao YD, Courtman DW, Deng Y, Kugathasan L, Zhang Q, Stewart DJ. Rescue of monocrotaline-induced pulmonary arterial hypertension using bone marrow-derived endothelial-like progenitor cells: efficacy of combined cell and eNOS gene therapy in established disease. Circ Res. 2005;96:442-50.
24. Chan SY, Loscalzo J. Pathogenic mechanisms of pulmonary arterial hypertension. J Mol Cell Cardiol. 2008;44:14-30.
25. Schannwell CM, Steiner S, Strauer BE. Diagnostics in pulmonary hypertension. J Physiol Pharmacol. 2007;58(Suppl 5):591-602.
26. Ahearn GS, Tapson VF, Rebeiz A, Greenfield JC Jr. Electrocardiography to define clinical status in primary pulmonary hypertension and pulmonary arterial hypertension secondary to collagen vascular disease. Chest. 2002;122:524-7.
27. Paciocco G, Martinez FJ, Bossone E, Pielsticker E, Gillespie B, Rubenfire M. Oxygen desaturation on the six-minute walk test and mortality in untreated primary pulmonary hypertension. Eur Respir J. 2001;17:647-52.
28. Miyamoto S, Nagaya N, Satoh T, Kyotani S, Sakamaki F, Fujita M, Nakanishi N, Miyatake K. Clinical correlates and prognostic significance of six-minute walk test in patients with primary pulmonary hypertension. Comparison with cardiopulmonary exercise testing. Am J Respir Crit Care Med. 2000;161:487-92.
29. Rhodes CJ, Davidson A, Gibbs JS, Wharton J, Wilkins MR. Therapeutic targets in pulmonary arterial hypertension. Pharmacol Ther. 2009;121:69-88.
30. Moncada S, Gryglewski R, Bunting S, Vane JR. An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation. Nature. 1976;263:663-5.
31. Tuder RM, Cool CD, Geraci MW, Wang J, Abman SH, Wright L, Badesch D, Voelkel NF. Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am J Respir Crit Care Med. 1999;159:1925-32.
32. Geraci MW, Gao B, Shepherd DC, Moore MD, Westcott JY, Fagan KA, Alger LA, Tuder RM, Voelkel NF. Pulmonary prostacyclin synthase overexpression in transgenic mice protects against development of hypoxic pulmonary hypertension. J Clin Invest. 1999;103:1509-15.
33. Nagaya N, Yokoyama C, Kyotani S, Shimonishi M, Morishita R, Uematsu M, Nishikimi T, Nakanishi N, Ogihara T, Yamagishi M, Miyatake K, Kaneda Y, Tanabe T. Gene transfer of human prostacyclin synthase ameliorates monocrotaline- induced pulmonary hypertension in rats. Circulation. 2000;102:2005-10.
34. Suhara H, Sawa Y, Fukushima N, Kagisaki K, Yokoyama C, Tanabe T, Ohtake S, Matsuda H. Gene transfer of human prostacyclin synthase into the liver is effective for the treatment of pulmonary hypertension in rats. J Thorac Cardiovasc Surg. 2002;123:855-61.
35. Tahara N, Kai H, Niiyama H, Mori T, Sugi Y, Takayama N, Yasukawa H, Numaguchi Y, Matsui H, Okumura K, Imaizumi T. Repeated gene transfer of naked prostacyclin synthase plasmid into skeletal muscles attenuates monocrotaline-induced pulmonary hypertension and prolongs survival in rats. Hum Gene Ther. 2004;15:1270-8.
36. Christman BW, McPherson CD, Newman JH, King GA, Bernard GR, Groves BM, Loyd JE. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med. 1992;327:70-5.
37. Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB, Groves BM, Tapson VF, Bourge RC, Brundage BH, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group. N Engl J Med. 1996;334:296-302.
38. McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation. 2002;106:1477-82.
39. Sitbon O, Humbert M, Nunes H, Parent F, Garcia G, Herve P, Rainisio M, Simonneau G. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol. 2002;40:780-8.
40. Simonneau G, Barst RJ, Galie N, Naeije R, Rich S, Bourge RC, Keogh A, Oudiz R, Frost A, Blackburn SD, Crow JW, Rubin LJ. 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. 2002;165:800-4.
41. Barst RJ, Galie N, Naeije R, Simonneau G, Jeffs R, Arneson C, Rubin LJ. Long-term outcome in pulmonary arterial hypertension patients treated with subcutaneous treprostinil. Eur Respir J. 2006;28:1195-203.
42. Tapson VF, Gomberg-Maitland M, McLaughlin VV, Benza RL, Widlitz AC, Krichman A, Barst RJ. Safety and efficacy of IV treprostinil for pulmonary arterial hypertension: a prospective, multicenter, open-label, 12-week trial. Chest. 2006;129:683-8.
43. Hoeper MM, Schwarze M, Ehlerding S, Adler-Schuermeyer A, Spiekerkoetter E, Niedermeyer J, Hamm M, Fabel H. Long-term treatment of primary pulmonary hypertension with aerosolized iloprost, a prostacyclin analogue. N Engl J Med. 2000;342:1866-70.
44. Olschewski H, Ghofrani HA, Schmehl T, Winkler J, Wilkens H, Hoper MM, Behr J, Kleber FX, Seeger W. Inhaled iloprost to treat severe pulmonary hypertension. An uncontrolled trial. German PPH Study Group. Ann Intern Med. 2000;132:435-43.
45. Ewert R, Opitz CF, Wensel R, Winkler J, Halank M, Felix SB. Continuous intravenous iloprost to revert treatment failure of first-line inhaled iloprost therapy in patients with idiopathic pulmonary arterial hypertension. Clin Res Cardiol. 2007;96:211-7.
46. Higenbottam TW, Butt AY, Dinh-Xaun AT, Takao M, Cremona G, Akamine S. Treatment of pulmonary hypertension with the continuous infusion of a prostacyclin analogue, iloprost. Heart. 1998;79:175-9.
47. Galie N, Humbert M, Vachiery JL, Vizza CD, Kneussl M, Manes A, Sitbon O, Torbicki A, Delcroix M, Naeije R, Hoeper M, Chaouat A, Morand S, Besse B, Simonneau G. Effects of beraprost sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled trial. J Am Coll Cardiol. 2002;39:1496-502.
48. Barst RJ, McGoon M, McLaughlin V, Tapson V, Rich S, Rubin L, Wasserman K, Oudiz R, Shapiro S, Robbins IM, Channick R, Badesch D, Rayburn BK, Flinchbaugh R, Sigman J, Arneson C, Jeffs R. Beraprost therapy for pulmonary arterial hypertension. J Am Coll Cardiol. 2003;41:2119-25.
49. Kuwano K, Hashino A, Noda K, Kosugi K, Kuwabara K. A long-acting and highly selective prostacyclin receptor agonist prodrug, 2-{4-[(5,6- diphenylpyrazin-2-yl)(isopropyl)amino] butoxy}-N-(methylsulfonyl )acetamide (NS-304), ameliorates rat pulmonary hypertension with unique relaxant responses of its active form, {4-[(5,6-diphenylpyrazin-2-yl) (isopropyl)amino]butoxy} acetic acid (MRE-269), on rat pulmonary artery. J Pharmacol Exp Ther. 2008;326:691-9.
50. Gomberg-Maitland M, Preston IR. Prostacyclin therapy for pulmonary arterial hypertension: new directions. Semin Respir Crit Care Med. 2005;26:394-401.
51. Bohm F, Pernow J. The importance of endothelin-1 for vascular dysfunction in cardiovascular disease. Cardiovasc Res. 2007;76:8-18.
52. Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988;332:411-5.
53. Giaid A, Yanagisawa M, Langleben D, Michel RP, Levy R, Shennib H, Kimura S, Masaki T, Duguid WP, Stewart DJ. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med. 1993;328:1732-9.
54. Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med. 2004;351:1425-36.
55. Elton TS, Oparil S, Taylor GR, Hicks PH, Yang RH, Jin H, Chen YF. Normobaric hypoxia stimulates endothelin-1 gene expression in the rat. Am J Physiol. 1992;263:R1260-4.
56. Miyauchi T, Yorikane R, Sakai S, Sakurai T, Okada M, Nishikibe M, Yano M, Yamaguchi I, Sugishita Y, Goto K. Contribution of endogenous endothelin-1 to the progression of cardiopulmonary alterations in rats with monocrotaline- induced pulmonary hypertension. Circ Res. 1993;73:887-97.
57. Stelzner TJ, O'Brien RF, Yanagisawa M, Sakurai T, Sato K, Webb S, Zamora M, McMurtry IF, Fisher JH. Increased lung endothelin-1 production in rats with idiopathic pulmonary hypertension. Am J Physiol. 1992;262:L614-20.
58. Stewart DJ, Levy RD, Cernacek P, Langleben D. Increased plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease? Ann Intern Med. 1991;114:464-9.
59. Abman SH. Role of endothelin receptor antagonists in the treatment of pulmonary arterial hypertension. Annu Rev Med. 2009;60:13-23.
60. Ivy DD, Parker TA, Ziegler JW, Galan HL, Kinsella JP, Tuder RM, Abman SH. Prolonged endothelin A receptor blockade attenuates chronic pulmonary hypertension in the ovine fetus. J Clin Invest. 1997;99:1179-86.
61. Ivy DD, Yanagisawa M, Gariepy CE, Gebb SA, Colvin KL, McMurtry IF. Exaggerated hypoxic pulmonary hypertension in endothelin B receptor-deficient rats. Am J Physiol Lung Cell Mol Physiol. 2002;282:L703-12.
62. Sakai S, Miyauchi T, Hara J, Goto K, Yamaguchi I. Hypotensive effect of endothelin-1 via endothelin-B-receptor pathway on pulmonary circulation is enhanced in rats with pulmonary hypertension. J Cardiovasc Pharmacol. 2000;36:S95-8.
63. Jasmin JF, Lucas M, Cernacek P, Dupuis J. Effectiveness of a nonselective ET(A/B) and a selective ET(A) antagonist in rats with monocrotaline-induced pulmonary hypertension. Circulation. 2001;103:314-8.
64. Clozel M. Effects of bosentan on cellular processes involved in pulmonary arterial hypertension: do they explain the long-term benefit? Ann Med. 2003;35:605-13.
65. Channick RN, Simonneau G, Sitbon O, Robbins IM, Frost A, Tapson VF, Badesch DB, Roux S, Rainisio M, Bodin F, Rubin LJ. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet. 2001;358:1119-23.
66. Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A, Pulido T, Frost A, Roux S, Leconte I, Landzberg M, Simonneau G. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346:896-903. (Pubitemid 34984638)
67. Oldfield V, Lyseng-Williamson KA. Bosentan: a review of its use in pulmonary arterial hypertension and systemic sclerosis. Am J Cardiovasc Drugs. 2006;6:189-208.
68. Dingemanse J, van Giersbergen PL. Clinical pharmacology of bosentan, a dual endothelin receptor antagonist. Clin Pharmacokinet. 2004;43:1089-15.
69. Galie N, Beghetti M, Gatzoulis MA, Granton J, Berger RM, Lauer A, Chiossi E, Landzberg M. Bosentan therapy in patients with Eisenmenger syndrome: a multicenter, double-blind, randomized, placebo-controlled study. Circulation. 2006;114:48-54.
70. Gatzoulis MA, Beghetti M, Galie N, Granton J, Berger RM, Lauer A, Chiossi E, Landzberg M. Longer-term bosentan therapy improves functional capacity in Eisenmenger syndrome: results of the BREATHE-5 open-label extension study. Int J Cardiol. 2008;127:27-32.
71. Barst RJ, Langleben D, Frost A, Horn EM, Oudiz R, Shapiro S, McLaughlin V, Hill N, Tapson VF, Robbins IM, Zwicke D, Duncan B, Dixon RA, Frumkin LR. Sitaxsentan therapy for pulmonary arterial hypertension. Am J Respir Crit Care Med. 2004;169:441-7.
72. Galie N, Olschewski H, Oudiz RJ, Torres F, Frost A, Ghofrani HA, Badesch DB, McGoon MD, McLaughlin VV, Roecker EB, Gerber MJ, Dufton C, Wiens BL, Rubin LJ. 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. 2008;117:3010-9.
73. Feil R, Lohmann SM, de Jonge H, Walter U, Hofmann F. Cyclic GMP-dependent protein kinases and the cardiovascular system: insights from genetically modified mice. Circ Res. 2003;93:907-16. (Pubitemid 37433228)
74. Bloch KD, Ichinose F, Roberts JD, Jr., Zapol WM. Inhaled NO as a therapeutic agent. Cardiovasc Res. 2007;75:339-48.
75. Hare JM, Stamler JS. NO/redox disequilibrium in the failing heart and cardiovascular system. J Clin Invest. 2005;115:509-17.
76. Rybalkin SD, Yan C, Bornfeldt KE, Beavo JA. Cyclic GMP phosphodiesterases and regulation of smooth muscle function. Circ Res. 2003;93:280-91. (Pubitemid 37048240)
77. Olsson KM, Hoeper MM. Novel approaches to the pharmacotherapy of pulmonary arterial hypertension. Drug Discov Today. 2009;14:284-90.
78. Shaul PW, Yuhanna IS, German Z, Chen Z, Steinhorn RH, Morin FC, 3rd. Pulmonary endothelial NO synthase gene expression is decreased in fetal lambs with pulmonary hypertension. Am J Physiol. 1997;272:L1005-12.
79. Steinhorn RH. Nitric oxide and beyond: new insights and therapies for pulmonary hypertension. J Perinatol. 2008;28(Suppl 3):S67-71.
80. Villanueva ME, Zaher FM, Svinarich DM, Konduri GG. Decreased gene expression of endothelial nitric oxide synthase in newborns with persistent pulmonary hypertension. Pediatr Res. 1998;44:338-43.
81. Demoncheaux EA, Higenbottam TW, Kiely DG, Wong JM, Wharton S, Varcoe R, Siddons T, Spivey AC, Hall K, Gize AP. Decreased whole body endogenous nitric oxide production in patients with primary pulmonary hypertension. J Vasc Res. 2005;42:133-6. (Pubitemid 41201978)
82. Frostell C, Fratacci MD, Wain JC, Jones R, Zapol WM. Inhaled nitric oxide. A selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction. Circulation. 1991;83:2038-47.
83. Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. The Neonatal Inhaled Nitric Oxide Study Group. N Engl J Med. 1997;336:597-604.
84. Clark RH, Kueser TJ, Walker MW, Southgate WM, Huckaby JL, Perez JA, Roy BJ, Keszler M, Kinsella JP. Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. Clinical Inhaled Nitric Oxide Research Group. N Engl J Med. 2000;342:469-74.
85. Kinsella JP, Neish SR, Shaffer E, Abman SH. Low-dose inhalation nitric oxide in persistent pulmonary hypertension of the newborn. Lancet. 1992;340:819-20.
86. Roberts JD, Jr., Fineman JR, Morin FC, 3rd, Shaul PW, Rimar S, Schreiber MD, Polin RA, Zwass MS, Zayek MM, Gross I, Heymann MA, Zapol WM. Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. The Inhaled Nitric Oxide Study Group. N Engl J Med. 1997;336:605-10.
87. Schermuly RT, Pullamsetti SS, Kwapiszewska G, Dumitrascu R, Tian X, Weissmann N, Ghofrani HA, Kaulen C, Dunkern T, Schudt C, Voswinckel R, Zhou J, Samidurai A, Klepetko W, Paddenberg R, Kummer W, Seeger W, Grimminger F. Phosphodiesterase 1 upregulation in pulmonary arterial hypertension: target for reverse-remodeling therapy. Circulation. 2007;115:2331-9.
88. Badesch DB, Abman SH, Ahearn GS, Barst RJ, McCrory DC, Simonneau G, McLaughlin VV. Medical therapy for pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126:35S-62S.
89. Galie N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, Fleming T, Parpia T, Burgess G, Branzi A, Grimminger F, Kurzyna M, Simonneau G. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med. 2005;353:2148-57.
90. Galie N, Brundage BH, Ghofrani HA, Oudiz RJ, Simonneau G, Safdar Z, Shapiro S, White RJ, Chan M, Beardsworth A, Frumkin L, Barst RJ. Tadalafil therapy for pulmonary arterial hypertension. Circulation. 2009;119:2894-903.
91. Vermeersch P, Buys E, Pokreisz P, Marsboom G, Ichinose F, Sips P, Pellens M, Gillijns H, Swinnen M, Graveline A, Collen D, Dewerchin M, Brouckaert P, Bloch KD, Janssens S. Soluble guanylate cyclase-alpha1 deficiency selectively inhibits the pulmonary vasodilator response to nitric oxide and increases the pulmonary vascular remodeling response to chronic hypoxia. Circulation. 2007;116:936-43. (Pubitemid 47300918)
92. Schermuly RT, Stasch JP, Pullamsetti SS, Middendorff R, Muller D, Schluter KD, Dingendorf A, Hackemack S, Kolosionek E, Kaulen C, Dumitrascu R, Weissmann N, Mittendorf J, Klepetko W, Seeger W, Ghofrani HA, Grimminger F. Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension. Eur Respir J. 2008;32:881-91.
93. Weissmann N, Hackemack S, Dahal BK, Pullamsetti SS, Savai R, Mittal M, Fuchs B, Medebach T, Dumitrascu R, Eickels M, Ghofrani HA, Seeger W, Grimminger F, Schermuly RT. The soluble guanylate cyclase activator HMR1766 reverses hypoxia-induced experimental pulmonary hypertension in mice. Am J Physiol Lung Cell Mol Physiol. 2009;297:L658-65.
94. Dumitrascu R, Weissmann N, Ghofrani HA, Dony E, Beuerlein K, Schmidt H, Stasch JP, Gnoth MJ, Seeger W, Grimminger F, Schermuly RT. Activation of soluble guanylate cyclase reverses experimental pulmonary hypertension and vascular remodeling. Circulation. 2006;113:286-95.
95. Ko FN, Wu CC, Kuo SC, Lee FY, Teng CM. YC-1, a novel activator of platelet guanylate cyclase. Blood. 1994;84:4226-33.
96. Deruelle P, Grover TR, Abman SH. Pulmonary vascular effects of nitric oxide-cGMP augmentation in a model of chronic pulmonary hypertension in fetal and neonatal sheep. Am J Physiol Lung Cell Mol Physiol. 2005;289:L798-806.
97. Evgenov OV, Ichinose F, Evgenov NV, Gnoth MJ, Falkowski GE, Chang Y, Bloch KD, Zapol WM. Soluble guanylate cyclase activator reverses acute pulmonary hypertension and augments the pulmonary vasodilator response to inhaled nitric oxide in awake lambs. Circulation. 2004;110:2253-9.
98. Belik J. Riociguat, an oral soluble guanylate cyclase stimulator for the treatment of pulmonary hypertension. Curr Opin Investig Drugs. 2009;10:971-9.
99. Yun S, Junbao D, Limin G, Chaomei Z, Xiuying T, Chaoshu T. The regulating effect of heme oxygenase/carbon monoxide on hypoxic pulmonary vascular structural remodeling. Biochem Biophys Res Commun. 2003;306:523-9.
100. Abe K, Kimura H. The possible role of hydrogen sulfide as an endogenous neuromodulator. J Neurosci. 1996;16:1066-71.
101. Chunyu Z, Junbao D, Dingfang B, Hui Y, Xiuying T, Chaoshu T. The regulatory effect of hydrogen sulfide on hypoxic pulmonary hypertension in rats. Biochem Biophys Res Commun. 2003;302:810-6.
102. Li XH, Du JB, Bu DF, Tang XY, Tang CS. Sodium hydrosulfide alleviated pulmonary vascular structural remodeling induced by high pulmonary blood flow in rats. Acta Pharmacol Sin. 2006;27:971-80.
103. Hartshorne DJ. Myosin phosphatase: subunits and interactions. Acta Physiol Scand. 1998;164:483-93.
104. 2+ desensitization in pulmonary vascular smooth muscle through inhibition of RhoA/ Rho kinase signaling. Am J Physiol Lung Cell Mol Physiol. 2004;287:L1220-9.
105. Weigand L, Sylvester JT, Shimoda LA. Mechanisms of endothelin-1-induced contraction in pulmonary arteries from chronically hypoxic rats. Am J Physiol Lung Cell Mol Physiol. 2006;290:L284-90.
106. Nagaoka T, Fagan KA, Gebb SA, Morris KG, Suzuki T, Shimokawa H, McMurtry IF, Oka M. Inhaled Rho kinase inhibitors are potent and selective vasodilators in rat pulmonary hypertension. Am J Respir Crit Care Med. 2005;171:494-9.
107. Wojciak-Stothard B. New drug targets for pulmonary hypertension: Rho GTPases in pulmonary vascular remodelling. Postgrad Med J. 2008;84:348-53.
108. Robertson TP, Dipp M, Ward JP, Aaronson PI, Evans AM. Inhibition of sustained hypoxic vasoconstriction by Y-27632 in isolated intrapulmonary arteries and perfused lung of the rat. Br J Pharmacol. 2000;131:5-9.
109. Abe K, Tawara S, Oi K, Hizume T, Uwatoku T, Fukumoto Y, Kaibuchi K, Shimokawa H. Long-term inhibition of Rho-kinase ameliorates hypoxia-induced pulmonary hypertension in mice. J Cardiovasc Pharmacol. 2006;48:280-5.
110. Fagan KA, Oka M, Bauer NR, Gebb SA, Ivy DD, Morris KG, McMurtry IF. Attenuation of acute hypoxic pulmonary vasoconstriction and hypoxic pulmonary hypertension in mice by inhibition of Rho-kinase. Am J Physiol Lung Cell Mol Physiol. 2004;287:L656-64.
111. Fukumoto Y, Matoba T, Ito A, Tanaka H, Kishi T, Hayashidani S, Abe K, Takeshita A, Shimokawa H. Acute vasodilator effects of a Rho-kinase inhibitor, fasudil, in patients with severe pulmonary hypertension. Heart. 2005;91:391-2.
112. Do e Z, Fukumoto Y, Takaki A, Tawara S, Ohashi J, Nakano M, Tada T, Saji K, Sugimura K, Fujita H, Hoshikawa Y, Nawata J, Kondo T, Shimokawa H. Evidence for Rho-kinase activation in patients with pulmonary arterial hypertension. Circ J. 2009;73:1731-9.
113. Guilluy C, Eddahibi S, Agard C, Guignabert C, Izikki M, Tu L, Savale L, Humbert M, Fadel E, Adnot S, Loirand G, Pacaud P. RhoA and Rho kinase activation in human pulmonary hypertension: role of 5-HT signaling. Am J Respir Crit Care Med. 2009;179:1151-8.
114. Laumanns IP, Fink L, Wilhelm J, Wolff JC, Mitnacht-Kraus R, Graef-Hoechst S, Stein MM, Bohle RM, Klepetko W, Hoda MA, Schermuly RT, Grimminger F, Seeger W, Voswinckel R. The noncanonical WNT pathway is operative in idiopathic pulmonary arterial hypertension. Am J Respir Cell Mol Biol. 2009;40:683-91.
115. Aikawa M, Rabkin E, Sugiyama S, Voglic SJ, Fukumoto Y, Furukawa Y, Shiomi M, Schoen FJ, Libby P. An HMG-CoA reductase inhibitor, cerivastatin, suppresses growth of macrophages expressing matrix metalloproteinases and tissue factor in vivo and in vitro. Circulation. 2001;103:276-83.
116. Hattori Y, Nakanishi N, Akimoto K, Yoshida M, Kasai K. HMG-CoA reductase inhibitor increases GTP cyclohydrolase I mRNA and tetrahydrobiopterin in vascular endothelial cells. Arterioscler Thromb Vasc Biol. 2003;23:176-82.
117. Jain MK, Ridker PM. Anti-inflammatory effects of statins: clinical evidence and basic mechanisms. Nat Rev Drug Discov. 2005;4:977-87.
118. Girgis RE, Li D, Zhan X, Garcia JG, Tuder RM, Hassoun PM, Johns RA. Attenuation of chronic hypoxic pulmonary hypertension by simvastatin. Am J Physiol Heart Circ Physiol. 2003;285:H938-45.
119. Kao PN. Simvastatin treatment of pulmonary hypertension: an observational case series. Chest. 2005;127:1446-52.
120. Wilkins MR, Ali O, Bradlow W, Wharton J, Taegtmeyer A, Rhodes CJ, Ghofrani HA, Howard L, Nihoyannopoulos P, Mohiaddin RH, Gibbs JS, The Sipht Study G. Simvastatin as a Treatment for Pulmonary Hypertension Trial (SiPHT). Am J Respir Crit Care Med. 2010 Jan 28 [Epub ahead of print].
121. Balasubramaniam V, Le Cras TD, Ivy DD, Grover TR, Kinsella JP, Abman SH. Role of platelet-derived growth factor in vascular remodeling during pulmonary hypertension in the ovine fetus. Am J Physiol Lung Cell Mol Physiol. 2003;284:L826-33.
122. Humbert M, Monti G, Fartoukh M, Magnan A, Brenot F, Rain B, Capron F, Galanaud P, Duroux P, Simonneau G, Emilie D. Platelet-derived growth factor expression in primary pulmonary hypertension: comparison of HIV seropositive and HIV seronegative patients. Eur Respir J. 1998;11:554-9.
123. Schermuly RT, Yilmaz H, Ghofrani HA, Woyda K, Pullamsetti S, Schulz A, Gessler T, Dumitrascu R, Weissmann N, Grimminger F, Seeger W. Inhaled iloprost reverses vascular remodeling in chronic experimental pulmonary hypertension. Am J Respir Crit Care Med. 2005;172:358-63.
124. Ghofrani HA, Seeger W, Grimminger F. Imatinib for the treatment of pulmonary arterial hypertension. N Engl J Med. 2005;353:1412-3.
125. Patterson KC, Weissmann A, Ahmadi T, Farber HW. Imatinib mesylate in the treatment of refractory idiopathic pulmonary arterial hypertension. Ann Intern Med. 2006;145:152-3.
126. Souza R, Sitbon O, Parent F, Simonneau G, Humbert M. Long term imatinib treatment in pulmonary arterial hypertension. Thorax. 2006;61:736.
127. Kerkela R, Grazette L, Yacobi R, Iliescu C, Patten R, Beahm C, Walters B, Shevtsov S, Pesant S, Clubb FJ, Rosenzweig A, Salomon RN, Van Etten RA, Alroy J, Durand JB, Force T. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med. 2006;12:908-16.
128. Klein M, Schermuly RT, Ellinghaus P, Milting H, Riedl B, Nikolova S, Pullamsetti SS, Weissmann N, Dony E, Savai R, Ghofrani HA, Grimminger F, Busch AE, Schafer S. Combined tyrosine and serine/threonine kinase inhibition by sorafenib prevents progression of experimental pulmonary hypertension and myocardial remodeling. Circulation. 2008;118:2081-90.
129. Said SI, Mutt V. Polypeptide with broad biological activity: isolation from small intestine. Science. 1970;169:1217-8.
130. Harmar AJ, Arimura A, Gozes I, Journot L, Laburthe M, Pisegna JR, Rawlings SR, Robberecht P, Said SI, Sreedharan SP, Wank SA, Waschek JA. International Union of Pharmacology. XVIII. Nomenclature of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide. Pharmacol Rev. 1998;50:265-70.
131. Petkov V, Mosgoeller W, Ziesche R, Raderer M, Stiebellehner L, Vonbank K, Funk GC, Hamilton G, Novotny C, Burian B, Block LH. Vasoactive intestinal peptide as a new drug for treatment of primary pulmonary hypertension. J Clin Invest. 2003;111:1339-46.
132. Said SI, Hamidi SA, Dickman KG, Szema AM, Lyubsky S, Lin RZ, Jiang YP, Chen JJ, Waschek JA, Kort S. Moderate pulmonary arterial hypertension in male mice lacking the vasoactive intestinal peptide gene. Circulation. 2007;115:1260-8.
133. Haydar S, Sarti JF, Grisoni ER. Intravenous vasoactive intestinal polypeptide lowers pulmonary-to-systemic vascular resistance ratio in a neonatal piglet model of pulmonary arterial hypertension. J Pediatr Surg. 2007;42:758-64.
134. McLatchie LM, Fraser NJ, Main MJ, Wise A, Brown J, Thompson N, Solari R, Lee MG, Foord SM. RAMPs regulate the transport and ligand specificity of the calcitonin-receptor- like receptor. Nature. 1998;393:333-9.
135. Nagaya N, Kangawa K. Adrenomedullin in the treatment of pulmonary hypertension. Peptides. 2004;25:2013-8.
136. Zhao L, Brown LA, Owji AA, Nunez DJ, Smith DM, Ghatei MA, Bloom SR, Wilkins MR. Adrenomedullin activity in chronically hypoxic rat lungs. Am J Physiol. 1996;271:H622-9.
137. Qi JG, Ding YG, Tang CS, Du JB. Chronic administration of adrenomedullin attenuates hypoxic pulmonary vascular structural remodeling and inhibits proadrenomedullin N-terminal 20-peptide production in rats. Peptides. 2007;28:910-9.
138. Yuan JX, Aldinger AM, Juhaszova M, Wang J, Conte JV Jr, Gaine SP, Orens JB, Rubin LJ. Dysfunctional voltage-gated K+ channels in pulmonary artery smooth muscle cells of patients with primary pulmonary hypertension. Circulation. 1998;98:1400-6.
139. Abenhaim L, Moride Y, Brenot F, Rich S, Benichou J, Kurz X, Higenbottam T, Oakley C, Wouters E, Aubier M, Simonneau G, Begaud B. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. International Primary Pulmonary Hypertension Study Group. N Engl J Med. 1996;335:609-16.
140. Weir EK, Hong Z, Varghese A. The serotonin transporter: a vehicle to elucidate pulmonary hypertension? Circ Res. 2004;94:1152-4.
141. Schweizer W. [Obstructive pulmonary arterial hypertension and Menocil]. Praxis. 1969;58:701-2.
142. Eddahibi S, Humbert M, Fadel E, Raffestin B, Darmon M, Capron F, Simonneau G, Dartevelle P, Hamon M, Adnot S. Serotonin transporter overexpression is responsible for pulmonary artery smooth muscle hyperplasia in primary pulmonary hypertension. J Clin Invest. 2001;108:1141-50.
143. Keegan A, Morecroft I, Smillie D, Hicks MN, MacLean MR. Contribution of the 5-HT(1B) receptor to hypoxia-induced pulmonary hypertension: converging evidence using 5-HT(1B)-receptor knockout mice and the 5-HT(1B/1D)-receptor antagonist GR127935. Circ Res. 2001;89:1231-9.
144. Eddahibi S, Hanoun N, Lanfumey L, Lesch KP, Raffestin B, Hamon M, Adnot S. Attenuated hypoxic pulmonary hypertension in mice lacking the 5-hydroxytryptamine transporter gene. J Clin Invest. 2000;105:1555-62.
145. Morecroft I, Heeley RP, Prentice HM, Kirk A, MacLean MR. 5-hydroxytryptamine receptors mediating contraction in human small muscular
146. Marcos E, Adnot S, Pham MH, Nosjean A, Raffestin B, Hamon M, Eddahibi S. Serotonin transporter inhibitors protect against hypoxic pulmonary hypertension. Am J Respir Crit Care Med. 2003;168:487-93.
147. Guignabert C, Tu L, Izikki M, Dewachter L, Zadigue P, Humbert M, Adnot S, Fadel E, Eddahibi S. Dichloroacetate treatment partially regresses established pulmonary hypertension in mice with SM22{alpha}-targeted overexpression of the serotonin transporter. FASEB J. 2009;23:4135-47.
148. Bonnet S, Michelakis ED, Porter CJ, Andrade-Navarro MA, Thebaud B, Haromy A, Harry G, Moudgil R, McMurtry MS, Weir EK, Archer SL. An abnormal mitochondrialhypoxia inducible factor-1alpha-Kv channel pathway disrupts oxygen sensing and triggers pulmonary arterial hypertension in fawn hooded rats: similarities to human pulmonary arterial hypertension. Circulation. 2006;113:2630-41.
149. Michelakis ED, McMurtry MS, Wu XC, Dyck JR, Moudgil R, Hopkins TA, Lopaschuk GD, Puttagunta L, Waite R, Archer SL. Dichloroacetate, a metabolic modulator, prevents and reverses chronic hypoxic pulmonary hypertension in rats: role of increased expression and activity of voltage-gated potassium channels. Circulation. 2002;105:244-50.
150. Gonzalez AM, Smith AP, Emery CJ, Higenbottam TW. The pulmonary hypertensive fawn-hooded rat has a normal serotonin transporter coding sequence. Am J Respir Cell Mol Biol. 1998;19:245-9.
151. Hristov M, Weber C. Endothelial progenitor cells: characterization, pathophysiology, and possible clinical relevance. J Cell Mol Med. 2004;8:498-508.
152. Raoul W, Wagner-Ballon O, Saber G, Hulin A, Marcos E, Giraudier S, Vainchenker W, Adnot S, Eddahibi S, Maitre B. Effects of bone marrow-derived cells on monocrotalineand hypoxia-induced pulmonary hypertension in mice. Respir Res. 2007;8:8.
153. Atkinson C, Stewart S, Upton PD, Machado R, Thomson JR, Trembath RC, Morrell NW. Primary pulmonary hypertension is associated with reduced pulmonary vascular expression of type II bone morphogenetic protein receptor. Circulation. 2002;105:1672-8.
154. Reynolds AM, Xia W, Holmes MD, Hodge SJ, Danilov S, Curiel DT, Morrell NW, Reynolds PN. Bone morphogenetic protein type 2 receptor gene therapy attenuates hypoxic pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol. 2007;292:L1182-92.
155. Upton PD, Morrell NW. TGF-beta and BMPR-II pharmacology - implications for pulmonary vascular diseases. Curr Opin Pharmacol. 2009;9:274-80.
156. Zaiman AL, Podowski M, Medicherla S, Gordy K, Xu F, Zhen L, Shimoda LA, Neptune E, Higgins L, Murphy A, Chakravarty S, Protter A, Sehgal PB, Champion HC, Tuder RM. Role of the TGF-beta/Alk5 signaling pathway in monocrotaline-induced pulmonary hypertension. Am J Respir Crit Care Med. 2008;177:896-905.
157. Yildiz P. Molecular mechanisms of pulmonary hypertension. Clin Chim Acta. 2009;403:9-16.
158. Frank H, Mlczoch J, Huber K, Schuster E, Gurtner HP, Kneussl M. The effect of anticoagulant therapy in primary and anorectic drug-induced pulmonary hypertension. Chest. 1997;112:714-21.
159. Galie N, Seeger W, Naeije R, Simonneau G, Rubin LJ. Comparative analysis of clinical trials and evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43:81S-88S.
160. Labiris NR, Dolovich MB. Pulmonary drug delivery. Part I: physiological factors affecting therapeutic effectiveness of aerosolized medications. Br J Clin Pharmacol. 2003;56:588-99.
161. Patton JS, Fishburn CS, Weers JG. The lungs as a portal of entry for systemic drug delivery. Proc Am Thorac Soc. 2004;1:338-44.
162. Scheuch G, Kohlhaeufl MJ, Brand P, Siekmeier R. Clinical perspectives on pulmonary systemic and macromolecular delivery. Adv Drug Deliv Rev. 2006;58:996-1008.
163. Keith IM, Olson EB, Jr., Wilson NM, Jefcoate CR. Immunological identification and effects of 3-methylcholanthrene and phenobarbital on rat pulmonary cytochrome P-450. Cancer Res. 1987;47:1878-82.
164. Tronde A, Norden B, Marchner H, Wendel AK, Lennernas H, Bengtsson UH. Pulmonary absorption rate and bioavailability of drugs in vivo in rats: structure-absorption relationships and physicochemical profiling of inhaled drugs. J Pharm Sci. 2003;92:1216-33.
165. Gomberg-Maitland M, Olschewski H. Prostacyclin therapies for the treatment of pulmonary arterial hypertension. Eur Respir J. 2008;31:891-901.
166. Olschewski H, Rohde B, Behr J, Ewert R, Gessler T, Ghofrani HA, Schmehl T. Pharmaco-dynamics and pharmacokinetics of inhaled iloprost, aerosolized by three different devices, in severe pulmonary hypertension. Chest. 2003;124:1294-304.
167. Schermuly RT, Schulz A, Ghofrani HA, Breitenbach CS, Weissmann N, Hildebrand M, Kurz J, Grimminger F, Seeger W. Comparison of pharmacokinetics and vasodilatory effect of nebulized and infused iloprost in experimental pulmonary hypertension: rapid tolerance development. J Aerosol Med. 2006;19:353-63.
168. Olschewski H, Walmrath D, Schermuly R, Ghofrani A, Grimminger F, Seeger W. Aerosolized prostacyclin and iloprost in severe pulmonary hypertension. Ann Intern Med. 1996;124:820-4.
169. Olschewski H, Simonneau G, Galie N, Higenbottam T, Naeije R, Rubin LJ, Nikkho S, Speich R, Hoeper MM, Behr J, Winkler J, Sitbon O, Popov W, Ghofrani HA, Manes A, Kiely DG, Ewert R, Meyer A, Corris PA, Delcroix M, Gomez-Sanchez M, Siedentop H, Seeger W. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med. 2002;347:322-9.
170. Hoeper MM, Olschewski H, Ghofrani HA, Wilkens H, Winkler J, Borst MM, Niedermeyer J, Fabel H, Seeger W. A comparison of the acute hemodynamic effects of inhaled nitric oxide and aerosolized iloprost in primary pulmonary hypertension. German PPH study group. J Am Coll Cardiol. 2000;35:176-82.
171. Opitz CF, Wensel R, Winkler J, Halank M, Bruch L, Kleber FX, Hoffken G, Anker SD, Negassa A, Felix SB, Hetzer R, Ewert R. Clinical efficacy and survival with first-line inhaled iloprost therapy in patients with idiopathic pulmonary arterial hypertension. Eur Heart J. 2005;26:1895-902.
172. McLaughlin VV, Oudiz RJ, Frost A, Tapson VF, Murali S, Channick RN, Badesch DB, Barst RJ, Hsu HH, Rubin LJ. Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2006;174:1257-63.
173. Ivy DD, Doran AK, Smith KJ, Mallory GB, Jr., Beghetti M, Barst RJ, Brady D, Law Y, Parker D, Claussen L, Abman SH. Short- and long-term effects of inhaled iloprost therapy in children with pulmonary arterial hypertension. J Am Coll Cardiol. 2008;51:161-9.
174. Dernaika TA, Beavin M, Kinasewitz GT. Iloprost improves gas exchange and exercise tolerance in patients with pulmonary hypertension and chronic obstructive pulmonary disease. Respiration. 2010;79:377-82.
175. Sandifer BL, Brigham KL, Lawrence EC, Mottola D, Cuppels C, Parker RE. Potent effects of aerosol compared with intravenous treprostinil on the pulmonary circulation. J Appl Physiol. 2005;99:2363-8.
176. Voswinckel R, Enke B, Reichenberger F, Kohstall M, Kreckel A, Krick S, Gall H, Gessler T, Schmehl T, Ghofrani HA, Schermuly RT, Grimminger F, Rubin LJ, Seeger W, Olschewski H. Favorable effects of inhaled treprostinil in severe pulmonary hypertension: results from randomized controlled pilot studies. J Am Coll Cardiol. 2006;48:1672-81.
177. Channick RN, Olschewski H, Seeger W, Staub T, Voswinckel R, Rubin LJ. Safety and efficacy of inhaled treprostinil as add-on therapy to bosentan in pulmonary arterial hypertension. J Am Coll Cardiol. 2006;48:1433-7.
178. Voswinckel R, Reichenberger F, Gall H, Schmehl T, Gessler T, Schermuly RT, Grimminger F, Rubin LJ, Seeger W, Ghofrani HA, Olschewski H. Metered dose inhaler delivery of treprostinil for the treatment of pulmonary hypertension. Pulm Pharmacol Ther. 2009;22:50-6.
179. Kunimoto F, Arai K, Isa Y, Koyano T, Kadoi Y, Saito S, Goto F. A comparative study of the vasodilator effects of prostaglandin E1 in patients with pulmonary hypertension after mitral valve replacement and with adult respiratory distress syndrome. Anesth Analg. 1997;85:507-13.
180. Shen J, He B, Wang B. Effects of lipo-prostaglandin E1 on pulmonary hemodynamics and clinical outcomes in patients with pulmonary arterial hypertension. Chest. 2005;128:714-9.
181. Meyer J, Theilmeier G, Van Aken H, Bone HG, Busse H, Waurick R, Hinder F, Booke M. Inhaled prostaglandin E1 for treatment of acute lung injury in severe multiple organ failure. Anesth Analg. 1998;86:753-8.
182. Nakazawa K, Uchida T, Matsuzawa Y, Yokoyama K, Makita K, Amaha K. Treatment of pulmonary hypertension and hypoxia due to oleic acid induced lung injury with intratracheal prostaglandin E1 during partial liquid ventilation. Anesthesiology. 1998;89:686-92.
183. Sood BG, Delaney-Black V, Aranda JV, Shankaran S. Aerosolized PGE1: a selective pulmonary vasodilator in neonatal hypoxemic respiratory failure results of a Phase I/II open label clinical trial. Pediatr Res. 2004;56:579-85.
184. Della Rocca G, Coccia C, Pompei L, Costa MG, Di Marco P, Pietropaoli P. Inhaled aerosolized prostaglandin E1, pulmonary hemodynamics, and oxygenation during lung transplantation. Minerva Anestesiol. 2008;74:627-33.
185. Altiere RJ, Kung M, Diamond L. Comparative effects of inhaled isoproterenol and vasoactive intestinal peptide on histamine-induced bronchoconstriction in human subjects. Chest. 1984;86:153-4.
186. Barnes PJ, Dixon CM. The effect of inhaled vasoactive intestinal peptide on bronchial reactivity to histamine in humans. Am Rev Respir Dis. 1984;130:162-6.
187. Bundgaard A, Enehjelm SD, Aggestrup S. Pretreatment of exercise-induced asthma with inhaled vasoactive intestinal peptide (VIP). Eur J Respir Dis Suppl. 1983;128(Pt 2):427-9.
188. Crimi N, Palermo F, Oliveri R, Palermo B, Vancheri C, Polosa R, Mistretta A. Effect of vasoactive intestinal peptide (VIP) on propranolol-induced bronchoconstriction. J Allergy Clin Immunol. 1988;82:617-21.
189. Leuchte HH, Baezner C, Baumgartner RA, Bevec D, Bacher G, Neurohr C, Behr J. Inhalation of vasoactive intestinal peptide in pulmonary hypertension. Eur Respir J. 2008;32:1289-94.
190. Hachisu M, Hiranuma T, Tani S, Iizuka T. Enzymatic degradation of helodermin and vasoactive intestinal polypeptide. J Pharmacobiodyn. 1991;14:126-31.
191. Nagaya N, Okumura H, Uematsu M, Shimizu W, Ono F, Shirai M, Mori H, Miyatake K, Kangawa K. Repeated inhalation of adrenomedullin ameliorates pulmonary hypertension and survival in monocrotaline rats. Am J Physiol Heart Circ Physiol. 2003;285:H2125-31.
192. von der Hardt K, Kandler MA, Chada M, Cubra A, Schoof E, Amann K, Rascher W, Dotsch J. Brief adrenomedullin inhalation leads to sustained reduction of pulmonary artery pressure. Eur Respir J. 2004;24:615-23.
193. Nagaya N, Kyotani S, Uematsu M, Ueno K, Oya H, Nakanishi N, Shirai M, Mori H, Miyatake K, Kangawa K. Effects of adrenomedullin inhalation on hemodynamics and exercise capacity in patients with idiopathic pulmonary arterial hypertension. Circulation. 2004;109:351-6.
194. Evgenov OV, Kohane DS, Bloch KD, Stasch JP, Volpato GP, Bellas E, Evgenov NV, Buys ES, Gnoth MJ, Graveline AR, Liu R, Hess DR, Langer R, Zapol WM. Inhaled agonists of soluble guanylate cyclase induce selective pulmonary vasodilation. Am J Respir Crit Care Med. 2007;176:1138-45.
195. Fiore VF, Lofton MC, Roser-Page S, Yang SC, Roman J, Murthy N, Barker TH. Polyketal microparticles for therapeutic delivery to the lung. Biomaterials. 2010;31:810-7.
196. Labiris NR, Dolovich MB. Pulmonary drug delivery. Part II: the role of inhalant delivery devices and drug formulations in therapeutic effectiveness of aerosolized medications. Br J Clin Pharmacol. 2003;56:600-12.
197. Gupta V, Rawat A, Ahsan F. Feasibility study of aerosolized prostaglandin E(1) microspheres as a noninvasive therapy for pulmonary arterial hypertension. J Pharm Sci. 2010;99:1774-89.
198. Ishihara T, Takahashi M, Higaki M, Takenaga M, Mizushima T, Mizushima Y. Prolonging the in vivo residence time of prostaglandin E(1) with biodegradable nanoparticles, Pharm Res. 2008;25:1686-95.
199. Huang Y, Marui A, Sakaguchi H, Esaki J, Arai Y, Hirose K, Bir SC, Horiuchi H, Maruyama T, Ikeda T, Tabata Y, Komeda M. Sustained release of prostaglandin E1 potentiates the impaired therapeutic angiogenesis by basic fibroblast growth factor in diabetic murine hindlimb ischemia. Circ J. 2008;72:1693-9.
200. Harada-Shiba M, Takamisawa I, Miyata K, Ishii T, Nishiyama N, Itaka K, Kangawa K, Yoshihara F, Asada Y, Hatakeyama K, Nagaya N, Kataoka K. Intratracheal gene transfer of adrenomedullin using polyplex nanomicelles attenuates monocrotaline-induced pulmonary hypertension in rats. Mol Ther. 2009;17:1180-6.
201. Kimura S, Egashira K, Chen L, Nakano K, Iwata E, Miyagawa M, Tsujimoto H, Hara K, Morishita R, Sueishi K, Tominaga R, Sunagawa K. Nanoparticle-mediated delivery of nuclear factor kappaB decoy into lungs ameliorates monocrotaline-induced pulmonary arterial hypertension. Hypertension. 2009;53:877-83.
202. Tomoda K, Ohkoshi T, Nakajima T, Makino K. Preparation and properties of inhalable nanocomposite particles: effects of the size, weight ratio of the primary nanoparticles in nanocomposite particles and temperature at a spray-dryer inlet upon properties of nanocomposite particles. Colloids Surf B Biointerfaces. 2008;64:70-6.
203. Kleemann E, Schmehl T, Gessler T, Bakowsky U, Kissel T, Seeger W. Iloprost-containing liposomes for aerosol application in pulmonary arterial hypertension: formulation aspects and stability. Pharm Res. 2007;24:277-87.
204. Stark B, Debbage P, Andreae F, Mosgoeller W, Prassl R. Association of vasoactive intestinal peptide with polymer-grafted liposomes: structural aspects for pulmonary delivery. Biochim Biophys Acta. 2007;1768:705-14.
205. Hajos F, Stark B, Hensler S, Prassl R, Mosgoeller W. Inhalable liposomal formulation for vasoactive intestinal peptide. Int J Pharm. 2008;357:286-94.