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CLINICAL RESEARCH: PULMONARY VASCULAR DISEASE

Favorable Effects of Inhaled Treprostinil in Severe Pulmonary Hypertension

Results From Randomized Controlled Pilot Studies

Robert Voswinckel, MD^_*, Beate Enke, MD^_*, Frank Reichenberger, MD^_*, Markus Kohstall, MD^_*, Andree Kreckel, MD^_*, Stefanie Krick, MD^_*, Henning Gall, MD^_*, Tobias Gessler, MD, PhD^_*,1, Thomas Schmehl, PhD^_*,1, Hossein A. Ghofrani, MD^_*,2, Ralph Theo Schermuly, PhD^_*, Friedrich Grimminger, MD, PhD^_*,3, Lewis J. Rubin, MD^,4, Werner Seeger, MD^_*,5 and Horst Olschewski, MD^_*,,6,_*

^_* Department of Internal Medicine, University Hospital Giessen, Giessen, Germany
Division of Pulmonary and Critical Care Medicine, University of California, San Diego School of Medicine, La Jolla, California
Division of Pulmonology, Medical University Graz, Graz, Austria.

Manuscript received February 21, 2006; revised manuscript received May 30, 2006, accepted June 13, 2006.

^_* Reprint requests and correspondence: Dr. Horst Olschewski, Division of Pulmonology, Auenbruggerplatz 20, A-8036 Graz, Austria. (Email: horst.olschewski{at}meduni-graz.at).

OBJECTIVES: This study sought to investigate the effects of inhaled treprostinil on pulmonary hemodynamics and gas exchange in severe pulmonary hypertension.

BACKGROUND: Inhaled iloprost therapy has a proven clinical efficacy in pulmonary arterial hypertension, but this therapy necessitates 6 to 9 inhalation sessions per day. Treprostinil has a longer plasma half-life and might provide favorable properties when applied by inhalation.

METHODS: Three different studies were conducted on a total of 123 patients by means of right heart catheterization: 1) a randomized crossover-design study (44 patients), 2) a dose escalation study (31 patients), and 3) a study of reduction of inhalation time while keeping the dose fixed (48 patients). The primary end point was the change in pulmonary vascular resistance (PVR).

RESULTS: The mean pulmonary arterial pressure of the enrolled patients was approximately 50 mm Hg in all studies. In study 1, both treprostinil and iloprost at an inhaled dose of 7.5 µg displayed a comparable PVR decrease, with a significantly different time course (p < 0.001), treprostinil showing a more sustained effect on PVR (p < 0.0001) and fewer systemic side effects. In study 2, effects of inhalation were observed for 3 h. A near-maximal acute PVR decrease was observed at 30 µg treprostinil. In study 3, treprostinil was inhaled at increasing concentrations with a pulsed ultrasonic nebulizer, mimicking a metered dose inhaler. A dose of 15 µg treprostinil was inhaled with 18, 9, 3, 2 pulses, or 1 pulse, each mode achieving comparable, sustained pulmonary vasodilation without significant side effects.

CONCLUSIONS: Inhaled treprostinil exerts sustained pulmonary vasodilation with excellent tolerability at relatively low doses and may be inhaled in a few breaths.

Abbreviations and Acronyms   PVR = pulmonary vascular resistance   AUC = area under the curve   ABC = areas between curves   PAP = pulmonary arterial pressure   SAP = systemic arterial pressure

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