Please cite this article in press as: Kreisel W, et al. The phosphodiesterase-5-inhibitor udenafil lowers portal pressure in compensated preascitic liver cirrhosis. A dose-finding phase-II-study. Dig Liver Dis (2014), http://dx.doi.org/10.1016/j.dld.2014.10.018 ARTICLE IN PRESS G Model YDLD-2767; No. of Pages 7 Digestive and Liver Disease xxx (2014) xxx–xxx Contents lists available at ScienceDirect Digestive and Liver Disease jou rnal h om epage: www.elsevier.com/locate/dld Liver, Pancreas and Biliary Tract The phosphodiesterase-5-inhibitor udenafil lowers portal pressure in compensated preascitic liver cirrhosis. A dose-finding phase-II-study Wolfgang Kreisel a,∗,1 , Peter Deibert a,1 , Limas Kupcinskas b , Jolanta Sumskiene b , Beate Appenrodt c , Susanne Roth a , Michaela Neagu a , Martin Rössle d , Alexander Zipprich e , Karel Caca f , Arnulf Ferlitsch g , Karin Dilger h , Ralf Mohrbacher h , Roland Greinwald h , Tilman Sauerbruch i a University Hospital Freiburg, Freiburg, Germany b Lithuanian University of Health Sciences, Kaunas, Lithuania c University Hospital, Homburg, Germany d Gastroenterology Centre, Freiburg, Germany e University Hospital, Halle, Germany f Klinikum Ludwigsburg, Ludwigsburg, Germany g Medical University, Wien, Austria h Dr. Falk Pharma GmbH, Freiburg, Germany i University Hospital, Bonn, Germany a r t i c l e i n f o Article history: Received 12 July 2014 Accepted 26 October 2014 Available online xxx Keywords: Liver cirrhosis Phosphodiesterase-5-inhibitors Portal hypertension Portal pressure Udenafil a b s t r a c t Background: Phosphodiesterase-5-inhibitors may lower portal pressure. Aims: To investigate the effect of the phosphodiesterase-5-inhibitor udenafil on hepatic and systemic haemodynamics in liver cirrhosis. Methods: In an open-label phase-II-study, patients with liver cirrhosis Child A/B and hepatic venous pressure-gradient ≥12 mmHg received 12.5 mg/day, 25 mg/day, 50 mg/day, 75 mg/day (n = 5, each), or 100 mg/day (n = 10) udenafil p.o. for one week. On days 0 and 6, hepatic venous pressure-gradient was measured prior to and one hour after drug ingestion. Endpoints were reduction of hepatic venous pressure-gradient from day 0 pre to day 6 post intake and reduction in the acute setting. Pharmacokinetics were measured in the two lowest dosage groups. Results: Combining the 75 and 100 mg/day groups hepatic venous pressure-gradient reduction after drug intake was 19.9% (p = 0.0006) on day 0. From day 0 pre-dose to day 6 post-dose hepatic venous pressure- gradient decreased by 15.7% (p = 0.040) and in 5/15 patients by ≥20% or to <12 mmHg. In the 100 mg/day group, mean arterial pressure decreased from 98.9 mmHg by 6.2 mmHg (p = 0.037) from day 0 pre-dose to day 6 post-dose. Heart rates or electrocardiograms were unchanged. Udenafil was eliminated with t 1/2 = 25 h. Conclusions: Oral application of 75–100 mg of the phosphodiesterase-5-inhibitor udenafil lowers portal pressure in the acute setting by about 20% without relevant systemic cardiovascular side effects. © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. 1. Introduction Portal hypertension is one of the major complications of liver cirrhosis [1–5]. It is caused by an increased resistance to portal venous blood following structural changes such as fibrotic scar ∗ Corresponding author at: University Hospital Freiburg, Department of Gastroen- terology, Hepatology, Endocrinology and Infectious Diseases, Hugstetter Str. 55, 79106 Freiburg, Germany. Tel.: +49 76127034010; fax: +49 76127074700. E-mail address: wolfgang.kreisel@uniklinik-freiburg.de (W. Kreisel). 1 These authors contributed equally to the manuscript. tissue and regenerative nodules compressing portal and central venules, and by swelling of hepatocytes and “capillarization” of sinusoids. This intrahepatic outflow obstruction is aggravated by an extrahepatic component, namely the increased portal tributary blood flow mainly induced by splanchnic vasodilation due to shear stress caused excess NO production [6,7]. A further intrahepatic factor contributing to increased intrahepatic resistance is an activa- tion of hepatic stellate cells (HSC), with reduced NO counterbalance [8–11]. NO is synthesized in endothelial cells by NO-synthase. NO activates soluble guanylate cyclase in HSC, leading to their relax- ation and decrease of intrahepatic resistance. In liver cirrhosis, NO-synthesis in endothelial cells is diminished resulting in lower http://dx.doi.org/10.1016/j.dld.2014.10.018 1590-8658/© 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.