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Digestive Diseases and Sciences

, Volume 60, Issue 11, pp 3491–3494 | Cite as

Pharmacokinetics and Tolerability of Intravenous Sildenafil in Two Subjects with Child–Turcotte–Pugh Class C Cirrhosis and Renal Dysfunction

  • Ayse L. Mindikoglu
  • Thomas C. Dowling
  • David J. Schaub
  • William R. Hutson
  • Darryn R. Potosky
  • Robert H. Christenson
  • Rolf N. Barth
  • John C. LaMattina
  • Steven I. Hanish
  • Matthew R. Weir
  • Jean-Pierre Raufman
Case Report

Introduction

Phosphodiesterase-5 (PDE-5) inhibitors play an important role in the treatment of complications of cirrhosis. They have been used successfully to treat portopulmonary hypertension (PPHTN) [1, 2, 3, 4], a complication in 5 % of subjects with cirrhosis [5]. Additionally, previous studies showed that PDE-5 inhibitors reduced portal pressures and hepatic venous pressure gradients, thereby improving hemodynamics in cirrhosis [6, 7, 8]. Moreover, in cirrhotic rats, PDE-5 inhibitors increased fractional excretion of Na, reduced plasma renin levels, and improved renal blood flow and glomerular filtration rate [9].

In cirrhosis, diminished intrahepatic nitric oxide (NO) levels [6] are associated with elevated asymmetric dimethylarginine levels that inhibit NO synthesis by competing with l-arginine for NO synthase [10, 11]. In turn, reduced intrahepatic NO levels result in dysfunction of NO-activated guanylate cyclase and, consequently, reduced sinusoidal cyclic guanosine 3′, 5′...

Keywords

Sildenafil Cirrhosis Pharmacokinetics Renal dysfunction 

Notes

Acknowledgments

The authors thank Heather L. Rebuck, MT (ASCP), CLS (NCA), and Sharon Y. Huang, MT (Clinical Chemistry Research Lab, University of Maryland Baltimore), University of Maryland General Clinical Research Center Staff and Galina Bikzhanova, Ph.D. (Discovery Bioanalytical Chemistry, Covance Laboratories, Inc.) for their support.

Conflict of interest

Robert H. Christenson, Ph.D. reported that he is a consultant for Roche Diagnostics and Siemens Healthcare Diagnostics and have research contracts with both.

Funding

The project described was supported in part by Grant Number 5 K23 DK089008-05 from the National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases (to Ayse L. Mindikoglu, M.D., M.P.H.), and its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institute of Diabetes and Digestive and Kidney Diseases or the NIH. This work was also supported by the University of Maryland School of Medicine, Department of Medicine funds (to Ayse L. Mindikoglu, M.D., M.P.H.), University of Maryland Clinical Translational Science Institute, and the University of Maryland General Clinical Research Center.

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Ayse L. Mindikoglu
    • 1
  • Thomas C. Dowling
    • 2
  • David J. Schaub
    • 3
  • William R. Hutson
    • 1
  • Darryn R. Potosky
    • 1
  • Robert H. Christenson
    • 4
  • Rolf N. Barth
    • 5
  • John C. LaMattina
    • 5
  • Steven I. Hanish
    • 5
  • Matthew R. Weir
    • 6
  • Jean-Pierre Raufman
    • 1
  1. 1.Division of Gastroenterology and Hepatology, Department of MedicineUniversity of Maryland School of MedicineBaltimoreUSA
  2. 2.College of PharmacyFerris State UniversityGrand RapidsUSA
  3. 3.Department of NeurologyUniversity of Maryland School of MedicineBaltimoreUSA
  4. 4.Department of PathologyUniversity of Maryland School of MedicineBaltimoreUSA
  5. 5.Department of SurgeryUniversity of Maryland School of MedicineBaltimoreUSA
  6. 6.Division of Nephrology, Department of MedicineUniversity of Maryland School of MedicineBaltimoreUSA

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