br Materials and methods br Results
Materials and methods
Results and discussion
Acknowledgments This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MEST) (No. 2011-0030635) and the MarineBio Research Program (NRF-C1ABA001-2011-0018561).
The Fontan operation is a palliative procedure for children born with functional single ventricle Fesoterodine Fumarate disease., This operation, which creates a total cavopulmonary connection, separates the systemic and pulmonary circuits and mitigates pre-existing chronic hypoxemia and ventricular volume overload. However, following the Fontan operation there is no ventricular pump to propel blood into the pulmonary arteries. Instead, blood returns to the lungs via passive flow from the systemic veins. The resulting physiology confers a degree of chronic heart failure, characterized by diastolic dysfunction, and a circulation dependent on low pulmonary vascular resistance (PVR) in order to maintain an adequate cardiac output with a modestly elevated central venous pressure., Phosphodiesterase Type 5 (PDE5) inhibitors are a unique class of medications that have demonstrated utility in reducing PVR and improving ventricular performance in patients with pulmonary hypertension and myocardial dysfunction., , , , , These characteristics make this class of drug an appealing therapy to consider for patients with the Fontan circulation, in which the maintenance of low PVR and normal myocardial function are crucial determinants of long-term clinical outcomes. Although preliminary studies have demonstrated a modest short-term benefit, there are no data regarding the long-term use of this class of medication in the Fontan population., , , , Udenafil is a novel PDE5 inhibitor that has an established record of safety and efficacy in adult males for the indication of erectile dysfunction., , In that population, the pharmacokinetics (PK) of udenafil (molecular weight 516 g/mol) and the major circulating metabolite, DA-8164 (molecular weight 405 g/mol), have been well characterized. Udenafil is rapidly absorbed following oral administration, followed by a log-linear decline in plasma concentration with a terminal half-life in the range of 16 hours. Both udenafil and DA-8164, which is equipotent, are cleared predominantly by hepatic metabolism and then excreted in the feces and urine. Udenafil bioavailability is known to increase greater than proportionally with increasing dose following single- and multiple-dose administration. Although udenafil has been studied in adult males, the safety, PK, and tolerability of udenafil have not been evaluated in children or adolescents, in females, or in those who have undergone the Fontan operation.
Introduction Portal hypertension is one of the major complications of liver cirrhosis , , , , . It is caused by an increased resistance to portal venous blood following structural changes such as fibrotic scar 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 , . A further intrahepatic factor contributing to increased intrahepatic resistance is an activation of hepatic stellate cells (HSC), with reduced NO counterbalance , , , . NO is synthesized in endothelial cells by NO-synthase. NO activates soluble guanylate cyclase in HSC, leading to their relaxation and decrease of intrahepatic resistance. In liver cirrhosis, NO-synthesis in endothelial cells is diminished resulting in lower cGMP production, whereas cGMP itself is more rapidly degraded to 5′-GMP by an overactive phosphodiesterase-5 , . Both phenomena lead to persistence of sinusoid constriction.