sildenafil-citrate and Liver-Cirrhosis

Topics: Diagnosis, Differential; Erectile Dysfunction; Estrogens; Humans; Liver; Liver Cirrhosis; Liver Cirrhosis, Alcoholic; Male; Piperazines; Purines; Sildenafil Citrate; Sulfones; Testosterone; Vasodilator Agents

To investigate if sildenafil increases splanchnic blood flow and changes the hepatic venous pressure gradient (HVPG) in patients with cirrhosis. Phosphodiesterase type-5 inhibitors are valuable in the treatment of erectile dysfunction and pulmonary hypertension in patients with end-stage liver disease. However, the effect of phosphodiesterase type-5 inhibitors on splanchnic blood flow and portal hypertension remains essentially unknown.. Ten patients with biopsy proven cirrhosis (five females/five males, mean age 54 +/- 8 years) and an HVPG above 12 mmHg were studied after informed consent. Measurement of splanchnic blood flow and the HVPG during liver vein catheterization were done before and 80 min after oral administration of 50 mg sildenafil. Blood flow was estimated by use of indocyanine green clearance technique and Fick's principle, with correction for non-steady state.. The plasma concentration of sildenafil was 222 +/- 136 ng/mL 80 min after administration. Mean arterial blood pressure decreased from 77 +/- 7 mmHg to 66 +/- 12 mmHg, P = 0.003, while the splanchnic blood flow and oxygen consumption remained unchanged at 1.14 +/- 0.71 L/min and 2.3 +/- 0.6 mmol/min, respectively. Also the HVPG remained unchanged (18 +/- 2 mmHg vs 16 +/- 2 mmHg) with individual changes ranging from -8 mmHg to +2 mmHg. In seven patients, HVPG decreased and in three it increased.. In spite of arterial blood pressure decreases 80 min after administration of the phosphodiesterase type-5 inhibitor sildenafil, the present study could not demonstrate any clinical relevant influence on splanichnic blood flow, oxygen consumption or the HVPG.

Topics: Administration, Oral; Adult; Female; Humans; Hypertension, Portal; Liver Cirrhosis; Male; Middle Aged; Oxygen Consumption; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Splanchnic Circulation; Sulfones; Time Factors; Treatment Outcome; Vasodilator Agents; Venous Pressure

In the present study, we tested the hypothesis that inhibition of renal phosphodiesterase type 5 (PDE5) in patients with liver cirrhosis and ascites increases sodium excretion. The effect of sildenafil citrate was studied in a randomized double-blind. placebo-controlled crossover study. Diuretics were withdrawn, and a fixed sodium diet (100 mmol/day) was given to the patients for 5 days before both study days. After a 60-min basal period, eight patients received either oral sildenafil (50 mg) or placebo. Glomerular filtration rate (GFR) and renal blood flow (RBF) were determined by 99mTc-diethylenetriamine-pentaacetate and (131)I-hippuran clearances. In human nephrectomy specimens, PDE5 mRNA was expressed at similar levels in the cortex (n = 6) and inner medulla (n = 4). Histochemical staining showed PDE5 immunoreactivity in collecting ducts and vascular smooth muscle. At baseline, cirrhotic patients exhibited elevated plasma concentrations of ANP, renin, ANG II, and aldosterone that did not differ on the 2 study days. Basal sodium excretion was similar at the 2 study days (median 17 and 18 mmol, respectively), and patients were in positive sodium balance. Sildenafil increased heart rate, plasma renin activity, plasma ANG II, and aldosterone concentrations significantly after 60 min. Plasma cGMP concentration was increased after 120 and 180 min, and urinary sodium excretion and mean arterial blood pressure were decreased significantly at 120 and 180 min. Plasma ANP concentration, GFR, and RBF did not change after sildenafil. In patients with ascites and cirrhosis, inhibition of PDE5 did not promote natriuresis but led to increased plasma levels of the renin-angiotensin-aldosterone system.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Adult; Animals; Ascites; Blood Pressure; Cross-Over Studies; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Female; Gene Expression Regulation, Enzymologic; Hormones; Humans; Hypertension, Renal; Kidney Medulla; Liver Cirrhosis; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Potassium; Purines; Rats; Sildenafil Citrate; Sodium; Sodium Chloride, Dietary; Sulfones; Water

Portopulmonary hypertension (PPHTN) is a rare complication of liver cirrhosis. Patients with severe PPHTN are contraindicated for liver transplant because of the associated risk of intraoperative acute right heart failure during reperfusion phase or massive volume infusion. Therefore, it has been recommended that patients with moderate to severe PPHTN undergo medical treatment to lower the pulmonary artery pressure before undergoing transplant. Herein, we report 3 patients with severe PPHTN who underwent sildenafil monotherapy before living donor liver transplant. None of the patients experienced associated adverse effects during sildenafil treatment, and the pulmonary artery pressure was effectively reduced before transplant. The first patient was diagnosed during anesthesia prior to transplant, and the mean pulmonary artery pressure was reduced by 34% after treatment. The second and third patients were followed-up with echography, and the estimated pulmonary artery systolic pressure were reduced by 34% and 47%, respectively. Pretransplant right heart catheterization also confirmed the reduction of the mean pulmonary artery pressure. Intraoperative hemodynamic parameters were stable, and the 3 patients were discharged uneventfully. After transplant, sildenafil was discontinued, and all patients remained in a stable clinical and functional status during follow-up.

Topics: Antihypertensive Agents; Female; Humans; Hypertension, Portal; Hypertension, Pulmonary; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Sildenafil Citrate; Vasodilator Agents

Topics: Administration, Oral; Adult; Antihypertensive Agents; Arterial Pressure; Drug Therapy, Combination; Female; Hepatitis, Autoimmune; Humans; Hypertension, Pulmonary; Liver Cirrhosis; Liver Transplantation; Pulmonary Artery; Pyrimidines; Severity of Illness Index; Sildenafil Citrate; Sulfonamides; Treatment Outcome

Topics: Drug Monitoring; Glomerular Filtration Rate; Humans; Injections, Intravenous; Kidney; Kidney Diseases; Liver Cirrhosis; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Severity of Illness Index; Sildenafil Citrate; Treatment Outcome

Sildenafil citrate is a phosphodiesterase-5 inhibitor, approved for the treatment of erectile dysfunction. It enhances nitric-oxide-induced vasodilatation and it promotes angiogenesis. A relationship between angiogenesis and hepatic fibrosis has long been speculated, where the 2 are believed to progress together. In this study, the ability of sildenafil (10 mg·(kg body mass)(-1), orally, once daily) to prevent and also reverse liver fibrosis/cirrhosis experimentally induced by thioacetamide injection (200 mg·kg(-1), intraperitoneal (i.p.), 3 times·week(-1)) in male Sprague-Dawley rats has been investigated. Sildenafil administration, either to prevent or to reverse liver fibrosis/cirrhosis significantly improved the estimated hepatic functions, reduced hepatic hydroxyproline and, in turn, hepatic collagen content, as well as reducing serum levels of the pro-fibrogenic mediator transforming growth factor β1. In co-ordination with such improvement, fibrosis grades declined and fibrosis retracted. Herein, the observed results provide evidence for the potential therapeutic efficacy of sildenafil as an antifibrotic agent.

Topics: Animals; Collagen; Disease Progression; Hydroxyproline; Liver; Liver Cirrhosis; Liver Cirrhosis, Experimental; Male; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones; Thioacetamide; Transforming Growth Factor beta1

Pharmacokinetics of sildenafil and its metabolite, N-desmethylsildenafil, in humans and rats with liver cirrhosis (LC) and diabetes mellitus (DM), alone and in combination (LCD) did not seem to be reported. Sildenafil was administered intravenously (10 mg/kg) and orally (20 mg/kg) to control, LC, DM, and LCD rats. Expression of intestinal CYP isozymes in those rats was also measured. In LC, DM, and LCD rats, the areas under the curve (AUCs) of intravenous sildenafil were significantly greater (by 195%, 54.2%, and 127%, respectively) than controls. In LC and LCD rats, AUCs of oral sildenafil were significantly greater (3010% and 2030%, respectively) than controls. In LC, DM, and LCD rats, significantly greater AUCs of intravenous sildenafil were due to the slower hepatic extraction of sildenafil (because of decrease in the protein expression of hepatic CYP2C11 and 3A subfamily in LC and LCD rats, and CYP2C11 in DM rats). In LC and LCD rats, greater magnitude of increase in AUCs of oral sildenafil than those after the intravenous administration could be mainly due to the decrease in the intestinal extraction of sildenafil (because of decrease in the protein expression of intestinal CYP2C11 in LC and LCD rats).

Topics: Administration, Oral; Animals; Blood Proteins; Cytochrome P-450 Enzyme System; Diabetes Mellitus, Experimental; Humans; Immunoblotting; Injections, Intravenous; Intestines; Liver Cirrhosis; Male; Microsomes, Liver; Piperazines; Protein Binding; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones; Vasodilator Agents

The reduction of portal pressure in patients with early compensated cirrhosis may be more responsive to drugs increasing intrahepatic vasodilatation than those reducing portal venous inflow. The phosphodiesterase-5 (PDE-V) inhibitor sildenafil can potentially reduce portal pressure by decreasing intrahepatic resistance, but its systemic vasodilatory effects may be deleterious. The aim of this study was to evaluate the effect of sildenafil on systemic and portal hemodynamics in an open-label pilot study.. Twelve patients with compensated cirrhosis and baseline hepatic venous pressure gradient (HVPG) >5 mm Hg received 25 mg of oral sildenafil. Mean arterial pressure (MAP), heart rate (HR), and HVPG were repeated after 30 and 60 minutes in 9/12 patients at 90 minutes (after an additional 25 mg of sildenafil). HVPG tracings were read by 3 blinded observers.. All 12 patients were Child A with median MAP of 92 mm Hg (interquartile range, 83-94) and HVPG 10.4 mm Hg (interquartile range, 6.6-13.0). While MAP decreased significantly at all time points, sildenafil had no effect on HVPG.. As shown with other vasodilators in compensated cirrhotic patients, sildenafil at therapeutic doses for erectile dysfunction reduces MAP without reducing portal pressure. The search should continue for specific intrahepatic vasodilators.

Topics: Blood Pressure; Heart Rate; Humans; Liver Cirrhosis; Male; Middle Aged; Pilot Projects; Piperazines; Prospective Studies; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Previous studies demonstrated increased phosphodiesterase-5 (PDE5) activity and expression in the kidneys of rats with liver cirrhosis. Acute intravenous administration of PDE5 inhibitors enhanced sodium excretion in these rats. The aim of the present study was to examine the effects of chronic administration of sildenafil on renal sodium handling and hemodynamics in rats with liver cirrhosis. Male Sprague-Dawley rats underwent bile-duct ligation and excision or sham operation and were housed in metabolic cages throughout the study. Body weight, food intake, water intake and urine volume were measured daily, and plasma samples were obtained twice weekly. Fourteen days following surgery sildenafil or its vehicle (dimethylsulfoxide) were administered (20 mg/kg subcutaneously 3 times/day). Two weeks later, systemic hemodynamics were measured under general anesthesia. Sildenafil enhanced the systemic vasodilatation associated with liver cirrhosis and reduced the arterial pressure. There was no reduction in the glomerular filtration rate, however. Despite these hemodynamic changes, sildenafil prevented the decrease in sodium excretion observed in the bile-duct-ligated group receiving vehicle and markedly increased fractional sodium excretion relative to the other groups. These results suggest that chronic sildenafil administration may help prevent or ameliorate sodium retention in cirrhosis, but that hemodynamic adverse effects may ensue.

Topics: Analysis of Variance; Animals; Blood Pressure; Cyclic GMP; Hemodynamics; Kidney; Liver Cirrhosis; Male; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sodium; Sulfones; Vasodilation

Cirrhotic livers have a deficient vasodilator response to nitric oxide (NO). The vasodilator effect of NO is normally limited by the degradation of its second messenger cyclic guanosine 3', 5' monophosphate by phosphodiesterases. We investigated (1) the phosphodiesterase-5 (PDE-5) expression in normal and cirrhotic rat livers, (2) the location of the deficient response to NO in cirrhotic livers, and (3) the effect of the PDE-5 inhibitor Sildenafil citrate on this deficient response.. Normal and ascitic cirrhotic rats were subjected to liver perfusion with continuous measurement of both perfusion and sinusoidal (wedge hepatic) pressures. After incubation with N-monomethyl-l-arginine and pre-constriction with Methoxamine, concentration-response curves to the spontaneous NO donor S-nitroso-N-acetylpenicillamine were obtained in the absence or presence of Sildenafil (10(-8)M).. PDE-5 expression (Western blot) in cirrhotic livers was higher than in normal livers (P=0.042). Compared to normal livers, cirrhotic livers showed a decreased response to S-nitroso-N-acetylpenicillamine in the pre-sinusoidal area (P=0.003) but not in the sinusoidal/post-sinusoidal area (P=0.433). In the presence of Sildenafil, normal and cirrhotic livers showed similar pre-sinusoidal (P=0.419) and sinusoidal/post-sinusoidal (P=0.875) responses to S-nitroso-N-acetylpenicillamine.. Increased PDE-5 expression is involved in the decreased vascular response to NO in cirrhotic livers.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Cyclic Nucleotide Phosphodiesterases, Type 5; Enzyme Inhibitors; Liver Circulation; Liver Cirrhosis; Male; Nitric Oxide; Nitric Oxide Synthase; omega-N-Methylarginine; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones; Vasodilation

Topics: Humans; Hypertension, Portal; Hypertension, Pulmonary; Liver Cirrhosis; Male; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Portopulmonary hypertension is a recognized but uncommon complication of cirrhosis. Liver transplantation may be contraindicated in patients with severe portopulmonary hypertension. In order to decrease the pulmonary arterial pressure, intravenous administration of epoprostenol has been shown to provide substantial beneficial results in these patients. Additionally, a recent case report demonstrated that long-term oral administration of sildenafil decreased pulmonary arterial pressure, but its effects on splanchnic hemodynamics were not measured. We report on a patient with cirrhosis and portopulmonary hypertension and the changes in the hemodynamic status after an oral administration of sildenafil. This case report clearly delineates that sildenafil decreases pulmonary arterial pressure but may exacerbate portal hypertension and hyperdynamic circulation in patients with cirrhosis and portopulmonary hypertension.

Topics: Adult; Humans; Hypertension, Portal; Hypertension, Pulmonary; Liver Cirrhosis; Male; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Portopulmonary hypertension is a poorly understood and uncommon complication of advanced chronic liver disease. Current therapy is based largely on treatment options proven in idiopathic pulmonary hypertension. The severity of the portopulmonary hypertension should best be attenuated medically before attempting combined liver and lung transplantation to avoid increased peri-operative mortality. This case report describes the successful use of sildenafil to decrease the pulmonary vascular resistance in a patient with hepatitis-C cirrhosis who was preparing for liver transplantation.

Topics: Female; Follow-Up Studies; Humans; Hypertension, Portal; Hypertension, Pulmonary; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vascular Resistance; Vasodilation; Vasodilator Agents

Liver transplantation (LT) may be indicated in cirrhotic patients with underlying pulmonary artery hypertension. However, severe pulmonary artery hypertension with mean pulmonary artery pressure (mPAP) above 50 mmHg has even been considered a contraindication to LT. We present a cirrhotic patient with an mPAP of 56 mmHg measured using right heart catheterization (RHC) and with severely compromised physical capacity. She was first treated with sildenafil (Viagra), a potent novel vasodilator, and successfully transplanted later. The mPAP decreased with sildenafil to the level of 28-31 mmHg and her general condition improved markedly. An LT using piggyback technique was performed 16 weeks later. Despite 2 reoperations for bleeding, the outcome has been excellent. In conclusion, treatment of severe portopulmonary hypertension (PHT) with sildenafil is effective. If a decrease in mPAP is achieved with sildenafil, it may improve the result of LT, even though no evidence of reversibility of PPHTN exists.

Topics: Adult; Blood Pressure; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Liver Cirrhosis; Piperazines; Purines; Sildenafil Citrate; Sulfones; Time Factors; Vasodilator Agents