ncx1000 and Liver-Cirrhosis

NCX-1000 (2(acetyloxy) benzoic acid-3(nitrooxymethyl)phenyl ester) is an nitric oxide (NO)-releasing derivative of ursodeoxycholic acid (UDCA), which showed selective vasodilatory effect on intrahepatic circulation in animal models of cirrhosis. This study was aimed at testing the efficacy and tolerability of this compound in patients with cirrhosis and portal hypertension.. This was a single-center, phase-2a, randomized (4:1), double-blind, parallel-group, dose-escalating study. Patients received progressive oral doses of NCX-1000 or placebo up to 2 g t.i.d. or maximum tolerated doses for 16 days. Efficacy on fasting and postprandial hepatic venous pressure gradient (HVPG) at baseline and after treatment was assessed. Hepatic blood flow (HBF) and arterial blood pressure were also measured.. Eleven patients (nine NCX-1000 and two placebo) were enrolled and completed the trial. After NCX-1000 treatment, HVPG did not change (16.7+/-3.8 vs. 17.1+/-3.8 mm Hg; P=0.596), and HBF decreased significantly (904+/-310 vs. 1,129+/-506 ml/min; P=0.043). The postprandial increase in portal pressure and HBF was not modified by NCX-1000. There was no significant effect on diastolic blood pressure, but systolic blood pressure was reduced by the treatment in a dose-dependent manner (121+/-11 mm Hg after NCX-1000 vs. 136+/-7 mm Hg at baseline; P=0.003). Seven non-serious adverse events were experienced by four patients (one on placebo).. In patients with cirrhosis and portal hypertension, NCX-1000 administration was safe, but it was not able to reduce portal pressure. A significant reduction of systolic blood pressure and HBF was observed in the treatment arm, suggesting that the drug had systemic effects and lacked selective release of NO at the intrahepatic circulation.

Topics: Administration, Oral; Aged; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Hypertension, Portal; Liver Circulation; Liver Cirrhosis; Male; Manometry; Maximum Tolerated Dose; Middle Aged; Nitrates; Nitric Oxide Donors; Portal Pressure; Reference Values; Risk Assessment; Severity of Illness Index; Treatment Failure; Ursodeoxycholic Acid

Portal hypertension, a common consequence of chronic liver diseases, is directly responsible for most complications of cirrhosis. In liver microcirculation, nitric oxide is considered a major fine tuner of vascular tone by counterbalancing vasoconstrictors (sympathetic nervous activity, the renin-angiotensin system, and endothelin-1) in normal and cirrhotic livers. The deficiency of endothelial nitric oxide release is a key factor in the hemodynamic abnormalities associated with the dynamic component of portal hypertension. Conventional nitric oxide donors release nitric oxide into the blood stream, causing systemic hypotension and progression of vasodilatory syndrome in cirrhotic patients. NCX1000 is a nitric oxide-releasing derivative of ursodeoxycholic acid-derived compounds, being capable of selectively releasing nitric oxide into the liver circulation. Administration of NCX1000 to portal hypertensive rats decreases intrahepatic resistance providing a novel therapy for the treatment of portal hypertension.

Topics: Adipocytes; Animals; Humans; Hypertension, Portal; Liver; Liver Cirrhosis; Nitrates; Nitric Oxide; Ursodeoxycholic Acid

We studied whether acute administration of NCX-1000, a nitric oxide (NO)-releasing derivative of ursodeoxycholic acid (UDCA), to animals with established liver cirrhosis decreases intrahepatic resistance and modulates hepatic vascular hypereactivity to norepinephrine (NE).. Four-week bile duct ligated (BDL) cirrhotic and control, sham-operated, rats were treated orally with 28 mg/kg per day NCX-1000 or 15 mg/kg per day UDCA for 5 days. Isolated normal and cirrhotic livers were perfused with NE, from 10 nM to 30 microM, in a recirculating system.. NCX-1000 administration to BDL cirrhotic rats decreased portal pressure (P<0.01) without affecting mean arterial pressure and heart rate. In the isolated perfused liver system, administration of NE resulted in a dose-dependent increase of intrahepatic resistance. Vasoconstriction caused by 30 microM NE was reduced by 60% in animals treated with NCX-1000 (P<0.001), while UDCA was uneffective. The same portal pressure lowering effect was documented in cirrhotic and sham operated rats. Administration of NCX-1000 to BDL and sham operated rats resulted in a similar increase of nitrite/nitrate and cGMP concentrations in the liver.. By selectively delivering NO to the liver, NCX-1000 increases cGMP concentrations and effectively counteracts the effect of endogenous vasoconstrictors on the hepatic vascular tone.

Topics: Animals; Bile; Blood Pressure; Drug Interactions; Hypertension, Portal; In Vitro Techniques; Liver Circulation; Liver Cirrhosis; Male; Nitrates; Nitric Oxide Donors; Norepinephrine; Perfusion; Rats; Rats, Wistar; Ursodeoxycholic Acid; Vascular Resistance; Vasoconstriction; Vasoconstrictor Agents

A decreased intra-hepatic nitric oxide (NO) production participates on the pathogenesis of portal hypertension in cirrhosis. We tested the hemodynamic effects of a liver-specific NO donor (NCX-1000) derived from ursodeoxycholic acid in portal hypertensive cirrhotic rats.. After a 14-day treatment with ursodeoxycholic acid or NCX-1000 by gavage, ascitic cirrhotic rats (CCl4-induced) were used in two studies: (1) in vivo mean arterial pressure (MAP), portal pressure (PP) and superior mesenteric artery (SMA) blood flow measurements before and during progressive blood volume expansion (blood infusion); and (2) in situ liver perfusion to obtain dose/response curves to methoxamine (alpha1-adrenergic agonist) and flow/pressure curves.. Basal heart rate, MAP, and PP were similar in both groups. During blood infusion, similar MAP and SMA flow increases were observed in both groups; however, PP increase observed in control rats was blunted in NCX-1000 treated rats (P=0.015). In liver perfusions, flow/pressure curves were similar in both groups; however, NCX-1000-treated livers showed a lower response to methoxamine (P=0.016). cGMP concentration in NCX-1000-treated livers was higher (P=0.015) than in controls.. Treatment with a liver-specific NO donor improves the portal system adaptability to portal blood flow increase and ameliorates the intra-hepatic response to methoxamine in cirrhotic rats.

Topics: Animals; Drug Interactions; Hypertension, Portal; Liver Circulation; Liver Cirrhosis; Male; Mesenteric Artery, Superior; Methoxamine; Nitrates; Nitric Oxide Donors; Portal Vein; Rats; Rats, Sprague-Dawley; Ursodeoxycholic Acid; Vascular Resistance; Vasoconstrictor Agents

Portal hypertension resulting from increased intrahepatic resistance is a common complication of chronic liver diseases and a leading cause of death in patients with liver cirrhosis, a scarring process of the liver that includes components of both increased fibrogenesis and wound contraction. A reduced production of nitric oxide (NO) resulting from an impaired enzymatic function of endothelial NO synthase and an increased contraction of hepatic stellate cells (HSCs) have been demonstrated to contribute to high intrahepatic resistance in the cirrhotic liver. 2-(Acetyloxy) benzoic acid 3-(nitrooxymethyl) phenyl ester (NCX-1000) is a chemical entity obtained by adding an NO-releasing moiety to ursodeoxycholic acid (UDCA), a compound that is selectively metabolized by hepatocytes. In this study we have examined the effect of NCX-1000 and UDCA on liver fibrosis and portal hypertension induced by i.p. injection of carbon tetrachloride in rats. Our results demonstrated that although both treatments reduced liver collagen deposition, NCX-1000, but not UDCA, prevented ascite formation and reduced intrahepatic resistance in carbon tetrachloride-treated rats as measured by assessing portal perfusion pressure. In contrast to UDCA, NCX-1000 inhibited HSC contraction and exerted a relaxing effect similar to the NO donor S-nitroso-N-acetylpenicillamine. HSCs were able to metabolize NCX-1000 and release nitrite/nitrate in cell supernatants. In aggregate these data indicate that NCX-1000, releasing NO into the liver microcirculation, may provide a novel therapy for the treatment of patients with portal hypertension.

Topics: Animals; Carbon Tetrachloride; Collagen; Hypertension, Portal; Liver; Liver Cirrhosis; Male; Nitrates; Nitric Oxide; Nitric Oxide Donors; Rats; Rats, Wistar; Salicylates; Ursodeoxycholic Acid