NCX-1000, a nitric oxide-releasing derivative of UDCA, does not decrease portal pressure in patients with cirrhosis: results of a randomized, double-blind, dose-escalating study.
OBJECTIVE
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.


METHODS
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.


RESULTS
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).


CONCLUSIONS
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.
Berzigotti
Annalisa
A
Hepatic Hemodynamics Laboratory, Hospital Clínic-IDIBAPS, University of Barcelona, Barcelona, Spain.
Bellot
Pau
P
De Gottardi
Andrea
A
Garcia-Pagan
Juan Carlos
JC
Gagnon
Caroline
C
Spénard
Jean
J
Bosch
Jaime
J
D000284:Administration, Oral; D000368:Aged; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006975:Hypertension, Portal / Q000175:diagnosis / Q000188:drug therapy* / Q000209:etiology; D008102:Liver Circulation / Q000187:drug effects; D008103:Liver Cirrhosis / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy*; D008297:Male; D008365:Manometry; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009566:Nitrates / Q000008:administration & dosage* / Q000009:adverse effects; D020030:Nitric Oxide Donors / Q000008:administration & dosage* / Q000009:adverse effects; D017082:Portal Pressure / Q000187:drug effects*; D012016:Reference Values; D018570:Risk Assessment; D012720:Severity of Illness Index; D017211:Treatment Failure; D014580:Ursodeoxycholic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*
C433771:2-methyl-3-(2-((4-nitrooxybutyloxy)carbonyl)vinyl)phenyl ursodeoxycholic acid ester; D009566:Nitrates; D020030:Nitric Oxide Donors; D014580:Ursodeoxycholic Acid