A Nitric Oxide-Donating Statin Decreases Portal Pressure with a Better Toxicity Profile than Conventional Statins in Cirrhotic Rats

Abstract

Statins present many beneficial effects in chronic liver disease, but concerns about safety exist. We evaluated the hepatic effects of a nitric oxide-releasing atorvastatin (NCX 6560) compared to conventional statins. Simvastatin, atorvastatin and NCX 6560 were evaluated in four-week bile duct-ligated rats (BDL) simulating decompensated cirrhosis and in thirteen-week carbon tetrachloride (CCl4) intoxicated rats, a model of early cirrhosis. In the BDL model, simvastatin treated rats showed high mortality and the remaining animals presented muscular and hepatic toxicity. At equivalent doses, NCX 6560 eliminated hepatic toxicity and reduced muscular toxicity (60–74%) caused by atorvastatin in the more advanced BDL model; toxicity was minimal in the CCl4 model. Atorvastatin and NCX 6560 similarly reduced portal pressure without changing systemic hemodynamics in both models. Atorvastatin and NCX 6560 caused a mild decrease in liver fibrosis and inflammation and a significant increase in intrahepatic cyclic guanosine monophosphate. NCX 6560 induced a higher intrahepatic vasoprotective profile (activated endothelial nitric oxide synthase and decreased platelet/endothelial cell adhesion molecule-1), especially in the CCl4 model, suggesting a higher benefit in early cirrhosis. In conclusion, NCX 6560 improves the liver profile and portal hypertension of cirrhotic rats similarly to conventional statins, but with a much better safety profile.

Use of Statins in Patients with Chronic Liver Disease and Cirrhosis: Current Views and Prospects

“…In a similar animal model of partial portal vein ligation (PPVL), administration of pravastatin, however, did not modify systemic and portal he-modynamics and collateral vascular response to endothelin-1 [30]. The role of NO was recently highlighted when a nitric oxide-donating statin (NCX 6560) showed similar effects on lowering portal pressure, but with higher vasoprotective properties and lower toxicity in liver and muscle [31]. …”

Reversal of liver fibrosis: From fiction to reality

“…These investigations were spured by rodent studies, where statins displayed antifibrotic, anti-inflammatory and vasoprotective effects and ameliorated microvascular dysfunction and portal hypertension (135)(136)(137)(138)(139)(140)(141). Similarly, in a M A N U S C R I P T…”

Prioritization of Therapeutic Targets and Trial Design in Cirrhotic Portal Hypertension

“…Additional references (#109 and #110) are provided as Supporting Information. (10,24,46) Antifibrotic (47) Rhabdomyolysis (24) Yes (16,48,49) Increased in ICG clearance (16) Rhabdomyolysis, liver toxicity (17) Yes (decrease mortality) (17) PDE5 inhibitors purported site of action and other potential benefits as well as potential deleterious effects. Of them, only statins have gone on to proof-of-concept (POC) clinical trials leading to a randomized controlled trial (RCT) with clinical outcomes.…”

“…However, a formal PK study in hepatically impaired individuals may not be necessary if a compound is entirely renally excreted with no involvement of the liver, or if a drug is gaseous or volatile and its active metabolite(s) are primarily eliminated by the lungs. (24) PK studies can have a basic full study design, a reduced study design, or a population PK approach. The basic full study design involves the entire Child-Pugh spectrum (at least 6 patients in each Child-Pugh category) and controls, whereas a reduced study design allows for the study to be limited to 8 patients with Child-Pugh B cirrhosis and 8 controls matched by age, sex, and comorbidities.…”