Drug & Device Development

Nitroflurbiprofen promising for cirrhotic portal hypertension

Last Updated: 2007-03-23 16:52:49 -0400 (Reuters Health)

By Megan Rauscher

NEW YORK (Reuters Health) - Nitroflurbiprofen, a nitric oxide-releasing derivative of flurbiprofen, improves cirrhosis-associated portal hypertension in rats without major adverse effects commonly seen with flurbiprofen, researchers from Belgium report.

"Portal hypertension is responsible for the more severe and often lethal complications of cirrhosis such as bleeding esophageal varices...and remains therefore the most important cause of morbidity and mortality in patients with cirrhosis," co-author Dr. Wim Laleman from University Hospital Gasthuisberg, Leuven, noted in an email to Reuters Health.

The introduction of non-selective beta-blockers for the prevention of bleeding and rebleeding of gastro-esophageal varices was a "milestone in therapy," the researcher added. "However, in practice, less than half the patients under beta-blockade are protected from these risks."

Recent advances in the knowledge of the pathophysiology of cirrhotic portal hypertension have directed future therapy towards the increased intrahepatic vascular resistance, which, in part, is determined by an increased hepatic vascular tone. Nitroflurbiprofen targets this aspect of portal hypertension.

In cirrhotic portal hypertensive rats, Dr. Laleman and colleagues observed that nitroflurbiprofen and flurbiprofen were equally effective in decreasing portal pressure and reducing intrahepatic vascular resistance, without causing systemic hypotension. Both drugs also improved endothelial dysfunction and hyperresponsiveness.

In vitro, nitroflurbiprofen more than flurbiprofen, decreased activated hepatic stellate cells, which fuel increased hepatic vascular tone, the researchers report in the March issue of Gastroenterology.

Additionally, flurbiprofen-treated rats showed severe gastrointestinal ulcerations and nephrotoxicity, which was not observed in nitroflurbiprofen-treated rats.

Summing up, Dr. Laleman said this study shows that nitroflurbiprofen "experimentally improves portal hypertension by decreasing the intrahepatic vascular resistance and without causing any of the major side effects typically seen with classical NO-donors (vasodilation) or cyclooxygenase-inhibitors (renal dysfunction, liver toxicity)."

Nitroflurbiprofen could lead to improved pharmacological management of cirrhotic portal hypertension and "warrants further study in patients," Dr. Laleman concluded.

Gastroenterology 2007;132:709-719.