COX-1 and COX-2 contribute differentially to the LPS-induced release of PGE2 and TxA2 in liver macrophages.

LPS induces an immediate release of thromboxane TxA2 and a delayed release of PGE2. Dexamethasone suppresses the LPS-induced release of TxA2 and PGE2. In the first 8 h after LPS addition, the specific COX-2 inhibitor SC236 inhibits the PGE2 and TxA2 release by about 80% and 20%, whereas the release of PGE2 and TxA2 between 8 and 24 h is inhibited by about 40% and 35%, respectively. Resident liver macrophages express substantial amounts of COX-1, TxAS, cPGES and mPGES-2, small amounts of COX-2 but almost no detectable amounts of mPGES-1. LPS induces an increase of COX-2 and mPGES-1, but does not change COX-1, cPGES, mPGES-2 and TxAS at protein level. Dexamethasone suppresses almost completely the LPS-induced effects on COX-2 and mPGES-1. It is concluded that (1) COX-1 and COX-2 are involved in the LPS-induced synthesis of TxA2 and PGE2; (2) TxA2 release is catalyzed at early time-points by the combined action of COX-1 and TxAs, whereas at later time points the newly expressed COX-2 couples to TxAS and contributes to the TxA2 release; (3) PGE2 release within the first 8 h is predominantly catalyzed by COX-2, whereas at later time-points COX-1 couples to the newly expressed mPGES-1 and contributes to the PGE2 release.

Effects of ursodeoxycholic acid (ursodiol) treatment on chronic viral hepatitis in heart transplant patients: results of a prospective, double-blind, placebo-randomized study.

BACKGROUND: Chronic viral hepatitis averages 15% to 20% in heart transplant patients. Several studies have shown that ursodiol may improve liver biochemistry in patients with chronic hepatitis. We used a double-blind randomized controlled trial to evaluate the effect of ursodiol in heart transplant patients with chronic viral hepatitis. METHODS: Thirty heart patients with chronic viral hepatitis B, C, or non-A-G received ursodiol, 800 mg per day (group 1), and 30 received placebo (group 2) for 12 months. Endpoints were improvement in liver biochemical tests and in total Knodell score. Intent-to-treat and per-protocol analyses were performed. RESULTS: At entry, both groups were comparable for all of the studied parameters. During the study period, serum alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transpeptidase variations were not different between group 1 and group 2 patients. Knodell score improved in 20% of group 1 patients and in 43% of group 2 patients (NS). Adverse events or mortality were not different in the two groups during the study period. Similar results were observed by intent-to-treat and per-protocol analyses. CONCLUSIONS: A 12-month course of ursodiol therapy had no effect on liver enzymes or liver histology in heart transplant patients with chronic hepatitis.

Effect of terlipressin (Glypressin) on hepatorenal syndrome in cirrhotic patients: results of a multicentre pilot study.

OBJECTIVES: Hepatorenal syndrome (HRS) is a severe complication of cirrhosis, leading to death in more than 90% of cases in the absence of liver transplantation. Several treatments have been attempted as a bridge to liver transplantation. Among such treatments, terlipressin has been studied in several reports, two prospective pilot studies and a double-blind, short-term, controlled haemodynamic study. Promising results have been shown with this drug. The purpose of this multicentre retrospective study was to evaluate the effects of terlipressin on renal function and survival of patients with HRS. PATIENTS AND METHODS: Eighteen patients recruited in three liver units with type 1 HRS in 16 cases and type 2 HRS in two cases were given 4 mg/day terlipressin (range 1.5-12) for 7 days (range 2-16). Electrolytes, renal function, mean urinary output, natriuresis, liver function tests, and tolerance of the treatment were monitored regularly. RESULTS: A total of 13/18 (72%) patients responded with a mean decline in serum creatinine ranging from 31 to 75% from day 0 to day 5. Eight of these 13 patients had a normal serum creatinine level at day 5. Liver function tests remained unaffected by terlipressin administration. Three local necrosis complications were noted in patients receiving terlipressin continuously via an infusion pump. Two responder patients survived: one of these underwent orthotopic liver transplantation with a follow-up of 24 months; the other is alive with a follow-up of more than 36 months. Patients who responded to terlipressin had lower baseline serum bilirubin and significantly higher serum sodium concentrations than patients who did not respond. CONCLUSION: In this pilot study, improvement in renal function was noted in 72% of cases after administration of terlipressin, and was associated with long-term survival in two patients. Parameters associated with response to terlipressin and increased survival should be defined better in a large cohort of cirrhotic patients with HRS.

Terlipressin in patients with cirrhosis and type 1 hepatorenal syndrome: a retrospective multicenter study.

BACKGROUND & AIMS: Type 1 hepatorenal syndrome (HRS) is a severe complication of cirrhosis associated with a short median survival time (<2 weeks). Although the administration of terlipressin improves renal function, its effect on survival is unknown. This study investigated predictive factors of survival in patients with type 1 HRS treated with terlipressin. METHODS: Ninety-nine patients with type 1 HRS treated with terlipressin in 24 centers were retrospectively studied. Terlipressin-induced improved renal function was defined as a decrease in serum creatinine value to <130 micromol/L or a decrease of at least 20% at the end of treatment. RESULTS: At inclusion, the Child-Pugh score was 11.8 +/- 1.6 (mean +/- SD). Terlipressin (3.2 +/- 1.3 mg/day) was administered for 11 +/- 12 days. Renal function improved in 58% of patients (serum creatinine decreased by 46% +/- 17% from 272 +/- 114 micromol/L). Median survival time was 21 days. Survival rate was 40% at 1 month. Multivariate analysis showed that improved renal function and Child-Pugh score < or =11 at inclusion were independent predictive factors of survival (P < 0.0001 and 0.02, respectively). Thirteen patients underwent liver transplantation (92 +/- 95 days after HRS onset), 10 of whom had received terlipressin and had had improved renal function. CONCLUSIONS: This retrospective uncontrolled study shows that in patients with type 1 HRS, terlipressin-induced improved renal function is associated with an increase in survival. Thus, a randomized trial investigating the effect of terlipressin on survival in patients with type 1 HRS should be performed.