PAF-acetylhydrolase

Pancreatitis is the most common major complication of diagnostic and therapeutic ERCP. Platelet-activating factor (PAF) has been implicated in the pathophysiologic events associated with acute pancreatitis. Animal and human studies suggested that recombinant PAF acetylhydrolase (rPAF-AH) might ameliorate the severity of acute pancreatitis.

Our purpose was to determine whether prophylactic rPAF-AH administration reduces the frequency or severity of post-ERCP pancreatitis in high-risk patients.

Randomized, multicenter, double-blind, placebo-controlled study.

Patients received rPAF-AH at a dose of either 1 or 5 mg/kg or placebo. Patients were administered a single intravenous infusion over 10 minutes of study drug or placebo <1 hour before ERCP.

Standardized criteria were used to diagnose and grade the severity of post-ERCP pancreatitis. Adverse events were prospectively recorded.

A total of 600 patients were enrolled. There were no statistically significant differences among the treatment groups with respect to patient demographics, ERCP indications, and patient and procedure risk factors for post-ERCP pancreatitis with the following exceptions: the rPAF-AH 5 mg/kg group had significantly fewer patients younger than 40 years old and scheduled to undergo a therapeutic ERCP involving the pancreatic sphincter or duct. Post-ERCP pancreatitis occurred in 17.5%, 15.9%, and 19.6% of patients receiving rPAF-AH (1 mg/kg), rPAF-AH (5 mg/kg), and placebo, respectively (P = .59 for rPAF-AH 1 mg/kg vs placebo and P = .337 for rPAF-AH 5 mg/kg vs placebo). There was no statistically significant difference between the groups with regard to the severity of pancreatitis, frequency of amylase/lipase elevation more than 3 times normal, or abdominal pain.

There was no apparent benefit of rPAF-AH treatment compared with placebo in reducing the incidence of post-ERCP pancreatitis in subjects at increased risk.

Platelet-activating factor (PAF) is a proinflammatory agent in infectious and inflammatory diseases, partly due to the activation of infiltrating phagocytes. PAF exerts its actions after binding to a monospecific PAF receptor (PAFR). The potent bioactivity is reflected by its ability to activate neutrophils at picomolar concentrations, as defined by changes in levels of intracellular Ca2+ ([Ca2+]i), and induction of chemotaxis and actin polymerization at nanomolar concentration. The role of PAF in neutrophil survival is, however, less well appreciated.In this study, the inhibitory effects of synthetic PAFR-antagonists on various neutrophil functions were compared with the effect of recombinant human plasma-derived PAF-acetylhydrolase (rPAF-AH), as an important enzyme for PAF degradation in blood and extracellular fluids. We found that endogenously produced PAF (–like) substances were involved in the spontaneous apoptosis of neutrophils. At concentrations of 8 µg/ml or higher than normal plasma levels, rPAF-AH prevented spontaneous neutrophil apoptosis (21 ± 4% of surviving cells (mean ± SD; control) versus 62 ± 12% of surviving cells (mean ± SD; rPAF-AH 20 µg/ml); P &lt; 0·01), during overnight cultures of 15 h. This effect depended on intact enzymatic activity of rPAF-AH and was not due to the resulting product lyso-PAF. The anti-inflammatory activity of rPAF-AH toward neutrophils was substantiated by its inhibition of PAF-induced chemotaxis and changes in [Ca2+]i.In conclusion, the efficient and stable enzymatic activity of rPAF-AH over so many hours of coculture with neutrophils demonstrates the potential for its use in the many inflammatory processes in which PAF (–like) substances are believed to be involved.