Randomized, double-blind phase II trial of Lexipafant, a platelet-activating factor antagonist, in human acute pancreatitis.

The aims of the study were to determine whether the platelet-activating factor antagonist Lexipafant could alter the clinical course and suppress the inflammatory response of human acute pancreatitis. In a double-blind, placebo-controlled study 83 patients were randomized to receive Lexipafant 60 mg intravenously for 3 days, or placebo. Clinical progression was assessed by daily Acute Physiology And Chronic Health Evaluation (APACHE) II score and organ failure score (OFS). The magnitude of the inflammatory response on days 1-5 was assessed by serial measurement of interleukin (IL) 8, IL-6, E-selectin, polymorphonuclear elastase-alpha1-antitrypsin (PMNE-alpha 1-AT), and C-reactive protein (CRP). At entry, patients receiving Lexipafant (n = 42) or placebo (n = 41) were matched for age and sex, aetiology, APACHE II score and OFS. The disease was classified as severe in 29 patients (APACHE II score eight or more). There was a significant reduction in the incidence of organ failure (P = 0.041) and in total OFS (P = 0.048) at the end of medication (72 h). During this time seven of 12 patients with severe acute pancreatitis who had Lexipafant recovered from an organ failure; only two of 11 with severe acute pancreatitis who had placebo recovered from an organ failure and two others developed new organ failure. Lexipafant treatment significantly reduced serum IL-8 (P = 0.038), and IL-6 declined on day 1. Plasma PMNE-alpha 1-AT complexes peaked on day 1; the gradual fall to baseline over 5 days observed in controls did not occur in patients given Lexipafant. No effect was observed on serum CRP. This study provides a rationale for further clinical trials with the potent PAF antagonist Lexipafant in human acute pancreatitis.

Inflammatory mediators in acute pancreatitis.

The cellular events leading to acute pancreatitis are not well defined and the mechanism by which known aetiological factors initiate the disease process remains to be established. Inflammatory mediators have recently been implicated as potential early markers of disease severity and may help elucidate the pathophysiology of the disease. Oxidative stress is emerging as a common effector of the acinar cell injury in experimental acute pancreatitis and clinical findings indicate that neutrophil activation is a significant early event. In common with neutrophil-mediated tissue damage in states of tissue hypoperfusion, acute pancreatitis shows many features of an ischaemia-reperfusion injury. Increased levels of phospholipase A2 have been demonstrated; this enzyme induces synthesis of prostaglandins and platelet-activating factor, a potent inflammatory mediator. New therapeutic approaches to the complications of acute pancreatitis may be through manipulation of such mediators of inflammation.

Amelioration of experimental acute pancreatitis with a potent platelet-activating factor antagonist.

The effect of a potent platelet-activating factor (PAF) antagonist, BB-882, on an experimental model of acute pancreatitis induced in male Wistar rats by a technique of microvascular ischaemia was studied. A single intraperitoneal injection of BB-882 (5 mg/kg) 30 min after induction of the disease in 12 animals significantly reduced (P < 0.001) the rise in the level of serum amylase (mean 2477 (range 2100-3280) units/l) compared with that in 12 control animals (mean 3928 (range 2800-5900) units/l) and significantly improved (P < 0.001) the mean pancreatic histology score (5.0 (range 3-10) versus 12.3 (range 8-18) in controls). PAF is a biologically active ether phosphorylcholine synthesized in cell membranes and a potent inflammatory mediator. Pancreatic tissue levels of this compound are increased in experimental acute pancreatitis and pretreatment with PAF receptor antagonists can ameliorate the progression of this disease. BB-882 alters the early course of experimental pancreatitis and may have a clinical therapeutic role.

Plasma gastrin and cholecystokinin responses after pylorus-preserving pancreatoduodenectomy and defunctioned Roux loop pancreaticojejunostomy.

Several methods can be used to re-establish gastrointestinal continuity after the standard Whipple's Billroth II procedure or Longmire pylorus-preserving pancreatoduodenectomy (PPPD). Standard pancreatoduodenectomy abolishes the postprandial gastrin response whereas the response after Longmire PPPD is similar to that in controls. A novel reconstruction after PPPD has been designed to separate the biliary and pancreatic secretions by restoring continuity in the Billroth I manner, retaining the gastric antrum and with the pancreatic remnant anastomosed to a separate defunctioned Roux loop. Gastrin and cholecystokinin (CCK) responses were measured in the fasting state and after a standard liquid meal of 250 ml containing 15 per cent protein, 30 per cent fat and 55 per cent carbohydrate with an energy value of 525 kJ. Basal gastrin and CCK concentrations were similar in five healthy unoperated controls, and after standard pancreatoduodenectomy (five patients) and isolated Roux loop PPPD (six patients). In controls and after the new PPPD operation, but not after standard pancreatoduodenectomy, mean(s.e.m.) postprandial plasma gastrin values rose from 8.66(0.33) to 13.00(0.33) pmol l-1 at 10 min (controls) and from 7.66(1.56) to 15.00(1.36) pmol l-1 at 10 min (defunctioned Roux loop PPPD); the concentration remained raised for 20 min then fell transiently; a second peak was maintained for 40 min (controls) to 60 min (modified PPPD). In controls, mean(s.e.m.) postprandial plasma CCK concentrations rose from 0.43(0.12) basal to 10.50(1.03) pmol l-1 and returned to basal after 60 min. After standard pancreatoduodenectomy postprandial CCK concentrations rose at a similar rate and remained raised for 80 min. After isolated Roux loop PPPD plasma CCK concentrations remained low (mean(s.e.m.) 0.38(0.29) pmol l-1) after the test meal.