Randomized, placebo-controlled trial of lazaroid effects on severe acute pancreatitis in rats

Objectives: To evaluate the therapeutic potential of lazaroids in severe ne crotizing acute pancreatitis and to investigate the association between oxi dative stress, protease activation, and local production of proinflammatory cytokines and the severity and lethality of the disease, Background: Oxidative stress is a crucial factor in the pathophysiology of acute pancreatitis and its systemic complications, Treatment with antioxida nts, however, failed to improve survival in most studies performed so far, Lazaroids are a novel class of antioxidants that potently protect pancreati c acinar cells against oxidant attack in vitro, Design: Prospective, randomized, controlled experimental study. Setting: University research laboratory. Subjects: Seventy-five anesthetized male Wistar rats (300-350 g). Interventions: Severe acute pancreatitis was induced by retrograde injectio n of 3.5% taurocholate-sodium into the common bile-pancreatic duct. interve ntions were performed to mimic the clinical situation, including continuous intravenous fluid substitution and administration of lazaroids in a therap eutic protocol. Therapy was started 1 hr after injection of the bile salt b y using three different lazaroids, lactated Ringer's solution (placebo), an d methylprednisolone as a corticosteroid control (n = 15 in each group). Al l the substances were given by continuous intravenous infusion throughout t he 20-hr trial period. Measurements and Main Results:Pancreatic homogenates and ascites were analy zed for indicators of oxidative stress, antioxidants, proteases, and proinf lammatory cytokines, Pancreatic edema, morphologic pancreatitis severity, a nd pancreatic histopathology also were assessed. All three lazaroids and me thylprednisolone diminished pancreatic tumor necrosis factor-or concentrati ons, Lethality was 33% in the placebo group, Neither the lazaroids nor meth ylprednisolone influenced survival. The local pancreatic and peritoneal con centrations of lipid peroxidation products, antioxidants, and proteases did not differ among the five groups. Nonsurviving rats, however, had a higher total protease activity in the pancreas and higher concentrations of tryps inogen activation peptide in ascites, as compared with surviving animals. T here were no differences between survivors and nonsurvivors with regard to variables of oxidative stress and cytokines, Conclusions: Lazaroid application under clinically relevant conditions (i.e ,, after induction of fulminant acute pancreatitis) does not influence leth ality or biochemical variables relevant to this disease, Protease activatio n rather than oxidative stress or local pancreatic cytokine production is a n important determinant of disease severity and survival in acute pancreati tis, In experimental studies evaluating novel therapeutics, the same strict criteria should be applied as in the human setting.