Objectives: To evaluate the therapeutic potential of lazaroids in severe necrotizing acute pancreatitis and to investigate the assocn. between oxidative stress, protease activation, and local prodn. of proinflammatory cytokines and the severity and lethality of the disease. Background: Oxidative stress is a crucial factor in the pathophysiol. of acute pancreatitis and its systemic complications. Treatment with antioxidants, however, failed to improve survival in most studies performed so far. Lazaroids are a novel class of antioxidants that potently protect pancreatic acinar cells against oxidant attack in vitro. Design: Prospective, randomized, controlled exptl. study. Setting: University research lab. Subjects: Seventy-five anesthetized male Wistar rats (300-350 g). Interventions: Severe acute pancreatitis was induced by retrograde injection of 3.5% taurocholate-sodium into the common bile-pancreatic duct. Interventions were performed to mimic the clin. situation, including continuous i.v. fluid substitution and administration of lazaroids in a therapeutic protocol. Therapy was started 1 h after injection of the bile salt by using three different lazaroids, lactated Ringer's soln. (placebo), and methylprednisolone as a corticosteroid control (n = 15 in each group). All the substances were given by continuous i.v. infusion throughout the 20-h trial period. Measurements and Main Results: Pancreatic homogenates and ascites were analyzed for indicators of oxidative stress, antioxidants, proteases, and proinflammatory cytokines. Pancreatic edema, morphol. pancreatitis severity, and pancreatic histopathol. also were assessed. All three lazaroids and methylprednisolone diminished pancreatic tumor necrosis factor-a concns. Lethality was 33% in the placebo group. Neither the lazaroids nor methylprednisolone influenced survival. The local pancreatic and peritoneal concns. of lipid peroxidn. 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 concns. of trypsinogen activation peptide in ascites, as compared with surviving animals. There were no differences between survivors and nonsurvivors with regard to variables of oxidative stress and cytokines. Conclusions: Lazaroid application under clin. relevant conditions (i.e., after induction of fulminant acute pancreatitis) does not influence lethality or biochem. variables relevant to this disease. Protease activation rather than oxidative stress or local pancreatic cytokine prodn. is an important determinant of disease severity and survival in acute pancreatitis. In exptl. studies evaluating novel therapeutics, the same strict criteria should be applied as in the human setting.