Abstracts
2000 Digestive Disease Week

# 2294 Superiority of ‘Therapeutical Cocktails’ Compared To Monotherapies In The Treatment of Acute Pancreatitis.
Jens Werner, Heiko Kaiser, Thobias Keck, Jan Schmidt, Martha Maria Gebhard, Christian Herfarth, Ernst Klar, Heidelberg, Germany

Trypsinogen activation, free radicals, cytokines, leukocyte adhesion, and ischemia are important steps in the pathogenesis of necrotizing pancreatitis (NP). Several drugs which inhibit those pathogenetic steps have been shown to attenuate biochemical and histological changes, while survival is still low. The aim of the present study was to evaluate the effect of a multidrug approach on pancreatic and systemic injury and survival in acute pancreatitis compared to monotherapies, and to analyze how many mediators need to be blocked. Methods: Severe NP was induced in rats by intraductal infusion of glycodeoxycholic acid and i.v. caerulein. 8 therapeutical regimens were started after a therapy free intervall of 6 hrs and the effects on pancreatic injury, systemic injury, 24-hour mortality and survival were assessed. In addition effects on pancreatic microcirculation were evaluated. We administered a complex ‘therapeutical cocktail 1’ which contained oxygen free radical scavengers (acetylcystein (AC), 4-Hydroxy TEMPO), NO donor Larginine (LA), protease antagonist gabexate mesilate (GB), a platelet activating factor antagonist, and an inhibitor of adhesion molecule ICAM-1 and a less complex ‘cocktail 2’ containing AC, LA and anti-ICAM-1. All drugs were solved in dextran, which specifically improves microcirculation. Efficiency was compared with monotherapies of dextran, GB, AC, LA, and anti ICAM-1 and standard volume therapy with Ringers solution. Results: Pancreatic injury (inflammation and necrosis: p<0.01) was significantly reduced compared to the different monotherapies and standard therapy. Microcirculatory disturbances (pancreatic perfusion: p<0.001; leukocyte adhesion: p<0.01) after induction of acute pancreatitis were also reduced significantly by both coctails . Treatment with cocktail 1 reduced 24- hour mortality to 0% (standard therapy 70%) and increased long term survival to 85% (standard therapy 15%). Coctail 2 was as effective as coctail 1. Conclusions: Treatment of acute necrotizing pancreatitis with a multidrug approach significantly lowers mortality and increases long term survival. Moreover, the therapeutical cocktail is still effective after a wide therapeutic window. A key role seems to be the effective treatment of microcirculatory distubances and leukocyte infiltration. The superiority of the combined inhibition of several pathogenetic steps justifies the use of a multidrug approach in the treatment of acute pancreatitis.