Abstracts
1999 Digestive Disease Week

# 2198 COMPARISON OF DELAYED THERAPY WITH ICAM-1 ANTIBODIES AND A SPECIFIC ENDOTHELIN-1 ANTAGONIST IN SEVERE EXPERIMENTAL PANCREATITIS
T Foitzik, Guido Eibl, Benjamin Franklin Clin, Free Univ of Berlin, Berlin Germany; M Kirchengast, Knoll AG, Ludwigshafen Germany; H J Buhr, Benjamin Franklin Clin, Free Univ of Berlin, Berlin Germany

Microcirculatory disorders (MD) are a hallmark of severe acute pancreatitis (AP). They are not confined to the pancreas but can also be shown in other organs where they contribute to organ dysfunction. Factors mediating MD, such as adhesion molecules (AM) and endothelin (ET), have lately aroused increasing interest. The present study evaluates the potential therapeutic role of AM and ET antagonists by comparing their effect on microcirculation, intravascular fluid volume, extravascular fluid sequestration and survival in experimental pancreatitis. Methods: AP was induced in 32 rats by a standardized intraductal infusion of bile salt followed by i.v. cerulein over 6 hrs. Six hours after AP induction and an additional 6-hour therapy-free interval, animals received i.v. fluid (4ml/kg/h Ringer's lactate) and were randomized for therapy with the specific ET-1 antagonist LU-135252 (40mg/kg; q12h), ICAM-1 antibody IA-29 (2mg/kg) or saline (vol.equiv.). After 24 hours animals were relaparotomized for intravital microscopic determination of capillary permeability (CP) in the colon and leucocyte rolling (LR) in mesenteric venules. Determination of organ function included measurements of heart rate, mean arterial pressure, arterial blood gases and urine production as well as ascites and pleural effusion (PE). Conclusion: The present study confirms the beneficial effect of ET and ICAM antagonists on capillary permeability, fluid homeostasis and survival in severe AP and demonstrates their efficiency even after 12-hour therapy-free interval (equivalent to more than 48hrs in humans). This makes both compounds candidates for further clinical evaluation in severe AP. ET blockade appears to be especially attractive for clinical use not only because it was superior to ICAM antibody in the present study but also because of its favorable pharmocokinetic properties and low costs. It has also been tested in several clinical phase II studies on other diseases.

Results: mean±SE M	CP#	LR (c/min)	Hct at 24h (%)	Ascites (ml)	PE (ml)	Urin 12 -24h (ml)	Mort
AP+SAL	235±14	16±2	49±1	20±3	1.4±0.1	1.6±0.5	8/12
AP+IA	176±8*	7±2*	45±2*	1.4±0.3	0.7±0.2*	2.5±0.5*	2/10
AP+LU	147±12*o	8±2*	42±1*o	1.1±0.4*	0.7±0.3*	3.3±0.5*o	2/10
# increase in perivasc.fluorescein intensity 30 min after i.v. FITC detran;
*=p<0.05 vs. AP=SAL;o=p<0.05 vs. AP+IA

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