A396 AGA ABSTRACTS GASTROENTEROLOGY, Vol. 108, No. 4

• COMPARISON OF THE ACTION OF THE CCK-RECEPTOR ANTAGONISTS LOXIGLUMIDE AND L-364,71g A N D OF THE MI- RECEPTOR ANTAGONIST TELENZEPINE ON THE PANCREATIC PROTEIN RESPONSE TO INTESTINAL TRYPTOPHAN. S. Teyssen, E. Niebergall, D. Wetzel, C. Beglinger* and M. !/. Singer. Univ. Hosp. of Heidelberg at Maanheim, Mannheim, Germany; *Univ. Hospital of Basel, Switzerland.

In six conscious dogs with gastric and pancreatic fistulas, we studied the effect of of the muscarinic Ml-receptor antagonist telenzepine (Tel; 20.25, 40.5 and 81 nmol/kg/h iv.), of the CCK-antagonist ioxiglumide (Lox; 2.5-, 5.0- and 10 mg/kg/h iv.), and of the CCK-antagonist L-364,718 (0.025, 0.05, and 0.1 mg/kg/h) on the pancreatic protein response to graded loads of id. infusion of TRP (0.12-10.0 retool/h), given against a background of secretin (S; 20.5 pmol/kg/h iv.). Lox+Tel were given together at different doses each: a) Lox (2.5 mg/kg/h) + Tel (20.25 nmol/kg/h); b) Lox (2.5 mg/kg/h) + Tel (40.5 nmol/kg/h); c) Lox (5 mg/kg/h) + Tel (40.5 nmol/kg/h); d) Lox (10 mg/kg/h) + Tel (81 nmol/kg/h). "L- 364,718+Tel were given together at different doses each in 4 dogs: a) L-364,718 (0.025 mg/kg/h) + Tel (20.25 nmol/kg/h); b) L-364,718 (0.025 mg/kg/h) + Tel (40.5 nmol/kg/h); c) L-364,718 (0.05 mg/kg/h) + Tel (40.5 nmol/kg/h); d) L- 364,718 (0.1 mg/kg/h) + Tel (81 nmol/kg/h). The 225 rain. integrated protein responses (IPR, g) to all loads of TRP were calculated. RESULTS: Except the lowest load (0.12 mmol/h), all loads of TRP significantly (I)<0.05) increased the pancreatic protein output dosc-dependantly over that seen with S alone (data not shown). The IPR to all loads of TRP was 24.0 g (100%). Except the lowest dose of Tel both higher doses significantly reduced the IPR by 71% and 63%. Except the lowest dose of Lox both higher doses significantly reduced the 1PR by 59% and 79%. A// doses of L-364,718 significantly reduced the IPR by 76% to 94%. Lox+Tel together significantly reduced the IPR dose-depandantly by 44% to 88% but L-364,718+Tel together abolished the IPR (by 90% to 98%); see table.

Tab!e: 225 rain. IPR (g) to all loads of tryptophan. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Control 24.0 Tel (20.25) 18.8 Lox (2.5) 23.5 L-364,718 (0.025) 5.8 Tel (40.5) 7.0 Lox (5.0) 9.9 L-364,718 (0.05) 5.8 Tel (81.0) 8.9 Lox (10) 5.0 L-364,718 (0.1) 1.5

Lox (2.5)+Tel (20:25) 13.5 L-364,718 (0.025) + Tel (20.25) 1.6 Lox (2.5)+Tel (40.5) 10.1 L-364,718 (0.025) + Tel (40.5) 2.4 Lox (5.0)+Tel (40.5) 5.3 L-364,718 (0.05) + Tel (40.5) 0.4 Lox (10)+Tel (81) 2.8 L-364,718 (0.1) + Tel (81) 1.2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

These findines indicate that 1) The Ml-receptor antagonist Tel and the CCK- antagonists Lox and L-364,718 inhibit the protein response to intestinal TRP. In the case of Tel this effect is an all-or-none effect, in the case of Lox the effect is dose- dependent and in the case of L-364,718 all doses inhibit. 2) The combination of both, Lox + Tel and L-364,718 + Tel together potentiate the inhibitory effect of each drug alone. In the case of Lox+Tel the effect is dose-dependent, in the case of L- 364,718 + Tel all combinations abolished pancreatic protein secretion.

• LOPERAMIDE INHIBITS BASAL AND AMINO ACID STIMULATED PANCREATIC ENZYME SECRETION IN MAN. P.W.L. Thimister, W.P.M. Hopman, J.L. Willems ~ R. Woestenborgh~ and J.B.M.J. Janselt. Depts. Of Gastroenterology and Clinical Chemistry t, University Hospital Nijmegan, The Netherlands and Drug, Metabolism and Pharmacokinetics 2, Janssen Pharmaceutica, Belgium.

Loperamide, a peripherally acting opiate receptor agonist, is clinically used to reduce chronic diarrhoea mainly by inhibiting ileal and colonic motor function. For patients being treated for diarrhoea (especially those with a short bowel or pancreatic insufficiency) it is important to know whether loperamide also affects pancreatic enzyme secretion. Methods: 2 studies were performed in 7 healthy subjects (2F,SM;23.1 + 1.1 yrs.). After an overnight fast saline was continuously perfiised intraduodenally (i.d.) for three hours (300 mL/h) in test 1. During the last test hour 6.9 g of an amino acid (AA) solution, containing valine, methionine, tryptophan and phenylalanine were also given i.d. The second test was performed on a separate occasion according to the same proto- col as test 1. However, 13 and 4 hours prior to the start of the AA perfusion, 8 mg of loperamide was given orally. Plasma CCK and loperamide levels (P, IA), and amylase output (duodenal spot sampling with PEG-4000 as a recovery mar- ker) were measured at regular intervals. Results: Plasma loperamide levels at the start of AA perfusion were 2.5_+0.3 ng/mL in the loperamide study. Basal (3.2_+0.5 kU/h)and AA stimulated amylase output (5.6_+0.9 kU/h) decreased (p<0.01) after pretreatment with lopuramide (0.9_+0.6 kU/h and 1.4_+0.4 kU/h respect.). Basal plasma CCK levels were comparable in both tests (3.2_+0.2 pM). After an initial rise to 4.7_+ 1.3 pM, AA stimulated plasma CCK levels declined, resulting in integrated levels of 22.5+8.6 pM*30min during the last 30 min of AA perfusion. Ingestion of Ioperamide increased AA stimulated CCK levels to a constant level of 5.5-+0.7 pM and integrated levels of 63.7-+ 11.7 pM*30min (p<0.01 vs AA alone). Conclusions: Loperamide inhibits basal and amino acid stimulated pancreatic enzyme secretion despite an enhance d amino acid stimulated CCK release. Therefore, gastrointestinal opiate receptors modulate pancreatic enzyme secretion in man. Clinicians, prescribing loperamide should be aware of this possible adverse effect.

• STUDY OF PREVALENCE, SEVERITY AND ETIOLOGICAL FACTORS ASSOCIATED WITH ACUTE PANCREATITIS IN PATIENTS INFECTED WITH HUMAN IRmUNODEFICIENCY VIRUS. CD Tinq, J Gradon, SK Dutta. Dept. of Medicine, Sinai Hospital of Baltimore, Johns Hopkins Univ. and Univ. of Maryland Schools of Medicine, Baltimore, Maryland. Acute pancreatitis (AP) and associated complications are frequently recognized in patients infected with the human immunodeficiency virus (HIV) (Modern Pathology 1990,3:49). However, the prevalence and severity of AP, and frequency of associated etiological factors have not been examined in any detail, The purpose of the present study was i) to determine the prevalence of AP, ii) to evaluate severity of pancreatic gland inflammation and iii) to identify commonly associated etiological factors of AP in HIV infected patients. Medical records of all Datients with positive serology for HIV who were seen in the Infectious Disease Clinic and/or admitted to sinai Hospital of Baltimore between 07-01-93 and 06-30-94 were reviewed. The diagnosis of AP was based on appropriate clinical symptoms and elevated plasma amylase and/or lipase activity. The severity of pancreatitis was assessed by Ranson's criteria and correlated with CD4 lymphocyte count at the time of AP (SGO 1976, 143:209). Results: A total of 321 HIV infected patients were treated during the study period. At least one episode of AP was documented in 45 patients during this period, giving rise to a prevalence rate of 14%. Eighteen out of 45 (40%) patients with HIV+ serology and AP had mild disease (<3 factors present). The remaining patients (60%) had AP with moderate severity as determined by the presence of 4-6 risk factors. A statistically significant (p<0.05) inverse correlation was found between serum amylase or lipase elevation and the number of CD4+ lymphocyte count. Patients with CD4 lymphocyte count >500/rmu3 did not develop hyperamylasemia or AP. Five of 18 suspected etiological factors were significantly (p<0.001) more common in this group of patients and included: i) pentamidine intake, 2) pneumocystis carinii infection 3) mycobacterium avium infection, 4) intravenous drug abuse and 5) gallstones. These observations suggest that AP is quite prevalent in HIV infected patients and the disease isusually mild to moderate in severity. Furthermore, AP in this population is frequently associated with microbial infections and medications used to treat HIV infection.

• PROGNOSTIC RELEVANCE OF DIFFERENT TYPES OF PHOSPHOLIPASE 2%2 IN EXPERIMENTAL ACUTE PANCREAT1TIS.

W. l Jh l , H.-J. S c h r a g , J. Aufanangar 1, T.J. Nevalainen 2, M.W. Biichlar Clinic of Visceral and Transplantation Surgery, University of Berne, Switzerland lIastitute for Clinical Chemistry, University of Mannheim, Germany 2 Department of Pathology, University of Turku, Finland

Secretory PLA2 in acute pancreatitis (AP) can be dovided into two types (Europ.J.Clin.Chem.Clin.Binchem.30,263;1992): the pancreatic Phospholilmse type I (PLA2 I) and an extrapancreatic type II (PLA2 II). We differentiated PLA2-activity in type I and II, and analyzed the pancreatic PLA2-protein concentration (pan-PLA2) in eerulein- (C) and codium-taurocholate (T) induced AP. Methods. 30 female Wistar rats were divided into three groups (G). GL" i.v. hyperstimulation by C (5~g/kg/h during 2 hrs) to induce the edematous Ap (n=10). G2: necrotizing AP (n=10) by intraductal injection of 3% T (0. lml/100g body wt. with constant pressure of 30 vm H20). G3:10 rats served as controls for pancreatic tissue samples. Via a central venous catheter- implantation blood samples were taken prior and afterwards to the AP-induftian (Gi:0, 3, 6, 12 hrs; G2: 0, 3, 6, 12, 18, 24 hrs). After the observation periods (GI: 12 hrs., G2:24 hrs.) the pancreatic glands were removed and frozen in dry ice. The following parameters were measured in rats sera and homogenized pancreatic tissue: pan-PLA2 by flanroiremuneaasay, total PLA2-activity by radinmetric E. coli-aasay and CA-PLA2-I and [1 differentiation by heat inactivation of CA-PLA2-II (60°). Results. In cerolein-AP (G/) median serum CA-PLA2-I activity w ~ markedly ,increased 3 hrs after &P-inductian (hrs:mU/mh 0:0; 3:4.52; 6:0.36~ 12:0.48), while CA-PLA2-II did not change (hrs:mU/mh 0:3.24; 3:3.49; 6:3.59; 12:5.18). Additionally, pan-PLA2 showed a similar course as CA-PLA2-I (hrs:ng/ml: 0:20.37; 3:33.55; 6:305.4; 12:53.22) and the regression analysis showed a positive correlation between CA-PLA2-I and pan-PLA2 (r=0.78). In the tissue samples the median of CA-PLA2-I and the pan-PLA2 were significantly increased as compared to controls (0.78:23:38 mU/ml, p<0.002; 500:1120 og/mg,p<0.05). In contrast, the median serum course of CA-PLA2-I in tanrocholate-AP (G2) ~ unchanged (<lreU/mi during the whole observation period). In this model the extrapancrcatic CA-PLA2-I1 rapidly increased, reaching values over 16-fold at 3 hrs and 2-fold at 6 hrs compared to model C (hrs:Tvs.C, mU/ml: 3: 58.41/3.49,p<0.002; 6: 6/3.59,p<0.05). We found a less strong correlation of ~ . 5 8 between CA-PLA-I and pan-PLA2. In the explanted tissues, CA-PLA2-1, II and pan-PLA2 were significantly reduced as compared to controls. Conclusio~ In the cerulaln model of AP serum and tissue pan-PLA2 protein concentration are elevated leading to increased serum activity CA-PLA2-I. In the mild form of AP serum CA-PLA2-II activity is not stimulated by cemlein, whereas in the taurocbolate-AP CA-PLA2-1I activity is markedly increased (10- fold) comparable to human AP and CA-PLA2-I activity did not change significantly pleading for the high prognostic relevances of type II PLA2 of extra-acinar origin.