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April 1995 AASLD Al111 • EFFECTS OF URSODEOXYCHOLIC ACID (UDCA) ON SURVIVAL IN PATIENTS WITH PRIMARY BILIARY CIRRHOSIS (PBC). KD Lindor, TM Therneau, RA Jorgensen, M Malinchoc, ER Dickson. Mayo Foundation, Rochester, MN. UDCA has been shown to be a safe and effective treatment for patients with PBC; however, its effect on patient survival is less certain. To better address this issue, we compared the course of patients receiving long-term UDCA to their expected survival based on the Mayo PBC natural history model, adjusting for the actual survival in the control patients. METHODS: 180 patients were randomized to receive either UDCA. 13-15 mg/kg/d, or placebo from May 1988 to June 1992. After the study closure in June of 1992, the patients originally receiving placebo were switched to active drug, and prospective follow up was continued on all patients. For analysis, patients were censored at the time of transplantation or voluntary withdrawal. The observed survival was compared to the expected survival which was based on covariate values at the time of entry to the ,- .............................. study and. calculated using. ,, .=° the prewously pubhshed, Mayo PBC model ', (Hepatol 10:1-7, 1989). '~ The overall distribution of t ® risk scores was similar in : '~ the UDCA and placebo groups as well as the patients from which the model was derived. Comparison of survival in the placebo group to the projected survival allowed us to adjust for improve- ment over time in baseline -t.......... I ............... Observed -- "'% "" "";*""'-, . . . . . . . . " ..... care of these patients and, o 1 a 3 4 5 6 hence, to increase the pre- ~ .............................. cision of the comparison of UDCA to placebo treatment. RESULTS: The patients receiving UDCA had significantly improved survival (relative risk= 0.49~ p=0.03) as compared to the placebo patients. The observed and expected survivals for the UDCA and placebo patient arms are shown in the graph. SUMMARY: UDCA improved survival over that expected from a validated, adjusted, model natural history. CONCLUSION: UDCA should be considered as a safe, effective, and life-extending treatment for patients with PBC. • POSSIBLE MECHANISMSOF INHIBITIONOR ENHANCEMENT OF HEPATIC SYNTHESISOF CHOLESTEROL BY LOVASTATIN IN THE RAT. W.G .Linscheer, A. Banerjee, U.K. Murthy, J. Nandi. Sections of Gastroenterology, Veterans Affairs and Health Science Medical Centers, SUNY, Syracuse, NY. Short term studies (5 h) (Pandak et al, J. Lipid res. 31:79,1990) demonstrated inhibition of HMG-CoA reductase (red) and cholesterol (CH) synthesis by mevinolinic acid, while our long term studies (7 to 21 days) with lovastatin (LS) showed increased enzyme activity and CH synthesis (Yamauchi et al, A. J. Physiol. 260:G265- 630). The aim of this study was to explain these opposite effects by investigating dose dependent binding of LS to isolated hepatic microsomal membranes in contro! rats, in rats treated for 7 days with LS (=17.5 mg/rat/day), in lean Zucker rats (LZ), that are sensitive to LS treatment and in LS resistent obese Zucker rats (OZ). In addition, we studied the effect of temperature on the maximal hepatic HMG-CoAred activity in the 4 groups of rats. Methods: Male Wistar rats' were divided into 2 groups on a w~ight basis. 4 rats served as controls (C) and 3 rats were treated for 7 days with LS. The Zucker rats (3 LZ and 40Z) were not treated. Analysis: Hepatic microsomes were isolated and binding of LS were measured at 0 ° using 14C-LS. HMG-CoA red activity was measured at temperatures between 10 and S0 ° C. Results: The microsomes of untreated control rats had a 1O0 fold higher affinity to LS than the LS treated rats (P < 0.0004). Maximum binding concentrations and Kd for LS in the microsomal fractions of controls and LS treated rats were respectively, 0.04 and 4.0 mM and 0.019 and 1.82 picoM (P<0.0004). The maximum microsomal binding concentrations and Kd for the LZ and OZ rats were respectively 0.17 and 3.87 mM (P<0.0001) and 0~956 and 0.160 piccM (P<O.004). Effect of temperature: Maximal hepatic HMG-CoA red activity was reached at 37 ° C for the control, LZ and the OZ rats. However the maximal activity for the LS treated rats was at 30 ° C with a four fold higher activity than the other groups, Conclusion: The sensitivity of "~hedifferent groups of rats to LS correlated with the affinity of the microsomal HMG-CoA red to LS. The shift in maximal enzyme activity from 37 to 30 ° C, including a 4-fold higher specific activity in LS treated rats, indicates a LS induced activation of HMG-CoA red and a change in the properties of th e microsomal membranes. • EFFECTS OF THE THROMBOXANE RECEPTOR ANTAGONIST BM13.505 ON RENAL FUNCTION IN BILE DUCT LIGATED RATS. ~ , Richard B Wait, and Kim U Kahng, Depts of Surgery, Medical ollege of Pennsylvania and SUNY-Brooklyn. In our previous studies, bile duct ligation (BDL) in the rat resulted in decreased urinary sodium excretion that was associated with a 7-fold increase in urinary thromboxane B2 excretion. This study was performed to investigate the renal effects of thromboxane receptor blockade in bile duct ligated rats. Male Sprague-Dawiey rats underwent either::S~am operation (SO) or BDL. Four days later, they were anesthetizedand instrumented to receive an IV infusion of normal saline 5 ml/kg/h, sodium pentobarbital 2.6 mg/kg/h, and 3H-inuiin 5 p.Ci/hr. Both ureters Were catheterized for urine collection.- Renal blood flow (RBF) was measured by ultrasonic flowmetry. An arterial catheter was placed for blood pressure measurement and blood sampling. After 60 min equilibration urine was collected for 30 rain for basal measurements. Rats then received either BM13.505 10 mg/kg in 0.15 ml Tris buffer IV bolus or vehicle alone. Another 30 min urine collection was performed. SO+Veh n=13 BP (ram Hg) 113±3 UNaV (p.Eo/m) 7.5 + 1.0 V (p.Vm) 5.2 + 0.3 RBF (ml/m/lO0g) 4.1 + 0.2 CIn (mVm/lOOg) 1.2 + 0.1 SO+BM n=10 116+5 7.0 + 0.9 5.7 + 0.5 3.9+0.2 1.1 ± 0.1 BDL+Veh BDL+BM n=11 n=11 1~ ±4 101±3" 8.9+1.4 12.1+1.8"t 7.1±0.5 8.1±0.7" 4.6+03 4.1+0.3 1.2±0.1 1.1±0.1 Values represent mean ± SEM after injection of BM13:505 or Veh. *p<0.05 BDL+BM vs SO+BM; tp<O.05 BDL+BM vs BDL+Veh by ANOVA, Student's unpaired t-test. Basal udnary sodium excretion (UNaV) and urine flow (V) were significantly greater in BDL rats (data not shown). BM 13.505 had no effect on renal [unction in SO rats. In contrast, thromboxane receptor blockade in the BDL rats further increased urinary sodium excretion w thout affecting RBF and glomerular filtration rate (Cm). This increase in urinary.sodium excretion occurred despite lower systemic arterial pressure. These findings suggest that thromboxane is a mediator of altered sodium excretion in cholestasis. DOES SPL~TAN~S BAC~RIAL PERITONITIS (SBP) HAVE A B~I'rER OUTCOME IN PATIENTS WITH PREVI(~/S SELECTIVE INTESTINAL DEC~TAMINATION (SID)?. JM Llovet, HP Rodrig~]ez-Iglesias, E Moitinho, M Menacho, R Bataller, R. Planas, M Navasa, A Casteils, E Cabre, V Arroyo, MA Gassull, J Rod,s. Hospital Germans Trias i Pujol, Badalona. Hospital Clinic, Barcelona, Catalunya, Spain. The incidence of SBP is decreased in high-risk cirrhotic patients with norfloxacin-induced SID. However, whether the outcome of SBP differs in SID an non SID patients has been scarcely evaluated. ~: To co,@are the clinical fetaures arid outcome of a large series of SBP episodes with and without prior norfloxacin induced SID. METHODS: 229 SBP episodes in 169 patients were analyzed: 187 without (Group A) and 42 with (Group B) SID (norfloxaein 400 mg/day at least for 7 days or 800 mg/day at least for 4 days), Indication of SID was prophylaxis of SBP recurrence in 22 cases arid recent acute GIB in 20. Clinical arid laboratory data, and outcome were compared between both groups. RESULTS: Clinical and biological features were similar in both groups, except for blood Hb (i0.6 g/L vs 9.7 g/L, p=O.O14) and ascitic fluid proteins that were lower in Group B (11.6 g/l vs 8.5 g/L, p=O.OIB). Functional renal failure occurred in 397~ of the episodes. Ascitic fluid culture was positive in 48% of cases, but the incidence of Gram (+) ascitic fluid culture was greater in group B (84% vs 31%, p=O.O08). No differences in treatment length (mean 7.7 vs 7.4 days) or hospital stay (mean 21.0 vs 21.8 days) were found. Overall SFB recovery rate was 93%, whitout differences between groups (42/42 vs 170/187, p=0.08). Likewise, hospital mortality was similar in non-SID (50/187, 27%) as compared to SID patients (7/42, 17%). CONCLUSION: SBP in patients with SID is mainly caused by Gram (+) bacteria. However, this does not result in either a higher SBP recovery rate or an improved hospital survival.

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