George Bonorris

Effects of Ursodeoxycholic Acid and Aspirin on the Formation of Lithogenic Bile and Gallstones during Loss of Weight

We attempted to determine whether the administration of aspirin or ursodeoxycholic acid during loss of weight could prevent the development of lithogenic changes in bile and the formation of gallstones. Sixty-eight obese subjects without gallstones who were entered in a program (520 kcal per day) to lose weight were randomly assigned to receive ursodeoxycholic acid (1200 mg per day), aspirin (1300 mg per day), or placebo in double-blind fashion for up to 16 weeks. At entry, at four weeks of treatment, and at three weeks after the completion of treatment, the subjects underwent ultrasonography to detect gallstones and duodenal drainage of bile to detect cholesterol crystals and to determine the bile saturation index and glycoprotein concentration. No gallstones or cholesterol crystals formed in the patients treated with ursodeoxycholic acid. Among the patients given placebo, gallstones formed in five (P less than 0.05 vs. ursodeoxycholic acid) and cholesterol crystals in six (P less than 0.001 vs. ursodeoxycholic acid); among those given aspirin, gallstones formed in two and cholesterol crystals in one (no significant difference from ursodeoxycholic acid treatment). By the fourth week, the bile saturation index increased in the placebo group (from 1.07 +/- 0.26 to 1.29 +/- 0.27; P less than 0.001), decreased in the ursodeoxycholic acid group (from 1.11 +/- 0.34 to 0.91 +/- 0.24; P less than 0.001), and did not change significantly in the aspirin group. The concentration of glycoprotein in bile increased in the placebo group (27.9 +/- 14.5 percent; P less than 0.001) but did not change significantly in the groups treated with ursodeoxycholic acid or aspirin. We conclude that ursodeoxycholic acid prevents lithogenic changes in bile and the formation of gallstones in obese subjects during loss of weight.

Bile acid stimulation of colonic adenylate cyclase and secretion in the rabbit

In vitro studies have suggested that the cyclic AMP system may be the mediator of bile acid-induced colonic secretion. The aims of our experiments were to quantify thein vivo effect of various doses of deoxycholic acid (DCA) on adenylate cyclase activity (AC) and net secretion in the rabbit colon. AC increased significantly (P<0.01) with each increasing concentration of DCA; at 8 mM the activity was 126±6 pmoles cAMP/mg protein/min, or 4 times the control. Phosphodiesterase activity (PDE) was affected and significantly decreased (P<0.01) only by 8 mM DCA. The volume of luminal fluid increased significantly (P<0.01) as a bicarbonate-rich solution with 4, 6, and 8 mM DCA in graded fashion. In conclusion, stimulation of a colonic mucosal cAMP system is strongly implicated as mediating DCA-induced colonic secretion.

Treatment of Gallstones with Chenodeoxycholic Acid and Phenobarbital

In a controlled trial, 36 patients with asymptomatic radiolucent gallstones were treated with chenodeoxycholic acid, 750 mg per day, phenobarbital, 180 mg per day, combination of both drugs, and placebo. After one year, chenodeoxycholic acid, phenobarbital and the combination, but not placebo, significantly decreased biliary cholesterol saturation. The effect was significantly greater with chenodeoxycholic acid and the combination than with phenobarbital. Gallstones size decreased more than 50 per cent in nine of 20 patients receiving chenodeoxycholic acid, either alone or combined with phenobarbital, but in no patient receiving only phenobarbital or placebo. Gallstones disappeared completely in tow patients. Abnormalities in liver-function tests in thriee of 36 patients and in five of 16 liver biopsies, occured with equal frequency in the four treatment groups. Thus, after one year, phenobarbital alone was ineffective in gallstone dissolution. Chenodeoxycholic acid alone or combined with phenobarbital, however, offered a partially effective and safe treatment for asymptomatic radiolucent gallstones.

The sequence of biliary events preceding the formation of gallstones in humans

The aim of the present study was to determine the sequence of events leading to formation of gallstones among obese patients predisposed to cholesterol gallstones by a very low-calorie diet. Nine obese patients beginning a 520-kcal diet had gallbladder bile collected from the duodenum before beginning the diet and seven times during the first 56 days of the diet. Biliary cholesterol saturation index and levels of arachidonate, prostaglandin E2, and glycoprotein increased significantly; nucleation time decreased; and total lipid concentration did not change. Decreases in nucleation time preceded the appearance of cholesterol crystals. Significant (P less than 0.05) increases in prostaglandin E2 level were preceded by significant increases in arachidonate level and followed by significant increases in glycoprotein level. These observations support the hypotheses that in obese patients predisposed to gallstones by very low-calorie diets (a) decreases in nucleation time are necessary before cholesterol crystals form in the gallbladder; (b) biliary arachidonate, through its conversion to prostaglandins, promotes biliary synthesis and secretion of glycoprotein; (c) biliary glycoprotein promotes nucleation; and (d) increases in the concentration of gallbladder bile are not necessary for cholesterol nucleation to occur in vivo.

Peppermint oil improves the manometric findings in diffuse esophageal spasm.

Background Diffuse esophageal spasm (DES) is an uncommon condition that results in simultaneous esophageal contractions. Current medical treatment of DES is frequently unsatisfactory. We hypothesized that, as a smooth muscle relaxant, peppermint oil may improve the manometric findings in DES. Study Eight consecutive patients with chest pain or dysphagia and who were found to have DES were enrolled during their diagnostic esophageal manometry. An eight-channel perfusion manometry system was used. Lower esophageal sphincter pressure and contractions of the esophageal body after 10 wet swallows were assessed before and 10 minutes after the ingestion of a solution containing five drops of peppermint oil in 10 mL of water. Each swallow was assessed for duration (seconds), amplitude (mm Hg), and proportion of simultaneous and multiphasic esophageal contractions. Results Lower esophageal sphincter pressures and contractile pressures and durations in both the upper and lower esophagus were no different before and after the peppermint oil. Peppermint oil completely eliminated simultaneous esophageal contractions in all patients (p < 0.01). The number of multiphasic, spontaneous, and missed contractions also improved. Because normal esophageal contractions are characteristically uniform in appearance, variability of esophageal contractions was compared before and after treatment. The variability of amplitude improved from 33.4 ± 36.7 to 24.9 ± 11.0 mm Hg (p < 0.05) after the peppermint oil. The variability for duration improved from 2.02 ± 1.80 to 1.36 ± 0.72 seconds (p < 0.01). Two of the eight patients had chest pain that resolved after the peppermint oil. Conclusions This data demonstrates that peppermint oil improves the manometric features of DES.

PROPRANOLOL INHIBITS ADENYLATE CYCLASE AND SECRETION STIMULATED BY DEOXYCHOLIC ACID IN THE RABBIT COLON

Bile acids cause diarrhea by inducing colonic secretion, probably mediated through the cyclic AMP system. The aim was to determine the effects of an adenylate cyclase inhibitor, propranolol, on deoxycholic acid (DCA) stimulation of net secretion and the cyclic AMP system in the colon. In each of 30 New Zealand white rabbits, 0.9% NaC1 as control and 6 mM and 8 mM DCA were injected in random sequence into three colonic loops in situ. Propranolol, 4 mg per kg was administered intravenously to 12 of the 30 rabbits 1/2 hr before preparation of the loops, i.e., 5 1/2 hr before the rabbits were killed. In the 18 untreated animals, 6 and 8 mM DCA significantly stimulated colonic net secretion and mucosal adenylate cyclase activity; 6 mM DCA caused no change in mucosal phosphodiesterase activity, whereas 8 mM DCA caused a 25% decrease (P less than 0.01). In propranolol-treated animals compared to untreated animals, the volume of luminal fluid in controls was not different, with 6 mM DCA it was 88% less (P less than 0.01), and with 8 mM DCA it was 45% less (P less than 0.01); adenylate cyclase activity in controls was 43% less (P less than 0.01), with 6 mM DCA it was 67% less (P less than 0.01), and with 8 mM DCA it was 65% less (P less than 0.01); phosphodiesterase activity in controls and with 6 mM DCA was not different and with 8 mM DCA it was 38% greater (P less than 0.02). In conclusion, propranolol prevented DCA stimulation of colonic net secretion and inhibited the cyclic AMP system. Propranolol, therefore, warrants investigation as therapy for diarrhea caused by bile acids in the colon.

Factors affecting the measurement of cholesterol nucleation in human gallbladder and duodenal bile

The study of cholesterol gallstone disease would be facilitated if the nucleation time of cholesterol crystals could be measured in duodenal bile and was correlated with nucleation occurring in vivo. Therefore, our aims were to determine (a) if nucleation time could be measured in duodenal bile, (b) the effect of bacteria, phospholipase, protease, and dilution on the measurement of nucleation time, and (c) the ability of nucleation time of duodenal bile to reflect changes occurring in vivo that promote the formation of gallstones and, therefore, the potential usefulness of nucleation time in predicting and studying the formation of gallstones. Gallbladder bile was obtained from 27 patients undergoing elective cholecystectomy and 19 patients undergoing diagnostic duodenal biliary drainage. Among the 14 bile samples collected by drainage that nucleated within 21 days, mean nucleation time was 6.3 +/- 2.8 days. The addition of inhibitors of phospholipase or protease prolonged nucleation time slightly. Bacteria were cultured from one bile sample at the time of collection and five samples at the time of nucleation. The addition of antibiotics had no effect on nucleation time. Dilution of bile collected at cholecystectomy to the concentration of duodenal bile prolonged nucleation time. In 4 of 5 obese patients receiving a very low calorie diet and predisposed to gallstones, the nucleation time in duodenal bile shortened, and the shortest nucleation times were associated with the formation of cholesterol crystals in vivo. Thus, measurement of nucleation time in duodenal bile may be useful in predicting and studying the formation of cholesterol gallstones.

Effect of Propranolol on Bile Acid- and Cholera Enterotoxin-Stimulated cAMP and Secretion in Rabbit Intestine

Stimulation of net secretion by deoxycholic acid (DCA) in the colon and by cholera enterotoxin (CE) in the jejunum is mediated by cAMP. Propranolol (Pr) inhibits adenylate cyclase (AC) activity and net secretion induced by bile acid in the colon. The aim of this study was to assess the organ specificity of DCA and CE as well as the selectivity of Pr inhibition. Three colonic and three jejunal loops were prepared in each of 8 rabbits treated intravenously with Pr, 4 mg per kg, 1/2 hr before loop construction and in each of 10 untreated control rabbits. One milliliter of DCA, 6 mM, CE, 10 mug per ml, or heat-inactivated CE or 0.9% NaCl, as basal controls were injected in random order into each of the loops. The volume of luminal fluid and mucosal AC were measured in each intestinal loop 5 hr later. DCA in the colon stimulated AC 2-fold (P less than 0.01) and luminal fluid 15-fold (P less than 0.01). CE in the jejunum stimulated AC 2.3-fold (P less than 0.01) and luminal fluid 9-fold (P less that 0.01). No significant effects on volume or AC occurred in response to CE in the colon or to DCA in the jejunum. Pr pretreatment completely prevented the stimulation of AC and luminal fluid by DCA in the colon but did not affect the action of CE in the jejunum of the same animals. Thus, DCA and CE are organ-specific stimulants of cAMP systems, and Pr is a selective inhibitor of certain inducers of cAMP and net secretion.

Estrogen Enhances Dietary Cholesterol Induction of Saturated Bile in the Hamster

The influence of ethinyl estradiol (EE) on the effects of dietary cholesterol on the biliary saturation index and on the rate-limiting hepatic enzymes of cholesterol synthesis, hydroxymethylglutaryl-CoA-reductase, and bile acid synthesis, 7 alpha-hydroxylase, were determined. Four groups of 12 male hamsters were treated for 1 month with EE, 15 micrograms per kg per day, or placebo vehicle administered intraperitoneally and fed either a standard diet, 0.8 mg of cholesterol per g of food, or high cholesterol diet, 2.4 mg of cholesterol per g. The high cholesterol diet increased the saturation index to 1.00 +/- 0.03 (P less than 0.01) from 0.65 +/- 0.02 in untreated hamsters on the standard diet. EE treatment on the high cholesterol diet further increased (P less than 0.01) the saturation index to 1.15 +/- 0.02. The high cholesterol diet decreased (P less than 0.01) hydroxymethylglutaryl-CoA-reductase activity from 308 +/- 16 pmoles per mg per min in untreated hamsters on the standard diet. The addition of EE treatment had no effect on hydroxymethylglutaryl-CoA-reductase activity. The high cholesterol diet increased (P less than 0.01) 7 alpha-hydroxylase activity from 23 +/- 1.0 pmoles per mg per min in untreated hamsters on the standard diet. The addition of EE decreased (P less than 0.01) 7 alpha-hydroxylase activity from that in untreated hamsters on the standard diet. The conclusions are as follows: (1) EE prevented dietary cholesterol-induced stimulation of cholesterol 7 alpha-hydroxylase activity; (2) EE enhanced the ability of dietary cholesterol to induce saturated bile; and (3) gallstone formation in estrogen-treated women may result from impaired metabolism of dietary cholesterol.

Gallstone prevalence and biliary lipid composition in inflammatory bowel disease.

Biliary cholesterol saturation has been correlated with disease variables that might effect bile acid loss in ileitis patients with (N=9) or without (N=8) intestinal resection having a defined prevalence of gallstones. In addition, cholesterol saturation was determined in ulcerative colitis patients (N=7) and gallstone patients (N=18) as well as in 5 normal controls. Biliary cholestrol saturation in ileitis patients both with and without resection was similar to that in gallstone patients yet the prevalence of gallstones was only 12%. Cholesterol saturation did not correlate with ileal resection nor the extent, duration, or activity of ileitis. Biliary cholesterol saturation was not different in ulcerative colitis patients from that in normal subjects. It is concluded that cholesterol saturation of bile alone does not account for the high prevalence of cholesterol gallstones that has been reported in ileitis patients.