Monooctanoin use for gallstone dissolution

Monooctanoin (Capmul 8210), a digestion product of medium chain triglycerides, is a cholesterol solvent that has been used for the dissolution of retained cholesterol gallstones following cholecystectomy. Bile duct infusion of monooctanoin is associated with little toxicity, although potentially serious problems can result from absorption of the drug or tissue infiltration. Gastrointestinal side effects such as anorexia, nausea, vomiting, diarrhea, and abdominal pain have been reported most commonly. Complete gallstone dissolution has occurred in approximately 50-75 percent of patients receiving monooctanoin. Although mechanical stone removal is still considered to be the treatment of choice for retained gallstones, monooctanoin use appears promising for stone dissolution in patients in whom mechanical removal has been unsuccessful or is impossible.     

Importance of viscosity in the dissolution rate of cholesterol in monooctanoin solutions

Several factors affecting the dissolution rate of cholesterol in monooctanoin were investigated. This solvent is used clinically for dissolution of residual cholesterol gallstones in the bile duct after cholecystectomy. The effect of added water on dissolution rate, measured using the static- or rotating-disk methods, was not consistent with the previously measured solubility. The discrepancy was found to be due to the decreasing viscosity of the solvent as water was added. Addition of cholesterol, however, increased the viscosity of monooctanoin. The viscosity effect on dissolution rate was investigated further by addition of polymers (povidone and poloxamer 237) which increased solvent viscosity. Dissolution rate was proportional to viscosity to the -0.4 power with these polymers. An equation was derived which predicts that dissolution rate should be proportional to viscosity to the -2/3 power. The predicted exponent was very close to reported experimental values for benzoic acid, but the dissolution rate/viscosity relationship for cholesterol in aqueous monooctanoin was nonlinear with apparent exponents of -0.65 to -2.3. Although the Arrhenius activation energies for viscosity (3.79 kcal/mol) and dissolution rate constant (3.66 kcal/mol) were almost equal for benzoic acid, a nonlinear relationship was again observed for cholesterol in aqueous monooctanoin with approximate Ea values of 5.6-10 kcal/mol. The strong influence of viscosity on dissolution rate in this system is attributed to the viscosity-increasing effect of cholesterol in the diffusion layer. The increased viscosity at higher cholesterol concentrations reduces the diffusion coefficient of cholesterol and causes the dissolution rate to be slower even though solubility may have been higher.(ABSTRACT TRUNCATED AT 250 WORDS)     

Free fatty acids in gallstones in mice fed a diet containing cholic acid

In mice, combined addition of 1% cholesterol and 0.5% cholic acid to a diet induced cholesterol gallstones within 40 days as a result of the supersaturation of cholesterol in the bile, as has been reported. The major component of the gallstone was cholesterol, which was measured by HPLC. In this study, however, single addition of 1% cholic acid to a diet, which did not decrease cholesterol solubilizing capacity in bile, contributed to gallstone formation in mice within 50 days. The gallstones thus formed contained a large amount of palmitic acid. In the hepatic bile of this animal, palmitic acid was also detected; however, no solid material was observed by light and polarized-light microscopes. Free fatty acids such as palmitic acid seem to be dissolved in a complex micelle composed of bile acids and lecithin. This probably causes gallstone formation by reducing cholesterol solubilizing capacity in bile.     

A practical guide to the nonsurgical treatment of gallstones.

Until recently, cholecystectomy was the only treatment available for symptomatic gallstone disease. During the past 20 years, better understanding of the pathogenesis of cholesterol gallstone disease has led to alternative nonsurgical methods for treating gallstones in selected groups of patients. Use of 2 naturally occurring bile acids, chenodeoxycholic acid (CDCA) and ursodeoxycholic acid (UDCA), was reported in 1972 and 1975, respectively, for successful dissolution of cholesterol gallstones in humans. Both these bile acids act by reducing cholesterol secretion in bile, thus enabling it to solubilise more cholesterol from the stone surface. Micellar solubilisation is involved, together with liquid crystal formation in the case of UDCA. Having been extensively studied in clinical trials to assess efficacy and safety, both these compounds are now available for general use. The efficacy of CDCA can be enhanced by single bedtime dose administration and by taking a low cholesterol diet. Bedtime administration also enhances the effect of a suboptimal dose of UDCA. CDCA induces dose-related diarrhoea and hypertransaminaemia, and UDCA can induce calcification of gallstones, thus rendering them resistant to medical dissolution. A combination of the 2 bile acids at half the recommended dose for each has become an accepted practice for reducing adverse effects, and this may also enhance efficacy. One of the main problems of bile acid therapy is that dissolution of gallstones is a very slow process. Use of extracorporeal shockwave lithotripsy (ESWL) to break the stones into smaller fragments, with concurrent use of bile acids, has been shown to speed dissolution rate and to achieve complete gallstone dissolution in 78% of selected cases within 12 months.(ABSTRACT TRUNCATED AT 250 WORDS)     

Medical management of cholesterol gallstones

Cholesterol gallstones are a significant cause of morbidity in the U.S. Methods used to treat gallstones include cholecystectomy or medical dissolution. The primary drugs used for the dissolution of cholesterol gallstones are two bile acids, chenodeoxycholic acid and ursodeoxycholic acid. Complete or partial gallstone dissolution rates using chenodeoxycholic acid have ranged from 30 to 80 percent. Factors affecting gallstone dissolution using the bile acids include the dosage and administration schedule, obesity, the stone characteristics, diet, and the duration of therapy. The adverse effects of chenodeoxycholic acid include gastrointestinal complaints, hepatotoxicity, and increased serum cholesterol. Ursodeoxycholic acid, which is investigational, differs from chenodeoxycholic acid in its mechanism of action. Ursodeoxycholic acid has similar efficacy with chenodeoxycholic acid, at a lower daily dosage, with less gastrointestinal and hepatic adverse effects. If appropriate patient selection is used, the response rate to medical therapy can range from 50 to 80 percent.     

Mechanism of dissolution of cholesterol-calcium bilirubinate compressed discs in monooctanoin

The dissolution of cholesterol monohydrate and calcium bilirubinate (neutral salt) mixtures in monooctanoin was investigated using the static disc method. The intrinsic dissolution rate of calcium bilirubinate was orders of magnitude (approximately 1000 fold) lower than that of cholesterol. Cholesterol release decreased as its weight fraction in the solid decreased. In model systems containing below 50% cholesterol dissolution became negligible. The release profiles deviated from the classical model for dissolution from two component mixtures. The observed dissolution profiles of both components were greater than predicted by theory. Anomalous positive curvatures in dissolution profiles suggested that calcium bilirubinate initially reduced the surface area available for cholesterol dissolution. A model, taking into account the change in surface area, was used to fit the cholesterol dissolution data. The results were consistent with the reported relationship between human gallbladder stone cholesterol content and average stone weight loss.     

Effects of fatty acid bile acid conjugates (FABACs) on biliary lithogenesis: potential consequences for non-surgical treatment of gallstones

Fatty acid bile acid conjugates (FABACs) are novel synthetic lipid molecules, which were designed for the treatment of cholesterol gallstones. The rationale was to combine a cholesterol solubilizing moiety (a saturated fatty acid) with a bile acid (cholic acid) as a vehicle to enable secretion into bile and entry into the enterohepatic circulation. An amide bond was used to provide stability against intestinal degradation. Initial in vitro studies showed that FABACs are indeed cholesterol solubilizers, able to prevent biliary cholesterol crystallization. Arachidyl-amido-cholanoic acid (Aramchol) was found to be the most potent FABAC in these studies. Animal studies revealed that Aramchol was absorbed after oral administration and could prevent cholesterol crystallization as well as dissolve preformed crystals in rodents fed a lithogenic diet. In gallstone susceptible mice, Aramchol prevented gallstone formation and dissolved gallstones. FABACs were found to be metabolically active substances, also able to decrease blood cholesterol, atherosclerotic plaques and fat accumulation in the liver in several animal species. The underlying mechanisms of action are under active investigation, and several effects, e.g. on cholesterol and bile salt metabolizing enzymes as well as cholesterol efflux from cells have been discovered. These findings are, however, only the beginning of our understanding of the metabolic actions as well as the potential of use of FABACs as therapeutic agents.     

Drugs affecting biliary lipid secretion and gallbladder motility: their potential role in gallstone treatment and prevention

Gallstone disease in the Western world has an estimated prevalence of 10-15% and more than 75% are cholesterol-enriched gallstones. Defective gallbladder motility has been identified as an important pathogenic factor for cholesterol gallstone disease. Various agents may enhance or impair postprandial gallbladder motility, and their effects on interdigestive gallbladder and intestinal motility should also be taken into account. Patients in high-risk situations for gallstone disease, and those chronically treated with drugs inhibiting gallbladder motility (e.g. somatostatin analogues) may benefit from improving gallbladder motility with prokinetic agents. Whether such a strategy can really prevent gallstone formation is still unknown, long-term studies are lacking so far. The efficacy of bile acid therapy with UDCA for gallstone dissolution or for prevention in high risk patients is limited and hampered by high recurrence rates. The efficacy of UDCA in prevention of colics or gallstone related complications in symptomatic patients with gallbladder stones with contraindications for operation or on the waiting list should be explored further, since several retrospective studies showed favourable outcomes with this strategy.     

Ursodeoxycholic acid alone or with chenodeoxycholic acid for dissolution of cholesterol gallstones: a randomized multicentre trial. The British-Italian Gallstone Study group

BACKGROUND: Combination therapy using ursodeoxycholic acid plus chenodeoxycholic acid has been advocated for dissolution of cholesterol gallstones because the two bile acids have complementary effects on biliary lipid metabolism and cholesterol solubilization. AIM: To compare the clinical efficacy of combination therapy with ursodeoxycholic acid monotherapy. PATIENTS AND METHODS: A total of 154 symptomatic patients with radiolucent stones (< or = 15 mm) in functioning gallbladders were enrolled from six centres in England and Italy. They were randomized to either a combination of chenodeoxycholic acid plus ursodeoxycholic acid (5 mg.day/kg each) or to ursodeoxycholic acid alone (10 mg.day/kg). Dissolution was assessed by 6-monthly oral cholecystography and ultrasonography for up to 24 months. RESULTS: Both regimens reduced the frequency of biliary pain and there was no significant difference between them in terms of side-effects or dropout rate. Complete gallstone dissolution on an intention-to-treat basis was similar at all time intervals. At 24 months this was 28% with ursodeoxycholic acid alone and 30% with combination therapy. The mean dissolution rates at 6 and 12 months were 47% and 59% with ursodeoxycholic acid, and 44% and 59% with combination therapy, respectively. CONCLUSION: There is no substantial difference in the efficacy of combined ursodeoxycholic acid and chenodeoxycholic acid and that of ursodeoxycholic acid alone in terms of gallstone dissolution rate, complete gallstone dissolution, or relief of biliary pain.     

Effects of leptin on biliary lipids: potential consequences for gallstone formation and therapy in obesity

Gallstone disease is exceptionally common, occurring especially in Western populations, with cholesterol gallstones predominating. Currently, it is believed that obesity is the most consistent and important risk factor for the development of cholesterol gallstones. Obesity has been shown to be associated with the supersaturation of bile with cholesterol because of increased hepatic secretion of the sterol. In accord with current information from experimental studies, leptin appears to be involved in biliary cholesterol secretion and cholesterol gallstone formation in humans. This review summarizes the current information on the role of obesity in biliary lipid secretion as well as the effect of leptin and its potential consequences for gallstone formation and therapy in the obese.     

Ursodiol: a cholesterol gallstone solubilizing agent

Ursodiol, a naturally occurring bile acid, has gained Food and Drug Administration approval for the dissolution of cholesterol gallstones. Ursodiol inhibits hepatic cholesterol synthesis and secretion. Lithocholic acid, a potentially hepatotoxic metabolite of ursodiol and chenodiol, may accumulate to a lesser extent with ursodiol than with chenodiol. Enterohepatic recirculation of ursodiol and its metabolites occurs and is essential to the dissolution of cholesterol gallstones. Complete dissolution has been achieved in 17 percent of patients with noncalcified, radiolucent, floating, cholesterol gallstones. Recurrence of cholesterol gallstones may occur in over one-half of initial responders. Diarrhea reported in up to 50 percent of the patients on chenodiol has been reported in only 4 percent of patients treated with ursodiol. Increased mean aspartate aminotransferase levels to more than twice the pretreatment level seen with chenodiol therapy have not been reported with ursodiol. Reportedly fewer adverse reactions may give ursodiol a major advantage over chenodiol in hospital formulary considerations.     

Effect of Larrea tridentata (creosote bush) on cholesterol gallstones and bile secretion in hamsters

Larrea tridentata (Sesse and Moc. ex DC.) Coville is used for the treatment of gallstones in traditional Mexican medicine. The possible prevention or elimination of gallstones by ethanolic and aqueous extracts of the leaves and twigs of L. tridentata was tested in hamsters fed a rich carbohydrate, fat-free diet. In addition, the effects of the ethanolic extract and its main metabolite, nordihydroguaiaretic acid, on bile secretion in the perfused liver were tested. In the experiment on prevention of gallstones, the dry ethanolic extract at a level of 0.5% of diet completely inhibited gallstone formation, lowered biliary moles percent cholesterol and increased the proportion of chenodeoxycholic acid of hepatic bile. The dry aqueous extract at a level of 1% of diet did not affect gallstone frequency or biliary parameters. In the experiment on elimination of gallstones, the ethanolic extract significantly reduced gallstone frequency, gallbladder bile cholesterol concentration and moles percent cholesterol. Both the ethanolic extract and nordihydroguaiaretic acid had cholestatic effects in the perfused liver, with an EC50 of 34 and 28 mg dL-1, respectively, when perfused for 10 min. This effect was reversible with concentrations up to 40 mg dL-1. The results indicate that L. tridentata could be useful in the treatment of gallstone disease, however care must be taken due to its hepatotoxicity.     

Effects of solvents on skin permeation of formoterol fumarate

Effects of various chemicals applied as penetration enhancers on the permeation of formoterol fumarate (FF) across excised rat skin were investigated. Remarkable enhancement was noted with terpenes, fatty acid esters, and higher alcohols, whereas no significant influence was observed in the case of lower alcohols, pyrrolidones, and amines. At high concentration, a cineole/N-methyl-2-pyrrolidone (NMP) mixed solvent system slightly enhanced the skin permeation of FF compared with cineole alone, and a l-menthol/NMP mixed solvent system caused significant further increase. Maximum skin permeation of FF was seen when the ratio of l-menthol/NMP was 60/40 w/w. From the present results, l-menthol/NMP and isopropyl myristate (IPM)/NMP mixed solvent systems can be considered effective for augmenting skin permeation of FF, with potential applications in transdermal delivery of the drug.     

Cholesterol solubility in organic solvents.

The 37 degree cholesterol solubilities in over 50 solvents, including the homologous n-alkanols through dodecanol and homologous ethyl carboxylates through the undecanoate, and the 37 degree beta-sitosterol solubilities in the n-alkanols through decanol are reported. Additionally, solubility data for cholesterol at 7, 17, and 27 degrees in the alcohol series were obtained. These measurements allowed the calculation of heats of solution for cholesterol in the alkanols, which range from 7.5 kcal for methanol to 4.3 kcal for decanol and which tend to decrease, although irregularly, with increasing alkanol chain length. A solubility maximum in all of these series for both solutes was observed between a chain length of six and seven. A surprisingly irregular, odd-even alternating solubility pattern was noted for cholesterol in the alkanols at all four temperatures. Experimental evidence indicated that this pattern was due to solvent-induced crystalline changes, presumably solvate formation, in each alkanol solvent through C10. Overall, the solubility studies screened solvents for their utility in dissolving cholesterol and, thus, cholesterol gallstones. To these ends, some limited dissolution experiments were performed, which indicated that the solution rate is directly related to the measured solubility in organic solvents. The dissolution behavior is thus different from micellar bile salt solutions, in which a significant interfacial barrier controls kinetics.     

Limits and perspective of oral therapy with statins and aspirin for the prevention of symptomatic cholesterol gallstone disease

The prevalence of gallstones disease in Western countries is 10 - 15%. Gallstones can be one of two types - cholesterol or pigment - with cholesterol gallstones representing nearly the 80% of the total. Cholesterol and pigment gallstones have different predisposing factors: cholesterol gallstones are related to supersaturated bile in cholesterol, whereas black pigment gallstones are related to hyperbilirubinbilia factors (hemolysis, etc.); these are necessary, but not sufficient, factors to produce gallstones in vivo. Gall bladder mucosa factors (gall bladder secretion of mucin, local bile stasis and production of endogenous biliary β-glucuronidase) may coexist with the aforementioned factors and facilitate gallstone nucleation and growth. The gold-standard treatment for symptomatic gallstones is laparoscopic cholecystectomy. Several studies have reported a significant reduction in the onset of symptomatic gallstones disease in patients undergoing chronic therapy with statins, which can reduce bile cholesterol saturation. Aspirin, which has been shown to reduce the local production of gall bladder mucins (mucosal or parietal factors of gallstone formation) in animal experimental models, does not appear to reduce the risk of symptomatic gallstones disease when tested alone. The new horizon of oral therapy for the prevention of symptomatic gallstone disease needs to evaluate the long-term effect of statins and chronic aspirin administration in patients with dyslipidemia and/or atherosclerosis.     

Limits and perspective of oral therapy with statins and aspirin for the prevention of symptomatic cholesterol gallstone disease

The prevalence of gallstones disease in Western countries is 10 – 15%. Gallstones can be one of two types – cholesterol or pigment – with cholesterol gallstones representing nearly the 80% of the total. Cholesterol and pigment gallstones have different predisposing factors: cholesterol gallstones are related to supersaturated bile in cholesterol, whereas black pigment gallstones are related to hyperbilirubinbilia factors (hemolysis, etc.); these are necessary, but not sufficient, factors to produce gallstones in vivo. Gall bladder mucosa factors (gall bladder secretion of mucin, local bile stasis and production of endogenous biliary β-glucuronidase) may coexist with the aforementioned factors and facilitate gallstone nucleation and growth. The gold-standard treatment for symptomatic gallstones is laparoscopic cholecystectomy. Several studies have reported a significant reduction in the onset of symptomatic gallstones disease in patients undergoing chronic therapy with statins, which can reduce bile cholesterol saturation. Aspirin, which has been shown to reduce the local production of gall bladder mucins (mucosal or parietal factors of gallstone formation) in animal experimental models, does not appear to reduce the risk of symptomatic gallstones disease when tested alone. The new horizon of oral therapy for the prevention of symptomatic gallstone disease needs to evaluate the long-term effect of statins and chronic aspirin administration in patients with dyslipidemia and/or atherosclerosis.     

Effects of fatty acid esters of cheno- and ursodeoxycholic acids on gallstone formation in hamsters

Fatty acid esters (at the 7 position) of chenodeoxycholic (CDCA) and ursodeoxycholic (UDCA) acids have been tested for their effects on formation and dissolution of gallstones in hamsters. The free bile acids were fed at a level of 0.2% of the diet and esters were fed at equimolar levels. The earlier finding that CDCA does not affect gallstone formation in hamsters fed the Dam and Christensen diet were confirmed. The acetic, butyric and lauric acid esters of CDCA had a very slight inhibitory effect on lithogenesis but CDCA 7 oleate and linoleate completely inhibited gallstone formation. UDCA and its 7 oleate inhibited both formation and progression of gallstones. The observed effects are probably a function of the form of the bile acid and not of the esterifying acid. The observation that ethyl oleate has a slight litholytic effect suggests that the acid moiety of the ester may exert a slight influence.     

熊去氧胆酸与牛磺熊去氧胆酸治疗胆固醇性胆结石的疗效比较

目的:比较熊去氧胆酸(UDCA)和牛磺熊去氧胆酸(TUDCA)治疗胆囊胆固醇性胆结石的疗效及安全性。方法:将74例胆固醇性胆结石患者随机分为2组,分别给予UDCA(每次250mg,每日3次)和TUDCA(每次250mg,每日3次)治疗6个月,分别在治疗3个月和6个月后通过B超对患者的溶石效果进行比较并观察2组不良反应发生情况。结果:经过3个月的治疗,UDCA和TUDCA对胆结石治疗的有效率分别为37.8%和56.8%,6个月治疗的有效率分别为75.7%(28/37)和78.4%(29/37)。2组比较,3个月时TUDCA对胆结石的疗效优于UDCA(P<0.01);但经过6个月的治疗,二者的疗效无显著性差异。2组不良反应发生率比较差异无统计学意义。结论:TUDCA和UDCA均可有效溶解胆固醇性胆结石,且安全性较好,但TUDCA的溶石速度大于UDCA。     

Lipid lowering drugs and gallstones: a therapeutic option?

Cholelithiasis is a common disease worldwide. The majority of gallstones can occur when the bile is supersaturated with cholesterol. Dyslipidaemia, obesity, insulin resistance are associated with an increased risk for cholesterol gallstone formation as well as with vascular risk. Statins and ezetimibe are used to treat dyslipidaemia and appear to have some effect on bile composition and cholesterol gallstone formation. Statin (e.g. pravastatin, simvastatin, fluvastatin and lovastatin) monotherapy or combined with ursodeoxycholic acid (UDCA) have shown reductions in bile cholesterol saturation, preventing gallstone formation and even dissolving pre-existing stones. However, this effect was not consistently reported in all studies. Statin use has also been associated with a reduced risk for cholecystectomy in 2 large epidemiological studies. Ezetimibe was shown to have a beneficial action against cholelithiasis in animal studies but data in humans - although promising - are very limited. The effect of these drugs on gallstone disease warrants further investigation in large human trials. We also consider the links between cholelithiasis, vascular risk and the use of lipid lowering drugs.     

Effect of sodium acetyl salicylate on cholesterol saturation of fasting gall bladder bile, with and without chenic acid.

The aims of this study were (a) to determine whether sodium acetyl salicylate by itself or in combination with chenodeoxycholic (chenic) acid would decrease the cholesterol saturation index (SI) of fasting gall bladder bile in man; and (b) to confirm prospectively that 8 mg kg-1 day-1 chenic acid given at bedtime together with a low cholesterol diet reduces gall bladder bile SI to a level where consistent gallstone dissolution would be expected. Seven patients were studied on each of the following regimens given in random order for 1 month each: bedtime chenic acid alone 8 mg kg-1 day-1; sodium acetyl salicylate alone 600 mg four times daily; bedtime chenic acid together with sodium acetyl salicylate; no treatment. Gall bladder samples were taken by nasoduodenal intubation at the end of each regimen and SI determined. SI (mean +/- s.e. mean) on low cholesterol diet with no drug treatment was 1.14 +/- 0.06. On bedtime chenic acid 8 mg kg-1 day-1 plus low cholesterol diet it fell to 0.83 +/- 0.03 (P less than 0.05). Sodium acetyl salicylate did not alter gall bladder bile SI. 95% confidence limits for the effect of sodium acetyl salicylate on SI were +0.03 and -0.05. We conclude that (a) sodium acetyl salicylate does not lower SI of gall bladder bile in man; (b) an adequate fall in SI for gallstone dissolution can be achieved with a reduced dose (8 mg kg-1 day-1) of chenic acid given at bedtime with a low cholesterol diet.