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.     

Pharmacological manipulation of biliary water and lipids: potential consequences for prevention of acute biliary pancreatitis

Acute biliary pancreatitis, caused by macroscopic cholesterol gallstones or microlithiasis, is often a severe disease with considerable morbidity and mortality. Formation of cholesterol gallstones and microlithiasis is caused by cholesterol crystallization from cholesterol supersaturated gallbladder bile. Particularly patients with fast and extensive crystallization, due to highly concentrated bile, low biliary phospholipid contents and gallbladder mucin hypersecretion seem at risk for pancreatitis. Patients who suffered from acute biliary pancreatitis should undergo cholecystectomy as secondary prevention strategy. For patients at high surgical risk, endoscopic sphincterotomy may be an appropriate alternative. Pharmacological manipulation of biliary lipids by the hydrophilic bile salt ursodeoxycholic acid is reserved for patients with recurrent pancreatitis despite previous cholecystectomy or sphincterotomy, or with contraindications to surgical and endoscopic treatment. Maintenance therapy with ursodeoxycholic acid is however a very effective secondary prevention strategy. Potentially, secondary prevention of acute biliary pancreatitis could also be achieved through decreasing biliary mucin contents by UDCA, NSAIDs or N-acetylcystein, or through achieving bile dilution (currently not feasible).     

19F NMR spectrometry evidence for bile acid conjugates of alpha-fluoro-beta-alanine as the main biliary metabolites of antineoplastic fluoropyrimidines in humans

The human biliary excretion of antineoplastic fluoropyrimidines was studied using 19F NMR. This method allows a direct detection of all the fluorinated metabolites of a fluorinated drug and requires no labeled compound. From a patient with an external bile derivation, treated with 5'-deoxy-5-fluorouridine (5'dFUrd), the biliary excretion of 5'dFUrd metabolites was low (0.8% of the injected dose) and made up of alpha-fluoro-beta-alanine (FBAL) and fluoride ion (F-) which represented approximately equal to 10% of the excreted metabolites and approximately equal to 90% of unknown metabolites. These unknown metabolites were conjugates of FBAL with the two "primary" bile acids only present in the bile of patients with an external bile drainage, i.e. cholic and chenodeoxycholic acids, in a 3:1 ratio. In the bile obtained at surgery from a patient treated with intrahepatic 5-fluorouracil, the major metabolites were conjugates of FBAL with the three major bile acids of human bile, i.e. cholic, deoxycholic, and chenodeoxycholic acids. Moreover, 19F NMR showed that only one of the two diastereoisomers of each conjugate of FBAL with bile acids was formed in vivo, confirming that metabolic FBAL is optically active.     

EBHU18, a novel derivative of fatty acid bile acid conjugates, prevents cholesterol gallstone formation in experimental mice

In this study, we tested whether the oral administration of EBHU18, one of the newly synthesized fatty acid bile acid conjugates (FABACs), was able to prevent the development of cholesterol gallstones. In the first study, gallstone-susceptible C57BL/6 mice were fed a lithogenic diet for 8?weeks, and then treated with ursodeoxycholic acid (UDCA, 10?mg?kg^?1?day^?1, i.g.), EBHU18-L (0.5?mg?kg^?1?day^?1 i.g.), or EBHU18-H (3?mg?kg^?1?day^?1 i.g.). In the second study, C57BL/6 mice were fed the lithogenic diet for 8?weeks and then treated with EBHU18 at a daily dose of 3?mg (EBHU18-H) or 0.5?mg (EBHU18-L) or with 10?mg of UDCA for another 8?weeks. Pre-treatment or post-treatment with EBHU18 at 3?mg?kg^?1?day^?1 significantly decreased gallstone formation and the fatty liver score. In the first study, EBHU18-H significantly decreased gallstone formation compared with the control animals. The fatty liver score decreased from a mean of 1.6?±?1.02 in the controls to 0.5?±?0.67 in the EBHU18-L group (P?<?0.05) and 0.3?±?0.64 in the EBHU18-H group (P?<?0.01). In the second study, the drug significantly lowered the gallstone formation rate in the EBHU18-H group. The fatty liver score decreased from a mean of 1.6?±?0.98 in the controls to 0.67?±?0.90 in the EBHU18-L group (P?<?0.05) and 0.4?±?0.74 in the EBHU18-H group (P?<?0.01). EBHU18 can prevent and reduce gallstone formation and/or fatty liver and can be developed as a potential therapeutic candidate for anti-gallstone therapy.     

Design of fatty acid conjugates for dermal delivery and topical therapeutics

The development of topical and transdermal drug delivery systems has aimed at overcoming the remarkably efficient barrier property of human skin by nontoxic and nonirritant methods. Numerous chemical and physical approaches have been investigated to overcome the skin's formidable barrier function. This article reviews two types of drug delivery approaches currently under investigation, which aim to increase drug permeability into and through the skin, by using fatty acid conjugates. The first approach uses fatty-acid conjugates as chemical enhancers for topical drugs while avoiding irritation, which is usually caused by the conventional use of free fatty acids. The second approach uses a conjugation of fatty acids to hydrophilic drug molecules to create effective topical prodrugs. The polyunsaturated fatty acid (PUFA) ester prodrugs for dermal delivery may be particularly promising and more advantageous by playing a role of mutual prodrugs. This article presents an overview of the ongoing research on fatty acid conjugates for dermal application. The concepts, potential uses, limitations as well as their safety considerations are described.     

Effects of butylated hydroxytoluene (BHT) on biliary excretion of xenobiotics and bile flow in rats

A significant enhancement in the biliary excretion of iv injected sulfobromophthalein (BSP), phenol- 3,6 -dibromphthalein disulfonate (DBSP), procaine amide ethobromide (PAEB) and ouabain was observed in rats maintained on diets containing 0.25% BHT for periods of 10 days. The enhanced biliary excretion of these drugs in BHT treated rats appears to be correlated with the increase in bile flow produced by BHT. The increased bile flow was due to an increase in canalicular bile production rather than a change in net ductular secretion or reabsorption of fluid since bile to plasma concentration ratios of erythritol were unchanged and no permeability change in the biliary tree was observed when mannitol was administered by retrograde intrabiliary injection. The increase in bile flow was not due to an enhanced excretion of bile salts into bile, because both the biliary bile acid concentration and total biliary excretion of bile acids were lower in BHT-treated rats than in control rats. It appears that the increase in bile flow produced by BHT is due to the osmotic choleresis related to the secretion of BHT and its metabolites into bile.     

胆道梗阻时胆道压力对胆汁中左氧氟沙星药物浓度的影响

目的前瞻性研究胆道梗阻对抗生素左氧氟沙星向胆汁中弥散产生的影响。为临床胆道梗阻合并胆道感染患者的抗生素选择提供实验证据。方法临床急性重症胆管炎（ACST）患者15例为研究对象,分别术前30 min静脉滴注抗生素左氧氟沙星0.3 g。术中测量胆道压力,于给药1 h后收集胆汁标本以高效液相色谱技术（HPLC）检测胆汁药物浓度。并与对照组进行胆道压力？胆汁内抗生素浓度的比较,应用统计软件进行差异显著性分析及相关性分析。结果ACST组患者胆道压力较对照组胆道压力明显升高（P〈0.01）。胆道压力升高时,静脉注射抗生素1h后的胆汁内抗生素浓度明显降低,两者呈负相关。结论左氧氟沙星在正常胆道压力情况下胆汁浓度难以达到有效杀菌浓度。当胆道压力升高到一定范围以上后,胆汁内无抗生素分布,此时行手术胆道减压是唯一有效的治疗途径。     

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.     

Modulation of cholesterol crystallization in bile. Implications for non-surgical treatment of cholesterol gallstone disease

The first step in cholesterol gallstone disease is precipitation of cholesterol crystals in bile. In gallbladder bile. cholesterol is normally solubilized together with bile salts and phospholipids to form mixed micellar structures. When cholesterol in bile is in excess, vesicles (i.e. phospholipid-cholesterol globular structures: liquid crystals) form which become supersaturated in cholesterol. Early aggregation and precipitation of cholesterol molecules into submicroscopic nuclei occurs from these supersaturated vesicles. This crucial step is followed by precipitation and agglomeration of cholesterol crystals which then become visible at light microscopy. Here we describe the mechanism of cholesterol crystallization and its modulation in vivo and in vitro. Recent advances on the role of ursodeoxycholate as an agent preventing the precipitation of cholesterol crystals in bile will be highligthed.     

Manipulation of biliary lipids by gene therapy: potential consequences for patients with progressive familial intrahepatic cholestasis

Gene therapy constitutes a great promise for the treatment of inherited diseases as well as cancer. Although the principle is extremely elegant, reality proves that several important problems remain to be solved before gene therapy becomes a standard application for these conditions. Meanwhile, and because of these problems alternatives are being considered as well. For the treatment of hepatic inherited disorders, hepatocyte transplantation has proven to be an attractive alternative, although this form of therapy also remains experimental at this moment. Problems and possibilities are discussed with the inherited disease, Progressive Familial Intrahepatic Cholestasis, as an example.     

Amino acid conjugates: metabolites of 2-propylpentanoic acid (valproic acid) in epileptic patients.

In this study, spectroscopic and chromatographic evidence is presented for the identification and characterization of the metabolites, valproyl glutamate (2-propylpentanoyl glutamate, VPA-GLU) and valproyl glutamine (2-propylpentanoyl glutamine, VPA-GLN) in the urine, serum, and cerebrospinal fluid (CSF) of patients on valproic acid (VPA) therapy. Moreover, the identification of valproyl glycine (2-propylpentanoyl glycine, VPA-GLY) in the serum and urine of patients on VPA, albeit in trace concentrations, is also reported here. The three amino acid conjugates excreted in urine accounted for about 1% of the VPA dose in four patients who were on VPA therapy chronically and had reached steady state. VPA-GLU was quantitatively the most prominent metabolite (0.66-13.1 microg/mg creatinine) compared with VPA-GLN (0.78-9.93 microg/mg creatinine) and VPA-GLY (trace-1.0 microg/mg creatinine) in overnight urine samples of all patients studied (n = 29). The relatively low serum concentrations of the three amino acid conjugates of VPA in six patients suggest that the metabolites are readily excreted once formed. In contrast, whereas VPA GLY was absent in the CSF of one patient on VPA, the concentrations of VPA-GLU and VPA-GLN in this CSF sample were 9 and 5 times, respectively, their corresponding serum concentrations.     

Obeticholic acid for the treatment of primary biliary cholangitis

Introduction: Primary biliary cholangitis (PBC) is an autoimmune disease of the liver characterized by destruction and inflammation of the intrahepatic bile ducts. The disease affects mainly women. The disease is often discovered through abnormal alkaline phosphatase (ALP) activity, and is confirmed when anti-mitochondrial antibodies (AMA) are present. The etiology of PBC is poorly understood. Cigarette smoking, immune dysregulation, nail polish, urinary tract infections, and low socioeconomic status have been implicated but none have been confirmed. Genome wide association studies (GWAS) have disclosed strong associations between certain human leukocyte antigen (HLA) alleles and PBC. PBC can progress to cirrhosis and end-stage liver disease. Hepatocellular carcinoma (HCC) develops in up to 3.5% of PBC patients. Ursodeoxycholic acid (UDCA) is the only medication approved for the treatment of PBC. The use of UDCA in PBC delays histological progression and extends the transplant-free survival. 40% of PBC patients do not respond adequately to UDCA, and these patients are at high risk for serious complications. Therefore, there is a critical need for more effective therapies for this problematic disease.

Multiple other agents have either been or are currently being studied as therapeutic options in UDCA non-responder PBC patients. Six-ethyl chenodeoxycholic acid (6-ECDCA), a potent farnesoid X receptor (FXR) agonist, has shown anti-cholestatic activity in rodent models of cholestasis. Obeticholic acid (OCA, 6-ECDCA, or INT-747), a first-in-class FXR agonist, has been examined in PBC patients with inadequate response to UDCA, and shown promising results. Particularly, initial clinical trials have demonstrated that the use of OCA (in addition to UDCA) in PBC patients with inadequate response to UDCA led to significant reduction of serum alkaline phosphatase (ALP, an important prognostic marker in PBC). More recently, the results of a randomized clinical trial of OCA monotherapy in PBC reported significant reduction of ALP in the treatment group compared to placebo.

Areas covered: This review covers the preclinical and clinical studies of OCA in PBC. In addition, other alternative therapies that are currently being examined in PBC patients will also be discussed in this review. A literature search was carried out using the PubMed database.

Expert opinion: If approved by the U.S. FDA, OCA will likely be an important alternative add-on therapy in PBC patients who have inadequate response to UDCA.     

Apical sodium dependent bile acid transporter (ASBT, SLC10A2): a potential prodrug target

A major hurdle impeding the successful clinical development of drug candidates can be poor intestinal permeability. Low intestinal permeability may be enhanced by a prodrug approach targeting membrane transporters in the small intestine. Transporter specificity, affinity, and capacity are three factors in targeted prodrug design. The human apical sodium dependent bile acid transporter (SLC10A2) belongs to the solute carrier family (SLC) of transporters and is an important carrier protein expressed in the small intestine. In spite of its appearing to be an excellent target for prodrug design, few studies have targeted human apical sodium dependent bile acid transporter (hASBT) to improve oral bioavailability. This review discusses bile acids including their chemistry and their absorptive disposition. Additionally, hASBT-mediated prodrug targeting is discussed, including QSAR, in vitro models for hASBT assay, and the current progress in utilizing hASBT as a drug delivery target.     

Obeticholic acid for the treatment of primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is characterized by progressive nonsuppurative destruction of small bile ducts, resulting in intrahepatic cholestasis, fibrosis and ultimately end-stage liver disease. Timely intervention with ursodeoxycholic acid is associated with excellent survival, although approximately one-third of all patients fail to achieve biochemical response, signifying a critical need for additional therapeutic strategies. Obeticholic acid (OCA) is a potent ligand of the nuclear hormone receptor farnesoid X receptor (FXR). Activation of FXR inhibits bile acid synthesis and protects against toxic accumulation in models of cholestasis and facilitates hepatic regeneration in preclinical studies. Data from recent Phase II and III controlled trials suggest a therapeutic impact of OCA in PBC biochemical nonresponders, as evidenced by change in proven laboratory surrogates of long-term outcome. Dose-dependent pruritus is a common adverse effect, but may be overcome through dose-titration. Longer term studies are needed with focus on safety and long-term clinical efficacy.     

Cathepsin K inhibitor-polymer conjugates: potential drugs for the treatment of osteoporosis and rheumatoid arthritis

The role of the newly discovered cysteine protease, cathepsin K, in osteoporosis and rheumatoid arthritis is reviewed. The current development of cathepsin K inhibitors and their targeted delivery using synthetic polymer carriers are discussed. Future challenges and possible strategies to improve these delivery systems are addressed.