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).     

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.     

Peptide YY: a potential therapy for obesity

Obesity now represents a modern epidemic in western society with major health and economic consequences. Unfortunately, previous pharmacological approaches to the treatment of obesity have been associated with life-threatening side effects and limited efficacy. Over recent years there has been a marked increase in our understanding of the physiological mechanisms that regulate body weight and how these are perturbed in obesity. One therapeutic strategy is to develop drugs which both mimic and enhance the body's own satiety signals. The gut hormone peptide tyrosine tyrosine (PYY), which is released postprandially from the gastrointestinal tract, has recently been shown to be a physiological regulator of food intake. Peripheral administration of PYY reduces feeding in rodents via a mechanism which requires the Y2 receptor and is thought to primarily involve modulation of the hypothalamic arcuate nucleus (ARC) circuitry. In humans a single 90-minute infusion of PYY has been shown to markedly reduce subsequent 24-hour caloric intake in lean, normal-weight and obese subjects. Moreover, obese subjects have been found to have low levels of fasting and postprandial PYY suggesting a role for this hormone in the pathogenesis of obesity. Although studies examining the effects of chronic peripheral administration of PYY to humans are awaited, the results from continuous infusion studies in a number of obese rodent models are encouraging with reductions in food intake, body weight and adiposity observed. Potential therapeutic manipulations based on the PYY system include development of Y2 agonists, exogenously administration of PYY or increased endogenous release from the gastrointestinal tract.     

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.     

Effects of obesity on pharmacokinetics implications for drug therapy

Obesity is a worldwide problem, with major health, social and economic implications. The adaptation of drug dosages to obese patients is a subject of concern, particularly for drugs with a narrow therapeutic index. The main factors that affect the tissue distribution of drugs are body composition, regional blood flow and the affinity of the drug for plasma proteins and/or tissue components. Obese people have larger absolute lean body masses as well as fat masses than non-obese individuals of the same age, gender and height. However, the percentage of fat per kg of total bodyweight (TBW) is markedly increased, whereas that chrome P450 isoforms are altered, but no clear overview of drug hepatic metabolism in obesity is currently available. Pharmacokinetic studies provide differing data on renal function in obese patients. This review analyses recent publications on several classes of drugs: antibacterials, anticancer drugs, psychotropic drugs, anticonvulsants, general anaesthetics, opioid analgesics, neuromuscular blockers, beta-blockers and drugs commonly used in the management of obesity. Pharmacokinetic studies in obesity show that the behaviour of molecules with weak or moderate lipophilicity (e.g. lithium and vecuronium) is generally rather predictable, as these drugs are distributed mainly in lean tissues. The dosage of these drugs should be based on the ideal bodyweight (IBW). However, some of these drugs (e.g. antibacterials and some anticancer drugs) are partly distributed in adipose tissues, and their dosage is based on IBW plus a percentage of the patient's excess bodyweight. There is no systematic relationship between the degree of lipophilicity of markedly lipophilic drugs (e.g. remifentanil and some beta-blockers) and their distribution in obese individuals. The distribution of a drug between fat and lean tissues may influence its pharmacokinetics in obese patients. Thus, the loading dose should be adjusted to the TBW or IBW, according to data from studies carried out in obese individuals. Adjustment of the maintenance dosage depends on the observed modifications in clearance. Our present knowledge of the influence of obesity on drug pharmacokinetics is limited. Drugs with a small therapeutic index should be used prudently and the dosage adjusted with the help of drug plasma concentrations.     

Effects of calcium supplementation on circulating lipids: potential pharmacoeconomic implications

For about a century there has been recognition that calcium and lipids bind to one another in the gut, each interfering with the other's absorption. Calcium also causes malabsorption of bile acids, which is likely to contribute further to malabsorption of fat. High dietary calcium intakes may also have stimulatory effects on lipolysis. These mechanisms provide a basis for hypothesising that calcium supplementation may impact on circulating lipid concentrations, and there is now a significant amount of observational and trial data indicating that this is the case. The largest randomised controlled trial of calcium effects on lipids was carried out in 223 healthy postmenopausal women, and found that low density lipoprotein-cholesterol (LDL-C) decreased 6.3% and high density lipoprotein-cholesterol (HDL-C) increased by 7.3% at 1-year. The resultant 16.4% increase in HDL-C/LDL-C ratio would be predicted to reduce cardiovascular event rates by 20-30%, which is consistent with the available observational data. There are no trial data addressing this question and it is possible that other lipid-lowering agents, such as hydroxymethylglutaryl coenzyme A reductase inhibitors, might impact on cardiac event rates by mechanisms other than by lowering cholesterol levels. Therefore, caution is appropriate in incorporating these findings into clinical practice, but the balance of evidence suggests that calcium is a cost-effective adjunct to the dietary management of hyperlipidaemia.     

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.     

Influence of beclobrate on gallstone formation in hamsters

Three groups of male Syrian hamsters were fed a lithogenic diet (L), L plus 0.04% ethyl-2-[4-(p-chlorophenyl) methylphenoxy]-2-methylbutyrate (beclobrate); or L plus 0.17% beclobrate. After 60 days, the percentage of hamsters with gallstones on the three diets was 28, 16 and 12, respectively. Biliary phospholipid was not affected, but biliary cholesterol and bile acid were reduced significantly in both test groups.     

Effects of fluvastatin on biliary lipids in subjects with an elevated cholesterol saturation index

OBJECTIVE: 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors have been suggested as agents to reduce the biliary cholesterol saturation index (CSI) in duodenal bile and therefore might be supportive in primary or secondary prevention of gallstones. However, the efficiency of the therapy seems to depend on both the HMG-CoA reductase inhibitor used and the study population selected. METHODS: We therefore investigated the effect of a high-dose application of fluvastatin on biliary lipid composition in 21 subjects exhibiting mild hypercholesterolaemia and a history of current gallstones or cholecystectomy due to gallstone disease. Subjects were treated either with 40 mg fluvastatin twice per day over a 3-month period (n = 14) or with placebo (n = 7). Bile samples were aspirated during endoscopy after intravenous ceruletid stimulation before and after therapy. RESULTS: Both groups were comparable in CSI (mean +/- SD) at baseline (1.78 +/- 0.2 placebo vs. 1.97 +/- 0.4 verum). CSI significantly decreased in the verum group to 1.45 +/- 0.4 (P = 0.003) mainly due to increased phospholipid levels, whereas no difference was observed in the placebo group (1.85 +/- 0.7, n.s.). In addition, the verum group exhibited a significant reduction of hydrophobic deoxycholic acid, which has been reported to induce cholesterol crystal precipitation, and an increase of hydrophilic cholic acid. CONCLUSION: Fluvastatin might decrease the risk of cholesterol gallstone formation in patients with elevated biliary CSI during long-term treatment by reduction of biliary cholesterol saturation and percentage change in deoxycholic acid content.     

New targets in and potential treatments for cholesterol gallstone disease

Gallstone disease is very common among American Indians and Hispanics, and approximately 20 million patients are treated for this disease annually in the US. Bile acid receptor (nuclear farnesoid X receptor; FXR) knockout mice fed a lithogenic diet are more susceptible to gallstone disease than wild-type mice. The C57L mouse is also susceptible to gallstone formation when fed a lithogenic diet, and in this model, the small-molecule FXR agonist GW-4064 prevents the precipitation of cholesterol. Bile acids (eg, P-muricholic acid) and their derivatives are also being developed as FXR agonists. Fatty acid bile acid conjugates have the potential to prevent and reverse cholesterol crystallization. Furthermore, agents that increase the expression of selected hepatocyte bile acid transporters may also be useful in the treatment of gall bladder disease.     

Cardiovascular consequences of the obesity pandemic: need for action

Due to changes in nutritional patterns and physical activity as well as economic growth in developing countries, the prevalence of obesity has reached pandemic proportions in the past decades. Consequences of diseases related to obesity, such as coronary heart disease, hypertension, diabetes and renal disease, account for much of the morbidity in these patients and are rarely treated adequately. There is an enormous need to provide information to the general population and particularly parents concerning the risks of childhood obesity and the importance of regular exercise. Physicians and scientists have now realised that obesity is a pathophysiological entity with important clinical complications. Current actions to prevent obesity should not only be directed towards the development of drugs controlling weight gain, but should also include educational programs, which will guarantee adequate awareness and prevention of this disease.     

Cardiovascular consequences of the obesity pandemic: need for action

Due to changes in nutritional patterns and physical activity as well as economic growth in developing countries, the prevalence of obesity has reached pandemic proportions in the past decades. Consequences of diseases related to obesity, such as coronary heart disease, hypertension, diabetes and renal disease, account for much of the morbidity in these patients and are rarely treated adequately. There is an enormous need to provide information to the general population and particularly parents concerning the risks of childhood obesity and the importance of regular exercise. Physicians and scientists have now realised that obesity is a pathophysiological entity with important clinical complications. Current actions to prevent obesity should not only be directed towards the development of drugs controlling weight gain, but should also include educational programs, which will guarantee adequate awareness and prevention of this disease.     

Liquid crystal solubilization of cholesterol: potential method for gallstone dissolution

Solubilization rate and phase equilibrium studies were conducted for cholesterol in aqueous sodium oleate solutions. The components interacted to form a lamellar liquid crystalline phase, and this phenomenon was investigated as a potential method for cholesterol gallstone dissolution. Phase equilibria data for cholesterol-sodium oleate-water showed that the mesophase contained approximately equimolar amounts of cholesterol and oleate with large amounts of water. The cholesterol solubilization rate from a static pellet in sodium oleate solutions was much faster than dissolution in sodium cholate solutions and was independent of oleate concentration from 2.5 to 10%. In these experiments, the medium became a cloudy dispersion of liquid crystalline phase in the micellar solutions. The rate-limiting step in the solubilization process appears to be dispersion of fragments from the liquid crystalline layer on the cholesterol surface. This hypothesis was consistent with the kinetic effects of viscosity, stirring rate, and oleate concentration. By converting cholesterol to a liquid crystalline phase, the solubilization process avoids the limitations for micellar solubility and interfacial resistance which control cholesterol dissolution in bile salt-containing media.     

Molecular mechanisms of central leptin resistance in obesity

The rapidly increasing prevalence of obesity confers a huge health burden globally. The hypothalamus plays a central role in the regulation of energy homeostasis by integrating multiple metabolic signals from peripheral organs and modulating feeding behavior and energy metabolism. Leptin, a key appetite-regulating hormone derived from the white adipose tissue, primarily acts on hypothalamic neurons to activate catabolic pathway and inhibit anabolic pathway, which can result in anorexia and weight reduction. Despite striking obesity resulting from leptin deficiency, treatment with this hormone in human obesity has been unsuccessful due to leptin resistance. In this review, we describe recent researches extending our understanding of obesity-associated hypothalamic leptin resistance.     

荷叶提取物黄酮对兔胆囊结石形成的影响

目的探讨黄酮对新西兰兔胆囊胆固醇结石形成的影响及其机制。方法(1)动物模型:45只雄性新西兰兔随机分成对照组(15只)、结石组(15只)和黄酮组(15只),对照组喂普通颗粒饲料,结石组喂含1.2%高胆固醇饲料,黄酮组则饲喂含1.2%胆固醇和0.4%黄酮的饲料,饲养时间各为4周。(2)氨肽酶N(APN)表达:利用RT-PCR方法,检测肝脏APNmRNA水平的变化。(3)血脂检测:放射免疫法检测血清总胆固醇(TG)、甘油三脂(TC)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)、载脂蛋白A(ApoA)和载脂蛋白B(ApoB)。(4)血清亮氨酸氨肽酶(LAP)检测:放射免疫法检测。结果结石组中10只(10/15)出现胆囊结石,12只(12/15)出现胆固醇结晶,黄酮组1只(1/15)和对照组2只(2/15)出现胆囊结石;结石组APNmRNAIOD比值(1.16±0.12)明显高于对照组(0.72±0.24)和黄酮组(0.86±0.38)(P<0.05);结石组血清TG、TC、LDL-C、ApoB较对照组和黄酮组明显升高(P<0.01),结石组血清HDL-C较对照组和黄酮组降低,但无显著性差异(P>0.05),结石组血清ApoA较对照组和黄酮组明显降低(P<0.01);LAP结石组明显较对照组和黄酮组升高(P<0.01)。黄酮组各项指标较对照组均无明显差异(P>0.05)。结论荷叶黄酮可降低肝脏APN的表达和血清LAP,改变血脂水平,从而有助于预防胆囊胆固醇结石的形成。     

针灸调节瘦素在单纯性肥胖中的作用机制研究进展

单纯性肥胖是一种病因复杂的代谢性疾病,瘦素及瘦素抵抗与单纯性肥胖的发生发展密切相关。研究表明,针灸可通过改善瘦素抵抗、促进瘦素受体基因表达、抑制NPY基因表达、激活瘦素信号通路等途径良性调节瘦素,达到减肥目的。本文从瘦素的生物学效应、瘦素与肥胖、针灸调节瘦素对肥胖的作用机制几方面做简要综述,以期为单纯性肥胖的针灸治疗提供新思路。     

Shp2 as a therapeutic target for leptin resistance and obesity

Most obese subjects exhibit leptin resistance, thus restricting the value of direct leptin administration for treatment of obesity. Understanding the leptin signalling mechanism has become crucial for design of novel therapeutic strategies for leptin-resistant/obese patients. The SH2-containing cytoplasmic tyrosine phosphatase Shp2 has recently been shown to play a critical role in leptin signalling and functions in hypothalamic control of energy balance and metabolism. Shp2 appears to downregulate the LepRb-STAT3 pathway while promoting extracellular-regulated kinase activation by leptin. Overall, Shp2 is a leptin signal enhancer, as evidenced by the obese and hyperleptinemic phenotype of mutant mice with Shp2 deleted in postmitotic forebrain neurons. Pharmaceutical enhancement of Shp2 activity may be a new approach worthy of consideration in clinical treatment of leptin resistance and obesity. This article discusses the significance of recent experimental data on Shp2 and also the prospects for using Shp2 as a therapeutic target for obese patients.