Idiopathic Bile Acid Diarrhoea Reconsidered

Two new cases of a rare entity provisionally coined ‘idiopathic bile acid diarrhoea’ are reported and compared with previous cases. The diarrhoeal syndrome has been identified as a cholegenic enteropathy. In the absence of conventional ileopathy the cause of the bile acid loss is obscure, but it is hypothesized that it may be due to a relative deficiency in ileal absorptive sites for bile acid anions. So far the diagnosis has partly been based on measurements of faecal bile acid losses. It is suggested that a carefully conducted therapeutic trial with cholestyramine may be almost equally helpful.     

ABCG5 基因突变致植物固醇血症1 例

目的探讨ABCG5基因突变所致的植物固醇血症的临床及基因变异特征。方法回顾分析1例ABCG5基因突变致植物固醇血症患儿的临床资料。结果 1岁3个月男性幼儿,约4月龄时腕、踝关节皮肤褶皱处开始出现线状黄瘤,后渐加重。血固醇谱检查示菜油固醇、二氢胆固醇明显升高。全外显子检测示ABCG5基因c.904+1(IVS7)GA剪切位点突变和c.-76(exonl)CT非编码区突变。经严格控制植物固醇摄入、少量限制动物固醇摄入以及口服消胆胺治疗40天后,复查患儿血固醇谱,植物固醇水平较前明显降低。结论 ABCG5变异可致植物固醇血症,及时诊断以及药物和饮食控制可改善预后。     

Alterations in membrane-bound and cytoplasmic K-ras protein levels in mouse lung induced by treatment with lovastatin,cholestyramine, or niacin: effects are highly mouse strain dependent

Agents that either increase (cholestyramine, CS) or decrease (lovastatin, Lov) de novo peripheral cholesterol synthesis may increase (CS) or decrease (Lov) ras protein membrane localization by altering protein prenylation, and potentially have pro- or anti-carcinogenic effects. Male A/J, Swiss, and C57/BL6 mice were treated with 2 or 4% CS, 1% dietary niacin, or 25mg/kg of Lov three times per week (Lov-3X) or five times per week (Lov-5X). After 3 weeks, serum cholesterol and triglycerides were determined enzymatically. Membrane and cytoplasmic K-ras proteins in lung were determined by immunoprecipitation followed by western blotting with a K-ras specific antibody. Results confirmed the hypothesis only in isolated instances. A/J mice had a significant 30% increase in cytoplasmic K-ras and a 40% decrease in membrane K-ras from Lov treatment, as predicted. C57/BL6 mice had a significant 77% increase in membrane K-ras, as expected from CS feeding. At variance with the hypothesis, Swiss mice had increased levels (3-28%) of membrane K-ras with all treatments (including Lov), and C57/BL6 mice treated with Lov had a 58-78% increase in cytoplasmic K-ras without any reduction in the levels of membrane K-ras. Niacin, predicted to have no effect on ras membrane localization, decreased cytoplasmic K-ras in A/J mice, increased both membrane and cytoplasmic K-ras in Swiss mice, and had no effect in C57/BL6 mice. Results may have differed from those predicted because of strain-dependent differences in response to the cholesterol-lowering agents. A difference in response among the mouse strains suggests that individual genetic differences may alter the effect of hypocholesterolemic agents on K-ras membrane localization, and potentially the risk of ras-dependent cancer.     

Combinations of ezetimibe with nonstatin drug regimens affecting lipid metabolism

In this article we discuss the available data on the effects of combined therapy of ezetimibe with agents affecting lipid metabolism other than statins. We consider studies evaluating the effects of combined therapy of ezetimibe with bile acid sequestrants, fenofibrate, niacin, n-3 fatty acids, plant sterols, orlistat, metformin, acarbose and glitazones. Combination of ezetimibe with bile acid sequestrants (especially colesevelam) was shown to have additional effects on lipid parameters in patients with hyperlipidemia. Combination of ezetimibe with fenofibrate may be a good approach to improve the overall lipid profile of patients with mixed hyperlipidemia. The addition of ezetimibe to niacin-based therapy can be useful for high-risk patients with dyslipidemia who are not achieving their assigned treatment goals. For patients who cannot tolerate statins there are useful combinations of ezetimibe with other drugs affecting lipid metabolism. These combinations improve many metabolic parameters, but more trials should be carried out to reach more robust conclusions about their effects on cardiovascular disease prevention.     

In Vitro Binding of Lorazepam and Lorazepam Glucuronide to Cholestyramine,Colestipol, and Activated Charcoal

Pharmaceutical Research -     

Attenuated gastropathy but not enteropathy of diclofenac–cholestyramine complex in rats

Diclofenac is a nonsteroidal anti‐inflammatory drug (NSAID) widely prescribed for pain and inflammation. Theoretically, the gastrointestinal (GI) complications of diclofenac could be minimized by administering a diclofenac resinate formulation, such as Flotac, where GI mucosal contact with free NSAID is minimized by its complexing with the cholestyramine resin. The objective of the present study was to investigate the influence of cholestyramine co‐treatment on diclofenac enteropathy in fed rats and diclofenac gastropathy in fasted rats. Male Sprague‐Dawley rats were gavaged with diclofenac (50 mg/kg), diclofenac (50 mg/kg) plus cholestyramine (50 mg/kg), or an equivalent amount of Flotac, a 1:1 wt/wt mixture of diclofenac and cholestyramine presently used in human therapeutics in Mexico. Ulceration of the GI tract, serum proteins, and bile salts were assessed at 3, 12, or 24 h. Cholestyramine alone produced no detectable alterations in small intestinal integrity or serum bile salts levels. Fed rats given Flotac or diclofenac plus cholestyramine showed patterns of small intestinal ulceration and serum protein decline that were similar to rats given only diclofenac. Thus, no influence on enteropathy was detected. In contrast, fasted rats given Flotac showed a modest reduction in the number and length of gastric lesions compared to rats given diclofenac. The observed attenuation of gastric lesions with Flotac is consistent with a role for direct cytotoxicity in NSAID gastropathy. Drug Dev. Res. 64:19–27, 2005. © 2005 Wiley‐Liss, Inc.     

Role of bile acids in the control of pancreatic secretion and CCK release

Abstract. In most species stimulated pancreatic enzyme secretion and CCK release are increased in the absence and inhibited in the presence of luminal bile acids. Changes in CCK release are almost unequivocal in all investigated species. With respect to enzyme secretion, physiological bile acid concentrations seem to be necessary to exert an inhibitory effect on stimulated enzyme output in humans. Bile acids administered in higher concentrations may enhance basal and stimulated pancreatic secretion. Furthermore, the chemical properties of different bile acids (i.e., hydroxylation, conjugation) seem to contribute to their stimulating effect on enzyme secretion as was observed in several species. The rank order of bile acids inhibiting stimulated enzyme secretion in humans is taurocholate taurodeoxycholate > taurocheno-deoxycholate. On the other hand, chenodeoxycholic acid exerts the strongest stimulating effect on secretin release, which may account for the stimulating effect of this bile acid on exocrine pancreatic secretion.
The strongest candidate for the mediator role in bile-acid-induced changes of exocrine pancreatic secretion is CCK (at least in dogs and rats).
The CCK cell may be influenced either directly or indirectly.
In conclusion, bile acids modulate pancreatic enzyme secretion and CCK release. CCK is a major candidate for this regulatory role under physiological conditions.     

Effects of acipimox and cholestyramine on serum lipoproteins,non-cholesterol sterols and cholesterol absorption and elimination

Summary The hypolipidaemic and metabolic effects of cholestyramine combined with acipimox or placebo have been evaluated in a double-blind ninety-day study in 18 patients with xanthomatous familial hypercholesterolaemia.Serum LDL-cholesterol was reduced by 35% in the cholestyramine group and 39% in the acipimoxcholestyramine group. The latter treatment increased the HDL-cholesterol level. Serum VLDL-cholesterol and triglyceride concentrations were unchanged.Cholesterol absorption efficiency was significantly reduced, and bile acid synthesis and faecal cholesterol elimination in both groups were increased. The metabolic changes were similar in the two treatment groups, but the increase in faecal neutral sterol excretion was significant only when acipimox was added.The serum cholesterol precursor sterol contents were similarly increased during the two treatments, indicating enhancement of endogenous cholesterol synthesis.The decrease in cholesterol absorption and the increase in neutral sterol excretion were more pronounced in subjects with >30% than in those with <30% reduction in LDL-cholesterol.The changes in serum total and LDL-cholesterol levels and cholesterol metabolism were not related to apoE phenotype, but the increase in HDL-cholesterol was higher in E4 then in E3 subjects.     

Cholestyramine treatment of type IIa hypercholesterolaemia normalizes platelet reactivity against prostacyclin

Abstract. The effect of lowering total plasma and low density lipoprotein (LDL) cholesterol in heterozygous familial hypercholesterolaemia type IIa (FH) on platelet function, thromboxane (TX) formation and platelet sensitivity against iloprost, a stable prostacyclin mimetic, was studied in platelet-rich plasma ex vivo . Seven FH patients were treated with cholestyramine (12 g day^-1) for 8–11 months and were compared with eight untreated FH patients and 11 healthy control subjects. In comparison with platelets from healthy controls, platelets from untreated FH patients exhibited a significantly increased aggregation response and TX formation, and a reduced reactivity against inhibition of platelet aggregation by prostacyclin. Treatment with cholestyramine for 8–11 months resulted in a 21% reduction in total serum and LDL-cholesterol. This was not accompanied by any change in platelet hyperreactivity or TX formation. However, cholestyramine treatment normalized the platelet reactivity of FH patients against iloprost, being no more different from healthy controls. It is concluded that reduction in plasma cholesterol by cholestyramine results in normalization of the reduced platelet sensitivity against prostacyclin. This might contribute to beneficial effects of cholestyramine treatment in preventing thrombembolic complications of atherosclerosis.