消炎利胆散的利胆作用及安全性考察

目的:制备消炎利胆散,研究其治疗胆囊炎、胆石症的作用机理及安全性.方法:(1)动物实验直接并引流测定胆汁分泌、排泄量.作急性、亚急性毒性试验及LD50测定.(2)化学分析测定胆红素、胆固醇分泌、排泄量.结果:(1)消炎利胆散组较利胆醇和纯化水组胆汁分泌、排泄量显著增加(P值分别＜0.05和0.01).(2)消炎利胆散组与利胆醇组较纯化水组胆汁中的胆红素含量差异有极显著性(P＜0.01),各组胆汁中胆固醇含量无差异.(3)消炎利胆散LD50＞82.8 g·kg-1.结论:(1)消炎利胆散利胆作用强.胆汁及其胆红素,胆固醇排出量增加与治疗胆囊炎、胆石症密切相关.(2)安全性好.     

金钱草颗粒剂的药效学研究

目的:探讨金钱草颗粒剂的药理作用.方法:建立动物实验模型,抗炎实验:通过小鼠耳廓二甲苯致炎,以左右耳片重量差为肿胀程度,计算各组肿胀度;利胆实验:采用胆管引流法测定金钱草颗粒对大鼠胆汁流量变化的影响.结果:金钱草颗粒可抑制由二甲苯所致小鼠耳廓肿胀,且各剂量组与空白对照组比较均有显著性差异(P<0.01);能明显增加胆汁分泌量,且中剂量组效果最佳,3h累积胆汁量为(1.68±0.02)mL,与空白对照组比有显著性差异(P<0.05,P<0.01).结论:金钱草颗粒有显著的消炎利胆作用,对胆囊炎有很好的治疗作用.     

虎杖水提液利胆保肝作用研究

目的初步研究虎杖水提液的利胆保肝作用。方法以大鼠胆管插管法,十二指肠给药,记录给药前1h,给药后1,2,3和4h胆汁流量及胆汁中胆红素(TBIL)和胆固醇(CHO)含量,观察虎杖水提液利胆作用;采用腹腔注射CCl4橄榄油溶液复制小鼠急性肝损伤模型,检测血清丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)含量,观察其对肝的保护作用。结果虎杖水提液可增加大鼠胆汁分泌量(P<0.05或P<0.01);可明显降低CCl4模型小鼠血清ALT和AST含量(P<0.05或P<0.01)。结论虎杖水提液具有利胆和保肝作用。     

雪域肝胆康胶囊对小鼠实验性肝损伤及胆汁的影响

目的 研究藏药雪域肝胆康胶囊(XYGD)的保肝利胆作用.方法 以CCl4制作动物急性肝损伤模型,测定血清ALT、AST、TBIL的含量,观察XYCD对动物急性肝损伤的影响;采用麻醉大鼠行胆汁引流术,测定正常大鼠的胆汁分泌量及胆汁成分.结果 雪域肝胆康胶囊能明显降低CCl4急性肝损伤动物血清ALT、AST水平;使正常大鼠的胆汁流量明显增加,降低胆汁中胆固醇的浓度.结论 XYGD有明显保肝、利胆作用.     

重楼含药血清对系膜细胞增殖及分泌纤维连接蛋白的影响

目的探讨中药重楼治疗肾小球疾病的作用机制。方法提取大鼠的含药血清作用于体外培养的大鼠系膜细胞(MC),观察重楼对MC增殖及分泌纤维连接蛋白(FN)的影响。结果①CCK-8比色法结果显示:脂多糖(LPS)能促进肾小球MC异常增殖(P<0.01)。重楼各剂量组OD值均较LPS组显著减低(P<0.01);在干预24 h时重楼随着剂量的增加,其OD值逐渐减低,3个剂量组两两比较均有显著性差异(P<0.01或P<0.05)。②ELISA法测定结果显示:重楼各剂量组均能明显抑制FN的分泌(P<0.01);随重楼剂量的增加MC分泌FN的水平呈递减变化,且重楼各剂量组间两两比较均有显著性差异(P<0.01)。③RT-PCR显示FN mRNA在正常组有少量表达,在LPS组其表达量显著增加(P<0.01),重楼各剂量组较LPS组均显著减低(P<0.05)。结论重楼含药血清可抑制MC的异常增生及MC过度分泌FN,此可能是重楼治疗肾小球疾病取得临床疗效的内在机制。     

芒果苷利胆作用及对胆囊平滑肌痉挛的影响

目的：探讨芒果苷利胆作用及对胆囊平滑肌痉挛的影响.方法：利用胆管引流法测定芒果苷对大鼠胆汁的流量及成分的影响;通过对豚鼠胆囊肌条的收缩试验观察芒果苷对乙酰胆碱所致胆囊平滑肌痉挛的影响.结果：芒果苷4.74×10-5 mol·kg-1剂量组可显著提高大鼠的胆汁流量,显著提高胆汁中胆红素浓度（P ＜0.01）;2.37×10-5 mol·L-1剂量组可显著抑制由乙酰 胆碱引起的豚鼠胆囊痉挛（P＜0.01）.结论：芒果苷具有利胆作用,可缓解乙酰胆碱引起胆囊痉挛.     

复方金钱草颗粒利胆及体外抗豚鼠胆囊平滑肌痉挛作用研究

目的探讨复方金钱草颗粒利胆作用及对胆囊平滑肌痉挛的影响。方法利用胆管引流法测定给复方金钱草颗粒前后大鼠胆汁的流量及成分;通过对豚鼠胆囊肌条的观察,探讨复方金钱草颗粒对乙酰胆碱所致胆囊平滑肌痉挛的影响。结果复方金钱草颗粒7．4g／kg剂量组可显著提高大鼠的胆汁流量,显著提高胆汁中胆红素浓度;62g／L剂量组可显著抑制由乙酰胆碱引起的豚鼠胆囊痉挛。结论复方金钱草颗粒具有利胆作用,可缓解乙酰胆碱引起的胆囊痉挛。     

健脾消胀片对大鼠胆汁分泌的影响

目的：观察健脾消胀片对大鼠胆汁分泌的影响。方法：大鼠60只,分为6组,分别灌服健脾消胀片（大、中、小剂量）混悬液;舒胆通混悬液;清肝利胆胶囊混悬液和同体积的0.5%羧甲基纤维素;每天给药1次,连续给药5 d。收集各组大鼠胆汁量,检测胆汁中总胆汁酸、总胆固醇、总胆红素等含量。结果：健脾消胀片可使大鼠胆汁中胆汁酸、胆红素含量显著升高（P〈0.01）,胆固醇含量显著降低（P〈0.01）。结论：健脾消胀片有促进胆汁分泌的作用。     

利胆宁口服液利胆抗炎镇痛作用的研究

目的研究利胆宁口服液利胆、抗炎、镇痛的作用。方法胆管引流法测定正常大鼠胆汁流量;重氮化法测定胆汁及血清总胆红素的含量;二甲苯致炎法测定小鼠两耳重量差;热板法和扭体法分别测定小鼠痛阈值及扭体次数。结果利胆宁口服液能明显增加大鼠胆汁流量和胆汁胆红素含量;明显降低二甲苯致炎小鼠两耳重量差;明显延长小鼠痛阈值;明显降低小鼠扭体次数。结论利胆宁口服液具有利胆、抗炎、镇痛的作用。     

清肝利胆浸膏保肝、利胆的实验研究

目的：观察清肝利胆浸膏对急性肝损伤的保护作用和利胆、退黄作用。方法：用CCL4－和D－GaL致小鼠急性肝损伤，观察血清ALT和AST；用麻醉大鼠胆管收集胆汁，测定胆汁中胆固醇和总胆红素的含量；用异硫氰酸－1－萘酯造成黄疸模型，测定血液中ALT和AST、总胆红素。结果：清肝利胆浸膏能显著降低CCL4致小鼠ALT和AST升高，对D－GaL致小鼠ALT和AST升高亦有明显降低，对大鼠胆汁分泌有增加，对胆汁成份胆固醇、总胆红素升高有明显的降低。结论：清肝利胆浸膏具有一定的保肝降酶、利胆和退黄作用。     

Choleretic Effect of Curcuma comosa Rhizome Extracts in Rats

Choleretic properties of various extracts of Curcuma comosa Roxb. (Zingiberaceae) were investigated in rats. Butanol and ethyl acetate extracts of the rhizome were the most effective in producing a choleretic effect. Intraduodenal administration of the ethyl acetate extract caused a dose-dependent stimulation of bile secretion. A high dose of the extract increased bile flow rate with decreased bile salt concentration whereas low doses increased the bile flow rate without altering bile salt concentration. With regard to the total output of biliary constituents, the high dose of extract did not alter secretory bile salt output, but markedly increased biliary cholesterol output. Concurrent with increased biliary cholesterol secretion, C. comosa caused a decrease in plasma cholesterol level. This result suggests potential development of this plant as a source of choleretic and hypocholesterolemic drugs.     

The effects of 3,5,5-trimethylcyclohexanol on hepatic cholesterol synthesis, bile flow and biliary lipid secretion in the rat.

The chemical trimethylcyclohexanol (TMC) is closely related to menthol, the major component of a terpene preparation with known choleretic and cholelitholytic activity. Its effects on hepatic cholesterol synthesis and bile secretion were examined in the rat. In both acute and long-term dosing experiments TMC significantly inhibited hepatic S-3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase. TMC was a potent choleretic, with detectable effects on bile flow at low doses, which also reduced coupling of cholesterol secretion to bile salt secretion. Single large doses tended to lower biliary cholesterol output and caused significant reduction in cholesterol saturation index after biliary diversion for 1 h. TMC and its widely prescribed ester cyclandelate, which is rapidly degraded to TMC after ingestion, should be investigated further as potential cholelitholytic treatments in man.     

Choleretic activity of phloracetophenone in rats: structure-function studies using acetophenone analogues

The relationship between the chemical structure and choleretic activity of phloracetophenone (2,4,6-trihydroxyacetophenone) was investigated in adult male rats. Fourteen acetophenone analogues, with different substituents on the benzene nucleus, were intraduodenally administered and bile samples were collected via a bile fistula. All of the compounds tested immediately induced choleresis. For the same number of substituents on the benzene ring, hydroxy analogues induced a greater choleresis. The number and position of hydroxy substituents on the benzene nucleus play an important role in determining choleretic activity and biliary secretion of bile acid, but had no relation to biliary excretion of cholesterol. The choleretic activity of the hydroxylated compounds was inversely related to hydrophobicity, as inferred by thin-layer chromatography (TLC). Among the hydroxylated acetophenone analogues, 2,4,6-trihydroxyacetophenone was identified as the most potent, with a choleretic activity of 231.8+/-6.1 microl/mmol/min. It induced both a high bile flow rate and a high bile salt output and led to lower plasma cholesterol levels. This bile had a low lithogenic potential. The results suggest that a structural requirement for high choleretic activity of 2,4,6-trihydroxyacetophenone is a substituent hydroxy group at 4-position. Additional hydroxy groups at 2- and 6-positions are essential for the induction of higher an output of bile acid, and possibly, other solid materials.     

Pharmacokinetics of ursodeoxycholic acid in rat

The pharmacokinetic behaviour and metabolism of ursodeoxycholic acid (UDCA) have been studied in the rat. After oral administration of both 3H-labelled (4 muCi/kg body wt) and unlabelled (20 mg) UDCA, UDCA appeared in serum almost entirely in conjugated form (taurine conjugated); UDCA was present in bile mostly as taurine conjugated; the more relevant metabolite is 3 alpha,6 alpha, 7 beta-trihydroxycholanoic acid which represents 10% of the total bile acid pool. UDCA increased bile flow and selectively decreased biliary cholesterol secretion, while phospholipid secretion was unaffected. Faecal UDCA excretion was 15-20% while the urinary extraction was 1.5% during 24 h. The data show that UDCA, when administered in high dose, is promptly secreted into bile almost entirely metabolized to tauroursodeoxycholic acid, where it (1) desaturates the cholesterol in bile, (2) exerts choleretic properties.     

Effect of ethinylestradiol and epomediol on bile flow and biliary lipid composition in rat.

Epomediol (1,3,3-trimethyl-2-oxabicyclo(2.2.2.)octan-6,7-endo,endo-diol) (EPO) is a terpenoid compound shown to reverse 17 alpha-ethinylestradiol (EE)-induced cholestasis in rat. The effect is related to the restoration of normal liver plasma membrane fluidity values. To further characterize the effect of EPO, bile flow and biliary lipid composition were measured in rats treated either with EE or EE associated with EPO. EE significantly reduced the bile flow; this reduction was prevented by concomitant treatment with EPO with an increase in the bile salt secretion rate. EPO alone showed a choleretic effect. The biliary secretion rate of cholesterol was also significantly reduced by EE while being comparable to controls in EE-EPO-treated animals. Phospholipid (PL) biliary excretion was significantly (P less than 0.002) increased by EE either alone or combined with EPO. After EE treatment, the biliary PL composition showed a reduction in phosphatidylcholine (PC) concentration with a parallel increase in lyso-phosphatidylcholine (LPC) when compared to control animals (PC:LPC ratio 5.0 +/- 2.5 vs 26.8 +/- 9.9, mean +/- SD, P less than 0.005). EPO administration to EE-treated rats restored the biliary PC:LPC ratio to control values (27.6 +/- 10.6). EPO alone did not show any appreciable effect as compared to both control and EE-EPO treated animals. As increased concentrations of LPC have been reported to induce an alteration in the function of membrane lipids and membrane-associated proteins, such as regulatory enzymes for bile acid, cholesterol and phospholipid metabolism, these results suggest that the protective effect of EPO in EE-induced cholestasis may be related to the reversal of the alterations in membrane lipid composition and function induced by EE.     

A possible mechanism of choleretic action of 3-(2,4,5-triethoxybenzoyl)-propionic acid (AA-149) in dogs

The choleretic action of 3-(2,4,5-triethoxybenzoyl)propionic acid (AA-149) was studied in anesthetized dogs. AA-149 produced a dose-dependent increase of the bile flow with both i.v. and intrajejunal administration of doses 1 mg/kg and higher. Biliary clearance of 14C-erythritol showed that AA-149 stimulated canalicular bile formation without enhancement of water secretion and/or inhibition of bile reabsorption in the biliary ductules and ducts. AA-149 did not increase the excretion of bile acids into the bile, but enhanced the excretion of the biliary electrolytes, in particular sodium ion, in proportion to an increase of the bile flow. About 3--4% of AA-149 administered i.v. was excreted into the bile during the first 1 h period, so that biliary AA-149 was insufficient to increase the bile flow via its osmotic effect. These results strongly suggest that the choleretic action of AA-149 is attributable to stimulation of a bile acid-independent bile formation in the canaliculi coupled with an active sodium transport system.     

Inhibition of biliary lipid and protein secretion by cyclosporine A in the rat.

We investigated the effect of cyclosporine A (CyA) administered as a single i.v. dose of 20 and 40 mg/kg body wt, on biliary secretion of cholesterol, phospholipid, bile acid, and lysosomal marker and canalicular plasma membrane marker enzymes in anaesthetized Wistar rats. CyA reduced the concentration and biliary secretion of cholesterol, phospholipid and bile acid to a considerable extent; the inhibitory effect of CyA on the biliary secretion of phospholipid and bile acid was greater than that on cholesterol. The biliary outputs of acid phosphatase (AcP) and gamma-glutamyltransferase (gamma-GT) were also diminished by the drug, all these effects being dose-dependent. Maximum decreases in bile acid secretion were observed 10 min after administration, whereas those of cholesterol and phospholipid were delayed. Bile acid concentrations and secretion returned to pretest values at 30-50 min after CyA injection whereas those of cholesterol and phospholipid remained significantly reduced at this time point. The greater inhibitory effect of CyA on the biliary outputs of phospholipid and bile acid relative to cholesterol secretion together with the asynchronous fall and recovery of bile acid, cholesterol and phospholipid concentrations and secretion alter the cholesterol/bile acid, phospholipid/bile acid and cholesterol/phospholipid molar ratios as well as the lithogenic index, thus suggesting that CyA would uncouple biliary lipid secretion from bile acid secretion. Since under physiological conditions biliary lipid and gamma-GT secretion is related to and dependent upon bile acid secretion, we propose that the CyA-induced inhibition on lipid and gamma-GT secretion is, at least partly, secondary to the fall in bile acid output caused by the drug. However, since CyA inhibits secretory processes independent of the hepatobiliary flux of bile acid, such as the exocytic discharge of AcP, and because it also uncouples biliary lipid from bile acid secretion, other mechanisms and factors involved in lipid and protein secretion (such as intracellular transport, canalicular membrane fluidity and/or intracanalicular events) might also be altered by this drug.     

Biliary lipids, cholesterol and bile synthesis: different adaptive mechanisms to dietary cholesterol in lean and obese subjects

BACKGROUND: Increased biliary cholesterol secretion together with elevated cholesterol synthesis may predispose obese subjects to cholesterol gallstone formation. AIM: To investigate whether processing of dietary cholesterol is altered in obesity, we enrolled eight lean and seven obese subjects in a double-blind crossover study. METHODS: Cholesterol consumption was 300 mg/day on low and 1300 mg/day on high cholesterol diet. After 3 weeks on either diet, hepatic bile was collected to determine biliary lipid secretion, and bile salt composition by high-performance liquid chromatography and cholesterol saturation index was calculated. Cholesterol synthesis was measured employing mass isotopomer distribution analysis. Bile acid synthesis via neutral and acidic pathway was assessed by serum levels of 7alpha-hydroxy-4-cholesten-3-one and 27-hydroxycholesterol. RESULTS: Cholesterol synthesis was increased in obese compared with lean and feedback inhibited only in obese. On low cholesterol diet, cholesterol secretion was doubled in obese but bile acid composition and synthesis was similar between the two groups. After high cholesterol diet, cholesterol saturation index and bile secretion were unchanged. In contrast to obese, lean increased bile acid synthesis only via the acidic pathway. CONCLUSIONS: Dietary cholesterol appears to preferentially induce bile acid synthesis via the acidic pathway in lean, whereas cholesterol synthesis was inhibited in obese. Thus, stable cholesterol saturation index may be achieved by different mechanisms.     

Effects of S 21403 on hormone secretion from isolated rat pancreas at different glucose concentrations

The plasma cholesterol-lowering effect and mechanism thereof of a choleretic phloracetophenone or 2,4,6-trihydroxyacetophenone (THA) were investigated in hypercholesterolemic male hamsters. Intragastric administration of THA (300-600 micromol/kg) twice a day for 7 days to these animals caused a dose- and time-dependent decrease in both plasma cholesterol and triglyceride levels. THA at a dose of 400 micromol/kg reduced the cholesterol and triglyceride levels in plasma to 52% and 25% of the level in corresponding cholesterol-fed controls, respectively, with decreases in both plasma very low density lipoprotein and low density lipoprotein cholesterol but not in high density lipoprotein cholesterol. THA did not significantly alter total hepatic cholesterol content but significantly increased the excretion of both bile acids and cholesterol into the intestinal lumen for elimination. Corresponding to the increase in bile acid excretion, THA caused a seven-fold increase in hepatic cholesterol 7alpha-hydroxylase activity. These results suggest that THA exerts its cholesterol lowering effect by increasing hepatic cholesterol 7alpha-hydroxylase activity which increases hepatic conversion of cholesterol to bile acid for disposal via biliary secretion. This compound may have a potential for future development as a therapeutic agent for lowering lipids in hypercholesterolemic patients.     

EFFECT OF INCREASED BILE FLOW AND BILE ACID SECRETION ON THE HEPATIC ELIMINATION OF SODIUM VALPROATE IN THE CAT

The effect of increased bile flow and hepatic bile acid flux on the systemic clearance and hepatic elimination of intravenously administered sodium valproate was studied in the bile fistula cat. Taurochenodeoxycholic acid (TCDC), tauro-3 alpha, 7 beta-dihydroxy-12-keto-5 beta-cholanoic acid (T12K), SC-2644, and secretin were infused intravenously to vary bile flow and biliary bile acid secretion. Control animals were infused with 0.15 mol/l NaCl. Less than 1% of the drug administered to controls appeared as unchanged valproate in the bile over 6 h. Although SC-2644, T12K, and secretin significantly increased biliary excretion of valproate, it did not exceed 2% of the intravenous dose. Biliary clearance was directly related to the rate of bile flow, but not to the bile acid flux. By contrast, 18-19% of the dose appeared in bile as metabolite in controls, and none of the choleretic agents significantly increased this percentage. As a result, systemic clearance of valproate was unaltered. We conclude that the movement of unchanged valproate into bile is consistent with a process of simple diffusion. The fact that choleretic agents do not increase metabolite excretion into bile suggests that metabolite formation may be the rate-limiting step in the hepatic elimination of valproate, rather than transport and excretion of metabolites into bile.