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PubMed1988

Regulation of bile acid pool size and plasma lipid levels in the SHR/N-corpulent rat: influence of the level of caloric intake.

In the obese progeny of the SHR/N-cp strain of the rat the bile acid pool was at least twice as large as that in their lean littermates even when only 6 weeks old. The composition of the pool remained unchanged in the obese females, but in their male counterparts the proportion of cholic acid was significantly increased. Cholestyramine feeding reduced the pool size by 26% in the obese rats, but a similar effect also occurred in the lean animals. The obese rats consumed about 60% more food per day than their lean littermates. When obese females were pair-fed to the intake of their lean controls from 6 to 11 weeks of age, the bile acid pool remained significantly enlarged, although not to the same extent as in the obese rats fed ad lib. Plasma cholesterol levels were reduced but remained significantly higher than the levels in the lean animals. The marked hypertriglyceridemia exhibited by the obese rats fed ad libitum did not develop in their pair-fed counterparts. In contrast, there was a comparatively smaller reduction in plasma cholesterol and triglyceride levels in the obese rats fed cholestyramine. Hepatic steatosis persisted in the pair-fed animals as well as in those given cholestyramine. Restricting caloric intake significantly reduced the body weight gain of the obese rats but had little effect on the extent of their corpulence. These studies show that at least some of the characteristics of this congenic strain, including hypertriglyceridemia and hepatic and intestinal hypertrophy, are due mainly to excess dietary intake.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1998

Clinical efficacy and safety of cerivastatin in the treatment of heterozygous familial hypercholesterolemia.

Patients with heterozygous familial hypercholesterolemia are at especially high risk of premature coronary artery disease and usually require aggressive long-term lipid-lowering drug therapy to decrease plasma low-density lipoprotein (LDL) cholesterol concentrations to normal levels. In the present study, the lipid-lowering effects of cerivastatin in combination with cholestyramine and probucol were investigated in 20 patients with heterozygous familial hypercholesterolemia over a 20-week treatment period. After an initial 4-week treatment with once-daily 0.2 mg cerivastatin, serum total cholesterol and LDL cholesterol levels had decreased by a significant 22% and 25%, respectively (p <0.01). The addition of 8 g/day cholestyramine or 1 g/day probucol to ongoing cerivastatin therapy produced further significant reductions in total cholesterol of 16% and 16%, respectively, and in LDL cholesterol of 22% and 15%, respectively (p <0.01), over the 12-week combination therapy period. The potent lipid-lowering effects of combined treatment were accompanied by excellent toleration of study drugs. Only 2 patients experienced gastrointestinal side effects associated with cholestyramine therapy. There was no evidence of any abnormalities in creatine phosphokinase in either treatment group and only 2 patients exhibited minor increases in hepatic transaminases. This study has shown that cerivastatin can be safely combined with either cholesytramine or probucol to provide a safe and highly effective hypolipidemic treatment regimen for patients with heterozygous familial hypercholesterolemia.

Adult↗

PubMed2000

Achievement of target plasma cholesterol levels in hypercholesterolaemic patients being treated in general practice.

A total of 1028 hypercholesterolaemic men and women aged 18-75 participated in an open label, randomised, parallel group, 6-month treatment-to-target study conducted in 240 general practices throughout Australia. The study compared atorvastatin monotherapy with simvastatin monotherapy or, if necessary, with the combination of simvastatin and cholestyramine in terms of their abilities to achieve a plasma total cholesterol target of<5.0 mmol/l. The initial daily dose of each drug was 10 mg. If the target was not achieved, the dose was doubled at 6 week intervals to a maximum daily dose of 80 mg atorvastatin or 40 mg simvastatin, with the simvastatin supplemented if necessary with 4 g cholestyramine. The percentage of patients achieving the target at 10 and 20 mg doses of atorvastatin were comparable to 20 and 40 mg of simvastatin, respectively. Despite relatively high baseline levels of plasma total cholesterol (mean levels of 7.41 and 7.31 mmol/l in the atorvastatin and simvastatin groups, respectively) the majority of patients in each group achieved the plasma total cholesterol target of<5.0 mmol/l. Treatment with atorvastatin achieved the target in 83% of patients, while simvastatin (or simvastatin plus cholestyramine) achieved the target in 66% of the patients (P<0.005). The target was achieved with 10 mg atorvastatin in 38% of patients and with 10 mg simvastatin in 26% of cases (P<0.005). In patients whose baseline cholesterol levels were between 5.6 and 6.5 mmol/l, 95% of the atorvastatin group and 86% of the simvastatin group reached the target. Even with baseline cholesterol levels between 7.6 and 8.5 mmol/l, the target was reached in 78% of the atorvastatin group and 61% of the simvastatin group. It is thus realistic for general practitioners to expect the majority of their at risk patients to achieve target plasma cholesterol levels that have been shown in population studies to be associated with relatively low rates of coronary heart disease. These targets are achieved in significantly more patients and at lower mg doses with atorvastatin than simvastatin.

Administration, Oral↗

PubMed2003

Assessing the zearalenone-binding activity of adsorbent materials during passage through a dynamic in vitro gastrointestinal model.

A novel approach is presented herein to study the intestinal absorption of mycotoxins by using a laboratory model that mimics the metabolic processes of the gastrointestinal (GI) tract of healthy pigs. This model was used to evaluate the small-intestinal absorption of zearalenone from contaminated wheat (4.1 mg/kg) and the effectiveness of activated carbon and cholestyramine at four inclusion levels (0.25, 0.5, 1 and 2%) in reducing toxin absorption. Approximately 32% of ZEA intake (247 microg) was released from the food matrix during 6 h of digestion and was rapidly absorbed at intestinal level. A significant reduction of intestinal absorption of ZEA was found after inclusion of activated carbon or cholestyramine, even at the lowest dose of adsorbents, with a more pronounced effect exhibited by activated carbon. In particular, when 2% of activated carbon or cholestyramine was added to the meal the ZEA intestinal absorption was lowered from 32% of ZEA intake to 5 and 16%, respectively. The sequestering effect of both adsorbents took place already during the first 2 h of digestion and persisted during the rest of the experiment. The GI-model is a rapid and physiologically relevant method to test the efficacy of adsorbent materials in binding mycotoxins and can be used to pre-screen mycotoxin/adsorbent combinations as an alternative to animal experiments.

Absorption↗

PubMed1979

Nuclear and cytosolic distribution of conjugated cholic acid and radiolabelled glycocholic acid in rat liver.

1. Normally fed and cholestyramine-treated rats were injected through the superior mesenteric vein with different amounts of radiolabelled glycoholic acid and the appearance of radioactivity in bile was measured. 2. In normally fed rats radioactivity appeared in bile within 30 s of injection and reached a maximum after 2 1/2 min; in the cholestyramine-treated animals the appearance of radioactivity was slower and less of the injected material was excreted into bile. 3. At 10 min after injection, livers were removed and the amounts of radioactive glycoholic acid and endogenous cholic acid conjugates in nuclei and cytosol were determined; most of the bile acid was found in the cytosol, only small amounts being found in nuclei. 4. Nuclear preparations from both normally fed and cholestyramine-fed rats were extracted with KCl (0.4 M) in an attempt to identify a putative bile acid receptor, but no such receptor was found. 5. Regulation of bile acid synthesis does not involve nuclear binding of bile acids.

Animals↗

PubMed2000

Additive effects of Simvastatin beyond its effects on LDL cholesterol in hypertensive type 2 diabetic patients.

BACKGROUND: Experimental evidence indicates that statins might have direct vascular effects independently from low-density lipoprotein (LDL) cholesterol reduction and we reported that the reduction in urinary albumin excretion rate during Simvastatin treatment in type 2 diabetic patients was not correlated with LDL-cholesterol decrease. However in humans there are no data regarding possible additional effects of Simvastatin on blood pressure and urinary albumin excretion beyond its capacity to lower serum cholesterol. PATIENTS AND METHODS: Twenty-six microalbuminuric hypertensive type 2 diabetic patients (diastolic blood pressure - after four months wash-out from the previous antihypertensive therapy - consistently > 90 and < 100 mmHg; plasma LDL-cholesterol > 3.9 and < 6.5 mmol L-1) were enrolled in the study. In random order, these patients received Simvastatin (20 mg day-1) or Cholestyramine (6 g three times a day) for a period of 10 months and after three months of wash-out (cross-over) the sequence was reversed for an additional 10 months. Blood pressure, lipid parameters, glycated haemoglobin and urinary albumin excretion were measured during the study. Additionally, in eight patients, urinary glycosaminoglycan excretion (GAG) was also measured during the study. RESULTS: Simvastatin and Cholestyramine were equally effective in reducing total and LDL cholesterol. Only during Simvastatin treatment a significant reduction in diastolic blood pressure and both 24 h urinary albumin and GAG excretion rates were observed, while no significant changes were seen with Cholestyramine treatment. CONCLUSIONS: Our results clearly show for the first time that the reduction of blood pressure, together with 24 h urinary albumin excretion rate - two established cardiovascular risk factors, obtained during Simvastatin therapy in hypertensive type 2 diabetic patients - is in large part independent from the reduction of LDL Cholesterol.

Albuminuria↗

PubMed1997

Arginine deficiency in bile duct-ligated rats after surgery: the role of plasma arginase and gut endotoxin restriction.

BACKGROUND & AIMS: Arginine deficiency may underlie the cellular immune depression after surgery in obstructive jaundice, which is associated with gut-derived endotoxemia. The aim of this study was to study arginine metabolism in the bile duct-ligated rat (BDL) after laparotomy. METHODS: Treatment with cholestyramine, a known endotoxin binder, was used to evaluate the role of gut-derived endotoxemia. RESULTS: In BDL rats, arginine levels were lower compared with those in sham-operated controls (P < 0.005), despite a three-fold increase in renal arginine release (P < 0.01). Liver and gut arginine handling also could not explain the reduced arginine levels. Higher plasma arginase activity (P < 0.0001) was measured in BDL rats, explaining both the lower arginine levels (r = 0.73, P < 0.01) and the increase in arginase product levels: ornithine (P < 0.005 and r = 0.72; P < 0.01) and urea (P < 0.01). Cholestyramine treatment prevented the decrease in postoperative arginine deficiency by reducing plasma arginase activity by 43% (P < 0.005). In addition, it significantly lowered plasma levels of the other liver enzymes (aspartate transaminase, alanine transaminase, gamma-glutamyl transpeptidase, and alkaline phosphatase; P < 0.05) in BDL rats. CONCLUSIONS: The study concluded that arginine deficiency in BDL rats after surgery is caused by high plasma liver arginase activity. Cholestyramine prevented the arginine deficiency by reducing plasma arginase activity through the inhibition of additional endotoxin-mediated hepatocellular damage after surgery in BDL rats.

Animals↗

PubMed1987

[Quantitative determination of LP-X in the differential diagnosis and treatment of direct hyperbilirubinemia in infancy].

Quantitative measurements of serum concentrations of LP-X were performed in 45 newborn and infants. The changes of LP-X concentrations before and after a 2-3 weeks' course of cholestyramine therapy differentiated extrahepatic biliary atresia (n = 6) from other causes of neonatal liver disease with a sensitivity of 100%, a specificity of 78.6 to 84.6% and an efficiency of 81.3 to 86.7%. The efficiency was decreased in children with alcoholic stools (75-80%). Cholestyramine treatment of 3-7 days did not allow to diagnose all children with extrahepatic biliary atresia. However, the test was superior to a combination of single measurements of LP-X and GGT. The changes of LP-X concentrations in serum were influenced by the individual course of the disease but not by the synthetic function of the liver (as indicated by CHE activities) or by parenteral nutrition or bacterial infections. LP-X was a valuable parameter in the management of cholestyramine therapy in infants with liver diseases.

Biliary Atresia↗

PubMed2003

Bile acid malabsorption in patients with chronic diarrhoea: clinical value of SeHCAT test.

BACKGROUND: Bile acid malabsorption (BAM), a cause of chronic diarrhoea, can be diagnosed by the SeHCAT test. The purpose of this study was to evaluate the usefulness of SeHCAT testing by assessing the extent of BAM and describing the clinical characteristics in a group of patients with chronic diarrhoea. Clinical outcome after treatment with cholestyramine was also evaluated. METHODS: During a 5-year period (1997-2001) the SeHCAT test was performed in 135 patients in whom a primary programme for diagnostic evaluation of chronic diarrhoea had not revealed a cause. File data from 133 patients could be evaluated. RESULTS: In 44% of patients, bile acid absorption was normal with SeHCAT retention > or = 15%. Impaired SeHCAT retention was found in 56%. All patients with ileocaecal resections had retention values < 10%. Patients with microscopic colitis presented with BAM in 39%. Only one patient with idiopathic BAM presented with steatorrhoea as opposed to 11 patients with type 1 and 3 BAM. Patients with idiopathic BAM and/or SeHCAT retention values < 5% had the best response to treatment with cholestyramine. CONCLUSIONS: The SeHCAT test is of value in evaluation of patients with chronic diarrhoea as a second-line investigation with a high diagnostic yield. The only a priori parameter to predict BAM was the existence of ileocaecal resections. The result of the SeHCAT test seems to predict the benefit of treatment with cholestyramine.

Adult↗

PubMed1999

Prognosis of adult-onset idiopathic bile acid malabsorption.

BACKGROUND: From 1986 to 1993, 150 patients were investigated with the 75Se-homocholic acid taurine (SeHCAT) test as a late step in the investigation of chronic diarrhoea. On basis of low SeHCAT values and response to cholestyramine treatment, 33 patients were initially classified as having idiopathic bile acid malabsorption (IBAM). The aim was to describe the long-term clinical course of the disease and to assess the reliability of the SeHCAT test in diagnosing IBAM. METHODS: The methods included 1) clinical follow-up with patient interview combined with information from medical records and 2) repeated SeHCAT test. RESULTS: The diagnosis of IBAM had to be revised in three cases (inflammatory bowel disease in two patients, Clostridium difficile infection in one). Six patients were lost to follow-up and a further four patients were excluded from re-examination either because of old age (>80 years) or bowel resection, leaving 20 patients for re-examination, of which 16 completed both clinical follow-up and a new SeHCAT test. The median duration of symptoms before initial SeHCAT test was 2.5 (1-30) years. In 13 of 16 patients symptoms persisted, and SeHCAT values remained low and almost identical to the initial value after a median observation time of 88 (51-113) months. Despite initial response to treatment with cholestyramine, six patients had to discontinue treatment because of adverse effects or other compliance problems. In three patients the SeHCAT value showed a considerable increase, and bowel function had correspondingly normalized in these cases. CONCLUSION: The study confirms the reliability of the SeHCAT test in diagnosing IBAM. Despite adult onset of symptoms, only a few patients improve after several years' observation. Treatment with cholestyramine is generally effective but not always tolerated.

Adult↗

PubMed1982

Effect of enhancement of cholesterol catabolism in guinea pigs after weaning on subsequent response to dietary cholesterol.

Cholesterol catabolism was stimulated (by cholestyramine) in post-weaned guinea pigs for a 4-wk period. The animals were then switched to regular Chow diet for another 4 wk. When subsequently challenged with 0.25% cholesterol-containing Chow, plasma cholesterol level was significantly (p less than 0.05) lower in cholestyramine pretreated guinea pigs when compared to control guinea pigs and this "hyporesponder" pattern was maintained throughout the study period. Cholestyramine pretreated animals continued to excrete significantly (p less than 0.05) higher bile acids even at 4 wk after switching to regular Chow diet. This study demonstrates that stimulation of cholesterol catabolism even at postweaning stages can still be as effective in improving subsequent cholesterol handling capacity as noted previously after manipulation at the neonatal stage.

Age Factors↗

PubMed1998

High-dose atorvastatin therapy in severe heterozygous familial hypercholesterolaemia.

Lipid targets can be difficult to attain in familial hypercholesterolaemia. To compare atorvastatin with simvastatin-fenofibrate and simvastatin-cholestyramine therapy, we studied 54 patients with familial hypercholesterolaemia over periods of 2-6 months on each therapeutic regimen. The atorvastatin regimen reduced total cholesterol by 41.2 +/- 11.2%, LDL by 45.6 +/- 15.5%, triglycerides by 33.8 +/- 24.8%, and increased HDL by 2.3 +/- 37.0%. Simvastatin-fenofibrate therapy achieved reductions of 33.9 +/- 8.5% in cholesterol, 42.0 +/- 12.2% in LDL, 34.7 +/- 38.3% for triglycerides, and a 25.4 +/- 55.1% increase in HDL. Simvastatin-cholestyramine gave a reduction of 31.3 +/- 11.8% in cholesterol, 36.0 +/- 14.4% in LDL, 13.7 +/- 36.3% in triglycerides, and a 1.1 +/- 30.3% rise in HDL. The atorvastatin regimen was marginally but not significantly better than simvastatin-fenofibrate in improving the LDL:HDL ratio, LDL:apoB and and apolipoprotein B:A1 ratios. Eleven patients (20.4%) had side-effects: two discontinued atorvastatin due to side-effects; two patients had rashes; six had myalgia and two had diarrhoea. Gastrointestinal side-effects were described in 16 (30.1%) patients on simvastatin-cholestyramine therapy and four cases of myalgia (11.2%) were seen with simvastatin-fenofibrate. In nine patients on atorvastatin (20.4%) a 30% or greater fall in HDL was observed, compared to five patients with resin therapy (9.2%) and two with fibrate therapy (5.5%). There were no significant differences in liver or muscle biochemistry between the regimens, but atorvastatin did raise transaminase and creatine kinase concentrations significantly compared to pre-treatment values (p = 0.001). Atorvastatin significantly improves the lipid profile in most patients compared with other regimens. It has a comparable incidence of side-effects to combination therapy regimens.

Adolescent↗

PubMed1989

Endogenous cholecystokinin regulates growth of human cholangiocarcinoma.

Exogenous administration of cholecystokinin (CCK) or caerulein inhibits growth of SLU-132, a human cholangiocarcinoma that we have shown to possess receptors for CCK. Chronic administration of cholestyramine, a resin that binds bile salts, increases release of CCK and growth of the pancreas in guinea pigs. Feeding the bile salt, taurocholate, inhibits meal-stimulated release of CCK. The purpose of this study was to determine whether endogenous CCK affects growth of the human cholangiocarcinoma, SLU-132. We implanted SLU-132 subcutaneously into athymic nude mice. The bile salt pool was depleted by feeding 4% cholestyramine for 40 days, either alone or enriched with 0.5% taurocholate for 32 days. When the mice were killed, tumors and pancreas were removed. Cholestyramine significantly inhibited the growth of SLU-132 and stimulated growth of the normal pancreas. Feeding of taurocholate acted to stimulate tumor growth. These results demonstrate that endogenous levels of CCK regulate growth of this human cholangiocarcinoma. Our findings suggest that manipulation of levels of endogenous gut hormones may, in the future, play a role in management of patients with certain gastrointestinal cancers.

Adenoma, Bile Duct↗

PubMed1979

Therapy of antibiotic-associated pseudomembranous colitis.

Seven patients treated with oral cholestyramine for antibiotic-associated pseudomembranous colitis are reported. Response was variable with only one patient having a totally satisfactory clinical outcome. Five of seven patients had continued systemic signs with fever and leukocytosis throughout the course of cholestyramine. Two observations were relatively consistent. First, six of the seven patient had a decrease in the number of daily stools during therapy. Second, all patients showed persistence of the cytopathic toxin in stools obtained after three to seven days of cholestyramine therapy. Six patients who were subsequently treated with oral vancomycin had a prompt clinical improvement and clearance of the cytopathic toxin in the stool.

Aged↗

PubMed1977

Effect of clofibrate and calcium in type II A hyperlipoproteinaemia.

In type II A hyperlipoproteinaemia, treatment with cholestyramine (12 g), calcium clofibrate (2 g) and a combination of calcium clofibrate and calcium carbonate (2 + 2 g) reduced the cholesterol concentration. The combination of calcium and clofibrate was at least as effective as cholestyramine. Calcium clofibrate decreased very low density and low density lipoprotein cholesterol, triglycerides and phospholipids, whereas no changes were found in high density lipoproteins. Cholestyramine decreased low density lipoprotein lipids.

Calcium↗

PubMed1988

Influence of bile acids on the biliary transport maximum of phenolsulfonphthalein in the rat.

1. The effect of changes in bile acid secretion induced by cholestyramine treatment or taurocholate infusion on the biliary transport maximum (Tm) of phenolsulfonphthalein (PSP) was studied in Wistar rats. 2. Five hours after oral administration of cholestyramine (1.5 g/kg bodyweight) the biliary output of bile acids decreased to 51% and bile flow to 76% of control values. The percentage of conjugated and unconjugated PSP excreted into bile and the Tm of the dye were not significantly modified by cholestyramine pretreatment. 3. Administration of sodium taurocholate at increasing rates (60-480 nmol/100 g bodyweight per min) enhanced bile flow and the biliary output of bile acids in a linear dose-related fashion. The Tm of PSP increased progressively until a maximum of 29% above the control values was reached at a taurocholate dose of 240 nmol/100 g bodyweight per min). The enhancement corresponded mainly to the unconjugated dye, the excretion of conjugated PSP not being significantly modified by the infusion of the bile acid. 4. The results indicate that bile acids can influence to some extent biliary excretion of PSP in the rat, although this component is of minor importance at low bile acid secretory rates.

Animals↗

PubMed1989

Simvastatin (MK 733): an effective treatment for hypercholesterolemia.

This study describes the efficacy of the drug simvastatin. It is likely to be the first HMG CoA reductase inhibitor in Australia and New Zealand available for the treatment of hyperlipidemia. Twenty-four patients, 12 men and 12 women with primary hypercholesterolemia were randomly allocated to treatment by cholestyramine (eight patients) or to simvastatin (16 patients) for a 12-week period. With simvastatin, total cholesterol levels decreased by 37.5% from a baseline mean of 10.33 mmol/L to 6.4 mmol/L after 12 weeks. Low density lipoprotein (LDL) cholesterol concentration decreased by 48.2% from 8.40 mmol/L to 4.39 mmol/L. These effects were better than observed for cholestyramine alone where cholesterol and LDL-cholesterol reductions were 24.9% and 33.1% respectively. Thirteen patients, however, did not achieve target LDL levels of 3.62 mmol/L, or below, and therefore were treated with a combination of cholestyramine and simvastatin, resulting in a decrease of total cholesterol and LDL-cholesterol by 45.5% and 53.5% of baseline values studied over an eight-week period. No major clinical side-effects were encountered. One patient appeared to have had a change in colour vision at the end of the study at 20 weeks, without loss of visual acuity.

Adult↗

PubMed1984

Effects of dietary fiber constituents on intestinal morphology and nutrient transport.

Adult male rats were fed for 4 wk on diets containing no addition, 10% fiber (methoxylated pectin or cellulose), or 2% cholestyramine. Weight gain and food intake in the fiber-fed groups were significantly greater than in control or cholestyramine-fed rats. The small intestine was examined for changes in jejunal villus structure and for in vitro transport characteristics by estimation of unidirectional influxes of 3-O-methylglucose (3-O-MG), alpha-aminoisobutyric acid (AIB), and sodium (Na). Feeding of either fiber component resulted in increases in intestinal villus length and width and in a marked increase in the influxes of 3-O-MG and AIB. Influx of Na also increased but less dramatically than the organic solutes. Cholestyramine feeding resulted in shortened villi and increased separation between villi in the jejunum. With this feeding regimen, influxes of 3-O-MG and AIB were increased, but Na influx was not changed. The results show that certain dietary fiber components may modify intestinal architecture and indicate that these structural changes may be correlated with altered functional characteristics.

Animals↗