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PubMed1983

Regulation of cholesterol synthesis in jejunal absorptive cells of the rat.

Cholesterol metabolism was studied in jejunal mucosa of the rat with special emphasis on cholesterol synthesis of villous cells, the site of intestinal lipid absorption. The type of diet and nutritional state clearly affected the cholesterologenesis of villous cells. Consequently, the incorporation of 14C-acetate into nonsaponifiable lipids (NSL; includes squalene and sterols) decreased in the following order of magnitude: 1) fat-free diet supplemented with safflower oil (FFD-SO), 2) FFD alone, 3) standard rat chow, 4) 1% cholesterol in FFD-S(, 5) total fast. Both the cholesterol feeding and the fast increased the total cholesterol concentrations in the villous cells, but the concentrations were unaffected by the other diets. In rats fed FFD-SO diet the cholesterol synthesis was significantly higher in the villous than in the crypt cells, although the cellular cholesterol concentrations were similar. The hepatic cholesterol synthesis from 14C-acetate was low in rats fed FFD-SO as compared with chow diet, whereas the incorporation of 14C-acetate into hepatic fatty acids and the incorporation of 3H-mevalonate into NSL were not affected by the diet. 5% cholestyramine had no significant effect on the cholesterol synthesis or cholesterol concentrations of the villous cells during high (FFD-SO diet) or low cholesterol synthesis (chow or cholesterol feeding). FFD-SO increased serum total cholesterol compared with chow diet and total fast, whereas cholestyramine and cholesterol feeding had no effect. Intraperitoneal administration of the hypocholesterolemic agent, 4-aminopyrazolopyrimidine, to fasting rats decreased markedly crypt cell cholesterol and increased cholesterol synthesis in the crypt cells and in the villous cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1987

The role of fat and bile acid malabsorption in diarrhoea of coeliac disease.

The contribution of various factors to diarrhoea in coeliac disease (CD) was evaluated by measuring jejunal villous height, faecal masses, faecal fat, and faecal bile acids in 8 healthy subjects and in 37 consecutive patients before and during a gluten-free diet (GFD) and while receiving cholestyramine. Jejunal villous height was inversely correlated with faecal fat but not with faecal mass or faecal bile acids. A strong positive correlation was found between faecal fat and faecal mass and between the respective changes caused by GFD in these variables, whereas the correlations between faecal bile acids and faecal volume or between these changes caused by GFD were weak or nonsignificant. The cholestyramine treatment enhanced faecal bile acid and fat excretions and increased faecal volume without a significant effect on faecal solids or on the frequency of bowel movements, which in turn was significantly reduced by GFD. Thus, the present results show that the impaired fat absorption owing to mucosal damage of the upper small intestine markedly contributes to faecal volume and the frequency of bowel movements in CD and may be an important factor responsible for diarrhoea in coeliac patients, whereas no evidence was obtained for bile acid diarrhoea in CD.

Bile Acids and Salts↗

PubMed1999

Some studies on the rodenticidal action of indomethacin.

The oral LD50 of indomethacin for a seven-day observation was found to be 12.58 +/- 1.15 mg/kg. At LD10 of 6.61 mg/kg, a dose to weight ratio of 28 was obtained for a 240 g rat, while at a maximum single dose of 3 mg/kg in man it is only 0.04. Neither diazepam nor phenobarbital influenced death at the doses of both drugs used. However, cholestyramine 2 g/kg/day was found to protect by 50% from the LD100 of indomethacin. Gross pathological studies showed dose-dependent ulceration and perforation (P < 0.001, 12 vs 24 mg/kg) and such lesions occurred in starved rats, were low in bile duct-ligated compared to sham-operated rats (P < 0.001) and were also low in cholestyramine-treated rats. Indomethacin-induced lethality in rats was found to be dose-dependent.

Administration, Oral↗

PubMed1978

A cause of hypercholesterolemia in alloxan diabetic rat.

In studies on the cause of hypercholesterolemia in alloxan diabetic rats, the pool size and basal daily synthesis of conjugated bile salts were measured by the washout method and neutral sterols in the luminal contents were determined using cholestyramine. The results showed that in diabetic rats: 1) the biliary excretions of cholesterol and bile salts were significantly increased; 2) the pool size of conjugated bile salts was increased and its rate of synthesis was higher than in controls; 3) the amount of neutral sterols in the luminal contents doubled when cholesterol absorption was inhibited by administration of cholestyramine; 4) the amount of neutral sterols excreted in the feces was the same as in controls. Thus, it was concluded that hypercholesterolemia may be partly caused by an increased rate of intestinal absorption of cholesterol, derived mainly from sloughed off epithelial cells and bile, and due to facilitated micellar formation by the increased amount of bile salts in the intestine.

Animals↗

PubMed1976

Effect of diethylstilbestrol, ascorbic acid and vitamin E on serum lipid patterns.

The effects of relatively high concentration of vitamin C, vitamin E and diethylstilbestrol, and various combinations of cholestyramine and diethylstilbestrol on the lipid compositions of chicken serum were studied were studied. After DES injection (at concentrations as low as 1 mg/day for 7 days), levels of triglycerides, phospholipids and cholesterol were much higher, the effect being much more pronounced in the hens. Cholestyramine caused a fourfold decrease in cholesterol in females, a 25% reduction males. DES consistently caused a redistribution of the esterfied fatty acids, increasing the percentage of oleic and reducing percentages of stearic and lionelic acids. Preparative TLC analysis of all constituents showed other variations in fatty acid composition, but there was no other common pattern of change. Vitamin E in the diet caused a significant rise in triglycerides and phospholipids in DES treated birds. When vitamins E and C were fed, triglyceride and phospholipid values decreased. Cholesterol concentration did not vary significantly. With birds receiving both vitamins, diethylstilbestrol seemes to have less effect in causing the shift to increase percentage of oleic acids in the total esterified fatty acids.

Animals↗

PubMed1992

Treatment of primary hypercholesterolaemia with pravastatin: efficacy and safety over three years.

OBJECTIVE: To assess the efficacy, safety and tolerability of pravastatin over three years of treatment. DESIGN: An open, multicentre randomised study. SETTING: Subjects receiving tertiary care at three hospital lipid clinics. PATIENTS: Subjects with primary hypercholesterolaemia (type IIa) or combined hyperlipidaemia (type IIb), already stabilised on a cholesterol-lowering diet, with low density lipoprotein (LDL) cholesterol levels of greater than 4.7 mmol/L and triglyceride levels of less than 4.5 mmol/L. Sixty-one subjects were randomly assigned to the treatment groups: 60 completed 12 weeks and 46 completed 30-36 months of treatment. INTERVENTIONS: Subjects were randomly assigned to receive either pravastatin 20 mg/day, pravastatin 40 mg/day or cholestyramine 16 g/day for a period of 12 weeks. Subsequently, dose titration of pravastatin up to 40 mg/day was permitted, if required, and all groups received supplementary therapy with other lipid-lowering drugs. MAIN OUTCOME MEASURES: Lipids, lipoproteins, haematological and biochemical safety parameters were measured at regular intervals. Adverse events were monitored. RESULTS: There were significant reductions in total and LDL cholesterol levels with all treatments over 12 weeks (P < 0.001). The mean reductions (+/- SD) in LDL cholesterol were 26% +/- 14% in the group taking pravastatin 20 mg/day (n = 21), 30% +/- 8% in the group taking pravastatin 40 mg/day (n = 21) and 34% +/- 13% in the group taking resin (n = 18). The percentage changes in LDL cholesterol were independent of age, baseline cholesterol level or lipid phenotype. High density lipoprotein (HDL) cholesterol levels were significantly increased, by 8%-18% with all treatments (P < 0.001). Triglyceride levels were reduced by high-dose pravastatin only (7% +/- 29%), but were found to increase with resin (45% +/- 63%). During long-term treatment over 36 months, still greater reductions in total and LDL cholesterol were found in patients taking pravastatin (n = 35), but not in those taking resin (n = 11). There was an apparent decrease in effect beyond 18 months in both groups, possibly related to reduced compliance with diet or cholestyramine intake. Eight subjects allocated to pravastatin and seven allocated to resin withdrew (one and two subjects respectively because of drug-induced adverse events). Adverse events during 12 weeks' monotherapy with pravastatin included central nervous system (CNS) symptoms (12%), gastrointestinal (GIT) symptoms (7%) and an acute hepatitic reaction (one subject). Of those in the resin therapy group, 22% developed GIT symptoms. Myalgia occurred in three subjects using a combination of pravastatin and clofibrate, but this resolved fully upon clofibrate withdrawal. CONCLUSIONS: Pravastatin was found to be a relatively effective, safe and well tolerated lipid-lowering drug. Still greater LDL reduction was achieved with pravastatin combination therapy and this was essentially maintained over three years.

Adult↗

PubMed1975

Importance of the fecal stream on the induction of colon tumors by azoxymethane in rats.

The effect of the fecal stream on intestinal carcinogenesis with azoxymethane was studied in male rats. Colostomies were performed approximately 2 cm distal to the cecum in 50 Sprague-Dawley rats to produce a 20-cm segment of nonfunctional large bowel; an additional 50 animals were left intact. Each of these groups was divided equally and was fed a normal diet or a diet containing 2% cholestyramine by weight. All animals were given azoxymethan s.c. At the end of 7 months all rats were sacrificed. The animals with colostomies developed significantly fewer tumors in the defunctionalized bowel than did intact animals in the same bowel segment. Cholestyramine appeared to increase the tumor yield in the large bowel of the intact animals but had no effect on the number of tumors in the defunctionalized bowel. Further, the intact animals on both dietary regimens developed a greater number of large tumors in the distal 20 cm of bowel. The results show that the fecal stream alters the carcinogenic activity of azoxymethane in the large bowel of the rat. It also appears that the carcinogen can reach its target tissue by a route other than the fecal stream.

Animals↗

PubMed1975

Effect of non-ionic detergents on the absorption of fat and alpha-tocopherol in the rat.

Malabsorption of rat and alpha-tocopherol was induced in rats by feeding cholestyramine and the effect of Tween 80 and Pluronic F 68 was assessed. Tween 80 did not influence the malabsorption of fat or alpha-tocopherol. Pluronic F68 did not change alpha-tocopherol absorption but did significantly improve fat absorption. The proportion of radioactivity remaining in the liver 5 days after a labelled dose of alpha-tocopherol was increased when Tween 80 or Pluronic F68 was present, perhaps indicating increased absorption via the portal vein. Serum cholesterol levels were not affected by the different diets. The greatly increased excretion of faecal bile salt on dietary cholestyramine was unchanged by the detergents.

Animals↗

PubMedDate not supplied

[The effect of water-soluble sorbents on the exocrine function of the liver].

The effect of water-soluble sorbents on exocrine function of the liver was studied in chronic experiments on 2 dogs with a brought out bile duct. It is shown that choline and digitonin sorbents exhibit choleretic properties similar to those of cholestyramine. Choline sorbent causes a drop in the concentration of (2-4-fold) cholic acid in the bile unlike digitonin sorbent. No prolonging action was seen upon cholestyramine administration, while choline sorbent do demonstrate it. Cholesterol and bilirubin levels do not respond noticeably to the above sorbents.

Adsorption↗

PubMed1992

[Lovastatin in primary hypercholesterolemia. A Norwegian multicenter study].

266 patients with primary hypercholesterolaemia were followed for 48 weeks at 27 different centres to evaluate the safety, tolerability and effect on plasma lipids of lovastatin ranging from 20 to 80 mg/day. Mean change from baseline after 12 weeks of treatment with lovastatin was -34% (CI:33-35) for total cholesterol, -42% (CI:40-43) for LDL-cholesterol, +14% (CI:12-17) for HDL-cholesterol and -14% (CI:10-18) for triglycerides. Combination therapy with cholestyramine (8-24 g/day) was optional, and was started in 89 patients from week 13. At week 48 only 25% of all patients had obtained the second objective of the study: a total cholesterol value below 5.2 mmol/l. At the same time 60% of all patients had a total cholesterol below 6.2 mmol/l. Four patients dropped out of the study owing to adverse clinical experience. Only three of these events were probably related to lovastatin. Six patients were withdrawn because of adverse laboratory experiences. One patient showed clinical signs of myositis and increase of CK. In severe primary hypercholesterolaemia combination therapy with lovastatin and a resin such as cholestyramine is required to obtain total cholesterol values below 5.2 mmol/l.

Adult↗

PubMed1992

Hormonal regulation of cholesterol 7 alpha-hydroxylase mRNA levels and transcriptional activity in primary rat hepatocyte cultures.

In primary cultures of adult rat hepatocytes the level of cholesterol 7 alpha-hydroxylase steady-state mRNA markedly decreased by 72 h. However, the addition of L-thyroxine (T4) and dexamethasone synergistically returned cholesterol 7 alpha-hydroxylase steady-state mRNA levels near to that of cholestyramine-fed animals. The maximal responses to T4 and dexamethasone in serum-free medium were at 1.0 and 0.1 microM, respectively. The addition of T4 in combination with dexamethasone resulted in an 11-fold increase in transcriptional activity of the cholesterol 7 alpha-hydroxylase gene as compared to no addition controls. The specific activities of cholesterol 7 alpha-hydroxylase in microsomes prepared from cultures treated with dexamethasone and T4 were 1.56 +/- 1.17 nmol/h/mg protein which is similar to that of intact liver (1.70 +/- 0.062 nmol/h/mg protein), but lower than cholestyramine-fed animals. Cholesterol 7 alpha-hydroxylase activity was not detectable (less than 0.020 nmol/h/mg protein) at 72 h in cultures without the addition of both dexamethasone and T4. In the presence of optimal concentrations of dexamethasone and T4, glucagon (0.2 microM), or dibutyryl cAMP (50 microM) decreased (90%) cholesterol 7 alpha-hydroxylase mRNA within 6 h. Transcriptional activity decreased (62%) in 6 h following the addition of glucagon (0.2 microM) to the culture medium. The results reported in this paper suggest an important role for multiple hormones in the regulation of cholesterol 7 alpha-hydroxylase in the liver.

Amino Acid Isomerases↗

PubMed1991

[Study of LDL receptors and response to lovastatin therapy in familial homozygotic hypercholesterolemia].

This study shows the results obtained with lovastatin as a combined therapy with probucol and cholestyramine on the lipid profile of two patients with homozygous familial hypercholesterolemia. Both have been diagnosed according to the clinical and biochemical criteria (tipe IIa hypercholesterolemia) as well as by the cholesterol or low density lipoprotein (LDL-C) receptor analysis. After the initial probucol and cholestyramine treatment we observed a drop of total cholesterol (T-C) of 41.7% and 46% as well as LDL-C of 51.6% and 49.3% in both patients. Respectively when lovastatin were associated an additional drop of T-C of 23.7%, LDL-C of 23.2%, high-density lipoprotein cholesterol (HDL-C) of 22.4% and the apoprotein B (Apo B) of 37% were obtained in one patient (receptor-defective) but no change in the lipid profile were obtained in the other patient (receptor-negative). No adverse effects were observed with this drug. This drug could be of help as a combined therapy in the treatment of homozygous familial hypercholesterolemia, even though the treatment of choice is the LDL-plasma feresis and/or liver transplantation. We expound the difficulties relate to LDL receptor study in homocygous receptor-negative patients.

Cholestyramine Resin↗

PubMed1991

Bile acid sequestrants: mechanisms of action on bile acid and cholesterol metabolism.

Interruption of the enterohepatic circulation of bile acids by cholestyramine or colestipol influences the hepatic metabolism of cholesterol in many ways. The synthesis of bile acids is increased, as reflected by a several-fold increase in the activity of the cholesterol 7 alpha hydroxylase, the rate-determining enzyme in bile acid synthesis. The increased metabolism of cholesterol to bile acids causes an enhanced demand of cholesterol in the hepatocytes which respond with both new synthesis of cholesterol, as reflected in a several-fold increase of the HMG-CoA reductase activity, and increased expression of LDL receptors. As a consequence, the plasma level of LDL-cholesterol is lowered. The hepatic secretion rate of VLDL particles is increased. Cholestyramine therapy does not affect the output of biliary lipids or the cholesterol saturation of bile, indicating that treatment with bile acid sequestrants should not be associated with any increased risk of gallstone formation.

Bile↗

PubMed1990

Regulation of squalene epoxidase activity in rat liver.

Regulation of squalene epoxidase activity was examined in rat hepatic microsomes. The hepatic squalene epoxidase activity was high in the dark period and low in the light period. Three percent cholestyramine feeding increased the hepatic squalene epoxidase activity by 2.5-fold, and the administration of lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, increased its activity by 2.1-fold. Co-administration of cholestyramine and lovastatin had a synergistic effect increasing the activity by 7.0-fold. On the other hand, cholesterol feeding reduced hepatic squalene epoxidase activity to 18%. The addition of sodium fluoride, a phosphatase inhibitor, and the treatment of the microsomes with ATP-Mg2+ had no effect on enzyme activity. HMG-CoA reductase activity has been reported to be regulated by cholesterol and unidentified metabolite(s) derived from mevalonate. However, since squalene epoxidase is less responsive than the reductase to the treatment with lovastatin, squalene epoxidase is thought to be regulated only by cholesterol pool.

Animals↗

PubMed1990

Reducing high blood cholesterol level with drugs. Cost-effectiveness of pharmacologic management.

We performed a cost-effectiveness analysis of pharmacologic treatment of high blood cholesterol levels. Agents modeled were cholestyramine, colestipol, gemfibrozil, lovastatin, niacin, and probucol. Pharmacologic effectiveness was estimated from reported studies. Cost estimates reflect societal resource consumption. Annual costs for therapy ranged from $327 (niacin) to $1881 (lovastatin, 80 mg/d). Niacin was the most efficient agent for reducing low-density lipoprotein cholesterol levels, having an average cost over 5 years of $139 per percent reduction in low-density lipoprotein cholesterol level. Lovastatin (20 mg/d) was also efficient ($177 per percent reduction). Cholestyramine was least efficient at $347. For high-density lipoprotein cholesterol, niacin was most efficient, at $116 per percent increase in high-density lipoprotein cholesterol level, followed by gemfibrozil at $271. Analyses combining low-density lipoprotein cholesterol and high-density lipoprotein cholesterol effects suggest that niacin and lovastatin (20 mg/d) were most efficient for reducing cardiovascular risk.

Anticholesteremic Agents↗

PubMed1990

Substrate stimulation of 7 alpha-hydroxylase, an enzyme located in the cholesterol-poor endoplasmic reticulum.

We examined the role of cholesterol in altering the activity of the microsomal cytochrome P-450 enzyme, cholesterol-NADPH:oxygen oxidoreductase (cholesterol 7 alpha-hydroxylase). Liposomes were used to deliver cholesterol to hepatic microsomes. Formation of 7 alpha-hydroxycholesterol was quantitated by isotope dilution/gas chromatography-mass spectrometry. As the liposomal cholesterol/phospholipid molar ratio increased, 7 alpha-hydroxylase activity increased, whereas the activity of another microsomal cytochrome P-450 enzyme, ethylmorphine N-demethylase, decreased. To determine if the degree of stimulation was affected by the endogenous activity (without liposomes), microsomes, from rats fed chow alone or chow containing cholestyramine, taurocholate, or cholesterol were challenged with cholesterol-enriched liposomes. The degree of stimulation was dependent upon the endogenous activity: cholestyramine-fed much greater than cholesterol = chow control greater than taurocholate-fed. To determine if cholesterol stimulates 7 alpha-hydroxylase by increasing membrane viscosity, microsomes were incubated with liposomes having the same cholesterol/phospholipid molar ratio as microsomes, but different viscosities. Dipalmitoylphosphatidylcholine (high viscosity) liposomes increased microsomal viscosity and decreased 7 alpha-hydroxylase activity. In contrast, dioleoylphosphatidylcholine (low viscosity) liposomes decreased microsomal viscosity and increased enzyme activity. Since greater viscosity inhibits 7 alpha-hydroxylase, cholesterol cannot stimulate the enzyme by increasing membrane viscosity. The data suggest that cholesterol stimulates production of 7 alpha-hydroxycholesterol by providing substrate.

1,2-Dipalmitoylphosphatidylcholine↗

PubMed1990

Increased plasma plant sterol levels in heterozygotes with sitosterolemia and xanthomatosis.

Plasma sterol levels in a family of sitosterolemia and xanthomatosis were determined by a high performance liquid chromatography. Three affected siblings manifested marked xanthomatosis including subcutaneous soft tissues and generalized atherosclerosis. Two other siblings as well as children of the patients did not show such clinical symptoms and signs. Plasma levels of cholesterol, sitosterol, campesterol, and cholestanol in three affected subjects were 190 +/- 18.5, 25.9 +/- 11.6, 16.1 +/- 7.8, 1.84 +/- 0.92 mg/dl (mean +/- SD), respectively. Four daughters of the affected subjects, who should be considered as obligatory heterozygotes, showed moderately increased levels of these sterols (195 +/- 41.7, 1.33 +/- 0.44, 1.56 +/- 0.69, 0.80 +/- 0.28 mg/dl), which were significantly higher than those of normal subjects. Treatment with cholestyramine had little effect on the increased plasma plant sterol levels, but markedly decreased plasma cholestanol concentrations in two affected siblings. This report presents the clinical features of the patients with sitosterolemia and xanthomatosis and also demonstrates that heterozygotes with this disorder have increased plasma levels of plant sterols as well as cholestanol, and suggests that this rare disease might be inherited as an autosomal co-dominant trait in certain cases. The data also indicate that cholestyramine administration was not effective in this family for treatment of sitosterolemia.

Adult↗

PubMed1989

[Treatment of essential hypercholesterolemia by normolipidemic drugs in children].

The authors list the principal normolipidemic drugs. Only cholestyramine (Questran) and some fibrates (fenofibrate: Lipanthyl for instance) are registered for pediatrics. Cholestyramine acts by sequestering biliary acids, and thereby inhibiting intestinal cholesterol resorption. It is the primary drug used for children, when diet has been unable to restore normal cholesterol values.

Adolescent↗