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PubMed1992

The Lipid Research Clinics Coronary Primary Prevention Trial. Results of 6 years of post-trial follow-up. The Lipid Research Clinics Investigators.

BACKGROUND: Participants in the Lipid Research Clinics Coronary Primary Prevention Trial, a randomized, cholesterol-lowering trial comparing cholestyramine (N = 1907) vs placebo (N = 1899) treatment in 35- and 59-year-old asymptomatic hypercholesterolemic men, conducted between 1973 and 1983, were followed up annually from 1985 until 1989. Post-trial treatment was not provided. METHODS: Eleven predefined hypotheses pertaining to possible benefits and adverse effects of in-trial cholestyramine treatment were tested by standard statistical comparisons of the two original Coronary Primary Prevention Trial treatment groups (cholestyramine and placebo). RESULTS: Similar increasing proportions of cholestyramine and placebo used cholesterol-lowering drugs post-trial. After 13.4 years of in-trial plus post-trial follow-up, there were 13 (143 vs 156) fewer deaths in the cholestyramine group than in the placebo group. Although not statistically significant, the mortality hazard ratio (0.89) was similar to that in other cholesterol-lowering trials. This trend, a result of reduced coronary heart disease mortality, occurred despite a post-trial narrowing of the in-trial cholestyramine-placebo difference in coronary heart disease incidence from 32 (155 vs 187) to 16 (268 vs 284). The cholestyramine and placebo groups had similar 13.4-year mortality rates from cancer, other medical causes, and trauma and similar cancer incidence rates. However, 13.4-year incidences of benign colorectal tumors (50 vs 34), cancer of the buccal cavity and pharynx (eight vs two), gallbladder disease (68 vs 53), and gallbladder surgery (58 vs 40) were nonsignificantly increased in the cholestyramine group. CONCLUSION: Overall, 6 years of post-Coronary Primary Prevention Trial follow-up have not provided conclusive evidence of benefit or long-term toxicity of cholestyramine treatment beyond that evident at the cessation of the trial.

Cause of Death↗

PubMed1987

Correlative studies of the hypocholesterolemic effect of a highly activated charcoal.

We have carried out in vitro and animal studies to determine the cholesterol lowering efficacy of activated charcoals vs. cholestyramine. In the in vitro studies, we determined the adsorption capacity (Qm) of cholestyramine and activated charcoals for cholesterol in glacial acetic acid. Mean (+/- SD) Qm's (mg cholesterol adsorbed/gm dry sorbent) decreased in the order Super Char highly activated charcoal (277 +/- 121), Norit USP XX charcoal (33 +/- 10), Acta-Char charcoal (26 +/- 4), Mallinckrodt USP charcoal (26 +/- 10), Norit A charcoal (22 +/- 4) and cholestyramine (0). For the bile salt sodium desoxycholate in ammonia: sodium bicarbonate, pH 8.2, the Qm with cholestyramine was 4641 +/- 2669 and with Super Char was 2814 +/- 667 (p = 0.11). We then contrasted the effect of cholestyramine (1%, added to the diet) and Super Char (1% or 2%) on plasma cholesterol concentrations in rabbits made hypercholesterolemic with a diet containing casein. The percent reductions were 61 in one rabbit fed cholestyramine, 61 and 67 in two rabbits fed 1% Super Char, and 90 in one rabbit fed 2% Super Char. In WHHL homozygous rabbits, reductions in plasma cholesterol from pre-treatment and post-treatment levels, respectively, averaged 52% and 38% with 2% cholestyramine (2 animals), 70% and 43% with 2% Super Char (2 animals), and 70% and 63% with 4% Super Char (3 animals). The effectiveness of cholestyramine in animals that lack functional cellular receptors for low density lipoprotein was unexpected. Super Char charcoal appears to be an effective hypocholesterolemic agent, warranting study in man.

Animals↗

PubMed1984

The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease.

The Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT), a multicenter, randomized, double-blind study, tested the efficacy of cholesterol lowering in reducing risk of coronary heart disease (CHD) in 3,806 asymptomatic middle-aged men with primary hypercholesterolemia (type II hyperlipoproteinemia). The treatment group received the bile acid sequestrant cholestyramine resin and the control group received a placebo for an average of 7.4 years. Both groups followed a moderate cholesterol-lowering diet. The cholestyramine group experienced average plasma total and low-density lipoprotein cholesterol (LDL-C) reductions of 13.4% and 20.3%, respectively, which were 8.5% and 12.6% greater reductions than those obtained in the placebo group. The cholestyramine group experienced a 19% reduction in risk (p less than .05) of the primary end point--definite CHD death and/or definite nonfatal myocardial infarction--reflecting a 24% reduction in definite CHD death and a 19% reduction in nonfatal myocardial infarction. The cumulative seven-year incidence of the primary end point was 7% in the cholestyramine group v 8.6% in the placebo group. In addition, the incidence rates for new positive exercise tests, angina, and coronary bypass surgery were reduced by 25%, 20%, and 21%, respectively, in the cholestyramine group. The risk of death from all causes was only slightly and not significantly reduced in the cholestyramine group. The magnitude of this decrease (7%) was less than for CHD end points because of a greater number of violent and accidental deaths in the cholestyramine group. The LRC-CPPT findings show that reducing total cholesterol by lowering LDL-C levels can diminish the incidence of CHD morbidity and mortality in men at high risk for CHD because of raised LDL-C levels. This clinical trial provides strong evidence for a causal role for these lipids in the pathogenesis of CHD.

Adult↗

PubMed1979

Intestinal absorption and lymphatic transport of cholesterol and beta-sitostanol in the rat.

The intestinal absorption of cholesterol and beta-sitostanol (the saturated analogue of beta-sitosterol) were measured and their absorptions compared in the presence and absence of cholestyramine. After test meals containing [(3)H]cholesterol and [(14)C]beta-sitostanol without added cholestyramine, 4-day fecal collections yielded an average of 51% of the fed cholesterol and 83% of the fed beta-sitostanol. In separate lymph transport studies without cholestyramine, 36% of the fed cholesterol was recovered in lymph in 24 hours compared to only 2% of the fed beta-sitostanol. Thus, while total recoveries of the two labeled compounds in feces plus lymph were nearly identical (51% + 36% = 87% for cholesterol and 83% + 2% = 85% for beta-sitostanol) their distribution in the two compartments was markedly different, reflecting the relative nonabsorbability of beta-sitostanol. Adding cholestyramine to the test meal caused fecal excretion of cholesterol to increase to 73%, independent of the dose of cholestyramine used. Cholestyramine had no effect on the fecal excretion of beta-sitostanol (average excretion after cholestyramine, 85%). The relative non-absorbability of beta-sitostanol compared to cholesterol is clearly evident in this study and leads us to suggest its possible use as a lipid-soluble, nonabsorbable reference compound for measurement of the absorption of cholesterol and other lipids. Further data are presented to justify its use for this purpose.-Hassan, A. S., and A. J. Rampone. Intestinal absorption and lymphatic transport of cholesterol and beta-sitostanol in the rat.

Animals↗

PubMed1996

Fluvastatin in combination with other lipid-lowering agents.

Fluvastatin, a new synthetic inhibitor of HMGCoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase, has been studied in several models to examine its effects when used in combination with other lipid-modifying agents such as derivatives of fibric acid (bezafibrate), resins (cholestyramine), and niacin. The combination of fluvastatin with bezafibrate has been studied in a double-blind trial involving patients with well-documented familial hypercholesterolaemia. Fluvastatin 40 mg/day, combined with either bezafibrate 400 mg/day or cholestyramine 8 g/day, resulted in reductions in levels of low-density lipoprotein cholesterol (LDL-C), these being indistinguishable between the groups; however, significantly greater increases in levels of high-density lipoprotein cholesterol (21.3%) and reductions in levels of triglycerides (25.1%) were seen with the fluvastatin-bezafibrate combination. No notable increases were seen in levels of serum creatine kinase, aspartate aminotransferase, or alanine aminotransferase, and no cases of myopathy were observed. In a study model that examined low-dose combinations of fluvastatin with cholestyramine, reductions in levels of LDL-C of 15.8% and 19.3% were seen with fluvastatin 10 mg and 20 mg, respectively. After an 8-week interval in which a daily dosage of cholestyramine 8 g was added, from baseline, reductions of 26.3% in the 10 mg fluvastatin-cholestyramine group and 31.2% in the 20 mg fluvastatin-cholestyramine group were observed, whereas the placebo-cholestyramine group displayed a reduction of 14.9%. Doubling the resin dosage to 16 g/day for the final 8 weeks of the study provided little additional benefit. Myotoxicity has been observed when lovastatin is coadministered with niacin, and so the combination of niacin with fluvastatin has also been studied to examine the possibility of this effect occurring. Patients were randomised to either fluvastatin 20 mg or placebo for 6 weeks, after which time open-label niacin was administered to all patients and titrated to a final dosage of 3 g/day. After 6 weeks, fluvastatin produced a 20.8% reduction in LDL-C levels from baseline. When combined with niacin, a 43.7% reduction was noted at the week 15 endpoint, against the 26.5% reduction seen with niacin monotherapy. The combination was well tolerated, with no reports of myopathy or of significant elevations in creatine kinase or liver transaminase levels. Combinations of fluvastatin with a variety of other agents have been shown to have significant effects on lipid profiles, with no evidence to date of clinically remarkable safety findings. Thus, the use of combination therapies may result in optimal management of patients with moderately severe hypercholesterolaemia and mixed dyslipidaemic profiles.

Anticholesteremic Agents↗

PubMed1998

The cholesterol-lowering effect of guar gum in rats is not accompanied by an interruption of bile acid cycling.

A viscous hydrocolloid (guar gum, GG; 2.5% of the diet) or a steroid sequestrant (cholestyramine; 0.5% of the diet) was included in semipurified diets containing 0.2% cholesterol to compare the cholesterol-lowering effects of each agent in rats. In the present model, GG significantly lowered plasma cholesterol (-25%), especially in the density < 1.040 kg/L fraction, whereas cholestyramine was less potent. Bile acid fecal excretion significantly increased only in rats fed cholestyramine, similar to the cecal bile acid pool; the biliary bile acid secretion was accelerated by GG, but not their fecal excretion, whereas GG effectively enhanced neutral sterol excretion. As a result, the total steroid balance (+13 micromol/d in the control) was shifted toward negative values in rats fed the GG or cholestyramine diets (-27 or -50 micromol/d, respectively). Both agents induced liver 3-hydroxy-3-methylglutaryl-CoA reductase, but cholestyramine was more potent than GG in this respect. The present data suggest that, at a relative low dose in the diet, GG may be more effective than cholestyramine in lowering plasma cholesterol by impairing cholesterol absorption and by accelerating the small intestine/liver cycling of bile acids, which is interestingly, accompanied by reduction of bile acid concentration in the large intestine.

Animals↗

PubMed1984

Lipid Research Clinics Coronary Primary Prevention Trial: results and implications.

The Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT) tested the efficacy of lowering cholesterol levels in reducing the risk of coronary heart disease (CHD) in 3,806 asymptomatic, middle-aged men with primary hypercholesterolemia. The group treated with cholestyramine had 8.5% and 12.6% greater reductions in total and low-density lipoprotein levels, respectively, than those achieved in the placebo group. The cholestyramine group had a 19% reduction in risk (p less than 0.05) of the primary endpoint of definite CHD, death or definite nonfatal myocardial infarction. Corresponding and significant reductions were also seen for angina, development of a positive exercise test, and coronary bypass surgery. All-cause mortality was only slightly, and not significantly, reduced in the cholestyramine group, reflecting more violent and accidental deaths in the cholestyramine subjects. When the cholestyramine group was analyzed separately, a 19% reduction in CHD risk was also associated with each decrement of 8% in the total cholesterol level. Moreover, CHD incidence in men in whom a decrease of 25% in total cholesterol was sustained, a typical response to the prescribed dosage (24 g/day) of cholestyramine resin, was half that of men who remained at the pretreatment level. The LRC-CPPT findings show that reducing the total cholesterol level by lowering the LDL cholesterol level can diminish the incidence of CHD morbidity and mortality in men at high risk for CHD because of increased LDL cholesterol levels. These results have considerable importance for the prevention of CHD through cholesterol lowering, at both the clinical and public health levels.

Adult↗

PubMed1991

Characteristics of cholesterol 7 alpha-hydroxylase and 7 alpha-hydroxycholesterol hydroxylase activities of rodent liver.

A second cholesterol-derived metabolite in addition to 7 alpha-hydroxycholesterol was observed to be produced from endogenous microsomal cholesterol in the presence of hamster liver microsomal fractions and NADPH, when analyzed by HPLC using the method of Ogishima and Okuda (Anal Biochem 158: 228-232, 1986). However, only 7 alpha-hydroxycholesterol was produced in the presence of rat hepatic microsomal protein fractions and NADPH. The second metabolite was facilely produced when endogenous 7 alpha-hydroxycholesterol was incubated with hamster liver microsomes and NADPH, but not with rat liver microsomes. The second metabolite derived from either endogenous cholesterol or exogenous 7 alpha-hydroxycholesterol contained three hydroxyl groups as shown by mass spectrometric analysis. After oxidation of the 3 beta-ol group by cholesterol oxidase, the metabolite comigrated with 7 beta-hydroxycholest-3-one on normal phase HPLC, but was resolved from both 7 alpha- and 7 beta-hydroxycholest-3-one on reverse phase HPLC. The data indicate that the second metabolite is a hydroxylated product of 7 alpha-hydroxycholesterol, possibly cholest-5-ene-3 beta,7 alpha, 12 alpha-triol. Cholestyramine feeding increased production of both 7 alpha-hydroxycholesterol and its metabolite from endogenous cholesterol by 3-fold in hamster liver microsomes in vitro. However, the direct conversion of 7 alpha-hydroxycholesterol to the metabolite by hamster liver microsomes was not increased appreciably after cholestyramine feeding (20-30%). The hydroxylation of 7 alpha-hydroxycholesterol was similar in characteristics to cholesterol 7 alpha-hydroxylase activity in that it was dependent on NADPH, was inhibited by several known P450 inhibitors, and was affected by an inhibitory autobody elicited against rat hepatic NADPH: cytochrome P450 oxidoreductase. 5,6- and 7,8-Benzoflavone were poor inhibitors (IC50 approximately 1 mM) of cholesterol 7 alpha-hydroxylase activity in liver microsomes from cholestyramine-fed rats, but caused a striking enhancement of the 7 alpha-hydroxylase activity of liver microsomes from untreated rats in vitro. In contrast, 7,8-benzoflavone inhibited cholesterol 7 alpha-hydroxylase and 7 alpha-hydroxycholesterol hydroxylase activities of microsomes from normal and cholestyramine-fed hamsters. However, 5,6-benzoflavone stimulated cholesterol 7 alpha-hydroxylase activity in liver microsomes from normal and cholestyramine-fed hamsters, but inhibited 7 alpha-hydroxycholesterol hydroxylase activity by approximately 50%. These results suggest that hepatic cholesterol 7 alpha-hydroxylase and 7 alpha-hydroxycholesterol hydroxylase activities apparently involve multiple forms of cytochrome P450 in untreated and cholestyramine-treated hamsters.

Animals↗

PubMed1992

Equilibrium and kinetic factors influencing bile sequestrant efficacy.

In vitro bile salt binding equilibria and kinetic studies were performed with cholestyramine to determine how these factors influence bile sequestrant efficacy in vivo. Chloride ion at physiologic concentrations caused more than a twofold reduction in glycocholate (GCH) binding, compared to binding in the absence of salt, over a range of GCH concentrations and was also observed to displace bound GCH. In addition, chloride ion displaced from cholestyramine as a result of bile salt binding was measured using a chloride selective electrode, and the results show that bile salt binding is due to ion exchange. Comparison of the results of the equilibrium binding experiments to human data shows that the effect of anion binding competition alone cannot account for the lack of efficacy of cholestyramine. Consideration of other effects, such as additional binding competition or poor availability for binding, based on data from the literature, shows that adequate bile salt binding potential exists and that these interferences are not major factors influencing resin efficacy. In kinetic studies, both binding uptake of GCH and displacement of GCH from cholestyramine by chloride ion were relatively rapid, indicating that cholestyramine should equilibrate rapidly with bile salts in the GI tract. Based on these findings, it is suggested that the low efficacy of cholestyramine is a result mainly of its relatively poor ability to prevent bile salt reabsorption in the ileum.

Anions↗

PubMed2006

Simvastatin maintains steady patterns of GFR and improves AER and expression of slit diaphragm proteins in type II diabetes.

The factors determining the course of glomerular filtration rate (GFR) and albumin excretion rate (AER) and the expression of mRNA of slit diaphragm (SD) and podocyte proteins in microalbuminuric, hypertensive type II diabetic patients are not fully understood. GFR, AER, and SD protein mRNA were studied in 86 microalbuminuric, hypertensive, type II diabetics at baseline and after 4-year random double-blind treatment either with 40 mg simvastatin (Group 1) or with 30 g cholestyramine (Group 2) per day. Both groups had at baseline a GFR decay per year in the previous 2-4 years of 3 ml/min/1.73 m(2). Both Groups 1 and 2 showed a significant decrease of low-density lipoprotein cholesterol levels after simvastatin and cholestyramine treatment (P<0.01). No change from base line values was observed as for hs-C-reactive protein and interleukin-6. A significant decrease of 8-hydroxydeoxyguanosine urinary excretion was observed after simvastatin treatment. GFR did not change from baseline with simvstatin, whereas a decrease was observed with cholestyramine treatment (simvastatin vs cholestyramine: -0.21 vs -2.75 ml/min/1.73 m(2), P<0.01). AER decreased in Group 1 (P<0.01), but not in Group 2 patients. Real-time polymerase chain reaction measurement of mRNA SD proteins (CD2AP, FAT, Actn 4, NPHS1, and NPHS2) significantly increased in kidney biopsy specimens after simvastatin, but not cholestyramine treatment. Simvastatin, but not cholestyramine, 4-year treatment maintains steady patterns of GFR, and improves AER and expression of SD proteins in type II diabetes, despite similar hypocholesterolemic effects in circulation.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed1988

Effect of diet during pregnancy and lactation on the activity of HMG-CoA reductase in the developing rat.

Wistar rats were fed a control diet or a diet containing either cholestyramine or high fat and cholesterol throughout gestation and the first 14 d of lactation. New-born litters were cross-fostered from rats fed the control diet to rats fed either cholestyramine or high fat and cholesterol, or from rats fed cholestyramine to rats fed the control diet. Hepatic hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase activity, plasma cholesterol and triglycerides were assayed on gestation d 20 and postnatal d 8, 14, 22 and 30. Cholestyramine had no effect on maternal or fetal plasma lipid levels but increased fetal hepatic HMG-CoA reductase activity by approximately 50%. The increased reductase activity persisted on postnatal d 8 and 14. Control pups suckled by dams fed cholestyramine also had significantly increased HMG-CoA reductase activities on postnatal d 8 and 14. The high fat and cholesterol diet significantly increased maternal plasma cholesterol but had no effect on HMG-CoA reductase activity in the fetus or suckling pups. Neither cholestyramine nor high fat and cholesterol altered the rat milk cholesterol levels. The studies demonstrate that HMG-CoA reductase activity in the developing rat can be altered by factors dependent on maternal diet. They do not support a hypothesis for regulation by maternal dietary or milk cholesterol supply.

Animals↗

PubMed1998

Gut endotoxin restriction improves postoperative hemodynamics in the bile duct-ligated rat.

BACKGROUND: Postoperative hemodynamic disturbances in obstructive jaundice are associated with complications such as shock and renal failure. Gut-derived endotoxemia may underlie these complications. Recently, we have shown that cholestyramine treatment prevents gut-derived endotoxemia in bile duct-ligated (BDL) rats (Houdijk APJ, Boermeester MA, Wesdorp RIC, Hack CE, van Leeuwen PAM: Tumor necrosis factor unresponsiveness following surgery in bile duct-ligated rats. Am J Physiol 271: G980-G986, 1996). METHODS: The effect of cholestyramine on systemic hemodynamics and organ blood flows after a laparotomy was studied in 2 wk BDL rats using radioactive microspheres. RESULTS: Compared with sham-operated rats, postoperative BDL rats had 1) lower blood pressure (p < .05) and heart rate (p < .001) with higher cardiac output (p < .05), 2) lower splanchnic blood flow (p < .05), 3) lower renal blood flow (p < .01), and 4) higher splanchnic organ and renal-vascular resistances. Cholestyramine treatment in BDL rats prevented the postoperative decrease in blood pressure by increasing cardiac output (p < .01). In addition, cholestyramine maintained splanchnic blood flow at sham levels (p < .05). Furthermore, cholestyramine also prevented the fall in renal blood flow after surgery in BDL rats. CONCLUSION: Gut endotoxin restriction using cholestyramine treatment maintained normal blood pressure, improved splanchnic blood flow, and completely prevented the fall in renal blood flow in BDL rats. Reducing the gut load of endotoxin in patients with obstructive jaundice scheduled for abdominal surgery may prevent postoperative hemodynamic complications.

Animals↗

PubMed1979

Biliary lipid composition during treatment with different hypolipidaemic drugs.

In an attempt to clarify the possible lithogenic effects of commonly used hypolipidaemic drugs, gallbladder bile was obtained from patients with primary hyperlipoproteinaemia before and during treatment with nicotinic acid (n = 13), cholestyramine (n = 19), clofibrate (n = 11), and a combination of cholestyramine and clofibrate (n = 11). Each treatment period was minimum 6 weeks, and standardized dietary conditions were obtained. Both nicotinic acid and clofibrate treatment caused an increase in biliary cholesterol concentration relative to biliary total lipids (bile acids, phospholipids, and cholesterol). During cholestyramine medication the relative cholesterol concentration fell. A combination of cholestyramine with clofibrate medication led to a decrease of bile saturation to pretreatment levels in nine of the eleven subjects. In the other two a further increase in the cholesterol saturation of the bile occurred. Treatment with nicotinic acid and clofibrate but not with cholestyramine is thus probably associated with an increased risk for development of cholesterol gallstones. It is suggested that addition of cholestyramine may be a possible way to prevent the lithogenic effect of clofibrate in patients with hyperlipoproteinaemia when not only hypocholesterolaemic but also hypotriglyceridaemic effects are wanted.

Adult↗

PubMed1979

Effects of plasma cholesterol lowering agents on hepatobiliary lipid metabolism and cholesterol turnover in the rhesus monkey.

The effects of clofibrate, cholestyramine, and neomycin on hepatobiliary lipid metabolism were studied in adult rhesus monkeys in metabolic steady state with intact but exteriorized enterohepatic circulations. Clofibrate (30 mg/kg, id) had no effect on lipid secretion while cholestyramine (150 mg/kg, id) decreased biliary cholesterol secretion rate from 0.19 +/- 0.03 to 0.13 +/- 0.02 mmol/24 h, p less than 0.05. Neomycin (30 mg/kg, id) decreased bile flow from 216 +/- 10 to 191 +/- 7mL/24 h, p less than 0.05, and tended only to decrease bile salt and phospholipid secretion rates. Cholestyramine decreased cholesterol composition from 1.81 +/- 0.22 to 1.30 +/- 0.22 mol %, p less than 0.05, while clofibrate and neomycin had insignificant effects. Cholestyramine and neomycin decreased bile salt pool size from 1 +/- 0.1 to 0.77 +/- 0.15 and from 1.45 +/- 0.16 to 1.13 +/- 0.21 mmol, p less than 0.05, respectively, while clofibrate had no effect. Bile salt synthetic rate was increased only by cholestyramine, i.e., from 0.63 +/- 0.04 to 1.48 +/- 0.26 mmol/24 h, p less than 0.01. Concomitant cholesterol turnover studies revealed that cholestyramine increased the production rate and excretion of cholesterol in the rapidly miscible cholesterol pool and increased the transfer of cholesterol from slow to rapidly miscible pools. Neomycin, on the other hand, decreased the size of the rapidly miscible pool by decreasing production rate without affecting the size of the slowly miscible pool, while clofibrate had insignificant effects.

Animals↗

PubMedDate not supplied

Cholesterol and bile acid synthesis in two families with homozygous and heterozygous hypercholesterolemia.

Measurements of cholesterol and bile acid synthesis and of cholesterol precursors were performed in two hypercholesterolemic families with two homozygous girls under basal conditions and during treatment with cholestyramine. The concentrations of serum methyl sterols, squalene, cholesterol, and triglycerides, and the responses to cholestyramine were not consistently different in the two families. However, in both families stimulation of cholesterol synthesis by cholestyramine markedly increased the methyl sterol content of serum lipoproteins both in heterozygotes (with a lowering of serum cholesterol) and in homozygotes (with virtually no lowering of serum cholesterol concentration). The bile acid and cholesterol synthesis rates were modestly low in one family and markedly high in the other both with and without cholestyramine treatment, the baseline production rates being significantly correlated with the increments in the synthesis caused by cholestyramine. The two families apparently represent low and high producing types of familial hypercholesterolemia. Cholesterol synthesis in the two homozygous girls was about twice that of their respective heterozygous parents with and without cholestyramine treatment, suggesting that the double dose of the mutant gene doubled cholesterol production. Furthermore, close child-to-parent correlations for the bile acid and cholesterol synthesis rates point to a genetic control of cholesterol metabolism.

Adult↗

PubMed1986

The Lipid Research Clinics Coronary Primary Prevention Trial.

The Lipid Research Clinics Coronary Primary Prevention Trial tested the efficacy of cholesterol lowering in reducing the risk of coronary heart disease in 3806 asymptomatic, middle-aged men with primary hypercholesterolaemia. The cholestyramine group experienced 8.5 and 12.6% greater reductions in total and low density lipoprotein (LDL), respectively, than those obtained in the placebo group. The cholestyramine group experienced a 19% reduction in risk (p less than 0.05) of the primary end-point of definite coronary heart disease death and/or definite non-fatal myocardial infarction. Corresponding and significant reductions were also seen for angina, development of a positive exercise test, and coronary bypass surgery. All-cause mortality was only slightly, and not significantly, reduced in the cholestyramine group, reflecting more violent and accidental deaths in the cholestyramine subjects. When the cholestyramine group was analysed separately, a 19% reduction in coronary heart disease risk was also associated with each decrement of 8% in total cholesterol. Moreover, coronary heart disease incidence in men in sustaining a fall of 25% in total cholesterol, a typical response to the prescribed dosage (24 g/day) of cholestyramine resin, was half that of men who remained at pretreatment level. The Lipid Research Clinics Coronary Primary Prevention Trial findings show that reducing total cholesterol by lowering LDL cholesterol levels, can diminish the incidence of coronary heart disease morbidity and mortality in men at high risk for the disease because of raised LDL cholesterol levels. These results have considerable importance for the prevention of coronary heart disease through cholesterol lowering, at both the clinical and public health levels.

Adult↗

PubMed1992

Differing effects of cholesterol and taurocholate on steady state hepatic HMG-CoA reductase and cholesterol 7 alpha-hydroxylase activities and mRNA levels in the rat.

We investigated the effects of cholesterol, cholestyramine, and taurocholate feeding on steady state specific activities and mRNA levels of hepatic 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase and cholesterol 7 alpha-hydroxylase in the rat. Interruption of the enterohepatic circulation of bile acids (cholestyramine feeding) increased total HMG-CoA reductase activity 5-fold. Cholesterol and taurocholate administration suppressed total microsomal HMG-CoA reductase activities 87% and 65%, respectively. HMG-CoA reductase mRNA levels increased 3-fold with cholestyramine, did not decrease significantly with cholesterol feeding, but were markedly decreased after taurocholate treatment. Cholesterol 7 alpha-hydroxylase activity increased 4-fold with cholestyramine and 29% during cholesterol feeding, but decreased 64% with taurocholate. Cholesterol 7 alpha-hydroxylase mRNA levels rose 150% and 50% with cholestyramine and cholesterol feeding, respectively, but decreased 73% with taurocholate. The administration of cholesterol together with taurocholate prevented the decline in cholesterol 7 alpha-hydroxylase mRNA levels, but inhibition of enzyme activity persisted (-76%). Hepatic microsomal cholesterol concentrations increased 2-fold with cholesterol feeding but did not change with taurocholate or cholestyramine treatment. These results demonstrate that mRNA levels of HMG-CoA reductase are controlled by the hepatic taurocholate flux, whereas mRNA levels of cholesterol 7 alpha-hydroxylase are controlled by the cholesterol substrate supply. These end products, cholesterol and bile acids, exert post-transcriptional regulation on HMG-CoA reductase and cholesterol 7 alpha-hydroxylase, respectively.

Administration, Oral↗

PubMed1985

Sorbent therapy of the porphyrias. IV. Adsorption of porphyrins by sorbents in vitro.

The adsorption capacities (Qm's) of the ion exchange resin cholestyramine and 8 activated charcoals for uroporphyrin, protoporphyrin and coproporphyrin, porphyrins that accumulate within tissues or vasculature in certain porphyrias, have been determined. Qm's (mg porphyrin/gm dry sorbent) were derived from Langmuir isotherms, which were constructed from experiments that assessed the amount of porphyrin adsorbed after the addition of varying amounts of porphyrin in solution to a constant amount of sorbent. These experiments were carried out at pH 8.2 in 0.5% desoxycholate, to simulate conditions of the small intestine. For uroporphyrin I, the Qm for Amoco Supersorb PX-21 highly activated charcoal was greater than that for cholestyramine (mean +/- SD of 26.5 +/- 12.7 vs. 17.0 +/- 2.6; t'32 = 2.46, P less than 0.025) and highly significantly greater than those of the other charcoals. For protoporphyrin IX, cholestyramine and Amoco Supersorb PX-21 charcoal had the highest Qm's (32.4 +/- 8.6 and 30.9 +/- 9.2), but these were not significantly greater than the Qm's of 5 other charcoals. Little difference was found among sorbents in the rate of adsorption of either porphyrin. For coproporphyrin III, the Qm's of cholestyramine and Amoco Supersorb PX-21 charcoal were not significantly different (39.2 +/- 13.7 vs. 35.1 +/- 4.0) but they were greater than that of Norit USP XX (20.0). Virtually no desorption of porphyrin from either cholestyramine or Amoco Supersorb PX-21 charcoal was detected. Both cholestyramine and Amoco Supersorb PX-21 charcoal appear to be highly avid sorbents for porphyrins of varied states of carboxylation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adsorption↗