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PubMed1994

Analysis of angiographic trial data in women.

There are few angiographic trials of cholesterol lowering in women. Two trials have included a sufficient number of women for meaningful assessment of lesion change, as determined by quantitative coronary angiography. In the University of California, San Francisco Specialized Center of Research in Arteriosclerosis (UCSF SCOR) trial, 72 patients (57% women) with familial hypercholesterolaemia (90% of whom had no overt coronary heart disease) were randomised to receive either diet and intensive drug therapy (combinations of colestipol, nicotinic acid and lovastatin) or diet and modest doses of colestipol, according to baseline low density lipoprotein cholesterol level. Coronary angiograms were obtained at 2-year intervals. Change in percentage area of stenosis (the primary end-point) in women receiving intensive drug treatment was -2.06% compared with +1.07% for the controls (p = 0.05). For the intensively treated men, corresponding values were -0.88% compared with +0.41% for the controls (difference not significant). In a recently completed trial in Canada, 269 men and 62 women with established coronary heart disease were randomised to receive either diet alone, or diet and lovastatin (up to 80 mg daily). In men, the increase in percentage diameter of stenosis was reduced by 43% (p = 0.05), and in women by 40% (not significant). By contrast, new lesions appeared in 4% of women assigned to intensive drug treatment, compared with 45% of those randomised to diet (p < 0.001). In men, new lesions appeared in 18% and 29% of patients, respectively (p = 0.047). These data suggest that coronary artery lesions in women respond at least as well as those in men to cholesterol lowering.

Arteriosclerosis↗
PubMed1998

The cost of reaching National Cholesterol Education Program (NCEP) goals in hypercholesterolaemic patients. A comparison of atorvastatin, simvastatin, lovastatin and fluvastatin.

OBJECTIVE: Recognising the importance of treating hyperlipidaemia, the National Cholesterol Education Program (NCEP) has established widely accepted treatment goals for low density lipoprotein cholesterol (LDL-C). Medications used most commonly to achieve these LDL-C goals are HMG-CoA reductase inhibitors. The relative resource utilisation and cost associated with the use of reductase inhibitors of different LDL-C lowering efficacy are unknown, but are major health and economic concerns. The objective of this study was to determine the mean total cost of care to reach NCEP goals with various reductase inhibitors. DESIGN: In a randomised, 54-week, 30-centre controlled trial we compared resources used and costs associated with treating patients to achieve NCEP goals using 4 reductase inhibitors: atorvastatin, simvastatin, lovastatin and fluvastatin. PATIENTS AND PARTICIPANTS: The trial studied 662 patients; 318 had known atherosclerotic disease. INTERVENTIONS: Reductase inhibitor therapy was initiated at recommended starting doses and increased according to NCEP guidelines and package insert information. For patients who did not reach the goal at the highest recommended dose of each reductase inhibitor, the resin colestipol was added. MAIN OUTCOME MEASURES AND RESULTS: Patients treated with atorvastatin, compared-with other reductase inhibitors, were more likely to reach NCEP goals during treatment (p < 0.05), required fewer office visits (p < 0.001) and less adjuvant colestipol therapy (p = 0.001). Consequently, the mean total cost of care (1996 values) to reach NCEP goals was lower with atorvastatin [$US1064; 95% confidence interval (CI): $US953 to $US1176] compared with simvastatin ($US1471, 95% CI: $US1304 to $US1648), lovastatin ($US1972; 95% CI: $US1758 to $US2186) and fluvastatin ($US1542; 95% CI: $US1384 to $US1710). Results were similar for patients with or without known atherosclerotic disease. CONCLUSIONS: In patients requiring drug therapy for hypercholesterolaemia, NCEP LDL-C goals are achieved significantly more often using fewer resources with atorvastatin compared with simvastatin, lovastatin or fluvastatin.

Aged↗
PubMed1985

Sulfhydryl/disulfide forms of rat liver 3-hydroxy-3-methylglutaryl coenzyme A reductase.

Using radiation inactivation and immunoblotting techniques, evidence for functionally active forms of rat liver 3-hydroxy-3-methylglutaryl coenzyme A reductase with molecular weights of about 100,000 and 200,000 was obtained. In liver microsomes isolated from rats fed both mevinolin and colestipol, the Mr 100,000 form was the predominant species, whereas in microsomes from animals fed only colestipol, the Mr 200,000 species was the major form. This Mr 200,000 form could be converted to the Mr 100,000 form by addition of dithiothreitol or beta-mercaptoethanol. Although both forms appear to possess catalytic activity, the Mr 200,000 species displays sigmoidal kinetics with respect to the concentration of NADPH, whereas the Mr 100,000 form exhibits typical hyperbolic kinetics.

Animals↗
PubMed1990

Bile acid sequestrants.

The bile acid sequestrants, cholestyramine and colestipol, are the drugs of choice for the treatment of patients with hypercholesterolemia caused by increases in LDL-cholesterol levels without concurrent hypertriglyceridemia (type IIA and type IIB hyperlipoproteinemia). Longitudinal clinical studies with these drugs have shown their ability to slow the progression of atherosclerosis and to limit the consequences of the disease. Bile acid sequestrants can be used with other lipid-lowering drugs such as nicotinic acid or HMG CoA reductase inhibitors, to maximize the cholesterol-lowering effects. The side effect profile of the bile acid sequestrants is tolerable, with most complaints related to effects on the gastrointestinal tract and the bulkiness of the resins.

Chemical Phenomena↗
PubMed1978

New microporous cholestyramine analog for treatment of hypercholesterolemia.

A new, microporous, uniformly reticulated preparation of cholestyramine is described. The preparation, cholpor, has a higher exchange capacity for chloride than does cholestyramine and swells very little in water. It is 15--20% more potent than chloestyramine in the in vitro binding of sodium cholate; moreover, the binding velocity is considerably higher than that of cholestyramine. Colestipol hydrochloride, also used as a reference anion-exchange resin, is about half as potent as the other two resins; its binding velocity is similar to that of cholpor. Cholpor may be prepared in a suspension form of good palatability. Preliminary clinical findings in short-term trials showed a cholesterol-lowering effect similar to that of cholestyramine with lower doses and fewer side effects.

Adult↗
PubMed2001

Regulation of hepatic lanosterol 14 alpha-demethylase gene expression by dietary cholesterol and cholesterol-lowering agents.

Binding of sterol response element binding protein 1a to sterol response element-1 (SRE-1) in the promoter region of lanosterol 14 alpha-demethylase (14DM) has been demonstrated previously. Decreased 14DM activity has been shown to result in accumulation of the intermediate, 3 beta-hydroxy-lanost-8-en-32-al, a known translational downregulator of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Since it has also been demonstrated that feedback regulation of hepatic HMG-CoA reductase occurs primarily at the level of translation, the effects of dietary cholesterol and cholesterol lowering agents on levels of hepatic 14DM mRNA and immunoreactive protein were investigated. Addition of 1% cholesterol to a chow diet markedly decreased hepatic 14DM mRNA and protein levels in Sprague-Dawley rats. The extent and time course of this decrease in 14DM immunoreactive protein closely paralleled that of HMG-CoA reductase. Supplementation of the diet with the HMG-CoA reductase inhibitor, Lovastatin, to a level of 0.02%, raised 14DM mRNA and protein levels 2- to 3-fold. Addition of 2% Colestipol, a bile acid binding resin, to the chow diet caused smaller increases. The highest level of 14DM protein expression was observed in liver, the major site of feedback regulation of HMG-CoA reductase by cholesterol. Taken together, these observations suggest a critical role for 14DM in the feedback regulation of hepatic HMG-CoA reductase.

Animals↗
PubMed1978

Dieldrin-14C elimination from turkeys.

A series of experiments were conducted to find ways of removing dieldrin2 residues from tissues of broiler-type turkeys (Meleagris gallopavo). The turkeys were contaminated with dieldrin and dieldrin-14C by oral dosing. Elimination was measured by assaying for 14C in the droppings. Carcass retention was measured by assaying the tissue for 14C, and in one experiment, dieldrin residues were measured by electron capture gas-liquid chromatography. Charcoal, Colestipol, and cholestyramine at dosages approximately equal to an intake of 5% of the diet were ineffective gastrointestinal adsorbants for removing dieldrin residues from the turkeys. Starvation accelerated the elimination of dieldrin from the turkeys, but only if the body lipids were reduced to approximately 10% or less of the carcass dry matter.

Aging↗
PubMed1982

Protection of myocardium by the compensatory mechanism of coronary collaterals after total occlusion of major coronary arteries shown in patients with familial hypercholesterolemia.

We report 11 in a group of 21 asymptomatic patients with heterozygous familial hypercholesterolemia (FH) and progressive coronary artery disease to evaluate the role of compensatory mechanism(s), especially coronary collaterals, in providing adequate blood supply to the myocardium, following complete occlusion of one or more major coronary arteries. Diet-colestipol-nicotinic acid treatment decreased their plasma total cholesterol and low density lipoprotein cholesterol (mg/dl, mean +/- SEM) from 442.9 +/- 25.8 and 363.0 +/-24.1, respectively, to 231.2 +/- 11.8 and 185.3 +/- 14.2, respectively, for 6 to 9 years. The initially stenotic lesions of these 11 patients slowly progressed to complete occlusion, while the patients remained free of myocardial ischemia or infarction and exhibited no abnormality on 24-hour ambulatory ECG monitoring, exercise stress, and thallium 201 stress tests. We conclude that coronary occlusion can be retarded in FH patients by strenuous hypocholesterolemic therapy to allow the development of compensatory mechanism including coronary collaterals. Apparently, the angiographically visualizable collaterals combined with subendocardial anastomosis can give adequate myocardial blood supply to this series of FH patients following occlusion of one or more of their major coronary arteries.

Adult↗
PubMed1987

Turnover rates of HMG-CoA reductase mRNA: role of pituitary and thyroid hormones.

When normal or hypophysectomized rats maintained on a diet containing mevinolin and colestipol were switched to a normal chow diet, HMG-CoA reductase mRNA fell rapidly with a half-life of 3 hrs. After a 90 min lag period, reductase activity and immunoreactive protein fell in parallel with the mRNA in normal rats. In hypophysectomized rats, reductase activity and protein required 10 and 18 hrs, respectively to fall to 50% of their original levels. Administration of thyroid hormones to hypophysectomized rats resulted in a 3 to 4 fold stabilization of reductase mRNA suggesting that the increased mRNA levels are due in part to a posttranscriptional regulatory effect of thyroid hormones.

Animals↗
PubMed1989

Hydroxycholesterols in serum from hypercholesterolaemic patients with and without bile acid sequestrant therapy.

To assess the effect of bile acid sequestrant therapy on bile acid precursors in plasma, we determined hydroxycholesterols in serum from patients with primary hypercholesterolaemia. Compared with a group of 5 male and 12 female patients without any lipid-lowering drug therapy, which has normal to slightly elevated 7 alpha-hydroxycholesterol, normal 7 beta-hydroxycholesterol and high normal to elevated 26-hydroxycholesterol levels, a group of 5 male and 9 female patients, using colestipol had higher 7 alpha-hydroxycholesterol without overlap, and higher 7 beta-hydroxycholesterol levels, but similar levels of 26-hydroxycholesterol. In the latter group, the ratio between 7 alpha-hydroxycholesterol and total cholesterol in serum was also higher without overlap. Both groups did not differ for age, body weight, body mass index and serum lipid levels. In the group of patients without lipid-lowering drug therapy, 7 alpha-hydroxycholesterol correlated positively with total and low-densitylipoprotein cholesterol, 7 beta-hydroxycholesterol negatively with body weight and body mass index, and 26-hydroxycholesterol positively with body weight. In both groups, 7 alpha-hydroxycholesterol correlated positively with 7 beta-hydroxycholesterol. These results suggest that (1) bile acid sequestrants enhance bile acid synthesis via the 7 alpha-hydroxylation but not via the 26-hydroxylation pathway, (2) serum 7 alpha-hydroxycholesterol level and the ratio between this hydroxycholesterol and total cholesterol in serum might be suitable parameters to check intake of bile acid sequestrants irrespective of dose, and (3) 7 beta-hydroxycholesterol is unlikely to be the result of cholesterol auto-oxidation in vitro.

Adult↗
PubMed1985

Carotenoids and vitamin A: the effect of hypocholesterolemic agents on serum levels.

Serum total carotenoid (STC) and vitamin A levels were done as part of the biochemical screening in comparative studies of lipid lowering agents in type Ila hyperlipoproteinemic patients. STC levels were reduced following bile acid sequestering agent administration (colestipol 30 g/d) by 30% (P less than 0.01). Clofibrate and avicel placebo had inconsistent and nonsignificant effects on the STC levels. Serum vitamin A levels were not significantly altered by any of the test agents. The STC level changes were not correlated with concomitant changes in low-density lipoprotein-cholesterol (LDL-C) during any of the treatment regimens. It is suggested that STC level changes are related to alterations in the absorption of carotenoids during bile acid sequestrant administration.

Adult↗
PubMed1985

The effect of cold-restraint stress on gastric emptying in rats.

The effects of drug treatment and of cold-restraint stress (a method used to produce experimental stomach ulcers) on gastric emptying of a resin (colestipol-phenol red complex) were investigated in rats. Gastric emptying was decreased by intraperitoneal treatment with atropine (0.3 mg/kg) or verapamil (4 mg/kg), and enhanced by bethanechol (1.2 mg/kg). Stress by restraint at 4 degrees C for 2 hr markedly reduced gastric emptying; the pattern of effects of drug pretreatment in these stressed rats was similar to that seen in their nonstressed controls. Further experiments, with stress for 3 hr, revealed that the gastric emptying rate was triphasic; increasing in the first hr, returning to normal and then slowing in the third hr of stress. Initial increase in emptying rate was probably due to predominant vagal overactivity. Hypothermia and possibly other factors induced by cold-restraint stress could have subsequently depressed gastric motility.

Animals↗
PubMed1988

In situ determination of the functional size of hepatic 3-hydroxy-3-methylglutaryl-CoA reductase by radiation inactivation analysis.

Radiation inactivation analysis of liver pieces yielded a target size of 210 kDa for hepatic 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase [S)-mevalonate:NADP+ oxidoreductase (CoA-acylating), EC 1.1.1.34) from rats fed a normal diet. Feeding a diet containing mevinolin and colestipol, which causes a marked increase in enzyme activity, resulted in a reduction of the target size to 120 kDa. These results are consistent with those obtained by radiation inactivation and immunoblotting analysis of isolated microsomes and suggest that the increase in HMG-CoA reductase activity caused by these dietary agents is accompanied by a change from a dimer to a monomer form of the enzyme.

Animals↗
PubMed1995

Design of crossover microcomputer program and application on drug bioequivalence data.

A simple microcomputer crossover program in BASIC is designed for the purpose of drug bioequivalence studies and other related fields of statistical investigation. An illustration of the application of the program is presented to compare the bioavailability of ibuprofen when administered alone or followed by colestipol hydrochloride or by cholestyramine.

Analysis of Variance↗
PubMed1987

The Cholesterol Lowering Atherosclerosis Study (CLAS): design, methods, and baseline results.

The Cholesterol Lowering Atherosclerosis Study (CLAS) is a prospective, placebo-controlled, angiographic trial designed to test the hypothesis that aggressive lowering of LDL cholesterol with concomitant increase in HDL cholesterol will reverse or retard the atherosclerotic process. Specifically, CLAS was designed to determine whether combined therapy with colestipol plus niacin will produce clinically significant change in coronary, carotid, and femoral artery atherosclerosis and coronary bypass graft lesions. To this purpose, 188 subjects were randomized to diet plus drug or diet plus placebo. We report on methodological aspects of planning and evaluating this study, including the choice of the study population, procedures for recruitment, the experimental design including sample size considerations, methods for evaluating outcome, and methods for evaluating compliance to treatment. Comparison of baseline data indicated no significant differences between groups at the time of randomization. Subjects were predominantly male, Caucasian, 54 years of age, 20% above ideal weight, with normal blood pressure. The average age at bypass was 50 years. The average lipids were cholesterol (243 mg/dL), HDL (45 mg/dL), and LDL (168 mg/dL). Finally, the distribution of baseline coronary stenosis was equivalent between the two groups (average number of lesions per subject = 10.6).

Adult↗
PubMed1992

Cholesterol lowering bile acid binding agents: novel lipophilic polyamines.

A series of novel lipophilic polyamines was synthesized by the sodium cyanoborohydride-mediated reductive amination of various ketones and aldehydes with the polyamine tris(2-aminoethyl)amine. Two of these compounds, N,N-bis[2-(cyclododecylamino)ethyl]-N'-benzyl-1,2-ethanediamine trihydrochloride (36.3HCl) and N,N-bis[2-(cyclododecylmethylamino)ethyl]-N',N'-dimethyl-1,2-ethan ediamine (23), are 29 and 24 times more potent than colestipol hydrochloride, respectively, for lowering animal serum cholesterol levels.

Animals↗
PubMed2000

Efficacy of two lipid-lowering treatments on quantitative coronary angiographic endpoints.

This study contrasts the sensitivity of four quantitative coronary angiography (QCA) measures (percent diameter stenosis [%S], minimum lumen diameter, average segment diameter, and percent involvement) in detecting 2-year treatment effects of two lipid-lowering therapies and reports on the longitudinal pattern after 4 years of treatment on the primary QCA trial endpoint (%S) for all, mild/moderate (<50%S), and severe lesions (> or =50%S). Patient cohorts were followed up from two randomized, placebo-controlled clinical trials of lipid-lowering therapies-colestipol/niacin in the Cholesterol Lowering Atherosclerosis Study (CLAS) and lovastatin in the Monitored Atherosclerosis Regression Study (MARS). Identical QCA methodology was used. In CLAS, the largest 2-year treatment effect size (=0.60) was noted for %S. In MARS, equivalent 2-year effect sizes (=0.15) were noted for three QCA measures. The largest 2-year effect size in %S was found in CLAS for mild/moderate lesions (=0.55) and in MARS for severe lesions (=0.31). Treatment in CLAS led to regression of disease in the first 2 years; treatment in MARS slowed progression of disease in the first 2 years and led to regression of disease after 4 years. Colestipol/niacin reduced progression of mild/moderate and severe lesions over the first 2 years of therapy; lovastatin reduced the progression of severe lesions over the last 2 years of therapy. We conclude that reducing the progression of atherosclerosis is not a simple proposition; maximal therapy for reducing and stabilizing atherosclerosis most likely will result from the selection of agents targeted at specific lesions.

Adult↗
PubMed1989

Noninvasive assessment of lipid disposition in treated and untreated atherosclerotic rabbits.

In an effort to visualize whole body cholesteryl ester (CE) deposition using the nuclear medicine imaging technique of gamma camera scintigraphy, 125I-cholesteryl iopanoate (125I-CI), a nonhydrolyzable CE analogue, was used as a marker for CE deposition in atherosclerotic New Zealand white rabbits. Groups of animals were fed either a cholesterol-enriched diet (2%, w/w) or the same diet supplemented with the hypolipidemic drugs colestipol (1%, w/w) and/or clofibrate (0.3%, w/w). Injections of 125I-CI were administered biweekly. At the end of 15 weeks, animals were scintigraphically scanned and sacrificed for tissue analysis. The results demonstrated that while drug treatment had no significant effect on plasma lipid levels, it substantially lessened atherosclerotic involvement in the thoracic-abdominal aorta. These differences in aortic lipid accumulation were reflected in the whole-body scans which showed a reduction in tissue accumulation of 125I-CI in the drug-treated groups. Gamma camera scintigraphy thus represents a rapid means of visualizing tissue CE accumulation which could facilitate the evaluation of lipid-lowering drug efficacy and possible antiatherosclerotic effect.

Animals↗