Biomedical subjects

LeAnne T Bloedon

Publications and source records attributed to LeAnne T Bloedon.

9 recordsLinked to original sources

PubMed2007

Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia.

BACKGROUND: Patients with homozygous familial hypercholesterolemia have markedly elevated cholesterol levels, which respond poorly to drug therapy, and a very high risk of premature cardiovascular disease. Inhibition of the microsomal triglyceride transfer protein may be effective in reducing cholesterol levels in these patients. METHODS: We conducted a dose-escalation study to examine the safety, tolerability, and effects on lipid levels of BMS-201038, an inhibitor of the microsomal triglyceride transfer protein, in six patients with homozygous familial hypercholesterolemia. All lipid-lowering therapies were suspended 4 weeks before treatment. The patients received BMS-201038 at four different doses (0.03, 0.1, 0.3, and 1.0 mg per kilogram of body weight per day), each for 4 weeks, and returned for a final visit after a 4-week drug washout period. Analysis of lipid levels, safety laboratory analyses, and magnetic resonance imaging of the liver for fat content were performed throughout the study. RESULTS: All patients tolerated titration to the highest dose, 1.0 mg per kilogram per day. Treatment at this dose decreased low-density lipoprotein (LDL) cholesterol levels by 50.9% and apolipoprotein B levels by 55.6% from baseline (P<0.001 for both comparisons). Kinetic studies showed a marked reduction in the production of apolipoprotein B. The most serious adverse events were elevation of liver aminotransferase levels and accumulation of hepatic fat, which at the highest dose ranged from less than 10% to more than 40%. CONCLUSIONS: Inhibition of the microsomal triglyceride transfer protein by BMS-201038 resulted in the reduction of LDL cholesterol levels in patients with homozygous familial hypercholesterolemia, owing to reduced production of apolipoprotein B. However, the therapy was associated with elevated liver aminotransferase levels and hepatic fat accumulation.

Adolescent↗

PubMed2005

Effects of rosiglitazone on lipids, adipokines, and inflammatory markers in nondiabetic patients with low high-density lipoprotein cholesterol and metabolic syndrome.

BACKGROUND: PPAR-gamma agonists improve insulin sensitivity and glycemic control in type 2 diabetes and may reduce atherosclerosis progression. Thus, PPAR-gamma agonists may be an effective therapy for metabolic syndrome. However, the full spectrum of potentially antiatherogenic mechanisms of PPAR-gamma agonists have not been fully tested in nondiabetic patients with metabolic syndrome. METHODS AND RESULTS: We performed a prospective, double-blinded, placebo-controlled study of 60 nondiabetic subjects with low high-density lipoprotein cholesterol (HDL-C) level and metabolic syndrome to rosiglitazone 8 mg daily or placebo for 12 weeks. We found no significant effect of rosiglitazone on HDL-C (+5.5% versus +5.8%, P=0.89), and an increase in total cholesterol (+8% versus -1%; P=0.03). Nevertheless, rosiglitazone significantly increased adiponectin (+168% versus +25%; P<0.001), and lowered resistin (-6% versus +4%; P=0.009), C-reactive protein (-32% versus +36%, P=0.002), interleukin (IL)-6 (-22% versus +4%, P<0.001), and soluble tumor-necrosis factor-alpha receptor-2 (-5% versus +7%, P<0.001). CONCLUSIONS: These findings suggest that rosiglitazone, presumably through its PPAR-gamma agonist properties, has direct effects on inflammatory markers and adipokines in the absence of favorable lipid effects. These findings may help explain the mechanism underlying the possible antiatherosclerotic effects of rosiglitazone.

Adiponectin↗

PubMed2005

Effects of pioglitazone on lipoproteins, inflammatory markers, and adipokines in nondiabetic patients with metabolic syndrome.

OBJECTIVE: The purpose of this research was to evaluate the short-term effects of pioglitazone (PIO) on high-density lipoprotein cholesterol (HDL-C) and other metabolic parameters in nondiabetic patients with metabolic syndrome (MetSyn). METHODS AND RESULTS: Sixty nondiabetic adults with low HDL-C and MetSyn were randomized to PIO or matching placebo for 12 weeks. PIO increased HDL-C by 15% and 14% at 6 and 12 weeks, respectively, compared with placebo (P<0.001). Changes in HDL-C were correlated to changes in adiponectin (r=0.34; P=0.01) but not to changes in insulin resistance. PIO did not affect serum triglycerides or low-density lipoprotein (LDL) cholesterol concentrations but reduced the number of small LDL particles by 18% (P<0.001). PIO reduced median C-reactive protein levels by 31% (P<0.001) and mean resistin levels by 10% (P=0.02) while increasing mean serum levels of adiponectin by 111% (P<0.001) compared with placebo. PIO did not affect weight and modestly decreased insulin resistance. CONCLUSIONS: In nondiabetic patients with low HDL-C and MetSyn, PIO significantly raised HDL-C and favorably affected lipoprotein particle size, markers of inflammation, and adipokines without changes in triglycerides, LDL-C, or weight. These results suggest that PIO has direct effects on HDL, which may contribute to its antiatherogenic effects.

Adiponectin↗

PubMed2004

Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol.

BACKGROUND: Decreased high-density lipoprotein (HDL) cholesterol levels constitute a major risk factor for coronary heart disease; however, there are no therapies that substantially raise HDL cholesterol levels. Inhibition of cholesteryl ester transfer protein (CETP) has been proposed as a strategy to raise HDL cholesterol levels. METHODS: We conducted a single-blind, placebo-controlled study to examine the effects of torcetrapib, a potent inhibitor of CETP, on plasma lipoprotein levels in 19 subjects with low levels of HDL cholesterol (<40 mg per deciliter [1.0 mmol per liter]), 9 of whom were also treated with 20 mg of atorvastatin daily. All the subjects received placebo for four weeks and then received 120 mg of torcetrapib daily for the following four weeks. Six of the subjects who did not receive atorvastatin also participated in a third phase, in which they received 120 mg of torcetrapib twice daily for four weeks. RESULTS: Treatment with 120 mg of torcetrapib daily increased plasma concentrations of HDL cholesterol by 61 percent (P<0.001) and 46 percent (P=0.001) in the atorvastatin and non-atorvastatin cohorts, respectively, and treatment with 120 mg twice daily increased HDL cholesterol by 106 percent (P<0.001). Torcetrapib also reduced low-density lipoprotein (LDL) cholesterol levels by 17 percent in the atorvastatin cohort (P=0.02). Finally, torcetrapib significantly altered the distribution of cholesterol among HDL and LDL subclasses, resulting in increases in the mean particle size of HDL and LDL in each cohort. CONCLUSIONS: In subjects with low HDL cholesterol levels, CETP inhibition with torcetrapib markedly increased HDL cholesterol levels and also decreased LDL cholesterol levels, both when administered as monotherapy and when administered in combination with a statin.

Adult↗

PubMed2004

Flaxseed and cardiovascular risk.

Flaxseed has recently gained attention in the area of cardiovascular disease primarily because it is the richest known source of both alpha-linolenic acid (ALA) and the phytoestrogen, lignans, as well as being a good source of soluble fiber. Human studies have shown that flaxseed can modestly reduce serum total and low-density lipoprotein cholesterol concentrations, reduce postprandial glucose absorption, decrease some markers of inflammation, and raise serum levels of the omega-3 fatty acids, ALA and eicosapentaenoic acid. Data on the antiplatelet, antioxidant, and hypotensive effects of flaxseed, however, are inconclusive. More research is needed to define the role of this functional food in reducing cardiovascular risk.

Animals↗

PubMed2003

Guggulipid for the treatment of hypercholesterolemia: a randomized controlled trial.

CONTEXT: Herbal extracts from Commiphora mukul (guggul) have been widely used in Asia as cholesterol-lowering agents, and their popularity is increasing in the United States. Recently, guggulsterones, the purported bioactive compounds of guggul, have been shown to be potent antagonists of 2 nuclear hormone receptors involved in cholesterol metabolism, establishing a plausible mechanism of action for the hypolipidemic effects of these extracts. However, there are currently no published safety or efficacy data on the use of guggul extracts in Western populations. OBJECTIVE: To study the short-term safety and efficacy of 2 doses of a standardized guggul extract (guggulipid, containing 2.5% guggulsterones) in healthy adults with hyperlipidemia eating a typical Western diet. DESIGN: Double-blind, randomized, placebo-controlled trial using a parallel design, conducted March 2000-August 2001. PARTICIPANTS AND SETTING: A total of 103 ambulatory, community-dwelling, healthy adults with hypercholesterolemia in the Philadelphia, Pa, metropolitan area. INTERVENTION: Oral, 3 times daily doses of standard-dose guggulipid (1000 mg), high-dose guggulipid (2000 mg), or matching placebo. MAIN OUTCOME MEASURES: Percentage change in levels of directly measured low-density lipoprotein cholesterol (LDL-C) after 8 weeks of therapy. Secondary outcome measures included levels of total cholesterol, high-density lipoprotein cholesterol (HDL-C), triglycerides, and directly measured very low-density lipoprotein cholesterol (VLDL-C), as well as adverse events reports and laboratory safety measures including electrolyte levels and hepatic and renal function. RESULTS: Compared with participants randomized to placebo (n = 36), in whom levels of LDL-C decreased by 5%, both standard-dose guggulipid (n = 33) and high-dose guggulipid (n = 34) raised levels of LDL-C by 4% (P =.01 vs placebo) and 5% (P =.006 vs placebo), respectively, at 8 weeks, for a net positive change of 9% to 10%. There were no significant changes in levels of total cholesterol, HDL-C, triglycerides, or VLDL-C in response to treatment with guggulipid in the intention-to-treat analysis. While guggulipid was generally well tolerated, 6 participants treated with guggulipid developed a hypersensitivity rash compared with none in the placebo group. CONCLUSIONS: Despite plausible mechanisms of action, guggulipid did not appear to improve levels of serum cholesterol over the short term in this population of adults with hypercholesterolemia, and might in fact raise levels of LDL-C. Guggulipid also appeared to cause a dermatologic hypersensitivity reaction in some patients.

Anticholesteremic Agents↗

PubMed2003

Physical activity and its effects on lipids.

Physical activity is an important component of weight control, and is widely recommended to prevent and treat obesity-related complications such as diabetes and coronary heart disease (CHD). Although the cardiovascular benefits of increased physical activity are likely multifactorial, much of the attention has been focused on the known high-density lipoprotein (HDL) cholesterol-raising properties of regular physical activity. Physical activity, however, can also reliably lower triglycerides and favorably affect both low-density lipoprotein (LDL) and HDL particle sizes. Limited data on resistance exercise suggest that this type of physical activity may reduce LDL cholesterol. Although these lipid effects are modest and variable, they are likely to be particularly important in reducing the morbidity and mortality from CHD on a population level, and may be especially important in patients with atherogenic dyslipidemia.

Cardiovascular Diseases↗

PubMed2002

Clinical characteristics and pharmacokinetics of purified soy isoflavones: single-dose administration to healthy men.

BACKGROUND: Soy isoflavones are potential cancer chemoprevention treatments. OBJECTIVE: We conducted safety studies of purified unconjugated genistein, daidzein, and glycitein, and defined pharmacokinetic parameters for their absorption and metabolism. DESIGN: Thirty healthy men ingested a single dose of 1 of 2 isoflavone preparations purified from soy. The delivered doses of genistein (1, 2, 4, 8, or 16 mg/kg body wt) were higher than those previously administered to humans. Formulation A was composed of 90 +/- 5% genistein, 10% daidzein, and 1% glycitein. Formulation B was composed of 43% genistein, 21% daidzein, and 2% glycitein. RESULTS: We observed no clinically significant behavioral or physical changes after treatment. We observed elevations in lipoprotein lipase and hypophosphatemia that were possibly related to the treatment but that were associated with no clinical toxicity. Considerable quantities of isoflavones were excreted in urine as conjugates. The terminal elimination rate, elimination half-life, area under the curve, maximum plasma concentration, apparent systemic clearance, and volume of distribution were estimated for genistein and daidzein. The mean elimination half-lives with both formulations were 3.2 h for free genistein and 4.2 h for free daidzein. The mean pseudo half-lives were 9.2 h for total genistein and 8.2 h for total daidzein. CONCLUSIONS: Dietary supplements of purified unconjugated isoflavones administered to humans in single doses exceeding normal dietary intake manyfold resulted in minimal clinical toxicity. Genistein and daidzein (free and total) were rapidly cleared from plasma and excreted in urine.

Adult↗

PubMed2002

Safety and pharmacokinetics of purified soy isoflavones: single-dose administration to postmenopausal women.

BACKGROUND: Soy isoflavones are being evaluated as chemopreventive agents for breast and other cancers. OBJECTIVE: The objective was to perform safety and pharmacokinetic studies of purified unconjugated isoflavone preparations containing genistein, daidzein, and glycitein in postmenopausal women. DESIGN: Twenty-four healthy postmenopausal women ingested a single dose of 1 of 2 purified (from soybeans) isoflavone preparations that delivered a genistein dose of 2, 4, 8, or 16 mg/kg body wt. These doses were higher than those previously administered to human females. Toxicity studies were performed 24 h and 3, 6, 14, and 30 d after isoflavone administration. Kinetic studies were performed during the first 24 h. RESULTS: We observed a 7% decrease in systolic and diastolic blood pressure and a 32% decrease in the neutrophil count 24 h after treatment with formulation A. Isolated episodes of nausea, pedal edema, and breast tenderness were judged to be possibly related to the study treatment. The terminal plasma half-lives for free genistein, daidzein, and glycitein averaged 3.8, 7.7, and 3.4 h, respectively. The terminal pseudo half-lives for total genistein and total daidzein in plasma averaged 10.1 and 10.8 h, respectively. The estimated bioavailabilities of both total genistein and total daidzein from each of the 2 formulations were not significantly different. CONCLUSIONS: A single-dose administration of purified unconjugated isoflavones at amounts that exceed normal dietary intakes had minimal clinical toxicity in healthy postmenopausal women. The pharmacokinetic data suggest that chronic dosing at 12-24-h intervals would not lead to progressive accumulation of these isoflavones.

Aged↗