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Biomedical subjects

Harold Bays

Publications and source records attributed to Harold Bays.

At least 19 recordsLinked to original sources
PubMed2006

Clinical overview of Omacor: a concentrated formulation of omega-3 polyunsaturated fatty acids.

Omacor (omega-3-acid ethyl esters; Reliant Pharmaceuticals, Inc., Liberty Corner, NJ) is a highly purified, prescription omega-3 fatty acid formulation with high concentrations of eicosapentaenoic acid (EPA) (465 mg) and docosahexaenoic acid (DHA) (375 mg) in each 1-g capsule, along with 4 mg (6 IU) of vitamin E. At a typical dose of 4 capsules/day, Omacor significantly lowers plasma triglyceride levels either as monotherapy or in combination with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) or fibrates. Omacor also modestly increases plasma levels of low-density lipoprotein cholesterol, increases high-density lipoprotein cholesterol levels, and has favorable effects on lipoprotein particle size and subclass distribution. Omacor is well tolerated, with few side effects other than mild gastrointestinal symptoms. Hyperglycemia, abnormal bleeding, elevations in muscle or liver enzymes, and/or abnormalities in kidney or nerve function have not been reported. Through its intensive purification process, Omacor has minimal "fishy" smell and taste, and it has not been reported to cause hypervitaminosis or illness due to exposure to environmental toxins. Omacor provides a safe, effective, well-tolerated approach to management of hypertriglyceridemia.

Cholesterol, HDL↗
PubMed2006

Statin safety: an overview and assessment of the data--2005.

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statin drugs, have been studied in numerous controlled human research trials involving hundreds of thousands of study participants. Statins have been prescribed for millions of patients. Based on this vast research and clinical experience, statins have been shown to improve lipid blood levels and reduce atherosclerotic coronary artery disease (CAD) risk, resulting in reduced CAD morbidity and mortality, and in several studies, reduced overall ("all-cause") mortality. From a safety perspective, both research trial evidence and clinical practice experience have demonstrated that statins are generally well tolerated. However, as with all pharmaceuticals, safety considerations exist with both monotherapy and combination statin therapy, mainly involving potential adverse effects on muscle, liver, kidney, and the nervous system. The evidence supporting statin-related potential adverse experiences on these organ systems is sometimes strong and based on clear clinical trial evidence (such as the increased risk of muscle enzyme elevation with higher statin doses). The evidence is at other times more speculative, being based on case reports and inconclusive clinical trial data (such as possible favorable or unfavorable effects of statins on cognition). Because the use of statins is so widespread, it is useful for the clinician to understand statin safety issues and the level of available evidence supporting the contention that various adverse effects are caused by statins. This review presents an assessment of statin safety based on an overview of the current statin safety data and their clinical implications.

Chemical and Drug Induced Liver Injury↗
PubMed2006

Adiposopathy is a more rational treatment target for metabolic disease than obesity alone.

Current guidelines recommend that weight-loss therapy should be primarily based upon specific body mass index (BMI) cut-off limits. However, in the adipocentric paradigm, it is acknowledged that co-morbidities, such as type 2 diabetes mellitus, hypertension, and dyslipidemia, occur at all levels of BMI. Excessive fat mass (adiposity) in genetically susceptible individuals results in fat dysfunction (adiposopathy), which then contributes to metabolic disorders that increase the risk of atherosclerotic cardiovascular disease. In this paradigm, the term "anti-obesity" treatment might best be replaced by "anti-adiposopathy" treatment, wherein the focus is not based solely on BMI, but instead directed towards physiologically improving fat cell function and clinically improving the metabolic health of patients. This may occur through appropriate diet, physical exercise, and other lifestyle changes, and/or from drug therapies. Cannabinoid receptor antagonists and peroxisome proliferator activated receptor agonists are examples of agents that physiologically improve fat function and clinically improve metabolic disease.

Anti-Obesity Agents↗
PubMed2006

Neuropeptide Y5 receptor antagonism does not induce clinically meaningful weight loss in overweight and obese adults.

Neuropeptide Y (NPY) is a potent orexigenic neuropeptide, and antagonism of NPY Y1 and NPY Y5 receptors (NPYxR) is considered a potentially important anti-obesity drug target. We tested the hypothesis that blockade of the NPY5R will lead to weight loss in humans using MK-0557, a potent, highly selective, orally active NPY5R antagonist. The initial series of experiments reported herein, including a multiple-dose positron-emission tomography study and a 12 week proof-of concept/dose-ranging study, suggested an optimal MK-0557 dose of 1 mg/day. The hypothesis was then tested in a 52 week, multicenter, randomized, double-blind, placebo-controlled trial involving 1661 overweight and obese patients. Although statistically significant at 52 weeks, the magnitude of induced weight loss was not clinically meaningful. These observations provide the first clinical insight into the human NPY-energy homeostatic pathway and suggest that solely targeting the NPY5R in future drug development programs is unlikely to produce therapeutic efficacy.

Administration, Oral↗
PubMed2006

Lipid-lowering effects of colesevelam HCl in combination with ezetimibe.

OBJECTIVE: The primary aim of this study was to compare the effect of colesevelam HCl in combination with ezetimibe to ezetimibe monotherapy on low-density lipoprotein cholesterol (LDL-C) levels in subjects with primary hypercholesterolemia. METHODS: Subjects with primary hypercholesterolemia (N = 86) were enrolled in a multicenter, randomized, double-blind, placebo-controlled, parallel-group study. After a 4- to 8-week washout period, subjects received colesevelam HCl 3.8 g/day plus ezetimibe 10 mg/day or colesevelam HCl placebo plus ezetimibe 10 mg/day for 6 weeks. The primary efficacy endpoint was the mean percent change in LDL-C during randomized treatment. Secondary endpoints included mean absolute change in LDL-C, mean absolute and mean percent change in levels of high-density lipoprotein cholesterol (HDL-C), non-HDL-C, total cholesterol (TC), apolipoprotein (apo) A-I and apo B, and median absolute and percent changes in triglycerides (TG) and high-sensitivity C-reactive protein from baseline to end of treatment. Of the 86 subjects randomized to treatment, 85 were included in the intent-to-treat analysis. RESULTS: After 6 weeks of treatment, colesevelam HCl plus ezetimibe produced a mean percent change in LDL-C of -32.3% versus -21.4% with ezetimibe monotherapy (p < 0.0001). Colesevelam HCl plus ezetimibe was significantly more effective than ezetimibe alone at producing mean percent reductions in TC, non-HDL-C, and apo B and increases in apo A-I (p < 0.005 for all). Neither treatment regimen resulted in significant changes in median TG levels compared with baseline (p = NS). Both treatments were safe and generally well tolerated. CONCLUSIONS: Colesevelam HCl plus ezetimibe combination therapy significantly reduced mean LDL-C, TC, non-HDL-C, and apo B levels and increased apo A-I levels (p < 0.005 for all) without significantly increasing median TG levels in hypercholesterolemic subjects compared with ezetimibe alone. Although limited in that atherosclerotic coronary heart disease outcomes were not evaluated, this study demonstrated that combining colesevelam HCl with ezetimibe is a therapeutic option in hypercholesterolemic patients, such as those in whom statins are contraindicated and/or who may have intolerances to statin therapy.

Adult↗
PubMed2006

Adiposopathy: how do diet, exercise and weight loss drug therapies improve metabolic disease in overweight patients?

An increase in bodyweight is generally associated with an increased risk of excessive fat-related metabolic diseases (EFRMD), including Type 2 diabetes mellitus, hypertension and dyslipidemia. However, not all patients who are overweight have EFRMD, and not all patients with EFRMD are significantly overweight. The adipocentric paradigm provides the basis for a unifying, pathophysiological process whereby fat gain in susceptible patients leads to fat dysfunction ('sick fat'), and wherein pathological abnormalities in fat function (adiposopathy) are more directly related to the onset of EFRMD than increases in fat mass (adiposity) alone. But just as worsening fat function worsens EFRMD, improved fat function improves EFRMD. Peroxisome proliferator-activated receptor-gamma agonists increase the recruitment, proliferation and differentiation of preadipocytes ('healthy fat') and cause apoptosis of hypertrophic and dysfunctional (including visceral) adipocytes resulting in improved fat function and improved metabolic parameters associated with EFRMD. Weight loss interventions, such as a hypocaloric diet and physical exercise, in addition to agents such as orlistat, sibutramine and cannabinoid receptor antagonists, may have favorable effects upon fat storage (lipogenesis and fat distribution), nutrient metabolism (such as free fatty acids), favorable effects upon adipose tissue factors involved in metabolic processes and inflammation, and enhanced 'cross-talk' with other major organ systems. In some cases, weight loss therapeutic agents may even affect metabolic parameters and adipocyte function independently of weight loss alone, suggesting that the benefit of these agents in improving EFRMD may go beyond their efficacy in weight reduction. This review describes how adiposopathy interventions may affect fat function, and thus improve EFRMD.

Adipose Tissue↗
PubMed2006

The melanocortin system as a therapeutic treatment target for adiposity and adiposopathy.

The melanocortin system is an important treatment target towards improving both adiposity (excessive body fat) and adiposopathy (dysfunctional body fat). Melanocortin agonism can be achieved by increasing CNS leptin and/or insulin activity, which is dependent upon peripheral leptin/insulin production, transport across the blood-brain barrier (potentially relevant to inhaled/nasal insulin), and effects upon CNS target receptors. Melanocortin agonism may also be achieved through inhibiting inverse agonists of melanocortin receptors (such as inhibition of agouti-related peptide), and directly through selective melanocortin receptor ligands such as piperazine, piperidine, pyridazinone, tetrahydropyran, thiadiazole and diazole derivatives. While the development of most (but not all) neuropeptide Y inhibitors as monotherapy interventions have demonstrated limited efficacy thus far, it is possible that the combination of a neuropeptide Y inhibitor with a selective melanocortin receptor ligand may provide improved weight loss over that of either agent alone. In general, melanocortin system agonism promotes weight loss through decreasing appetite, increasing sympathetic nervous system activity, and modulating thyroid-releasing hormone, corticotropin-releasing hormone, brain-derived neurotrophic factor, melanin-concentrating hormone and orexin. Of particular interest, given the development of cannabinoid receptor antagonists as weight loss agents, is the fact that receptors in the endocannabinoid system are also affected by the melanocortin system. It will only be through the conduct of human clinical trials that melanocortin agonists will be proven to reduce adiposity to a meaningful degree, and, as importantly, be proven to improve adiposopathy, and thus effectively treat excessive fat-related metabolic diseases.

Adiposity↗
PubMed2005

Efficacy and safety profile of fenofibrate-coated microgranules 130 mg, with and without food, in patients with hypertriglyceridemia and the metabolic syndrome: an 8-week, randomized, double-blind, placebo-controlled study.

BACKGROUND: The limited bioavailability of certain fenofibrate formulations necessitates administration with food, raising concerns about efficacy and compliance. There is a need for new formulations that have improved bioavailability and eliminate the requirement for administration with food. OBJECTIVE: The aim of this study was to assess the food-related efficacy of a new formulation of micronized fenofibrate coated on inert microgranules (FF-muG) for the treatment of hypertriglyceridemia in patients exhibiting the metabolic syndrome. METHODS: This was a randomized, double-blind, placebo-controlled, double-dummy, parallel-group study in patients who had fasting triglyceride (TG) concentrations > or =300 mg/dL and <1000 mg/dL and met National Cholesterol Education Program Adult Treatment Panel III criteria for the metabolic syndrome. A 6-week washout and diet lead-in period was followed by an 8-week treatment period. Eligible patients were randomized to receive either FF-muG 130 mg with food, FF-muG 130 mg without food, or placebo every day for 8 weeks. The primary end point was the mean percent change in TG levels from baseline to the end of treatment; changes in other lipid end points were also assessed. Safety profiles were assessed based on adverse-event reports, changes in clinical laboratory values and vital signs (including electrocardiography), and the findings of physical examinations. RESULTS: One hundred forty-six patients took part in the study: 54 received FF-muG 130 mg with food, 42 received FF-muG 130 mg without food, and 50 received placebo. The groups were similar in terms of mean age (56 years), sex (59.5%-63.0% men; 37.0%-40.5% women), race (83.3%-100% white), mean body weight (92 kg), mean height (172 cm), mean fasting baseline TG concentrations (480 mg/dL), and other components of the metabolic syndrome. The 2 FF-muG groups (with and without food) showed similar improvements in the dyslipidemia associated with the metabolic syndrome: TG levels decreased a mean of 36.7% and 36.6%, respectively (P < 0.001 vs placebo). The overall frequency of adverse events was similar in the 2 FF-muG groups and did not differ significantly from placebo (63.0%, 61.9%, and 52.0%, respectively). Gastrointestinal disturbances (eg, diarrhea, dyspepsia) occurred more frequently in the 2 FF-muG groups compared with the placebo group (31.5%, 26.2%, and 12.0%; P = NS). Significant increases from baseline in alanine aminotransferase were seen in both FF-muG groups (mean [SEM], 3.77 [2.60] and 11.69 [7.42] U/L, respectively; P < or = 0.05 vs placebo); however, these increases were considered clinically significant in only 5 cases, none of them requiring discontinuation of study drug. CONCLUSIONS: This study found no inequivalence in the TG-lowering effects of the 2 fenofibrate regimens compared with placebo. Both regimens were well tolerated. Thus, FF-muG 130 mg administered without regard to meals appears to be efficacious and well tolerated for the treatment of hypertriglyceridemia in patients exhibiting the metabolic syndrome.

Capsules↗
PubMed2005

Adiposopathy, metabolic syndrome, quantum physics, general relativity, chaos and the Theory of Everything.

Excessive fat (adiposity) and dysfunctional fat (adiposopathy) constitute the most common worldwide epidemics of our time -- and perhaps of all time. Ongoing efforts to explain how the micro (adipocyte) and macro (body organ) biologic systems interact through function and dysfunction in promoting Type 2 diabetes mellitus, hypertension and dyslipidemia are not unlike the mechanistic and philosophical thinking processes involved in reconciling the micro (quantum physics) and macro (general relativity) theories in physics. Currently, the term metabolic syndrome refers to a constellation of consequences often associated with excess body fat and is an attempt to unify the associations known to exist between the four fundamental metabolic diseases of obesity, hyperglycemia (including Type 2 diabetes mellitus), hypertension and dyslipidemia. However, the association of adiposity with these metabolic disorders is not absolute and the metabolic syndrome does not describe underlying causality, nor does the metabolic syndrome necessarily reflect any reasonably related pathophysiologic process. Just as with quantum physics, general relativity and the four fundamental forces of the universe, the lack of an adequate unifying theory of micro causality and macro consequence is unsatisfying, and in medicine, impairs the development of agents that may globally improve both obesity and obesity-related metabolic disease. Emerging scientific and clinical evidence strongly supports the novel concept that it is not adiposity alone, but rather it is adiposopathy that is the underlying cause of most cases of Type 2 diabetes mellitus, hypertension and dyslipidemia. Adiposopathy is a plausible Theory of Everything for mankind's greatest metabolic epidemics.

Adipose Tissue↗
PubMed2005

Torcetrapib/atorvastatin combination therapy.

Elevated blood levels of low-density lipoprotein cholesterol (LDL-C) are associated with an increased risk for atherosclerotic coronary heart disease (CHD). Atorvastatin is a statin drug that inhibits 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (the rate-limiting step of cholesterol production) and primarily lowers LDL-C levels. Atorvastatin has also been shown to significantly reduce CHD events. However, as with all statins (and all other monotherapy lipid-altering drugs), atorvastatin alone reduces the risk of CHD in only a minority of patients relative to placebo. Conversely, it is low levels of high-density lipoprotein cholesterol that are associated with increased CHD risk. Torcetrapib is a cholesteryl ester transfer protein inhibitor that primarily raises high-density lipoprotein cholesterol levels, and cholesteryl ester transfer protein inhibition has generally been shown to reduce atherosclerosis in rabbits. Taken together, atorvastatin and torcetrapib provide striking improvements in lipid levels, and complementary actions upon important lipid parameters. This review examines the chemistry, mechanism of action, pharmacokinetics, metabolism, safety/tolerability and efficacy of the combination torcetrapib/atorvastatin agent that is currently in development and that provides complementary lipid benefits towards the goal of reducing CHD risk beyond that of atorvastatin alone.

Animals↗
PubMed2004

Effects of lipid-altering treatment in diabetes mellitus and the metabolic syndrome.

The metabolic syndrome (MS) poses an increased risk for the development of diabetes mellitus and cardiovascular events. The syndrome typically includes dyslipidemia, characterized by elevated plasma triglycerides and low high-density lipoprotein cholesterol concentrations. Retrospective analyses of coronary artery disease outcomes trials in patient subpopulations with diabetes or the MS indicate that lipid-altering therapies provide benefits for patients with the MS at least as much as observed in patients without diabetes or the MS. Analyses of the effects of lipid-altering therapy on the lipid profile in patients with the MS also indicate that beneficial lipid changes are similar in patients with the MS compared with those in patients without the MS. The benefits of statin treatment in patients with the MS have become increasingly clear, and it is likely that further improvements in treatment may be achieved with newer statins or a combination of lipid-altering drugs. Prospective data from clinical trials examining the preventive effects of lipid-altering therapy in MS patients are needed to better define potential benefits and optimal treatment in this population.

Adult↗
PubMed2003

Effects of simvastatin, an HMG-CoA reductase inhibitor, in patients with hypertriglyceridemia.

BACKGROUND: Patients with elevated levels of serum triglycerides (TG) often have other associated lipid abnormalities (e.g., low levels of high-density lipoprotein cholesterol [HDL-C]) and are at increased risk of developing coronary heart disease. Although the therapeutic benefits of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) in hypercholesterolemic patients have been well established, less is known about the effects of statins in patient populations with hypertriglyceridemia. HYPOTHESIS: The purpose of this study was to evaluate the lipoprotein-altering efficacy of simvastatin in hypertriglyceridemic patients. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled study. In all, 195 patients with fasting serum triglyceride levels between 300 and 900 mg/dl received once daily doses of placebo or simvastatin 20, 40, or 80 mg for 6 weeks. RESULTS: Compared with placebo, simvastatin treatment across all doses resulted in significant reductions (p < 0.05 - < 0.001) in serum levels of triglycerides (-20 to -31% decrease) and TG-rich lipoprotein particles. Significant (p < 0.001) reductions were also seen in low-density lipoprotein cholesterol (-25 to -35%) and non-HDL-C (-26 to -40%). Levels of HDL-C were increased (7-11%) in the simvastatin groups compared with placebo (p < 0.05 - < 0.001). CONCLUSION: The results of this study demonstrate the beneficial effects of simvastatin in patients with hypertriglyceridemia.

Adult↗
PubMed2003

Pharmacotherapy for dyslipidaemia--current therapies and future agents.

Current lipid-altering agents that lower low density lipoprotein cholesterol (LDL-C) primarily through increased hepatic LDL receptor activity include statins, bile acid sequestrants/resins and cholesterol absorption inhibitors such as ezetimibe, plant stanols/sterols, polyphenols, as well as nutraceuticals such as oat bran, psyllium and soy proteins; those currently in development include newer statins, phytostanol analogues, squalene synthase inhibitors, bile acid transport inhibitors and SREBP cleavage-activating protein (SCAP) activating ligands. Other current agents that affect lipid metabolism include nicotinic acid (niacin), acipimox, high-dose fish oils, antioxidants and policosanol, whilst those in development include microsomal triglyceride transfer protein (MTP) inhibitors, acylcoenzyme A: cholesterol acyltransferase (ACAT) inhibitors, gemcabene, lifibrol, pantothenic acid analogues, nicotinic acid-receptor agonists, anti-inflammatory agents (such as Lp-PLA(2) antagonists and AGI1067) and functional oils. Current agents that affect nuclear receptors include PPAR-alpha and -gamma agonists, while in development are newer PPAR-alpha, -gamma and -delta agonists, as well as dual PPAR-alpha/gamma and 'pan' PPAR-alpha/gamma/delta agonists. Liver X receptor (LXR), farnesoid X receptor (FXR) and sterol-regulatory element binding protein (SREBP) are also nuclear receptor targets of investigational agents. Agents in development also may affect high density lipoprotein cholesterol (HDL-C) blood levels or flux and include cholesteryl ester transfer protein (CETP) inhibitors (such as torcetrapib), CETP vaccines, various HDL 'therapies' and upregulators of ATP-binding cassette transporter (ABC) A1, lecithin cholesterol acyltransferase (LCAT) and scavenger receptor class B Type 1 (SRB1), as well as synthetic apolipoprotein (Apo)E-related peptides. Fixed-dose combination lipid-altering drugs are currently available such as extended-release niacin/lovastatin, whilst atorvastatin/amlodipine, ezetimibe/simvastatin, atorvastatin/CETP inhibitor, statin/PPAR agonist, extended-release niacin/simvastatin and pravastatin/aspirin are under development. Finally, current and future lipid-altering drugs may include anti-obesity agents which could favourably affect lipid levels.

Animals↗
PubMed2003

Colesevelam HCl: a non-systemic lipid-altering drug.

Colesevelam HCl (WelChol, Sankyo Pharmaceuticals Inc.) is a bile acid sequestrant polymer, which has been shown to significantly lower low density lipoprotein cholesterol and favourably affect high-density lipoprotein cholesterol blood levels in monotherapy and in combination with statins (HMG-CoA reductase inhibitors). Although it is similar to other bile acid sequestrants in that it binds bile acids and is non-systemic, colesevelam HCl differs in that it has a unique polymer structure that allows for greater tolerability with less potential drug interactions than with resins. Currently, statins are the most commonly prescribed lipid-altering drugs. However, it is not uncommon that patients demonstrate true or perceived intolerances to statin therapy, that are often dose-related and may include elevations in liver or muscle enzyme blood levels, or myalgias or muscle weakness without muscle enzyme elevation. In rare circumstances, myopathy and even rhabdomyolysis can occur with statins. In addition, many statins also have important potential drug interactions. Finally, statin monotherapy is often not sufficient in achieving lipid treatment goals in many severely dyslipidaemic patients and the availability of colesevelam HCl provides a lipid-altering treatment addition to other lipid-altering drugs. From a clinical perspective, such combination therapy is often required to achieve treatment goals [1] in patients with more complicated or severe dyslipidaemia. Colesevelam HCl may also be an alternative in monotherapy for many patients with mild-to-moderate hypercholesterolaemia, as well as in some patients at potential risk from systemic exposure to alternative lipid-altering drugs (such as young children and fertile women).

Allylamine↗
PubMed2002

Existing and investigational combination drug therapy for high-density lipoprotein cholesterol.

For the past 3 to 4 decades, clinical outcomes trials have shown that drugs that favorably alter serum lipid levels reduce the risk of coronary artery disease (CAD) events. However, despite these successes, the reduction in serum low-density lipoprotein (LDL) cholesterol levels with monotherapy lipid-altering drugs does not "cure" CAD to the same degree that antibiotics "cure" many infections, nor do they "prevent" CAD in the same way that childhood immunizations "prevent" the onset of such conditions as measles, mumps, and rubella. Clinical outcome trials of monotherapy lipid-altering drugs have demonstrated a reduction in the relative risk of CAD in only a minority of patients. Thus, although safe and very effective in lowering serum LDL cholesterol levels, drugs that predominantly lower cholesterol do not "cure" atherosclerotic disease, nor have they been shown to "prevent" most CAD events in numerous clinical outcome trials. The reason for the suboptimal CAD outcomes benefits of monotherapy lipid-altering drugs is likely because atherosclerosis is a complex pathologic process with many important risk factors involved in the initiation and progression of atherosclerotic lesions and involved in the onset of the CAD event itself. An elevated serum LDL cholesterol level is an important CAD risk factor, but it is not the only lipid risk factor. A decreased serum high-density lipoprotein (HDL) cholesterol level is another important risk factor for CAD. Combination therapy through existing drugs (or possibly, in the future, through investigational lipid-altering drugs) may not only improve LDL cholesterol but also improve serum HDL cholesterol levels. This more global, multidimensional approach to lipid-altering drug treatment may provide the best chance to prevent CAD.

Anticholesteremic Agents↗