piperidines and Dyslipidemias

Janus kinase (JAK) inhibitors have emerged as a novel orally administered small-molecule therapy for the treatment of ulcerative colitis and possibly Crohn disease. These molecules are designed to selectively target the activity of specific JAKs and to offer a targeted mechanism of action without risk of immunogenicity. Based on data from clinical trials in rheumatoid arthritis and phase 2 studies in inflammatory bowel disease, tofacitinib and other JAK inhibitors are likely to become a new form of medical therapy for the treatment of inflammatory bowel disease.

Topics: Animals; Dyslipidemias; Humans; Inflammatory Bowel Diseases; Janus Kinases; Opportunistic Infections; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Signal Transduction

Cardiometabolic risk factors affect more than 47 million adults in the United States today. Although certain risk factors (e.g., obesity, dyslipidemia, hypertension, and hyperglycemia) contribute independently to the global risk, dyslipidemia is one of the most important risk factors for cardiovascular disease. Successful treatment requires a well-coordinated multifaceted approach, with commitment to a long-term program for disease management. Although initial attempts should focus on dietary changes and increased physical activity, most patients also need effective, safe, and well-monitored pharmacotherapy. Experimental studies have shown that overactivation of the endocannabinoid system-a physiologic signaling system involved in regulating energy intake, fatty acid synthesis and storage, and glucose and lipid metabolism-is associated with obesity, dyslipidemia, and insulin resistance. In clinical trials, selective blockade of CB1 receptors has resulted in substantial weight loss and significant improvement in lipid profiles. The effects of rimonabant, the first selective CB1 receptor blocker, were evaluated in 6600 obese or overweight adults who participated in one of 4 multicenter, placebo-controlled, randomized clinical trials for at least 1 year. Significant improvement in lipid profiles (specifically HDL and triglyceride levels and ratio of total cholesterol to HDL cholesterol) was seen in the 2503 patients taking rimonabant 20 mg/day, independent of its substantial effects on weight loss. No significant changes in LDL or total cholesterol were observed. Results of clinical trials with rimonabant are promising. Additional long-term controlled studies with appropriate follow-up are warranted to confirm the clinical potential of this drug, particularly its effects on dyslipidemia and other cardiovascular endpoints.

Topics: Cannabinoid Receptor Modulators; Cardiovascular Diseases; Dyslipidemias; Endocannabinoids; Humans; Insulin Resistance; Lipid Metabolism; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Risk Factors; Signal Transduction

Rimonabant (Acomplia) is the first selective CB1 receptor blocker of the endocannabinoid system. Clinical trials showed that, compared to placebo, rimonabant 20 mg/ day consistently increases weight loss, reduces waist circumference, improves atherogenic dyslipidaemia (low HDL cholesterol, high triglycerides, high small dense LDL), diminishes insulin resistance, reduces HbA1c levels, and contributes to lower blood pressure and C-reactive protein levels. Almost half of the most important metabolic effects occur beyond weight loss, suggesting direct peripheral effects of rimonabant, especially in visceral adipose tissue as suggested by the increase in adiponectin levels. Rimonabant at a daily dose of 20 mg is indicated as an adjunct to diet and exercise for the treatment of obese patients, or overweight patients with associated risk factor(s) such as type 2 diabetes or dyslipidaemia. Adverse effects concern digestive tract (nausea, mostly transient) and psychological disorders (depressed mood, anxiety), in relation to the mechanism of action of the drug. Therefore, rimonabant is contra-indicated in case of depression and/or in patients receiving antidepressants.

Topics: Anti-Obesity Agents; Cannabinoid Receptor Antagonists; Diabetes Mellitus, Type 2; Dyslipidemias; Humans; Piperidines; Pyrazoles; Rimonabant

Rimonabant (Acomplia) is the first selective CB1 receptor blocker of the endocannabinoid system. It has been evaluated in the RIO ("Rimonabant In Obesity and related disorders") programme including above 6.600 overweight/obese patients with or without comorbidities followed for 1 to 2 years. Compared to placebo, rimonabant 20 mg/day consistently increases weight loss, reduces waist circumference, increases HDL cholesterol, lowers triglyceride levels, diminishes insulin resistance, and reduces the prevalence of metabolic syndrome. In patients with type 2 diabetes, rimonabant also diminishes HbA1c levels, an effect confirmed in the recent SERENADE trial. Almost half of the metabolic effects occurs beyond weight loss, suggesting direct peripheral effects of rimonabant. Rimonabant is indicated in Europe as an adjunct to diet and exercise for the treatment of obese patients, or overweight patients with associated risk factor(s), such as type 2 diabetes or dyslipidaemia.

Topics: Anti-Obesity Agents; Bradykinin; Cannabinoids; Cholesterol, HDL; Diabetes Mellitus, Type 2; Dyslipidemias; Follow-Up Studies; Glycated Hemoglobin; Heart; Humans; Insulin Resistance; Metabolic Syndrome; Obesity; Overweight; Piperidines; Placebos; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Risk Factors; Triglycerides; Waist-Hip Ratio; Weight Loss

The growing prevalence of obesity is associated with a dramatic increase in a number of related risk factors for cardiovascular disease and diabetes, including high triglyceride and fasting glucose levels, reduced high-density lipoprotein cholesterol, and increased blood pressure. For many patients, lifestyle interventions (eg, exercise and a reduced-calorie diet) are insufficient for overcoming obesity, and pharmacotherapy becomes necessary. Unfortunately, the currently available agents are associated with side effects such as gastrointestinal distress and increased blood pressure. A new class of drugs targeting the cannabinoid receptors is poised to join the obesity-management armamentarium, with one agent-rimonabant-demonstrating efficacy in 4 recent phase III multinational trials. Patients randomized to rimonabant 20 mg/d showed significant reductions in weight and significant improvements in lipid profiles and other measures of cardiometabolic risk factors.

Topics: Anti-Obesity Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diet; Dyslipidemias; Exercise; Humans; Insulin Resistance; Life Style; Lipids; Metabolic Syndrome; Obesity; Piperidines; Pyrazoles; Rimonabant; Risk Assessment; Risk Factors; Treatment Outcome; Weight Loss

Atherogenic dyslipidemia is one of the major components of the metabolic syndrome, a complex cluster of several risk factors within a single patient that according to the National Cholesterol Education Program (NCEP) Adult Treatment Panel III includes at least 3 of the following: large waist circumference, elevated triglyceride levels, low levels of high-density lipoprotein cholesterol (HDL-C), hypertension, and elevated fasting glucose levels, which are directly related to the incidence of coronary heart disease. Atherogenic dyslipidemia clinically presents as elevated serum triglyceride levels, increased levels of small dense low-density lipoprotein (sdLDL) particles, and decreased levels of HDL-C. An important component of atherogenic dyslipidemia is central obesity, which is defined as increased waist circumference and has recently been identified as a chief predictor of the metabolic syndrome in certain patients. Another recent study found that both body mass index and waist circumference were highly predictive of eventual development of the metabolic syndrome. Because atherogenic dyslipidemia usually precedes the clinical manifestation of the metabolic syndrome, strategies to treat it are the focus of pharmacologic intervention. For example, the 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors, commonly known as statins, benefit hypercholesterolemic patients who have atherogenic dyslipidemia that is associated with the metabolic syndrome. Pioglitazone, an antidiabetic agent that acts primarily by decreasing insulin resistance, improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic gluconeogenesis. Pioglitazone improves glycemic control while reducing circulating insulin levels. The investigational agent, rimonabant--a centrally and peripherally acting, selective cannabinoid type-1 receptor blocker--is the first therapy developed for managing several cardiovascular risk factors at one time. Rimonabant has shown promise in attacking atherogenic dyslipidemia from several vantage points by affecting glucose, HDL-C, triglycerides, and waist circumference in patients who are prone to atherogenic dyslipidemia.

Topics: Arteriosclerosis; Cholesterol, HDL; Cholesterol, LDL; Coronary Disease; Diabetes Mellitus, Type 2; Drugs, Investigational; Dyslipidemias; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemic Agents; Insulin Resistance; Intra-Abdominal Fat; Metabolic Syndrome; Obesity; Pioglitazone; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Thiazolidinediones

Second generation antipsychotics are prescribed for an increasing number of psychiatric conditions, despite variable associations with weight gain, dyslipidemia, and impaired glucose tolerance. The mechanism(s) of the apparent causal relationships between these medications and metabolic effects have been inadequately defined and are potentially confounded by genetic risk of mental illness, attendant lifestyle, and concomitant medications. Therefore, we conducted a study in which 24 healthy volunteers were randomized to olanzapine (highly weight-gain liability), iloperidone (less weight-gain liability), or placebo treatment for 28 days under double-blind conditions. We hypothesized that antipsychotics induce weight gain primarily through increased caloric intake, which causes secondary dyslipidemia and insulin resistance. Subjects were phenotyped pre- and post-treatment for body weight, adiposity by dual energy X-ray absorptiometry, energy expenditure by indirect calorimetry, food intake, oral glucose tolerance, plasma lipids, glucose, insulin, and other hormones. We found significantly increased food intake and body weight but no change in energy expenditure in olanzapine-treated subjects, with associated trends towards lipid abnormalities and insulin resistance the extent of which were presumably limited by the duration of treatment. Iloperidone treatment led to modest non-significant and placebo no weightgain, lipid increases and alterations in insulin metabolism. We conclude that second generation antipsychotic drugs, as represented by olanzapine, produce their weight and metabolic effects, predominantly, by increasing food intake which leads to weight gain that in turn induces metabolic consequences, but also through other direct effects on lipid and glucose metabolism independant of food intake and weight gain.

Topics: Adolescent; Adult; Antipsychotic Agents; Blood Glucose; Body Weight; Double-Blind Method; Dyslipidemias; Eating; Energy Metabolism; Female; Glucose Tolerance Test; Healthy Volunteers; Humans; Insulin; Insulin Resistance; Isoxazoles; Lipids; Male; Obesity; Olanzapine; Piperidines; Weight Gain; Young Adult

Type 2 diabetes (T2D) is an established risk factor for cardiovascular disease (CVD) and is associated with disturbed metabolism of lipids and lipoproteins. Curcuminoids are natural products with anti-diabetic and lipid-modifying actions but their efficacy in improving dyslipidemia in diabetic individuals has not been sufficiently studied.. To investigate the efficacy of supplementation with curcuminoids, plus piperine as an absorption enhancer, in improving serum lipids in patients with T2D.. In this 12-week randomized double-blind placebo-controlled trial, subjects with T2D (n=118) were assigned to curcuminoids (1000mg/day plus piperine 10mg/day) or placebo plus standard of care for T2D. Serum concentrations of lipids including total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), lipoprotein(a) [Lp(a)], and non-HDL-C were determined at baseline and at the end of trial.. Between-group comparison of change in the study parameters revealed significant reductions in serum levels of TC (-21.86±25.78 versus -17.06±41.51, respectively; p=0.023), non-HDL-C (-23.42±25.13 versus -16.84±41.42, respectively; p=0.014) and Lp(a) (-1.50±1.61 versus -0.34±1.73, respectively; p=0.001) and elevations in serum HDL-C levels (1.56±4.25 versus -0.22±4.62, respectively; p=0.048) in the curcuminoids group as compared with the placebo group (p<0.05). Serum TG and LDL-C changes did not show any significant difference between the study groups (p>0.05).. Curcuminoids supplementation can reduce serum levels of atherogenic lipid indices including non-HDL-C and Lp(a). Therefore, curcuminoids supplementation could contribute to a reduced risk of cardiovascular events in dyslipidemic patients with T2D.

Topics: Adult; Alkaloids; Benzodioxoles; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Curcuma; Curcumin; Diabetes Mellitus, Type 2; Dietary Supplements; Double-Blind Method; Dyslipidemias; Female; Humans; Lipids; Lipoprotein(a); Male; Middle Aged; Phytotherapy; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Triglycerides

Weight loss and hypolipidemic drugs can improve lipid and adipokine levels. We assessed the effects of rimonabant, alone and in combination with fenofibrate or ezetimibe, on adipokine levels in obese/overweight patients with dyslipidemia. Overweight/obese patients (n = 60, body mass index = 27-40 kg/m(2)) with mixed dyslipidemia were recruited. Patients received a hypocaloric diet and were randomized to rimonabant 20 mg/d (group R, n = 20), rimonabant 20 mg/d plus fenofibrate 200 mg/d (group RF, n = 20), or rimonabant 20 mg/d plus ezetimibe 10 mg/d (group RE, n = 20). After 3 months, leptin concentration was significantly reduced in all groups (-38%, P < .005; -40%, P < .005; and -44%, P < .001 in the R, RF, and RE groups, respectively). Total adiponectin remained unaltered. Visfatin concentration decreased significantly only in the RE and RF groups (-18% and -38%, respectively; P < .047). Treatment with rimonabant may improve adipokine levels in overweight/obese patients with dyslipidemia. The addition of fenofibrate or ezetimibe may reinforce this effect.

Topics: Adipokines; Adult; Aged; Azetidines; Body Mass Index; Diet, Reducing; Drug Therapy, Combination; Dyslipidemias; Ezetimibe; Female; Fenofibrate; Humans; Hypolipidemic Agents; Male; Middle Aged; Obesity; Piperidines; Pyrazoles; Rimonabant; Weight Loss

Rimonabant, the first selective cannabinoid type 1 (CB1) receptor antagonist, improves cardiometabolic risk factors in overweight/obese patients. ADAGIO-Lipids assessed the effect of rimonabant on cardiometabolic risk factors and intraabdominal and liver fat.. 803 abdominally obese patients with atherogenic dyslipidemia (increased triglycerides [TG] or reduced high-density lipoprotein-cholesterol [HDL-C]) were randomized to placebo or rimonabant 20 mg/d for 1 year. HDL-C and TG were coprimary end points. Intraabdominal (visceral) and liver fat were measured by computed tomography in a subgroup of 231 patients. In total, 73% of rimonabant- and 70% of placebo-treated patients completed the study treatment. Rimonabant 20 mg produced significantly greater changes from baseline versus placebo in HDL-C (+7.4%) and TG levels (-18%; P<0.0001), as well as low-density lipoprotein (LDL) and HDL particle sizes, apolipoprotein A1 and B, HDL2, HDL3, C-reactive protein, and adiponectin levels (all P<0.05). Rimonabant decreased abdominal subcutaneous adipose tissue (AT) cross-sectional area by 5.1% compared to placebo (P<0.005), with a greater reduction in visceral AT (-10.1% compared to placebo; P<0.0005), thereby reducing the ratio of visceral/subcutaneous AT (P<0.05). Rimonabant significantly reduced liver fat content (liver/spleen attenuation ratio; P<0.005). Systolic (-3.3 mm Hg) and diastolic (-2.4 mm Hg) blood pressure were significantly reduced with rimonabant versus placebo (P<0.0001). The safety profile of rimonabant was consistent with previous studies; gastrointestinal, nervous system, psychiatric, and general adverse events were more common with rimonabant 20 mg.. In abdominally obese patients with atherogenic dyslipidemia, rimonabant 20 mg significantly improved multiple cardiometabolic risk markers and induced significant reductions in both intraabdominal and liver fat.

Topics: Adiponectin; Adiposity; Adult; Anti-Obesity Agents; Apolipoproteins; Blood Glucose; Blood Pressure; Body Weight; C-Reactive Protein; Cholesterol, HDL; Double-Blind Method; Dyslipidemias; Female; Humans; Insulin; Intra-Abdominal Fat; Lipoproteins, LDL; Liver; Male; Middle Aged; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Time Factors; Tomography, X-Ray Computed; Treatment Outcome; Triglycerides

To compare the effects of ezetimibe plus orlistat or rimonabant on anthropometric and lipid parameters in nondiabetic statin-intolerant overweight/obese patients with dyslipidemia.. Thirty participants received a hypocaloric diet and were randomized to open-label combination of ezetimibe (10 mg/day) with orlistat (120 mg, 3 times a day with meals; ezetimibe/orlistat [EO], n = 15) or rimonabant (20 mg/day; ezetimibe/rimonabant [ER], n = 15). Anthropometric and metabolic variables were assessed at baseline and 3 months posttreatment. Similar reductions in body weight, body mass index, and waist circumference were recorded in both groups (-8.3%, -8.6%, and -5.2% in the EO group and -7.3%, -7.2%, and -7.0% in the ER group, P < .01 vs baseline for all). Low-density lipoprotein cholesterol (LDL-C) levels decreased in both treatment groups, but this reduction tended to be more pronounced in the EO group (28.4% vs 15.3%, respectively; P < .01 vs baseline for both). Triglycerides tended to decrease more in the ER compared with the EO group (-20.4% vs -14.1%, P < .01 vs baseline for both). High-density lipoprotein cholesterol (HDL-C) levels tended to decrease in EO group, but remained unaltered with ER treatment. Apolipoprotein B levels were equally reduced in both treatment groups.. For similar body weight reduction, the combination of ezetimibe with orlistat may be more efficient in LDL-C lowering, whereas the combination of ezetimibe with rimonabant may be more potent in terms of improving HDL-C and triglycerides.

Topics: Anti-Obesity Agents; Anticholesteremic Agents; Azetidines; Body Weight; Drug Therapy, Combination; Dyslipidemias; Ezetimibe; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lactones; Male; Middle Aged; Obesity; Orlistat; Overweight; Piperidines; Pyrazoles; Rimonabant

Rimonabant, the first selective cannabinoid type 1 (CB1) receptor blocker, has been shown to improve multiple cardiometabolic risk factors in overweight/obese patients. This analysis assessed the impact of rimonabant on blood pressure in the pooled population from four large trials with similar design - the Rimonabant-In-Obesity (RIO) programme.. RIO-Europe (n = 1507) and RIO-North America (n = 3040) recruited overweight/obese patients, and RIO-Lipids (n = 1033) and RIO-Diabetes (n = 1045) recruited overweight/obese patients with untreated dyslipidaemia or type 2 diabetes, respectively. At study entry (screening), 37.2% (n = 2463) of patients had hypertension, 71.4% (n = 1757) of whom were taking an antihypertensive treatment.. After 1 year of treatment, mean change in systolic blood pressure (SBP) from baseline was -0.8 mmHg for rimonabant 20 mg versus +0.3 mmHg for placebo (P = 0.007); diastolic blood pressure (DBP) decreased by -0.8 versus -0.3 mmHg (P = 0.029) respectively. In the subgroup of patients with high blood pressure at baseline, SBP change was -7.5 mmHg for rimonabant 20 mg versus -4.7 mmHg for placebo (P = 0.005); DBP change was -5.2 versus -3.0 mmHg (P < 0.001). Reductions were more pronounced in patients with dyslipidaemia and type 2 diabetes. There was no effect of rimonabant 20 mg on blood pressure beyond that expected from weight loss alone. Overall, there was a similar incidence of adverse events (AEs) at 1 year in the placebo (81.8%) and rimonabant 20 mg (86.0%). The most common AEs occurring with rimonabant were nausea, dizziness, arthralgia and diarrhoea. A slightly higher proportion of patients in the rimonabant 20 mg group discontinued as a result of AEs (13.8%) versus placebo (7.2%).. Rimonabant 20 mg led to modest, but significant SBP and DBP reductions in overweight/obese patients. The effect of rimonabant on blood pressure appears to be mediated by weight loss.

Topics: Adult; Blood Pressure; Cannabinoid Receptor Antagonists; Diabetes Mellitus, Type 2; Double-Blind Method; Dyslipidemias; Female; Humans; Hypertension; Male; Middle Aged; Obesity; Piperidines; Pyrazoles; Rimonabant; Weight Loss

Rimonabant (Acomplia) is the first selective CB1 receptor blocker of the endocannabinoid system. It has been evaluated in the RIO ("Rimonabant In Obesity and related disorders") programme including above 6.600 overweight/obese patients with or without comorbidities followed for 1 to 2 years. Compared to placebo, rimonabant 20 mg/day consistently increases weight loss, reduces waist circumference, increases HDL cholesterol, lowers triglyceride levels, diminishes insulin resistance, and reduces the prevalence of metabolic syndrome. In patients with type 2 diabetes, rimonabant also diminishes HbA1c levels, an effect confirmed in the recent SERENADE trial. Almost half of the metabolic effects occurs beyond weight loss, suggesting direct peripheral effects of rimonabant. Rimonabant is indicated in Europe as an adjunct to diet and exercise for the treatment of obese patients, or overweight patients with associated risk factor(s), such as type 2 diabetes or dyslipidaemia.

Topics: Anti-Obesity Agents; Bradykinin; Cannabinoids; Cholesterol, HDL; Diabetes Mellitus, Type 2; Dyslipidemias; Follow-Up Studies; Glycated Hemoglobin; Heart; Humans; Insulin Resistance; Metabolic Syndrome; Obesity; Overweight; Piperidines; Placebos; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Risk Factors; Triglycerides; Waist-Hip Ratio; Weight Loss

Rimonabant, a selective cannabinoid-1 receptor (CB1) blocker, has been shown to reduce body weight and improve cardiovascular risk factors in obese patients. The Rimonabant in Obesity-Lipids (RIO-Lipids) study examined the effects of rimonabant on metabolic risk factors, including adiponectin levels, in high-risk patients who are overweight or obese and have dyslipidemia.. We randomly assigned 1036 overweight or obese patients (body-mass index [the weight in kilograms divided by the square of the height in meters], 27 to 40) with untreated dyslipidemia (triglyceride levels >1.69 to 7.90 mmol per liter, or a ratio of cholesterol to high-density lipoprotein [HDL] cholesterol of >4.5 among women and >5 among men) to double-blinded therapy with either placebo or rimonabant at a dose of 5 mg or 20 mg daily for 12 months in addition to a hypocaloric diet.. The rates of completion of the study were 62.6 percent, 60.3 percent, and 63.9 percent in the placebo group, the group receiving 5 mg of rimonabant, and the group receiving 20 mg of rimonabant, respectively. The most frequent adverse events resulting in discontinuation of the drug were depression, anxiety, and nausea. As compared with placebo, rimonabant at a dose of 20 mg was associated with a significant (P<0.001) mean weight loss (repeated-measures method, -6.7+/-0.5 kg, and last-observation-carried-forward analyses, -5.4+/-0.4 kg), reduction in waist circumference (repeated-measures method, -5.8+/-0.5 cm, and last-observation-carried-forward analyses, -4.7+/-0.5 cm), increase in HDL cholesterol (repeated-measures method, +10.0+/-1.6 percent, and last-observation-carried-forward analyses, +8.1+/-1.5 percent), and reduction in triglycerides (repeated-measures method, -13.0+/-3.5 percent, and last-observation-carried-forward analyses, -12.4+/-3.2 percent). Rimonabant at a dose of 20 mg also resulted in an increase in plasma adiponectin levels (repeated-measures method, 57.7 percent, and last-observation-carried-forward analyses, 46.2 percent; P<0.001), for a change that was partly independent of weight loss alone.. Selective CB1-receptor blockade with rimonabant significantly reduces body weight and waist circumference and improves the profile of several metabolic risk factors in high-risk patients who are overweight or obese and have an atherogenic dyslipidemia.

Topics: Adiponectin; Adult; Aged; Anti-Obesity Agents; Blood Glucose; Cannabinoid Receptor Antagonists; Cholesterol; Double-Blind Method; Dyslipidemias; Female; Humans; Insulin; Leptin; Male; Metabolic Syndrome; Middle Aged; Obesity; Overweight; Piperidines; Pyrazoles; Rimonabant; Risk Factors; Triglycerides; Weight Loss

Piperine has been widely used as a bioenhancer. Simvastatin belongs to a group of medicines known as statins. It acts by inhibiting HMG CoA reductase and acts primarily as a hypolipidemic agent. In this study some derivatives of Piperine were synthesized. They were studied for their bioenhencing effect (10 mg kg

Topics: Administration, Oral; Alkaloids; Animals; Benzodioxoles; Biological Availability; Drug Compounding; Drug Synergism; Dyslipidemias; Feasibility Studies; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Simvastatin

The effects of farnesoid X receptor (FXR) antagonists on plasma lipid profile in mice have not been investigated thus far. The aim of this study was to investigate the antidyslipidemic effects of an FXR antagonist in dyslipidemic mice, and to clarify the mechanisms underlying the lipid modulatory effect.. Compound-T0 (1-100 mg/kg) was orally administered to C57BL/6J mice fed a Western-type diet or low-density lipoprotein receptor knockout (LDLR-/-) mice fed a Western-type diet for a week, and plasma lipid levels were investigated. Effects on lipid clearance, hepatic triglyceride secretion after Triton WR-1339 challenge, and intestinal lipid absorption were investigated after multiple dosing.. It was found that the FXR antagonist, compound-T0 exacerbated dyslipidemia in mice because it enhanced intestinal lipid absorption via acceleration of bile acid excretion.

Topics: Animals; Benzoates; Bile Acids and Salts; Biomarkers; Cholesterol; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Dyslipidemias; Genetic Predisposition to Disease; Intestinal Absorption; Intestinal Elimination; Lipids; Liver; Male; Mice, Inbred C57BL; Mice, Knockout; Phenotype; Piperidines; Pyrazoles; Receptors, Cytoplasmic and Nuclear; Receptors, LDL; Signal Transduction; Time Factors; Triglycerides

We attempted to clarify the therapeutic capability of antagonists of the farnesoid X receptor (FXR), a nuclear receptor that regulates lipid and bile acid metabolism. Herein, we report the antidyslipidemic effects of a novel synthesized FXR antagonist, compound-T1, utilizing a dyslipidemic hamster model. Compound-T1 selectively inhibited chenodeoxycholic acid-induced FXR activation (IC

Topics: Animals; Apolipoprotein A-I; Benzoates; Bile Acids and Salts; Cell Line, Tumor; Cholestenones; Cholesterol; Cricetinae; Disease Models, Animal; Dose-Response Relationship, Drug; Dyslipidemias; Feces; Humans; Hypolipidemic Agents; Lipid Metabolism; Male; Mesocricetus; Piperidines; Receptors, Cytoplasmic and Nuclear; Triglycerides

The antidyslipidemic effect of the ethanolic extract of Dysoxylum binectariferum stem bark and its major active constituent rohitukine was evaluated in a high fat diet (HFD)-fed dyslipidemic rat model. Chronic feeding of ethanolic extract (200 mg/kg) in HFD-fed rats showed significant lipid lowering activity. The bioassay guided fractionation of ethanolic extract resulted in the identification of known alkaloid rohitukine as major active constituent. Rohitukine (50 mg/kg) significantly decreased the plasma levels of total cholesterol (24 %), phospholipids (25 %), triglycerides (27 %), very low density lipoprotein (27 %) and low density lipoprotein (32 %) accompanied with an increase in high density lipoprotein (21 %). The present study demonstrated that ethanolic extract of Dysoxylum binectariferum stem bark and its major constituent rohitukine both have antidyslipidemic as well as antioxidant potentials. The antidyslipidemic activity of rohitukine can be correlated to its effect on enzymes involved in lipid metabolism.

Topics: Animals; Antioxidants; Chromones; Dyslipidemias; Lipid Metabolism; Male; Piperidines; Rats

The effect of compound ZB-16 (a new GPR1 19 receptor agonist) after two-week administration on the endothelial function, glucose and lipid metabolism (total cholesterol, LDL, HDL and triglycerides), lipid peroxidation, and antioxidant system status in rats with experimental type-2 diabetes mellitus (T2DM) has been studied. It was found that the untreated control group of animals exhibited, in addition to sustained hyperglycemia, a decrease in endothelium-dependent vaso- dilation and antioxidant system activity, and increase in the content of LDL and the dyslipidemic index. Administration of ZB-16 (1 mg/kg, p.o.) in rats with T2DM model resulted in reduction of the endothelial dysfunction (improved endothelium-dependent vasodilation by 83% as compared to the control group, p < 0.05). ZB-16 also produced a moderate antioxidant effect of reducing the content of TBA-active products (by 30% as compared to the untreated control, p <0.05) and favored normalization of lipid metabolism indicators.

Topics: Animals; Antioxidants; Blood Glucose; Cell Count; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Experimental; Dyslipidemias; Endothelial Cells; Female; Gene Expression; Hypoglycemic Agents; Hypolipidemic Agents; Lipid Metabolism; Lipid Peroxidation; Piperidines; Pyrimidines; Rats; Receptors, G-Protein-Coupled; Streptozocin; Thiobarbituric Acid Reactive Substances; Triglycerides; Vasodilation

Psoriasis is a systemic inflammatory condition that is associated with a higher risk of cardiovascular (CV) disease. Tofacitinib is being investigated as a treatment for psoriasis.. We sought to evaluate the effects of tofacitinib on CV risk factors and major adverse CV events (MACEs) in patients with plaque psoriasis.. Changes in select CV risk factors and the incidence rate (IR) of MACEs were evaluated in patients who were treated with tofacitinib.. Tofacitinib treatment was associated with small, dose-dependent increases in total cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol, while the total/HDL cholesterol ratio was unchanged. There were no changes in blood pressure and glycated hemoglobin levels; C-reactive protein levels decreased. The IRs of a MACE were low and similar for both tofacitinib doses. Among 3623 subjects treated with tofacitinib, the total patient-years of exposure was 5204, with a median follow-up of 527 days, and the IR of MACEs was 0.37 (95% confidence interval, 0.22-0.57) patients with events per 100 patient-years.. There was relatively short follow-up time for patients who had MACEs.. While treatment with tofacitinib is associated with a small increase in cholesterol levels, the total/HDL cholesterol ratio does not change, there are no unfavorable changes in several CV risk factors, and the incidence of MACEs is low.

Topics: Adult; Blood Pressure; C-Reactive Protein; Cardiovascular Diseases; Cholesterol; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Comorbidity; Dyslipidemias; Female; Glycated Hemoglobin; Humans; Male; Metabolic Syndrome; Middle Aged; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Risk Factors; Treatment Outcome; Triglycerides

Estrogen deficiency and increase in protein tyrosine phosphatase (PTPase) activity may be a key mechanism in postmenopausal dyslipidemia-induced vascular dysfunction and dementia. Thus, the present study has been designed to investigate the effect of biochanin A (BCA, a phytoestrogen) and sodium orthovanadate (SOV), an inhibitor of PTPase in dyslipidemia-induced vascular dementia in ovariectomized rats.. Female Wistar rats were ovariectomized and fed on high fat diet for 4 weeks to produce dyslipidemia. Dyslipidemia was assessed by estimation of serum lipid levels including total cholesterol, triglyceride, HDL, and LDL levels. Dementia was assessed in terms of increase in brain acetylcholinesterase (AChE) activity and attenuation of learning ability (escape latency time) and memory retention (time spent in target quadrant) using Morris water maze. Vascular dysfunction was assessed in terms of attenuation of acetylcholine-induced endothelium-dependent relaxation (isolated carotid ring preparation), mRNA expression of endothelial nitric oxide synthase, and increase in serum thiobarbituric acid reactive species, superoxide anion level. Neurodegeneration was assessed in hippocampus by hematoxylin and eosin staining. BCA (2.5 and 5 mg/kg) and SOV (5 and 10 mg/kg) were administered alone and in low-dose combination to ovariectomized dyslipidemic rats.. BCA (2.5 and 5 mg/kg), SOV (5 and 10 mg/kg), and donepezil (1 mg/kg) significantly improves vascular function, and learning and memory ability and decreases the neuronal cell death, oxidative stress, and AChE in ovariectomized dyslipidemic rats.. Thus, it may be concluded that BCA and SOV attenuate vascular dysfunction and dementia in dyslipidemic ovariectomized rats.

Topics: Acetylcholinesterase; Animals; Avoidance Learning; Brain; Dementia, Vascular; Donepezil; Dyslipidemias; Enzyme Inhibitors; Female; Gene Expression Regulation; Genistein; Indans; Lipids; Mental Recall; Nitric Oxide Synthase Type III; Ovariectomy; Oxidative Stress; Phytoestrogens; Piperidines; Rats; Rats, Wistar; Reaction Time; Vanadates

We developed a common feature pharmacophore model using known antiadipogenic compounds (CFPMA). We identified rohitukine, a reported chromone anticancer alkaloid as a potential hit through in silico mapping of the in-house natural product library on CFPMA. Studies were designed to assess the antiadipogenic potential of rohitukine. Rohitukine was isolated from Dysoxylum binacteriferum Hook. to ⬧95% purity. As predicted by CFPMA, rohitukine was indeed found to be an antiadipogenic molecule. Rohitukine inhibited lipid accumulation and adipogenic differentiation in a concentration- and exposure-time-dependent manner in 3T3-L1 and C3H10T1/2 cells. Rohitukine downregulated expression of PPARγ, CCAAT/enhancer binding protein α, adipocyte protein 2 (aP2), FAS, and glucose transporter 4. It also suppressed mRNA expression of LPL, sterol-regulatory element binding protein (SREBP) 1c, FAS, and aP2, the downstream targets of PPARγ. Rohitukine arrests cells in S phase during mitotic clonal expansion. Rohitukine was bioavailable, and 25.7% of orally administered compound reached systemic circulation. We evaluated the effect of rohitukine on dyslipidemia induced by high-fat diet in the hamster model. Rohitukine increased hepatic expression of liver X receptor α and decreased expression of SREBP-2 and associated targets. Rohitukine decreased hepatic and gonadal lipid accumulation and ameliorated dyslipidemia significantly. In summary, our strategy to identify a novel antiadipogenic molecule using CFPMA successfully resulted in identification of rohitukine, which confirmed antiadipogenic activity and also exhibited in vivo antidyslipidemic activity.

Topics: 3T3-L1 Cells; Adipogenesis; Animals; Chromones; Dyslipidemias; Female; Male; Mesocricetus; Mice; Mitosis; Piperidines; S Phase Cell Cycle Checkpoints

The endocannabinoid system is an important player in energy metabolism by regulating appetite, lipolysis, and energy expenditure. Chronic blockade of the cannabinoid 1 receptor (CB1R) leads to long-term maintenance of weight loss and reduction of dyslipidemia in experimental and human obesity. The molecular mechanism by which CB1R blockade reverses dyslipidemia in obesity has not yet been clarified. In this study, we showed that CB1R blockade with the systemic CB1R blocker rimonabant enhanced whole-body energy expenditure and activated brown adipose tissue (BAT), indicated by increased expression of genes involved in BAT thermogenesis and decreased lipid droplet size in BAT. This was accompanied by selectively increased triglyceride (TG) uptake by BAT and lower plasma TG levels. Interestingly, the effects on BAT activation were still present at thermoneutrality and could be recapitulated by using the strictly peripheral CB1R antagonist AM6545, indicating direct peripheral activation of BAT. Indeed, CB1R blockade directly activated T37i brown adipocytes, resulting in enhanced uncoupled respiration, most likely via enhancing cAMP/PKA signaling via the adrenergic receptor pathway. Our data indicate that selective targeting of the peripheral CB1R in BAT has therapeutic potential in attenuating dyslipidemia and obesity.

Topics: 3T3-L1 Cells; Absorptiometry, Photon; Adipose Tissue, Brown; Animals; Base Sequence; DNA Primers; Dyslipidemias; Mice; Mice, Transgenic; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Reverse Transcriptase Polymerase Chain Reaction; Rimonabant

Adiponectin secreted from adipocytes binds to adiponectin receptors AdipoR1 and AdipoR2, and exerts antidiabetic effects via activation of AMPK and PPAR-α pathways, respectively. Levels of adiponectin in plasma are reduced in obesity, which causes insulin resistance and type 2 diabetes. Thus, orally active small molecules that bind to and activate AdipoR1 and AdipoR2 could ameliorate obesity-related diseases such as type 2 diabetes. Here we report the identification of orally active synthetic small-molecule AdipoR agonists. One of these compounds, AdipoR agonist (AdipoRon), bound to both AdipoR1 and AdipoR2 in vitro. AdipoRon showed very similar effects to adiponectin in muscle and liver, such as activation of AMPK and PPAR-α pathways, and ameliorated insulin resistance and glucose intolerance in mice fed a high-fat diet, which was completely obliterated in AdipoR1 and AdipoR2 double-knockout mice. Moreover, AdipoRon ameliorated diabetes of genetically obese rodent model db/db mice, and prolonged the shortened lifespan of db/db mice on a high-fat diet. Thus, orally active AdipoR agonists such as AdipoRon are a promising therapeutic approach for the treatment of obesity-related diseases such as type 2 diabetes.

Topics: Adenylate Kinase; Adiponectin; Adipose Tissue, White; Administration, Oral; Animals; Diabetes Mellitus, Type 2; Diet, High-Fat; Drug Evaluation, Preclinical; Dyslipidemias; Enzyme Activation; Glucose Intolerance; Inflammation; Insulin Resistance; Liver; Longevity; Mice; Mitochondria; Muscle Fibers, Skeletal; Muscles; Obesity; Oxidative Stress; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Piperidines; PPAR alpha; Receptors, Adiponectin; Signal Transduction; Small Molecule Libraries; Transcription Factors; Triglycerides

It is well established that inactivation of the central endocannabinoid system (ECS) through antagonism of cannabinoid receptor 1 (CB1R) reduces food intake and improves several pathological features associated with obesity, such as dyslipidemia and liver steatosis. Nevertheless, recent data indicate that inactivation of peripheral CB1R could also be directly involved in the control of lipid metabolism independently of central CB1R. To further investigate this notion, we tested the direct effect of the specific CB1R antagonist, SR141716, on hepatic carbohydrate and lipid metabolism using cultured liver slices. CB1R messenger RNA expression was strongly decreased by SR141716, whereas it was increased by the CB1R agonist, arachidonic acid N-hydroxyethylamide (AEA), indicating the effectiveness of treatments in modulating ECS activity in liver explants both from lean or ob/ob mice. The measurement of O(2) consumption revealed that SR141716 increased carbohydrate or fatty acid utilization, according to the cellular hormonal environment. In line with this, SR141716 stimulated ß-oxidation activity, and the role of CB1R in regulating this pathway was particularly emphasized when ECS was hyperactivated by AEA and in ob/ob tissue. SR141716 also improved carbohydrate and lipid metabolism, blunting the AEA-induced increase in gene expression of proteins related to lipogenesis. In addition, we showed that SR141716 induced cholesterol de novo synthesis and high-density lipoprotein uptake, revealing a relationship between CB1R and cholesterol metabolism.. These data suggest that blocking hepatic CB1R improves both carbohydrate and lipid metabolism and confirm that peripheral CB1R should be considered as a promising target to reduce cardiometabolic risk in obesity.

Topics: AMP-Activated Protein Kinase Kinases; Animals; Carbohydrate Metabolism; Cholesterol; Disease Models, Animal; Dyslipidemias; Fatty Liver; Gene Expression Regulation; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Obesity; Oxygen Consumption; Piperidines; Protein Kinases; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; RNA, Messenger; Tissue Culture Techniques

G-protein coupled receptor 26 (GPR26) is a brain-specific orphan GPCR with high expression in the brain region that controls satiety. Depletion of GPR26 has been shown to increase fat storage in C. elegans, whereas GPR26 deficiency in the hypothalamus is associated with high genetic susceptibility to the onset of obesity in mice. However, the metabolic function of GPR26 in mammals remains elusive. Herein, we investigated a role of GPR26 in regulating energy homeostasis by generating mice with targeted deletion of the GPR26 gene. We show that GPR26 deficiency causes hyperphagia and hypometabolism, leading to early onset of diet-induced obesity. Accordingly, GPR26 deficiency also caused metabolic complications commonly associated with obesity, including glucose intolerance, hyperinsulinemia, and dyslipidemia. Moreover, consistent with hyperphagia in GPR26 null mice, GPR26 deficiency significantly increased hypothalamic activity of AMPK, a key signaling event that stimulates appetite. In further support of a regulatory role of GPR26 in satiety, GPR26 knockout mice also demonstrate hypersensitivity to treatment of rimonabant, an endocannabinoid receptor-1 antagonist commonly used to treat obesity by suppressing appetite in humans. Together, these findings identified a key role of GPR26 as a central regulator of energy homeostasis though modulation of hypothalamic AMPK activation.

Topics: Adiposity; AMP-Activated Protein Kinases; Animals; Diet; Dyslipidemias; Energy Metabolism; Enzyme Activation; Gene Silencing; Gene Targeting; Glucose Intolerance; Hyperinsulinism; Hyperphagia; Hypothalamus; Mice; Mice, Inbred C57BL; Obesity; Phosphorylation; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptors, G-Protein-Coupled; Rimonabant; Weight Loss

To characterize the biological profiles of MJ08, a novel selective CB(1) receptor antagonist.. Radioligand binding assays were performed using rat brain and spleen membrane preparations. CB(1) and CB(2) receptor redistribution and intracellular Ca(2+) ([Ca(2+)](i)) assays were performed with IN CELL Analyzer. Inverse agonism was studied using intracellular cAMP assays, and in guinea-pig ileum and mouse vas deferens smooth muscle preparations. In vivo pharmacologic profile was assessed in diet-induced obesity (DIO) mice.. In radioligand binding assay, MJ08 selectively antagonized CB(1) receptor (IC(50)=99.9 nmol/L). In EGFP-CB(1)_U2OS cells, its IC(50) value against CB(1) receptor activation was 30.23 nmol/L (SR141716A: 32.16 nmol/L). WIN 55,212-2 (1 μmol/L) increased [Ca(2+)](i) in the primary cultured hippocampal neuronal cells and decreased cAMP accumulation in CHO-hCB(1) cells. MJ08 (10 nmol/L-10 μmol/L) blocked both the WIN 55,212-2-induced effects. Furthermore, MJ08 reversed the inhibition of electrically evoked twitches of mouse vas deferens by WIN 55,212-2 (pA(2)=10.29±1.05). MJ08 and SR141716A both showed an inverse agonism activity by markedly promoting the contraction force and frequency of guinea pig ileum muscle. MJ08 significantly increased the cAMP level in CHO-hCB(1) cells with an EC(50) value of 78.6 nmol/L, which was lower than the EC(50) value for SR141716A (159.2 nmol/L). Besides the more potent pharmacological effects of cannabinoid CB(1) receptor antagonism in DIO mice, such as reducing food intake, decreasing body weight, and ameliorating dyslipidemia, MJ08 (10 mg/kg) unexpectedly raised the fasted blood glucose in vivo.. MJ08 is a novel, potent and selective CB(1) receptor antagonist/inverse agonist with potent bioactive responses in vitro and in vivo that may be useful for disclosure the versatile nature of CB(1) receptors.

Topics: Animals; Calcium Signaling; Cell Line; Cell Membrane; Cyclic AMP; Dyslipidemias; Guinea Pigs; Ileum; Male; Mice; Mice, Inbred C57BL; Muscle Contraction; Muscle, Smooth; Neurons; Obesity; Piperidines; Pyrazoles; Rats; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Vas Deferens

Value-based pricing (VBP) is a method of setting prices for products based on perceived benefits to the consumer. When information is symmetric and freely available and agency is perfect, VBP is efficient and desirable. Because of substantial information asymmetries, medical insurance distortions, and the prescribing monopoly of physicians, VBP is rare for prescription drugs, though a number of countries have recently moved in this direction. Because the potential benefits can be sizable, it is high time for a review of actual VBP-based decision-making in practice. Sweden, with its pharmaceutical benefits board (TLV), was an early adopter of VBP decision-making. We illustrate actual decision-making, thus, using the case of Acomplia for the treatment of obesity in Sweden, with and without the presence of co-morbid conditions. This example has a number of features that will be useful in illustrating the strengths and weaknesses of VBP in actual practice, including multiple indications, a need for not just one but two economic simulation models, considerable sub-group analysis, and requirements for additional evidence development. TLV concluded, in 2006, that Acomplia was cost-effective for patients with a body mass index (BMI) exceeding 35 kg/m2 and patients with a BMI exceeding 28 kg/m2 and either dyslipidemia or type 2 diabetes. Because of uncertainty in some of the underlying assumptions, reimbursement was granted only until 31 December 2008, at which time the manufacturer would be required to submit additional documentation of the long-term effects and cost-effectiveness in order to obtain continued reimbursement. Deciding on reimbursement coverage for pharmaceutical products is difficult. Ex ante VBP assessment is a form of risk sharing, which has been used by TLV to speed up reimbursement and dispersion of effective new drugs despite uncertainty in their true cost-effectiveness. Manufacturers are often asked in return to generate additional health economic evidence that will establish cost-effectiveness as part of ex post review. The alternative is to delay the reimbursement approval until satisfactory evidence is available.

Topics: Body Mass Index; Comorbidity; Cost-Benefit Analysis; Decision Making, Organizational; Drug Prescriptions; Dyslipidemias; Economics, Pharmaceutical; Humans; Insurance, Pharmaceutical Services; Obesity; Piperidines; Pyrazoles; Reimbursement Mechanisms; Rimonabant; State Medicine; Sweden

Topics: Adiponectin; Adiposity; Animals; Anti-Obesity Agents; Blood Glucose; Body Weight; C-Reactive Protein; Dyslipidemias; Humans; Insulin; Intra-Abdominal Fat; Lipids; Liver; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Time Factors; Treatment Outcome

Visceral (intra-abdominal) obesity is associated with a cluster of cardiovascular risk factors that together promote macrovascular and microvascular disease. An atherogenic dyslipidemia, characterized by an increase in serum triglyceride-rich lipoproteins, a decrease in plasma levels of high-density lipoprotein cholesterol and increased prevalence of small, dense low-density lipoprotein particles (although low-density lipoprotein cholesterol levels are normal or only modestly elevated), as well as chronic inflammation, play key roles in the pathogenesis of visceral obesity-related complication. These abnormalities may be consequent to a global metabolic effect of insulin resistance. Pharmacological treatments, such as 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, fibric acid derivatives, insulin sensitizers and cannabinoid receptor type 1 blockers, are often required to correct the dyslipidemia of visceral obesity. The basis for a multiple approach to correcting dyslipoproteinemia in visceral obesity and the metabolic syndrome relies on understanding the mechanisms of action of the individual therapeutic components.

Topics: Atherosclerosis; Bradykinin; Cannabinoid Receptor Antagonists; Cannabinoids; Cardiovascular Diseases; Cholesterol, HDL; Clofibric Acid; Dyslipidemias; Female; Humans; Hypolipidemic Agents; Lipoproteins, HDL; Lipoproteins, LDL; Male; Meta-Analysis as Topic; Obesity; Piperidines; Prospective Studies; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant; Sex Factors

We describe the discovery of novel potent inhibitors of 2,3-oxidosqualene:lanosterol cyclase inhibitors (OSCi) from a focused pharmacophore-based screen. Optimization of the most tractable hits gave a series of compounds showing inhibition of cholesterol biosynthesis at 2mg/kg in the rat with distinct pharmacokinetic profiles. Two compounds were selected for toxicological study in the rat for 21 days in order to test the hypothesis that low systemic exposure could be used as a strategy to avoid the ocular side effects previously described with OSCi. We demonstrate that for this series of inhibitors, a reduction of systemic exposure is not sufficient to circumvent cataract liabilities.

Topics: Animals; Anticholesteremic Agents; Cataract; Cell Line, Tumor; Dyslipidemias; Enzyme Inhibitors; Eye; Female; Humans; Intramolecular Transferases; Liver; Male; Oxazoles; Piperazines; Piperidines; Rats; Rats, Sprague-Dawley

A new class of compounds, known as squalene synthase inhibitors, has recently reached phase III clinical trials and may provide another therapeutic option for clinicians to improve risk management of low-density lipoprotein cholesterol (LDL-C). The clinical need for another LDL-C-lowering therapy is evident by the inability to achieve an LDL-C target of less than 70 mg/dL in the majority of very high-risk patients on statin monotherapy. Human clinical trial data with TAK-475, a novel and potent inhibitor of squalene synthase, have not yet been published.

Topics: Clinical Trials, Phase III as Topic; Drug Delivery Systems; Dyslipidemias; Farnesyl-Diphosphate Farnesyltransferase; Humans; Oxazepines; Piperidines

Topics: Anesthesia, General; Bundle-Branch Block; Dermatomyositis; Dyslipidemias; Epoprostenol; Female; Fentanyl; Furosemide; Humans; Hypertension; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Mediastinal Diseases; Mediastinoscopy; Methyl Ethers; Middle Aged; Oxygen Inhalation Therapy; Piperidines; Preoperative Care; Raynaud Disease; Remifentanil; Sevoflurane; Spironolactone

Topics: Benzazepines; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dyslipidemias; Humans; Obesity; Piperidines; Prevalence; Pyrazoles; Quinoxalines; Rimonabant; Risk Factors; Smoking; Smoking Cessation; Tobacco Use Disorder; Varenicline

Topics: Anti-Obesity Agents; Cardiovascular Diseases; Dyslipidemias; Glucose Intolerance; Humans; Obesity; Overweight; Piperidines; Pyrazoles; Rimonabant; Weight Loss

Topics: Cardiovascular Diseases; Dyslipidemias; Humans; Obesity; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Receptor, Cannabinoid, CB1; Rimonabant; Risk Factors

Topics: Anti-Obesity Agents; Appetite Depressants; Cannabinoid Receptor Antagonists; Cyclobutanes; Dyslipidemias; Humans; Obesity; Piperidines; Pyrazoles; Rimonabant; Weight Loss