piperidines and Hyperlipidemias

Lapaquistat was the only squalene synthase inhibitor in Phase III clinical trials in Europe and the United States, but was recently discontinued from clinical development. Unlike statins, the inhibition of de novo cholesterol biosynthesis by lapaquistat does not deplete mevalonate, a precursor of isoprenoids. Isoprenoids are critical in cell growth and metabolism.. The present review will focus on the chemistry, pharmacology, and lipid-lowering effects of novel squalene synthase inhibitors.. A search of Pubmed, IPA, and GoogleScholar for studies (animal and human) and review articles published in English between 1990 and April 2008, using the search terms "squalene synthase inhibitors" or "lapaquistat". All clinical trials identified were then cross-referenced for their citations. All literature identified was then complied for this analysis.. Lapaquistat mainly targets LDL-C, but may have some effect on HDL-C and TG. Preliminary reports on Phase II and Phase III associated lapaquistat 100 mg with elevated hepatic enzymes. Hepatotoxicity, possible drug-drug interaction with statins, and the investigation of a statin/coenzyme Q10 combination are among the few challenges that impeded lapaquistat's clinical development.

Topics: Animals; Cardiovascular Diseases; Clinical Trials as Topic; Drug Design; Enzyme Inhibitors; Farnesyl-Diphosphate Farnesyltransferase; Humans; Hyperlipidemias; Hypolipidemic Agents; Oxazepines; Piperidines

The obesity pandemic will likely have a significant impact on the global incidence of cardiovascular disease. Although the mechanisms linking obesity and cardiovascular disease are unclear, recent studies have implicated the adipocyte as a potentially important mediator of vascular complications. The adipocyte is no longer considered a passive storage depot for triglycerides and fatty acids, but rather an active metabolic organ capable of producing several factors, commonly referred to as adipokines, that may have effects on many physiological and pathophysiological processes. With increasing fat mass, several adipose-related factors are upregulated that may affect local and distant inflammatory processes, including atherothrombosis. Other factors, such as adiponectin, are downregulated with increasing fat mass. Although most adipokines are thought to promote vascular disease, several studies over the past few years indicate adiponectin is actually protective against both diabetes and vascular disease. There are now available pharmacologic agents capable of altering the adipocyte transcription profile. This review will focus on the potential impact of adipocyte-derived factors towards vascular disease and emerging therapeutic strategies that may alter these effects.

Topics: Adiponectin; Anti-Obesity Agents; Cardiovascular Diseases; Cyclobutanes; Diabetes Mellitus, Type 2; Humans; Hyperlipidemias; Hypertension; Lactones; Obesity; Orlistat; Piperidines; Pyrazoles; Rimonabant; Risk Factors

Diabetes mellitus and cognitive decline are major public health concerns among the elderly. In diabetic subjects without dementia, certain cognitive domains are impaired, such as memory, attention, and executive/frontal lobe function (diabetic cognitive dysfunction). Recent epidemiological studies have suggested that diabetes increases the risks for vascular dementia as well as Alzheimer's disease. There are accumulating evidences that indicate biological linkage between impaired brain glucose metabolism homeostasis and cognitive decline. Diabetes may cause serious brain damages through several mechanisms and induce a variety of cognitive decline. Most critical issue to be resolved is to identify the mechanism of dementia leading from diabetic cognitive dysfunction. Once elderly diabetics had severe cognitive decline, effective treatment of diabetes were hardly obtained. Thus, diabetic cognitive decline should be considered as an important comorbidity of the elderly diabetes and long-term management of hyperglycemia is required from a view point to sustain healthy brain function. In this short review, we are summarizing the clinical features and current biological findings of diabetic cognitive decline. Also, we introduce the comprehensive treatment of demented diabetic elderly, including therapeutic strategy, nursing and care.

Topics: Aged; Antihypertensive Agents; Brain; Cognition Disorders; Dementia; Diabetes Mellitus, Type 2; Donepezil; Glucose; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperglycemia; Hyperlipidemias; Hypertension; Indans; Piperidines; Risk; Risk Factors

The endocannabinoid system modulates synaptic neurotransmission centrally and peripherally and is involved in the brain pathways concerned with addiction, central regulation of body weight and adipose tissue function. The system is overactivated in animal models of obesity and nicotine use. This review discusses the role of rimonabant, a cannabinoid receptor 1 blocker, which has undergone Phase III clinical testing, in the treatment of obesity and tobacco dependence.. Results of Phase III clinical trials have shown that rimonabant has promising efficacy in the treatment of obesity, dyslipidaemia and diabetes associated with obesity, in preventing weight gain following smoking cessation, and possibly in smoking cessation. No critical problems with the tolerance and safety of the compound have appeared in studies to date.. Rimonabant may prove to be a useful aid in the treatment of the most widespread cardiometabolic risk factors.

Topics: Cannabinoid Receptor Antagonists; Cardiovascular Diseases; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Humans; Hyperlipidemias; Metabolic Syndrome; Obesity; Piperidines; Pyrazoles; Rimonabant; Risk Factors; Smoking Cessation; Tobacco Use Disorder; Treatment Outcome; Weight Gain

Topics: Animals; Apolipoproteins B; Arteriosclerosis; Carrier Proteins; Humans; Hyperlipidemias; Indoles; Isoindoles; Lipoproteins, VLDL; Methaqualone; Piperidines

This study was designed to compare the effects of metformin and repaglinide on the fasting plasma glucose (FPG) and glycated haemoglobin (HbA1c) in newly diagnosed type 2 diabetes in China.. A total of 107 newly diagnosed type 2 diabetic patients (46 women and 61 men) participated in the study. All patients received 3-month treatment of metformin or repaglinide. Fasting blood glucose and HbA1c were determined at baseline and at the end of the 3-month of treatment.. FPG and HbA1c decreased in both metformin and repaglinide groups after 3 months treatment (P < 0.01). The reduction of HbA1c was significantly greater in the repaglinide group (P < 0.01). Metformin decreases fasting insulin concentration and HOMA-IR (P < 0.01), and repaglinide improves HOMA-β(P < 0.01). Triglycerides (TG) were reduced in both groups (P < 0.01 in metformin group; P < 0.05 in repaglinide group), but total cholesterol (TC) and low-density lipoprotein (LDL) were decreased only after metformin treatment (P < 0.05).. Both repaglinide and metformin were effective in glycaemic control in new onset patients with type 2 diabetes in China. Repaglinide had no effect on insulin sensitivity, but it improved β-cell function.

Topics: Body Mass Index; Carbamates; China; Combined Modality Therapy; Diabetes Mellitus, Type 2; Diet, Diabetic; Diet, Reducing; Drug Monitoring; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Hyperlipidemias; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Male; Metformin; Middle Aged; Overweight; Piperidines; Weight Loss

Postprandial hyperlipidemia impairs endothelial function and participates in the development of atherosclerosis. We investigated the postprandial effects of a dipeptidyl peptidase IV inhibitor, alogliptin, on endothelial dysfunction and the lipid profile.. A randomized cross-over trial design in 10 healthy volunteers (8 males and 2 females, 35 ± 10 years) was performed. The postprandial effects before and after a 1-week treatment of 25 mg/day alogliptin on endothelial function were assessed with brachial artery flow-mediated dilation (FMD) and changing levels of lipids, apolipoprotein B48 (apoB-48), glucose, glucagon, insulin, and glucagon-like peptide-1 (GLP-1) during fasting and at 2, 4, 6, and 8 h after a standard meal loading test.. Alogliptin treatment significantly suppressed the postprandial elevation in serum triglyceride (incremental area under the curve [AUC]; 279 ± 31 vs. 182 ± 32 mg h/dl, p = 0.01), apoB-48 (incremental AUC; 15.4 ± 1.7 vs. 11.7 ± 1.1 μg h/ml, p = 0.04), and remnant lipoprotein cholesterol (RLP-C) (incremental AUC: 29.3 ± 3.2 vs. 17.6 ± 3.3 mg h/dl, p = 0.01). GLP-1 secretion was significantly increased after alogliptin treatment. Postprandial endothelial dysfunction (maximum decrease in%FMD, from -4.2 ± 0.5% to -2.6 ± 0.4%, p = 0.03) was significantly associated with the maximum change in apoB-48 (r = -0.46, p = 0.03) and RLP-C (r = -0.45, p = 0.04).. Alogliptin significantly improved postprandial endothelial dysfunction and postprandial lipemia, suggesting that alogliptin may be a promising anti-atherogenic agent.

Topics: Adult; Cross-Over Studies; Diabetes Mellitus, Type 2; Endothelium, Vascular; Female; Humans; Hyperlipidemias; Hypoglycemic Agents; Male; Middle Aged; Piperidines; Postprandial Period; Uracil

The objectives of this study is to evaluate the efficacy and safety of alogliptin versus very low fat/calorie traditional Japanese diet (non-inferiority trial) as an initial therapy for newly diagnosed, drug naïve subjects with type 2 diabetes (T2DM). Study design was prospective, randomized, non-double-blind, controlled trial. The study was conducted at outpatient units of municipal hospital. Patients were newly diagnosed, drug naïve patients who visited the outpatient units. The patients randomly received 12.5-25 mg/day alogliptin (n = 25) or severe low calorie traditional Japanese diet (n = 26). The procedure of this trial was assessed by the consolidated standards of reporting trials statement. The primary end point was the change of HbA1c at 3 months. Secondary end points included the changes of fasting blood glucose, insulin, homeostasis model assessment-R (HOMA-R), HOMA-B, body mass index (BMI), and lipid parameters. Similar, significant reductions of HbA1c levels were observed in both groups (from 10.51 to 8.74% for alogliptin and from 10.01 to 8.39% for traditional Japanese diet) without any clinically significant adverse events. In the alogliptin group, some subjects (16%) had mild hypoglycemic evens which could be managed by taking glucose drinks by themselves. HOMA-B significantly increased in both groups with varying degrees, whereas HOMA-R significantly decreased only in the Japanese diet group. Atherogenic lipids, such as, total cholesterol, non-high density lipoprotein cholesterol, and low density lipoprotein cholesterol levels significantly decreased in both groups. BMI had no change in the alogliptin group, whereas it significantly decreased in the Japanese diet group. (1) Concerning its glycemic efficacy, alogliptin is effective and non-inferior to traditional Japanese diet as an initial therapeutic option for newly diagnosed T2DM. However, regarding the reductions of body weight and insulin resistance, traditional Japanese diet is superior. (2) Both alogliptin and traditional Japanese diet have favorable effects on atherogenic lipid profiles.

Topics: Adult; Diabetes Mellitus, Type 2; Diet, Diabetic; Diet, Fat-Restricted; Dipeptidyl-Peptidase IV Inhibitors; Female; Glycated Hemoglobin; Hospitals, Municipal; Humans; Hyperglycemia; Hyperlipidemias; Hypoglycemia; Insulin Resistance; Japan; Male; Middle Aged; Outpatient Clinics, Hospital; Patient Dropouts; Piperidines; Uracil; Weight Loss

The effect of acute repaglinide administration (2 mg) on postprandial glycaemia and lipaemia has been examined in 20 subjects with type 2 diabetes mellitus. Each subject received in the morning, after a 12 to 14 h fast, a standard mixed meal (total energy 783 kcal), preceded by one tablet of 2 mg repaglinide or placebo. Chylomicrons and chylomicron-deficient plasma were prepared by ultracentrifugation. Triglyceride levels in CM fraction (CM-triglycerides) in total plasma as well as in CM-deficient plasma (non-CM-triglycerides) were determined. A significant reduction in postprandial glycaemia was observed after repaglinide administration compared to placebo ( p < 0.001). Plasma concentrations of total triglycerides, CM-triglycerides, non-CM-triglycerides, free fatty acids and the other plasma lipids measured, were not significantly different between the two phases of the study. It is concluded that, in contrast to sulphonylureas, acute repaglinide administration does not improve postprandial lipaemia in patients with type 2 diabetes.

Topics: Analysis of Variance; Blood Glucose; C-Peptide; Carbamates; Cholesterol; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Glycated Hemoglobin; Humans; Hyperlipidemias; Hypoglycemic Agents; Insulin; Kinetics; Piperidines; Postprandial Period; Triglycerides

The effects of tibric acid, clofibrate, and placebo were compared in type IV hyperlipidemic patients for a 6-month period. The patients were divided into two pathological level groups according to their baseline triglyceride levels. Compared to the placebo, both tibric acid and clofibrate reduced the mean serum triglyceride concentration in the high pathological level group; however, clofibrate was also effective in the low pathological level group. The effects on total cholesterol were less pronounced with the two drugs. No effect was observed on esterified cholesterol, phospholipids, free fatty acids, and fasting blood sugar. After a 6-week follow-up period under placebo, no rebound of the triglyceride and cholesterol levels could be observed after discontinuation of the two active drugs. The other biochemical changes observed after each active treatment are discussed in relation to the different degree of activity of each active drug and to the different baseline levels of triglycerides.

Topics: Adult; Aged; Cholesterol; Clinical Trials as Topic; Clofibrate; Female; Humans; Hyperlipidemias; Lipoproteins, VLDL; Male; Middle Aged; Piperidines; Triglycerides

Tibric acid [CP-18.524; 2-chloro-5-(3,5-dimethyl-piperidino-sulfonyl-benzoic acid], a new hypolipidemic drug was given to 20 patients with primary endogenous hyperlipoproteinemia of type II, III, IV and V Fredrickson in a daily dose of 1.5 g for 1 year. As compared to a 4-week placebo period, the treatment with tibric acid led to a significant decrease in plasma cholesterol in 6 type-II patients (p less than 0.02) and to a significant decrease in plasma cholesterol and triglycerides in 6 type-III patients (p less than 0.001 and p less than 0.001, resp.) and in 4 type-IV patients (p less than 0.001 and p less than 0.001, resp.). No significant effect of tibric acid on plasma lipids was noted in 4 type-V patients. Apart from a moderate nausea in two patients, no side effects occurred.

Topics: Adult; Aged; Cholesterol; Drug Evaluation; Humans; Hyperlipidemias; Hypolipidemic Agents; Lipids; Middle Aged; Piperidines; Triglycerides

Topics: Aged; Clinical Trials as Topic; Drug Evaluation; Female; Humans; Hyperlipidemias; Hypolipidemic Agents; Male; Middle Aged; Piperidines; Placebos

This double-blind study compares the effects of tibric acid at four different doses to that of placebo in type IV hyperlipidemic patients. Fifty patients, divided at random in five groups of 10 patients each, received one of the following treatments: placebo, tibric acid 500 mg, 750 mg, 1,000 mg, or 1,250 mg per 24 hr. The data suggest that the 1,000 mg and the 1,250 mg doses are effective in lowering the serum triglyceride levels after 6 wk of treatment; the effect on total cholesterol is less pronouced. No effect is observed on the concentration of serum esterified cholesterol, phospholipids, and free fatty acids. It is also shown that in the dose range studied, the best fitting curve defining the four mean values of triglycerides and total cholesterol obtained with the four active treatments did not deviate significantly from linearity. Due to lack of toxicity, tibric acid may be useful in the treatment of type IV hyperlipoproteinemia.

Topics: Adult; Aged; Analysis of Variance; Benzoates; Cholesterol; Clinical Trials as Topic; Dose-Response Relationship, Drug; Humans; Hyperlipidemias; Hypolipidemic Agents; Lipoproteins, VLDL; Middle Aged; Piperidines; Placebos; Sulfones; Triglycerides

Topics: Adult; Aged; Benzoates; Body Weight; Cholesterol; Clinical Trials as Topic; Coronary Disease; Female; Humans; Hyperlipidemias; Hypolipidemic Agents; Lipids; Male; Middle Aged; Piperidines; Sulfonic Acids; Triglycerides; Uric Acid

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). The implications of treatment with tofacitinib on cardiovascular (CV) risk in RA are unknown. Therefore, CV adverse events (AEs), and blood pressure and lipid level changes, in tofacitinib-treated patients with RA were evaluated.. Data were pooled from six Phase (P)3 studies (24 months) and two open-label long-term extension (LTE) studies (60 months) of tofacitinib in patients with RA and inadequate response to DMARDs. Tofacitinib was administered alone or with non-biologic DMARDs. CV events, including major adverse CV events (MACE: CV death and non-fatal CV events) and congestive heart failure (CHF), were assessed by a blinded adjudication committee.. Overall, 4271 patients from P3 studies and 4827 enrolled from P2/P3 studies into LTE studies were evaluated, representing 3942 and 8699 patient-years of exposure to tofacitinib, respectively. Blood pressure remained stable over time across studies. The number of investigator-reported hypertension-related AEs in tofacitinib-treated patients was low in P3 studies (Months 0-3: 2.8%; Months 3-6: 1.4%; >6 months: 2.8%). Across studies, lipid level increases were generally observed within 1-3 months of treatment and stabilized thereafter. Patients with events (incidence rate [IR]/100 patient-years) for MACE and CHF, respectively, were: 23 (0.58) and 9 (0.23) in P3 studies, and 32 (0.37) and 8 (0.09) in LTE studies; IRs were comparable with placebo (P3) and did not increase over time (LTE).. Tofacitinib was associated with a low incidence of CV events in a large Phase 3 program, including LTE studies. Further long-term studies are underway.

Topics: Arthritis, Rheumatoid; Blood Pressure; Cardiovascular Diseases; Cholesterol, HDL; Cholesterol, LDL; Clinical Trials, Phase III as Topic; Heart Failure; Humans; Hyperlipidemias; Hypertension; Incidence; Janus Kinases; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Triglycerides

The present study investigated the comparative effects of piperine (PIP) - the active ingredient of black and long peppers - and simvastatin (SIM) on hepatic steatosis in hyperlipidemic rats. Male Wistar rats were fed a cholesterol mixture daily by intragastric gavage for 8 weeks. Piperine was given by oral gavage 8 h after cholesterol feeding. The animals were divided into 4 groups: control, high fat (HF), high fat plus 40 mg PIP/kg, and high fat plus 2 mg SIM/kg. At the end of the treatment, liver cholesterol, triglyceride, thiobaribituric reacting substances, superoxide dismutase (SOD), serum aminotransferase (AST), and alanine transferase (ALT) were measured. The result demonstrated that PIP and SIM significantly reduced the accumulation of cholesterol, triglyceride, and lipid peroxidation in the liver, while elevation of SOD was observed. The activities of AST and ALT significantly decreased in PIP when compared with the HF group. Our in vitro study of pancreatic lipase also showed the inhibitory effect of PIP higher than 30% at 5 mmol/L. These results demonstrate that PIP has beneficial effects in the treatment and (or) prevention of fat accumulation in the liver and that this mechanism is due to the inhibition of pancreatic lipase and the improvement of oxidative status.

Topics: Adipose Tissue; Alkaloids; Animals; Antioxidants; Benzodioxoles; Diet, High-Fat; Dietary Fats; Fatty Liver; Hyperlipidemias; Male; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Simvastatin

Effects of cannabinoid receptor 1 (CB1R) blockade were observed by comparing 9-day and 6-week SR141716 treatments in monosodium glutamate (MSG)-induced hypometabolic and hypothalamic obesity (HO) in rats for the first time and molecular mechanisms were investigated. Compared with normal rats, the MSG rats display typical symptoms of the metabolic syndrome, i.e., excessive abdominal obesity, hypertriglyceridemia, hyperinsulinemia, insulin resistance, and hepatic steatosis, but with lower food intake. Although both the 9-day and 6-week treatments with the specific CB1R antagonist SR141716 effectively lowered body weight, intraperitoneal adipose tissue mass, serum triglyceride (TG), and insulin level, the effect of chronic treatment is more impressive. Moreover, serum cholesterol, free fatty acids (FFA), fasted and postprandial blood glucose, and insulin insensitivity were more effectively improved by 6-week exposure to SR141716, whereas hypophagia was only effective within the initial 2 weeks. In addition, hepatic steatosis as well as hepatic and adipocyte morphology was improved. Western blot analysis revealed that the markedly increased CB1R expression and decreased insulin receptor (INR) expression in liver and adipose tissues were effectively corrected by SR141716. Consistent with this, deregulated gene expression of lipogenesis and lipolysis as well as glucose metabolic key enzymes were also restored by SR141716. In conclusion, based on present data we found that: (1) alteration of the hypothalamus in MSG rats leads to a lower expression of INR in crucially insulin-targeted tissues and hyperinsulinemia that was reversed by SR141716, (2) the abnormally increased expression of CB1R in liver and adipose tissues plays a vital role in the pathophysiological process of MSG rats, and (3) chronic CB1R blockade leads to a sustained improvement of the metabolic dysfunctions of MSG rats.

Topics: Adipose Tissue; Animals; Animals, Newborn; Cannabinoid Receptor Antagonists; Fatty Liver; Female; Glucose Intolerance; Hyperlipidemias; Insulin Resistance; Liver; Male; Obesity; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptor, Insulin; Rimonabant; Sodium Glutamate

The effects of effective part group on hyperlipidemia in animal were studied. The SD rats, hamsters and Kunming mouse were divided into blank group, model group. The positive control group and test group were fed with normal diet, blank and other groups were fed with high fat diet (mouse only a single intraperitoneal injection of egg yolk ). The corresponding concentration of solvent, simvastatin, effective part group of emulsion were given gavage once daily. The animal serum total cholesterol (TC) , triglyceride (TG) , low density lipoprotein (LDL) , high density lipoprotein (HDL) and liver TC, TG contents were determined to observe the effects of the effective fractions on blood lipid regulating function. Comparing with control group, the animial hyperlipidemia models of the SD rat (TC increase), mouse (TC, TG, LDL increase), hamsters ( TC, TG, LDL increase, HDL decrease) (P <0. 05, P < 0. 001) were successfully established. Piper longum effective part group could decrease the serum TC, TG, LDL (P <0.05, P < 0. 001) and liver TC, TG content, and elevate serum HDL levels (P <0.05, P <0.001). The golden hamster is ideal for hyperlipidemia model.

Topics: Alkaloids; Animals; Benzodioxoles; Cholesterol; Cricetinae; Drugs, Chinese Herbal; Female; Hyperlipidemias; Lipid Metabolism; Lipoproteins, HDL; Lipoproteins, LDL; Liver; Male; Mice; Piper; Piperidines; Polyunsaturated Alkamides; Rats; Triglycerides

Diabetes mellitus is a chronic metabolic disorder characterized by hyperglycaemia and other symptoms like polyuria (frequent urination), polydipsia (increased thirst) and polyphagia (increased hunger) which ultimately causes various other complications like retinopathy, neuropathy, nephropathy and microangiopathy.. The antidiabetic and antihyperlipidemic potential of oil from Piper longum (PLO) and piperine was investigated with their possible mechanism using α-glucosidase, aldose reductase (AR), and pancreatic lipase inhibitory activity.. The biochemical parameters, viz. glucose level, insulin level, liver glycogen content, glycosylated hemoglobin, total plasma cholesterol, triglyceride, and antioxidant parameters, were estimated for all treated groups in acute and chronic antihyperglycemic animal models.. PLO (100 and 200 mg/kg), piperine (25 and 50 mg/kg), and glibenclamide (0.6 mg/kg) in respective groups of diabetic animals administered for 28 days reduced the blood glucose level in streptozotocin-induced diabetic rats. There was significant increase in body weight, liver glycogen content, plasma insulin, and high-density lipoprotein and decrease in glycosylated hemoglobin, triglyceride, and total plasma cholesterol in PLO-administered groups as compared to control group. The IC50 value of PLO for α-glucosidase, AR, and pancreatic lipase was found to be 150 ± 2.5, 120 ± 1.2, and 175 ± 1.2 μg/ml, respectively, which was found comparable with the standard drugs acarbose (90 ± 2.3 μg/ml), quercetin (80 ± 2.3 μg/ml), and orlistat (25 ± 0.5 μg/ml), respectively.. The investigation done reveals that PLO has significant antidiabetic and antihyperlipidemic activity.

Topics: Aldehyde Reductase; Alkaloids; alpha-Glucosidases; Animals; Benzodioxoles; Blood Glucose; Cholesterol; Diabetes Mellitus, Experimental; Glutathione; Glycogen; Hyperlipidemias; Hypoglycemic Agents; Hypolipidemic Agents; Insulin; Lipase; Liver; Piper; Piperidines; Plant Oils; Polyunsaturated Alkamides; Rats; Rats, Wistar; Triglycerides

Topics: Carbamates; Cyclohexanes; Glipizide; Humans; Hyperglycemia; Hyperlipidemias; Hypoglycemic Agents; Nateglinide; Phenylalanine; Piperidines; Postprandial Period; Sulfonylurea Compounds

To study the effect of piperine, an alkaloid, on thyroid hormones and apolipoproteins in high-fat-diet (HFD) and antithyroid drug-induced hyperlipidemic rats.. Male Wistar rats were first divided into two groups, control diet and high-fat diet (HFD) and then subdivided into four subgroups of ten animals each. The animals were treated with the following regimens for 10 weeks: 1% carboxymethyl cellulose; 10 mg carbimazole (CM)/kg body weight; 10 mg CM + 40 mg piperine/kg body weight, and 10 mg CM + 2 mg atorvastatin /ATV//kg body weight. Lipid profiles, hormone levels, and apolipoprotein levels were studied in all groups.. HFD and/or CM administration significantly elevated the plasma levels of total cholesterol, VLDL, LDL, triglycerides, free fatty acids, and phospholipids, but significantly reduced the HDL levels. Moreover, CM administration significantly reduced apo A-I levels and T3, T4 and testosterone levels while significantly elevating plasma apo B, thyroid stimulating hormone (TSH) and insulin levels. The simultaneous administration of piperine and HFD significantly reduced plasma lipids and lipoproteins levels, except for HDL, which was significantly elevated. Piperine supplementation also improved the plasma levels of apo A-I, T3, T4, testosterone, and I and significantly reduced apo B, TSH, and insulin to near normal levels.. The data presented here provide evidence that piperine possesses thyrogenic activity, thus modulating apolipoprotein levels and insulin resistance in HFD-fed rats, opening a new view in the management of dyslipidemia by dietary supplementation with nutrients.

Topics: Alkaloids; Animals; Apolipoproteins; Benzodioxoles; Dietary Fats; Hormones; Hyperlipidemias; Hypolipidemic Agents; Insulin; Lipids; Male; Piper; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Testosterone; Thyroid Hormones

In the field of dyslipidemia and metabolic syndrome, four innovative therapies are reviewed: Ezetimibe (Ezétrol) is a selective cholesterol absorption inhibitor. Co-administration of ezetimibe with low dose of statins shows LDL lowering comparable to that of the highest dose of the respective statin alone. Combination therapy helps more patients in achieving target LDL-cholesterol. Nicotinic acid (Niacin) favourably modifies all lipoprotein level (including Lp(a)). Extended release niacin (Niaspanâ) is a new galenic form, with less side effects (flushing and hepatotoxicity) than the native nicotinic acid. This new preparation represents an effective option in the management of dyslipidemia. The polyunsatured fatty acids (PUFA) omega-3 (Omacor) decreases cardiovascular deaths and mainly fatal arrhythmias after myocardial infarction. Their favourable effects are linked mainly to their anti-inflammatory and antiarrhythmic properties. The PUFA omega-3 could be added to the secondary prevention after myocardial infarction. The blockade of the endocannabinoid system by a specific inhibitor of CB1 receptor (rimonabant or Acomplia) decreases food intake and weight and increases adiponectin and insulin sensitivity. Clinical studies on obesity and tobacco dependence are very encouraging.

Topics: Anticholesteremic Agents; Azetidines; Ezetimibe; Fatty Acids, Omega-3; Humans; Hyperlipidemias; Hypolipidemic Agents; Metabolic Syndrome; Niacin; Piperidines; Pyrazoles; Rimonabant

The effects of the angiotensin-converting enzyme (ACE) inhibitor monopril and the angiotensin II receptor blocker losartan on serum glucose, protein levels and some serum lipid components were compared in normal and diabetic rats receiving oral antidiabetic drugs 'repaglinide or gliclazide'. The two antihypertensive agents, when administered concurrently with oral hypoglycemic agents 'repaglinide or gliclazide' in normal and diabetic rats exerted a significant hypoglycemic effect. Serum protein levels were mainly unaffected by the two antihypertensive drugs. Monopril and losartan exhibit a hypolipidemic effect in normal and diabetic rats when administered in combination with oral hypoglycemic agents 'gliclazide or repaglinide'. Monopril or losartan when used alone exerted insignificant effect in high density lipoprotein (HDL) in normal rats, while in combination with gliclazide or repaglinide caused a significant increase in HDL in normal rats. Concomitantly, monopril or losartan, when administered alone or in combination with repaglinide or gliclazide in diabetic rats exerted a significant increase in serum HDL. On the other hand, all the investigated drugs showed a significant decrease in serum low density lipoprotein (LDL) in normal and diabetic rats.

Topics: Alloxan; Animals; Blood Glucose; Blood Proteins; Carbamates; Cholesterol, LDL; Diabetes Mellitus, Experimental; Disease Models, Animal; Drug Therapy, Combination; Egypt; Fosinopril; Gliclazide; Hyperlipidemias; Hypolipidemic Agents; Lipids; Losartan; Male; Piperidines; Rats; Rats, Sprague-Dawley; Triglycerides

The estrogen antagonist EM-652.HCl behaves as a highly potent and pure antiestrogen in human breast and uterine cancer cells. Because of its pure antiestrogenic activity in these cells, and because its prodrug, EM-800, reduces bone loss and decreases serum cholesterol and triglycerides in the rat, EM-652.HCl can be classified as a pure selective estrogen receptor modulator (SERM). This study was conducted to assess the ability of EM-652.HCl to prevent obesity and abnormalities of lipid metabolism induced by ovariectomy in a rat model.. Female rats were left intact or ovariectomized (OVX), and OVX rats were treated with placebo, estradiol (E2), or EM-652.HCl for 20 days. At the end of the treatment period, parameters of energy balance and determinants of lipid metabolism were assessed.. As expected, OVX increased energy intake, which in turn was accompanied by an increased energy, fat and protein gain and higher food efficiency. OVX also increased the triglyceride content of the liver and produced hypercholesterolemia and hyperinsulinemia. The weight of representative white adipose depots was higher in OVX than in intact rats. Lipoprotein lipase activity was higher in white adipose tissues of OVX rats than in those of intact animals, whereas its activity was lower in oxidative tissues (brown adipose and soleus muscle). Replacement therapy with a physiological dose of E2 prevented most of the abnormalities in energy and lipid metabolism brought about by OVX, although its orexigenic effect was only partially corrected. In contrast, treatment of OVX rats with EM-652. HCl completely abolished OVX-induced obesity and its related abnormalities in lipid metabolism and glucose/insulin homeostasis.. These findings demonstrate that EM-652.HCl can be considered as an effective agent to prevent OVX-induced obesity. The present study also shows that EM-652.HCl reduces cardiovascular risk factors associated with obesity such as hyperlipidemia and insulin resistance.

Topics: Animals; Cardiovascular Diseases; Disease Models, Animal; Energy Metabolism; Estrogen Antagonists; Female; Hyperlipidemias; Insulin Resistance; Lipid Metabolism; Obesity; Ovariectomy; Piperidines; Rats; Rats, Sprague-Dawley; Risk Factors; Selective Estrogen Receptor Modulators

Patients with abetalipoproteinemia, a disease caused by defects in the microsomal triglyceride transfer protein (MTP), do not produce apolipoprotein B-containing lipoproteins. It was hypothesized that small molecule inhibitors of MTP would prevent the assembly and secretion of these atherogenic lipoproteins. To test this hypothesis, two compounds identified in a high-throughput screen for MTP inhibitors were used to direct the synthesis of a highly potent MTP inhibitor. This molecule (compound 9) inhibited the production of lipoprotein particles in rodent models and normalized plasma lipoprotein levels in Watanabe-heritable hyperlipidemic (WHHL) rabbits, which are a model for human homozygous familial hypercholesterolemia. These results suggest that compound 9, or derivatives thereof, has potential applications for the therapeutic lowering of atherogenic lipoprotein levels in humans.

Topics: Alanine Transaminase; Animals; Apolipoproteins B; Aspartate Aminotransferases; Carrier Proteins; Cholesterol; Cricetinae; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Design; Drug Evaluation, Preclinical; Fluorenes; Humans; Hyperlipidemias; Hyperlipoproteinemia Type II; Lipids; Lipoproteins; Liver; Mice; Piperidines; Rabbits; Rats; Triglycerides; Tumor Cells, Cultured

Topics: Adult; Cholesterol; Clofibrate; Humans; Hyperlipidemias; Lipoproteins, VLDL; Middle Aged; Piperidines; Triglycerides

Topics: Anticholesteremic Agents; Cholesterol; Clofibrate; Drug Evaluation; Female; Humans; Hyperlipidemias; Hypolipidemic Agents; Lipoproteins; Male; Middle Aged; Piperidines; Placebos; Research Design; Triglycerides

The hypobetalipoproteinemic activity of U-41,792 (1-[p-(1-adamantyloxy)-phenyl]-piperidine) is a marked and selective reduction of heparin precipitating lipoproteins (low density plus very low density lipoproteins) in cholesterol-cholic acid induced hypercholesterolemic rats. This activity consists of both a reduction in heparin precipitating lipoproteins (HPL) and an increase in high density lipoproteins that are not precipitated by heparin. The increase in high density lipoproteins is routinely noted by decreases in HPL/cholesterol ratios. The pattern of response following single 100 mg/kg doses of U-418792 was determined. After an I.V. dose was administered in a cottonseed oil emulsion, serum cholesterol levels were reduced, beginning at 8 hr after administration and persisting for 96 hr. Similar results, though delayed somewhat, were obtained after a single oral dose. Activity was accompanied by increases in weight and cholesterol content of livers. After multiple, daily, oral doses, liver weights, total lipids, and cholesterol contents were reduced. Hypobetalipopreteinmeic activity was enhanced by prolonged treatments as demonstrated by analyses of serum obtained weekly throughout 7 wk.

Topics: Adamantane; Animals; Bridged-Ring Compounds; Cholesterol; Hypercholesterolemia; Hyperlipidemias; Lipoproteins, HDL; Lipoproteins, LDL; Lipoproteins, VLDL; Liver; Male; Organ Size; Organ Specificity; Piperidines; Rats

Topics: Cholesterol; Feces; Humans; Hyperlipidemias; Hypolipidemic Agents; Lipid Metabolism; Neomycin; Phenols; Piperidines; Probucol

Topics: Dose-Response Relationship, Drug; Drug Evaluation; Humans; Hyperlipidemias; Hypolipidemic Agents; Piperidines

Topics: Adult; Aged; Benzoates; Chylomicrons; Drug Evaluation; Drug Tolerance; Female; Humans; Hypercholesterolemia; Hyperlipidemias; Hypolipidemic Agents; Lipoproteins; Liver; Male; Middle Aged; Piperidines; Sulfonic Acids; Triglycerides

Topics: Anticholesteremic Agents; Blood Cell Count; Chemical and Drug Induced Liver Injury; Female; Glycolates; Humans; Hyperlipidemias; Leukocyte Count; Lipids; Phenols; Piperidines; Time Factors

Topics: Acetates; Animals; Anticholesteremic Agents; Body Weight; Butyrates; Carbon Isotopes; Cholesterol; Hyperlipidemias; Hypolipidemic Agents; Lipids; Liver; Male; Organ Size; Phospholipids; Piperidines; Propylthiouracil; Rats; Triglycerides