piperidines and Hypercholesterolemia

Mevalonate Kinase Deficiency (MKD, OMIM #610377) is a rare autosomal recessive metabolic and inflammatory disease. In MKD, defective function of the enzyme mevalonate kinase, due to a mutation in the MVK gene, leads to the shortage of mevalonate- derived intermediates, which results in unbalanced prenylation of proteins and altered metabolism of sterols. These defects lead to a complex multisystem inflammatory and metabolic syndrome.. Although biologic therapies aimed at blocking the inflammatory cytokine interleukin- 1 can significantly reduce inflammation, they cannot completely control the clinical symptoms that affect the nervous system. For this reason, MKD can still be considered an orphan drug disease. The availability of MKD models reproducing the MKD-systematic inflammation, is crucial to improve the knowledge on its pathogenesis, which is still unknown. New therapies are also required in order to improve pateints' conditions and their quality of life.. MKD-cellular models can be obtained by biochemical inhibition of mevalonatederived isoprenoids. Of note, these cells present an exaggerated response to inflammatory stimuli that can be reduced by treatment with zaragozic acid, an inhibitor of squalene synthase, thus increasing the availability of isoprenoids intermediates upstream the enzymatic block.. A similar action might be obtained by lapaquistat acetate (TAK-475, Takeda), a drug that underwent extensive clinical trials as a cholesterol lowering agent 10 years ago, with a good safety profile.. Here we describe the preclinical evidence supporting the possible repositioning of TAK-475 from its originally intended use to the treatment of MKD and discuss its potential to modulate the mevalonate pathway in inflammatory diseases.

Topics: Acyl Coenzyme A; Cholesterol; Drug Repositioning; Farnesyl-Diphosphate Farnesyltransferase; Humans; Hypercholesterolemia; Mevalonate Kinase Deficiency; Oxazepines; Phosphotransferases (Alcohol Group Acceptor); Piperidines

Lapaquistat acetate is a squalene synthase inhibitor investigated for the treatment of hypercholesterolemia.. This report summarizes the phase 2 and 3 results from the lapaquistat clinical program, which was halted at an advanced stage as a result of potential hepatic safety issues. Efficacy and safety data were pooled from 12 studies (n=6151). These were 6- to 96-week randomized, double-blind, parallel, placebo- or active-controlled trials with lapaquistat monotherapy or coadministration with other lipid-altering drugs in dyslipidemic patients, including a large (n=2121) 96-week safety study. All studies included lapaquistat 100 mg daily; 5 included 50 mg; and 1 included 25 mg. The main outcome measures were the percent change in low-density lipoprotein cholesterol, secondary lipid/metabolic parameters, and overall safety. Lapaquistat 100 mg significantly decreased low-density lipoprotein cholesterol by 21.6% in monotherapy and by 18.0% in combination with a statin. It also reduced other cardiovascular risk markers, such as C-reactive protein. Total adverse events were higher for lapaquistat than placebo, although individual events were generally similar. At 100 mg, there was an increase in alanine aminotransferase value ≥3 times the upper limit of normal on ≥2 consecutive visits (2.0% versus 0.3% for placebo in the pooled efficacy studies; 2.7% versus 0.7% for low-dose atorvastatin in the long-term study). Two patients receiving lapaquistat 100 mg met the Hy Law criteria of alanine aminotransferase elevation plus increased total bilirubin.. Squalene synthase inhibition with lapaquistat acetate, alone or in combination with statins, effectively lowered low-density lipoprotein cholesterol in a dose-dependent manner. Elevations in alanine aminotransferase, combined with a rare increase in bilirubin, presented potential hepatic safety issues, resulting in termination of development. The lapaquistat experience illustrates the current challenges in lipid-altering drug development.. URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00487994, NCT00143663, NCT00143676, NCT00864643, NCT00263081, NCT00286481, NCT00249899, NCT00249912, NCT00813527, NCT00256178, NCT00268697, and NCT00251680.

Topics: Adult; Aged; Anticholesteremic Agents; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Farnesyl-Diphosphate Farnesyltransferase; Female; Humans; Hypercholesterolemia; Liver Diseases; Male; Middle Aged; Oxazepines; Piperidines; Randomized Controlled Trials as Topic

There remains an unmet need to reduce elevated low-density lipoprotein cholesterol (LDL-C) in patients who are maximized on current therapy or intolerant to statins. Several novel agents have been developed to lower LDL-C, either as monotherapy or in combination with statins. These novel therapies include squalene synthase inhibitors, microsomal triglyceride transfer protein inhibitors, and antisense apolipoprotein B. Although each of these novel therapies effectively lowers LDL-C, challenges remain in the clinical development to assess long-term safety.

Topics: Animals; Anticholesteremic Agents; Azetidines; Benzimidazoles; Carrier Proteins; Cholesterol, LDL; Ezetimibe; Farnesyl-Diphosphate Farnesyltransferase; Humans; Hypercholesterolemia; Indoles; Oligonucleotides; Oxazepines; Piperidines; Proprotein Convertase 9; Proprotein Convertases; Pyridines; Serine Endopeptidases; Serine Proteinase Inhibitors

Endothelin blocking drugs have vasodilator effects mediated at least in part via the nitric oxide system. Hypercholesterolaemia is associated with vascular dysfunction manifest as impaired nitric oxide-mediated vasodilatation and arterial stiffness. Treatment with HMG CoA reductase inhibitors (statins) has proven mortality benefits in a range of patient populations. Subjects (n = 5) received either placebo or 800 mug cerivastatin for an 8-week period in a double-blind, placebo-controlled, cross-over study. Cerivastatin reduced the total plasma cholesterol compared with baseline by 27% (5.4 +/- 0.4 mmol/L versus 7.3 +/- 0.4 mmol/L, P = 0.04). Selective endothelin-A receptor blockade caused an increase in forearm blood flow (FBF) (18.0 +/- 7.2%, P = 0.04). Compared with placebo, cerivastatin therapy caused a trend towards a further increase in FBF (18.0 +/- 7.2% versus 52.0 +/- 19.0%, P = 0.06). Selective endothelin-B receptor blockade reduced FBF (-11.0 +/- 3.9%, P = 0.02) with no difference between placebo and cerivastatin therapy (-11.0 +/- 3.9% versus -13.0 +/- 3.6%, P = 0.9). Combined endothelin-A/endothelin-B receptor blockade increased FBF (39.8 +/- 13.4%, P < 0.01) with no difference between placebo and cerivastatin therapy (39.8 +/- 13.4% versus 42.4 +/- 19.0%, P = 0.7). There was a trend towards a reduction in the augmentation index between cerivastatin and placebo (6.2 +/- 2.7 versus 9.1 +/- 2.4, n = 5, P = 0.4) compared with baseline (7.2 +/- 1.0). In conclusion, statin therapy may decrease large artery stiffness and increase the vasodilating effects of endothelin-A receptor blockade.

Topics: Cholesterol, LDL; Compliance; Cross-Over Studies; Double-Blind Method; Down-Regulation; Drug Therapy, Combination; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Forearm; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Oligopeptides; Peptides, Cyclic; Piperidines; Pyridines; Receptor, Endothelin A; Receptor, Endothelin B; Time Factors; Treatment Outcome; Vasodilation; Vasodilator Agents

To evaluate the efficacy and tolerability of donepezil in patients with vascular dementia (VaD).. Patients (n = 616; mean age, 75.0 years) with probable or possible VaD, according to National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche en l'Enseignement en Neurosciences criteria, were randomized to receive donepezil 5 mg/day (n = 208), donepezil 10 mg/day (after 5 mg/day for the first 28 days) (n = 215), or placebo (n = 193) for 24 weeks.. Seventy-six percent of the patients enrolled had probable VaD. A total of 75.3% of the 10 mg donepezil group and 80.8% of the 5 mg group completed the study compared with 83.4% of the placebo group. Both donepezil-treated groups showed improvements in cognitive function on the Alzheimer's Disease Assessment Scale-cognitive subscale compared with placebo, with a mean endpoint treatment difference, as measured by the change from baseline score, of approximately 2 points (donepezil 5 mg, -1.65 [p = 0.003]; 10 mg, -2.09 [p = 0.0002]). Greater improvements on the Clinician's Interview-Based Impression of Change-plus version were observed with both donepezil groups than with the placebo group (overall donepezil treatment vs placebo p = 0.008); 25% of the placebo group showed improvement compared with 39% (p = 0.004) of the 5 mg group and 32% (p = 0.047) of the 10 mg group. Withdrawal rates due to adverse events were low (placebo, 8.8%; donepezil 5 mg, 10.1%; 10 mg, 16.3%).. Donepezil-treated patients demonstrated significant improvements in cognition and global function compared with placebo-treated patients, and donepezil was well tolerated.

Topics: Adult; Aged; Aged, 80 and over; Cholinesterase Inhibitors; Dementia, Vascular; Donepezil; Double-Blind Method; Female; Heart Diseases; Humans; Hypercholesterolemia; Hypertension; Indans; Male; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; Risk Factors; Smoking; Stroke; Treatment Outcome

Mitochondrial reactive oxygen species (ROS) contribute to inflammation and vascular remodeling during atherosclerotic plaque formation. C57BL/6N (6N) and C57BL/6J (6J) mice display distinct mitochondrial redox balance due to the absence of nicotinamide nucleotide transhydrogenase (NNT) in 6J mice. We hypothesize that differential NNT expression between these animals alters plaque development.. 6N and 6J mice were treated with AAV8-PCSK9 (adeno-associated virus serotype 8/proprotein convertase subtilisin/kexin type 9) virus leading to hypercholesterolemia, increased low-density lipoprotein, and atherosclerosis in mice fed a high-fat diet (HFD). Mice were co-treated with the mitochondria-targeted superoxide dismutase mimetic MitoTEMPO to assess the contribution of mitochondrial ROS to atherosclerosis.. Baseline and HFD-induced vascular superoxide is increased in 6J compared to 6N mice. MitoTEMPO diminished superoxide in both groups demonstrating differential production of mitochondrial ROS among these strains. PCSK9 treatment and HFD led to similar increases in plasma lipids in both 6N and 6J mice. However, 6J animals displayed significantly higher levels of plaque formation. MitoTEMPO reduced plasma lipids but did not affect plaque formation in 6N mice. In contrast, MitoTEMPO surprisingly increased plaque formation in 6J mice.. These data indicate that loss of NNT increases vascular ROS production and exacerbates atherosclerotic plaque development.

Topics: Animals; Antioxidants; Aorta; Aortic Diseases; Atherosclerosis; Cholesterol; Disease Models, Animal; Genetic Predisposition to Disease; Hypercholesterolemia; Male; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Mitochondrial Proteins; NADP Transhydrogenase, AB-Specific; Organophosphorus Compounds; Phenotype; Piperidines; Plaque, Atherosclerotic; Proprotein Convertase 9; Superoxides; Time Factors

Insulin resistance has been recognized as the most significant predictor of further development of type 2 diabetes mellitus (T2DM). Here we investigated the effect of a heat shock protein (HSP) co-inducer, BGP-15, on insulin sensitivity in different insulin-resistant animal models and compared its effect with insulin secretagogues and insulin sensitizers.. Insulin sensitivity was assessed by the hyperinsulinemic euglycemic glucose clamp technique in normal and cholesterol-fed rabbits and in healthy Wistar and Goto-Kakizaki (GK) rats in dose-ranging studies. We also examined the effect of BGP-15 on streptozotocin-induced changes in the vasorelaxation of the aorta in Sprague-Dawley rats.. BGP-15 doses of 10 and 30 mg/kg increased insulin sensitivity by 50% and 70%, respectively, in cholesterol-fed but not in normal rabbits. After 5 days of treatment with BGP-15, the glucose infusion rate was increased in a dose-dependent manner in genetically insulin-resistant GK rats. The most effective dose was 20 mg/kg, which showed a 71% increase in insulin sensitivity compared to control group. Administration of BGP-15 protected against streptozotocin-induced changes in vasorelaxation, which was similar to the effect of rosiglitazone.. Our results indicate that the insulin-sensitizing effect of BGP-15 is comparable to conventional insulin sensitizers. This might be of clinical utility in the treatment of T2DM.

Topics: Animals; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Hypercholesterolemia; Hypoglycemic Agents; Insulin Resistance; Male; Oximes; Piperidines; Rabbits; Rats; Rats, Sprague-Dawley; Rats, Wistar; Vasodilation

Piperidine-based peroxisome proliferator-activated receptor-α agonists are agents that are efficacious in improving lipid, glycemic, and inflammatory indicators in diabetes and obesity. This study sought to determine whether CP-900691 ((S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester; CP), a member of this novel class of agents, by decreasing plasma triglycerides, could prevent diabetic nephropathy in the Black and Tan, BRachyuric (BTBR) ob/ob mouse model of type 2 diabetes mellitus. Four-week old female BTBR WT and BTBR ob/ob mice received either regular chow or one containing CP (3 mg/kg per day) for 14 weeks. CP elevated plasma high-density lipoprotein, albuminuria, and urinary excretion of 8-epi PGF(2α), a product of the nonenzymatic metabolism of arachidonic acid and whose production is elevated in oxidative stress, in BTBR WT mice. In BTBR ob/ob mice, CP reduced plasma triglycerides and non-esterified fatty acids, fasting blood glucose, body weight, and plasma interleukin-6, while concomitantly improving insulin resistance. Despite these beneficial metabolic effects, CP had no effect on elevated plasma insulin, 8-epi PGF(2α) excretion, and albuminuria, and surprisingly, did not ameliorate the development of diabetic nephropathy, having no effect on the accumulation of renal macrophages, glomerular hypertrophy, and increased mesangial matrix expansion. In addition, CP did not increase plasma high-density lipoprotein in BTBR ob/ob mice, while paradoxically increasing total cholesterol levels. These findings indicate that 8-epi PGF(2α), possibly along with hyperinsulinemia and inflammatory and dysfunctional lipoproteins, is integral to the development of diabetic nephropathy and should be considered as a potential target of therapy in the treatment of diabetic nephropathy.

Topics: Albuminuria; Animals; Anti-Obesity Agents; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dinoprost; Disease Progression; Female; Glomerular Mesangium; Hypercholesterolemia; Hypertriglyceridemia; Hypertrophy; Hypoglycemic Agents; Hypolipidemic Agents; Insulin Resistance; Kidney; Mice; Mice, Inbred Strains; Mice, Obese; Obesity; Piperidines; PPAR alpha; Propionates

Translational animal models are essential in the prediction of the efficacy and side effects of new chemical entities. We have carried out a thorough study of three distinct disease-modifying antirheumatic drugs (DMARDs) in an adjuvant-induced arthritis (AIA) model in the rat and critically appraised the results in the context of the reported clinical experience in rheumatoid arthritis (RA) patients.. Teriflunomide - a dihydroorotate dehydrogenase (DHODH) inhibitor; AL8697 - a selective p38 MAPK inhibitor; and tofacitinib - a Janus kinase (JAK) inhibitor; were selected as representatives of their class and dose-response studies carried out using a therapeutic 10-day administration scheme in arthritic rats. Paw swelling and body weight were periodically monitored, and joint radiology and histology, lymph organ weight and haematological and biochemical parameters evaluated at study completion.. All three drugs demonstrated beneficial effects on paw swelling, bone lesions and splenomegalia, with p38 inhibition providing the best anti-inflammatory effect and JAK inhibition the best DMARD effect. Leukopenia, body weight loss and gastrointestinal toxicity were dose-dependently observed with teriflunomide treatment. p38 MAPK inhibition induced leukocytosis and increased total plasma cholesterol. JAK inhibition, normalized platelet, reticulocyte and neutrophil counts, and alanine aminotransferase (ALT) levels while inducing lymphopenia and cholesterolemia.. This multiparametric approach can reveal specific drug properties and provide translational information. Whereas the complex profile for p38 inhibition in AIA is not observed in human RA, immunosuppressants such as DHODH and JAK inhibitors show DMARD properties and side effects seen in both AIA and RA.

Topics: Animals; Antirheumatic Agents; Arthritis, Experimental; Benzamides; Bridged Bicyclo Compounds, Heterocyclic; Crotonates; Dihydroorotate Dehydrogenase; Dose-Response Relationship, Drug; Edema; Enzyme Inhibitors; Gastrointestinal Tract; Half-Life; Hydroxybutyrates; Hypercholesterolemia; Immunosuppressive Agents; Janus Kinases; Joints; Leukocyte Disorders; Male; Nitriles; Oxidoreductases Acting on CH-CH Group Donors; p38 Mitogen-Activated Protein Kinases; Piperidines; Pyrimidines; Pyrroles; Rats; Rats, Wistar; Splenomegaly; Toluidines; Weight Loss

Topics: Adult; Biomarkers; Cannabinoid Receptor Modulators; Cholesterol; Fatty Liver; Female; Humans; Hypercholesterolemia; Insulin Resistance; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Obesity, Morbid; Piperidines; Pyrazoles; Retrospective Studies; Rimonabant; Safety-Based Drug Withdrawals; Triglycerides; Weight Loss

Retinol-binding protein 4 (RBP4) is an adipocyte-secreted hormone proposed to link obesity with insulin resistance. However, the role of RBP4 in cardiovascular complications is yet to be fully understood. The present study is aimed to decipher the association between RBP4 with pro-inflammatory cytokines and low-density lipoprotein (LDL) cholesterol in diet-induced obese and hyperlipidaemic mice. To understand the correlation, rimonabant, an anti-obesity drug, has been used to relieve the atherosclerotic predisposition.. Adipose and/or aortic tissue expressions of RBP4, pro-inflammatory cytokine genes and circulating LDL levels were measured in high fat (HF)-fed female C57BL/6 and high cholesterol (HC)-fed apolipoprotein E3 (ApoE3) Leiden mice.. Mice fed a HF diet had a significantly increased adipose expression of RBP4, TNF-α and monocyte chemoattractant protein 1 (MCP-1) and down-regulated adiponectin mRNA levels. A significant increase in aortic RBP4 and MCP-1 expression and circulating levels of LDL and C-reactive protein (CRP) was found in the ApoE3 mice fed a HC diet. Interestingly, rimonabant treatment lowered the elevated aortic RBP4, MCP-1 expressions and significantly reduced the serum levels of LDL, CRP, RBP4 and MCP-1.. Our results indicate that RBP4 is positively associated with markers of inflammation in obese and pro-atherogenic conditions and could play a role in a predisposition to atherosclerosis. Furthermore, our results indicate that rimonabant may improve vascular function by modulating RBP4 along with pro-inflammatory cytokines.

Topics: 3T3-L1 Cells; Adipokines; Animals; Apolipoprotein E3; Atherosclerosis; Base Sequence; Cardiovascular Diseases; Cholesterol; DNA Primers; Female; Gene Expression Regulation; Hypercholesterolemia; Inflammation; Mice; Mice, Inbred C57BL; Obesity; Piperidines; Pyrazoles; Real-Time Polymerase Chain Reaction; Retinol-Binding Proteins, Plasma; Rimonabant

In this study we examined the antioxidant effect of curcumin on lipid oxidation in vitro and in vivo. In vitro, curcumin at 5 microgM concentration completely prevented low-density lipoprotein (LDL) oxidation by CuS0(4), indicating that curcumin is an effective antioxidant in vitro. In vivo, feeding a pure cholesterol (PC)-rich diet to rabbits significantly increased the plasma and liver lipids as well as thiobarbituric acid reactive substances (TBARS) levels. Addition of curcumin to the PC diet did not show any effect on either plasma lipid and TBARS or liver lipids. Liver TBARS tended to decrease but that decrease was not significant. Erythrocyte glutathione peroxidase (GSH-Px) activity was significantly decreased while catalase activity was significantly increased in rabbits fed a PC diet. The addition of curcumin to a PC diet did not show any significant effect on erythrocyte enzyme activities compared to the rabbits fed a PC diet. The liver GSH-Px and catalase activities were significantly decreased in rabbits fed a PC diet, but the addition of curcumin to the PC diet enhanced the liver GSH-Px activity, which became nonsignificantly different from the control group. These results were discussed considering that curcumin may not be well absorbed and it did not reach a level high enough in vivo to overcome the severe hypercholesterolemia and oxidative stress produced by the PC-rich diet.

Topics: Alkaloids; Animals; Antioxidants; Benzodioxoles; Catalase; Cholesterol, Dietary; Curcumin; Glutathione Peroxidase; Hypercholesterolemia; Lipid Peroxidation; Lipids; Lipoproteins, LDL; Liver; Male; Oxidation-Reduction; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Rabbits

Inhibition of squalene synthesis could transform unstable, macrophage/lipid-rich coronary plaques into stable, fibromuscular plaques. We have here treated WHHLMI rabbits, a model for coronary atherosclerosis and myocardial infarction, with a novel squalene synthase inhibitor, lapaquistat acetate (TAK-475).. Young male WHHLMI rabbits were fed a diet supplemented with lapaquistat acetate (100 or 200 mg per kg body weight per day) for 32 weeks. Serum lipid levels were monitored every 4 weeks. After the treatment, lipoprotein lipid and coenzyme Q10 levels were assayed, and coronary atherosclerosis and xanthomas were examined histopathologically or immunohistochemically. From histopathological and immunohistochemical sections, the composition of the plaque was analysed quantitatively with computer-assisted image analysis. Xanthoma was evaluated grossly.. Lapaquistat acetate decreased plasma cholesterol and triglyceride levels, by lowering lipoproteins containing apoB100. Development of atherosclerosis and xanthomatosis was suppressed. Accumulation of oxidized lipoproteins, macrophages and extracellular lipid was decreased in coronary plaques of treated animals. Treatment with lapaquistat acetate increased collagen concentration and transformed coronary plaques into fibromuscular plaques. Lapaquistat acetate also suppressed the expression of matrix metalloproteinase-1 and plasminogen activator inhibitor-1 in the plaque and increased peripheral coenzyme Q10 levels. Increased coenzyme Q10 levels and decreased very low-density lipoprotein cholesterol levels were correlated with improvement of coronary plaque composition.. Inhibition of squalene synthase by lapaquistat acetate delayed progression of coronary atherosclerosis and changed coronary atheromatous plaques from unstable, macrophage/lipid accumulation-rich, lesions to stable fibromuscular lesions.

Topics: Animals; Apolipoprotein B-100; Cholesterol; Collagen; Coronary Artery Disease; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Enzyme Inhibitors; Farnesyl-Diphosphate Farnesyltransferase; Hypercholesterolemia; Hypolipidemic Agents; Image Interpretation, Computer-Assisted; Immunohistochemistry; Lipid Metabolism; Lipoproteins, LDL; Macrophages; Male; Matrix Metalloproteinase 1; Oxazepines; Piperidines; Plasminogen Activator Inhibitor 1; Rabbits; Triglycerides; Ubiquinone; Xanthomatosis

Acolbifene (ACOL) is a fourth-generation selective estrogen receptor modulator (SERM) that has strong and pure antiestrogenic properties toward estrogen-sensitive cancers, but improves energy and lipid metabolism in an estrogen-like fashion in rodent models. The aim of this study was to determine the potency of ACOL to reduce cholesterolemia in a dietary model of hypercholesterolemia and to establish its mechanisms of action. Intact and ovariectomized (OVX) female rats were treated for 3 weeks with ACOL, and serum cholesterol and liver determinants of cholesterol metabolism were assessed. Acolbifene prevented both diet- and ovariectomy-induced weight gain and completely prevented diet-induced hypercholesterolemia. Relative to a reference chow diet, the high-cholesterol diet decreased the high-density lipoprotein (HDL) cholesterol fraction, which remained unaffected by ACOL, indicating that in hypercholesterolemic conditions, ACOL modulated only the non-HDL fraction. No impact of ACOL on determinants of liver cholesterol synthesis was observed. In contrast, ACOL increased hepatic low-density lipoprotein receptor protein in both intact and OVX rats, which was negatively correlated with serum total and non-HDL cholesterol (r=-0.59, P<.0001), suggesting a contribution of receptor-mediated hepatic uptake of cholesterol-rich lipoproteins to the hypocholesterolemic effect of ACOL. These findings establish that ACOL retains its powerful cholesterol-lowering action in diet-induced hypercholesterolemia and suggest that the SERM acts in such conditions through favoring hepatic low-density lipoprotein receptor-mediated uptake of cholesterol transported by non-HDL lipoprotein fractions.

Topics: Animals; ATP-Binding Cassette Transporters; Blood Glucose; Cholesterol, Dietary; Female; Hydroxymethylglutaryl CoA Reductases; Hypercholesterolemia; Liver; Ovariectomy; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, LDL; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Selective Estrogen Receptor Modulators; Statistics, Nonparametric; Sterol Regulatory Element Binding Proteins; Weight Gain

Vascular dementia (VaD) is the second most common form of dementia after Alzheimer's disease (AD), and one of the major causes of mental and physical disability in developed countries. As such, the identification and implementation of strategies which prevent the development of the condition or enable improvements in patients with VaD are healthcare objectives of the first order. VaD is now regarded as a combined group of clinical-pathological entities rather than one disease, that is, multiple pathogenic mechanisms and lesion types underlie a cognitive impairment of vascular origin. The clinical diagnosis of VaD is complex and difficult because of the heterogeneous nature of its clinical presentation and progression and the low sensitivity of existing clinical criteria. Moreover, there is growing evidence of the epidemiological significance of mixed forms of dementia, and that ischemic processes may precipitate and exacerbate cognitive impairment in AD. Numerous compounds have been proposed as potentially useful in the treatment of patients with VaD, comprising vasodilatative, antithrombotic, hemorrheological, nootropic, antiserotoninergic and, most recently, antiglutamatergic and cholinergic approaches. In spite of some initially favorable reports based on the use of memantine, donepezil and galantamine, there is as yet no conclusive evidence of a definitive treatment for VaD. Unsatisfactory results from VaD drug trials may be attributed in part to the diversity of the patients included (underlying pathogenic mechanisms, number, type, and location of vascular lesions), and to methodological limitations in the design of the trials (outcome measures, end-points, size, follow-up period). The treatment of modifiable vascular risk factors - hypertension, diabetes mellitus, hypercholesterolemia and heart disease - is an important strategy for the reduction of the risk of dementia, and is likely to slow the progress of cognitive decline.

Topics: Animals; Cholinesterase Inhibitors; Dementia, Vascular; Donepezil; Excitatory Amino Acid Antagonists; Galantamine; Heart Diseases; Humans; Hypercholesterolemia; Hypertension; Indans; Memantine; Neuroprotective Agents; Patient Selection; Piperidines; Randomized Controlled Trials as Topic; Research Design; Risk Factors; Stroke

Topics: Aspirin; Cardiovascular Diseases; Cholesterol, LDL; Clopidogrel; Humans; Hypercholesterolemia; Obesity; Piperidines; Platelet Aggregation Inhibitors; Pyrazoles; Rimonabant; Stroke; Ticlopidine

The cancer-preventing selective estrogen receptor modulator (SERM) acolbifene (ACOL) exerts a potent and pure antiestrogenic action in the mammary gland and uterus, yet it displays beneficial, estrogen-like actions on energy and lipid metabolism in rodents. The compound reduces food intake and strongly decreases cholesterolemia in rats fed a cholesterol-free diet. This study was designed to establish whether the anorectic effect of ACOL is involved in its cholesterol-lowering action, and whether the compound retains its ability to lower cholesterol concentrations in rats with diet-induced hypercholesterolemia. Female rats were fed a purified diet devoid of cholesterol (reference diet) or containing 2% cholesterol (C-diet); they were either not treated or treated daily with ACOL or not treated and pair-fed to the ACOL-treated rats. The C-diet did not affect food intake or weight and fat gains. ACOL reduced food intake (16%) and weight gain (45%, mainly fat) similarly in both dietary cohorts. ACOL, but not pair feeding, reduced cholesterolemia by 33% in rats fed the reference diet. As expected, the C-diet raised serum total cholesterol almost 3-fold and this increase was largely prevented by ACOL but not by pair feeding. Cholesterol was reduced by ACOL, mainly in the HDL fraction, in rats fed the reference diet, but only in the non-HDL fraction in those fed the C-diet. In livers of rats fed the reference diet, ACOL, but not pair feeding, increased protein abundance of the scavenger receptor, class B, type 1, and the LDL receptor, thought to be involved in ACOL-mediated cholesterol lowering. These findings demonstrate that the potent hypocholesterolemic action of ACOL is independent of the concomitant reduction in food intake and fat accretion, and that such action occurs in rats with overt diet-induced hypercholesterolemia.

Topics: Animals; Anorexia; Cholesterol; Cholesterol, Dietary; Female; Hypercholesterolemia; Liver; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, LDL; Scavenger Receptors, Class B; Selective Estrogen Receptor Modulators

Topics: Humans; Hypercholesterolemia; Piperidines; Pyrazoles; Rimonabant

New fibrates containing piperidine, 4-hydroxypiperidine, piperidin-3-ene, and piperazine moieties in the structures were synthesized and evaluated. Among the synthesized compounds, 2-[3-[1-(4-fluorobenzoyl)-piperidin-4yl]phenoxyl-2-methylpropanoic acid (9aA: AHL-157) showed very superior activities in decreasing triglyceride, cholesterol, and blood sugar compared to bezafibrate in mice and rats.

Topics: Animals; Disease Models, Animal; Hypercholesterolemia; Hypertriglyceridemia; Hypoglycemic Agents; Hypolipidemic Agents; Male; Mice; Mice, Inbred ICR; Piperazine; Piperazines; Piperidines; Propionates; Rats; Rats, Sprague-Dawley

The coronary vasoconstrictor effects of endothelins, mediated by both endothelin ETA and ETB receptors, may be differentially altered in pathophysiological states associated with endothelial dysfunction and elevated endothelin levels. Experimental hypercholesterolemia is associated with coronary endothelial dysfunction and increased circulating endothelin concentrations. These studies were designed to test the hypothesis that experimental hypercholesterolemia is characterized by a differentially altered coronary contractile response to ETA- and ETB-receptor stimulation, in vitro. Pigs were fed either a normal or a high-cholesterol diet for 10 to 13 weeks. Changes in the intraluminal diameter of pressurized small coronary arteries (< 481 +/- 25 microns in diameter) to cumulative concentrations (10(-10) to 10(-6) mol/L) of endothelin-1 (ET-1), and sarafotoxin 6c (S6c), a specific ETB-receptor agonist, were measured using a video dimension analyzer. The maximal contraction attained with ET-1 was greater than with S6c in both normal (86 +/- 7% versus 47 +/- 7%, P = .001) and hypercholesterolemic (77 +/- 6% versus 37 +/- 7%, P < .001) pigs. At 10(-10) mol/L, vessels from hypercholesterolemic pigs manifested greater contraction to both ET-1 (23 +/- 6% versus 8 +/- 3%, P = .02) and S6c (17 +/- 5% versus 4 +/- 2%, P = .02). Incubation of arteries from hypercholesterolemic pigs with BQ-788 (ETB-receptor antagonist), but not FR-139317 (ETA-receptor antagonist), altered the contractile response to ET-1 at 10(-10) mol/L. Removal of the endothelium abolished the difference in response to S6c between normal and hypercholesterolemic pigs. These studies demonstrate that experimental hypercholesterolemia is characterized by enhanced coronary vasoconstriction to endothelins in vitro, the mechanism of which is mediated mainly through the ETB receptor. Thus, the ETB receptor has a role in regulation of coronary artery tone in both the steady-state and pathophysiological states.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Azepines; Cholesterol, Dietary; Coronary Vessels; Diet, Atherogenic; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Endothelium, Vascular; Female; Hypercholesterolemia; Indoles; Lipids; Oligopeptides; Piperidines; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Swine; Vasoconstriction; Vasoconstrictor Agents; Viper Venoms

The effects of the nonpeptide orally effective vasopressin V1 receptor antagonist OPC-21268 were studied in progressive focal glomerulosclerosis (FGS) which developed in spontaneously hypercholesterolemic (SHC) rats with manifestations of hypercholesterolemia and proteinuria. Unilateral nephrectomy was performed at 7 weeks of age to accelerate spontaneous FGS. After nephrectomy, OPC-administered rats were fed chow containing 1% OPC-21268 for 9 weeks. Treatment with vasopressin V1 antagonist significantly reduced the rate of increase in the levels of triglyceride, systolic blood pressure, serum creatinine and BUN, and prevented a significant deterioration in creatinine clearance. Rats were sacrificed at 16 weeks of age. Histologically, the index of glomerular sclerosis in the OPC group showed a significant decrease compared to that in the control group (2.2 +/- 0.1 vs. 2.6 +/- 0.1, p < 0.01). Relative interstitial volume and glomerular volume in the OPC group showed a tendency to decrease compared to those in the control group. These results indicate that vasopressin plays an important role through V1 receptors in the development of glomerulosclerosis, and vasopressin V1 antagonist may prevent the progression of renal injury in glomerulosclerosis.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Blood Pressure; Blood Urea Nitrogen; Glomerulosclerosis, Focal Segmental; Hypercholesterolemia; Kidney; Kidney Function Tests; Lipids; Male; Nephrectomy; Piperidines; Proteinuria; Quinolones; Rats; Rats, Inbred Strains

Topics: Cholesterol; Drug Design; Humans; Hypercholesterolemia; Naphthols; Piperidines

Mature male rats (SD strain, 8-week-old) were fed with a normal diet or a high cholesterol diet (HC: 1.5% cholesterol and 0.5% Na cholate in the normal diet) up to 8 weeks, and we examined how the vascular function level of the isolated thoracic aorta and the histological figures of some tissues including the aorta would change. 1) The contracting reactivity to phenylephrine (Phe, 10 microM) and the relaxing reactivity to acetylcholine (1 microM) measured thereafter remained unchanged during the period of aging and were not influenced by HC-feeding. The addition of L-arginine (Arg, 100 microM) did not affect the results. 2) The ability of the aorta to release NO and to relax, which was evaluated as the extent of the endothelium-dependent potentiation by NG-monomethyl-L-arginine (NMA) of the Phe contraction, did not change by HC-feeding up to 4 weeks, but appears to be attenuated after 8-week feeding. 3) The EC50 of NMA for the potentiation estimated without the addition of Arg remained unchanged, while the one in the presence of Arg gradually increased with aging but not with HC-feeding. 4) The histopathological study of the aorta and other tissues failed to detect any notable atherogenic changes in any of the HC-fed groups. The results indicate that under the experimental conditions employed, HC-feeding would not develop any significant atherogenic histopathological changes in the endothelium-smooth muscle preparation, but may induce some dysfunction in the NO-release mediated and auto-regulatory function of the vascular tone.

Topics: Acetylcholine; Aging; Animals; Aorta, Thoracic; Arginine; Body Weight; Cholesterol, Dietary; Endothelium, Vascular; Hypercholesterolemia; In Vitro Techniques; Male; Muscle, Smooth, Vascular; omega-N-Methylarginine; Phenylephrine; Piperidines; Pyrimidinones; Rats; Rats, Inbred Strains; Vasoconstriction

Vasoconstrictor responses to serotonin and norepinephrine were examined in: normal cynomolgus monkeys, atherosclerotic monkeys that were fed atherogenic diet for 3-5 years and hypercholesterolaemic but non-atherosclerotic monkeys that were fed atherogenic diet for 4-5 months. Serotonin decreased total hindlimb resistance in normal and hypercholesterolaemic monkeys, but increased total resistance in atherosclerotic monkeys. There was a greater than 10-fold increase in constrictor responses of large arteries to serotonin in atherosclerotic compared with normal and hypercholesterolaemic monkeys. In contrast, responses to norepinephrine were not increased in atherosclerotic monkeys. Thus, atherosclerosis greatly potentiates constrictor responses to serotonin in large arteries of the limb. This potentiation appears to be somewhat selective for serotonin, as it is not observed with norepinephrine.

Topics: Animals; Arteriosclerosis; Hindlimb; Hypercholesterolemia; Ketanserin; Macaca fascicularis; Methysergide; Piperidines; Serotonin; Vasoconstriction

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

A new -ind of pharmacologic activity called hypobetalipoproteinemia is described. Iperationally the activity consists of a marked reduction of heparin precipitating lipoproteins (beta and/or pre-beta electrophoretic mobility) in hypercholesterolemic animals with a simultaneous decrease in the heparin precipitating lipoprotein: cholesterol ratio. As determined by ultracentrifugal fractionation of the lipoproteins from hypercholesterolemic rat serum, this activity consists of both a reduction in heparin precipitating lipoproteins and an increase high density lipoproteins that are not precipitated by heparin. Changes in composition were also induced in both lipoprotein fractions. The greatest changes were observed for free and esterified cholesterol, which were markedly reduced in the heparin precipitating lipoproteins and concomitantly increased in the high density lipoproteins. The hypobetalipoproteinemic agent exhibiting this activity is 1-[p-(1'-adamantyloxy) phenyl]-piperidine (U-41792). This agent is active in hypercholesterolemic rats, mice, quail, and pigeons.

Topics: Adamantane; Animals; Bridged-Ring Compounds; Cholesterol; Cholesterol, Dietary; Cholic Acids; Columbidae; Diet, Atherogenic; Dose-Response Relationship, Drug; Hypercholesterolemia; Hypolipidemic Agents; Lipoproteins, LDL; Male; Mice; Piperidines; Quail; Rats

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