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Since the first discovery of an inverse correlation between high-density lipoprotein-cholesterol (HDL-C) levels and coronary heart disease in the 1950s the life cycle of HDL, its role in atherosclerosis and the therapeutic modification of HDL-C levels have been major research topics. The Framingham study and others that followed could show that HDL-C is an independent cardiovascular risk factor and that the increase of HDL-C of only 10 mg·L−1 leads to a risk reduction of 2-3%. While statin therapy and therefore low-density lipoprotein-cholesterol (LDL-C) reduction could lower coronary heart disease considerably; cardiovascular morbidity and mortality still occur in a significant portion of subjects already receiving therapy. Therefore, new strategies and therapies are needed to further reduce the risk. Raising HDL-C was thought to achieve this goal. However, established drug therapies resulting in substantial HDL-C increase are scarce and their effect is controversial. Furthermore, it is becoming increasingly evident that HDL particle functionality is at least as important as HDL-C levels since HDL particles not only promote reverse cholesterol transport from the periphery (mainly macrophages) to the liver but also exert pleiotropic effects on inflammation, haemostasis and apoptosis. This review deals with the biology of HDL particles, the established and future therapeutic options to increase HDL-C and discusses the results and conclusions of the most important studies published in the last years. Finally, an outlook on future diagnostic tools and therapeutic opportunities regarding coronary artery disease is given. [ABSTRACT FROM AUTHOR]

The 26-week oral toxicity of diheptyl phthalate (DHP), a peroxisome proliferator-activated receptor α (PPARα) agonist, with special emphasis on the potential induction of hepatocellular proliferative lesions was investigated in this study. DHP was administered to male F344 rats via gavage at 0 (control), 1,000 or 2,000 mg/kg/day for 26 weeks. Body weight gain was significantly lower, whereas food and water consumption was significantly higher in DHP-treated rats compared with controls. DHP-treated rats exhibited decreases in blood triglyceride, total cholesterol, phospholipid and glucose levels, which were likely related to biological effects of the PPARα agonist. Absolute and relative organ weights of the livers with pale brown discoloration and dark brown spots significantly increased in DHP-treated rats. Histopathological examinations revealed remarkable diffuse hypertrophy of hepatocytes with ground-glass appearance, intracytoplasmic inclusion bodies and/or vacuolation in the DHP-treated groups. These findings were associated with increases in serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and γ-glutamyltranspeptidase. The number and area of glutathione S-transferase placental form positive foci, a marker of hepatocellular preneoplastic lesions in rats, significantly increased in DHP-treated groups. Additionally, proliferating cell nuclear antigen positive liver cell counts in DHP-treated groups were significantly higher than those of the controls. Testicular alterations were not detected histopathologically, whereas absolute and relative prostate weights significantly decreased at both doses. These results indicate that DHP induces liver pre-neoplastic foci, and suggest the possibility that DHP is a possible genotoxic carcinogen in the liver of rats. [ABSTRACT FROM AUTHOR]

Abstract: Activation of peroxisome proliferator-activated receptor (PPAR) subtypes offers a promising strategy for the treatment of diabetes mellitus and metabolic diseases. Selective and dual PPAR agonists have been developed and the systematic characterization of their structure–activity relationships (SAR) is of major significance. Herein, we report a systematic description of the SAR of 168 compounds screened against the three PPAR subtypes using the principles of activity landscape modeling. As part of our effort to develop and apply chemoinformatic tools to navigate through activity landscapes, we employed consensus dual-activity difference maps recently reported. The analysis is based on pairwise relationships of potency difference and structure-similarity which were calculated from the combination of four different 2D and 3D structure representations. Dual-activity difference maps uncovered regions in the landscape with similar SAR for two or three receptor subtypes as well as regions with inverse SAR, that is, changes in structure that increase activity for one subtype but decrease activity for the other subtype. Analysis of pairs of compounds with high structure similarity revealed the presence of single-, dual-, and ‘pan-receptor’ activity cliffs, that is, small changes in structure with high changes in potency for one, two, or three receptor subtypes, respectively. Single-, dual-, and pan-receptor scaffold hops are also discussed. The analysis of the chemical structures of selected data points reported in this paper points to specific structural features that are helpful for the design of new PPAR agonists. The approach presented in this work is general and can be extended to analyze larger data sets. [Copyright &y& Elsevier]

Abstract: Background: Aleglitazar is a dual peroxisome proliferator-activated receptor (PPAR)-α/γ agonist with a balanced activity (similar half-maximal effective concentrations) toward PPAR-α and -γ that is in clinical development for the treatment of patients who have experienced an acute coronary syndrome and have type 2 diabetes mellitus. Objective: This study aimed to characterize the metabolic profile and the routes and rates of elimination of aleglitazar and its major metabolites in humans. Methods: In this Phase I, nonrandomized, open-label, single-center, single-dose study, 6 healthy male subjects each received a single oral dose of 300 μg [14C]-labeled aleglitazar. Total urine and feces were collected for up to 15 days. Venous blood samples were collected to determine the plasma concentrations of aleglitazar and its metabolites and for radioactivity counting. Results: The median age (range) and mean (SD) body mass index of subjects were 48 (41–60) years and 24.8 (3.0) kg/m2, respectively. Recovery of total radioactivity, as a percentage of the dose administered, was high (93 [3]%). Aleglitazar was predominantly eliminated in feces (mean, 66% [range, 55%–74%]), with only 28% (range, 22%–36%) of the radioactivity recovered in urine. Only a mean (SD) of 1.8 (0.8)% of aleglitazar was eliminated unchanged as parent compound in feces and only 0.3 (0.4)% was eliminated in urine. Almost all excreted drug-related material could be attributed to its 2 main metabolites, M1 (21%) and M6 (38%). Treatment with aleglitazar was well tolerated, and no serious adverse events were reported. Conclusions: In healthy volunteers, aleglitazar was excreted mainly in the form of inactive metabolites, mostly M1 and M6, with only a small proportion eliminated unchanged. [Copyright &y& Elsevier]

Background: Phyto-remedies for diabetic control are popular among patients with Type II Diabetes mellitus (DM), in addition to other diabetic control measures. A number of plant species are known to possess diabetic control properties. Costus pictus D. Don is popularly known as "Insulin Plant" in Southern India whose leaves have been reported to increase insulin pools in blood plasma. Next Generation Sequencing is employed as a powerful tool for identifying molecular signatures in the transcriptome related to physiological functions of plant tissues. We sequenced the leaf transcriptome of C. pictus using Illumina reversible dye terminator sequencing technology and used combination of bioinformatics tools for identifying transcripts related to anti-diabetic properties of C. pictus. Results: A total of 55,006 transcripts were identified, of which 69.15% transcripts could be annotated. We identified transcripts related to pathways of bixin biosynthesis and geraniol and geranial biosynthesis as major transcripts from the class of isoprenoid secondary metabolites and validated the presence of putative norbixin methyltransferase, a precursor of Bixin. The transcripts encoding these terpenoids are known to be Peroxisome Proliferator-Activated Receptor (PPAR) agonists and anti-glycation agents. Sequential extraction and High Performance Liquid Chromatography (HPLC) confirmed the presence of bixin in C. pictus methanolic extracts. Another significant transcript identified in relation to anti-diabetic, anti-obesity and immuno-modulation is of Abscisic Acid biosynthetic pathway. We also report many other transcripts for the biosynthesis of antitumor, anti-oxidant and antimicrobial metabolites of C. pictus leaves. Conclusion: Solid molecular signatures (transcripts related to bixin, abscisic acid, and geranial and geraniol biosynthesis) for the anti-diabetic properties of C. pictus leaves and vital clues related to the other phytochemical functions like antitumor, anti-oxidant, immuno-modulatory, anti-microbial and anti-malarial properties through the secondary metabolite pathway annotations are reported. The data provided will be of immense help to researchers working in the treatment of DM using herbal therapies. [ABSTRACT FROM AUTHOR]

Abstract: Introduction of an alkylcarboxylic acid unit, which is a partial structure of endogenous peroxisome proliferator-activated receptor (PPAR) ligands, into a phenethylphenylphthalimide skeleton, which possesses liver X receptor (LXR) antagonistic activity, afforded novel PPAR ligands. The results of structure–activity relationship analysis and docking studies led us to the potent PPAR agonists 13c–e. The absolute configuration of 13c–e affects the PPAR subtype selectivity. [Copyright &y& Elsevier]

Abstract: A novel series of oxime containing benzyl-1,3-dioxane-r-2-carboxylic acid derivatives (6a–k) were designed as selective PPARα agonists, through bioisosteric modification in the lipophilic tail region of PPARα/γ dual agonist. Some of the test compounds (6a, 6b, 6c and 6f) showed high selectivity towards PPARα over PPARγ in vitro. Further, highly potent and selective PPARα agonist 6c exhibited significant antihyperglycemic and antihyperlipidemic activity in vivo, along with its improved pharmacokinetic profile. Favorable in-silico interaction of 6c with PPARα binding pocket correlate its in vitro selectivity profile toward PPARα over PPARγ. Together, these results confirm discovery of novel series of oxime based selective PPARα agonists for the safe and effective treatment of various metabolic disorders. [ABSTRACT FROM AUTHOR]

Abstract: A novel series of thaizole and oxazole containing phenoxy acetic acid derivatives is reported as PPAR-pan agonists. Incorporation of structurally constrained oxime–ether based linker in the chemotype of a potent PPARδ selective agonist GW-501516 was adapted as designing strategy. In vitro, selected test compounds 12a, 12c, 17a and 18a showed PPAR-pan agonists activities and among these four compounds tested, 12a emerged as highly potent and efficacious compound, while 17a exhibited moderate and balanced PPAR-pan agonistic activity. In vivo, selected test compounds 12a and 17a exhibited significant anti-hyperglycemic and anti-hyperlipidemic activities in relevant animal models. These results support our hypothesis that the introduction of structurally constrained oxime–ether linker between lipophilic tail and acidic head plays an important role in modulating subtype selectivity and subsequently led to the discovery of potent PPAR-pan agonists. [ABSTRACT FROM AUTHOR]

Abstract: To elucidate the molecular basis of peroxisome proliferator-activated receptor (PPAR) δ partial agonism, X-ray crystal structures of complexes of the PPARδ ligand-binding site with partial agonists are required. Unfortunately, reported PPARδ partial agonists, biphenylcarboxylic acids 1 and 2, possess insufficient aqueous solubility to allow such crystals to be obtained. To improve the aqueous solubility of 1 and 2, substituents were introduced at the 2-position of the biaryl moiety, focusing on disruption of molecular planarity and symmetry. All 2-substituted biphenyl analogs examined showed more potent PPARδ agonistic activity with greater aqueous solubility than 1 or 2. Among these biphenyls, 25 showed potent and selective PPARδ partial agonistic activity (EC50: 5.7nM), with adequate solubility in phosphate buffer (0.022mg/mL). The 2-substituted pyridyl analog 27 showed weaker PPARδ partial agonistic activity (EC50: 76nM) with excellent solubility in phosphate buffer (2.7mg/mL; at least 2700 times more soluble than 2). Our results indicate that two strategies to improve aqueous solubility, that is, introduction of substituent(s) to modify the dihedral angle and to disrupt molecular symmetry, may be generally applicable to bicyclic molecules. Combination of these approaches with the traditional approach of reducing the molecular hydrophobicity may be particularly effective. [ABSTRACT FROM AUTHOR]

Atherosclerosis regression has been demonstrated clearly in animal experimental models and, to a lesser extent, in human clinical studies. Imaging techniques for study of the arterial wall are playing a key role in promoting our appreciation of regression. LDL lowering remains the mainstay of current lipid treatment, but given the multiple antiatherosclerotic functions of HDL, including reverse cholesterol transport, agents that target HDL may represent the next generation of treatment for atherosclerotic disease. Currently available agents, including nicotinic acid, have documented antiatherosclerotic effects and trials examining clinical outcomes in the context of contemporary LDL treatment are now underway. Future approaches to HDL treatment may include cholesteryl ester transfer protein inhibitors and apolipoprotein A-I mimetics. INSET: Key issues. [ABSTRACT FROM AUTHOR]

The carcinogenic potential of naveglitazar, a γ-dominant peroxisome proliferator-activated receptor (PPAR) α/γ dual agonist, was evaluated in a two-year study in F344 rats (0, 0.3, 1.0, or 3.0 mg/kg, males; 0, 0.1, 0.3, or 1.0 mg/kg, females). Increased mortality in male rats of the high-dose group was related to cardiac-associated lesions, neoplasms, and undetermined causes. Degeneration and hypertrophy of the myocardium occurred with dose-responsive increased incidence and severity. Neoplasms with increased incidence included sarcomas in male rats and urinary bladder neoplasms in female rats. Most sarcomas in male rats occurred in the adipose tissue of the subcutis and were diagnosed as fibrosarcomas, with fewer liposarcomas and other histologic types. Non-neoplastic changes in adipose tissue included expansion of adipose tissue in multiple sites, alterations in cytoplasmic vesicular pattern in brown and white fat, increases in stroma and mesenchymal cells, and fibrosis. The severity of chronic progressive nephropathy was decreased in a dose-responsive manner in males, and hyperplasia and neoplasia of the mammary gland were decreased in incidence in females. The adverse effects of cardiotoxicity and increased incidence of neoplasms occurred with dose-responsive incidence and/or severity, and a no-effect level for these effects was not achieved in this study. [ABSTRACT FROM PUBLISHER]

Muraglitazar is a dual (α/γ) PPAR activator. Dual receptor activation may improve glycaemic and lipid profiles in patients with type 2 diabetes mellitus.This randomised double-blind trial in 1,477 drug-naive patients with type 2 diabetes compared the efficacy and safety of muraglitazar (0.5, 1.5, 5, 10, and 20 mg) with pioglitazone (15 mg). Endpoints included changes in HbA1C and plasma lipids, last observation carried forward over 24 weeks. At week 24, mean changes from baseline in HbA1C ranged from —0.25% to —1.76% with muraglitazar (p≤0.0008, 0.5 mg versus each higher muraglitazar dose), compared with —0.57% with pioglitazone. At week 12, tri-glycerides decreased 4—41% with muraglitazar and 9% with pioglitazone. High-density lipoprotein cholesterol increased 6—23% with muraglitazar and 10% with pioglitazone. Oedema-related events occurred with muraglitazar in a dose-dependent incidence (range 9—40%), and at 14% with pioglitazone. Overall, muraglitazar produced simultaneous dose-dependent improvements in glycaemic and lipid parameters in drug-naive patients with type 2 diabetes mellitus. [ABSTRACT FROM PUBLISHER]

In this trial we evaluated the efficacy and safety of muraglitazar, a dual (α/γ) peroxisome proliferator-activated receptor activator, plus glyburide in patients with type 2 diabetes not controlled with sulphonylurea monotherapy. After 2 weeks of open-label glyburide (15 mg/day), 583 patients were randomised to additionally receive muraglitazar 2.5 mg, 5 mg, or placebo. End points included changes in HbA1C and fasting plasma glucose (FPG) at weeks 24 and 102, and changes in lipid parameters at weeks 11/12 and 102.At week 24, mean changes from baseline in HbA1C and FPG were significantly greater with glyburide plus muraglitazar 2.5 mg or 5 mg than with glyburide plus placebo (p<0.0001). At week 11/12, triglyceride levels were significantly reduced with muraglitazar (p<0.0001). During the extension phase, muraglitazar demonstrated long-term glycaemic and lipid effects through week 102. Although generally well tolerated, muraglitazar was associated with higher rates of congestive heart failure, cardiovascular events, weight gain and oedema. [ABSTRACT FROM PUBLISHER]

Six-week-old rasH2 mice were injected intraperitoneally with N-diethylnitrosamine (DEN) after partial hepatectomy and administrated 0 or 6,000 ppm troglitazone (TRG) for 10 weeks. Relative liver weight of females increased significantly in the DEN + TRG group compared to the DEN-alone group. The numbers of γ-glutamyltranspeptidase- and proliferating cell nuclear antigen (PCNA)-positive cells tended to increase in both the sexes in the DEN + TRG group; however, these changes were not significantly different from those in the DEN-alone group. Levels of gene expressions for vascular endothelial growth factor (VEGF) and VEGFB (related to angiogenesis), tropomyosin 1 (Tpm1) and transforming growth factor-β (related to ras/MAPK cascade activation), and PCNA (related to cell proliferation) in females were significantly higher in the DEN + TRG than in the untreated control group but not in the DEN-alone group. Only Tpm1 gene had significantly higher expression in the DEN + TRG group than in the DEN-alone group. These results suggest that rasH2 mice are not susceptible to TRG in a two-stage hepatocarcinogenesis model. [ABSTRACT FROM AUTHOR]

Diabetes is a complex disorder characterized by impaired insulin formation, release or action (insulin resistance), elevated blood glucose, and multiple long-term complications. It is a common endocrine disorder of humans and is associated with abnormalities of carbohydrate and lipid metabolism. There are two forms of diabetes, classified as type 1 and type 2. In type 1 diabetes, hyperglycemia is due to an absolute lack of insulin, whereas in type 2 diabetes, hyperglycemia is due to a relative lack of insulin and insulin resistance. More than 90% of people with diabetes have type 2 with varied degrees of insulin resistance. Insulin resistance is often associated with impaired insulin secretion, and hyperglycemia is a common feature in both types of diabetes, but failure to make a distinction between the types of diabetes in different animal models has led to confusion in the literature. This is particularly true in relation to cardiovascular disease in the presence of diabetes and especially the response to vascular injury, in which there are major differences between the two types of diabetes. Animal models do not completely mimic the clinical disease seen in humans. Animal models are at best analogies of the pathologic process they are designed to represent. The focus of this review is an analysis of intimal hyperplasia following catheter-induced vascular injury, including factors that may complicate comparisons between different animal models or between in vitro and in vivo studies. We examine the variables, pitfalls, and caveats that follow from the manner of induction of the injury and the diabetic state of the animal. The efficacy of selected antidiabetic drugs in inhibiting the development of the hyperplastic response is also discussed. Le diabète est un trouble complexe caractérisé par une défaillance de la formation, de la libération ou de l’action (insulinorésistance) de l’insuline, par une augmentation du glucose sanguin et par le développement de multiples complications à long terme. C’est un trouble endocrinien courant chez les humains, qui est associé à des perturbations du métabolisme des lipides et des glucides. Il existe deux formes de diabète, le type 1 et le type 2; dans le diabète de type 1, l’hyperglycémie est due à un manque absolu d’insuline, alors que dans le type 2, l’hyperglycémie est due à un manque relatif d’insuline et à une insulinorésistance. L’insulinorésistance est souvent associée à une altération de la sécrétion d’insuline. L’hyperglycémie est une caractéristique commune aux deux types de diabète et l’incapacité à faire la distinction entre les types de diabète dans différents modèles animaux a été une source de confusion dans la littérature. Cela est particulièrement vrai dans le cas de la maladie cardiaque en présence de diabète, et encore plus dans les études sur la réponse à une lésion vasculaire, où il y a des différences majeures entre les deux types de diabète. Les modèles animaux ne miment pas exactement la maladie clinique observée chez l’humain. Il présentent au mieux des analogies avec les processus pathologiques qu’ils sont censés représenter. Cet article se concentre sur l’analyse de l’hyperplasie de l’intima après une lésion vasculaire induite par cathéter, ainsi que sur les variables, les lacunes, et les mises en garde, selon l’induction de la lésion et de l’état diabétique de l’animal, qui pourraient compliquer les comparaisons entre les modèles animaux et les comparaisons entre les études in vitro et in vivo. L’efficacité d’antidiabétiques choisis pour inhiber le développement de la réponse hyperplasique est aussi discutée. [ABSTRACT FROM AUTHOR]

Abstract: A series of novel 1,3-dioxane-2-carboxylic acid derivatives containing alkyl chain tether and substituted phenyl group as a lipophilic tail have been prepared as agonists of PPARα and γ. c-5-[6-(4-Methanesulfonyloxyphenyl)hexyl]-2-methyl-1,3-dioxane-r-2-carboxylic acid 13c exhibited potent hypoglycemic and lipid lowering activity with high oral bioavailability in animal models. [Copyright &y& Elsevier]

To examine the tumor-promoting effect of troglitazone (TRG), a novel thiazolidinedione insulin-sensitizing agent, on splenic hemangiosarcomas in rasH2 mice, histopathological and molecular analyses were performed in the spleen of female rasH2 mice fed a diet containing 6,000 or 0 ppm TRG for 16 weeks after 1,000 or 0 mg/kg urethane (UR) initiation. Histopathologically, splenic hemangiosarcomas were observed in the UR-alone and UR + TRG groups, but there was no significant difference in the incidence of splenic hemangiosarcomas between the UR-alone and UR+TRG groups. There were increasing tendencies in the number of positive cells for anti-PCNA antibody and gene expression in the UR + TRG group, but such a change was not statistically significant as compared to that in the UR-alone group. The gene expressions of VEGF, VEGFR1, VEGFC, VEGFR2 and Tie2 related to angiogenesis; c- fos related to MAPK cascade activation; and cyclin D1 related to cell cycle in the UR-alone and UR + TRG groups were significantly higher than those in the untreated control group. However, only the Tie2 gene in the UR + TRG group was significantly increased as compared to that in the UR-alone group. These results suggest that the vascular tumor-promoting activity of TRG in rasH2 mice is extremely low in the present experimental condition and a part of the gene related to angiogenesis probably contributes to the promotion of splenic hemangiosarcomas in rasH2 mice given TRG. [ABSTRACT FROM AUTHOR]

Abstract: A few novel 1,3-dioxane carboxylic acid derivatives were designed and synthesized to aid in the characterization of PPAR α/γ dual agonists. Structural requirements for PPARα/γ dual agonism of 1,3-dioxane carboxylic acid derivatives included the structural similarity with potent glitazones in fibric acid chemotype. The compounds with this pharmacophore and substituted oxazole as a lipophilic heterocyclic tail were synthesized and evaluated for their in vitro PPAR agonistic potential and in vivo hypoglycemic and hypolipidemic efficacy in animal models. Lead compound 2-methyl-c-5-[4-(5-methyl-2-(4-methylphenyl)-oxazol-4-ylmethoxy)-benzyl]-1,3-dioxane-r-2-carboxylic acid 13b exhibited potent hypoglycemic, hypolipidemic and insulin sensitizing effects in db/db mice and Zucker fa/fa rats. [Copyright &y& Elsevier]

Naveglitazar, a -dominant peroxisome proliferator-activated receptor (PPAR) α/ dual agonist, was tested for carcinogenicity in F344 rats in a 2-year study. Changes in urine composition and urothelial morphology were characterized in a companion 18-month investigative study. A significant increase in neoplasms of the bladder occurred only in females of the high-dose group (14/60) in the carcinogenicity study. Trends toward increased cell proliferation in the urothelium were noted in both sexes at all time points evaluated in the 18-month study. Group means for urothelial mitogen-esis were increased statistically significantly only in high-dose females at 12 and 18 months. Urothelial hyperplasia occurred in high-dose females at 18 months. Morphologic changes in the urothelium at earlier time points were limited to hypertrophy and decreased immunolabeling of the superficial cells for cytokeratin 20 (a marker of terminal differentiation in urothelial cells) in both males and females. No treatment-related changes in urinary parameters, including urinary sediments, were associated with the occurrence of urothelial proliferation. Urinary pH was unaffected by treatment in both males and females, but expected diurnal changes were demonstrated. Collectively, these data indicate that naveglitazar was associated with hypertrophic and proliferative effects on the urothelium, but a link with changes in urinary parameters was not demonstrated. [ABSTRACT FROM PUBLISHER]

To evaluate the carcinogenicity of troglitazone in rasH2 mice, 7-week-old male and female rasH2 mice were fed a diet containing 0, 3,000 or 6,000 ppm troglitazone for 26 weeks. An increased tendency in the incidence of vascular tumors was observed in females of the 6,000 ppm group. The preliminary analysis using a high-density oligonucleotide microarray on a splenic hemangiosarcoma of a high dose female that could be obtained as a fresh sample showed that several genes related to the ras/MAPK pathway activation, angiogenesis, cell cycle and cell multiplication were up-regulated. In addition, most of the genes up-regulated were confirmed by the reverse transcriptase-polymerase chain reaction (RT-PCR). These results may suggest that the carcinogenic susceptibility of rasH2 mice to troglitazone is relatively low and up-regulations of the ras/MAPK pathway and angiogenesis-related genes are probably involved in the production of splenic hemangiosarcomas in rasH2 mice given troglitazone. [ABSTRACT FROM AUTHOR]

Abstract: The role of PPARs in the regulation of human adipose tissue secretome has received little attention despite its potential importance in the therapeutic actions of PPAR agonists. Here, we have investigated the effect of selective PPARγ, PPARα, and PPARβ/δ agonists on the production of adipokines by human subcutaneous adipose tissue. Antibody arrays were used to measure secreted factors in media from cultured adipose tissue explants. Sixteen proteins were produced in significant amounts. Activation of PPARs regulated the production of five proteins. Treatments with the three PPAR agonists decreased the secretion of leptin and interleukin-6. PPARα and β/δ agonists markedly enhanced hepatocyte growth factor secretion whereas PPARβ/δ down-regulated angiogenin and up-regulated TIMP-1 release. Hepatocyte growth factor, interleukin-6, and TIMP-1 are chiefly expressed in cells from the stromal vascular fraction whereas angiogenin is expressed in both adipocytes and cells from the stromal vascular fraction. Our data show that PPAR agonists modulate secretion of bioactive molecules from the different cell types composing human adipose tissue. [Copyright &y& Elsevier]

Abstract: Modulation of PPAR activities represents an attractive approach for the treatment of diabetes with associated cardiovascular complications. The indanylacetic acid structural motif has proven useful in the generation of potent and tunable PPAR ligands. Modification of the substituents on the linker and the heterocycle tail group allowed for the modulation of the selectivity at the different receptor subtypes. Compound 33 was evaluated in vivo, where it displayed the desired reduction of glucose levels and increase in HDL levels in various animal models. [Copyright &y& Elsevier]

Abstract: A series of PPARδ-selective agonists was investigated and optimized for a favorable in vivo pharmacokinetic profile. Isoxazole LCI765 (17d) was found to be a potent and selective PPARδ agonist with good in vivo PK properties in mouse (C max =5.1μM, t 1/2 =3.1h). LCI765 regulated expression of genes involved in energy homeostasis in relevant tissues when dosed orally in C57BL6 mice. A co-crystal structure of compound LCI765 and the LBD of PPARδ is discussed. [Copyright &y& Elsevier]

Presents several studies about antihypertensive drugs and pharmacology. "Fixed-Dose Combination Improves Medication Compliance: A Meta-Analysis," by Sripal Bangalore et al; "Clinical Management of Essential Hypertensive Patients Treated With Lercanidipine or Other Dyhidropyiridines: The Tolerance Study," by V. Barrios et al; "Blood Pressure Control Rates With Lercanidipine and Other Dyhidropyridines at High Doses: The Tolerance Study," by J. Honorato et al.

Abstract: Arylsulfamoyl imidazolium triflates, readily prepared from the corresponding chlorides, react with amines under neutral conditions to form arylsulfamides in high yields. This methodology, which contrasts with the slow and inefficient reactions of amines with arylsulfamoyl chlorides, is applied to the synthesis of arylsulfamide 3a , a bioisotere of muraglitazar. [Copyright &y& Elsevier]

Abstract Background:: Peroxisome proliferator-activated receptors (PPARs) present a therapeutic target, and simultaneous activation of PPAR-α and PPAR-γ may provide improvements in glycemic control and dyslipidemia in patients with type 2 diabetes. Objective:: The goal of this study was to evaluate the efficacy and safety of muraglitazar, a dual (α/γ) PPAR activator, in adult patients with type 2 diabetes whose disease was inadequately controlled by diet and exercise. Methods:: This was a randomized, double-blind, placebo-controlled, parallel-group, multicenter, 24-week monotherapy study in drug-naive, type 2 diabetes patients with inadequate glycemic control. Men and women aged 18 to 70 years with a body mass index ≤41 kg/m2 and serum triglyceride levels ≤600 mg/dL were eligible for study participation. The study included double-blind and open-label treatment phases. Patients with glycosylated hemoglobin (HbA1c) levels ≥7.0% and ≤10.0% at screening were enrolled in the double-blind treatment phase. These patients received treatment with muraglitazar 2.5 mg, muraglitazar 5 mg, or placebo. Patients with HbA1c levels >10.0% and ≤12.0% who met all other study criteria were eligible for enrollment in a 24-week, open-label evaluation of muraglitazar 5 mg. The primary end point was the mean change from baseline in HbA1c levels after 24 weeks of treatment. Results:: A total of 340 patients (179 men, 161 women) participated in the double-blind treatment phase of the study. Patients had mean baseline HbA1c levels of 7.9% to 8.0%. Monotherapy with muraglitazar 2.5 and 5 mg significantly reduced HbA1c levels (−1.05% and −1.23%, respectively) compared with placebo (−0.32%; P < 0.001). At week 24, 58%, 72%, and 30% of the patients receiving muraglitazar 2.5 mg, muraglitazar 5 mg, and placebo, respectively, achieved the American Diabetes Association-recommended HbA1c goal of <7.0%. Fasting plasma glucose, free fatty acids, and fasting plasma insulin levels significantly decreased during muraglitazar treatment (P < 0.001), suggesting an increase in insulin sensitivity. Muraglitazar 2.5 and 5 mg provided improvements from baseline in triglyceride (−18% and −27%), high-density lipoprotein (HDL) cholesterol (10% and 16%), apolipoprotein B (−7% and −12%), and non-HDL cholesterol levels (−3% and −5%) (P < 0.05 vs placebo for each). In a parallel, open-label cohort of 109 drug-naive patients (56 men, 53 women; mean baseline HbA1c level, 10.6%), muraglitazar 5 mg decreased the overall mean HbA1c level from baseline by 2.62% (last observation carried forward) and by 3.49% in the 62 patients completing 24 weeks of study. Changes in lipid parameters during open-label treatment were similar to those observed during double-blind treatment. Muraglitazar was generally well tolerated. Edema-related adverse events of mild to moderate severity occurred in 8% to 11% of patients in all groups. Mean changes from baseline weight in the double-blind treatment groups were 1.1 kg for muraglitazar 2.5 mg, 2.1 kg for muraglitazar 5 mg, and −0.8 kg for placebo (P < 0.001); there was a mean 2.9-kg increase in the open-label muraglitazar 5-mg group. Conclusion:: In this study, 24 weeks of treatment with muraglitazar 2.5 or 5 mg was an effective treatment option for these patients with type 2 diabetes whose disease was inadequately controlled with diet and exercise. [Copyright &y& Elsevier]

Summary: Background and aim: There are only little data about the effects of lipid-lowering drugs (LLDs) on the metabolism of essential n-6 and n-3 fatty acids in patients with established coronary heart disease (CHD). Methods and results: Male patients with CHD and high cholesterol levels (>6.2mmol/L) were randomized (double-blind protocol) to receive either simvastatin 20mg (S) or fenofibrate 200mg daily (F) for 3 months. Dietary habits and plasma fatty acids were not different in the two groups at baseline. After treatment, there were significant changes in both the groups for the main n-6 fatty acids, with an increase in arachidonate (from 6.5±1.7% of total fatty acids to 7.5±2.1, p &#60;0.001 in S and from 6.2±1.4 to 6.8±1.4, p &#60;0.005 in F) and a decrease in linoleate (from 26.9±3.9 to 24.2±3.6, p &#60;0.001, and from 27.8±3.4 to 26.1±4.2, p &#60;0.05, in S and F, respectively). In addition, there was a decrease in two major n-3 fatty acids (alpha-linolenate and docosahexanoate, both p &#60;0.05), but only in F. Conclusions: For the first time in a double-blind randomized study in CHD patients, we report that LLDs significantly alter the metabolism of essential fatty acids that are critically important for the pathogenesis and prevention of CHD. Further studies are urgently needed to examine the effects of higher dosages of statins (as currently proposed to reduce more cholesterol) on these essential fatty acids in the clinical setting and the crucial questions of whether specific dietary intervention (combining low intake of n-6 fatty acids and high intake of n-3 fatty acids) may improve the effectiveness of these drugs. [Copyright &y& Elsevier]

Cardiovascular disease (CVD) remains the leading cause of mortality in developed countries. Several risk factors are associated with CVD, including type 2 diabetes, obesity, insulin resistance, dyslipidaemia and hypertension. Different pharmacological therapies have been developed to control these risk factors. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors, which belong to the nuclear receptor superfamily that controls lipid and glucose metabolism as well as inflammatory risk factors for CVD. PPARα agonists, such as the fibrates, correct dyslipidaemia, thus decreasing CVD risk. PPARγ agonists, such as the glitazones, increase insulin sensitivity and decrease plasma glucose levels in patients with diabetes. Moreover, both PPARα and PPARγ agonists exert anti-inflammatory activities in liver, adipose and vascular tissues. In this review, we focus on the mode of action of PPARα and PPARγ agonists, illustrating the potential of the newly developed dual PPAR agonists for the treatment of global risk in patients with the metabolic syndrome or type 2 diabetes. [ABSTRACT FROM AUTHOR]