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Development of new, safe, and effective microbicides to prevent human immunodeficiency virus HIV sexual transmission is needed. Unfortunately, most microbicides proved ineffective to prevent the risk of HIV-infection in clinical trials. We are working with G2-S16 polyanionic carbosilane dendrimer (PCD) as a new possible vaginal topical microbicide, based on its short reaction times, wide availability, high reproducibility, and quantitative yields of reaction. G2-S16 PCD exerts anti-HIV activity at an early stage of viral replication, by blocking gp120/CD4/CCR5 interaction, and providing a barrier against infection for long periods of time. G2-S16 PCD was stable at different pH values, as well as in the presence of seminal fluids. It maintained the anti-HIV activity against R5/X4 HIV over time, did not generate any type of drug resistance, and retained the anti-HIV effect when exposed to semen-enhanced viral infection. Importantly, G2-S16 PCD did not modify vaginal microbiota neither in vitro or in vivo. Histopathological examination did not show vaginal irritation, inflammation, lesions, or damage in the vaginal mucosa, after administration of G2-S16 PCD at different concentrations and times in female mice and rabbit animal models. Based on these promising data, G2-S16 PCD could become a good, safe, and readily available candidate to use as a topical vaginal microbicide against HIV.

Anionic carbosilane dendrimers such as G2-S16 are very effective in preventing HSV-2 infection both in vitro and in vivo. We present the main achievements obtained for the G2-S16 dendrimer in vivo, especially related to its efficacy against HSV-2 infection. Moreover, we discuss the mechanisms by which the G2-S16 dendrimer applied vaginally as a topical microbicide has been demonstrated to be safe and harmless for the vaginal microbiome balance, as both conditions present an essential step that has to be overcome during microbicide development. This review points to the marked protective effect of the G2-S16 dendrimer against sexually transmitted HSV-2 infection, supporting its role as a possible microbicide against HSV-2 infection., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

In this work, we investigate the potential of highly sulfated synthetic glycomimetics to act as inhibitors of viral binding/infection. Our results indicate that both long-chain glycopolymers and short-chain glycooligomers are capable of preventing viral infection. Notably, glycopolymers efficiently inhibit Human Papillomavirus (HPV16) infection in vitro and maintain their antiviral activity in vivo, while the glycooligomers exert their inhibitory function post attachment of viruses to cells. Moreover, when we tested the potential for broader activity against several other human pathogenic viruses, we observed broad-spectrum antiviral activity of these compounds beyond our initial assumptions. While the compounds tested displayed a range of antiviral efficacies, viruses with rather diverse glycan specificities such as Herpes Simplex Virus (HSV), Influenza A Virus (IAV), and Merkel Cell Polyomavirus (MCPyV) could be targeted. This opens new opportunities to develop broadly active glycomimetic inhibitors of viral entry and infection.

The excessive production of inflammatory mediators by inflammatory cells contributes to the pathogenesis of rheumatoid arthritis. Tenascin-C (TN-C) is expressed in rheumatoid joint, and is associated with levels of inflammatory mediators. FC-99 (N1-[(4-methoxy)methyl]-4-methyl-1,2-Benzenediamine), a novel 1,2-benzenediamine derivative, was previously reported to block the prolonged expression of key rheumatoid arthritis inflammatory cytokines and relieve zymosan-induced joint inflammation. However, the specific mechanism is unknown. This study aimed to examine the effects of FC-99 on TN-C expression and inflammation and investigate its possible molecular mechanism. The results showed that FC-99 treatment reduced the high expression of TN-C in ankle joints of arthritis mice. Besides, FC-99 reduced the increased number of macrophages in arthritis mice, while did not change the number of synovioblasts. Concomitantly, expression of TN-C in synovial fibroblasts exhibited no difference between control and ZIA groups, and was not apparently altered following FC-99 treatment, while FC-99 decreased TN-C expression in macrophages both in vivo and in vitro. Meanwhile, TargetScan and luciferase assays indicated that TN-C was negatively regulated by miR-494. Transfection assay further demonstrated that FC-99 inhibited TN-C by targeting miR-494. Furthermore, the reduction of miR-494 mimic on expression of TN-C was associated with NF-κB pathway. Similarly, the down-regulation of FC-99 on TN-C was considerably decreased when NF-κB pathway was inhibited. These results indicated that FC-99 relieved macrophages inflammation via the miR-494/TN-C/NF-κB pathway, finally leading to the relief of inflammation in arthritis. The findings suggested that FC-99 might be a potential therapeutic candidate for the treatment of rheumatoid arthritis., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Dendritic cells (DCs) play an important role in the development and maintenance of immune tolerance. Activation of TLR7, which is expressed in DCs, is thought to contribute to the complex pathophysiology of systemic lupus erythematosus (SLE). In this study, we analyzed the in vitro and in vivo function of a novel small-molecule compound, FC-99, which was previously reported to have immunomodulatory functions. We found that FC-99 inhibited the expression of CD40 and inflammatory mediators (IL-6, IL-12, and CXCL-10), as well as R848-induced phosphorylation of IκB-α. We also present evidence that FC-99 is remarkably efficacious in the treatment of murine lupus. Interestingly, FC-99 affected the maturation and percentage of DCs in lupus-prone mice. Therefore, FC-99 may serve as a potential drug candidate for treatment of SLE., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: In the accompanying article, we showed that activation of peroxisome proliferator-activated receptor alpha (PPARα) signaling by fenofibrate and tesaglitazar decreases ethanol (EtOH) consumption in mice. In this study, we determined the role of these PPAR agonists in EtOH-related behaviors and other actions that may be important in regulating EtOH consumption., Methods: The effects of fenofibrate (150 mg/kg) and tesaglitazar (1.5 mg/kg) were examined on the following responses in male and female C57BL/6J (B6) and B6 × 129S4 mice: preference for saccharin, EtOH-induced conditioned place preference (CPP), conditioned taste aversion (CTA), loss of righting reflex, and withdrawal, acoustic startle reflex, response to novelty, and EtOH clearance. Because the B6 inbred strain usually displays weak EtOH-induced CPP and weak EtOH-induced acute withdrawal, B6 × 129S4 mice were also studied., Results: Fenofibrate and tesaglitazar decreased the novelty response and increased acute EtOH withdrawal severity, and fenofibrate increased EtOH-induced CTA. Two important factors for EtOH consumption (saccharin preference and EtOH-induced CPP) were not altered by fenofibrate or tesaglitazar. EtOH clearance was increased by both fenofibrate and tesaglitazar. Response to novelty, acute withdrawal, and EtOH clearance show sex differences and could contribute to the reduced EtOH consumption following fenofibrate administration., Conclusions: These studies indicate the complexity of EtOH-dependent and EtOH-independent behaviors that are altered by PPAR agonists and provide evidence for novel behavioral actions of these drugs that may contribute to PPAR-mediated effects on alcohol drinking., (Copyright © 2016 by the Research Society on Alcoholism.)

Background: Several peroxisome proliferator-activated receptor (PPAR) agonists reduce voluntary alcohol consumption in rodent models, and evidence suggests that PPARα and γ subunits play an important role in this effect. To define the subunit dependence of this action, we tested selective PPARα and α/γ agonists and antagonists in addition to null mutant mice lacking PPARα., Methods: The effects of fenofibrate (PPARα agonist) and tesaglitazar (PPARα/γ agonist) on continuous and intermittent 2-bottle choice drinking tests were examined in male and female wild-type mice and in male mice lacking PPARα. We compared the ability of MK886 (PPARα antagonist) and GW9662 (PPARγ antagonist) to inhibit the effects of fenofibrate and tesaglitazar in wild-type mice. The estrogen receptor antagonist, tamoxifen, can inhibit PPARγ-dependent transcription and was also studied in male and female mice., Results: Fenofibrate and tesaglitazar reduced ethanol (EtOH) consumption and preference in wild-type mice, but these effects were not observed in mice lacking PPARα. MK886 inhibited the action of fenofibrate, but not tesaglitazer, while GW9662 did not inhibit either agonist. The PPAR agonists were more effective in male mice compared to females, and drinking in the continuous 2-bottle choice test was more sensitive to fenofibrate and tesaglitazar compared to drinking in the intermittent access test. Tamoxifen also reduced EtOH consumption in male mice and this action was inhibited by GW9662, but not MK886, suggesting that it acts by activation of PPARγ., Conclusions: Our study using selective PPAR agonists, antagonists, and null mutant mice indicates a key role for PPARα in mediating reduced EtOH consumption by fenofibrate and tesaglitazar., (Copyright © 2016 by the Research Society on Alcoholism.)

Background: Peroxisome proliferator-activated receptor (PPAR) agonists reduce voluntary ethanol (EtOH) consumption in rat models and are promising therapeutics in the treatment for drug addictions. We studied the effects of different classes of PPAR agonists on chronic EtOH intake and preference in mice with a genetic predisposition for high alcohol consumption and then examined human genomewide association data for polymorphisms in PPAR genes in alcohol-dependent subjects., Methods: Two different behavioral tests were used to measure intake of 15% EtOH in C57BL/6J male mice: 24-hour 2-bottle choice and limited access (3-hour) 2-bottle choice, drinking in the dark. We measured the effects of pioglitazone (10 and 30 mg/kg), fenofibrate (50 and 150 mg/kg), GW0742 (10 mg/kg), tesaglitazar (1.5 mg/kg), and bezafibrate (25 and 75 mg/kg) on EtOH intake and preference. Fenofibric acid, the active metabolite of fenofibrate, was quantified in mouse plasma, liver, and brain by liquid chromatography tandem mass spectrometry. Data from a human genome-wide association study (GWAS) completed in the Collaborative Study on the Genetics of Alcoholism (COGA) were then used to analyze the association of single nucleotide polymorphisms (SNPs) in different PPAR genes (PPARA, PPARD, PPARG, and PPARGC1A) with 2 phenotypes: DSM-IV alcohol dependence (AD) and the DSM-IV criterion of withdrawal., Results: Activation of 2 isoforms of PPARs, α and γ, reduced EtOH intake and preference in the 2 different consumption tests in mice. However, a selective PPARδ agonist or a pan agonist for all 3 PPAR isoforms did not decrease EtOH consumption. Fenofibric acid, the active metabolite of the PPARα agonist fenofibrate, was detected in liver, plasma, and brain after 1 or 8 days of oral treatment. The GWAS from COGA supported an association of SNPs in PPARA and PPARG with alcohol withdrawal and PPARGC1A with AD but found no association for PPARD with either phenotype., Conclusions: We provide convergent evidence using both mouse and human data for specific PPARs in alcohol action. Reduced EtOH intake in mice and the genetic association between AD or withdrawal in humans highlight the potential for repurposing FDA-approved PPARα or PPARγ agonists for the treatment of AD., (Copyright © 2014 by the Research Society on Alcoholism.)

Background and Purpose: Sepsis is a clinical condition characterized by overwhelming systemic inflammation with high mortality rate and high prevalence, but effective treatment is still lacking. Toll-like receptor 3 (TLR3) is an endogenous sensor, thought to regulate the amplification of immune response during sepsis. Modulators of TLR3 have an advantage in the treatment of sepsis. Here, we aimed to explore the mechanism of a monosubstituted 1,2-benzenediamine derivative FC-99 {N(1) -[(4-methoxy)methyl]-4-methyl-1,2-benzenediamine}on modulating TLR3 expression and its therapeutic potential on mouse model of sepsis., Experimental Approach: Cells were pretreated with FC-99 followed by poly(I:C) or IFN-α stimulation; TLR3 and other indicators were assayed. Female C57BL/6 mice were subjected to sham or caecal ligation puncture (CLP) surgery after i.p. injection of vehicle or FC-99; serum and tissues were collected for further experiments., Key Results: FC-99 suppressed inflammatory response induced by poly(I:C) with no effect on cell viability or uptake of poly(I:C). FC-99 also inhibited TLR3 expression induced by not only poly(I:C) but also by exogenous IFN-α. This inhibition of FC-99 was related to the poly(I:C)-evoked IRF3/IFN-α/JAK/STAT1 signalling pathway. In CLP-induced model of sepsis, FC-99 administration decreased mice mortality and serum levels of inflammatory factors, attenuated multiple organ dysfunction and enhanced bacterial clearance. Accordingly, systemic and local expression of TLR3 was reduced by FC-99 in vivo., Conclusion and Implications: FC-99 reversed TLR3 expression and ameliorate CLP-induced sepsis in mice. Thus, FC-99 will be a potential therapeutic candidate for sepsis., (© 2014 The British Pharmacological Society.)

The main threat to controlling malaria is the emerging multidrug resistance of Plasmodium sp. parasites. Bis-alkylamidines were developed as a potential new chemotherapy that targets plasmodial phospholipid metabolism. Unfortunately, these compounds are not orally available. To solve this absorption issue, we investigated a prodrug strategy based on sulfonate derivatives of alkylamidoximes. A total of 25 sulfonates were synthesized as prodrug candidates of one bis-N-alkylamidine and of six N-substituted bis-C-alkylamidines. Their antimalarial activities were evaluated in vitro against P. falciparum and in vivo against P. vinckei in mice to define structure-activity relationships. Small alkyl substituents on the sulfonate group of both C-alkyl- and N-alkylamidines led to the best oral antimalarial activities; alkylsulfonate derivatives are chemically transformed into the corresponding alkylamidines., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Metabolic syndrome increases the risk of developing diabetes as well as cardiovascular and kidney diseases. This research studied the effects of tesaglitazar, a dual-acting peroxisome proliferator-activated receptor (PPAR)alpha/gamma agonist, on metabolic abnormalities and kidney injury in obese Zucker rats (OZR). Lean Zucker rats (LZR) and OZR were used as control groups. Tesaglitazar (1 micromol/kg/day) was given for 8 weeks in the treatment group (OZR-T). Metabolic parameters, 24-hour urine albumin excretion, and tail blood pressure were measured. Glomerular filtration rate by inulin clearance, abdominal fat and renal histology were determined at the end of the study. In comparison with the OZR and OZR-T groups, the LZR control animals' parameters were significantly more favorable in all measures. Tesaglitazar treatment in OZR significantly reduced nonfasting glucose, C-reactive protein levels and improved dyslipidemia. Body weight, blood pressure and urine albumin excretion were lower, but the adjusted glomerular filtration rate higher, in the OZR-T group than in the OZR controls. Glomerular area, mesangial expansion and tubulointerstitial changes were ameliorated, and the glomerular expression of desmin was markedly more decreased in the OZR-T group than in the OZR controls. Therefore, the PPAR alpha/gamma agonist tesaglitazar significantly improved metabolic abnormalities and renal function, decreased blood pressure, and protected against glomerular and interstitial damage in OZR., ((c) 2009 S. Karger AG, Basel.)

Pharmacokinetic (PK) pharmacodynamic (PD) modeling was applied to understand and quantitate the interplay between tesaglitazar (a peroxisome proliferator-activated receptor alpha/gamma agonist) exposure, fasting plasma glucose (FPG), hemoglobin (Hb), and glycosylated hemoglobin (HbA1c) in type 2 diabetic patients. Data originated from a 12-week dose-ranging study with tesaglitazar. The primary objective was to develop a mechanism-based PD model for the FPG-HbA1c relationship. The secondary objective was to investigate possible mechanisms for the tesaglitazar effect on Hb. Following initiation of tesaglitazar therapy, time to new FPG steady state was approximately 9 weeks, and tesaglitazar potency in females was twice that in males. The model included aging of red blood cells (RBCs) using a transit compartment approach. The RBC life span was estimated to 135 days. The transformation from RBC to HbA1c was modeled as an FPG-dependent process. The model indicated that the tesaglitazar effect on Hb was caused by hemodilution of RBCs.

This randomised, double-blind, parallel-group study assessed the effects of addition of the dual peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonist, tesaglitazar, for 24 weeks to the therapeutic regimen of 392 poorly controlled (glycosylated haemoglobin [HbA1C] 7.5-10%) insulin-treated, type 2 diabetes patients. At 24 weeks, tesaglitazar 0.5 mg resulted in a 0.66% (95% confidence intervals: -0.85, -0.47; p<0.0001) reduction from baseline in HbA1C, and reduced fasting plasma glucose (p<0.0001) and daily insulin dose (p=0.014) versus placebo. After 24 weeks, tesaglitazar caused greater improvements from baseline in triglycerides (p<0.0001), high-density lipoprotein cholesterol (HDL-C) (p<0.001), non-HDL-C (p<0.05), apolipoprotein (apo)A-I (p<0.05) and apoB levels (p<0.01) than placebo. Tesaglitazar was generally well tolerated but was associated with a greater increase in serum creatinine level than placebo. The clinical development of tesaglitazar is no longer continuing; its effects on the glucose and lipid abnormalities of type 2 diabetes suggest that the concept of dual PPARalpha/gamma agonism is worthy of further investigation.

This randomised, double-blind, parallel-group, multicentre study investigated the effects of the dual peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonist, tesaglitazar (0.5 and 1 mg), as add-on treatment in 568 patients with type 2 diabetes that was poorly controlled with sulphonylurea therapy titrated to the highest tolerated dose. There was a significant placebo-corrected reduction in glycosylated haemoglobin (HbA1C) from baseline to week 24 with tesaglitazar 0.5 mg and 1 mg (mean [95% confidence interval]: -0.93% [-1.09, -0.77] and -1.3% [-1.46, -1.14]; p<0.0001). Significant reductions were observed in insulin, fasting plasma glucose (FPG), triglyceride (all p<0.001) and non-high-density lipoprotein (HDL) cholesterol (p<0.001). Tesaglitazar increased levels of HDL-cholesterol (p<0.0001), adiponectin (p<0.0001) and leptin (p<0.001), but was associated with dose-dependent increases in serum creatinine and decreases in haemoglobin. This study showed improvements in glycaemic control and dyslipidaemia in patients with type 2 diabetes poorly controlled with existing sulphonylurea therapy. Although tesaglitazar has now been discontinued from clinical development, these results remain relevant to future research into PPAR agonists.

This study assessed the effects of tesaglitazar (0.5 or 1 mg/day), a dual peroxisome proliferator-activated receptor alpha/gamma agonist, when added to maximally tolerated metformin (2-2.5 g/day) in patients with poorly controlled type 2 diabetes. The primary end point of this 24-week, randomised, placebo-controlled study was the absolute change from baseline in glycosylated haemoglobin (HbA1C). Tesaglitazar significantly reduced HbA1C, fasting plasma glucose and insulin levels compared with placebo (p<0.0001 for all) when added to metformin. Triglycerides, high-density lipoprotein cholesterol (HDL-C) and non-HDL-C levels also improved with tesaglitazar treatment (p<0.0001 for all). Adverse events were generally similar across treatments, except for higher frequencies of peripheral oedema and weight gain in the tesaglitazar 1 mg group. Although reversibility was not fully evaluated, dose-dependent changes in mean serum creatinine levels and haematology measures tended to return towards baseline at follow-up. Despite the clinical discontinuation of tesaglitazar, this study has demonstrated the potential benefits of dual PPAR agonism as add-on therapy to metformin, in patients with poorly controlled type 2 diabetes.

The efficacy and safety of tesaglitazar (0.5 and 1 mg) and pioglitazone (15, 30 and 45 mg) were compared in a 24-week, randomised, double-blind study in 1,707 patients with type 2 diabetes mellitus. Tesaglitazar 1 mg was non-inferior to pioglitazone 45 mg for change from baseline in glycosylated haemoglobin (HbA1C) at 24 weeks (difference: -0.056 [95% confidence intervals -0.161, 0.049], pNI<0.001 for non-inferiority hypothesis). Tesaglitazar 1 mg improved triglyceride (TG), high-density lipoprotein cholesterol (HDL-C) and non-HDL-C levels compared with all pioglitazone doses at 24 weeks (p<0.001). Low-density lipoprotein cholesterol (LDL-C) was lower with tesaglitazar for all pioglitazone comparisons (p<0.05), except for tesaglitazar 0.5 mg versus pioglitazone 15 mg. Tesaglitazar 1 mg decreased LDL particle number, when compared with all pioglitazone doses (p<0.01). Both agents increased body weight and peripheral oedema in a dose-dependent manner, but only tesaglitazar increased serum creatinine. In summary, tesaglitazar provided similar glycaemic control to pioglitazone, was associated with significant improvement in lipid and lipoprotein variables, and increased serum creatinine in a dose-dependent manner.

The discovery of the crucial role of peroxisome proliferator-activated receptors (PPARs) as regulators of lipid and glucose metabolism has raised interest in the development of synthetic ligands as potential tools for therapeutic intervention in type 2 diabetes and the metabolic syndrome. PPARalpha activators primarily improve dyslipidemia, whereas thiazolidinediones are potent PPARgamma activators that improve insulin resistance. Important research programs to develop agonists that combine the therapeutic effects of both PPARalpha- and PPARgamma-selective agonists, creating the expectation of greater efficacy and other advantages in the treatment of type 2 diabetes and the metabolic syndrome, have therefore been undertaken. Among these dual PPARalpha/gamma agonists, compounds that belong to the glitazar class are in the most advanced stage of development. However, although they demonstrated beneficial impact over selective PPAR agonists by improving both lipid and glucose homeostasis, safety has been a critical issue and has led to the discontinuation of their development because of adverse toxicity profiles. However, the target-related mechanism responsible for the identified safety issues and the relevance of rodent toxicities to the human situation are unclear. Therefore, future development of dual PPARalpha/gamma agonists with selective PPAR modulator activity appears appropriate and should be feasible.

Objective: The Glucose and Lipid Assessment in Diabetes (GLAD) trial examined the dose-response relationship of the dual peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonist tesaglitazar in type 2 diabetic patients., Study Design: GLAD was a 12-week, multicenter, international, randomized, parallel-group trial. Five-hundred men and women aged 30-80 years with type 2 diabetes (fasting plasma glucose [FPG] > or = 126 mg/dL [> or = 7.0 mmol/L]) received once-daily, double-blind placebo or tesaglitazar (0.1 mg, 0.5 mg, 1.0 mg, 2.0 mg, or 3.0 mg) or open-label pioglitazone (45 mg), included as a therapeutic benchmark., Main Outcome Measures: Placebo-corrected changes from baseline in FPG (primary end point), plasma lipids, and insulin-resistance measures., Results: At baseline, the mean patient age was 56.1 years, 57.5 years, and 58.9 years for placebo, across tesaglitazar groups, and for pioglitazone, respectively. For the corresponding groups, mean body mass index was 30.6 kg/m2, 30.9 kg/m2, and 29.7 kg/m2, and mean HbA1c was 7.0%, 7.2%, and 7.0%, respectively. At 12 weeks, tesaglitazar 0.5 mg, 1.0 mg, 2.0 mg, and 3.0 mg produced statistically significant reductions in FPG (-30.3 mg/dL, -41.1 mg/dL, -55.0 mg/dL, -60.9 mg/dL; p < 0.0001), triglycerides (-17.2%, -32.9%, -41.0%, -40.9%; p < 0.01), and apolipoprotein B (-15.0%, -15.7%, -21.0%, -22.3%, respectively; p < 0.0001). Tesaglitazar at doses > or = 1.0 mg significantly increased high-density lipoprotein-cholesterol (HDL-C) (15.0%, 13.0%, 12.9%; p < 0.001), and reduced non-HDL-C (-13.2%, -22.2%, -25.0%; p < 0.0001), very-low-density lipoprotein-cholesterol (VLDL-C) (-36.9%, -49.8%, -52.5%; p < 0.0001), and total cholesterol (-6.8%, -14.1%, -15.5%, respectively; p < 0.01). Tesaglitazar > or = 0.5 mg improved insulin-resistance measures. Although no formal statistical analyses were performed between active treatments, improvements in efficacy measures with tesaglitazar 1.0 mg were numerically similar to or greater than those with pioglitazone. Similar numbers of adverse events occurred in the tesaglitazar < or = 1.0 mg, placebo, and pioglitazone arms, but there was an increasing frequency of discontinuations due to pre-specified hematologic and clinical-chemistry criteria with tesaglitazar doses > or = 1.0 mg., Conclusions: In type 2 diabetic patients, tesaglitazar dose-dependently reduced FPG levels at doses > or = 0.5 mg. Other markers of glycemic control, atherogenic dyslipidemia, and measures associated with insulin resistance were improved at doses > or = 0.5 mg or > or = 1.0 mg. Study limitations included that the majority of patients were white, patients had good glycemic control at baseline, and the increased number of early withdrawals in the tesaglitazar 2.0 mg and 3.0 mg doses limits conclusions about the efficacy of these doses. The 0.5 mg and 1.0 mg tesaglitazar doses were identified for further investigation.

Type 2 diabetes is recognised as a major cardiovascular risk factor, and future therapies must therefore address more than just blood glucose levels. Novel approaches to the treatment of type 2 diabetes are now at various stages of development or regulatory approval. Exenatide and pramlintide, analogues of gut-derived hormones glucagon-like peptide-1 (GLP-1) and amylin, respectively, have demonstrated improvements in glycaemic control and bodyweight in clinical studies and have been recently approved for treatment of type 2 diabetes. Initial studies have indicated that agents that activate both peroxisome proliferator-activated receptor (PPAR)alpha and gamma improve glycaemic control and have beneficial effects on lipid profiles. Two dual PPARalpha/gamma agonists, muraglitazar and tesaglitazar, are under regulatory review and in phase III trials, respectively. Modulation of the endogenous endocannabinoid system by rimonabant, which is under regulatory review, has been shown to improve body weight, atherogenic lipid profiles and glycaemic control. In addition, enhanced understanding of the pathophysiology underlying the microvascular complications of type 2 diabetes has led to the development of targeted therapies for conditions such as diabetic retinopathy, including the protein kinase C (PKC)-antagonist ruboxistaurin, now in phase III trials. Such therapies should enable physicians to achieve more for their patients with type 2 diabetes.

While glycemic control remains the cornerstone of clinical management for patients with type 2 diabetes, the importance of a more comprehensive approach that addresses the multiple metabolic abnormalities seen in this population is now widely recognized. Abnormal lipid metabolism resulting in dyslipidemia contributes greatly to the markedly increased risks of cardiovascular disease observed in diabetic patients and in prediabetic patients with signs of insulin resistance. The peroxisome proliferator-activated receptors (PPARs) play a key role in the regulation of energy homeostasis and the coordination of inflammatory responses. As such, they are interesting targets for addressing both the glucose and lipid abnormalities associated with insulin resistance. The thiazolidinediones (TZDs), which activate PPARgamma, appear to improve glycemic control primarily by increasing peripheral insulin sensitivity and reducing hepatic glucose production, thereby helping to preserve beta-cell function. They have also demonstrated modest beneficial effects on some lipid parameters. The fibrate drugs, which activate PPARalpha, produce robust improvements in dyslipidemia, decrease atherosclerotic lesions and may have an effect on cardiovascular events, but do not affect glycemia. Theoretically, a compound targeting both the alpha and gamma PPARs simultaneously might combine the benefits of TZDs and fibrates. Tesaglitazar is a dual-acting PPARalpha/gamma agonist currently being investigated in phase III clinical trials as an alternative treatment for insulin resistance and the characteristic dyslypidemia of type 2 diabetes. This article reviews the available data on the clinical efficacy and safety of tesaglitazar in patients with type 2 diabetes and in individuals without diabetes but with insulin resistance.

AstraZeneca plc is developing tesaglitazar, an oral dual peroxisome proliferator-activated receptor alpha/gamma agonist, for the potential improvement of dyslipidemia and glycemic control in type 2 diabetic patients.

Aims/hypothesis: Insulin resistance is associated with abnormalities in lipid and glucose metabolism, which are major components of metabolic syndrome and risk factors for vascular disease. This study examined the effect of tesaglitazar (Galida), a novel, dual-acting peroxisome proliferator-activated receptor alpha/gamma agonist, on lipid and glucose metabolism in patients with evidence of insulin resistance., Methods: A 12-week, multicentre, randomised, double-blind, placebo-controlled, dose-finding study compared the efficacy and safety of oral tesaglitazar (0.1, 0.25, 0.5 and 1.0 mg/day) and placebo in 390 non-diabetic patients with hypertriglyceridaemia (plasma triglyceride concentration >1.7 mmol/l) and abdominal obesity (waist-to-hip ratio >0.90 for men and >0.85 for women)., Results: A 1.0-mg dose of tesaglitazar reduced fasting triglycerides (the primary endpoint) by 37% (95% CI: -43% to -30%; p<0.0001), non-HDL-cholesterol by 15% (95% CI: -20% to -10%; p<0.0001) and NEFA by 40% (95% CI: -51% to -27%; p<0.0001), and increased HDL-cholesterol by 16% (95% CI: 8 to -24%; p<0.0001). At the end of treatment there was a dose-dependent increase in patients with pattern A LDL particle diameter (40% at baseline vs 87% at 12 weeks for tesaglitazar 1.0 mg). Tesaglitazar produced significant reductions in fasting insulin concentration (-35%; p<0.0001) and plasma glucose concentration (-0.47 mmol/l; p<0.0001). Respiratory infection and gastrointestinal symptoms were the most common adverse events and were similarly frequent in all groups., Conclusions/interpretation: Tesaglitazar was well tolerated and produced significant, dose-dependent improvements in lipid and glucose metabolism and insulin sensitivity. Tesaglitazar may have the potential to prevent vascular complications and delay progression to diabetes in these patients.

Cardiovascular diseases are the leading cause of morbidity and mortality in the US. Proper management and/or prevention of atherosclerosis and hypertension, two complex and chronic disorders, would significantly reduce the risk for cardiovascular events such as myocardial infarction and stroke, but this requires an understanding of the mechanisms underlying their development and progression. Whereas a great deal has been learned and applied toward the management of these disorders, especially hypertension, morbidity and mortality remains unacceptably high, most likely because there are disease-causing mechanisms that have yet to be fully recognized. Understanding these disease mechanisms is necessary so that novel management strategies can be developed. One of these novel mechanisms centers on peroxisome proliferator-activated receptor (PPAR)-gamma. PPAR-gamma is a member of the nuclear receptor superfamily of ligand-activated transcription factors known to play a role in glucose homeostasis and adipocyte differentiation and, more recently, has been shown to have anti-inflammatory, antiatherogenic, and antihypertensive effects. Thiazolidinediones, a class of drugs used in the treatment of type 2 diabetes mellitus, are high-affinity ligands for PPAR-gamma. In this review, the anti-inflammatory, anti-atherosclerotic, and anti-hypertensive mechanisms by which PPAR-gamma and its agonists are thought to exert protective effects on the cardiovascular system are discussed. Ongoing clinical trials using PPAR-gamma activators for the management of cardiovascular diseases, especially in patients with type 2 diabetes mellitus, are summarized.

3-[2-Cyano-3-(trifluoromethyl)phenoxy]phenyl-4,4,4-trifluoro-1-butanesulfonate (BAY 59-3074) is a novel, selective cannabinoid CB(1)/CB(2) receptor ligand (K(i) = 55.4, 48.3, and 45.5 nM at rat and human cannabinoid CB(1) and human CB(2) receptors, respectively), with partial agonist properties at these receptors in guanosine 5-[gamma(35)S]-thiophosphate triethyl-ammonium salt ([(35)S]GTPgammaS) binding assays. In rats, generalization of BAY 59-3074 to the cue induced by the cannabinoid CB(1) receptor agonist (-)-(R)-3-(2-hydroxymethylindanyl-4-oxy)phenyl-4,4,4-trifluoro-1-butanesulfonate (BAY 38-7271) in a drug discrimination procedure, as well as its hypothermic and analgesic effects in a hot plate assay, were blocked by the cannabinoid CB(1) receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR 141716A). BAY 59-3074 (0.3-3 mg/kg, p.o.) induced antihyperalgesic and antiallodynic effects against thermal or mechanical stimuli in rat models of chronic neuropathic (chronic constriction injury, spared nerve injury, tibial nerve injury, and spinal nerve ligation models) and inflammatory pain (carrageenan and complete Freund's adjuvant models). Antiallodynic efficacy of BAY 59-3074 (1 mg/kg, p.o.) in the spared nerve injury model was maintained after 2 weeks of daily administration. However, tolerance developed rapidly (within 5 days) for cannabinoid-related side effects, which occur at doses above 1 mg/kg (e.g., hypothermia). Uptitration from 1 to 32 mg/kg p.o. (doubling of daily dose every 4th day) prevented the occurrence of such side effects, whereas antihyperalgesic and antiallodynic efficacy was maintained/increased. No withdrawal symptoms were seen after abrupt withdrawal following 14 daily applications of 1 to 10 mg/kg p.o. It is concluded that BAY 59-3074 may offer a valuable therapeutic approach to treat diverse chronic pain conditions.

Amyloid is a term for extracellular protein fibril deposits that have characteristic tinctorial and structural properties. Heparan sulphate, or the heparan sulphate proteoglycan perlecan, has been identified in all amyloids and implicated in the earliest stages of inflammation-associated (AA) amyloid induction. Heparan sulphate interacts with the AA amyloid precursor and the beta-peptide of Alzheimer's amyloid, imparting characteristic secondary and tertiary amyloid structural features. These observations suggest that molecules that interfere with this interaction may prevent or arrest amyloidogenesis. We synthesized low-molecular-weight (135-1,000) anionic sulphonate or sulphate compounds. When administered orally, these compounds substantially reduced murine splenic AA amyloid progression. They also interfered with heparan sulphate-stimulated beta-peptide fibril aggregation in vitro.

In a field experiment in the Mallee district of Victoria, Merlno xBorder Leicester ewes and wethers grazed Heliotropium europaeum (heliotrope) over periods of 3 to 4 months in 4 successive years. By the end of the second year 12% (14 of 120) of the sheep had died; after 4 years the loss attributable to heliotrope was between 18% and 35%. Mortality was not affected by intraruminal treatment with cobalt or antimethanogen. At the end of the experiment the highest concentration of copper in the liver was 1.95 mmol/kg wet weight (approximately 413 micrograms/g dry weight). The relatively low mortality from primary heliotrope poisoning and the low concentration of copper in the liver of sheep grazing the plant are discussed in relation to the contrasting situation that prevails in the Riverina area of New South Wales. The importance of local environmental factors in the management of heliotrope grazing by sheep is emphasised, particularly in relation to the number of seasons in which the plant may be a major component of the diet.

Homologous dialkanesulfonic esters of 2,2'-iminodiethanol, 3,3'-iminodi-1-propanol, N-(2-hydroxyethyl)-6-amino-1-hexanol, and N-(3-hydroxypropyl)-6-amino-1-hexanol were prepared via the N-trityl derivatives and screened for L1210 activity. For each active agent significant increases in life-span in L1210 tests (ILS) were correlated by linear least-squares regression with the corresponding log doses. The maximum ILS, taken from this regression line at the determined LD10, was used as a quantitative measure of antileukemic effectivenss. Within each homologoud series log ILSmax could be correlated with a binomial expression in lipophilic-hydrophilic balance, as measured by Rm values, but all active members from the four series could not be successfully included in a single correlation. By modification of Rm values with an ionization factor, log (H+/H+ + Ka), all active compounds could then be included in a significant correlation equation.

A combination of trimethoprim and sulfamethoxazole was effective in the prevention and treatment of Pneumocystis carinii pneumonitis in cortisonetreated rats. Although all of 15 untreated rats died with P. carinii pneumonitis, none of 15 given trimethoprim-sulfamethoxazole prophylactically acquired the infection. After P. carinii pneumonitis was established, 9 of 14 rats recovered after treatment with trimethoprim-sulfamethoxazole compared with only 2 of 14 treated with pentamidine isethionate. Rifampin and clindamycin, separately or in combination with pentamidine, were ineffective in the prevention and treatment of P. carinii infection.

A series of omega-aminoalkanesulfonic acids (1-5) and omega-guanidinoalkanesulfonic acids (6-9) has been tested for antistaphylococcal and antifibrinolytic activities. Most of the omega-aminoalkanesulfonic acids and 6 produced better protection against Staphylococcus aureus infections in mice than gamma-aminobutyryl-L-histidine. Compound 4 was the best antistaphylococcal agent among the omega-aminoalkanesulfonic acids and compound 6 among the omega-guanidinoalkanesulfonic acids. Most of the omega-aminoalkanesulfonic acids have antifibrinolytic activity, while none of the omega-guanidinoalkanesulfonic acids has significant antifibrinolytic activity. Compound 4 possessed the highest antifibrinolytic activity which was equal to or greater than that of epsilon-aminohexanoic acid.

Two patients with renal transplants were admitted for evaluation of fever. During the course of hospitalization both had hectic fever and arthralgia. Pulmonary symptoms were absent or minimal. In one patient the admitting chest roentgenogram was entirely normal and in the other only a small focal abnormality was apparent. Hypoxemia occurred even in the presence of normal or nearly normal chest roentgenograms. The diagnosis of Pneumocystis carinii infection was made by bronchoscopic brush biopsy in both patients. Therapy with pentamidine isethionate was successful. It is suggested that in patients with renal transplants and in others with similar immonosuppression, even with a normal chest roentgenogram, Pneumocystis carinii infection be considered as the cause of a fever of unknown origin. This should be evaluated initially with blood gas studies; if these are abnormal, further studies, including biopsy, are justified.