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Background and Purpose: Chemotherapy‐induced peripheral neuropathy (CIPN) is a common side effect of paclitaxel, affecting 30‐50% of patients. Increased survival and concern with patients' quality of life have encouraged the search for new tools to prevent paclitaxel‐induced neuropathy. This study presents the glitazone 4‐[(Z)‐(2,4‐dioxo‐1,3‐thiazolidin‐5‐ylidene)methyl]‐N‐phenylbenzene‐sulfonamide (TZD‐A1) as a partial agonist of peroxisome proliferator‐activated receptor γ (PPARγ), its toxicological profile and effects on paclitaxel‐induced CIPN in mice. Experimental Approach: Interactions of TZD‐A1 with PPARγ were analysed using in silico docking and in vitro reporter gene assays. Pharmacokinetics and toxicity were evaluated using in silico, in vitro and in vivo (C57Bl/6 mice) analyses. Effects of TZD‐A1 on CIPN were investigated in paclitaxel‐injected mice. Axonal and dorsal root ganglion damage, mitochondrial complex activity and cytokine levels, brain‐derived neurotrophic factor (BDNF), nuclear factor erythroid 2‐related factor 2 (Nrf2) and PPARγ, were also measured. Key Results: Docking analysis predicted TZD‐A1 interactions with PPARγ compatible with partial agonism, which were corroborated by in vitro reporter gene assays. Good oral bioavailability and safety profile of TZD‐A1 were shown in silico, in vitro and in vivo. Paclitaxel‐injected mice, concomitantly treated with TZD‐A1 by i.p. or oral administration, exhibited decreased mechanical and thermal hypersensitivity, effects apparently mediated by inhibition of neuroinflammation and mitochondrial damage, through increasing Nrf2 and PPARγ levels, and up‐regulating BDNF. Conclusion and Implications: TZD‐A1, a partial agonist of PPARγ, provided neuroprotection and reduced hypersensitivity induced by paclitaxel. Allied to its safety profile and good bioavailability, TZD‐A1 is a promising drug candidate to prevent and treat CIPN in cancer patients. [ABSTRACT FROM AUTHOR]

N-Alkylation of thiazolidine-2,4-diones (TZDs) commonly employs the conversion of TZD to a salt with a strong base, which is then reacted with alkyl halides or alkyl tosylates. This two-step approach suffers from low overall yields, long reaction times, use of high temperatures, and generation of large amounts of waste. Herein, we describe a one-step N-alkylation of TZD with alkyl bromides at room temperature using a small amount of triethylamine as base and solvent. The reaction is fast and convenient, and it exclusively affords N-alkylated products in high yields. [ABSTRACT FROM AUTHOR]

Diabetes Mellitus remains a serious threat to human life and the global economy and hence its cure remains a challenge. In an attempt to find potent α-glucosidase inhibitors, herein a series of ethyl-(2-(5-arylidine)-2,4-dioxothiazolidin-3-yl) and 2-oxo-4-thioxothiazolidin-3-yl) acetamido) esters (IXa–o) and (IXp–v) were synthesized by utilizing Knoevenagel condensation as final step in low to good yields. All compounds were elucidated using spectral analysis (1H NMR, 13C NMR, MS and IR). The compounds were evaluated for their in vitro α-glucosidase activity using Saccharomyces cerevisiae α-glucosidase enzyme. The results of the in vitro cytotoxicity screening of compounds (IXa–v) revealed that most of the synthesized compounds were nontoxic. In vitro α-glucosidase screening results of the synthesized compounds (IXa–v) showed lower to moderate inhibitory when compared to the standard EGCG at concentration ranging from 10–200 µM. [ABSTRACT FROM AUTHOR]

This manuscript consists of a compacted review of pioglitazone, a thiazolidinedione which over the years has showed multiple beneficial effects in the treatment of type 2 diabetes that go beyond glycemic control and whose description intends to give to this glitazone the fair value that it has at the present time within the therapeutic arsenal and international recommendations for the management of patients with this disease. [ABSTRACT FROM AUTHOR]

Background: The thiazolidinedione (TZD) class of oral antidiabetic agents are used to treat type 2 diabetes mellitus (DM). This meta-analysis aimed to understand the protective effect of TZD on Parkinson's disease (PD) in people with diabetes. Method: A literature search was performed in PubMed, Embase, and Cochrane central from inception to until 30 September 2019. We included all real-world evidence studies assessing the use of TZD class of drugs and the risk of PD in people with diabetes. Quality of the studies was evaluated using the Newcastle-Ottawa scale. The primary outcome was the pooled hazard ratio (HR) of PD among type 2 DM TZD users as compared with TZD non-users in people with diabetes. The secondary outcome was the HR of PD among type 2 DM TZD users as compared with non-users (include both diabetic and nondiabetic population). Meta-analysis was performed using RevMan software. Results: Out of five studies selected for inclusion, four studies fulfilled the criteria for primary outcomes. The participants' mean age and follow-up duration were 66.23 ± 9.59 years and 5.25 years (2.97–7.9 years), respectively. There was a significant reduction in the risk of PD (pooled adjusted HR of 0.81 [95% CI 0.70–0.93, p = 0.004]) in TZD users compared with non-TZD users in people with diabetes. A significant protective effect of TZD was observed in Caucasian population (3 studies) (HR 0.78 (95% CI 0.66–0.92), p = 0.003). Conclusion: This meta-analysis demonstrates a potential neuroprotective effect of TZD for PD risk in the population with DM. [ABSTRACT FROM AUTHOR]

Glitazone are known to exhibit antihyperglycemic activity by decreasing peripheral insulin resistance. Glitazone are agonists for the peroxisome proliferator-activated receptor, PPARγ, which regulates the transcription of insulinresponsive genes involved in the control of glucose production, transport, and utilization. Several new insulin sensitizers are currently under investigation. Some of these belong to the Glitazone class, but others have different chemical structures in the present study, we have designed some novel glitazones based on the structure-activity relationships as possible PPARγ Agonists. The manually designed Thiazolidine-2,4-Dione derivative were synthesized by using the appropriate synthetic schemes and screened for their in vitro antihyperglycemic activity by Sucrose loaded model (SLM) and Alloxan induced diabetic model (AIDM). Infrared (IR), proton (H) nuclear magnetic resonance was used to characterize the newly synthesized Thiazolidine-2,4-Dione derivative. Compound S-07 exhibit great antihyperglycemic activity So the consideration for the use of these compounds as lead material for the further development of antidiabetic agents is encouraged. [ABSTRACT FROM AUTHOR]

Several studies have shown that blood pressure can be lowered by the use of drugs that are not traditional antihypertensive drugs. This might be of clinical importance when many risk patients are treated by combination drug therapy in order to prevent cardiovascular disease by way of improving the cardiovascular risk factor profile.

Thiazolidinediones (TZDs) represent a new class of antidiabetic drugs having an insulin sensitizing effect in patients with type2 diabetes. This article reports synthesis and evaluation of two novel derivatives of rosiglitazone (an effective drug of 5-arylidene-2,4-thiazolidinedione family) containing chlorophenyl instead of phenyl, s-triazine-morpholine instead of pyridine, and a double bond adjacent to the TZD ring (compounds V and VI).The new chemical entities were tested for antihyperglycemic and antihyperlipidemic activity on the alloxan-induced diabetic rat model. Results indicated that both new drugs showed hypoglycemic and hypolipidemic activity comparable to the control group, but compound V exhibited more significant blood lipid lowering activity as compared to other groups. Moreover, the new drugs displayed high efficiency in increasing HDL level and also HDL/LDL ratio, as good lipid profiles compared to others, which provide useful results for the interpretation of hypolipidemic activity of 2,4-thiazolidinedionedrugs. [ABSTRACT FROM AUTHOR]

Troglitazone causes severe hepatic injury in certain individuals and multiple mechanisms related to hepato-toxicity has been reported creating confusion. In the present study, the mechanism for the hepatic injury of glitazones was investigated by PASS. The results suggest that chromane containing glitazones are apoptic agonist (activating p53 by intrinsic pathway leading to the apoptosis) and those which do not contain the chromane are devoid of this. In case of hepato-toxicity by non-chromane glitazone and their metabolite such as M-3, RM-3, rosiglitazone and pioglitazone; PASS suggest that these chemicals are not apoptic agonist but they are the substrate for CYP enzyme (Phase-I Oxidative Enzyme) and Phase-II conjugating enzymes; interfering with bile acid metabolism rendering bile acid more toxic (cholestasis). This unmetabolised bile salt further initiates the process apoptosis via intrinsic and extrinsic pathway leading to the apoptosis. Immunoblot analysis further confirm our hypothesis that troglitazone (chromane containing glitazone), but not rosiglitazone and pioglitazone (non-chromane containing glitazone) increased the levels of p53 in a time-dependent manner. Hence our prediction related to the mechanism of hepato-toxicity by apoptosis and structural insight of glitazone can be helpful in improving the drug profile of this category. [ABSTRACT FROM AUTHOR]

Objective: Rosiglitazone improves insulin sensitivity and promotes weight gain in patients with type 2 diabetes mellitus, which could be useful in wasting and cachexia. However, its effects on cardiac function are controversial. The aim of this study was to investigate the effects of rosiglitazone on body wasting, body composition, cardiac function, and survival in a rat model of cancer cachexia. Methods: Rats were injected with Yoshida AH-130 hepatoma tumor cells and randomized to receive placebo or rosiglitazone 4 mg/kg daily. Treatment started 1 d after tumor inoculation and the rats were sacrificed 14 d thereafter. Body weight and body composition was measured at baseline and after removal of tumor. Echocardiography was performed at baseline and on day 11. At the end of the study, organs were weighed and the proteasome activity in gastrocnemius muscle was measured. Results: Survival analysis showed a significant benefit from treatment with rosiglitazone (hazard ratio = 0.38, 95% confidence interval: 0.15-0.86). Rosiglitazone reduced average daily weight loss (2.33 g/d rosiglitazone versus 3.93 g/d placebo; P < 0.05) as a result of both fat and lean mass preservation. It decelerated white and brown tissue wasting, but had no effect on skeletal muscle mass and heart mass. However, peptidyl-glutamyl-protein-hydrolysing and trypsin-like activity in gastrocnemius muscle was significantly reduced by rosiglitazone. Finally, it increased left ventricular ejection fraction, fractional shortening, and systolic volume and improved cardiac output in cachectic cancer rats. Conclusions: Rosiglitazone prevents weight loss and improves survival in a rat model of cancer cachexia. It exerts beneficial effects on cardiac function. [ABSTRACT FROM AUTHOR]

Aims PPARγ stimulation improves cardiovascular ( CV) risk factors, but without improving overall clinical outcomes. PPARγ agonists interfere with endothelial cell ( EC), monocyte and smooth muscle cell ( SMC) activation, function and proliferation, physiological processes critical for arterial collateral growth (arteriogenesis). We therefore assessed the effect of PPARγ stimulation on cerebral adaptive and therapeutic collateral growth. Methods In a rat model of adaptive cerebral arteriogenesis (3- VO), collateral growth and function were assessed (i) in controls, (ii) after PPARγ stimulation (pioglitazone 2.8 mg kg−1; 10 mg kg−1 compared with metformin 62.2 mg kg−1 or sitagliptin 6.34 mg kg−1) for 21 days or (iii) after adding pioglitazone to G- CSF (40 μg kg−1 every other day) to induce therapeutic arteriogenesis for 1 week. Pioglitazone effects on endothelial and SMC morphology and proliferation, monocyte activation and migration were studied. Results PPARγ stimulation decreased cerebrovascular collateral growth and recovery of hemodynamic reserve capacity ( CVRC controls: 12 ± 7%; pio low: −2 ± 9%; pio high: 1 ± 7%; metformin: 9 ± 13%; sitagliptin: 11 ± 12%), counteracted G- CSF-induced therapeutic arteriogenesis and interfered with EC activation, SMC proliferation, monocyte activation and migration. Conclusion Pharmacologic PPARγ stimulation inhibits pro-arteriogenic EC activation, monocyte function, SMC proliferation and thus adaptive as well as G- CSF-induced cerebral arteriogenesis. Further studies should evaluate whether this effect may underlie the CV risk associated with thiazolidinedione use in patients. [ABSTRACT FROM AUTHOR]

Highlights: [•] PCOS is associated with insulin resistance, obesity and dyslipidemia. [•] Cardiometabolic risk in PCOS should be evaluated at regular intervals. [•] Lifestyle intervention is the first management of metabolic dysfunction in PCOS. [•] Metformin and statins can be used selectively for metabolic dysfunction. [•] Oral contraceptive use in PCOS is unassociated with adverse cardiometabolic outcome. [Copyright &y& Elsevier]

Abstract: Diabetic macular edema (DME) is the most common cause of vision loss in patients with type 1 and type 2 diabetes. Glycemic control, hypertension, and dyslipidemia are known to be important risks factors for DME. In addition, nephropathy, anemia, sleep apnea, glitazone usage, and pregnancy are also important modifiable risk factors. It is important for physicians of different subspecialties to work together and understand multiple aspects of DME and diabetic healthcare. [Copyright &y& Elsevier]

BACKGROUND AND OBJECTIVE: The impetus for this review was recent increased warnings of cardiovascular toxicity, fractures and bladder cancer associated with glitazone use. METHODS: A drug utilization review was performed regarding the use of Actos (pioglitazone) and Avandia (rosiglitazone) at Cooper Green Mercy Hospital (CGMH), an inner city safety net hospital in Birmingham, Alabama. Pharmacy records were reviewed hospital-wide to determine usage patterns of all anti-diabetic medications. Medline and the FDA websites were searched for articles on safety and efficacy of pioglitazone and rosiglitazone. Considerations were relative utilization profile, comparative efficacy, indications, relative cost, and safety profile of the two available medications in this drug class. RESULTS: On the basis of all of these factors, a hospital-wide switch of all rosiglitazone prescriptions to all pioglitazone was implemented, which was estimated to result in savings of $83,000 for the first year. No episodes of worsening of control of diabetes were anticipated, nor were episodes of decreased efficacy or adverse effects as a result of automatically switching patients from rosiglitazone to pioglitazone at the time of prescription filling. CONCLUSIONS: The conclusions can be summarized in a number of key points. • Clinicians should follow the American Diabetes Association guidelines [1] for treatment. • The basis for diabetic control is weight loss, diet and exercise. • Initial medication management for type II Diabetes Mellitus includes metformin and insulin. • There are no circumstances in which use of glitazone medications is preferable to other medication groups, and there are no clinical circumstances in which use of glitazone medications is absolutely necessary, as opposed to other classes of diabetic medication. • There are significant contraindications, warnings and precautions to use of glitazones, which must be taken into consideration before use in every individual patient. • Glitazones in particular should not be used in the following circumstances: congestive heart failure (CHF), concurrent bladder cancer or severe osteoporosis. [ABSTRACT FROM AUTHOR]

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Summary: Despite the availability of excellent antibiotics, the mortality from community-acquired pneumonia (CAP) remains substantial. Most deaths occur during the first week of hospitalization. Because antibiotics rapidly eradicate bacteria from pulmonary secretions, an ongoing inflammatory response may be responsible for the poor outcome, and treatment with immunomodulatory drugs might be beneficial in this setting. Macrolides and statins exert a broad range of anti-inflammatory effects. Although randomized control trials have not been done, clinical evidence favors the addition of a macrolide to a beta-lactam for the treatment of pneumococcal pneumonia and supports a role for macrolides in the treatment of all-cause CAP without regard to their anti-microbial activity. The weight of several retrospective studies suggests that statins be considered in treating acute CAP. Further support for the use of statins derives from the high association between pneumonia and acute myocardial infarction. Aspirin might also be of benefit in treating patients hospitalized for pneumonia because of its anti-inflammatory activity as well as its benefits in acute myocardial infarction. Treatment of CAP with corticosteroids has yielded mixed results and the value of this approach is not well established, although further research is currently underway. Ibuprofen is not of benefit in treating sepsis in humans and glitazones may increase the risk of severe pneumonia. [ABSTRACT FROM AUTHOR]

Statin therapy has became the most important advance in stroke prevention since the introduction of aspirin and blood pressure-lowering therapies. Other lipid-modifying drugs have been less successful in reducing the incidence of stroke, but because of evidence for the use of triglyceride-lowering drugs and treatments that raise concentrations of high-density lipoprotein (HDL) cholesterol, further investigations are needed, particularly in patients with an atherogenic dyslipidemia profile (high triglycerides and low HDL cholesterol levels). Furthermore, beyond reducing low-density lipoprotein cholesterol and possibly improving other lipids fractions in patients who are at high risk of stroke, the present review shoes that lipid-modifying drugs might have neuroprotective effects that should also be further explored. [ABSTRACT FROM AUTHOR]

A randomised controlled trial (RCT), the PROactive study, was undertaken to see if pioglitazone improved cardiovascular outcomes in type 2 diabetes. Initially the results were controversial and pioglitazone was not widely recognised as a beneficial agent for cardiovascular disease. A meta-analysis of rosiglitazone studies raising the possibility that it was associated with cardiovascular harm received worldwide media attention and the negative concern spread to involve pioglitazone through presumed ‘class-effect’. A careful re-look at the detail of the PROactive’s primary composite endpoint, which led to the controversy over the outcome, suggests that medical statistics may have been inadequate to reveal the real clinical effect. A number of other studies support the interpretation that pioglitazone significantly improves cardiovascular outcomes. While the potential risk:benefit of pioglitazone needs to be acknowledged, it now also needs to be recognised that pioglitazone and metformin are the only glucose-lowering agents with RCT data demonstrating a reduction in stroke, myocardial infarction and death in type 2 diabetes. Furthermore there now exists a strong case that even in type 2 diabetes patients without known cardiovascular disease, the modern paradigm for management should involve the combination of metformin, pioglitazone and glucagon-like peptide 1 agonists used early and aggressively to achieve a target glycated haemoglobin A1C <6%. [ABSTRACT FROM PUBLISHER]

The thiazolidinedione (TZD) class of antihyperglycaemic agents has been shown to improve glycaemic control by improving peripheral insulin sensitivity but may worsen or precipitate congestive heart failure (CHF). Randomized controlled trials have shown an increased risk of CHF in patients treated with TZDs. The use of TZDs in clinical practice has the potential to increase morbidity and health care costs. The purpose of this study was to compare the incidence of CHF in TZD and non-TZD-treated patients in a clinical setting. A retrospective cohort study of all male patients with type 2 diabetes seen in the South Central US Veterans Administration health care network between 1 October 1996 and 31 December 2004. We constructed a Cox proportional hazards model to evaluate the impact of TZD therapy on time to incidence of CHF. Of 3956 patients, 29% (n = 1157) developed CHF during the study period. The incidence of CHF was higher in patients who received TZD medications than in those who received TZDs. After adjustment for multiple cardiac risk factors, the hazard ratio for the development of CHF for TZD versus non-TZD-treated patients was 0.69 with a 95% confidence interval of 0.60-0.79. Patients in this cohort who received TZD medications had a lower incidence of heart failure than patients who did not receive TZDs. [ABSTRACT FROM AUTHOR]

Several studies have shown that blood pressure can be lowered by the use of drugs that are not traditional antihypertensive drugs. This might be of clinical importance when many risk patients are treated by combination drug therapy in order to prevent cardiovascular disease by way of improving the cardiovascular risk factor profile. [ABSTRACT FROM AUTHOR]

Diabet. Med. 27, 1178–1187 (2010) Aims Beradinelli–Seip congenital generalized lipodystrophy is a rare autosomal recessive disorder characterized by near-complete absence of adipose tissue, Herculean appearance, insulin resistance, hypoleptinaemia and diabetes mellitus. The aim of this study was to investigate the in vitro effects of pioglitazone on the expression of genes involved in adipogenesis in fibroblasts from a patient with this condition due to a seipin mutation. Methods Primary cultures of fibroblasts from the skin of the patient were obtained. Fibroblasts were treated with classic adipose differentiation medium, with and without pioglitazone. Several adipogenes were evaluated by real-time reverse transcriptase-polymerase chain reaction and western blotting. Intracellular localization of prelamin A was studied by immunofluorescence microscopy. Results The expression of the adipogenic genes PPARG, LPL, LEP and SLC2A4 was reduced in lipodystrophic fibroblasts, while treatment with pioglitazone increased the expression of these genes. Moreover, and unexpectedly, we found an accumulation of farnesylated prelamin A in lipodystrophic fibroblasts. Conclusions The process of adipocyte differentiation is compromised in patients with Beradinelli-Seip congenital lipodystrophy owing to diminished expression of the regulatory genes involved, which pioglitazone treatment partially rescues. Prelamin A accumulation establishes a link with other types of familial lipodystrophies, as familial partial lipodystrophy. [ABSTRACT FROM AUTHOR]

Abstract: It is recently reported that galanin plays a role in memory decline that is the primary behavioral symptom of Alzheimer''s disease. The aim of the present study was to study the impact of administration of two antidiabetic drugs that might inhibit galanin, namely glibenclamide and pioglitazone, on the behavioral, and neurochemical changes in Alzheimer''s disease — induced in rats by intracerebroventricular (i.c.v.) injection of beta amyloid (Aβ). The present study was conducted on 60 male Wistar rats that were divided into 6 groups: group I (control group) which received i.c.v. scrambled peptide, group II (i.c.v.-Aβ group) which received i.c.v.-Aβ, groups III and IV that received, respectively, glibenclamide and pioglitazone daily orally for 3weeks following scrambled peptide administration as well as groups V and VI that received, respectively, glibenclamide and pioglitazone daily orally for 3weeks following Aβ administration. i.c.v.-Aβ resulted in significant behavioral alterations suggesting Alzheimer''s disease, where there was significant impairment in spatial cognition, evaluated by Morris water maze task, and in learning and memory performance, assessed using passive-avoidance learning task. i.c.v.-Aβ also resulted in significant increase in hippocampal hyperphosphorylated tau protein as well as galanin. Administration of studied antidiabetic drugs, glibenclamide and pioglitazone, resulted in significant improvement in spatial cognition and in learning and memory performance, as well as significant decrease in hippocampal hyperphosphorylated tau protein and hippocampal galanin. Our findings suggest that a pharmacologic approach to inhibit galanin in the brain, either by glibenclamide or pioglitazone might dramatically improve symptoms in Alzheimer''s disease. [Copyright &y& Elsevier]

Aims: Thiazolidinediones (glitazones) are frequently prescribed antidiabetic drugs commonly used in combination drug regimens. To evaluate the risk of drug-drug interactions, we therefore aimed to systematically investigate the inhibitory and inductive effects of all glitazones on 2 of the most relevant drug transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), in vitro. Methods: The inhibition of P-gp and BCRP was assessed by fluorometric assays quantifying the increase in the intracellular concentration of fluorescent P-gp or BCRP substrates caused by their combination with the glitazones. The induction of mRNA expression was quantified by real-time RT-PCR after the treatment of HuH-7 cells with the respective compounds for 4 days. Results: Rosiglitazone and troglitazone significantly inhibited P-gp and BCRP function and induced mRNA expression of BCRP but not of P-gp. Pioglitazone, which exhibited very low solubility, could only be tested up to 0.5 μmol/l and did not provoke an effect in any of the assays. Conclusions: After comparison of the in vitro data and published clinical studies, it seems unlikely that the inhibition of BCRP and P-gp by rosiglitazone plays a role in the clinical situation. In contrast, BCRP induction by rosiglitazone might be of relevance in vivo, but has to be verified in dedicated clinical studies. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Gras D, Chanez P, Urbach V, Vachier I, Godard P, Bonnans C. Thiazolidinediones induce proliferation of human bronchial epithelial cells through the GPR4O receptor. Am J Physiol Lung Cell Mol Physiol 296: L970-L978, 2009. First published April 3, 2009; doi: 10.1152/ajplung.90219.2008.-Thiazolidinediones (TZDs) are synthetic peroxisome proliferator-activated receptor-γ (PPARγ) ligands that are widely used in type 11 diabetes treatment. In addition to their ability to improve glucose homeostasis, TZDs possess antiinflammatory properties and inhibit growth of many cells, particularly cancerous airway epithelial cells. However, the functional effects of PPARγ ligands on nonmalignant human bronchial epithelial cells have never been investigated. In the present study, we questioned whether PPAR-γ ligands may regulate proliferation of human bronchial epithelial cells, and we studied their potential molecular mechanisms. We found that synthetic PPAR-γ agonists, rosiglitazone (RGZ) and troglitazone (TGZ), induced proliferation of human bronchial epithelial cells, whereas the endogenous PPARγ ligand, 15deoxy-Δ[sup12.14]-prostaglandin J[sub2] (15d-PGJ[sub2]), inhibited cell growth. RGZ and TGZ (10 μM) induced a rapid and transient intracellular Ca[sup2+] mobilization from thapsigargin-sensitive intracellular stores, whereas lsd-PGJ[sub2] (5 μM) did not induce any Ca[sup2+] signal. The PPARγ antagonist GW-9662 did not inhibit any biological responses, but it reversed the effect of 15d-PGJ[sub2] on cell growth. Using RT-PCR, we detected mRNA expression of the GPR4O receptor, a G proteincoupled receptor recently identified as a receptor for free fatty acids and TZDs, in human bronchial epithelial cells. Downregulation of GPR4O by small-interfering RNA led to a significant inhibition of TZD-induced Ca[sup2+] mobilization and proliferation. This study provides evidence for the proliferative effect of anti-diabetic drug TZDs in nonmalignant human bronchial epithelial cells through GPR40 receptor activation, involving an intracellular Ca[sup2+] signaling pathway. [ABSTRACT FROM AUTHOR]

Aim: This study investigates the treatment choice between, and the effectiveness of, adding sulphonylurea or glitazone to ongoing metformin therapy for patients with type 2 diabetes mellitus in the clinical practice setting. Methods: A multicentre observational study using data from clinical records was conducted in Finland, France, Germany, Norway, Poland, Spain and the UK. Data were collected for patients who added sulphonylurea or glitazone to metformin. Effectiveness was defined as a change in haemoglobin A1c (HbA1c) from baseline to approximately 1 year after the initiation of additional therapy. To allow for comparisons between the two medication regimens, propensity score matching was employed. Treatment choice was analysed using a probit regression model. We hypothesized that treatment choice was associated with factors reflecting patient’s characteristics, patient’s experience with diabetes, patient‘s health or to physician’s characteristics at baseline. Results: Compared with baseline, adding sulphonylurea to metformin reduced HbA1c by 0.8% (p < 0.0001), while adding glitazone to metformin reduced HbA1c by 0.9% (p < 0.0001). Percentage at HbA1c goal (6.5%) increased from 6.9 to 23.8% for the sulphonylurea group and 8.3 to 33.3% for the glitazone group. Both groups had similar changes in high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and triglycerides. In the probit regression model, age, HbA1c, weight, treatment for weight reduction, history of macrovascular complications and type of physician were significant factors associated with treatment choice. Conclusions: This study is consistent with the results of long-term randomized clinical trials in a clinical practice setting. Both regimens were able to reduce HbA1c by about 1%. [ABSTRACT FROM AUTHOR]

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Copyright of Der Diabetologe is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Der Diabetologe is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Abstract: Objective: Recent reports have suggested that dual peroxisome proliferator-activated receptor (PPAR) α/γ agonists are associated with adverse cardiovascular events. This study aimed to investigate the actions of the non-thiazolidinedione PPARα/γ agonist, compound 3q, on plaque development in the apolipoprotein E knockout (apoE KO) mouse, a recognised model of accelerated plaque development. Methods: Six-week-old male apoE KO mice were randomised to receive the dual PPARα/γ agonist, compound 3q (3mg/kg/day), the PPARγ agonist, rosiglitazone (20mg/kg/day), the PPARα agonist, gemfibrozil (100mg/kg/day) by gavage or no treatment for 20 weeks (n =12/group). Results: Gemfibrozil and rosiglitazone significantly reduced lesion area. However, compound 3q was associated with a three-fold increase in total plaque area (versus control p <0.001). This was associated with an upregulation of markers of plaque instability including vascular cell adhesion molecule-1 (3.5-fold, p <0.001), P-selectin (3.4-fold, p <0.001) monocyte chemoattractant protein-1 (3.4-fold; p <0.001) as well as the scavenger receptor, CD36 (2-fold, p <0.01). These disparate effects were observed with the dual PPAR agonist despite lowering LDL cholesterol and improving insulin sensitivity to a similar extent to PPARα and γ agonists used individually. Conclusion: The finding of increased atherogenesis following a dual PPARα/γ agonist is consistent with recent clinical findings. These data provide an important framework for further exploring the potential utility and safety of combinatorial approaches. [Copyright &y& Elsevier]

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Copyright of Diabetes & Metabolism is the property of Masson Editeur and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Glitazones are efficient insulin sensitizers that blunt the effects of angiotensin II (ANG II) in the rat. Sodium chloride is another important modulator of the systemic and renal effects of ANG II. Whether glitazones interfere with the interaction between sodium and the response to ANG II is not known. Therefore, we investigated the effects of pioglitazone on the relationship between sodium and the systemic and renal effects of ANG II in rats. Pioglitazone, or vehicle, was administered for 4 wk to 8-wk-old obese Zucker rats. Animals were fed a normal-sodium (NS) or a high-sodium (HS) diet. Intravenous glucose tolerance tests, systemic and renal hemodynamic responses to ANG II, and the renal ANG II binding and expression of ANG II type 1 (AT1) receptors were measured. The results of our study were that food intake and body weight increased, whereas blood pressure, heart rate, filtration fraction, and insulin levels decreased significantly with pioglitazone in obese rats on both diets. Pioglitazone blunted the systemic response to ANG II and abolished the increased responsiveness to ANG II induced by a HS diet. Pioglitazone modified the renal hemodynamic response to changes in salt intake while maintaining a lower filtration fraction with ANG II perfusion. These effects were associated with a decrease in the number and expression of the AT1 receptor in the kidney. In conclusion; these data demonstrate that the peroxisome proliferator-activated receptor-γ agonist pioglitazone modifies the physiological relationship between sodium chloride and the response to ANG II in insulin-resistant rats. [ABSTRACT FROM AUTHOR]

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Aim: The adipocyte-secreted hormone resistin has been implicated in obesity-induced insulin resistance and type 2 diabetes, but pharmacological and dietary factors that regulate resistin gene expression and the effects of resistin on cellular glucose uptake in muscle have not been clearly defined. Methods: Expression of resistin mRNA was studied in differentiated 3T3-L1 adipocytes by using real-time semiquantitative reverse transcription-polymerase chain reaction. The effects of resistin on insulin-stimulated and insulin-independent 2-deoxyglucose uptake were evaluated in L6 muscle cells. Results: Insulin 1 µ m and rosiglitazone 10 µ m markedly reduced resistin mRNA expression (relative to the control gene TF2D) by 4.7-fold (p < 0.05) and 5.3-fold (p < 0.02), respectively. Similar reductions in resistin mRNA were demonstrated with metformin 100 µ m (6.2-fold reduction, p < 0.02) and oleic acid 100 µ m (3.9-fold reduction, p < 0.03). Resistin 1 µ m significantly reduced maximum insulin-stimulated 2-deoxyglucose uptake in L6 cells from 634 to 383% (relative to 100% for control, p < 0.001), and co-administration of rosiglitazone had no effect on resistin-induced insulin resistance. In the absence of insulin, however, resistin increased glucose uptake dose-dependently (e.g., 1.75-fold at 5 µ m, p < 0.001) via a mitogen-activated protein kinase-dependent pathway. Conclusions: These results demonstrate that various glucose-lowering therapies and oleic acid reduce resistin gene expression in isolated adipocytes, and that resistin impairs insulin-stimulated glucose uptake in skeletal muscle-derived cells. [ABSTRACT FROM AUTHOR]

Abstract: The thiazolidinedione (TZD) or glitazone class of peroxisome proliferator-activated-γ (PPAR-γ) ligands not only induce adipocyte differentiation and increase insulin sensitivity, but also exert growth inhibitory effects on several carcinoma cell lines in vitro as well as in vivo. In the current study the in vitro effect of four PPAR-γ agonists (ciglitazone, pioglitazone, troglitazone, rosiglitazone) on the cell growth of seven human neuroblastoma cell lines (Kelly, LAN-1, LAN-5, LS, IMR-32, SK-N-SH, SH-SY5Y) was investigated. Growth rates were assessed by a colorimetric XTT-based assay kit. Expression of PPAR-γ protein was examined by immunohistochemistry and Western blot analysis. All glitazones inhibited in vitro growth and viability of the human neuroblastoma cell lines in a dose-dependent manner showing considerable effects only at high concentrations (10μM and 100μM). Effectiveness of the glitazones on neuroblastoma cell growth differed depending on the cell line and the agent. The presence of PPAR-γ protein was demonstrated in all cell lines. Our findings indicate that ligands for PPAR-γ may be useful therapeutic agents for the treatment of neuroblastoma. Thus the effect of glitazones on the growth of neuroblastoma should now be investigated in an in vivo animal model. [Copyright &y& Elsevier]

A generic, highly selective, and robust capillary electrophoresis (CE) method was developed for separation of a racemic mixture of three available glitazone compounds (also known as thiazolidinediones) in active pharmaceutical ingredients (API) and tablets. The method separated the R and S enantiomers of balaglitazone, pioglitazone and rosiglitazone, and showed that the samples contained an equal (50:50) quantity of the enantiomers as a mixture. After a simple extraction of samples with acetonitrile:water (80:20), separation was performed using a combination of two cyclodextrins: sulfobuthylether-β-cyclodextrin (SB-β-CD) and dimethyl-β-cyclodextrin (DM-β-CD) in the electrolyte at pH 8.0. The method showed a very good specificity, and all separations were achieved with a resolution (Rs) over 3.0. The developed CE method was then validated. The Rs for the separations were 3.5 for balaglitazone enantiomers, 3.5 for pioglitazone enantiomers, and 3.7 for rosiglitazone. The squared correlation coefficients (r2) were found to be 0.999 for all three compounds. The range of the CE method (injection volume was approximately 4nl) was demonstrated to be from 1.0 to 2.4ng. The R.S.D. in the repeatability study was found to be less than 0.5 for area/area ratio (and 3.0% for area) for all three compounds. The R.S.D. in the intermediate precision study was found to be less than 0.7 for area/area ratio (and 4.5% for area) for all three compounds. Generally, the method showed good robustness. Resolution between the enantiomers peak was maintained acceptable throughout the small variations around the pH value of the buffer, different capillary, CE instrument and electrolytes ion strength capacity, but changes in concentration of cyclodextrins and acetonitrile showed significant effects on separations and affected the resolution. The validation results showed that the CE method was suitable for separation of the racemic mixtures of the three glitazone drugs. The CE method was then applied for routine test during the drug and formulation development work of balaglitazone. Due to the achieved results from this work, it is the authors’ belief that this method can easily separate other glitazone racemic mixtures. [Copyright &y& Elsevier]

Copyright of Herz is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Herz is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Diabetes & Metabolism is the property of Masson Editeur and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

1: Peroxisome proliferator activated receptor ? (PPAR?) has been implicated in several cellular pathways assumed to beneficially affect heart failure progression. In contrast, population-based studies demonstrate an increased incidence of heart failure in patients treated with PPAR? agonists. Therefore, we examined the effect of pioglitazone, a PPAR? agonist, on chronic left ventricular remodeling after experimental myocardial infarction (MI) in mice. 2: Mice were treated with placebo or pioglitazone (20?mg?kg-1 by gavage) from week 1 to week 6 after ligation of the left anterior descending artery. Serial transthoracic echocardiography was performed at weeks 1, 3, and 6. 3: Over 6 weeks, there was no difference in mortality (placebo 12%, pioglitazone 10%). Echocardiography showed significant left ventricular dilatation in animals with MI (week 6, end-systolic area, placebo sham 9.6±1.3 vs placebo MI 14.4±2.5?mm2). However, there was no difference between the placebo and pioglitazone groups (week 6, end-systolic area, pioglitazone MI 14.8±2.9?mm2, P=NS vs placebo). 4: Moreover, there were no changes in metabolic parameters, inflammation, and collagen deposition. Endothelial function in the aorta was not changed by PPAR? activation. 5: In conclusion, PPAR? activation did not adversely affect left ventricular remodeling and survival in mice with chronic MI. However, we were also not able to identify a protective effect of pioglitazone.British Journal of Pharmacology (2004) 141, 9-14. doi:10.1038/sj.bjp.0705585 [ABSTRACT FROM AUTHOR]

Prior to the introduction of troglitazone, it had been more than 30 years since the last significant improvement in antidiabetic therapy. In view of the pressing need for more effective oral agents for the treatment of Type 2 diabetes mellitus, troglitazone was granted priority review by the FDA and was launched in the USA in 1997. The first of the thiazolidinedione insulin sensitizing agents, troglitazone was quickly followed by rosiglitazone and pioglitazone. The glitazones proved to be effective not only in lowering blood glucose, but also to have beneficial effects on cardiovascular risk. Troglitazone was subsequently withdrawn because of concerns about hepatotoxicity, which appears to be less of a problem with rosiglitazone and pioglitazone. Recent insights into the molecular mechanism of action of the glitazones, which are ligands for the peroxisome proliferator-activated receptors, open the prospect of designing more effective, selective and safer antidiabetic agents. This document will review the history of troglitazone from discovery through clinical development. [Copyright &y& Elsevier]