Rosiglitazone Therapy Research Articles

Rosiglitazone Does Not Affect the Risk of Inflammatory Bowel Disease: A Retrospective Cohort Study in Taiwanese Type 2 Diabetes Patients.

Human studies on the effect of rosiglitazone on inflammatory bowel disease (IBD) are still lacking. We investigated whether rosiglitazone might affect IBD risk by using the reimbursement database of Taiwan's National Health Insurance to enroll a propensity-score-matched cohort of ever users and never users of rosiglitazone. The patients should have been newly diagnosed with diabetes mellitus between 1999 and 2006 and should have been alive on 1 January 2007. We then started to follow the patients from 1 January 2007 until 31 December 2011 for a new diagnosis of IBD. Propensity-score-weighted hazard ratios were estimated with regards to rosiglitazone exposure in terms of ever users versus never users and in terms of cumulative duration and cumulative dose of rosiglitazone therapy for dose-response analyses. The joint effects and interactions between rosiglitazone and risk factors of psoriasis/arthropathies, dorsopathies, and chronic obstructive pulmonary disease/tobacco abuse and the use of metformin were estimated by Cox regression after adjustment for all covariates. A total of 6226 ever users and 6226 never users were identified and the respective numbers of incident IBD were 95 and 111. When we compared the risk of IBD in ever users to that of the never users, the estimated hazard ratio (0.870, 95% confidence interval: 0.661-1.144) was not statistically significant. When cumulative duration and cumulative dose of rosiglitazone therapy were categorized by tertiles and hazard ratios were estimated by comparing the tertiles of rosiglitazone exposure to the never users, none of the hazard ratios reached statistical significance. In secondary analyses, rosiglitazone has a null association with Crohn's disease, but a potential benefit on ulcerative colitis (UC) could not be excluded. However, because of the low incidence of UC, we were not able to perform detailed dose-response analyses for UC. In the joint effect analyses, only the subgroup of psoriasis/arthropathies (-)/rosiglitazone (-) showed a significantly lower risk in comparison to the subgroup of psoriasis/arthropathies (+)/rosiglitazone (-). No interactions between rosiglitazone and the major risk factors or metformin use were observed. We concluded that rosiglitazone has a null effect on the risk of IBD, but the potential benefit on UC awaits further investigation.

Anticancer Effect of Rosiglitazone, a PPAR-γ Agonist against Diethylnitrosamine-Induced Lung Carcinogenesis.

Multiple effects on cancer cells are exerted by the peroxisome proliferator-activated receptor γ (PPAR-γ). Recent studies have shown that rosiglitazone, a synthetic PPAR-γ ligand, inhibits the growth of cells. This research was designed to assess the impact of rosiglitazone on diethylnitrosamine (DENA)-induced lung carcinogenesis in Wistar rats and to study the underlying molecular mechanism. A total of 40 adult male Wistar rats were separated into four groups as follows: group 1 is known as a control. Group 2 is known as the DENA group (150 mg/kg, i.p.). Group 3 and group 4 denote DENA-induced rats treated with 5 and 10 mg/kg rosiglitazone, respectively. Lipid peroxidation, various antioxidant enzymes, histological perceptions, and caspase-3, Bcl2, and Bax gene expression were measured in lung tissues. Rosiglitazone treatment reverted the DENA-induced changes in the expression of these genes, inflammatory cytokines, and oxidative stress. However, blotting analysis discovered reduced caspase-3 and BAX expressions and elevated Bcl-2 expression in DENA-induced rats. The expression of such proteins causing DENA lung cancer was restored by rosiglitazone therapy.

Systematic Review on Therapeutic Strategies to Minimize Corneal Stromal Scarring After Injury.

To evaluate recent studies on available and experimental therapies in preventing or minimizing corneal stromal scarring after injury. We performed an Entrez PubMed literature search using keywords "cornea," "scarring," "haze," "opacity," "ulcer," "treatments," "therapies," "treatment complications," and "pathophysiology" resulting in 390 articles of which 12 were analyzed after filtering, based on English language and publication within 8 years, and curation for relevance by the authors. The 12 articles selected included four randomized control trials (RCTs) (two were double-blinded placebo-controlled RCTs, one was a prospective partially masked RCT, and one was an open-label RCT), two retrospective observational studies, and six laboratory-based studies including two studies having in vivo and in vitro experiments, one was in vivo study, one was ex vivo study, and the last two were in vitro studies. The current mainstay for preventing or minimizing corneal scarring involves the use of topical corticosteroids and local application of mitomycin C. However, supportive evidence for their use in clinical practice from well-designed RCTs is lacking. Laboratory studies on topical rosiglitazone therapy, vitamin C prophylaxis, gene therapy, and stem cell therapy have shown promising results but have yet to be translated to clinical research. There is a need for more robust randomized controlled trials to support treatments using topical corticosteroids and mitomycin C. Furthermore, their clinical efficacy and safety profile should be compared with new treatments that have shown promising results in the laboratory setting. Ultimately, the goal should be to personalize cornea scarring treatment according to the most effective treatment for the specific underlying pathology.

Rosiglitazone has a neutral effect on the risk of dementia in type 2 diabetes patients.

This study investigated whether rosiglitazone might increase or reduce dementia risk. Taiwan’s National Health Insurance database was used to enroll a cohort of 1:1 matched-pairs of ever and never users of rosiglitazone based on propensity score from patients with new-onset type 2 diabetes during 1999-2006. The patients were alive on January 1, 2007 and were followed up for dementia until December 31, 2011. A total of 5,048 pairs of never users and ever users were identified. The incident case numbers were 127 and 121, respectively. The adjusted hazard ratio for ever versus never users was 0.895 (95% confidence interval: 0.696-1.151). The adjusted hazard ratios for the first (<12.1 months), second (12.1-25.1 months) and third (>25.1 months) tertiles of cumulative duration of rosiglitazone therapy were 0.756 (0.509-1.123), 0.964 (0.685-1.357) and 0.949 (0.671-1.341), respectively. When cumulative duration was treated as a continuous variable, the adjusted hazard ratio was 1.000 (0.992-1.008). Subgroup analyses conducted in ever users and never users of metformin and in patients diagnosed with diabetes during three different periods of time, i.e., 1999-2000, 2001-2003 and 2004-2006, all supported a neutral effect of rosiglitazone. In conclusion, rosiglitazone does not increase or redcue the risk of dementia.

Rosiglitazone Infusion Therapy Following Minimally Invasive Surgery for Intracranial Hemorrhage Evacuation Decreased Perihematomal Glutamate Content and Blood-Brain Barrier Permeability in Rabbits.

To observe effects of rosiglitazone (RSG) infusion therapy on perihematomal peroxisome-proliferator-activated receptor gamma (PPARγ), glutamate, blood-brain barrier (BBB) permeability, and brain edema. Fifty male rabbits (2.8-3.4 kg) were randomly assigned to a normal control (NC) group, model control (MC) group, RSG group, minimally invasive surgery (MIS) group, or MIS and RSG (MIS+RSG) group. Intracranial hemorrhage was induced in all rabbits except for the NC group. MIS procedures were performed to evacuate the intracranial hemorrhage 6 hours after the intracranial hemorrhage model was prepared successfully. The animals were sacrificed on day 7, and the perihematomal brain tissue was obtained to determine PPARγ, glutamate, and BBB permeability. Compared with the MC group, the MIS group displayed a remarkable decrease in PPARγ, glutamate, and BBB permeability. The RSG group showed similar results in glutamate level and BBB permeability but a significant increase in PPARγ. The MIS+RSG group displayed an increase in PPARγ and a more significant decrease in glutamate, BBB permeability, and neurologicl deficit scores compared with the other groups. Performing MIS followed by RSG infusion therapy might increase PPARγ expression and might be more efficacious for reducing glutamate level and BBB permeability and improving neurologic function than MIS or RSG therapy used alone.

Metformin in combination with rosiglitazone contribute to the increased serum adiponectin levels in people with type 2 diabetes mellitus.

To evaluate how metformin plus rosiglitazone affect serum adiponectin levels in people suffering from type 2 diabetes mellitus (T2DM), 240 patients having T2DM were selected in this cohort study. Included subjects were randomly and equally separated into three subsets: i) Group A (rosiglitazone group); ii) group B (metformin group); and iii) group C (rosiglitazone + metformin group). Furthermore, meta-analysis of previous studies was performed by searching the general search engines and bibliographic databases. Compared with before treatment, the serum amount of adiponectin grew considerably in the three groups after treatment, and the levels in the group C was much greater than those of groups A and B (all P<0.05). Corresponding meta-analysis results suggested post-treatment serum adiponectin level to be greater than pretreatment level in T2DM patients (P<0.001). Further subgroup analyses indicated that combination therapy of metformin and rosiglitazone may increase the amount of serum adiponectin in T2DM sufferers among the majority subgroups (all P<0.05). The combination of metformin and rosiglitazone treatment increased serum adiponectin levels, suggesting that metformin plus rosiglitazone therapy is a suitable choice to treat T2DM.

Beneficial Effects of Aerobic Exercise Training Combined with Rosiglitazone on Glucose Metabolism in Otsuka Long Evans Tokushima Fatty Rats.

BackgroundRegular aerobic exercise is essential for the prevention and management of type 2 diabetes mellitus and may be particularly beneficial for those treated with thiazolidinediones, since it may prevent associated weight gain. This study aimed to evaluate the effect of combined exercise and rosiglitazone treatment on body composition and glucose metabolism in obese diabetes-prone animals.MethodsWe analyzed metabolic parameters, body composition, and islet profiles in Otsuka Long Evans Tokushima Fatty rats after 28 weeks of aerobic exercise, rosiglitazone treatment, and combined exercise and rosiglitazone treatment.ResultsCombined exercise with rosiglitazone showed significantly less increase in weight and epididymal fat compared to rosiglitazone treatment. Aerobic exercise alone and combined rosiglitazone and exercise treatment led to similar retention of lean body mass. All experimental groups showed a decrease in fasting glucose. However, the combined exercise and rosiglitazone therapy group showed prominent improvement in glucose tolerance compared to the other groups. Rescue of islet destruction was observed in all experimental groups, but was most prominent in the combined therapy group.ConclusionRegular aerobic exercise combined with rosiglitazone treatment can compensate for the adverse effect of rosiglitazone treatment and has benefit for islet preservation.

Rosiglitazone influences adipose tissue distribution without deleterious impact on heart rate variability in coronary heart disease patients with type 2 diabetes.

Obesity is associated with decreased heart rate variability (HRV). Rosiglitazone, a PPARγ agonist, is generally associated with increases in body mass. To assess whether the gain in body mass and adiposity expected from rosiglitazone treatment has an influence on HRV in patients with type 2 diabetes and coronary artery disease. One hundred and twenty-five patients with type 2 diabetes and coronary artery disease aged between 40 and 75years were studied. Anthropometric measurements: (1) body mass index (BMI), (2) waist circumference (WC), (3) abdominal computed tomography (CT) scan, and HRV (using a 24h Holter) were measured at baseline and after 12months of treatment. Patients were randomized to rosiglitazone or placebo regimen. In the rosiglitazone vs. placebo group, there were significant increases in body mass [3.5 (2.6;4.4); mean (95% CI) vs. 0.2 (-0.4;0.8)] kg), BMI [1.3 (1.0;1.6) vs. 0.1 (-0.1;0.3) kg/m2], WC [2.1 (0.9;3.3) vs. 0.4 (-0.4;1.2) cm, all p≤0.001] and subcutaneous adipose tissue [253 (187;319) vs. 6 (-24;36) cm3, p≤0.001] without statistically significant changes in visceral adipose tissue [-22 (-91;47) vs. 57 (43;71) cm3, p=0.546], respectively. There was no change in HRV in either group after 12months. There were no correlations between changes in HRV variables and fat distribution. Our results suggest that changes in adiposity indices observed after 12months of rosiglitazone therapy have no deleterious influence on HRV in patients with type 2 diabetes and coronary artery disease.

Effect of Recombinant Human Growth Hormone and Rosiglitazone for HIV-Associated Abdominal Fat Accumulation on Adiponectin and other Markers of Inflammation

Background/Objective: In a previous report of HIV-infected patients with fat redistribution, we found that recombinant human growth hormone (rhGH) therapy reduced visceral adipose tissue (VAT) but increased insulin resistance, and that the addition of rosiglitazone reversed the negative effects of rhGH on insulin sensitivity. In this study, we sought to determine the effects of rhGH and rosiglitazone therapy on an array of inflammatory and fibrinolytic markers.Methods: 72 patients with HIV-associated abdominal obesity and insulin resistance were randomized to treatment with rhGH, rosiglitazone, the combination of rhGH and rosiglitazone, or placebo for 12 weeks. Subjects with plasma and serum samples available at weeks 0 (n = 63) and 12 (n = 46–48) were assessed for adiponectin, C-reactive protein, homocysteine, interleukin-1, interleukin-6, tumor necrosis factor alpha, interferon gamma, fibrinogen, plasminogen activator inhibitor-1 antigen, and tissue plasminogen activator antigen.Results: Treatment with both rosiglitazone alone and the combination of rosiglitazone and rhGH for 12 weeks resulted in significant increases in adiponectin levels from baseline. Adiponectin levels did not change significantly in the rhGH arm alone . There were no significant changes in the other biomarkers among the different treatment groups.Discussion: In this study of HIV-infected patients with altered fat distribution, treatment with rosiglitazone had beneficial effects on adiponectin concentrations, an effect that was also seen with a combination of rosiglitazone and rhGH. RhGH administration alone, however, did not demonstrate any significant impact on adiponectin levels despite reductions in VAT.

Effect of Rosiglitazone and Insulin Combination Therapy on Inflammation Parameters and Adipocytokine Levels in Patients with Type 1 DM.

Aim. To investigate the efficacy of combined therapy of insulin and rosiglitazone on metabolic and inflammatory parameters, insulin sensitivity, and adipocytokine levels in patients with type 1 diabetes mellitus (type 1 DM). Material and Methods. A total of 61 adults with type 1 DM were randomly and prospectively assigned in open-label fashion to take insulin and rosiglitazone 4 mg/day (n = 30) or insulin alone (n = 31) for a period of 18 weeks while undergoing insulin therapy without acute metabolic complications. Results. Combination therapy did not significantly improve metabolic and inflammatory parameters, insulin sensitivity, and adiponectin levels. While leptin and resistin levels decreased in both groups (group 1: resistin 6.96 ± 3.06 to 4.99 ± 2.64, P = 0.006; leptin 25.8 ± 17.6 to 20.1 ± 12.55, P = 0.006; group 2: resistin 7.16 ± 2.30 to 5.57 ± 2.48, P = 0.031; leptin 16.72 ± 16.1 to 14.0 ± 13.4, P = 0.007) Hgb and fibrinogen levels decreased only in group 1 (Hgb 13.72 ± 1.98 to 13.16 ± 1.98, P = 0.015, and fibrinogen 4.00 ± 1.08 to 3.46 ± 0.90, P = 0.002). Patients in both groups showed weight gain and the incidence of hypoglycemia was not lower. Discussion. The diverse favorable effects of TZDs were not fully experienced in patients with type 1 DM. These results are suggesting that insulin sensitizing and anti-inflammatory characteristics of TZDs were likely to be more pronounced in patients who were not totally devoid of endogenous insulin secretion.

Synergistic effects of atorvastatin and rosiglitazone on endothelium protection in rats with dyslipidemia.

BackgroundEndothelial dysfunction is implicated in the initiation and progression of atherosclerosis. Whether atorvastatin combined with rosiglitazone has synergistic effects on endothelial function improvement in the setting of dyslipidemia is unknown.MethodsDyslipidemia rat model was produced with high-fat and high-cholesterol diet administration. Thereafter, atorvastatin, rosiglitazone or atorvastatin combined with rosiglitazone were prescribed for 2 weeks. At baseline, 6 weeks of dyslipidemia model production, and 2 weeks of medical intervention, fasting blood was drawn for parameters of interest evaluation. At the end, myocardium was used for 15-deoxy-delta-12,14-PGJ2 (15-d-PGJ2) assessment.ResultsInitially, there was no significant difference of parameters between sham and dyslipidemia groups. With 6 weeks’ high-fat and high-cholesterol diet administration, as compared to sham group, serum levels of triglyceride (TG), total cholesterol (TC) and low density lipoprotein-cholesterol (LDL-C) were significantly increased. Additionally, nitric oxide (NO) production was reduced and serum levels of malondialdehyde (MDA), C-reactive protein (CRP) and asymmetric dimethylarginine (ADMA) were profoundly elevated in dyslipidemia group. After 2 weeks’ medical intervention, lipid profile was slightly improved in atorvastatin and combined groups as compared to control group. Nevertheless, in comparison to control group, NO production was profoundly increased and serum levels of MDA, CRP and ADMA were significantly decreased with atorvastatin or rosiglitazone therapy. 15-d-PGJ2 expression of myocardium was also significantly elevated with atorvastatin or rosiglitazone treatment. Notably, these effects were further enhanced with combined therapy, suggesting that atorvastatin and rosiglitazone had synergistic effects on endothelial protection, and inflammation and oxidation amelioration.ConclusionAtorvastatin and rosiglitazone therapy had synergistic effects on endothelium protection as well as amelioration of oxidative stress and inflammatory reaction in rats with dyslipidemia.

Hepatic molecular effects of rosiglitazone in human non‐alcoholic steatohepatitis suggest long‐term pro‐inflammatory damage

Glitazones are agonists of peroxisome proliferator-activated receptor-γ (PPAR-γ) and have been proposed for the treatment of non-alcoholic steatohepatitis (NASH). However, efficacy results are conflicting and hepatic molecular changes induced by glitazones are mostly unknown. The aim of this study was to analyze the hepatic inflammatory and fibrogenic molecular effects of rosiglitazone in NASH patients. Hepatic expression of PPAR-γ and several inflammatory/immune and fibrogenic genes were studied before and after a 12-month treatment with rosiglitazone or placebo in 25 patients with NASH from the Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) trial. Treatment with rosiglitazone induced hepatic PPAR-γ expression but increased the expression of several pro-inflammatory genes such as SOCS3 and TLR4. There was a significant reduction in mRNA and protein levels of α-smooth muscle actin, compatible with previously documented antifibrotic actions of rosiglitazone on stellate cells. However, there was no change in type 1 collagen and transforming growth factor-β expression thus suggesting an offset of the antifibrogenic actions by long-term pro-inflammatory changes. In NASH patients, hepatic PPAR-γ induction by rosiglitazone was associated with increased hepatic expression of pro-inflammatory genes which may explain the lack of long-term histological benefit shown in human studies with this drug. It is unclear whether these results are a class effect of PPAR-γ agonists or a specific effect of rosiglitazone.

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Effects of rosiglitazone on serum paraoxonase activity and metabolic parameters in patients with type 2 diabetes mellitus

Human serum paraoxonase contributes to the anti-atherogenic effect of high-density lipoprotein cholesterol (HDL-C) and has been shown to protect both low-density lipoprotein cholesterol (LDL-C) and HDL-C against lipid peroxidation. We investigated the effects of rosiglitazone on paraoxonase activity and metabolic parameters in patients with type 2 diabetes mellitus [50 patients (30 males, 20 females); mean±SD age: 58.7±9.2 years, body mass index: 28.2±4.1'kg/m2], in whom glucose control could not be achieved despite treatment with metformin, sulphonylurea, and/or insulin. The patients were given 4'mg/day rosiglitazone for 3 months in addition to their usual treatment. Serum paraoxonase activity, malondialdehyde, homocysteine, and lipid profile were measured at the time of initiation and at the end of therapy with rosiglitazone. After rosiglitazone therapy, serum levels of HDL-C, apolipoprotein A-1, and paraoxonase activity increased significantly (P<0.05) and malondialdehyde, homocysteine, lipoprotein(a), and glucose levels decreased significantly (P<0.05), but no significant changes in levels of total cholesterol and apolipoprotein B were observed. Triglyceride levels also increased significantly (P<0.05). Rosiglitazone treatment led to an improvement in glycemic control and to an increase in paraoxonase activity and HDL-C levels. Although rosiglitazone showed favorable effects on oxidant/antioxidant balance and lipid profile, further studies are needed to determine the effect of rosiglitazone on cardiovascular risk factors and cardiovascular morbidity and mortality.

PPARγAgonist Rosiglitazone Suppresses Renal mPGES-1/PGE2 Pathway in db/db Mice

Evidence had shown the detrimental effect of prostaglandin (PG) E2 in diabetic nephropathy (DN) of STZ-induced type-1 diabetes but its role in the development of DN of type-2 diabetes remains uncertain. The present study was undertaken to investigate the regulation of PGE2 synthetic pathway and the interaction between peroxisome proliferator-activated receptor (PPAR)γ and PGE2 synthesis in the kidneys of db/db mice. Strikingly, urinary PGE2 was remarkably elevated in db/db mice paralleled with the increased protein expressions of COX-2 and mPGES-1. In contrast, the protein expressions of COX-1, mPGES-2, cPGES, and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) were not altered. Following 1-week rosiglitazone (Rosi) therapy, urinary PGE2, but not other prostanoids, was reduced by 57% in parallel with significant reduction of mPGES-1 protein and EP4 mRNA expressions. By immunohistochemistry, mPGES-1 was significantly induced in the glomeruli of db/db mice, which was almost entirely abolished by Rosi. In line with the reduction of glomerular mPGES-1, the glomerular injury score showed a tendency of improvement after 1 week of Rosi therapy. Collectively, the present study demonstrated an inhibitory effect of PPARγ activation on renal mPGES-1/PGE2/EP4 pathway in type-2 diabetes and suggested that mPGES-1 may potentially serve as a therapeutic target for treating type-2 diabetes-associated DN.

Short-Term Therapy with Rosiglitazone, a PPAR-γAgonist, Improves Metabolic Profile and Vascular Function in Nonobese Lean Wistar Rats

A number of preclinical and clinical studies have reported blood-pressure-lowering benefits of thiazolidinediones in diabetic subjects and animal models of diabetes. This study was designed to further elucidate vascular effects of rosiglitazone, on healthy nonobese, lean animals. Adult male Wistar rats were randomized and assigned to control and rosiglitazone-treated groups and were dosed daily with either vehicle or rosiglitazone (10 mg kg−1 day−1) by oral gavage for 5 days. Compared with control group, rosiglitazone treatment significantly reduced plasma levels of triglycerides (>240%) and nonesterified free fatty acids (>268%) (both, P < 0.001). There were no changes in vascular contractility to KCl or noradrenaline between two groups. However, rosiglitazone therapy improved carbamylcholine-induced vasorelaxation (93 ± 3 % versus control 78 ± 2, P < 0.01) an effect which was abolished by L-NAME. There was no difference in sodium nitroprusside-induced vasorelaxation between the control and rosiglitazone-treated animals. These results indicate that short-term rosiglitazone therapy improves both metabolic profile and vascular function in lean rats. The vascular effect of rosiglitazone appears to be mediated by alteration in NO production possibly by activation of endothelial PPARγ. This increased NO production together with improved lipid profile may explain mechanism(s) of blood-pressure-lowering effects of thiazolidinediones on both human and experimental animals.

Abstract 1554: Rosiglitazone and Gemcitabine combination therapy reduces immune suppression and modulates T cell populations in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDA) is a leading cause of cancer mortality with a dismal 2-5% 5-year survival rate. Monotherapy with Gemcitabine has limited success, highlighting the need for additional therapies that enhance the efficacy of current treatments. We evaluated the combination of Gemcitabine and Rosiglitazone Maleate, an FDA-approved drug for the treatment of type II diabetes, in an immunocompetent transplantable mouse model of pancreatic cancer. Tumor progression, survival and metastases were evaluated in mice with subcutaneous or orthotopic pancreatic tumors treated with Pioglitazone, Rosiglitazone, Gemcitabine or combinations of these. We characterized the impact of high dose Rosiglitazone and Gemcitabine therapy on immune suppressive mediators, including MDSC and T regulatory cells, and on modulation of peripheral and intra-tumoral T cell populations. Combinations of Rosiglitazone and Gemcitabine significantly reduced tumor progression and metastases, enhanced apoptosis, and significantly extended overall survival compared to Gemcitabine alone. Rosiglitazone altered tumor-associated immune suppressive mediators by limiting early MDSC accumulation and intra-tumoral T regulatory cells. Combination therapy with Rosiglitazone and Gemcitabine modulated T cell populations by enhancing circulating CD8+ T cells and intra-tumoral CD4+ and CD8+ T cells while limiting T regulatory cells. The results suggest that Rosiglitazone, in combination with Gemcitabine, decreases immune suppressive mechanisms in immunocompetent animals and provide pre-clinical data in support of combining Rosiglitazone and Gemcitabine as a clinical therapy for pancreatic cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1554. doi:1538-7445.AM2012-1554

Rosiglitazone and Cardiovascular Risk – A Review

The thiazolidinediones (TZDs) are a class of oral drugs used for the management of type 2 diabetes mellitus and act as ligands for the transcription factor Peroxisome Proliferator-Activated Receptor gamma (PPARγ). Rosiglitazone, an example of TZD, is an anti-diabetic agent acting as a potent insulin sensitizer and is used clinically to enhance insulin-stimulated glucose uptake in tissues. However, in spite of the beneficial effects of TZDs in management of type 2 diabetes, the safety of rosiglitazone has recently been called into question. The debate about the risks associated with rosiglitazone therapy heightened in 2007, when it was reported that rosiglitazone was associated with an increase risk of myocardial infarction and death from cardiovascular causes. The cardiovascular risk associated with rosiglitazone use remains to be further elucidated, but there are several reasonable hypotheses. Keywords: Thiazolidinediones; Rosiglitazone; Type 2 Diabetes; Cardiovascular risk

Determinants of evolving metabolic and cardiovascular benefit/risk profiles of rosiglitazone therapy during the natural history of diabetes: molecular mechanisms in the context of integrated pathophysiology

Rosiglitazone is a thiazolidinedione, a synthetic PPARγ receptor agonist with insulin-sensitizing properties that is used as an antidiabetic drug. In addition to improving glycemic control through actions in metabolic target tissues, rosiglitazone has numerous biological actions that impact on cardiovascular homeostasis. Some of these actions are helpful (e.g., improving endothelial function), whereas others are potentially harmful (e.g., promoting fluid retention). Since cardiovascular morbidity and mortality are major endpoints for diabetes, it is essential to understand how the natural history of diabetes alters the net benefits and risks of rosiglitazone therapy. This complex issue is an important determinant of optimal use of rosiglitazone and is critical for understanding cardiovascular safety issues. We give special attention to the effects of rosiglitazone in diabetic patients with stable coronary artery disease and the impact of rosiglitazone actions on atherosclerosis and plaque instability. This provides a rational conceptual framework for predicting evolving benefit/risk profiles that inform optimal use of rosiglitazone in the clinical setting and help explain the results of recent large clinical intervention trials where rosiglitazone had disappointing cardiovascular outcomes. Thus, in this perspective, we describe what is known about the molecular mechanisms of action of rosiglitazone on cardiovascular targets in the context of the evolving pathophysiology of diabetes over its natural history.

Pioglitazone therapy in progressive differentiated thyroid carcinoma

Rosiglitazone achieved promising results in progressive differentiated thyroid carcinoma (DTC) with redifferentiative and antiproliferative effects, but has been taken off the market. Thus we evaluated another glitazone, pioglitazone, expecting similar positive results. PATIENT, MATERIALS, METHODS: Five patients with progressive DTC and no or only negligible iodine uptake were enrolled. Oral pioglitazone treatment was applied for 6 months. The re-differentiative effect was assessed by 124I-NaI PET/CT dosimetry and the anti-proliferative effect by 18F-FDG PET/CT imaging. A redifferentiative effect of pioglitazone could not be shown. Lesion dosimetry indicated that 3/5 patients had unchanged no lesion absorbed dose per administered activity (LDpA) in any tumour lesion, 2/5 patients had a deterioration of LDpA within some lesions, thus radioiodine therapy was not performed in any patient. Volumetric analysis, using RECIST criteria, revealed progressive disease in 3/5 patients and stable disease in 2/5 patients. Metabolic changes, using EORTC criteria, revealed 3/5 patients with progressive metabolic disease, 1/5 patient with stable metabolic disease and 1/5 patients with partial metabolic response. The medication was well-tolerated, and no patient developed clinically important toxicity associated with the treatment. Pioglitazone revealed some positive effects in radioiodine negative and progressive DTC patients but it did not fulfill the expectations given by the results of rosiglitazone therapy.