Comparison of Vildagliptin and Pioglitazone in Korean Patients with Type 2 Diabetes Inadequately Controlled with Metformin.

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Kim, Jong Ho; Kim, Sang Soo; Baek, Hong Sun; Lee, In Kyu; Chung, Dong Jin; Sohn, Ho Sang; Bae, Hak Yeon; Kim, Mi Kyung; Park, Jeong Hyun; Choi, Young Sik; Kim, Young Il; Hahm, Jong Ryeal; Lee, Chang Won; Jo, Sung Rae; Park, Mi Kyung; Lee, Kwang Jae; Kim, In Joo

2016-06-01

We compared the efficacies of vildagliptin (50 mg twice daily) relative to pioglitazone (15 mg once daily) as an add-on treatment to metformin for reducing glycosylated hemoglobin (HbA1c) levels in Korean patients with type 2 diabetes. The present study was a multicenter, randomized, active-controlled investigation comparing the effects of vildagliptin and pioglitazone in Korean patients receiving a stable dose of metformin but exhibiting inadequate glycemic control. Each patient underwent a 16-week treatment period with either vildagliptin or pioglitazone as an add-on treatment to metformin. The mean changes in HbA1c levels from baseline were -0.94% in the vildagliptin group and -0.6% in the pioglitazone group and the difference between the treatments was below the non-inferiority margin of 0.3%. The mean changes in postprandial plasma glucose (PPG) levels were -60.2 mg/dL in the vildagliptin group and -38.2 mg/dL in the pioglitazone group and these values significantly differed (P=0.040). There were significant decreases in the levels of total, low density lipoprotein, high density lipoprotein (HDL), and non-HDL cholesterol in the vildagliptin group but increases in the pioglitazone group. The mean change in body weight was -0.07 kg in the vildagliptin group and 0.69 kg in the pioglitazone group, which were also significantly different (P=0.002). As an add-on to metformin, the efficacy of vildagliptin for the improvement of glycemic control is not inferior to that of pioglitazone in Korean patients with type 2 diabetes. In addition, add-on treatment with vildagliptin had beneficial effects on PPG levels, lipid profiles, and body weight compared to pioglitazone.

Comparison of Vildagliptin and Pioglitazone in Korean Patients with Type 2 Diabetes Inadequately Controlled with Metformin

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Jong Ho Kim

2016-04-01

Full Text Available BackgroundWe compared the efficacies of vildagliptin (50 mg twice daily relative to pioglitazone (15 mg once daily as an add-on treatment to metformin for reducing glycosylated hemoglobin (HbA1c levels in Korean patients with type 2 diabetes.MethodsThe present study was a multicenter, randomized, active-controlled investigation comparing the effects of vildagliptin and pioglitazone in Korean patients receiving a stable dose of metformin but exhibiting inadequate glycemic control. Each patient underwent a 16-week treatment period with either vildagliptin or pioglitazone as an add-on treatment to metformin.ResultsThe mean changes in HbA1c levels from baseline were –0.94% in the vildagliptin group and –0.6% in the pioglitazone group and the difference between the treatments was below the non-inferiority margin of 0.3%. The mean changes in postprandial plasma glucose (PPG levels were –60.2 mg/dL in the vildagliptin group and –38.2 mg/dL in the pioglitazone group and these values significantly differed (P=0.040. There were significant decreases in the levels of total, low density lipoprotein, high density lipoprotein (HDL, and non-HDL cholesterol in the vildagliptin group but increases in the pioglitazone group. The mean change in body weight was –0.07 kg in the vildagliptin group and 0.69 kg in the pioglitazone group, which were also significantly different (P=0.002.ConclusionAs an add-on to metformin, the efficacy of vildagliptin for the improvement of glycemic control is not inferior to that of pioglitazone in Korean patients with type 2 diabetes. In addition, add-on treatment with vildagliptin had beneficial effects on PPG levels, lipid profiles, and body weight compared to pioglitazone.

Decreased incidence of gout in diabetic patients using pioglitazone.

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Niu, Sheng-Wen; Chang, Kai-Ting; Lin, Hugo You-Hsien; Kuo, I-Ching; Chang, Yu-Han; Chen, Yu-Han; Hung, Chi-Chih; Chiu, Yi-Wen; Hwang, Shang-Jyh

2018-01-01

The incidence and prevalence of gout are increasing, but the management is poor. Considering the increased prevalence of gout in the diabetic population, this study evaluated the effects of pioglitazone, an insulin resistance inhibitor, on the incidence of gout in the diabetic population. We used data from the National Health Insurance program in Taiwan. The pioglitazone cohort contained 30 100 patients and each patient was age and sex matched with three non-pioglitazone users who were randomly selected from the diabetic population. Cox proportional hazards regression analysis was conducted to estimate the effects of pioglitazone on the incidence of gout in the diabetic population. The incidence of gout was significantly lower in pioglitazone users than in non-pioglitazone users [adjusted hazard ratio (aHR) 0.81 (95% CI 0.78, 0.85)]. The HR for the incidence of gout was lower in both male [aHR 0.80 (95% CI 0.75, 0.85)] and female [aHR 0.83 (95% CI 0.78, 0.88)] pioglitazone users than in non-pioglitazone users. An analysis of three age groups (gout in the diabetic population using pioglitazone was less. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Total and high molecular weight (HMW) adiponectin levels and measures of glucose and lipid metabolism following pioglitazone treatment in a randomized placebo-controlled study in polycystic ovary syndrome

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Glintborg, Dorte; Frystyk, Jan; Højlund, Kurt

2008-01-01

and controls and examined possible mechanisms for increased insulin sensitivity during pioglitazone treatment. STUDY SUBJECTS: Thirty PCOS patients randomized to pioglitazone, 30 mg/day, or placebo for 16 weeks and 14 weight-matched healthy females were studied. DESIGN: Total and HMW adiponectin levels were...... measured, and euglycaemic hyperinsulinaemic clamps and indirect calorimetry were performed. Delta-values denoted changes during pioglitazone treatment (16 weeks--basal). RESULTS: Pretreatment adiponectin levels were decreased in PCOS patients vs. controls (P ...OBJECTIVE: Recent studies suggested that the effect of adiponectin on insulin-stimulated glucose metabolism is mediated primarily by the high molecular weight (HMW) form of adiponectin. In the present study we evaluated total and HMW adiponectin in polycystic ovary syndrome (PCOS) patients...

Baseline adiponectin levels do not influence the response to pioglitazone in ACT NOW.

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Tripathy, Devjit; Clement, Stephen C; Schwenke, Dawn C; Banerji, MaryAnn; Bray, George A; Buchanan, Thomas A; Gastaldelli, Amalia; Henry, Robert R; Kitabchi, Abbas E; Mudaliar, Sunder; Ratner, Robert E; Stentz, Frankie B; Musi, Nicolas; Reaven, Peter D; DeFronzo, Ralph A

2014-06-01

Plasma adiponectin levels are reduced in type 2 diabetes mellitus (T2DM) and other insulin-resistant states. We examined whether plasma adiponectin levels at baseline and after pioglitazone treatment in impaired glucose tolerance (IGT) subjects were associated with improved insulin sensitivity (SI) and glucose tolerance status. A total of 602 high-risk IGT subjects in ACT NOW were randomized to receive pioglitazone or placebo with a median follow-up of 2.4 years. Pioglitazone reduced IGT conversion to diabetes by 72% in association with improved β-cell function by 64% (insulin secretion/insulin resistance index) and increased tissue sensitivity by 88% (Matsuda index). In pioglitazone-treated subjects, plasma adiponectin concentration increased threefold from 13 ± 0.5 to 38 ± 2.5 μg/mL (P < 0.001) and was strongly correlated with the improvement in SI (r = 0.436, P < 0.001) and modestly correlated with glucose area under the curve during oral glucose tolerance test (r = 0.238, P < 0.005) and insulin secretion/insulin resistance index (r = 0.306, P < 0.005). The increase in adiponectin was a strong predictor of reversion to normal glucose tolerance and prevention of T2DM. In the placebo group, plasma adiponectin did not change and was not correlated with changes in glucose levels. There was an inverse association between baseline plasma adiponectin concentration and progression to diabetes in the placebo group but not in the pioglitazone group. Baseline adiponectin does not predict the response to pioglitazone. The increase in plasma adiponectin concentration after pioglitazone therapy in IGT subjects is strongly related to improved glucose tolerance status and enhanced tissue sensitivity to insulin. © 2014 by the American Diabetes Association.

Pioglitazone slows progression of atherosclerosis in prediabetes independent of changes in cardiovascular risk factors

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Saremi, Aramesh; Schwenke, Dawn C.; Buchanan, Thomas A.; Hodis, Howard N.; Mack, Wendy J.; Banerji, MaryAnn; Bray, George A.; Clement, Stephen C.; Henry, Robert R.; Kitabchi, Abbas E.; Mudaliar, Sunder; Ratner, Robert E.; Stentz, Frankie B.; Musi, Nicolas; Tripathy, Devjit; DeFronzo, Ralph A.; Reaven, Peter D.

2013-01-01

Objective To determine whether changes in standard and novel risk factors during the ACT NOW trial explained the slower rate of CIMT progression with pioglitazone treatment in persons with prediabetes. Methods and Results CIMT was measured in 382 participants at the beginning and up to three additional times during follow-up of the ACT NOW trial. During an average follow-up of 2.3 years, the mean unadjusted annual rate of CIMT progression was significantly (P=0.01) lower with pioglitazone treatment (4.76 × 10−3 mm/year, 95% CI, 2.39 × 10−3 – 7.14 × 10−3 mm/year) compared with placebo (9.69 × 10−3 mm/year, 95% CI, 7.24 × 10−3 – 12.15 × 10−3 mm/year). High-density lipoprotein cholesterol, fasting and 2-hour glucose, HbA1c, fasting insulin, Matsuda insulin sensitivity index, adiponectin and plasminogen activator inhibitor-1 levels improved significantly with pioglitazone treatment compared with placebo (P < 0.001). However, the effect of pioglitazone on CIMT progression was not attenuated by multiple methods of adjustment for traditional, metabolic and inflammatory risk factors and concomitant medications, and was independent of changes in risk factors during pioglitazone treatment. Conclusions Pioglitazone slowed progression of CIMT, independent of improvement in hyperglycemia, insulin resistance, dyslipidemia and systemic inflammation in prediabetes. These results suggest a possible direct vascular benefit of pioglitazone. PMID:23175674

Effect of pioglitazone versus insulin glargine on cardiac size, function, and measures of fluid retention in patients with type 2 diabetes

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Groop Leif

2009-03-01

Full Text Available Abstract Background Both insulin and thiazolidinediones (TZDs are effective in the treatment of hyperglycaemia and amelioration of insulin resistance in type 2 diabetes but have side effects including weight gain and fluid retention. The use of TZDs has been further hampered by the risk of adverse cardiovascular events including heart failure. The present study evaluated the effect of pioglitazone or insulin glargine on cardiac function and size as well as on surrogate markers of fluid retention such as weight, haemoglobin and natriuretic peptides. Methods Thirty patients with inadequate glycaemic control on metformin and sulfonylurea were randomised to receive add-on therapy with insulin glargine or pioglitazone for 26 weeks. Echocardiographic data and blood samples were collected from the two groups before the start of the treatment and after 26 weeks. Left ventricular end-diastolic and left atrial end-systolic volumes were quantified, weight measured and blood samples analyzed. Results After 26 weeks of treatment, the changes in HbA1c, weight and haemoglobin were similar between the two groups. HDL increased significantly in the pioglitazone group. While there was an increase in natriuretic peptides in the pioglitazone group (NT-proBNP 11.4 ± 19.6 to 22.8 ± 44.0, p = 0.046, the difference between the treatment groups was not significant. Left ventricular end-diastolic volume increased by 11% and left atrial end-systolic volume by 17% in the pioglitazone group (Both, p Conclusion This randomised pilot-study showed that six-month treatment with pioglitazone induced significant increases in natriuretic peptides and alterations of cardiac size. These changes were not observed with insulin glargine, which also is known to induce fluid retention. Larger randomised trials are warranted to confirm these findings.

Pioglitazone retrieves hepatic antioxidant DNA repair in a mice model of high fat diet

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Yang Ching-Hsiu

2008-09-01

Full Text Available Abstract Background Pioglitazone was reported to improve hepatic steatosis and necroinflammation in human studies. To investigate whether the hepato-protective effect of pioglitazone was associated with an improvement of antioxidant defense mechanism, oxidative DNA damage and repair activity were determined in a high fat diet model. Male C57BL/6 mice were respectively fed with a 30% fat diet, the same diet with pioglitazone 100 mg/kg/day, or a chow diet as control for 8 weeks. Tissue oxidative stress was indicated by malondialdehyde concentration. Oxidative DNA damage was detected by immunohistochemical 8-oxoG staining. Enzymatic antioxidant defense was detected by the real-time PCR of superoxide dismutase (Sod1, Sod2 and DNA glycosylase (Ogg1, MutY. Oxidative DNA repair was detected by immunohistochemical staining and western blotting of OGG1 expression. Results Our results show that hepatic steatosis was induced by a high-fat diet and improved by adding pioglitazone. Malondialdehyde concentration and 8-oxoG staining were strongly increased in the high-fat diet group, but attenuated by pioglitazone. Gene expressions of antioxidant defense mechanism: Sod1, Sod2, Ogg1 and MutY significantly decreased in the high-fat diet group but reversed by pioglitazone co-administration. Conclusion The attenuation of hepatic oxidative DNA damage by pioglitazone in a high-fat diet may be mediated by up-regulation of the antioxidant defense mechanism and oxidative DNA repair activity. The diminution of oxidative damage may explain the clinical benefit of pioglitazone treatment in patients with non-alcoholic fatty liver disease.

Pioglitazone retrieves hepatic antioxidant DNA repair in a mice model of high fat diet

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Hsiao, Pi-Jung; Hsieh, Tusty-Jiuan; Kuo, Kung-Kai; Hung, Wei-Wen; Tsai, Kun-Bow; Yang, Ching-Hsiu; Yu, Ming-Lung; Shin, Shyi-Jang

2008-01-01

Background Pioglitazone was reported to improve hepatic steatosis and necroinflammation in human studies. To investigate whether the hepato-protective effect of pioglitazone was associated with an improvement of antioxidant defense mechanism, oxidative DNA damage and repair activity were determined in a high fat diet model. Male C57BL/6 mice were respectively fed with a 30% fat diet, the same diet with pioglitazone 100 mg/kg/day, or a chow diet as control for 8 weeks. Tissue oxidative stress was indicated by malondialdehyde concentration. Oxidative DNA damage was detected by immunohistochemical 8-oxoG staining. Enzymatic antioxidant defense was detected by the real-time PCR of superoxide dismutase (Sod1, Sod2) and DNA glycosylase (Ogg1, MutY). Oxidative DNA repair was detected by immunohistochemical staining and western blotting of OGG1 expression. Results Our results show that hepatic steatosis was induced by a high-fat diet and improved by adding pioglitazone. Malondialdehyde concentration and 8-oxoG staining were strongly increased in the high-fat diet group, but attenuated by pioglitazone. Gene expressions of antioxidant defense mechanism: Sod1, Sod2, Ogg1 and MutY significantly decreased in the high-fat diet group but reversed by pioglitazone co-administration. Conclusion The attenuation of hepatic oxidative DNA damage by pioglitazone in a high-fat diet may be mediated by up-regulation of the antioxidant defense mechanism and oxidative DNA repair activity. The diminution of oxidative damage may explain the clinical benefit of pioglitazone treatment in patients with non-alcoholic fatty liver disease. PMID:18822121

Pioglitazone could induce remission in major depression: a meta-analysis

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Colle R

2016-12-01

Full Text Available Romain Colle,1,* Delphine de Larminat,1,* Samuel Rotenberg,1 Franz Hozer,1 Patrick Hardy,1 Céline Verstuyft,2 Bruno Fève,3,* Emmanuelle Corruble1,* 1Psychiatry Department, Hôpital Bicêtre, INSERM, UMR S1178, University Paris-Sud, Assistance Publique-Hôpitaux de Paris, Le Kremlin Bicêtre, France; 2Molecular Genetic, Pharmacogenetics and Hormonology Department, Hôpital Bicêtre, INSERM UMR_S1184, Centre IMVA, University Paris-Sud, Assistance Publique-Hôpitaux de Paris, Le Kremlin Bicêtre, France; 3Endocrinology Department, INSERM UMR_S938, Hôpital Saint-Antoine, Centre de Recherche Saint-Antoine, Institut Hospitalo-Universitaire ICAN, Sorbonne Universités, Université Pierre et Marie Curie, Assistance Publique des Hôpitaux de Paris, Paris, France *These authors contributed equally to this work Background: Pioglitazone, a selective agonist of the nuclear transcription factor peroxisome proliferator-activated receptor-gamma (PPAR-γ, prescribed for the treatment of type 2 diabetes, could have antidepressant properties. However, its potential to induce remission of major depressive episodes, the optimal clinical target for an antidepressant drug, is a matter of concern. Indeed, only one out of four double-blind randomized controlled trials show higher remission rates with pioglitazone than with control treatments. Hence, the main aim of this study was to perform a meta-analysis of the efficacy of pioglitazone for the treatment of MDE, focusing on remission rates.Methods: Four double-blind randomized controlled trials, comprising 161 patients with an MDE, were included in this meta-analysis. Pioglitazone was studied either alone (one study or as add-on therapy to conventional treatments (antidepressant drugs or lithium salts. It was compared either to placebo (three studies or to metformin (one study. Remission was defined by a Hamilton Depression Rating Scale score <8 after treatment.Results: Pioglitazone could induce higher remission

Comparison of the effect between pioglitazone and metformin in treating patients with PCOS:a meta-analysis.

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Xu, Yifeng; Wu, Yanxiang; Huang, Qin

2017-10-01

Pioglitazone was used to treat patients of PCOS in many researches, but the treatment has not been recognized by public or recommended by all the guidelines. We conducted a meta-analysis of the related literatures to objectively evaluate the clinical effectiveness and safety by comparing pioglitazone with metformin administrated by PCOS patients. Searches were performed in Cochrane Library, EMBASE and PubMed (last updated December 2016). Eleven studies among 486 related articles were identified through searches. Fixed effects and random effects models were used to calculate the overall risk estimates. The results of the meta-analysis suggest that improvement of the menstrual cycle and ovulation in pioglitazone treatment group was better than metformin group [OR = 2.31, 95% CI (1.37, 3.91), P treatment group was better than pioglitazone group [SMD = 0.29, 95% CI (0.0, 0.59), P = 0.048, I 2  = 0.0%]. BMI was more elevated in pioglitazone group than in metformin group [SMD = 0.83, 95% CI (0.24, 1.41), P = 0.006, I 2  = 82.8%]. There were no significant differences of the other data between the two groups. This meta-analysis indicated that pioglitazone ameliorated menstrual cycle and ovulation better than metformin and metformin ameliorated BMI and F-G scores better than pioglitazone in treating patients with PCOS. Pioglitazone might be a good choice for the patients with PCOS who were intolerant or invalid to metformin for the treatment.

Renal function preservation with pioglitazone or with basal insulin as an add-on therapy for patients with type 2 diabetes mellitus.

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Chang, Yu-Hung; Hwu, Der-Wei; Chang, Dao-Ming; An, Ling-Wang; Hsieh, Chang-Hsun; Lee, Yau-Jiunn

2017-06-01

Clinical outcome may differ owing to the distinct pharmacological characteristics of insulin sensitizers and insulin. This study was performed to compare the metabolic and renal function changes with add-on pioglitazone treatment versus basal insulin in patients with type 2 diabetes mellitus (DM) in whom sulfonylurea and metformin regimens failed. Patients who were consecutively managed in the diabetes comprehensive program with add-on pioglitazone or detemir/glargine treatment for at least 2 years following sulfonylurea and metformin treatment failure were included. A total of 1002 patients were enrolled (pioglitazone: 559, detemir: 264, glargine: 179). After propensity score matching, there were 105 patients with matchable baseline characteristics in each group. After a mean of 3.5 years of follow-up, the pioglitazone group showed a greater HbA1c reduction than the detemir group and the glargine group. Despite patients in all three groups exhibiting significant body weight gain, those in the pioglitazone group and the glargine group showed greater body weight increases than the patients in the detemir group (2.1, 1.6 and 0.8 kg, respectively, p 1.79-3.88) and 3.13 (95% CI 2.01-4.87), respectively. Our study first showed that treatment with both pioglitazone and basal insulin improved glycemic control, while only pioglitazone treatment was observed to be advantageous in terms of preserving renal function when used as an add-on therapy for patients with type 2 DM in whom sulfonylurea and metformin regimens failed.

Cost-effectiveness of pioglitazone in type 2 diabetes patients with a history of macrovascular disease: a German perspective

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Massi-Benedetti Massimo

2009-05-01

Full Text Available Abstract Background The aim of this study was to project health-economic outcomes relevant to the German setting for the addition of pioglitazone to existing treatment regimens in patients with type 2 diabetes, evidence of macrovascular disease and at high risk of cardiovascular events. Methods Event rates corresponding to macrovascular outcomes from the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive study of pioglitazone were used with a modified version of the CORE Diabetes Model to simulate outcomes over a 35-year time horizon. Direct medical costs were accounted from a healthcare payer perspective in year 2005 values. Germany specific costs were applied for patient treatment, hospitalization and management. Both costs and clinical benefits were discounted at 5.0% per annum. Results Over patient lifetimes pioglitazone treatment improved undiscounted life expectancy by 0.406 years and improved quality-adjusted life expectancy by 0.120 quality-adjusted life years (QALYs compared to placebo. Direct medical costs (treatment plus complication costs were marginally higher for pioglitazone treatment and calculation of the incremental cost-effectiveness ratio (ICER produced a value of €13,294 per QALY gained with the pioglitazone regimen versus placebo. Acceptability curve analysis showed that there was a 78.2% likelihood that pioglitazone would be considered cost-effective in Germany, using a "good value for money" threshold of €50,000 per QALY gained. Sensitivity analyses showed that the results were most sensitive to changes in the simulation time horizon. After adjustment for the potential stabilization of pancreatic β-cell function with pioglitazone treatment, the ICER was €6,667 per QALY gained for pioglitazone versus placebo. Conclusion The findings of this modelling analysis indicated that, for patients with a history of macrovascular disease, addition of pioglitazone to existing therapy reduces the long

Combination therapy with DPP-4 inhibitors and pioglitazone in type 2 diabetes: theoretical consideration and therapeutic potential

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Nasser Mikhail

2008-12-01

Full Text Available Nasser MikhailEndocrinology Division, Olive View-UCLA Medical Center, David-Geffen School of Medicine, CA, USAAbstract: Sitagliptin and vildagliptin represent a new class of anti-diabetic agents that enhance the action of incretin hormones through inhibition of dipeptidyl peptidase-4 (DPP-4, the enzyme that normally inactivates incretin hormones. Because of their distinct mechanism of action, DPP-4 inhibitors can be used as add-on therapy to other classes of drugs for treatment of type 2 diabetes. The objective of this review is to critically evaluate clinical trials of sitagliptin and vildagliptin in combination with pioglitazone. The addition of either sitagliptin or vildagliptin to ongoing pioglitazone therapy is associated with reduction in average hemoglobin A1c (HbA1c levels of approximately 0.7% compared with placebo and 1% compared with baseline after 24 weeks. When started concomitantly in drug-naïve patients, the combination of pioglitazone 30 mg and vildagliptin 100 mg qd reduces HbA1c by 1.9% after 24 weeks, compared with 1.1% with pioglitazone monotherapy. In general, the addition of DPP-4 inhibitors to pioglitazone was well tolerated, did not increase the incidence of hypoglycemia, and did not substantially worsen the weight-gain induced by pioglitazone. The combination of sitagliptpin or vildagliptin with pioglitazone can be a useful therapeutic approach in patients with type 2 diabetes who cannot tolerate metformin or a sulfonylurea.Keywords: incretins, sitagliptin, vildagliptin, dipeptidyl peptidase inhibitors, pioglitazone, type 2 diabetes

Protective effect of pioglitazone on cardiomyocyte apoptosis in low-dose streptozotocin & high-fat diet-induced type-2 diabetes in rats

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Uma Bhandari

2015-01-01

Full Text Available Background & objectives: Cardiomyocyte apoptosis is one of the pathologic phenomena associated with diabetes and related conditions including obesity, insulin resistance and hyperlipidaemia. In the present study, the protective effects of pioglitazone on cardiomyocyte apoptosis was evaluated in experimental diabetes induced by low dose of streptozoticin (STZ combined with high fat diet (HFD in rats. Methods: Male Wistar rats (150-200 g were injected with low-dose STZ (45 mg/kg, i.v., single dose and orally fed with a HFD (20 g/day/rat for a period of 28 days and simultaneously treated with pioglitazone (20 mg/kg/p.o. for a period of 21 days (from 8 th day to 28 th day. On 29 th day blood was collected, serum separated and used for biochemical parameters. Heart tissue was used for cardiomyocyte apoptosis measurement and also for histopathological examination. Results: Pioglitazone treatment resulted in a decrease in cardiomyocyte apoptosis as revealed by a decrease in cardiac caspase-3, lactate dehydrogenase (LDH levels and DNA fragmentation, and an increase in Na+K+ATPase levels in diabetic rats. Cardiac histology of diabetic control rats showed dense focal fatty infiltration in the myocardial cells whereas normal architecture with regular morphology and well preserved cytoplasm was observed with pioglitazone treatment. Pioglitazone treatment significantly reduced the heart rate, mean arterial blood pressure, body mass index (BMI and levels of serum glucose, leptin, insulin, HOMA-IR, total cholesterol (TC and triglycerides (TGs, apoliproprotein-B glycosylated haemoglobin (HbA1c levels and atherogenic index, and increased the levels of serum high density lipoprotein cholesterol (HDL-C and cardiac antioxidant enzymes. Interpretation & conclusions: The present study results suggest that pioglitazone possesses cardiac anti-apoptotic potential in diabetic rat model and can be further explored for its use for treatment of diabetic cardiomyopathy.

Enhancing pancreatic Beta-cell regeneration in vivo with pioglitazone and alogliptin.

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Hao Yin

Full Text Available Pancreatic beta-cells retain limited ability to regenerate and proliferate after various physiologic triggers. Identifying therapies that are able to enhance beta-cell regeneration may therefore be useful for the treatment of both type 1 and type 2 diabetes.In this study we investigated endogenous and transplanted beta-cell regeneration by serially quantifying changes in bioluminescence from beta-cells from transgenic mice expressing firefly luciferase under the control of the mouse insulin I promoter. We tested the ability of pioglitazone and alogliptin, two drugs developed for the treatment of type 2 diabetes, to enhance beta-cell regeneration, and also defined the effect of the immunosuppression with rapamycin and tacrolimus on transplanted islet beta mass.Pioglitazone is a stimulator of nuclear receptor peroxisome proliferator-activated receptor gamma while alogliptin is a selective dipeptidyl peptidase IV inhibitor. Pioglitazone alone, or in combination with alogliptin, enhanced endogenous beta-cell regeneration in streptozotocin-treated mice, while alogliptin alone had modest effects. In a model of syngeneic islet transplantation, immunosuppression with rapamycin and tacrolimus induced an early loss of beta-cell mass, while treatment with insulin implants to maintain normoglycemia and pioglitazone plus alogliptin was able to partially promote beta-cell mass recovery.These data highlight the utility of bioluminescence for serially quantifying functional beta-cell mass in living mice. They also demonstrate the ability of pioglitazone, used either alone or in combination with alogliptin, to enhance regeneration of endogenous islet beta-cells as well as transplanted islets into recipients treated with rapamycin and tacrolimus.

The Preventive Role of Pioglitazone in Glycerol-Induced Acute Kidney Injury in Rats during Two Different Treatment Periods

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Rama Mousleh

2018-03-01

Full Text Available Background: Acute kidney injury is the most life-threatening complication of rhabdomyolysis. Glycerol is commonly used to induce this injury. The aim was to investigate the renoprotective effects of pioglitazone and the possible advantage of administering the drug for a longer period. Methods: Twenty-four male Albino Wistar rats were randomly divided into 4 groups (n=6/group: (A control, (B glycerol (50%, 10 mL/kg intramuscularly, (C glycerol+pioglitazone (10 mg/kg orally for 3 days, and (D glycerol+pioglitazone (for 6 days. Serum urea and creatinine levels were measured to assess the renal function. Reduced glutathione (GSH levels and histological alterations were also measured. Statistical analysis was performed using Prism (version 6. The numerical data were evaluated by ANOVA, followed by the Tukey tests. The categorical data were evaluated by the Mann–Whitney test and the Fisher exact tests. P<0.05 was considered significant. Results: In the glycerol-injected rats, the serum urea and creatinine levels were increased (P<0.001, while the GSH levels were decreased (P<0.001 compared to Group A. The nephrotoxicity showed significant tubular (P=0.01 and glomerular (P=0.02 injuries. In the pioglitazone-treated rats, the changes in the serum biomarkers and in the GSH levels were reversed in Group C (P=0.01 and in Group D (P=0.01. The microscopic examinations of the kidneys also showed some improvement. No obvious statistically significant difference was found between these 2 preventive groups in most studied features. Conclusion: These results indicate that pioglitazone might have nephroprotective effects in this injury model. Pioglitazone succeeded in producing this effect within 3 days. Doubling the drug administration period did not produce any significant superior benefit.

Pioglitazone after Ischemic Stroke or Transient Ischemic Attack.

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Kernan, Walter N; Viscoli, Catherine M; Furie, Karen L; Young, Lawrence H; Inzucchi, Silvio E; Gorman, Mark; Guarino, Peter D; Lovejoy, Anne M; Peduzzi, Peter N; Conwit, Robin; Brass, Lawrence M; Schwartz, Gregory G; Adams, Harold P; Berger, Leo; Carolei, Antonio; Clark, Wayne; Coull, Bruce; Ford, Gary A; Kleindorfer, Dawn; O'Leary, John R; Parsons, Mark W; Ringleb, Peter; Sen, Souvik; Spence, J David; Tanne, David; Wang, David; Winder, Toni R

2016-04-07

Patients with ischemic stroke or transient ischemic attack (TIA) are at increased risk for future cardiovascular events despite current preventive therapies. The identification of insulin resistance as a risk factor for stroke and myocardial infarction raised the possibility that pioglitazone, which improves insulin sensitivity, might benefit patients with cerebrovascular disease. In this multicenter, double-blind trial, we randomly assigned 3876 patients who had had a recent ischemic stroke or TIA to receive either pioglitazone (target dose, 45 mg daily) or placebo. Eligible patients did not have diabetes but were found to have insulin resistance on the basis of a score of more than 3.0 on the homeostasis model assessment of insulin resistance (HOMA-IR) index. The primary outcome was fatal or nonfatal stroke or myocardial infarction. By 4.8 years, a primary outcome had occurred in 175 of 1939 patients (9.0%) in the pioglitazone group and in 228 of 1937 (11.8%) in the placebo group (hazard ratio in the pioglitazone group, 0.76; 95% confidence interval [CI], 0.62 to 0.93; P=0.007). Diabetes developed in 73 patients (3.8%) and 149 patients (7.7%), respectively (hazard ratio, 0.48; 95% CI, 0.33 to 0.69; Pischemic stroke or TIA, the risk of stroke or myocardial infarction was lower among patients who received pioglitazone than among those who received placebo. Pioglitazone was also associated with a lower risk of diabetes but with higher risks of weight gain, edema, and fracture. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT00091949.).

Pioglitazone and the risk of cardiovascular events in patients with Type 2 diabetes receiving concomitant treatment with nitrates, renin-angiotensin system blockers, or insulin: results from the PROactive study (PROactive 20).

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Erdmann, Erland; Spanheimer, Robert; Charbonnel, Bernard

2010-09-01

Patients with Type 2 diabetes mellitus (T2DM) are often treated with multiple glucose-lowering and cardiovascular agents. The concomitant use of nitrates, renin-angiotensin system (RAS) blockers, or insulin has been linked to a potential increase in myocardial ischemic risk with rosiglitazone. The PROactive database provides an opportunity to investigate the effects of these medications on the potential macrovascular benefits reported with pioglitazone. The PROactive study was a randomized double-blind prospective trial that evaluated mortality and cardiovascular morbidity in 5238 patients with T2DM and macrovascular disease. Patients received pioglitazone or placebo in addition to their baseline glucose-lowering and cardiovascular medications. The effect of pioglitazone on composite endpoints was evaluated, including all-cause death, myocardial infarction (MI), and stroke, as well as safety events of edema and serious heart failure, in subgroups using nitrates, RAS blockers, or insulin at baseline. The risk of all-cause death, MI, and stroke for pioglitazone versus placebo was similar regardless of the baseline use of nitrates, RAS blockers, or insulin, with hazard ratios ranging from 0.81 to 0.87. Similar results were obtained for the other composite endpoints analyzed. There were no significant interactions between baseline medication subgroups and treatment. The increased risk of edema and serious heart failure was consistent across the baseline medication subgroups. This post hoc analysis did not reveal an increased risk of macrovascular events with pioglitazone in patients receiving nitrates, RAS blockers, or insulin. Rather, all patients realized the same trend towards benefit with pioglitazone, and adverse events of edema and heart failure were predictable. © 2010 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Blackwell Publishing Asia Pty Ltd.

Effects of pioglitazone therapy on blood parameters, weight and BMI: a meta-analysis

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Elena Filipova

2017-11-01

Full Text Available Abstract Background Type 2 diabetes mellitus (T2DM is one of the most common diseases worldwide and insulin insufficiency and insulin resistance are two main metabolic issues connected with it. The dyslipidemia associated with insulin resistance and T2DM is characterized by higher triglycerides (TGs, higher very-low-density lipoprotein cholesterol and lower apo A1. Pioglitazone, a member of the thiazolidinedione class, with a proven antihyperglycemic effect, is known to positively influence insulin sensitivity and β-cell function and to have the potential to alter the lipid profile. Methods The aim of our meta-analysis is to summarize and determine the influence of pioglitazone on the glycemic profile and lipoprotein metabolism as well as on weight and BMI in order to highlight the benefit of pioglitazone therapy in patients with T2DM. A comprehensive literature search was conducted through the electronic databases PubMed, MEDLINE, Scopus, PsyInfo, eLIBRARY.ru (from 2000 until February 2016 to identify studies that investigate the effect of pioglitazone on the glycemic and lipid profile and on the weight and BMI. We chose the random-effects method as the primary analysis. Forest plots depict estimated results from the studies included in the analysis and funnel plots are used to evaluate publication bias. Sensitivity analyses were performed in order to evaluate the degree of influence of the consequent elimination of each individual study on the final result. Results Of the 1536 identified sources only 15 randomised trials were included in the meta-analysis. Pioglitazone treatment was associated with improvement in the glycemic profile. It reduced FPG levels by a mean of 1.1–2 mmol/l and HbA1c by a mean of 0.9–1.3%. Our results reaffirmed the hypothesis that pioglitazone has a positive influence on the lipid profile of T2DM patients with increase in TC and HDL, no significant changes in LDL and notable decrease in TGs. Results also showed

Association of pioglitazone treatment with decreased bone mineral density in obese premenopausal patients with polycystic ovary syndrome: a randomized, placebo-controlled trial

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Glintborg, D.; Andersen, Mikael; Hagen, C.

2008-01-01

OBJECTIVE: Our objective was to investigate the effect of pioglitazone on bone mineral density (BMD) and bone turnover markers in polycystic ovary syndrome (PCOS). DESIGN AND SETTING: We conducted a randomized, placebo-controlled study at an outpatient clinic at a university hospital. PATIENTS......, sex hormones, and body composition. CONCLUSION: Pioglitazone treatment was followed by decreased lumbar and hip BMD and decreased measures of bone turnover in a premenopausal study population relatively protected from bone mineral loss Udgivelsesdato: 2008/5...

Toxicological evaluation of subchronic use of pioglitazone in mice

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Said Said Elshama

2016-07-01

Full Text Available Objective(s: Pioglitazone (Actos is one of the most controversial recent oral antidiabetic drugs. It was originally authorized in the European Union in 2000, and approved as an oral monotherapy for overweight second type of diabetic patients in 2002. It belongs to the thiazolidinedione group which some of its members have been withdrawn from the market due to the hepatotoxicity or cardiotoxicity effects.This studyinvestigates sub-chronic use of pioglitazone induced toxicity in mice by the assessment of renal and liver function tests, cardiac enzymes, and some hematological indices with histological changes of liver, kidney, heart, and bladder. Materials and Methods: 120 albino mice were divided into four groups; 30 in each. The first group (control received water, second (diabetic group received alloxan only, while the third and the fourth groups received alloxan with 200 and 400 mg/kg/day of pioglitazone, respectively for 90 days. Results: Prolonged use of pioglitazone induced significant abnormalities of hepatic, renal, and cardiac biomarkers and some hematological indices associated with histopathological changes in the liver, kidney, heart, and bladder that increased based on administered dose. Conclusion: Subchronic use of pioglitazone leads to hepatic, renal, cardiac, hematological, and bladder affection depending on the applied dose.

Pioglitazone and the risk of bladder cancer: An Indian retrospective cohort study

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Sunil Gupta

2015-01-01

Full Text Available Aim: To determine whether pioglitazone is associated with an increased risk of bladder cancer among Indian type 2 diabetic patients. Methods: A retrospective data analysis of 2222 type 2 diabetic patients was conducted. The study subjects were divided into two equal groups: 1111 pioglitazone users and 1111 pioglitazone non-users. The safety of pioglitazone therapy was analyzed in terms of occurrence of bladder and other types of cancers along with its efficacy in terms of glycemic control. Parameters for assessing safety were duration of disease, duration of usage and total dose of pioglitazone consumed across age groups, glycemic control, obesity and family history of any cancer. Bladder cancer prevalence was analyzed on the basis of urinary cytology, urine routine and microscopy, hematuria, urinary nuclear matrix protein 22 analysis and ultrasonography. Results: Of the 2222 cases analysed, there was no evidence of bladder cancer in any of the studied groups, (p=not significant which was also evident among 1111 patients on Pioglitazone therapy with a cumulative dose consumption of 2737 mg to 1,31,400 mg. On subgroup analysis, there was no evidence of bladder cancer amongst patients with age >60 years, duration of diabetes > 10 years and uncontrolled diabetics (HbA1c >8% with cumulative pioglitazone consumption of >28,000 mg. A significant number of patients achieved good glycemic control (HbA1c <7.5% with pioglitazone therapy. Conclusion: Pioglitazone therapy was not associated with occurrence of bladder cancer among Indian type 2 diabetic patients and demonstrated good glycemic control.

Comparison clinical and metabolic effects of metformin and pioglitazone in polycystic ovary syndrome

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Karoon Shahebrahimi

2016-01-01

Full Text Available Introduction: Polycystic ovary syndrome (PCOS is one of the most common endocrine disorders in women. PCOS comprises a broad spectrum of anomalies, including hyperandrogenism, chronic anovulation, obesity, and infertility. Insulin resistance and its compensatory hyperinsulinemia play a key role in the pathogenicity of PCOS. This study compares the effects of 2 types of insulin sensitizer drugs, metformin and pioglitazone, on clinical, metabolic, and endocrine characteristics of women with PCOS. Methods: In this randomized clinical trial, 56 women with PCOS (ages 20–49 years were treated orally with either metformin (500 mg 3 times daily or pioglitazone (30 mg daily for 3 months. Clinical (body weight, blood pressure [BP], and body mass index and laboratory indices (fasting blood sugar [FBS], serum triglyceride [TG], cholesterol, low-density lipoprotein, high-density lipoprotein, insulin, testosterone, and dehydroepiandrosterone [DHEA] were measured before and after therapy. Data were analyzed by Chi-square and McNemar's tests. Results: Significant decreases were seen after treatment with metformin in extent of hair loss (P = 0.008, wrist circle (P = 0.011, weight (P = 0.047, diastolic BP (P = 0.023, and DHEA (P = 0.035. A significant decrease in TG was seen with pioglitazone treatment (P = 0.047. In both groups, significant decreases in acne, menstrual disturbance, FBS, and serum insulin were seen. Conclusion: There is a significant amelioration of endocrine and metabolic indices with pioglitazone in PCOS patients. Although we were not able to recommend one treatment regime over the other, pioglitazone offers a useful, alternate treatment in women with PCOS who are not able to tolerate metformin.

Effect of pioglitazone on glucose metabolism and luteinizing hormone secretion in women with polycystic ovary syndrome

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Glintborg, Dorte; Hermann, Anne Pernille; Andersen, Marianne

2006-01-01

OBJECTIVE: To thoroughly examine the mechanisms for insulin resistance in polycystic ovary syndrome (PCOS) and to evaluate the effects of pioglitazone treatment on insulin resistance, beta-cell function, LH secretion, and glucose metabolism. DESIGN: Randomized, blinded, placebo-controlled study. ......, impaired insulin-stimulated oxidative and nonoxidative glucose metabolism, which was partly reversed by pioglitazone treatment....

Comparative study of telmisartan with pioglitazone on insulin resistance in type 2 diabetic mice

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Khan, A.; Qayyum, A.; Khan, B.T.

2017-01-01

Objective: To evaluate and compare the effects of telmisartan and pioglitazone on peripheral insulin resistance in diabetic mice. Study Design: Randomized control trail. Place and Duration of Study: National Institute of Health, Islamabad and pharmacology dept, Army Medical College, from 17th March to 17th June 2014. Material and Methods: Twenty four BALB/c mice, both male and female, of 35 to 40 grams were used for this study. Animals were randomly divided into four groups. Two were taken as control groups, one was normal control and the other was diabetic control. Two were taken as interventional groups and received either pioglitazone or telmisartan for four weeks after induction of diabetes. Results: After treatment, pioglitazone reduced all the biochemical parameters significantly when compared with diabetic control. Negative correlation between glucose and insulin was changed into positive correlation (r-value, 0.92) with significant p-value (0.015) in pioglitazone treated group, while telmisartan only managed to convert a negative correlation between insulin and glucose into statistically non-significant positive. Conclusion: Telmisartan although reduces glucose levels and improves beta cell mass but the effect is statistically non-significant as compared to pioglitazone. In hypertensive type 2 diabetics a combination of these two drugs may help in reducing the dose of pioglitazone and consequently the cardiovascular adverse effects of pioglitazone. (author)

Nanoparticle-mediated delivery of pioglitazone enhances therapeutic neovascularization in a murine model of hindlimb ischemia.

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Nagahama, Ryoji; Matoba, Tetsuya; Nakano, Kaku; Kim-Mitsuyama, Shokei; Sunagawa, Kenji; Egashira, Kensuke

2012-10-01

Critical limb ischemia is a severe form of peripheral artery disease (PAD) for which neither surgical revascularization nor endovascular therapy nor current medicinal therapy has sufficient therapeutic effects. Peroxisome proliferator activated receptor-γ agonists present angiogenic activity in vitro; however, systemic administration of peroxisome proliferator-activated receptor-γ agonists is hampered by its side effects, including heart failure. Here, we demonstrate that the nanoparticle (NP)-mediated delivery of the peroxisome proliferator activated receptor-γ agonist pioglitazone enhances its therapeutic efficacy on ischemia-induced neovascularization in a murine model. In a nondiabetic murine model of hindlimb ischemia, a single intramuscular injection of pioglitazone-incorporated NP (1 µg/kg) into ischemic muscles significantly improved the blood flow recovery in the ischemic limbs, significantly increasing the number of CD31-positive capillaries and α-smooth muscle actin-positive arterioles. The therapeutic effects of pioglitazone-incorporated NP were diminished by the peroxisome proliferator activated receptor-γ antagonist GW9662 and were not observed in endothelial NO synthase-deficient mice. Pioglitazone-incorporated NP induced endothelial NO synthase phosphorylation, as demonstrated by Western blot analysis, as well as expression of multiple angiogenic growth factors in vivo, including vascular endothelial growth factor-A, vascular endothelial growth factor-B, and fibroblast growth factor-1, as demonstrated by real-time polymerase chain reaction. Intramuscular injection of pioglitazone (1 µg/kg) was ineffective, and oral administration necessitated a >500 μg/kg per day dose to produce therapeutic effects equivalent to those of pioglitazone-incorporated NP. NP-mediated drug delivery is a novel modality that may enhance the effectiveness of therapeutic neovascularization, surpassing the effectiveness of current treatments for peripheral artery

Pioglitazone Improves In Vitro Viability and Function of Endothelial Progenitor Cells from Individuals with Impaired Glucose Tolerance

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Spigoni, Valentina; Picconi, Angela; Cito, Monia; Ridolfi, Valentina; Bonomini, Sabrina; Casali, Chiara; Zavaroni, Ivana; Gnudi, Luigi; Metra, Marco; Dei Cas, Alessandra

2012-01-01

Background Evidence suggests that the PPARγ-agonist insulin sensitizer pioglitazone, may provide potential beneficial cardiovascular (CV) effects beyond its anti-hyperglycaemic function. A reduced endothelial progenitor cell (EPC) number is associated with impaired glucose tolerance (IGT) or diabetes, conditions characterised by increased CV risk. Aim To evaluate whether pioglitazone can provide benefit in vitro in EPCs obtained from IGT subjects. Materials and Methods Early and late-outgrowth EPCs were obtained from peripheral blood mononuclear cells of 14 IGT subjects. The in vitro effect of pioglitazone (10 µM) with/without PPARγ-antagonist GW9662 (1 µM) was assessed on EPC viability, apoptosis, ability to form tubular-like structures and pro-inflammatory molecule expression. Results Pioglitazone increased early and late-outgrowth EPC viability, with negligible effects on apoptosis. The capacity of EPCs to form tubular-like structures was improved by pioglitazone in early (mean increase 28%; p = 0.005) and late-outgrowth (mean increase 30%; p = 0.037) EPCs. Pioglitazone reduced ICAM-1 and VCAM-1 adhesion molecule expression in both early (p = 0.001 and p = 0.012 respectively) and late-outgrowth (p = 0.047 and p = 0.048, respectively) EPCs. Similarly, pioglitazone reduced TNFα gene and protein expression in both early (p = 0.034;p = 0.022) and late-outgrowth (p = 0.026;p = 0.017) EPCs compared to control. These effects were prevented by incubation with the PPARγ-antagonist GW9662. Conclusion Pioglitazone exerts beneficial effects in vitro on EPCs isolated from IGT subjects, supporting the potential implication of pioglitazone as a CV protective agents. PMID:23139771

Metformin and pioglitazone combination therapy ameliorate polycystic ovary syndrome through AMPK/PI3K/JNK pathway

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Wu, Yuanyuan; Li, Pengfen; Zhang, Dan; Sun, Yingpu

2018-01-01

Polycystic ovary syndrome (PCOS) is a common gynecological endocrine disorder, which results in health problems such as menstrual disorders, hyperandrogenism and persistent anovulation. Hyperandrogenism and insulin resistance are the basic characteristics of PCOS. To investigate the combined effect of metformin and pioglitazone on POCS and the potential mechanisms, a rat model of PCOS was established by intramuscular injection of estradiol valerate (EV). The effect of metformin and pioglitazone monotherapy or combination therapy in control rats and PCOS rats was evaluated, involving the testosterone level, follicular development and insulin resistance. The potential mechanism for the therapeutic effect of metformin and pioglitazone on POCS was explored through using three inhibitors of the 5′adenosine monophosphate-activated protein kinase (AMPK)/phosphoinositide-3 kinase (PI3K)/c-Jun N-terminal kinase (JNK) pathway (Compound C, Wortmannin and SP600125). The results showed that EV-induced PCOS rats demonstrated hyperandrogenemia, hyperinsulinemia and follicular dysplasia. Metformin or pioglitazone monotherapy significantly suppressed the high level of testosterone, reduced the raised percentage of cystic follicles and primary follicles, promoted the number of early antral follicles, and markedly decreased the high concentration of fasting insulin and homeostatic model assessment for insulin resistance index in PCOS rats. In addition, metformin and pioglitazone combination therapy demonstrated greater efficacy than its individual components. Furthermore, individual or joint treatment with metformin and pioglitazone affected the phosphorylation level of JNK in PCOS rats. Compound C and Wortmannin eliminated the effect of metformin and pioglitazone combination therapy on improving the follicular growth in PCOS rats, whereas SP600125 treatment enhanced this combination therapy effect. These data suggested that metformin and pioglitazone combination therapy

The effect of pioglitazone and resistance training on body composition in older men and women undergoing hypocaloric weight loss.

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Shea, M Kyla; Nicklas, Barbara J; Marsh, Anthony P; Houston, Denise K; Miller, Gary D; Isom, Scott; Miller, Michael E; Carr, J Jeffrey; Lyles, Mary F; Harris, Tamara B; Kritchevsky, Stephen B

2011-08-01

Age-related increases in ectopic fat accumulation are associated with greater risk for metabolic and cardiovascular diseases, and physical disability. Reducing skeletal muscle fat and preserving lean tissue are associated with improved physical function in older adults. PPARγ-agonist treatment decreases abdominal visceral adipose tissue (VAT) and resistance training preserves lean tissue, but their effect on ectopic fat depots in nondiabetic overweight adults is unclear. We examined the influence of pioglitazone and resistance training on body composition in older (65-79 years) nondiabetic overweight/obese men (n = 48, BMI = 32.3 ± 3.8 kg/m(2)) and women (n = 40, BMI = 33.3 ± 4.9 kg/m(2)) during weight loss. All participants underwent a 16-week hypocaloric weight-loss program and were randomized to receive pioglitazone (30 mg/day) or no pioglitazone with or without resistance training, following a 2 × 2 factorial design. Regional body composition was measured at baseline and follow-up using computed tomography (CT). Lean mass was measured using dual X-ray absorptiometry. Men lost 6.6% and women lost 6.5% of initial body mass. The percent of fat loss varied across individual compartments. Men who were given pioglitazone lost more visceral abdominal fat than men who were not given pioglitazone (-1,160 vs. -647 cm(3), P = 0.007). Women who were given pioglitazone lost less thigh subcutaneous fat (-104 vs. -298 cm(3), P = 0.002). Pioglitazone did not affect any other outcomes. Resistance training diminished thigh muscle loss in men and women (resistance training vs. no resistance training men: -43 vs. -88 cm(3), P = 0.005; women: -34 vs. -59 cm(3), P = 0.04). In overweight/obese older men undergoing weight loss, pioglitazone increased visceral fat loss and resistance training reduced skeletal muscle loss. Additional studies are needed to clarify the observed gender differences and evaluate how these changes in body composition influence functional status.

PPARγ agonist pioglitazone improves cerebellar dysfunction at pre-Aβ deposition stage in APPswe/PS1dE9 Alzheimer's disease model mice

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Toba, Junya; Nikkuni, Miyu; Ishizeki, Masato; Yoshii, Aya; Watamura, Naoto; Inoue, Takafumi; Ohshima, Toshio

2016-01-01

Alzheimer's disease (AD) is one of the best known neurodegenerative diseases; it causes dementia and its pathological features include accumulation of amyloid β (Aβ) and neurofibrillary tangles (NFTs) in the brain. Elevated Cdk5 activity and CRMP2 phosphorylation have been reported in the brains of AD model mice at the early stage of the disease, but the significance thereof in human AD remains unelucidated. We have recently reported that Aβ accumulation in the cerebellum of AD model APPswe/PS1dE9 (APP/PS1) mice, and cerebellar dysfunctions, such as impairment of motor coordination ability and long-term depression (LTD) induction, at the pre-Aβ accumulation stage. In the present study, we found increased phosphorylation levels of CRMP2 as well as increased p35 protein levels in the cerebellum of APP/PS1 mice. Interestingly, we show that pioglitazone, an agonist of peroxisome proliferator-activated receptor γ, normalized the p35 protein and CRMP2 phosphorylation levels in the cerebellum. Impaired motor coordination ability and LTD in APP/PS1 mice were ameliorated by pioglitazone treatment at the pre-Aβ accumulation stage. These results suggest a correlation between CRMP2 phosphorylation and AD pathophysiology, and indicate the effectiveness of pioglitazone treatment at the pre-Aβ accumulation stage in AD model mice. -- Highlights: •Phosphorylation level of CRMP2 increased in the cerebellum of APP/PS1 mice. •p35 protein levels increased in the cerebellum of APP/PS1 mice. •Pioglitazone treatment improved cerebellar dysfunction of APP/PS1 mice.

Evaluation of the PPAR-γ Agonist Pioglitazone in Mild Asthma: A Double-Blind Randomized Controlled Trial.

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J R Anderson

Full Text Available Peroxisome proliferator-activated receptor gamma (PPAR-γ is a nuclear receptor that modulates inflammation in models of asthma. To determine whether pioglitazone improves measures of asthma control and airway inflammation, we performed a single-center randomized, double-blind, placebo-controlled, parallel-group trial.Sixty-eight participants with mild asthma were randomized to 12 weeks pioglitazone (30 mg for 4 weeks, then 45 mg for 8 weeks or placebo. The primary outcome was the adjusted mean forced expiratory volume in one second (FEV1 at 12 weeks. The secondary outcomes were mean peak expiratory flow (PEF, scores on the Juniper Asthma Control Questionnaire (ACQ and Asthma Quality of Life Questionnaire (AQLQ, fractional exhaled nitric oxide (FeNO, bronchial hyperresponsiveness (PD20, induced sputum counts, and sputum supernatant interferon gamma-inducible protein-10 (IP-10, vascular endothelial growth factor (VEGF, monocyte chemotactic protein-1 (MCP-1, and eosinophil cationic protein (ECP levels. Study recruitment was closed early after considering the European Medicines Agency's reports of a potential increased risk of bladder cancer with pioglitazone treatment. Fifty-five cases were included in the full analysis (FA and 52 in the per-protocol (PP analysis.There was no difference in the adjusted FEV1 at 12 weeks (-0.014 L, 95% confidence interval [CI] -0.15 to 0.12, p = 0.84 or in any of the secondary outcomes in the FA. The PP analysis replicated the FA, with the exception of a lower evening PEF in the pioglitazone group (-21 L/min, 95% CI -39 to -4, p = 0.02.We found no evidence that treatment with 12 weeks of pioglitazone improved asthma control or airway inflammation in mild asthma.ClinicalTrials.gov NCT01134835.

Pioglitazone administration alters ovarian gene expression in aging obese lethal yellow mice

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Weber Mitch

2008-03-01

Full Text Available Abstract Background Women with polycystic ovary syndrome (PCOS are often treated with insulin-sensitizing agents, e.g. thiazolidinediones (TZD, which have been shown to reduce androgen levels and improved ovulatory function. Acting via peroxisome proliferator-activated receptor (PPAR gamma, TZD alter the expression of a large variety of genes. Lethal yellow (LY; C57BL/6J Ay/a mice, possessing a mutation (Ay in the agouti gene locus, exhibit progressive obesity, reproductive dysfunction, and altered metabolic regulation similar to women with PCOS. The current study was designed to test the hypothesis that prolonged treatment of aging LY mice with the TZD, pioglitazone, alters the ovarian expression of genes that may impact reproduction. Methods Female LY mice received daily oral doses of either 0.01 mg pioglitazone (n = 4 or an equal volume of vehicle (DMSO; n = 4 for 8 weeks. At the end of treatment, ovaries were removed and DNA microarrays were used to analyze differential gene expression. Results Twenty-seven genes showed at least a two-fold difference in ovarian expression with pioglitazone treatment. These included leptin, angiopoietin, angiopoietin-like 4, Foxa3, PGE1 receptor, resistin-like molecule-alpha (RELM, and actin-related protein 6 homolog (ARP6. For most altered genes, pioglitazone changed levels of expression to those seen in untreated C57BL/6J(a/a non-mutant lean mice. Conclusion TZD administration may influence ovarian function via numerous diverse mechanisms that may or may not be directly related to insulin/IGF signaling.

PPARγ agonist pioglitazone improves cerebellar dysfunction at pre-Aβ deposition stage in APPswe/PS1dE9 Alzheimer's disease model mice

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Toba, Junya; Nikkuni, Miyu [Laboratory for Molecular Brain Science, Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, 162-8480 Japan (Japan); Ishizeki, Masato [Laboratory for Neurophysiology, Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, 162-8480 Japan (Japan); Yoshii, Aya; Watamura, Naoto [Laboratory for Molecular Brain Science, Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, 162-8480 Japan (Japan); Inoue, Takafumi [Laboratory for Neurophysiology, Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, 162-8480 Japan (Japan); Ohshima, Toshio, E-mail: ohshima@waseda.jp [Laboratory for Molecular Brain Science, Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, 162-8480 Japan (Japan)

2016-05-13

Alzheimer's disease (AD) is one of the best known neurodegenerative diseases; it causes dementia and its pathological features include accumulation of amyloid β (Aβ) and neurofibrillary tangles (NFTs) in the brain. Elevated Cdk5 activity and CRMP2 phosphorylation have been reported in the brains of AD model mice at the early stage of the disease, but the significance thereof in human AD remains unelucidated. We have recently reported that Aβ accumulation in the cerebellum of AD model APPswe/PS1dE9 (APP/PS1) mice, and cerebellar dysfunctions, such as impairment of motor coordination ability and long-term depression (LTD) induction, at the pre-Aβ accumulation stage. In the present study, we found increased phosphorylation levels of CRMP2 as well as increased p35 protein levels in the cerebellum of APP/PS1 mice. Interestingly, we show that pioglitazone, an agonist of peroxisome proliferator-activated receptor γ, normalized the p35 protein and CRMP2 phosphorylation levels in the cerebellum. Impaired motor coordination ability and LTD in APP/PS1 mice were ameliorated by pioglitazone treatment at the pre-Aβ accumulation stage. These results suggest a correlation between CRMP2 phosphorylation and AD pathophysiology, and indicate the effectiveness of pioglitazone treatment at the pre-Aβ accumulation stage in AD model mice. -- Highlights: •Phosphorylation level of CRMP2 increased in the cerebellum of APP/PS1 mice. •p35 protein levels increased in the cerebellum of APP/PS1 mice. •Pioglitazone treatment improved cerebellar dysfunction of APP/PS1 mice.

Pioglitazone Upregulates Angiotensin Converting Enzyme 2 Expression in Insulin-Sensitive Tissues in Rats with High-Fat Diet-Induced Nonalcoholic Steatohepatitis

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Wei Zhang

2014-01-01

Full Text Available Background and Aim. Thiazolidinediones (TZDs can improve hepatic steatosis in nonalcoholic steatohepatitis (NASH. Angiotensin (Ang II, the primary effector of renin-angiotensin system (RAS, plays vital roles in the development and progression of NASH. And some AngII-mediated effects can be regulated by TZDs. Angiotensin-converting enzyme (ACE 2, a new component of RAS, can degrade Ang II to attenuate its subsequent physiological actions. We aimed to evaluate the effects of TZDs on ACE2 expression in insulin-sensitive tissues in NASH rats. Methods. Forty rats were divided into the normal control, high-fat diet (HFD, pioglitazone control, and HFD plus pioglitazone groups. After 24 weeks of treatment, we evaluated changes in liver histology and tissue-specific ACE2 expression. Results. ACE2 gene and protein expression was significantly greater in liver and adipose tissue in the HFD group compared with normal control group, while was significantly reduced in skeletal muscle. Pioglitazone significantly reduced the degree of hepatic steatosis compared with the HFD group. Pioglitazone significantly increased ACE2 protein expression in liver, adipose tissue, and skeletal muscle compared with the HFD group. Conclusions. Pioglitazone improves hepatic steatosis in the rats with HFD-induced NASH and upregulates ACE2 expression in insulin-sensitive tissues.

Pioglitazone attenuates the opioid withdrawal and vulnerability to relapse to heroin seeking in rodents.

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de Guglielmo, Giordano; Kallupi, Marsida; Scuppa, Giulia; Demopulos, Gregory; Gaitanaris, George; Ciccocioppo, Roberto

2017-01-01

Relapse to opioids is often driven by the avoidance of the aversive states of opioid withdrawal. We recently demonstrated that activation of peroxisome proliferator-activated receptor gamma (PPARγ) by pioglitazone reduces the motivation for heroin and attenuates its rewarding properties. However, the role of PPARγ in withdrawal and other forms of relapse to heroin is unknown. To further address this issue, we investigated the role of PPARγ on the development and expression of morphine withdrawal in mice and the effect of pioglitazone on several forms of heroin relapse in rats. We induced physical dependence to morphine in mice by injecting morphine twice daily for 6 days. Withdrawal syndrome was precipitated on day 6 with an injection of naloxone. In addition, different groups of rats were trained to self-administer heroin and, after the extinction, the relapse was elicited by cues, priming, or stress. The effect of different doses of pioglitazone was tested on these different paradigms. Data show that chronic and acute administration of pioglitazone attenuates morphine withdrawal symptoms, and these effects are mediated by activation of PPARγ receptors. Activation of PPARγ by pioglitazone also abolishes yohimbine-induced reinstatement of heroin seeking and reduces heroin-induced reinstatement, while it does not affect cue-induced relapse. These findings provide new insights on the role of PPARγ on opioid dependence and suggest that pioglitazone may be useful for the treatment of opioid withdrawal in opioid-addicted individuals.

Impact of the CYP2C8 *3 polymorphism on the drug-drug interaction between gemfibrozil and pioglitazone.

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Aquilante, Christina L; Kosmiski, Lisa A; Bourne, David W A; Bushman, Lane R; Daily, Elizabeth B; Hammond, Kyle P; Hopley, Charles W; Kadam, Rajendra S; Kanack, Alexander T; Kompella, Uday B; Le, Merry; Predhomme, Julie A; Rower, Joseph E; Sidhom, Maha S

2013-01-01

The objective of this study was to determine the extent to which the CYP2C8*3 allele influences pharmacokinetic variability in the drug-drug interaction between gemfibrozil (CYP2C8 inhibitor) and pioglitazone (CYP2C8 substrate). In this randomized, two phase crossover study, 30 healthy Caucasian subjects were enrolled based on CYP2C8*3 genotype (n = 15, CYP2C8*1/*1; n = 15, CYP2C8*3 carriers). Subjects received a single 15 mg dose of pioglitazone or gemfibrozil 600 mg every 12 h for 4 days with a single 15 mg dose of pioglitazone administered on the morning of day 3. A 48 h pharmacokinetic study followed each pioglitazone dose and the study phases were separated by a 14 day washout period. Gemfibrozil significantly increased mean pioglitazone AUC(0,∞) by 4.3-fold (P gemfibrozil administration was significantly influenced by CYP2C8 genotype. Specifically, CYP2C8*3 carriers had a 5.2-fold mean increase in pioglitazone AUC(0,∞) compared with a 3.3-fold mean increase in CYP2C8*1 homozygotes (P = 0.02). CYP2C8*3 is associated with decreased pioglitazone plasma exposure in vivo and significantly influences the pharmacokinetic magnitude of the gemfibrozil-pioglitazone drug-drug interaction. Additional studies are needed to evaluate the impact of CYP2C8 genetics on the pharmacokinetics of other CYP2C8-mediated drug-drug interactions. © 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

Impact of the CYP2C8 *3 polymorphism on the drug–drug interaction between gemfibrozil and pioglitazone

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Aquilante, Christina L; Kosmiski, Lisa A; Bourne, David W A; Bushman, Lane R; Daily, Elizabeth B; Hammond, Kyle P; Hopley, Charles W; Kadam, Rajendra S; Kanack, Alexander T; Kompella, Uday B; Le, Merry; Predhomme, Julie A; Rower, Joseph E; Sidhom, Maha S

2013-01-01

AIM The objective of this study was to determine the extent to which the CYP2C8*3 allele influences pharmacokinetic variability in the drug–drug interaction between gemfibrozil (CYP2C8 inhibitor) and pioglitazone (CYP2C8 substrate). METHODS In this randomized, two phase crossover study, 30 healthy Caucasian subjects were enrolled based on CYP2C8*3 genotype (n = 15, CYP2C8*1/*1; n = 15, CYP2C8*3 carriers). Subjects received a single 15 mg dose of pioglitazone or gemfibrozil 600 mg every 12 h for 4 days with a single 15 mg dose of pioglitazone administered on the morning of day 3. A 48 h pharmacokinetic study followed each pioglitazone dose and the study phases were separated by a 14 day washout period. RESULTS Gemfibrozil significantly increased mean pioglitazone AUC(0,∞) by 4.3-fold (P gemfibrozil administration was significantly influenced by CYP2C8 genotype. Specifically, CYP2C8*3 carriers had a 5.2-fold mean increase in pioglitazone AUC(0,∞) compared with a 3.3-fold mean increase in CYP2C8*1 homozygotes (P= 0.02). CONCLUSION CYP2C8*3 is associated with decreased pioglitazone plasma exposure in vivo and significantly influences the pharmacokinetic magnitude of the gemfibrozil–pioglitazone drug-drug interaction. Additional studies are needed to evaluate the impact of CYP2C8 genetics on the pharmacokinetics of other CYP2C8-mediated drug–drug interactions. PMID:22625877

A Study of Effects of Pioglitazone and Rosiglitazone on Various Parameters in Patients of Type-2 Diabetes Mellitus with Special Reference to Lipid Profile.

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Sharma, S K; Verma, S H

2016-09-01

level decreased by 8.62% with pioglitazone but in group B there was no significant decrease in total cholesterol level after 18 weeks of therapy with rosiglitazone. There was no significant reduction in mean LDL cholesterol level in both groups. HDL-c level increased by 17.14% with pioglitazone in group A and decreased by 1.2% with rosiglitazone in group B. Triglycerides levels decreased by 12.33% with pioglitazone in group A and 6.16% with rosiglitazone in group B. Treatment with pioglitazone and rosiglitazone both were associated with reduction in fasting and postprandial blood sugar levels but more with pioglitazone. There was significant reduction in HbA1c with both pioglitazone and rosiglitazone but more with rosiglitazone. The total cholesterol level decreased by pioglitazone significantly but not with rosiglitazone. The LDL levels were not affected much by both drugs, while HDL levels were significantly increased with pioglitazone. Triglycerides levels were decreased with both pioglitazone and rosiglitazone but more with pioglitazone. Both drugs are useful but pioglitazone proved to be more beneficial on deranged lipid profile as compared to rosiglitazone in Type 2 Diabetes mellitus patients on OHA/insulin.

Synergism effects of pioglitazone and Urtica dioica extract in streptozotocin-induced nephropathy via attenuation of oxidative stress

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Mohammad Shokrzadeh

2017-05-01

Full Text Available Objective(s: Hyperglycemia promotes oxidative stress that plays a crucial role in the pathogenesis of Diabetic nephropathy (DN. In this study, we investigated the synergism effects of hydroalcoholic extract of Urtica dioica and pioglitazone (PIO on the prevention of DN in streptozotocin induced-diabetic mice. Materials and Methods: Forty-two mice were divided into six groups as follows: non-diabetic control group, DMSO group (as solvent, diabetic group and four treatment groups which received U. dioica, pioglitazone, U. dioica plus pioglitazone and vitE. Diabetes was induced by a single dose of streptozotocin (STZ (200 mg/kg body wt, IP diluted in citrate buffer (pH= 4.6. After 4 weeks treatment, all animals were anaesthetized and blood was collected for serum urea and creatinine levels assessment in plasma and kidney tissue were excised for evaluation of oxidative stress markers. Results: Treatment with U. dioica significantly inhibited increase in serum urea and creatinine in plasma that were observed in diabetic mice. Furthermore, the elevated level of oxidative stress markers (glutathione oxidation, lipid peroxidation (LPO, protein carbonyl in renal supernatant of diabetic mice was inhibited by U. dioica treatment.  Interestingly, U. dioica promoted beneficial effects of PIO in reducing STZ-induced hyperglycemia, renal damage and oxidative stress markers. Conclusion: Our findings showed that PIO plus U. dioica have synergism protective effects against STZ-induced nephropathy that can be a candidate as a therapeutic approach in order to treatment of DN.

Synergism effects of pioglitazone and Urtica dioica extract in streptozotocin-induced nephropathy via attenuation of oxidative stress.

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Shokrzadeh, Mohammad; Sadat-Hosseini, Sara; Fallah, Marjan; Shaki, Fatemeh

2017-05-01

Hyperglycemia promotes oxidative stress that plays a crucial role in the pathogenesis of Diabetic nephropathy (DN). In this study, we investigated the synergism effects of hydroalcoholic extract of Urtica dioica and pioglitazone (PIO) on the prevention of DN in streptozotocin induced-diabetic mice. Forty-two mice were divided into six groups as follows: non-diabetic control group, DMSO group (as solvent), diabetic group and four treatment groups which received U. dioica , pioglitazone, U. dioica plus pioglitazone and vitE. Diabetes was induced by a single dose of streptozotocin (STZ) (200 mg/kg body wt, IP) diluted in citrate buffer (pH= 4.6). After 4 weeks treatment, all animals were anaesthetized and blood was collected for serum urea and creatinine levels assessment in plasma and kidney tissue were excised for evaluation of oxidative stress markers. Treatment with U. dioica significantly inhibited increase in serum urea and creatinine in plasma that were observed in diabetic mice. Furthermore, the elevated level of oxidative stress markers (glutathione oxidation, lipid peroxidation (LPO), protein carbonyl) in renal supernatant of diabetic mice was inhibited by U. dioica treatment. Interestingly, U. dioica promoted beneficial effects of PIO in reducing STZ-induced hyperglycemia, renal damage and oxidative stress markers. Our findings showed that PIO plus U. dioica have synergism protective effects against STZ-induced nephropathy that can be a candidate as a therapeutic approach in order to treatment of DN.

Increased Risk of Hospitalization for Heart Failure with Newly Prescribed Dipeptidyl Peptidase-4 Inhibitors and Pioglitazone Using the Korean Health Insurance Claims Database

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Sunghwan Suh

2015-06-01

Full Text Available BackgroundWe assessed the association of dipeptidyl peptidase 4 inhibitors (DPP4i with hospitalization for heart failure (HF using the Korean Health Insurance claims database.MethodsWe collected data on newly prescribed sitagliptin, vildagliptin, and pioglitazone between January 1, 2009 and December 31, 2012 (mean follow-up of 336.8 days to 935,519 patients with diabetes (518,614 males and 416,905 females aged 40 to 79 years (mean age of 59.4 years.ResultsDuring the study, 998 patients were hospitalized for primary HF (115.7 per 100,000 patient-years. The incidence rate of hospitalization for HF was 117.7 per 100,000 per patient-years among patients on pioglitazone, 105.7 for sitagliptin, and 135.8 for vildagliptin. The hospitalization rate for HF was greatest in the first 30 days after starting the medication, which corresponded to a significantly higher incidence at days 0 to 30 compared with days 31 to 360 for all three drugs. The hazard ratios were 1.85 (pioglitazone, 2.00 (sitagliptin, and 1.79 (vildagliptin. The incidence of hospitalization for HF did not differ between the drugs for any time period.ConclusionThis study showed an increase in hospitalization for HF in the initial 30 days of the DPP4i and pioglitazone compared with the subsequent follow-up period. However, the differences between the drugs were not significant.

Targeting Pioglitazone Hydrochloride Therapy After Stroke or Transient Ischemic Attack According to Pretreatment Risk for Stroke or Myocardial Infarction.

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Kernan, Walter N; Viscoli, Catherine M; Dearborn, Jennifer L; Kent, David M; Conwit, Robin; Fayad, Pierre; Furie, Karen L; Gorman, Mark; Guarino, Peter D; Inzucchi, Silvio E; Stuart, Amber; Young, Lawrence H

2017-11-01

There is growing recognition that patients may respond differently to therapy and that the average treatment effect from a clinical trial may not apply equally to all candidates for a therapy. To determine whether, among patients with an ischemic stroke or transient ischemic attack and insulin resistance, those at higher risk for future stroke or myocardial infarction (MI) derive more benefit from the insulin-sensitizing drug pioglitazone hydrochloride compared with patients at lower risk. A secondary analysis was conducted of the Insulin Resistance Intervention After Stroke trial, a double-blind, placebo-controlled trial of pioglitazone for secondary prevention. Patients were enrolled from 179 research sites in 7 countries from February 7, 2005, to January 15, 2013, and were followed up for a mean of 4.1 years through the study's end on July 28, 2015. Eligible participants had a qualifying ischemic stroke or transient ischemic attack within 180 days of entry and insulin resistance without type 1 or type 2 diabetes. Pioglitazone or matching placebo. A Cox proportional hazards regression model was created using baseline features to stratify patients above or below the median risk for stroke or MI within 5 years. Within each stratum, the efficacy of pioglitazone for preventing stroke or MI was calculated. Safety outcomes were death, heart failure, weight gain, and bone fracture. Among 3876 participants (1338 women and 2538 men; mean [SD] age, 63 [11] years), the 5-year risk for stroke or MI was 6.0% in the pioglitazone group among patients at lower baseline risk compared with 7.9% in the placebo group (absolute risk difference, -1.9% [95% CI, -4.4% to 0.6%]). Among patients at higher risk, the risk was 14.7% in the pioglitazone group vs 19.6% for placebo (absolute risk difference, -4.9% [95% CI, -8.6% to 1.2%]). Hazard ratios were similar for patients below or above the median risk (0.77 vs 0.75; P = .92). Pioglitazone increased weight less among patients at

A review of pioglitazone HCL and glimepiride in the treatment of type 2 diabetes

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Mozhgan Dorkhan

2007-11-01

Full Text Available Mozhgan Dorkhan, Anders FridDepartment of Clinical Sciences, Division of Diabetes and Endocrinology, Lund University, Malmö University Hospital, SwedenAbstract: Type 2 diabetes (T2D is a progressive disorder with a consistent and steady increase in glycosylated hemoglobin (HbA1c over time associated with enhanced risk of micro- and macrovascular complications and a substantial reduction in life expectancy. There are three major pathophysiologic abnormalities associated with T2D: impaired insulin secretion, excessive hepatic glucose output, and insulin resistance in skeletal muscle, liver, and adipose tissue. These defects have been treated in clinical praxis by use of oral insulin secretagogues (sulfonylureas/glinides or insulin, biguanides, and thiazolidinediones (TZDs respectively. Pioglitazone HCL is an insulin sensitizer in the TZD family and glimepiride is an insulin secretagogue in the SU family. This article reviews mechanisms of action and clinical data behind the use of these two commonly used oral hypoglycemic agents with documented efficacy and good safety profile of once-daily administration, alone or in combination with insulin or metformin, in the management of T2D in terms of glycemic and non-glycemic effects, tolerability and side effects, and impact on vascular health.Keywords: pioglitazone, glimepiride, type 2 diabetes, thiazolidinediones, sulfonylureas

Effects of Pioglitazone on Asymmetric Dimethylarginine and Components of the Metabolic Syndrome in Nondiabetic Patients (EPICAMP Study: A Double-Blind, Randomized Clinical Trial

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Pedram Shokouh

2013-01-01

Full Text Available The present trial aimed to investigate the effects of pioglitazone on the serum level of asymmetric dimethylarginine (ADMA, a marker of endothelial function, and some indices of inflammation and glucose and lipid metabolism in nondiabetic metabolic syndrome patients. 104 eligible participants (57% female; age between 20 and 70 were enrolled in a double-blind placebo-controlled trial and were randomized to receive either pioglitazone (uptitrated to 30 mg/day or matching placebo for 24 weeks. Participants were clinically examined and a blood sample was obtained at baseline and at the end of the trial. Pioglitazone significantly improved C-reactive protein level irrespective of changes in insulin sensitivity. Compared with the placebo group, alanine and aspartate transaminases were decreased and high-density lipoprotein cholesterol was increased after treatment with pioglitazone. A considerably greater weight gain was also recorded in the intervention group. We failed to observe any significant changes in serum ADMA in either group and between groups with and without adjustment for age, sex, and components of the metabolic syndrome. In a nutshell, pioglitazone seems to have positive effects on lipid profile, liver transaminases, and systemic inflammation. However, its previously demonstrated endothelial function-improving properties do not seem to be mediated by ADMA.

Long-term pioglitazone treatment enhances lipolysis in rat adipose tissue

Czech Academy of Sciences Publication Activity Database

Pravenec, Michal; Kazdová, L.; Maxová, M.; Zídek, Václav; Mlejnek, Petr; Šimáková, Miroslava; Kurtz, T. W.

2008-01-01

Roč. 32, č. 12 (2008), s. 1848-1853 ISSN 0307-0565 R&D Projects: GA MŠk(CZ) 1M0520; GA MŠk(CZ) 1P05ME791; GA AV ČR(CZ) IAA500110604; GA MZd NR9387; GA MZd(CZ) NR9359 Grant - others:EURATools(XE) LSHG-CT-2005-019015 Institutional research plan: CEZ:AV0Z50110509 Keywords : pioglitazone * adipose tissue * lipolysis Subject RIV: FB - Endocrinology, Diabetology, Metabolism, Nutrition Impact factor: 3.640, year: 2008

Anti-diabetes drug pioglitazone ameliorates synaptic defects in AD transgenic mice by inhibiting cyclin-dependent kinase5 activity.

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Jinan Chen

Full Text Available Cyclin-dependent kinase 5 (Cdk5 is a serine/threonine kinase that is activated by the neuron specific activators p35/p39 and plays many important roles in neuronal development. However, aberrant activation of Cdk5 is believed to be associated with the pathogenesis of several neurodegenerative diseases, including Alzheimer's disease (AD and Parkinson's disease (PD. Here in the present study, enhanced Cdk5 activity was observed in mouse models of AD; whereas soluble amyloid-β oligomers (Aβ, which contribute to synaptic failures during AD pathogenesis, induced Cdk5 hyperactivation in cultured hippocampal neurons. Inhibition of Cdk5 activity by pharmacological or genetic approaches reversed dendritic spine loss caused by soluble amyloid-β oligomers (Aβ treatment. Interestingly, we found that the anti-diabetes drug pioglitazone could inhibit Cdk5 activity by decreasing p35 protein level. More importantly, pioglitazone treatment corrected long-term potentiation (LTP deficit caused by Aβ exposure in cultured slices and pioglitazone administration rescued impaired LTP and spatial memory in AD mouse models. Taken together, our study describes an unanticipated role of pioglitazone in alleviating AD and reveals a potential therapeutic drug for AD curing.

The association of pioglitazone and urinary tract disease in type 2 diabetic Taiwanese: bladder cancer and chronic kidney disease.

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Mei-Yueh Lee

Full Text Available OBJECTIVE: Although studies have shown an association between pioglitazone and bladder cancer, the associated factors have not been identified. The aim of this study was to investigate the factors that may link pioglitazone to bladder cancer. MATERIALS AND METHODS: In total, 34,970 study subjects were identified from the National Health Insurance Research Database in 2003 with follow-up from 2005 to 2009. The demographic characteristics of patients who had used and had never used pioglitazone, including age, sex, diabetes duration, urinary tract disease, nephropathy, bladder cancer, and cumulative dose and duration of pioglitazone therapy, were analyzed using the χ2 test. Cox proportional hazard regression models were used to determine the independent effects of pioglitazone on bladder cancer and newly developed chronic kidney disease. RESULTS: Among 3,497 ever users and 31,473 never users of pioglitazone, the respective incident cases of bladder cancer were 12 (0.4% and 72 (0.2%, and for newly developed chronic kidney disease 245 (8.1% and 663 (2.3%, respectively. Ever use of pioglitazone [1.59(1.32-1.91], cumulative dose of pioglitazone 10,500 mg [1.34 (1.04-1.73], and duration of therapy 12 months [1.39 (1.09-1.76] were associated with the development of chronic kidney disease. CONCLUSIONS: There was no association of pioglitazone use with bladder cancer development, however, there was an association with an increased risk of newly developed chronic kidney disease.

Chronic treatment with pioglitazone does not protect obese patients with diabetes mellitus type II from free fatty acid-induced insulin resistance

NARCIS (Netherlands)

Serlie, Mireille J.; Allick, Gideon; Groener, Johanna E.; Ackermans, Mariette T.; Heijligenberg, Rik; Voermans, Barbara C.; Aerts, Johannes M.; Meijer, Alfred J.; Sauerwein, Hans P.

2007-01-01

CONTEXT: Thiazolidinediones increase peripheral insulin sensitivity and decrease plasma free fatty acids (FFA). However, their exact mechanism of action has not been fully elucidated. OBJECTIVE: We studied the protective effect of pioglitazone on FFA-induced insulin resistance and the effects on

A pilot double-blind placebo-controlled trial of pioglitazone as adjunctive treatment to risperidone: Effects on aberrant behavior in children with autism.

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Ghaleiha, Ali; Rasa, Soudeh Mohebbi; Nikoo, Mohammadali; Farokhnia, Mehdi; Mohammadi, Mohammad-Reza; Akhondzadeh, Shahin

2015-09-30

To assess the safety and efficacy of pioglitazone added to risperidone in the treatment of irritability in autistic disorder (AD), we conducted this study. In a 10-week, randomized, double-blind, parallel-group, placebo-controlled clinical trial, 44 outpatients of both genders aged 4-12 years with a diagnosis of AD and a score of ≥12 on the Aberrant Behavior Checklist-Community (ABC-C) irritability subscale were included. Mean change of ABC-C irritability subscale score as primary outcome, change in other ABC-C subscale scores and partial and complete responses were compared between two groups. Twenty patients completed the trial in each group. Level of reduction and effect of time×treatment interaction in the treatment group were significant for irritability (P=0.03), lethargy/social withdrawal (P=0.04) and hyperactivity/non-compliance (P=0.03) but not for stereotypic behavior and inappropriate speech subscales compared with the placebo group. Vomiting and headache were the most frequent reported side-effects. Results of this preliminary study indicate positive effects of pioglitazone compared with placebo in improving the behavioral symptoms of AD. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

PPARγ agonist pioglitazone reduces matrix metalloproteinase-9 activity and neuronal damage after focal cerebral ischemia

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Lee, Seong-Ryong; Kim, Hahn-Young; Hong, Jung-Suk; Baek, Won-Ki; Park, Jong-Wook

2009-01-01

Pioglitazone, a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, has shown protective effects against ischemic insult in various tissues. Pioglitazone is also reported to reduce matrix metalloproteinase (MMP) activity. MMPs can remodel extracellular matrix components in many pathological conditions. The current study was designed to investigate whether the neuroprotection of pioglitazone is related to its MMP inhibition in focal cerebral ischemia. Mice were subjected to 90 min focal ischemia and reperfusion. In gel zymography, pioglitazone reduced the upregulation of active form of MMP-9 after ischemia. In in situ zymograms, pioglitazone also reduced the gelatinase activity induced by ischemia. After co-incubation with pioglitazone, in situ gelatinase activity was directly reduced. Pioglitazone reduced the infarct volume significantly compared with controls. These results demonstrate that pioglitazone may reduce MMP-9 activity and neuronal damage following focal ischemia. The reduction of MMP-9 activity may have a possible therapeutic effect for the management of brain injury after focal ischemia.

Effect of pioglitazone on plasma ceramides in adults with metabolic syndrome.

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Warshauer, Jeremy T; Lopez, Ximena; Gordillo, Ruth; Hicks, Jessica; Holland, William L; Anuwe, Estelle; Blankfard, Martin B; Scherer, Philipp E; Lingvay, Ildiko

2015-10-01

Metabolic syndrome (MetS) appears closely linked with ceramide accumulation, inducing insulin resistance and toxicity to multiple cell types. Animal studies demonstrate that thiazolidinediones (TZDs) reduce ceramide concentrations in plasma and skeletal muscle and support lowering of ceramide levels as a potential mediator of TZDs' mechanism of action in reducing insulin resistance; however, studies in humans have yet to be reported. This study investigated the effects of pioglitazone therapy on plasma ceramides to understand the mechanism by which TZDs improve insulin resistance in MetS. Thirty-seven subjects with MetS were studied in a single-centre, randomized, double-blind, placebo-controlled trial comparing pioglitazone to placebo. Data were collected at baseline and after 6 months of therapy. The primary endpoint was the change from baseline in plasma ceramide concentrations. Treatment with pioglitazone for 6 months, compared with placebo, significantly reduced multiple plasma ceramide concentrations: C18:0 (p = 0.001), C20:0 (p = 0.0004), C24 : 1 (p = 0.009), dihydroceramide C18 :0 (p = 0.005), dihydroceramide C24:1 (p = 0.004), lactosylceramide C16:0 (p = 0.02) and the hexosylceramides C16:0 (p = 0.0003), C18 : 0 (p = 0.00001), C22:0 (p = 0.00002) and C24:1 (p = 0.0006). Additionally, significant reductions were found when ceramides were grouped by species: ceramides (p = 0.03), dihydroceramides (p = 0.02), hexosylceramides (p = 0.00001) and lactosylceramides (p = 0.02). The total of all measured ceramides was also significantly reduced (p = 0.001). Following treatment with pioglitazone, the decrease in some ceramide species correlated negatively with the change in insulin sensitivity (dihydroceramide C16:0, r = -0.54; p = 0.02) and positively with total (lactosylceramide C24:0, r = 0.53; p = 0.02) and high molecular weight (lactosylceramide C24:0, r = 0.48; p = 0

Adverse drug effects observed with vildagliptin versus pioglitazone or rosiglitazone in the treatment of patients with type 2 diabetes mellitus: a systematic review and meta-analysis of randomized controlled trials.

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Bundhun, Pravesh Kumar; Janoo, Girish; Teeluck, Abhishek Rishikesh; Huang, Feng

2017-10-23

vildagliptin and pioglitazone/rosiglitazone are acceptable for the treatment of patients with T2DM on the basis that they are not significantly different in terms of overall adverse drug events. However, weight gain and peripheral edema would have to be re-assessed in further larger randomized controlled trials.

Pioglitazone and cause-specific risk of mortality in patients with type 2 diabetes: extended analysis from a European multidatabase cohort study.

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Strongman, Helen; Christopher, Solomon; Majak, Maila; Williams, Rachael; Bahmanyar, Shahram; Linder, Marie; Heintjes, Edith M; Bennett, Dimitri; Korhonen, Pasi; Hoti, Fabian

2018-01-01

Describe and compare the risk of cardiovascular and non-cardiovascular mortality in patients whose antidiabetic therapy is modified to include pioglitazone compared with an alternative antidiabetic medication at the same stage of disease progression. This exploratory linked database cohort analysis used pooled health and mortality data from three European countries: Finland, Sweden and the UK. Propensity score together with exact matching was used to match 31 133 patients with type 2 diabetes first prescribed pioglitazone from 2000 to 2011, to 31 133 patients never prescribed pioglitazone. Exact matching variables were treatment stage, history of diabetes, diabetes complications and cardiovascular disease, and year of cohort entry. Mean follow-up time was 2.60 (SD 2.00) and 2.69 (SD 2.31) years in the pioglitazone and non-pioglitazone-exposed groups, respectively. Crude cause-specific mortality rates were ascertained. Association with pioglitazone use was estimated using Cox proportional hazards models adjusted a priori for country, age, sex, the propensity score quintile and time-dependent variables representing use of antidiabetic drugs. Stepwise testing identified no additional confounders to include in adjusted models. The crude mortality rate was lower in the pioglitazone-exposed group than the non-exposed group for both cardiovascular and non-cardiovascular mortality. Adjusted HRs comparing pioglitazone to alternative antidiabetic exposure were 0.58 (95% CI 0.52 to 0.63) and 0.63 (95% CI 0.58 to 0.68) for cardiovascular and non-cardiovascular mortality, respectively. A protective effect associated with pioglitazone was also found for all specific cardiovascular causes. This analysis suggests that pioglitazone is associated with a decrease in both cardiovascular and non-cardiovascular mortality. Results should be interpreted with caution due to the potential for residual confounding in this exploratory analysis. Further studies, specifically designed to test

Effects of pioglitazone mediated activation of PPAR-γ on CIDEC and obesity related changes in mice.

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Bilal Haider Shamsi

Full Text Available OBJECTIVE: Obesity is a metabolic disorder that can lead to high blood pressure, increased blood cholesterol and triglycerides, insulin resistance, and diabetes mellitus. The aim was to study the effects of pioglitazone mediated sensitization of peroxisome proliferator-activated receptor gamma (PPAR-γ on the relationship of Cell death-inducing DFFA-like effector C (CIDEC with obesity related changes in mice. METHODS: Sixty C57B/L6 mice weighing 10-12g at 3 weeks of age were randomly divided into 3 groups. Mice in Group 1 were fed on normal diet (ND while Group 2 mice were given high fat diet (HFD, and Group 3 mice were given high fat diet and treated with Pioglitazone (HFD+P. Body weight, length and level of blood sugar were measured weekly. Quantitative real-time PCR, fluorescence microscopy, and ELISA were performed to analyze the expression of CIDEC and PPAR-γ in visceral adipose tissue (VAT and subcutaneous adipose tissue (SAT. RESULTS: Body weight and length of mice increased gradually with time in all groups. Blood sugar in HFD mice started to increase significantly from the mid of late phase of obesity while pioglitazone attenuated blood sugar level in HFD+P mice. The mRNA expressions and protein levels of PPAR-γ and CIDEC genes started to increase in HFD mice as compared to ND mice and decreased gradually during the late phase of obesity in VAT. Pioglitazone enhanced the expression of PPAR-γ and CIDEC genes in HFD+P mice even during the late phase of obesity. CONCLUSION: It is insinuated that VAT is associated with late phase obesity CIDEC decrease and insulin resistance, while pioglitazone enhances CIDEC through activation of PPAR-γ, increases its expression, and decreases lipolysis, hence preventing an increase of blood sugar in mice exposed to HFD.

Pioglitazone is equally effective for diabetes prevention in older versus younger adults with impaired glucose tolerance.

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Espinoza, Sara E; Wang, Chen-Pin; Tripathy, Devjit; Clement, Stephen C; Schwenke, Dawn C; Banerji, Mary Ann; Bray, George A; Buchanan, Thomas A; Henry, Robert R; Kitabchi, Abbas E; Mudaliar, Sunder; Stentz, Frankie B; Reaven, Peter D; DeFronzo, Ralph A; Musi, Nicolas

2016-12-01

To determine the efficacy of pioglitazone to prevent type 2 diabetes in older compared to younger adults with pre-diabetes. Six hundred two participants with impaired glucose tolerance (IGT) were randomized in double blind fashion to placebo or pioglitazone for diabetes prevention in the ACT NOW study (NEJM 364:1104-1115, 2011). Cox proportional hazard regression was used to compare time to development of diabetes over a mean of 2 years between older (≥61 years) and younger participants. We compared effects of pioglitazone versus placebo on metabolic profiles, inflammatory markers, adipokines, β cell function (disposition index), insulin sensitivity (Matsuda index), and body composition by ANOVA. Diabetes incidence was reduced by 85 % in older and 69 % in younger subjects (p = 0.41). β cell function (disposition index) increased by 35.0 % in the older and 26.7 % in younger subjects (p = 0.83). Insulin sensitivity (Matsuda index) increased by 3.07 (5.2-fold) in older and by 2.54 (3.8-fold) in younger participants (p = 0.58). Pioglitazone more effectively increased adiponectin in older versus younger subjects (22.9 ± 3.2 μg/mL [2.7-fold] vs. 12.7 ± 1.4 μg/mL [2.2-fold], respectively; p = 0.04). Younger subjects tended to have a greater increase in whole body fat mass compared to older subjects (3.6 vs. 3.1 kg; p = 0.061). Younger and older subjects had similar decreases in bone mineral density (0.018 ± 0.0071 vs. 0.0138 ± 0.021 g/cm 2 ). Younger and older pre-diabetic adults taking pioglitazone had similar reductions in conversion to diabetes and older adults had similar or greater improvements in metabolic risk factors, demonstrating that pioglitazone is useful in preventing diabetes in older adults.

Taurine and pioglitazone attenuate diabetes-induced testicular damage by abrogation of oxidative stress and up-regulation of the pituitary-gonadal axis.

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Abd El-Twab, Sanaa M; Mohamed, Hanaa M; Mahmoud, Ayman M

2016-06-01

Chronic hyperglycemia is associated with impairment of testicular function. The current study aimed to investigate the protective effects and the possible mechanisms of taurine and pioglitazone against diabetes-induced testicular dysfunction in rats. Diabetes was induced by streptozotocin injection. Both normal and diabetic rats received taurine (100 mg/kg) or pioglitazone (10 mg/kg) orally and daily for 6 weeks. Diabetic rats showed a significant (P Taurine and pioglitazone alleviated hyperglycemia, decreased pro-inflammatory cytokines, and increased circulating levels of insulin, testosterone, LH, and FSH. Gene and protein expression of LH and FSH receptors and cytochrome P450 17α-hydroxylase (CYP17) was significantly (P taurine and pioglitazone. In addition, taurine and pioglitazone significantly decreased lipid peroxidation and DNA damage, and enhanced activity of the antioxidant enzymes in testes of diabetic rats. In conclusion, taurine and pioglitazone exerted protective effects against diabetes-induced testicular damage through attenuation of hyperglycemia, inflammation, oxidative stress and DNA damage, and up-regulation of the pituitary/gonadal axis.

Effects of exenatide, insulin, and pioglitazone on liver fat content and body fat distributions in drug-naive subjects with type 2 diabetes.

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Bi, Yan; Zhang, Bing; Xu, Wen; Yang, Huijie; Feng, Wenhuan; Li, Cuiliu; Tong, Guoyu; Li, Ming; Wang, Xin; Shen, Shanmei; Zhu, Bin; Weng, Jianping; Zhu, Dalong

2014-10-01

Ectopic accumulation of lipids in nonadipose tissues plays a primary role in the pathogenesis of type 2 diabetes mellitus (T2DM). This study was to examine the effects of exenatide, insulin, and pioglitazone on liver fat content and body fat distributions in T2DM. Thirty-three drug-naive T2DM patients (age 52.7 ± 1.7 years, HbA1c 8.7 ± 0.2 %, body mass index 24.5 ± 0.5 kg/m(2)) were randomized into exenatide, insulin, or pioglitazone for 6 months. Intrahepatic fat (IHF), visceral fat (VF), and subcutaneous fat (SF) were measured using proton nuclear magnetic resonance spectroscopy. Plasma tumor necrosis factor α (TNFα) and adiponectin were assayed by ELISA. HbA1c declined significantly in all three groups. Body weight, waist, and serum triglycerides decreased with exenatide. After interventions, IHF significantly reduced with three treatments (exenatide Δ = -68 %, insulin Δ = -58 %, pioglitazone Δ = -49 %). Exenatide reduced VF (Δ = -36 %) and SF (Δ = -13 %), and pioglitazone decreased VF (Δ = -30 %) with no impact on SF, whereas insulin had no impact on VF or SF. Levels of TNFα (exenatide/insulin/pioglitazone) decreased, and levels of adiponectin (exenatide/pioglitazone) increased. Analysis showed that ΔIHF correlated with ΔHbA1c and Δweight. Besides, ΔIHF correlated with Δtriglycerides and ΔTNFα, but the correlations fell short of significance after BMI adjustment. By linear regression analysis, ΔHbA1c alone explained 41.5 % of the variance of ΔIHF, and ΔHbA1c + Δweight explained 57.6 % of the variance. Liver fat content can be significantly reduced irrespective of using exenatide, insulin, and pioglitazone. Early glycaemic control plays an important role in slowing progression of fatty liver in T2DM.

Pioglitazone reverses down-regulation of cardiac PPARγ expression in Zucker diabetic fatty rats

International Nuclear Information System (INIS)

Pelzer, Theo; Jazbutyte, Virginija; Arias-Loza, Paula Anahi; Segerer, Stephan; Lichtenwald, Margit; Law, Marilyn P.; Schaefers, Michael; Ertl, Georg; Neyses, Ludwig

2005-01-01

Peroxisome proliferator-activated receptor-γ (PPARγ) plays a critical role in peripheral glucose homeostasis and energy metabolism, and inhibits cardiac hypertrophy in non-diabetic animal models. The functional role of PPARγ in the diabetic heart, however, is not fully understood. Therefore, we analyzed cardiac gene expression, metabolic control, and cardiac glucose uptake in male Zucker diabetic fatty rats (ZDF fa/fa) and lean ZDF rats (+/+) treated with the high affinity PPARγ agonist pioglitazone or placebo from 12 to 24 weeks of age. Hyperglycemia, hyperinsulinemia, and hypertriglyceridemia as well as lower cardiac PPARγ, glucose transporter-4 and α-myosin heavy chain expression levels were detected in diabetic ZDF rats compared to lean animals. Pioglitazone increased body weight and improved metabolic control, cardiac PPARγ, glut-4, and α-MHC expression levels in diabetic ZDF rats. Cardiac [ 18 F]fluorodeoxyglucose uptake was not detectable by micro-PET studies in untreated and pioglitazone treated ZDF fa/fa rats but was observed after administration of insulin to pioglitazone treated ZDF fa/fa rats. PPARγ agonists favorably affect cardiac gene expression in type-2 diabetic rats via activation and up-regulation of cardiac PPARγ expression whereas improvement of impaired cardiac glucose uptake in advanced type-2 diabetes requires co-administration of insulin

The PPARgamma agonist pioglitazone is effective in the MPTP mouse model of Parkinson's disease through inhibition of monoamine oxidase B.

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Quinn, L P; Crook, B; Hows, M E; Vidgeon-Hart, M; Chapman, H; Upton, N; Medhurst, A D; Virley, D J

2008-05-01

The peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist pioglitazone has previously been shown to attenuate dopaminergic cell loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease, an effect attributed to its anti-inflammatory properties. In the present investigation, we provide evidence that pioglitazone is effective in the MPTP mouse model, not via an anti-inflammatory action, but through inhibition of MAO-B, the enzyme required to biotransform MPTP to its active neurotoxic metabolite 1-methyl-4-phenylpyridinium (MPP+). Mice were treated with pioglitazone (20 mg kg(-1) b.i.d. (twice a day), p.o., for 7 days), prior and post or post-MPTP (30 mg kg(-1) s.c.) treatment. Mice were then assessed for motor impairments on a beam-walking apparatus and for reductions in TH immunoreactivity in the substantia nigra and depletions in striatal dopamine. The effects of pioglitazone on striatal MPP+ levels and MAO-B activity were also assessed. Mice treated with MPTP showed deficits in motor performance, marked depletions in striatal dopamine levels and a concomitant reduction in TH immunoreactivity in the substantia nigra. Pretreatment with pioglitazone completely prevented these effects of MPTP. However, pretreatment with pioglitazone also significantly inhibited the MPTP-induced production of striatal MPP+ and the activity of MAO-B in the striatum. The neuroprotection observed with pioglitazone pretreatment in the MPTP mouse model was due to the blockade of the conversion of MPTP to its active toxic metabolite MPP+, via inhibition of MAO-B.

A Pilot Trial of Pioglitazone HCl and Tretinoin in ALS: Cerebrospinal Fluid Biomarkers to Monitor Drug Efficacy and Predict Rate of Disease Progression

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Todd D. Levine

2012-01-01

Full Text Available Objectives. To determine if therapy with pioglitazone HCl and tretinoin could slow disease progression in patients with ALS. Levels of tau and pNFH in the cerebrospinal fluid were measured to see if they could serve as prognostic indicators. Methods. 27 subjects on stable doses of riluzole were enrolled. Subjects were randomized to receive pioglitazone 30 mg/d and tretinoin 10 mg/BID for six months or two matching placebos. ALSFRS-R scores were followed monthly. At baseline and at the final visit, lumbar punctures (LPs were performed to measure cerebrospinal fluid (CSF biomarker levels. Results. Subjects treated with tretinoin, pioglitazone, and riluzole had an average rate of decline on the ALSFRS-R scale of −1.02 points per month; subjects treated with placebo and riluzole had a rate of decline of -.86 (P=.18. Over six months of therapy, CSF tau levels decreased in subjects randomized to active treatment and increased in subjects on placebo. Further higher levels of pNF-H at baseline correlated with a faster rate of progression. Conclusion. ALS patients who were treated with tretinoin and pioglitazone demonstrated no slowing on their disease progression. Interestingly, the rate of disease progression was strongly correlated with levels of pNFH in the CSF at baseline.

Pioglitazone metabolic effect in metformin-intolerant obese patients treated with sibutramine.

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Derosa, Giuseppe; Mereu, Roberto; Salvadeo, Sibilla A T; D'Angelo, Angela; Ciccarelli, Leonardina; Piccinni, Mario N; Ferrari, Ilaria; Gravina, Alessia; Maffioli, Pamela; Cicero, Arrigo F G

2009-01-01

Metformin is the drug of choice to treat obese type 2 diabetes patients because it reduces either insulin-resistance and body weight. We aimed to comparatively test the efficacy and tolerability of pioglitazone and sibutramine in metformin-intolerant obese type 2 diabetic patients treated with sibutramine. Five hundred and seventy-six consecutive Caucasian obese type 2 diabetic patients were evaluated during a 12-months period and fifty-two patients were resulted intolerant to metformin at maximum dosage (3,000 mg/day). All intolerant patients to metformin received a treatment with pioglitazone (45 mg/day) and sibutramine (10 mg/day) and they were compared with fifty-three patients treated with metformin (3,000 mg/day) and sibutramine (10 mg/day) for 6 months in a single-blind controlled trial. We assessed body mass index, waist circumference, glycated hemoglobin, Fasting Plasma glucose, postprandial plasma glucose, fasting plasma insulin, postprandial plasma insulin, lipid profile, systolic blood pressure, diastolic blood pressure and heart rate at baseline and after 3, and 6 months. No body mass index change was observed at 3, and 6 months in pioglitazone + sibutramine group, while a significant reduction of body mass index and waist circumference was observed after 6 months in metformin + sibutramine group (psibutramine combination appears to be a short-term equally efficacious and well-tolerated therapeutic alternative respect to metformin-intolerant obese type 2 diabetic patients treated with sibutramine.

The ε3 and ε4 alleles of human APOE differentially affect tau phosphorylation in hyperinsulinemic and pioglitazone treated mice.

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Alvina W M To

2011-02-01

Full Text Available Impaired insulin signalling is increasingly thought to contribute to Alzheimer's disease (AD. The ε4 isoform of the APOE gene is the greatest genetic risk factor for sporadic, late onset AD, and is also associated with risk for type 2 diabetes mellitus (T2DM. Neuropathological studies reported the highest number of AD lesions in brain tissue of ε4 diabetic patients. However other studies assessing AD pathology amongst the diabetic population have produced conflicting reports and have failed to show an increase in AD-related pathology in diabetic brain. The thiazolidinediones (TZDs, peroxisome proliferator-activated receptor gamma agonists, are peripheral insulin sensitisers used to treat T2DM. The TZD, pioglitazone, improved memory and cognitive functions in mild to moderate AD patients. Since it is not yet clear how apoE isoforms influence the development of T2DM and its progression to AD, we investigated amyloid beta and tau pathology in APOE knockout mice, carrying human APOEε3 or ε4 transgenes after diet-induced insulin resistance with and without pioglitazone treatment.Male APOE knockout, APOEε3-transgenic and APOEε4-transgenic mice, together with background strain C57BL6 mice were kept on a high fat diet (HFD or low fat diet (LFD for 32 weeks, or were all fed HFD for 32 weeks and during the final 3 weeks animals were treated with pioglitazone or vehicle.All HFD animals developed hyperglycaemia with elevated plasma insulin. Tau phosphorylation was reduced at 3 epitopes (Ser396, Ser202/Thr205 and Thr231 in all HFD, compared to LFD, animals independent of APOE genotype. The introduction of pioglitazone to HFD animals led to a significant reduction in tau phosphorylation at the Ser202/Thr205 epitope in APOEε3 animals only. We found no changes in APP processing however the levels of soluble amyloid beta 40 was reduced in APOE knockout animals treated with pioglitazone.

Efficacy and safety of hydroxychloroquine in the treatment of type 2 diabetes mellitus: a double blind, randomized comparison with pioglitazone.

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Pareek, Anil; Chandurkar, Nitin; Thomas, Nihal; Viswanathan, Vijay; Deshpande, Alaka; Gupta, O P; Shah, Asha; Kakrani, Arjun; Bhandari, Sudhir; Thulasidharan, N K; Saboo, Banshi; Devaramani, Shashidhar; Vijaykumar, N B; Sharma, Shrikant; Agrawal, Navneet; Mahesh, M; Kothari, Kunal

2014-07-01

To compare efficacy and safety of hydroxychloroquine with pioglitazone in type 2 diabetes mellitus (T2DM). This double-blind study randomized 267 uncontrolled type 2 diabetes patients (HbA1c ≥7.5% and ≤11.5%), post 3 months' treatment with glimepiride/gliclazide and metformin, to additionally receive hydroxychloroquine 400 mg/day (n = 135) or pioglitazone 15 mg/day (n = 132) for 24 weeks. Efficacy was assessed by changes in HbA1c, fasting (FBG) and post-prandial (PPG) blood glucose at Week 12 and Week 24. At Week 12 and Week 24, HbA1c, FBG and PPG significantly reduced from baseline in both groups. Mean reduction in glycemic parameters at Week 12 (HbA1c: -0.56% vs -0.72%, p = 0.394; FBG: -0.99 mmol/L vs -1.05 mmol/L, p = 0.878; PPG: -1.93 mmol/L vs -1.52 mmol/L, p = 0.423) and Week 24 (HbA1c: -0.87% vs -0.90%, p = 0.909; FBG: -0.79 mmol/L vs -1.02 mmol/L, p = 0.648; PPG: -1.77 mmol/L vs -1.36 mmol/L, p = 0.415) was not significantly different between the hydroxychloroquine and pioglitazone groups. Change in total cholesterol (TC) and LDL-C was significant in favor of hydroxychloroquine (TC: -0.37 mmol/L vs 0.03 mmol/L, p = 0.002; LDL-C: -0.23 mmol/L vs 0.09 mmol/L, p = 0.003). Triglycerides significantly reduced in both groups at Week 24. Mean HDL-C remained unchanged. Study treatments were well tolerated. With favorable effects on glycemic parameters and lipids, hydroxychloroquine may emerge as well tolerated therapeutic option for T2DM. The sample size for this study was small. However, based on the encouraging results of this proof-of-concept study, longer duration studies in larger population can be conducted to further confirm these findings. TRIAL REGISTRATION DETAILS: Clinical Trial Registry-India URL: http://ctri.nic.in, Registration Number: CTRI/2009/091/001036.

Effects of pioglitazone on cardiac ion currents and action potential morphology in canine ventricular myocytes.

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Kistamás, Kornél; Szentandrássy, Norbert; Hegyi, Bence; Ruzsnavszky, Ferenc; Váczi, Krisztina; Bárándi, László; Horváth, Balázs; Szebeni, Andrea; Magyar, János; Bányász, Tamás; Kecskeméti, Valéria; Nánási, Péter P

2013-06-15

Despite its widespread therapeutical use there is little information on the cellular cardiac effects of the antidiabetic drug pioglitazone in larger mammals. In the present study, therefore, the concentration-dependent effects of pioglitazone on ion currents and action potential configuration were studied in isolated canine ventricular myocytes using standard microelectrode, conventional whole cell patch clamp, and action potential voltage clamp techniques. Pioglitazone decreased the maximum velocity of depolarization and the amplitude of phase-1 repolarization at concentrations ≥3 μM. Action potentials were shortened by pioglitazone at concentrations ≥10 μM, which effect was accompanied with significant reduction of beat-to-beat variability of action potential duration. Several transmembrane ion currents, including the transient outward K(+) current (Ito), the L-type Ca(2+) current (ICa), the rapid and slow components of the delayed rectifier K(+) current (IKr and IKs, respectively), and the inward rectifier K(+) current (IK1) were inhibited by pioglitazone under conventional voltage clamp conditions. Ito was blocked significantly at concentrations ≥3 μM, ICa, IKr, IKs at concentrations ≥10 μM, while IK1 at concentrations ≥30 μM. Suppression of Ito, ICa, IKr, and IK1 has been confirmed also under action potential voltage clamp conditions. ATP-sensitive K(+) current, when activated by lemakalim, was effectively blocked by pioglitazone. Accordingly, action potentials were prolonged by 10 μM pioglitazone when the drug was applied in the presence of lemakalim. All these effects developed rapidly and were readily reversible upon washout. In conclusion, pioglitazone seems to be a harmless agent at usual therapeutic concentrations. Copyright © 2013 Elsevier B.V. All rights reserved.

Metabolomics reveals reduction of metabolic oxidation in women with polycystic ovary syndrome after pioglitazone-flutamide-metformin polytherapy.

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Maria Vinaixa

Full Text Available Polycystic ovary syndrome (PCOS is a variable disorder characterized by a broad spectrum of anomalies, including hyperandrogenemia, insulin resistance, dyslipidemia, body adiposity, low-grade inflammation and increased cardiovascular disease risks. Recently, a new polytherapy consisting of low-dose flutamide, metformin and pioglitazone in combination with an estro-progestagen resulted in the regulation of endocrine clinical markers in young and non-obese PCOS women. However, the metabolic processes involved in this phenotypic amelioration remain unidentified. In this work, we used NMR and MS-based untargeted metabolomics to study serum samples of young non-obese PCOS women prior to and at the end of a 30 months polytherapy receiving low-dose flutamide, metformin and pioglitazone in combination with an estro-progestagen. Our results reveal that the treatment decreased the levels of oxidized LDL particles in serum, as well as downstream metabolic oxidation products of LDL particles such as 9- and 13-HODE, azelaic acid and glutaric acid. In contrast, the radiuses of small dense LDL and large HDL particles were substantially increased after the treatment. Clinical and endocrine-metabolic markers were also monitored, showing that the level of HDL cholesterol was increased after the treatment, whereas the level of androgens and the carotid intima-media thickness were reduced. Significantly, the abundance of azelaic acid and the carotid intima-media thickness resulted in a high degree of correlation. Altogether, our results reveal that this new polytherapy markedly reverts the oxidant status of untreated PCOS women, and potentially improves the pro-atherosclerosis condition in these patients.

Glimepiride versus pioglitazone combination therapy in subjects with type 2 diabetes inadequately controlled on metformin monotherapy: results of a randomized clinical trial.

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Umpierrez, Guillermo; Issa, Maher; Vlajnic, Aleksandra

2006-04-01

To compare the effect of add-on glimepiride or pioglitazone in subjects with type 2 diabetes inadequately controlled on metformin monotherapy. Multicenter, randomized, parallel-group, open-label, forcedtitration study involving 203 adults with poorly controlled type 2 diabetes (A1C 7.5-10%) on metformin monotherapy. Subjects were randomized to receive glimepiride or pioglitazone, titrated to the maximum dose for 26 weeks. Subjects were evaluated for A1C changes, fasting plasma glucose (FPG), insulin, C-peptide, and lipid levels. Safety outcomes and diabetes-related healthcare resource utilization were also evaluated. Both treatment groups achieved similar and significant mean decreases from baseline to endpoint (week 26) in A1C (p = 0.0001) and FPG (p use of fasting C-peptide concentration > or = 0.27 nmol/L in the inclusion criteria was a potential limitation as it may have included those patients with an improved probability for glimepiride or pioglitazone response. In addition, a larger patient population would have provided a greater degree of data applicability. In patients with type 2 diabetes inadequately controlled on metformin monotherapy, add-on glimepiride or pioglitazone results in similar overall improvements in glycemic control. Compared with pioglitazone, glimepiride is associated with faster glycemic control, lower total and LDL cholesterol levels and reduced short-term healthcare costs.

22(R)-hydroxycholesterol and pioglitazone synergistically decrease cholesterol ester via the PPARγ–LXRα–ABCA1 pathway in cholesterosis of the gallbladder

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Wang, Jing-Min; Wang, Dong; Tan, Yu-Yan; Zhao, Gang; Ji, Zhen-Ling

2014-01-01

Highlights: • Cholesterosis is a metabolic disease characterized by excessive lipid droplets. • Lipid droplet efflux is mediated by the ABCA1 transporter. • 22(R)-hydroxycholesterol can activate LXRα and up-regulate ABCA1. • Pioglitazone up-regulates ABCA1 in a PPARγ–LXRα–ABCA1-dependent manner. • 22(R)-hydroxycholesterol and pioglitazone synergistically decrease lipid droplets. - Abstract: Cholesterosis is a disease of cholesterol metabolism characterized by the presence of excessive lipid droplets in the cytoplasm. These lipid droplets are mainly composed of cholesterol esters derived from free cholesterol. The removal of excess cholesterol from gallbladder epithelial cells (GBECs) is very important for the maintenance of intracellular cholesterol homeostasis and the preservation of gallbladder function. Several lines of evidence have indicated that the activation of either peroxisome proliferator-activated receptor gamma (PPARγ) or liver X receptor α (LXRα) relates to cholesterol efflux. While pioglitazone can regulate the activation of PPARγ, 22(R)-hydroxycholesterol can activate LXRα and is a metabolic intermediate in the biosynthesis of steroid hormones. However, the effect of 22(R)-hydroxycholesterol in combination with pioglitazone on cholesterosis of the gallbladder is unclear. GBECs were treated with pioglitazone, 22(R)-hydroxycholesterol or PPARγ siRNA followed by Western blot analysis for ATP-binding cassette transporter A1 (ABCA1), PPARγ and LXRα. Cholesterol efflux to apoA-I was determined, and Oil Red O staining was performed to monitor variations in lipid levels in treated GBECs. Our data showed that 22(R)-hydroxycholesterol can modestly up-regulate LXRα while simultaneously increasing ABCA1 by 56%. The combination of 22(R)-hydroxycholesterol and pioglitazone resulted in a 3.64-fold increase in ABCA1 expression and a high rate of cholesterol efflux. Oil Red O staining showed an obvious reduction in the lipid droplets

Pioglitazone, a PPARγ agonist rescues depression associated with obesity using chronic unpredictable mild stress model in experimental mice

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Yeshwant Kurhe

2016-06-01

Full Text Available Pioglitazone, a peroxisome proliferator activated receptor gamma (PPARγ agonist belonging to thiazolidinedione class, is mainly used in diabetes mellitus. Obese subjects are twice likely to become depressed than non-obese individuals. The biological mechanisms linking depression with obesity still remain poorly understood and there is immense need for better therapeutic intervention against such co-morbid disorders. The present study investigates the effect of pioglitazone on the chronic unpredictable mild stress (CUMS induced depression in obese mice by using behavioral tests and biochemical estimations. Mice were fed with high fat diet (HFD for 14 weeks and were further subjected to different stress procedures for 28 days to induce depressive behavior. Animals were administered orally with pioglitazone (30 mg/kg p.o./escitalopram (10 mg/kg p.o./vehicle (10 ml/kg p.o. daily from day 15–28. Various behavioral paradigms such as sucrose preference test, forced swim test (FST, tail suspension test (TST and elevated plus maze (EPM were performed. Biochemical estimations including plasma glucose, total cholesterol, triglycerides, and total proteins were performed. The data obtained from behavioral assays and biochemical assessments indicated that obese animals exhibited severe depressive-like behavior compared to non-obese animals. Furthermore, obese animals subjected to CUMS worsen the depressive behavior compared to obese control animals. Repetitive treatment with pioglitazone reversed the CUMS induced behavioral and biochemical alterations in HFD fed obese mice which atleast in part may be mediated through improving altered plasma glucose. The study suggests that pioglitazone needs further attention with respect to molecular mechanisms that could provide a better therapeutic strategy against depression associated with obesity.

Impaired insulin activation and dephosphorylation of glycogen synthase in skeletal muscle of women with polycystic ovary syndrome is reversed by pioglitazone treatment

DEFF Research Database (Denmark)

Glintborg, Dorte; Højlund, Kurt; Andersen, Nicoline Resen

2008-01-01

CONTEXT: Insulin resistance is a major risk factor for type 2 diabetes in women with polycystic ovary syndrome (PCOS). The molecular mechanisms underlying reduced insulin-mediated glycogen synthesis in skeletal muscle of patients with PCOS have not been established. SUBJECTS AND METHODS: We...... metabolically characterized by euglycemic-hyperinsulinemic clamps and indirect calorimetry. RESULTS: Reduced insulin-mediated glucose disposal (P .... No significant abnormalities in GSK-3alpha or -3beta were found in PCOS subjects. Pioglitazone treatment improved insulin-stimulated glucose metabolism and GS activity in PCOS (all P

PPAR-gamma agonist pioglitazone modifies craving intensity and brain white matter integrity in patients with primary cocaine use disorder: a double-blind randomized controlled pilot trial.

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Schmitz, Joy M; Green, Charles E; Hasan, Khader M; Vincent, Jessica; Suchting, Robert; Weaver, Michael F; Moeller, F Gerard; Narayana, Ponnada A; Cunningham, Kathryn A; Dineley, Kelly T; Lane, Scott D

2017-10-01

Pioglitazone (PIO), a potent agonist of PPAR-gamma, is a promising candidate treatment for cocaine use disorder (CUD). We tested the effects of PIO on targeted mechanisms relevant to CUD: cocaine craving and brain white matter (WM) integrity. Feasibility, medication compliance and tolerability were evaluated. Two-arm double-blind randomized controlled proof-of-concept pilot trial of PIO or placebo (PLC). Single-site out-patient treatment research clinic in Houston, TX, USA. Thirty treatment-seeking adults, 18 to 60 years old, with CUD. Eighteen participants (8 = PIO; 10 = PLC) completed diffusion tensor imaging (DTI) of WM integrity at pre-/post-treatment. Study medication was dispensed at thrice weekly visits along with once-weekly cognitive behavioral therapy for 12 weeks. Measures of target engagement mechanisms of interest included cocaine craving assessed by the Brief Substance Craving Scale (BSCS), the Obsessive Compulsive Drug Use Scale (OCDUS), a visual analog scale (VAS) and change in WM integrity. Feasibility measures included number completing treatment, medication compliance (riboflavin detection) and tolerability (side effects, serious adverse events). Target engagement change in mechanisms of interest, defined as a ≥ 0.75 Bayesian posterior probability of an interaction existing favoring PIO over PLC, was demonstrated on measures of craving (BSCS, VAS) and WM integrity indexed by fractional anisotropy (FA) values. Outcomes indicated greater decrease in craving and greater increase in FA values in the PIO group. Feasibility was demonstrated by high completion rates among those starting treatment (21/26 = 80%) and medication compliance (≥ 80%). There were no reported serious adverse events for PIO. Compared with placebo, patients receiving pioglitazone show a higher likelihood of reduced cocaine craving and improved brain white matter integrity as a function of time in treatment. Pioglitazone shows good feasibility as a treatment for cocaine

Pioglitazone and bladder cancer in human studies: Is it diabetes itself, diabetes drugs, flawed analyses or different ethnicities?

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Chin-Hsiao Tseng

2012-03-01

Full Text Available This article reviews human observations on pioglitazone and bladder cancer risk. The PROspective pioglitAzone Clinical Trial In macroVascular Events trial showed an imbalance in bladder cancer between users of pioglitazone and placebo (14 versus six cases, p = 0.069. However, after excluding bladder cancer probably ascribed to other etiology, a blind assessment concluded that the imbalance might not be related to pioglitazone. Epidemiologic studies conducted in the United States and France using insurance databases independently suggested that pioglitazone use for >2 years might confer a 20%–40% higher risk. Another study evaluating bladder cancer risk in diabetic patients using the National Health Insurance in Taiwan did not find any incident bladder cancer case among 422 pioglitazone users for a follow-up of up to 3 years. Because observational studies may suffer from selection and information bias, and inadequate adjustment for confounders may inflate the estimated risk, causal inference from these studies should be interpreted with caution. While investigating cancer risk associated with a medication, indication bias should also be attended, especially when the medication is used at a late stage of the disease. Because pioglitazone is usually a second or third line antidiabetic agent, the users are always characterized by older age, longer diabetes duration, poorer glycemic control, and higher rates of complications and comorbidities. Biased estimates will also result if these differences are not appropriately addressed in the analyses. Current evidence neither concludes nor excludes a causal role of pioglitazone on bladder cancer. Clinical trials aiming at evaluating the risk of cancer associated with a medication is not ethical and may not be expected to provide an answer on the issue of pioglitazone-related bladder cancer. However, a meta-analysis using all available clinical trials to compare the bladder cancer risk between

Effects of Vildagliptin or Pioglitazone on Glycemic Variability and Oxidative Stress in Patients with Type 2 Diabetes Inadequately Controlled with Metformin Monotherapy: A 16-Week, Randomised, Open Label, Pilot Study

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Nam Hoon Kim

2017-06-01

Full Text Available BackgroundGlycemic variability is associated with the development of diabetic complications through the activation of oxidative stress. This study aimed to evaluate the effects of a dipeptidyl peptidase 4 inhibitor, vildagliptin, or a thiazolidinedione, pioglitazone, on glycemic variability and oxidative stress in patients with type 2 diabetes.MethodsIn this open label, randomised, active-controlled, pilot trial, individuals who were inadequately controlled with metformin monotherapy were assigned to either vildagliptin (50 mg twice daily, n=17 or pioglitazone (15 mg once daily, n=14 treatment groups for 16 weeks. Glycemic variability was assessed by calculating the mean amplitude of glycemic excursions (MAGE, which was obtained from continuous glucose monitoring. Urinary 8-iso prostaglandin F2α, serum oxidised low density lipoprotein, and high-sensitivity C-reactive protein were used as markers of oxidative stress or inflammation.ResultsBoth vildagliptin and pioglitazone significantly reduced glycated hemoglobin and mean plasma glucose levels during the 16-week treatment. Vildagliptin also significantly reduced the MAGE (from 93.8±38.0 to 70.8±19.2 mg/dL, P=0.046, and mean standard deviation of 24 hours glucose (from 38±17.3 to 27.7±6.9, P=0.026; however, pioglitazone did not, although the magnitude of decline was similar in both groups. Markers of oxidative stress or inflammation including urinary 8-iso prostaglandin F2α did not change after treatment in both groups.ConclusionIn this 16-week treatment trial, vildagliptin, but not pioglitazone, reduced glycemic variability in individuals with type 2 diabetes who was inadequately controlled with metformin monotherapy, although a reduction of oxidative stress markers was not observed.

Differential cardiovascular outcomes after dipeptidyl peptidase-4 inhibitor, sulfonylurea, and pioglitazone therapy, all in combination with metformin, for type 2 diabetes: a population-based cohort study.

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Seong, Jong-Mi; Choi, Nam-Kyong; Shin, Ju-Young; Chang, Yoosoo; Kim, Ye-Jee; Lee, Joongyub; Kim, Ju-Young; Park, Byung-Joo

2015-01-01

Data on the comparative effectiveness of oral antidiabetics on cardiovascular outcomes in a clinical practice setting are limited. This study sought to determine whether a differential risk of cardiovascular disease (CVD) exists for the combination of a dipeptidyl peptidase-4 (DPP-4) inhibitor plus metformin versus a sulfonylurea derivative plus metformin or pioglitazone plus metformin. We conducted a cohort study of 349,476 patients who received treatment with a DPP-4 inhibitor, sulfonylurea, or pioglitazone plus metformin for type 2 diabetes using the Korean national health insurance claims database. The incidence of total CVD and individual outcomes of myocardial infarction (MI), heart failure (HF), and ischemic stroke (IS) were assessed using the hazard ratios (HRs) estimated from a Cox proportional-hazards model weighted for a propensity score. During follow-up, 3,881 patients developed a CVD, including 428 MIs, 212 HFs, and 1,487 ISs. The adjusted HR with 95% confidence interval (CI) for a sulfonylurea derivative plus metformin compared with a DPP-4 inhibitor plus metformin was 1.20 (1.09-1.32) for total CVD; 1.14 (1.04-1.91) for MI; 1.07 (0.71-1.62) for HF; and 1.51 (1.28-1.79) for IS. The HRs with 95% CI for total CVD, MI, HF, and IS for pioglitazone plus metformin were 0.89 (0.81-0.99), 1.05 (0.76-1.46), 4.81 (3.53-6.56), and 0.81 (0.67-0.99), respectively. Compared with a DPP-4 inhibitor plus metformin, treatment with a sulfonylurea drug plus metformin was associated with increased risks of total CVD, MI, and IS, whereas the use of pioglitazone plus metformin was associated with decreased total CVD and IS risks.

Differential cardiovascular outcomes after dipeptidyl peptidase-4 inhibitor, sulfonylurea, and pioglitazone therapy, all in combination with metformin, for type 2 diabetes: a population-based cohort study.

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Jong-Mi Seong

Full Text Available Data on the comparative effectiveness of oral antidiabetics on cardiovascular outcomes in a clinical practice setting are limited. This study sought to determine whether a differential risk of cardiovascular disease (CVD exists for the combination of a dipeptidyl peptidase-4 (DPP-4 inhibitor plus metformin versus a sulfonylurea derivative plus metformin or pioglitazone plus metformin.We conducted a cohort study of 349,476 patients who received treatment with a DPP-4 inhibitor, sulfonylurea, or pioglitazone plus metformin for type 2 diabetes using the Korean national health insurance claims database. The incidence of total CVD and individual outcomes of myocardial infarction (MI, heart failure (HF, and ischemic stroke (IS were assessed using the hazard ratios (HRs estimated from a Cox proportional-hazards model weighted for a propensity score.During follow-up, 3,881 patients developed a CVD, including 428 MIs, 212 HFs, and 1,487 ISs. The adjusted HR with 95% confidence interval (CI for a sulfonylurea derivative plus metformin compared with a DPP-4 inhibitor plus metformin was 1.20 (1.09-1.32 for total CVD; 1.14 (1.04-1.91 for MI; 1.07 (0.71-1.62 for HF; and 1.51 (1.28-1.79 for IS. The HRs with 95% CI for total CVD, MI, HF, and IS for pioglitazone plus metformin were 0.89 (0.81-0.99, 1.05 (0.76-1.46, 4.81 (3.53-6.56, and 0.81 (0.67-0.99, respectively.Compared with a DPP-4 inhibitor plus metformin, treatment with a sulfonylurea drug plus metformin was associated with increased risks of total CVD, MI, and IS, whereas the use of pioglitazone plus metformin was associated with decreased total CVD and IS risks.

Pioglitazone improves reversal learning and exerts mixed cerebrovascular effects in a mouse model of Alzheimer's disease with combined amyloid-β and cerebrovascular pathology.

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Panayiota Papadopoulos

Full Text Available Animal models of Alzheimer's disease (AD are invaluable in dissecting the pathogenic mechanisms and assessing the efficacy of potential new therapies. Here, we used the peroxisome proliferator-activated receptor gamma agonist pioglitazone in an attempt to rescue the pathogenic phenotype in adult (12 months and aged (>18 months bitransgenic A/T mice that overexpress a mutated human amyloid precursor protein (APPSwe,Ind and a constitutively active form of transforming growth factor-β1 (TGF-β1. A/T mice recapitulate the AD-related cognitive deficits, amyloid beta (Aβ and cerebrovascular pathologies, as well as the altered metabolic and vascular coupling responses to increased neuronal activity. Pioglitazone normalized neurometabolic and neurovascular coupling responses to sensory stimulation, and reduced cortical astroglial and hippocampal microglial activation in both age groups. Spatial learning and memory deficits in the Morris water maze were not rescued by pioglitazone, but reversal learning was improved in the adult cohort notwithstanding a progressing Aβ pathology. While pioglitazone preserved the constitutive nitric oxide synthesis in the vessel wall, it unexpectedly failed to restore cerebrovascular reactivity in A/T mice and even exacerbated the dilatory deficits. These data demonstrate pioglitazone's efficacy on selective AD hallmarks in a complex AD mouse model of comorbid amyloidosis and cerebrovascular pathology. They further suggest a potential benefit of pioglitazone in managing neuroinflammation, cerebral perfusion and glucose metabolism in AD patients devoid of cerebrovascular pathology.

Pioglitazone Confers Neuroprotection Against Ischemia-Induced Pyroptosis due to its Inhibitory Effects on HMGB-1/RAGE and Rac1/ROS Pathway by Activating PPAR-ɤ

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Pingping Xia

2018-03-01

Full Text Available Background/Aims: Recent researches highlighted the protective potential of pioglitazone, a PPAR-γ agonist, in the progression of cerebral ischemia-reperfusion injury. However, there has been no study on the application of pioglitazone in treating ischemic stroke through mechanisms involving pyroptosis. Methods: The cerebral injury was established by middle cerebral artery occlusion (MCAO. in vitro ischemia in primary cultured astrocytes was induced by the oxygen-glucose deprivation (OGD. ELISA and Western Blot analysis were employed to the levels of PPAR-γ, pyroptosis-related biomarkers and cytoplasmic translocation of HMGB-1 and RAGE expression as well as Rac1 activity, respectively. Results: We demonstrated that repeated intraperitoneal administration of pioglitazone remarkably reduced the infarct volume, improved neurological deficits and suppressed the Rac1 activity with significant reduction of excessive ROS in rat model of middle cerebral artery occlusion (MCAO. Moreover, pioglitazone alleviated the up-regulation of pyroptosis-related biomarkers and the increased cytoplasmic translocation of HMGB-1 and RAGE expression in cerebral penumbra cortex. Similarly, the protective effects of pioglitazone on cultured astrocytes were characterized by reduced Rac1 activity, pyroptosis related protein expressions and lactate dehydrogenase (LDH release. However, these protective effects of pioglitazone were neutralized with the use of GW9662, a PPAR-γ inhibitor. Interestingly, Rac1 knockdown in lentivirus with the Rac1 small hair RNA (shRNA could inhibit the OGD-induced pyroptosis of primary cultured astrocytes. Furthermore, the combination of Rac1-shRNA and pioglitazone can further strengthen the inhibitory effects on pyroptosis induced by OGD. Conclusion: The neuroprotection of pioglitazone was attributable to the alleviated ischemia/hypoxia-induced pyroptosis and was also associated with the PPARγ-mediated suppression of HGMB-1/RAGE signaling

Pioglitazone Confers Neuroprotection Against Ischemia-Induced Pyroptosis due to its Inhibitory Effects on HMGB-1/RAGE and Rac1/ROS Pathway by Activating PPAR-ɤ.

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Xia, Pingping; Pan, Yundan; Zhang, Fan; Wang, Na; Wang, E; Guo, Qulian; Ye, Zhi

2018-01-01

Recent researches highlighted the protective potential of pioglitazone, a PPAR-γ agonist, in the progression of cerebral ischemia-reperfusion injury. However, there has been no study on the application of pioglitazone in treating ischemic stroke through mechanisms involving pyroptosis. The cerebral injury was established by middle cerebral artery occlusion (MCAO). in vitro ischemia in primary cultured astrocytes was induced by the oxygen-glucose deprivation (OGD). ELISA and Western Blot analysis were employed to the levels of PPAR-γ, pyroptosis-related biomarkers and cytoplasmic translocation of HMGB-1 and RAGE expression as well as Rac1 activity, respectively. We demonstrated that repeated intraperitoneal administration of pioglitazone remarkably reduced the infarct volume, improved neurological deficits and suppressed the Rac1 activity with significant reduction of excessive ROS in rat model of middle cerebral artery occlusion (MCAO). Moreover, pioglitazone alleviated the up-regulation of pyroptosis-related biomarkers and the increased cytoplasmic translocation of HMGB-1 and RAGE expression in cerebral penumbra cortex. Similarly, the protective effects of pioglitazone on cultured astrocytes were characterized by reduced Rac1 activity, pyroptosis related protein expressions and lactate dehydrogenase (LDH) release. However, these protective effects of pioglitazone were neutralized with the use of GW9662, a PPAR-γ inhibitor. Interestingly, Rac1 knockdown in lentivirus with the Rac1 small hair RNA (shRNA) could inhibit the OGD-induced pyroptosis of primary cultured astrocytes. Furthermore, the combination of Rac1-shRNA and pioglitazone can further strengthen the inhibitory effects on pyroptosis induced by OGD. The neuroprotection of pioglitazone was attributable to the alleviated ischemia/hypoxia-induced pyroptosis and was also associated with the PPARγ-mediated suppression of HGMB-1/RAGE signaling pathway. Moreover, the inhibition of Rac1 promoted this function

Cardiac Outcomes After Ischemic Stroke or Transient Ischemic Attack: Effects of Pioglitazone in Patients With Insulin Resistance Without Diabetes Mellitus.

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Young, Lawrence H; Viscoli, Catherine M; Curtis, Jeptha P; Inzucchi, Silvio E; Schwartz, Gregory G; Lovejoy, Anne M; Furie, Karen L; Gorman, Mark J; Conwit, Robin; Abbott, J Dawn; Jacoby, Daniel L; Kolansky, Daniel M; Pfau, Steven E; Ling, Frederick S; Kernan, Walter N

2017-05-16

Insulin resistance is highly prevalent among patients with atherosclerosis and is associated with an increased risk for myocardial infarction (MI) and stroke. The IRIS trial (Insulin Resistance Intervention after Stroke) demonstrated that pioglitazone decreased the composite risk for fatal or nonfatal stroke and MI in patients with insulin resistance without diabetes mellitus, after a recent ischemic stroke or transient ischemic attack. The type and severity of cardiac events in this population and the impact of pioglitazone on these events have not been described. We performed a secondary analysis of the effects of pioglitazone, in comparison with placebo, on acute coronary syndromes (MI and unstable angina) among IRIS participants. All potential acute coronary syndrome episodes were adjudicated in a blinded fashion by an independent clinical events committee. The study cohort was composed of 3876 IRIS participants, mean age 63 years, 65% male, 89% white race, and 12% with a history of coronary artery disease. Over a median follow-up of 4.8 years, there were 225 acute coronary syndrome events, including 141 MIs and 84 episodes of unstable angina. The MIs included 28 (19%) with ST-segment elevation. The majority of MIs were type 1 (94, 65%), followed by type 2 (45, 32%). Serum troponin was 10× to 100× upper limit of normal in 49 (35%) and >100× upper limit of normal in 39 (28%). Pioglitazone reduced the risk of acute coronary syndrome (hazard ratio, 0.71; 95% confidence interval, 0.54-0.94; P =0.02). Pioglitazone also reduced the risk of type 1 MI (hazard ratio, 0.62; 95% confidence interval, 0.40-0.96; log-rank P =0.03), but not type 2 MI (hazard ratio, 1.05; 95% confidence interval, 0.58-1.91; P =0.87). Similarly, pioglitazone reduced the risk of large MIs with serum troponin >100× upper limit of normal (hazard ratio, 0.44; 95% confidence interval, 0.22-0.87; P =0.02), but not smaller MIs. Among patients with insulin resistance without diabetes mellitus

Effects of the insulin sensitizer pioglitazone on menstrual irregularity, insulin resistance and hyperandrogenism in young women with polycystic ovary syndrome.

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Stabile, Gaspare; Borrielli, Irene; Artenisio, Alfredo Carducci; Bruno, Lucia Maria; Benvenga, Salvatore; Giunta, Loretta; La Marca, Antonio; Volpe, Annibale; Pizzo, Alfonsa

2014-06-01

Polycystic ovary syndrome (PCOS) is the most common endocrine cause of menstrual irregularities, hirsutism and acne. Women with PCOS present elevated plasma insulin levels, both fasting and after a glucose load, as an indirect evidence of insulin resistance. PCOS women may also present hypertension, low levels of HDL cholesterol, hypertriglyceridemia, visceral obesity and a higher level of CRP and fibrinogen that can predict an atherosclerotic risk. This study was carried out on 15 young women with PCOS selected according to the 2003 diagnostic criteria of The Rotterdam Consensus Statement and 15 Control women. PCOS women were treated with pioglitazone 30 mg/day and at the beginning and after 6 months of treatment were evaluated: menstrual cycle trend, hirsutism and acne, total cholesterolemia and HDL, triglyceridemia, fibrinogenemia, C-reactive protein, oral glucose tolerance test, glycated hemoglobin, FSH, LH, 17OH-progesterone, 17β-estradiol, free and total testosterone, SHBG, DHEA-S, Δ4-androstenedione and adiponectin. Treatment with pioglitazone improves the irregularities of menses and hirsutism. Six months of treatment modify other parameters linked with a higher risk of type 2 diabetes mellitus and cardiovascular diseases: adiponectin increased with reduction of insulin resistance while fibrinogen and CRP levels decreased. Copyright © 2014 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.

Evaluation of exposure to pioglitazone and risk of prostate cancer: a nested case–control study

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Boxall, Naomi; Bennett, Dimitri; Hunger, Matthias; Dolin, Paul; Thompson, Paula L

2016-01-01

Objectives Investigate potential association between pioglitazone exposure and risk of prostate cancer. Research design and methods Nested, matched case–control study. UK primary care data (Clinical Practice Research Datalink (CPRD) GOLD) linked to inpatient (Hospital Episode Statistics (HES)) and cancer registry (National Cancer Information Network (NCIN)) data. English men aged ≥40 years diagnosed with type 2 diabetes mellitus, January 1, 2001 to January 5, 2015. Cases, with prostate cancer diagnosis, matched with up to 4 controls by age, cohort entry date and region. ORs for association of exposure to pioglitazone to incident prostate cancer, adjusted for potential confounders. Results From a cohort of 47 772 men with 243 923 person-years follow-up, 756 definite cases of prostate cancer were identified. Incidence was 309.9/100 000 person-years (95% CI 288.6 to 332.8). Pioglitazone use was not associated with prostate cancer risk; adjusted OR 0.759, 95% CI 0.502 to 1.148. Analyses showed no difference when possible cases, prostate cancer in CPRD GOLD only, included (adjusted OR 0.726, 95% CI 0.510 to 1.034). No association when adjusted for channeling bias (OR 0.778, 95% CI 0.511 to 1.184) or limited to an index date prior to July 1, 2011 (adjusted OR 0.508, 95% CI 0.294 to 0.879), despite prostate-specific antigen screening occurring more frequently among cases than controls (81.6% of 756 definite cases cf. 24.2% of 2942 controls (pworld, nested matched case–control study, exposure to pioglitazone was not associated with increased risk of prostate cancer. PMID:28074141

Long-term rates of mitochondrial protein synthesis are increased in mouse skeletal muscle with high-fat feeding regardless of insulin-sensitizing treatment.

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Newsom, Sean A; Miller, Benjamin F; Hamilton, Karyn L; Ehrlicher, Sarah E; Stierwalt, Harrison D; Robinson, Matthew M

2017-11-01

Skeletal muscle mitochondrial protein synthesis is regulated in part by insulin. The development of insulin resistance with diet-induced obesity may therefore contribute to impairments to protein synthesis and decreased mitochondrial respiration. Yet the impact of diet-induced obesity and insulin resistance on mitochondrial energetics is controversial, with reports varying from decreases to increases in mitochondrial respiration. We investigated the impact of changes in insulin sensitivity on long-term rates of mitochondrial protein synthesis as a mechanism for changes to mitochondrial respiration in skeletal muscle. Insulin resistance was induced in C57BL/6J mice using 4 wk of a high-fat compared with a low-fat diet. For 8 additional weeks, diets were enriched with pioglitazone to restore insulin sensitivity compared with nonenriched control low-fat or high-fat diets. Skeletal muscle mitochondrial protein synthesis was measured using deuterium oxide labeling during weeks 10-12 High-resolution respirometry was performed using palmitoyl-l-carnitine, glutamate+malate, and glutamate+malate+succinate as substrates for mitochondria isolated from quadriceps. Mitochondrial protein synthesis and palmitoyl- l-carnitine oxidation were increased in mice consuming a high-fat diet, regardless of differences in insulin sensitivity with pioglitazone treatment. There was no effect of diet or pioglitazone treatment on ADP-stimulated respiration or H 2 O 2 emission using glutamate+malate or glutamate+malate+succinate. The results demonstrate no impairments to mitochondrial protein synthesis or respiration following induction of insulin resistance. Instead, mitochondrial protein synthesis was increased with a high-fat diet and may contribute to remodeling of the mitochondria to increase lipid oxidation capacity. Mitochondrial adaptations with a high-fat diet appear driven by nutrient availability, not intrinsic defects that contribute to insulin resistance. Copyright © 2017 the

Additive effects of glucagon-like peptide 1 and pioglitazone in patients with type 2 diabetes

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Zander, Mette; Christiansen, Allan; Madsbad, Sten

2004-01-01

plasma levels of glucose, insulin, glucagon, free fatty acids (FFAs), and sensation of appetite. RESULTS: Fasting plasma glucose decreased from 13.5 +/- 1.2 mmol/l (saline) to 11.7 +/- 1.2 (GLP-1) and 11.5 +/- 1.2 (pioglitazone) and further decreased to 9.9 +/- 1.0 (combination) (P ...-hour mean plasma glucose levels were reduced from 13.7 +/- 1.1 mmol/l (saline) to 10.6 +/- 1.0 (GLP-1) and 12.0 +/- 1.2 (pioglitazone) and were further reduced to 9.5 +/- 0.8 (combination) (P ....01). Glucagon levels were reduced in GLP-1 and combination therapy compared with saline and monotherapy with pioglitazone (P Sensation of appetite was reduced during monotherapy...

Do thiazolidinediones still have a role in treatment of type 2 diabetes mellitus?

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Consoli, A; Formoso, G

2013-11-01

Thiazolidinediones have been introduced in the treatment of type 2 diabetes mellitus (T2DM) since the late 1990s. Although troglitazone was withdrawn from the market a few years later due to liver toxicity, both rosiglitazone and pioglitazone gained widespread use for T2DM treatment. In 2010, however, due to increased risk of cardiovascular events associated with its use, the European Medicines Agency recommended suspension of rosiglitazone use and the Food and Drug Administration severely restricted its use. Thus pioglitazone is the only thiazolidinedione still significantly employed for treating T2DM and it is the only molecule of this class still listed in the American Diabetes Association-European Association for the Study of Diabetes 2012 Position Statement. However, as for the other thiazolidinediones, use of pioglitazone is itself limited by several side effects, some of them potentially dangerous. This, together with the development of novel therapeutic strategies approved in the last couple of years, has made it questionable whether or not thiazolidinediones (namely pioglitazone) should still be used in the treatment of T2DM. This article will attempt to formulate an answer to this question by critically reviewing the available data on the numerous advantages and the potentially worrying shortcomings of pioglitazone treatment in T2DM. © 2013 John Wiley & Sons Ltd.

15-PGDH inhibitors: the antiulcer effects of carbenoxolone, pioglitazone and verapamil in indomethacin induced peptic ulcer rats.

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Moustafa, Y M; El-Azab, M F; Fouda, A

2013-01-01

15-hydroxyprostaglandin dehydrogenase (15-PGDH) is the enzyme responsible for prostaglandins (PGs) metabolism. PGs have an important role in the protection of stomach mucosa against destructive stimuli. The aim of the present study is to investigate the inhibitory effect of carbenoxolone, pioglitazone and verapamil on 15-PGDH enzyme. The experiments were carried out in the Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt from May 2011 to August 2011. Adult male albino rats were fasted for 18 hours before administration of high dose of indomethacin (30 mg/kg, p.o.), except for the negative control group which received saline only, followed by pyloric ligation to induce acute gastric ulcers. The rats were pretreated orally with saline, pioglitazone (20 mg/kg), verapamil (25 mg/kg), carbenoxolone (30 mg/kg) or their combinations 30 minutes before indomethacin. The rats were sacrificed after four hours of pyloric ligation. The effects of the previous treatments on the ulcer index (Ui), the microscopic appearance of gastric mucosa, the gastric acid output, the gastric barrier mucus content, and 15-PGDH enzyme activity were determined. Indomethacin resulted in severe ulceration and increased gastric acid output (p ulcer index, gastric acid output and 15-PGDH activity (p ulcer index, gastric acid output and 15-PGDH activity (p stomach mucosa.

PPARγ agonist pioglitazone reverses pulmonary hypertension and prevents right heart failure via fatty acid oxidation.

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Legchenko, Ekaterina; Chouvarine, Philippe; Borchert, Paul; Fernandez-Gonzalez, Angeles; Snay, Erin; Meier, Martin; Maegel, Lavinia; Mitsialis, S Alex; Rog-Zielinska, Eva A; Kourembanas, Stella; Jonigk, Danny; Hansmann, Georg

2018-04-25

Right ventricular (RV) heart failure is the leading cause of death in pulmonary arterial hypertension (PAH). Peroxisome proliferator-activated receptor γ (PPARγ) acts as a vasoprotective metabolic regulator in smooth muscle and endothelial cells; however, its role in the heart is unclear. We report that deletion of PPARγ in cardiomyocytes leads to biventricular systolic dysfunction and intramyocellular lipid accumulation in mice. In the SU5416/hypoxia (SuHx) rat model, oral treatment with the PPARγ agonist pioglitazone completely reverses severe PAH and vascular remodeling and prevents RV failure. Failing RV cardiomyocytes exhibited mitochondrial disarray and increased intramyocellular lipids (lipotoxicity) in the SuHx heart, which was prevented by pioglitazone. Unbiased ventricular microRNA (miRNA) arrays, mRNA sequencing, and lipid metabolism studies revealed dysregulation of cardiac hypertrophy, fibrosis, myocardial contractility, fatty acid transport/oxidation (FAO), and transforming growth factor-β signaling in the failing RV. These epigenetic, transcriptional, and metabolic alterations were modulated by pioglitazone through miRNA/mRNA networks previously not associated with PAH/RV dysfunction. Consistently, pre-miR-197 and pre-miR-146b repressed genes that drive FAO ( Cpt1b and Fabp4 ) in primary cardiomyocytes. We recapitulated our major pathogenic findings in human end-stage PAH: (i) in the pressure-overloaded failing RV (miR-197 and miR-146b up-regulated), (ii) in peripheral pulmonary arteries (miR-146b up-regulated, miR-133b down-regulated), and (iii) in plexiform vasculopathy (miR-133b up-regulated, miR-146b down-regulated). Together, PPARγ activation can normalize epigenetic and transcriptional regulation primarily related to disturbed lipid metabolism and mitochondrial morphology/function in the failing RV and the hypertensive pulmonary vasculature, representing a therapeutic approach for PAH and other cardiovascular/pulmonary diseases. Copyright

Comparative Study on Adding Pioglitazone or Sitagliptin to Patients with Type 2 Diabetes Mellitus Insufficiently Controlled With Metformin

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Maryam Jameshorani

2017-12-01

CONCLUSION: Sitagliptin and Pioglitazone demonstrated similar improvements in glycemic control in type 2 diabetes mellitus patients whose diabetes had been inadequately controlled with metformin. Nevertheless, sitagliptin was more effective than pioglitazone regarding lipid and body weight change.

A review of pioglitazone HCL and glimepiride in the treatment of type 2 diabetes.

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Dorkhan, Mozhgan; Frid, Anders

2007-01-01

Type 2 diabetes (T2D) is a progressive disorder with a consistent and steady increase in glycosylated hemoglobin (HbA1c) over time associated with enhanced risk of micro- and macrovascular complications and a substantial reduction in life expectancy. There are three major pathophysiologic abnormalities associated with T2D: impaired insulin secretion, excessive hepatic glucose output, and insulin resistance in skeletal muscle, liver, and adipose tissue. These defects have been treated in clinical praxis by use of oral insulin secretagogues (sulfonylureas/ glinides) or insulin, biguanides, and thiazolidinediones (TZDs) respectively. Pioglitazone HCL is an insulin sensitizer in the TZD family and glimepiride is an insulin secretagogue in the SU family. This article reviews mechanisms of action and clinical data behind the use of these two commonly used oral hypoglycemic agents with documented efficacy and good safety profile of once-daily administration, alone or in combination with insulin or metformin, in the management of T2D in terms of glycemic and non-glycemic effects, tolerability and side effects, and impact on vascular health.

Association of pioglitazone treatment with decreased bone mineral density in obese premenopausal patients with polycystic ovary syndrome: a randomized, placebo-controlled trial

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Glintborg, D.; Andersen, Mikael; Hagen, C.

2008-01-01

OBJECTIVE: Our objective was to investigate the effect of pioglitazone on bone mineral density (BMD) and bone turnover markers in polycystic ovary syndrome (PCOS). DESIGN AND SETTING: We conducted a randomized, placebo-controlled study at an outpatient clinic at a university hospital. PATIENTS......: Thirty premenopausal patients with PCOS and 14 age- and weight-matched healthy females participated. INTERVENTIONS: Pioglitazone (30 mg/d) or placebo was given for 16 wk. MAIN OUTCOME MEASURES: Measurements of BMD [hip (neck and total) and lumbar spine (L2-L4)], bone metabolic parameters [alkaline...... phosphatase (ALP), 25-hydroxyvitamin D, C-telopeptide of type I collagen (ICTP), osteocalcin, and PTH], endocrine profiles (testosterone, estradiol, and insulin), and body composition (waist to hip ratio, body mass index, and whole-body dual-energy x-ray absorptiometry scans) were performed. RESULTS: Patients...

Pioglitazone enhances mitochondrial biogenesis and ribosomal protein biosynthesis in skeletal muscle in polycystic ovary syndrome

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Skov, Vibe; Glintborg, Dorte; Knudsen, Steen

2008-01-01

indicate that pioglitazone therapy restores insulin sensitivity, in part, by a coordinated upregulation of genes involved in mitochondrial OXPHOS and ribosomal protein biosynthesis in muscle in PCOS. These transcriptional effects of pioglitazone may contribute to prevent the onset of type 2 diabetes...... by changes in the transcriptional profile of muscle favoring insulin sensitivity. Using Affymetrix microarrays, we examined the effect of pioglitazone (30 mg/day for 16 weeks) on gene expression in skeletal muscle of 10 obese women with PCOS metabolically characterized by a euglycemic-hyperinsulinemic clamp...... Annotator and Pathway Profiler (GenMAPP 2.1) and Gene Set Enrichment Analysis (GSEA 2.0.1) revealed a significant upregulation of genes representing mitochondrial oxidative phosphorylation (OXPHOS), ribosomal proteins, mRNA processing reactome, translation factors, and proteasome degradation in PCOS after...

Combination Therapy with Losartan and Pioglitazone Additively Reduces Renal Oxidative and Nitrative Stress Induced by Chronic High Fat, Sucrose, and Sodium Intake

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Xiang Kong

2012-01-01

Full Text Available We recently showed that combination therapy with losartan and pioglitazone provided synergistic effects compared with monotherapy in improving lesions of renal structure and function in Sprague-Dawley rats fed with a high-fat, high-sodium diet and 20% sucrose solution. This study was designed to explore the underlying mechanisms of additive renoprotection provided by combination therapy. Losartan, pioglitazone, and their combination were orally administered for 8 weeks. The increased level of renal malondialdehyde and expression of nicotinamide adenine dinucleotide phosphate oxidase subunit p47phox and nitrotyrosine as well as the decreased total superoxide dismutase activity and copper, zinc-superoxide dismutase expression were tangible evidence for the presence of oxidative and nitrative stress in the kidney of model rats. Treatment with both drugs, individually and in combination, improved these abnormal changes. Combination therapy showed synergistic effects in reducing malondialdehyde level, p47phox, and nitrotyrosine expression to almost the normal level compared with monotherapy. All these results suggest that the additive renoprotection provided by combination therapy might be attributed to a further reduction of oxidative and nitrative stress.

Pioglitazone modulates vascular inflammation in atherosclerotic rabbits : noninvasive assessment with FDG-PET-CT and dynamic contrast-enhanced MR imaging

NARCIS (Netherlands)

Vucic, E.; Dickson, S.D.; Calcagno, C.; Rudd, J.H.F.; Moshier, E.; Hayashi, K.; Mounessa, J.S.; Roytman, M.; Moon, M.J.; Lin, J.; Tsimikas, S.; Fisher, E.A.; Nicolay, K.; Fuster, V.; Fayad, Z.A.

2011-01-01

Objectives We sought to determine the antiatherosclerotic properties of pioglitazone using multimethod noninvasive imaging techniques. Background Inflammation is an essential component of vulnerable or high-risk atheromas. Pioglitazone, a peroxisome proliferator-activated receptor-gamma agonist,

Expression of REST4 in human gliomas in vivo and influence of pioglitazone on REST in vitro

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Ren, Huan [Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008 (China); Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410078 (China); Gao, Zhangfeng [Department of Neurosurgery, Second Xiangya Hospital of Central South University, Changsha 410008 (China); Wu, Nayiyuan; Zeng, Liu; Tang, Xinyue; Chen, Xiaoping; Liu, Zhaoqian; Zhang, Wei; Wang, Liansheng [Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008 (China); Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410078 (China); Li, Zhi, E-mail: lizhi489@163.com [Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008 (China); Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410078 (China)

2015-08-07

The repressor element-1 (RE1) silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) has an irreplaceable role during the differentiation of neurons. REST has multiple splice variants which link to various types of cancer. Previous work had highlighted the role of REST in glioma, where the expression of REST is enhanced. But whether alternative splicing of REST is expressed in glioma has not been described. Here, we show that a specific isoform REST4 is expressed in glioma specimens, and will influence the mRNA level of REST in vivo. Peroxisome proliferator-activated receptor-γ (PPARγ) agonists have a role of antineoplastic in various tumor cells, which including glioma cells. Moreover, study indicated that PPARγ agonist pioglitazone can promote alternative splicing of REST pre-mRNA. In this study, we selected pioglitazone as a tool drug to explore whether the role of pioglitazone in anti-glioma is mediated by regulating REST expression or promoting alternative splicing of REST in glioma cells. Results show that pioglitazone can inhibit proliferation and induce apoptosis of glioma cell in vitro, which may be mediated by down-regulating REST mRNA level but not by inducing alternative splicing of REST pre-mRNA. Our study firstly reports the expression of REST4 in glioma tissue samples. And we recommend that pioglitazone, which can reduce the expression level of REST, represents a promising drug for therapy of glioma. - Highlights: • A specific isoform REST4 is expressed in glioma specimens in vivo. • REST4 will influence the mRNA level of REST in vivo. • Pioglitazone can inhibit proliferation and induce apoptosis of glioma cells. • The role of pioglitazone in anti-glioma may be mediated by down-regulating REST.

Expression of REST4 in human gliomas in vivo and influence of pioglitazone on REST in vitro

International Nuclear Information System (INIS)

Ren, Huan; Gao, Zhangfeng; Wu, Nayiyuan; Zeng, Liu; Tang, Xinyue; Chen, Xiaoping; Liu, Zhaoqian; Zhang, Wei; Wang, Liansheng; Li, Zhi

2015-01-01

The repressor element-1 (RE1) silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) has an irreplaceable role during the differentiation of neurons. REST has multiple splice variants which link to various types of cancer. Previous work had highlighted the role of REST in glioma, where the expression of REST is enhanced. But whether alternative splicing of REST is expressed in glioma has not been described. Here, we show that a specific isoform REST4 is expressed in glioma specimens, and will influence the mRNA level of REST in vivo. Peroxisome proliferator-activated receptor-γ (PPARγ) agonists have a role of antineoplastic in various tumor cells, which including glioma cells. Moreover, study indicated that PPARγ agonist pioglitazone can promote alternative splicing of REST pre-mRNA. In this study, we selected pioglitazone as a tool drug to explore whether the role of pioglitazone in anti-glioma is mediated by regulating REST expression or promoting alternative splicing of REST in glioma cells. Results show that pioglitazone can inhibit proliferation and induce apoptosis of glioma cell in vitro, which may be mediated by down-regulating REST mRNA level but not by inducing alternative splicing of REST pre-mRNA. Our study firstly reports the expression of REST4 in glioma tissue samples. And we recommend that pioglitazone, which can reduce the expression level of REST, represents a promising drug for therapy of glioma. - Highlights: • A specific isoform REST4 is expressed in glioma specimens in vivo. • REST4 will influence the mRNA level of REST in vivo. • Pioglitazone can inhibit proliferation and induce apoptosis of glioma cells. • The role of pioglitazone in anti-glioma may be mediated by down-regulating REST

The disposition index does not reflect β-cell function in IGT subjects treated with pioglitazone.

Science.gov (United States)

DeFronzo, Ralph A; Tripathy, Devjit; Abdul-Ghani, Muhammad; Musi, Nicolas; Gastaldelli, Amalia

2014-10-01

The insulin secretion/insulin resistance (IR) (disposition) index (ΔI/ΔG ÷ IR, where Δ is change from baseline, I is insulin, and G is glucose) is commonly used as a measure of β-cell function. This relationship is curvilinear and becomes linear when log transformed. ΔI is determined by 2 variables: insulin secretion rate (ISR) and metabolic clearance of insulin. We postulated that the characteristic curvilinear relationship would be lost if Δ plasma C-peptide (ΔCP) (instead of Δ plasma insulin) was plotted against insulin sensitivity. A total of 441 individuals with impaired glucose tolerance (IGT) from ACT NOW received an oral glucose tolerance test and were randomized to pioglitazone or placebo for 2.4 years. Pioglitazone reduced IGT conversion to diabetes by 72% (P < .0001). ΔI/ΔG vs the Matsuda index of insulin sensitivity showed the characteristic curvilinear relationship. However, when ΔCP/ΔG or ΔISR/ΔG was plotted against the Matsuda index, the curvilinear relationship was completely lost. This discordance was explained by 2 distinct physiologic effects that altered plasma insulin response in opposite directions: 1) increased ISR and 2) augmented metabolic clearance of insulin. The net result was a decline in the plasma insulin response to hyperglycemia during the oral glucose tolerance test. These findings demonstrate a physiologic control mechanism wherein the increase in ISR ensures adequate insulin delivery into the portal circulation to suppress hepatic glucose production while delivering a reduced but sufficient amount of insulin to peripheral tissues to maintain the pioglitazone-mediated improvement in insulin sensitivity without excessive hyperinsulinemia. These results demonstrate the validity of the disposition index when relating the plasma insulin response to insulin sensitivity but underscore the pitfall of this index when drawing conclusions about β-cell function, because insulin secretion declined despite an increase in the

Comparison of the effects of pioglitazone and rosiglitazone on macrophage foam cell formation

International Nuclear Information System (INIS)

Hirakata, Masao; Tozawa, Ryuichi; Imura, Yoshimi; Sugiyama, Yasuo

2004-01-01

In order to elucidate the antiatherogenic effects of pioglitazone (a peroxisome proliferator-activated receptor [PPAR]γ agonist with PPARα agonistic activity) and rosiglitazone (a more selective PPARγ agonist), we examined gene expression and cholesteryl ester accumulation in THP-1-derived macrophages. Pioglitazone enhanced the mRNA expression of the proatherogenic factors CD36 and adipophilin, but was approximately 10 times less potent than rosiglitazone. The potencies of the two agents appeared to correspond to their PPARγ agonistic activities in this respect. However, both agents were similarly potent in enhancing the mRNA expression of the antiatherogenic factors liver X receptor α and ATP-binding cassette-transporter A1. Furthermore, both agents enhanced cholesteryl ester hydrolase mRNA expression and inhibited acyl-CoA cholesterol acyltransferase-1 mRNA expression and cholesteryl ester accumulation in macrophages. In this respect, their potencies appeared to correspond to their PPARα agonistic activities. These results suggest that pioglitazone has an equally beneficial effect on antiatherogenic events to rosiglitazone, despite being almost 10 times less potent than a PPARγ agonist

Pioglitazone Attenuates Drug-Eluting Stent-Induced Proinflammatory State in Patients by Blocking Ubiquitination of PPAR

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Zhongxia Wang

2016-01-01

Full Text Available The inflammatory response after polymer-based drug-eluting stent (DES placement has recently emerged as a major concern. The biologic roles of peroxisome proliferator-activated receptor-γ (PPAR-γ activators thiazolidinedione (TZD remain controversial in cardiovascular disease. Herein, we investigated the antiinflammatory effects of pioglitazone (PIO on circulating peripheral blood mononuclear cells (MNCs in patients after coronary DES implantation. Methods and Results. Twenty-eight patients with coronary artery disease and who underwent DES implantations were randomly assigned to pioglitazone (30 mg/d; PIO or placebo (control; Con treatment in addition to optimal standard therapy. After 12 weeks of treatment, plasma concentrations of high-sensitivity C-reactive protein (hs-CRP, interleukin-6 (IL-6, tumor necrosis factor-α (TNF-α, and matrix metalloproteinase-9 (MMP-9 were significantly decreased in PIO group compared to the Con group (P=0.035, 0.011, 0.008, and 0.012, resp.. DES-induced mRNA expressions of IL-6, TNF-α, and MMP-9 in circulating MNC were significantly blocked by PIO (P=0.031, 0.012, and 0.007, resp.. In addition, PIO markedly inhibited DES-enhanced NF-κB function and DES-blocked PPAR-γ activity. Mechanically, DES induced PPAR-γ ubiquitination and degradation in protein level, which can be totally reversed by PIO. Conclusion. PIO treatment attenuated DES-induced PPAR loss, NF-κB activation, and proinflammation, indicating that PIO may have a novel direct protective role in modulating proinflammation in DES era.

Patient factors associated with hemoglobin A1C change with pioglitazone as adjunctive therapy in type 2 Diabetes Mellitus

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Tran MT

2008-06-01

Full Text Available Objective: To identify patient factors associated with change in hemoglobin A1C (A1C with adjunct pioglitazone therapy in routine clinical practice. Methods: This was a retrospective analysis of adult type 2 diabetes mellitus patients in a health maintenance organization setting who were newly-initiated on pioglitazone between January 2002 and December 2005. Eligible patients were receiving at least one other oral antihyperglycemic medication prior to initiating pioglitazone and maintained a stable dose of pioglitazone for 90 days. Data on eligible patients’ characteristics, pharmacy purchases, comorbidities, and A1C measurement 90 days prior to the pioglitazone purchase date (baseline and 90 days after achieving a stable dose (follow-up were obtained from electronic records. Multivariate regression modeling was used to assess factors independently associated with: 1 absolute change in A1C, 2 achieving a ≥1 percentage point decrease in A1C, and 3 achieving an A1C8%. At follow-up, the mean A1C change was -1.2 percentage points (interquartile range= -0.4, -2.1, 59% achieved a ≥1 unit decrease in A1C, and 44% achieved an A1C<7%. Independent predictors in all models were baseline A1C and time (in days between baseline and follow-up A1C measurements (p<0.05. Conclusions: Adjunct pioglitazone therapy in routine clinical practice was associated with clinically meaningful reductions in A1C levels. Patients with higher baseline A1C achieved the greatest absolute reduction in A1C but were less likely to achieve levels <7%.

A comparison of glycemic control, water retention, and musculoskeletal effects of balaglitazone and pioglitazone in diet-induced obese rats

DEFF Research Database (Denmark)

Henriksen, Kim; Byrjalsen, Inger; Nielsen, Rasmus H

2009-01-01

: vehicle, pioglitazone 10 mg/kg, pioglitazone 30 mg/kg, balaglitazone 5 mg/kg, balaglitazone 10 mg/kg. At day -7, 21 and 42 fasting serum samples were collected and whole body tissue composition was evaluated by MR scanning. Food intake and bodyweights were monitored during the study period. At day 42...

Efficacy and safety of the partial PPARγ agonist balaglitazone compared with pioglitazone and placebo: A phase III, randomised, parallel-group study in patients with type 2 diabetes on stable insulin therapy

DEFF Research Database (Denmark)

Henriksen, Kim; Byrjalsen, Inger; Qvist, Per

2011-01-01

Treatment of patients with full PPARγ agonists is associated with weight gain, heart failure, peripheral oedema and bone loss. However, the safety of partial PPARγ agonists has not been established in a clinical trial. The BALLET trial aimed to establish the glucose-lowering effects and safety...... in all treatment arms. DXA analyses showed balaglitazone 10mg led to less fat and fluid accumulation and no change in bone mineral density, when compared to pioglitazone. In the balaglitazone 10mg treated group clinically relevant reductions in HbA(1c) and glucose levels were observed, although...... it appeared to be a little less potent that pioglitazone 45mg. On the other hand significantly less fluid and fat accumulation were observed, highlighting this treatment regimen for further studies....

Effects of PPARγ Agonist Pioglitazone on Redox-Sensitive Cellular Signaling in Young Spontaneously Hypertensive Rats

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Ima Dovinová

2013-01-01

Full Text Available PPARγ receptor plays an important role in oxidative stress response. Its agonists can influence vascular contractility in experimental hypertension. Our study was focused on the effects of a PPARγ agonist pioglitazone (PIO on blood pressure regulation, vasoactivity of vessels, and redox-sensitive signaling at the central (brainstem, BS and peripheral (left ventricle, LV levels in young prehypertensive rats. 5-week-old SHR were treated either with PIO (10 mg/kg/day, 2 weeks or with saline using gastric gavage. Administration of PIO significantly slowed down blood pressure increase and improved lipid profile and aortic relaxation after insulin stimulation. A significant increase in PPARγ expression was found only in BS, not in LV. PIO treatment did not influence NOS changes, but had tissue-dependent effect on SOD regulation and increased SOD activity, observed in LV. The treatment with PIO differentially affected also the levels of other intracellular signaling components: Akt kinase increased in the the BS, while β-catenin level was down-regulated in the BS and up-regulated in the LV. We found that the lowering of blood pressure in young SHR can be connected with insulin sensitivity of vessels and that β-catenin and SOD levels are important agents mediating PIO effects in the BS and LV.

Pioglitazone utilization, efficacy & safety in Indian type 2 diabetic patients: A systematic review & comparison with European Medicines Agency Assessment Report.

Science.gov (United States)

Pai, Sarayu A; Kshirsagar, Nilima A

2016-11-01

With pioglitazone ban and subsequent revoking in India along with varying regulatory decisions in other countries, it was decided to carry out a systematic review on its safety, efficacy and drug utilization in patients with type 2 diabetes mellitus (T2DM) in India and compare with the data from the European Medicines Agency Assessment Report (EMA-AR). Systematic review was performed as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, searching Medline/PubMed, Google Scholar and Science Direct databases using 'pioglitazone AND India AND human' and 'pioglitazone AND India AND human AND patient' and compared with EMA-AR. Spontaneous reports in World Health Organization VigiBase from India were compared with VigiBase data from other countries. Sixty six publications, 26 (efficacy), 32 (drug utilization) and eight (safety), were retrieved. In India, pioglitazone was used at 15-30 mg/day mostly with metformin and sulphonylurea, being prescribed to 26.7 and 8.4 per cent patients in north and south, respectively. The efficacy in clinical trials (CTs) was similar to those in EMA-AR. Incidence of bladder cancer in pioglitazone exposed and non-exposed patients was not significantly different in an Indian retrospective cohort study. There were two cases and a series of eight cases of bladder cancer published but none reported in VigiBase. In India, probably due to lower dose, lower background incidence of bladder cancer and smaller sample size in epidemiological studies, association of bladder cancer with pioglitazone was not found to be significant. Reporting of CTs and adverse drug reactions to Clinical Trials Registry of India and Pharmacovigilance Programme of India, respectively, along with compliance studies with warning given in package insert and epidemiological studies with larger sample size are needed.

Impaired insulin-stimulated phosphorylation of Akt and AS160 in skeletal muscle of women with polycystic ovary syndrome is reversed by pioglitazone treatment

DEFF Research Database (Denmark)

Højlund, Kurt; Glintborg, Dorte; Andersen, Nicoline R

2008-01-01

, and we examined the effect of 16 weeks of treatment with pioglitazone in PCOS patients. RESULTS: Impaired insulin-mediated total (R(d)) oxidative and nonoxidative glucose disposal (NOGD) was paralleled by reduced insulin-stimulated Akt phosphorylation at Ser473 and Thr308 and AS160 phosphorylation......OBJECTIVE: Insulin resistance in skeletal muscle is a major risk factor for type 2 diabetes in women with polycystic ovary syndrome (PCOS). However, the molecular mechanisms underlying skeletal muscle insulin resistance and the insulin-sensitizing effect of thiazolidinediones in PCOS in vivo...... are less well characterized. RESEARCH DESIGN AND METHODS: We determined molecular mediators of insulin signaling to glucose transport in skeletal muscle biopsies of 24 PCOS patients and 14 matched control subjects metabolically characterized by euglycemic-hyperinsulinemic clamps and indirect calorimetry...

A comparison of pioglitazone with metformin in management of type 2 diabetes mellitus

International Nuclear Information System (INIS)

Razzaq, K.; Ahmed, W.; Anwar, R.; Khan, A.M.; Taj, M.A.; Iqbal, M.; Yousaf, M.A.

2011-01-01

Objectives: To compare hypo glycemic effect of Pioglitazone and Metformin in type 2 Diabetes Mellitus. Study Design: Quasi experimental study. Place and Duration of study: Department of Medicine, Military Hospital Rawalpindi Cantt. from 11-01-2007 to 12-08-2007. Material and Methods: Sixty patients of type 2 diabetes mellitus from outdoor department were selected. On arrival at OPD each patient was examined thoroughly. Therapeutic option was allocated to the patients simply by using a table of random numbers and dividing them in two equal groups. Informed written consent was obtained. Each patient was followed on monthly subsequent visits (six in total) and his HbA1c, fasting and random blood glucose were recorded carefully. All the data thus obtained was processed and analyzed using SPSS version 10.0. Mean and SD were calculated for age, BMI, fasting blood glucose, random blood glucose and HbA1c levels. Results: Mean drop of all three parameters were compared among two groups. At the end of six months, it was revealed that fasting and random (2 hours postprandial) blood glucose dropped more in Pioglitazone group; P=0.000 and 0.02 respectively. While almost comparable effect was observed in HbA1c (P=0.2). Conclusion: Pioglitazone has significantly better hypo glycemic effect than Metformin in type 2 diabetes mellitus at the end of six months therapy. (author)

A randomized placebo-controlled study on the effects of pioglitazone on cortisol metabolism in polycystic ovary syndrome

DEFF Research Database (Denmark)

Glintborg, Dorte; Hermann, Anne Pernille; Hagen, Claus

2009-01-01

by allotetrahydrocortisol (alloTHF)/THF and androsterone/etiocholanolone (A/E) ratios. Delta values denoted changes during the treatment period (16 weeks--basal). Pyridostigmine growth hormone (GH) stimulation tests were performed, and testosterone (T), dihydrotestosterone (DHT), DHEA, DHEAS, adiponectin, and insulin...... levels. Delta A/E ratio inversely correlated with Delta IGF-I and Delta peak GH during GH stimulation tests. No significant changes were measured in T, DHT, DHEA, DHEAS, 24 h mean cortisol, or urinary excretion of steroid metabolites. CONCLUSION(S): Pioglitazone decreased relative 5alpha...

Long-term pioglitazone treatment augments insulin sensitivity and PKC-epsilon and PKC-theta activation in skeletal muscles in sucrose fed rats

Czech Academy of Sciences Publication Activity Database

Marková, I.; Zídek, Václav; Musilová, Alena; Šimáková, Miroslava; Mlejnek, Petr; Kazdová, L.; Pravenec, Michal

2010-01-01

Roč. 59, č. 4 (2010), s. 509-516 ISSN 0862-8408 R&D Projects: GA MŠk(CZ) 1M0520; GA MŠk(CZ) ME08006; GA AV ČR(CZ) IAA500110604; GA MZd(CZ) NR9387; GA MZd(CZ) NR9359; GA MZd(CZ) NS9759 Institutional research plan: CEZ:AV0Z50110509 Keywords : pioglitazone * PKC * insulin resistance Subject RIV: FB - Endocrinology, Diabetology, Metabolism, Nutrition Impact factor: 1.646, year: 2010

Liquid chromatographic determination of pioglitazone in pharmaceuticals, serum and urine samples

International Nuclear Information System (INIS)

Abro, K.; Memon, N.; Bhanger, M.I.; Mahesar, S.A.; Parveen, S.

2011-01-01

A rapid and reliable analytical method based on high-performance liquid chromatography (HPLC) with UV detection (221 nm) has been developed for the determination of the anti-hyper glycemic agent Pioglitazone in pharmaceutical formulations and biological fluids (serum and urine) after clean-up with solid-phase extraction. Chromatographic separation was achieved with a Chromolith Performance RP-18e (10 4.6mm) column using mobile phase composition of acetonitrile: mixed phosphate buffer (pH 2.5; 10mM) (30:70, v/v) with a flow rate of 2.0mL/min. The total run time was 2 min. under optimized conditions. The calibration curve was found to be linear in the range of 1-10 mu g mL/sup -1/ with regression coefficient of 0.9996, and the lower limit of detection 72 ng/20 mu L injection. The method has been validated for the system suitability, linearity, precision and accuracy, limits of detection, specificity, stability and robustness. The %recovery of Pioglitazone in pharmaceutical formulations was found to be 104.7%. The assay has been applied successfully to the pharmaceutical Tablet samples and biological fluids (serum and urine) of healthy volunteers. (author)

Impact of regulatory spin of pioglitazone on prescription of antidiabetic drugs among physicians in India: A multicentre questionnaire-based observational study

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Aman Goyal

2017-01-01

Interpretation & conclusions: Majority of the physicians though were aware of the regulatory changes with regard to pioglitazone, but their prescribing patterns were not changed for this drug. However, it was being used at lower than the recommended dose. There is a need for generating more evidence through improved pharmacovigilance activities and large-scale population-based prospective studies regarding the safety issues of pioglitazone, so as to make effectual risk-benefit analysis for its continual use in T2DM.

Underlying mechanism of drug-drug interaction between pioglitazone and gemfibrozil: Gemfibrozil acyl-glucuronide is a mechanism-based inhibitor of CYP2C8.

Science.gov (United States)

Takagi, Motoi; Sakamoto, Masaya; Itoh, Tomoo; Fujiwara, Ryoichi

2015-08-01

While co-administered gemfibrozil can increase the area under the concentration/time curve (AUC) of pioglitazone more than 3-fold, the underlying mechanism of the drug-drug interaction between gemfibrozil and pioglitazone has not been fully understood. In the present study, gemfibrozil preincubation time-dependently inhibited the metabolism of pioglitazone in the cytochrome P450 (CYP)- and UDP-glucuronosyltransferase (UGT)-activated human liver microsomes. We estimated the kinact and K'app values, which are the maximum inactivation rate constant and the apparent dissociation constant, of gemfibrozil to be 0.071 min(-1) and 57.3 μM, respectively. In this study, the kobs, in vivo value was defined as a parameter that indicates the potency of the mechanism-based inhibitory effect at the blood drug concentration in vivo. The kobs, in vivo values of potent mechanism-based inhibitors, clarithromycin and erythromycin, were estimated to be 0.0096 min(-1) and 0.0051 min(-1), respectively. The kobs, in vivo value of gemfibrozil was 0.0060 min(-1), which was comparable to those of clarithromycin and erythromycin, suggesting that gemfibrozil could be a mechanism-based inhibitor as potent as clarithromycin and erythromycin in vivo. Copyright © 2015 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

Soluble CD36 and risk markers of insulin resistance and atherosclerosis are elevated in polycystic ovary syndrome and significantly reduced during pioglitazone treatment

DEFF Research Database (Denmark)

Glintborg, Dorte; Højlund, Kurt; Andersen, Marianne

2007-01-01

Objective: We investigated the relation between soluble CD36 (sCD36), risk markers of atherosclerosis and body composition, and glucose and lipid metabolism in polycystic ovary syndrome (PCOS) Research Design and Methods: Thirty PCOS patients were randomized to pioglitazone, 30 mg/day or placebo...... units), oxLDL (44.9 (26.9 - 75.1) vs. 36.1 (23.4 - 55.5) U/l), and hsCRP (0.26 (0.03 - 2.41) vs. 0.12 (0.02 - 0.81) mg/dl) were significantly increased in PCOS patients vs. controls (geometric mean (+/- 2SD)). In PCOS, positive correlations were found between central fat mass and sCD36 (r=0.43), hs......CRP (r=0.43), and IL-6 (r=0.42), all pPCOS patients and controls (n=44). sCD36 and oxLDL were significant...

Formulation and evaluation of sustained release matrix tablets of pioglitazone hydrochloride using processed Aloe vera mucilage as release modifier

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Manoj Choudhary

2015-01-01

Full Text Available Background: Natural gums and mucilage which hydrates and swells on contact with aqueous media are used as additives in the formulation of hydrophilic drug delivery system. Aim: The purpose of this study was to develop a new monolithic matrix system for complete delivery of Pioglitazone hydrochloride (HCl, in a zero-order manner over an extended time period using processed Aloe vera gel mucilage (PAG as a release modifier. Materials and Methods: The matrices were prepared by dry blending of selected ratios of polymer and ingredients using direct compression technique. Physicochemical properties of dried powdered mucilage of A. vera were studied. Various formulations of pioglitazone HCl and A. vera mucilage were prepared using different drug: Polymer ratios viz., 1:1, 1:2, 1:3, 1:4, 1:5 for PAG by direct compression technique. Results: The formulated matrix tablets were found to have better uniformity of weight and drug content with low statistical deviation. The swelling behavior and in vitro release rate characteristics were also studied. Conclusion: The study proved that the dried A. vera mucilage can be used as a matrix forming material for controlled release of Pioglitazone HCl matrix tablets.

Additive effects of glucagon-like peptide 1 and pioglitazone in patients with type 2 diabetes

DEFF Research Database (Denmark)

Zander, Mette; Christiansen, Allan; Madsbad, Sten

2004-01-01

.01). Glucagon levels were reduced in GLP-1 and combination therapy compared with saline and monotherapy with pioglitazone (P breakfast (area under the curve, 0-3 h) were reduced in combination therapy compared with saline (P = 0.03). Sensation of appetite was reduced during monotherapy...

Pioglitazone improves cardiac function and alters myocardial substrate metabolism without affecting cardiac triglyceride accumulation and high-energy phosphate metabolism in patients with well-controlled type 2 diabetes mellitus

NARCIS (Netherlands)

van der Meer, Rutger W.; Rijzewijk, Luuk J.; de Jong, Hugo W. A. M.; Lamb, Hildo J.; Lubberink, Mark; Romijn, Johannes A.; Bax, Jeroen J.; de Roos, Albert; Kamp, Otto; Paulus, Walter J.; Heine, Robert J.; Lammertsma, Adriaan A.; Smit, Johannes W. A.; Diamant, Michaela

2009-01-01

Cardiac disease is the leading cause of mortality in type 2 diabetes mellitus (T2DM). Pioglitazone has been associated with improved cardiac outcome but also with an elevated risk of heart failure. We determined the effects of pioglitazone on myocardial function in relation to cardiac high-energy

Vildagliptin/pioglitazone combination improved the overall glycemic control in type I diabetic rats.

Science.gov (United States)

Abdelhamid, Amir Mohamed; Abdelaziz, Rania Ramadan; Salem, Hatem Abdelrahman Ali

2018-03-06

Type I diabetes (TID) is generally assumed to be caused by an immune associated, if not directly immune-mediated, destruction of pancreatic β-cells. In patients with long-term diabetes, the pancreas lacks insulin-producing cells and the residual β-cells are unable to regenerate. Patients with TID are subjected to a lifelong insulin therapy which shows risks of hypoglycemia, suboptimal control and ketosis. In this study, we investigated the potential role of vildagliptin (Vilda) alone or in combination with pioglitazone (Pio), as treatment regimens for TID using streptozotocin (STZ)-induced TID model in rats. Daily oral administration of Vilda (5 mg/kg) alone or in combination with Pio (20 mg/kg) for 7 weeks significantly reduced blood glucose levels and HbA 1c . It increased serum insulin levels and decreased serum glucagon. It also showed a strong antioxidant activity. Immunohistochemical analysis showed a marked improvement in β-cells in treated groups when compared with the diabetic group, which appeared in the normal cellular and architecture restoration of β-cells in the islets of Langerhans. Vilda alone or in combination with Pio has the ability to improve the overall glycemic control in type I diabetic rats and may be considered a hopeful and effective remedy for TID.

Pioglitazone enhances expression of genes involved in mitochondrial oxidative metabolism in skeletal muscle of women with polycystic ovary syndrome (PCOS)

DEFF Research Database (Denmark)

Skov, Vibe

Aims                Polycystic ovary syndrome (PCOS) is a common endocrine disorder in premenopausal women and is associated with insulin resistance increasing the risk for developing type 2 diabetes mellitus. Studies have shown that thiazolidinediones (TZD) improve metabolic disturbances in PCOS...... patients. We hypothesized that the effect of TZD in PCOS is in part mediated by changes in the transcriptional profile of muscle favoring insulin sensitivity. Methods Using the HG-U133 2.0 Plus expression array from Affymetrix, we examined the effect of pioglitazone (30 mg/day for 16 weeks) on gene...... expression in skeletal muscle of 10 obese women with PCOS (dataset 1). Furthermore, evaluation of gene expression changes between PCOS patients before treatment and control subjects were performed (dataset 2). All subjects were metabolically characterised by a euglycemic-hyperinsulinemic clamp combined...

Metformin and pioglitazone are effective in reducing the levels of leptin and omentin

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A K Lipatenkova

2013-03-01

Full Text Available Реферат по материалам статьи Esteghamati A, Noshad S, Rabizadeh S, Ghavami M, Zandieh A, Nakhjavani M. Comparative effects of metformin and pioglitazone on omentin and leptin concentrations in patients with newly diagnosed diabetes: A randomized clinical trial. Regul Pept. 2013 Jan 14;182C:1-6.

Characterization of pioglitazone cyclodextrin complexes: Molecular modeling to in vivo evaluation

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Dinesh M Bramhane

2016-01-01

Full Text Available Aims: The objective of present study was to study the influence of different β-cyclodextrin derivatives and different methods of complexation on aqueous solubility and consequent translation in in vivo performance of Pioglitazone (PE. Material and Methods: Three cyclodextrins: β-cyclodextrin (BCD, hydroxypropyl-β-cyclodextrin (HPBCD and Sulfobutylether-7-β-cyclodextrin (SBEBCD were employed in preparation of 1:1 Pioglitazone complexes by three methods viz. co-grinding, kneading and co-evaporation. Complexation was confirmed by phase solubility, proton NMR, Fourier Transform Infrared spectroscopy, Differential Scanning Calorimetry (DSC and X-Ray diffraction (XRD. Mode of complexation was investigated by molecular dynamic studies. Pharmacodynamic study of blood glucose lowering activity of PE complexes was performed in Alloxan induced diabetic rat model. Results: Aqueous solubility of PE was significantly improved in presence of cyclodextrin. Apparent solubility constants were observed to be 254.33 M–1 for BCD-PE, 737.48 M–1 for HPBCD-PE and 5959.06 M–1 for SBEBCD-PE. The in silico predictions of mode of inclusion were in close agreement with the experimental proton NMR observation. DSC and XRD demonstrated complete amorphization of crystalline PE upon inclusion. All complexes exhibited >95% dissolution within 10 min compared to drug powder that showed <40% at the same time. Marked lowering of blood glucose was recorded for all complexes. Conclusion: Complexation of PE with different BCD significantly influenced its aqueous solubility, improved in vitro dissolution and consequently translated into enhanced pharmacodynamic activity in rats

Thiazolidinediones abrogate cervical cancer growth

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Wuertz, Beverly R., E-mail: knier003@umn.edu; Darrah, Lindsay, E-mail: ldarrah@obgynmn.com; Wudel, Justin, E-mail: drwudel@drwudel.com; Ondrey, Frank G., E-mail: ondre002@umn.edu

2017-04-15

Peroxisome proliferator-activated receptor gamma (PPAR γ) is activated by thiazolidinedione drugs (TZDs) and can promote anti-cancer properties. We used three TZDs (pioglitazone, rosiglitazone, and ciglitazone) to target cervical cancer cell lines and a nude mouse animal model. Each agent increased activation of PPAR γ, as judged by a luciferase reporter gene assay in three HPV-associated cell lines (CaSki, SiHa, and HeLa cells) while decreasing cellular proliferation in a dose-dependent manner. They also promoted Oil Red O accumulation in treated cell lines and upregulated the lipid differentiation marker adipsin. Interestingly, xenograft HeLa tumors in nude mice treated with 100 mg/kg/day pioglitazone exhibited decreased growth compared to control mice or mice treated with standard cervical chemotherapy. In conclusion, TZDs slow tumor cell growth in vitro and in vivo with decreases in cell proliferation and increases in PPAR γ and adipsin. These agents may be interesting treatments or treatment adjuncts for HPV-associated cancers or perhaps even precancerous conditions. - Highlights: • Thiazolidinediones decreases cervical cancer proliferation. • Pioglitazone increases cervical cancer differentiation. • Pioglitazone decreases tumor growth in mice. • Pioglitazone may be a useful treatment adjunct.

Inflammation in Depression and the Potential for Anti-Inflammatory Treatment

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Köhler, Karl Ole; Krogh, Jesper; Mors, Ole

2016-01-01

, nonsteroidal anti-inflammatory drugs (NSAIDs) and cytokine-inhibitors have shown antidepressant treatment effects compared to placebo, but also statins, poly-unsaturated fatty acids, pioglitazone, minocycline, modafinil, and corticosteroids may yield antidepressant treatment effects. However, the complexity...

A review of thiazolidinediones and metformin in the treatment of type 2 diabetes with focus on cardiovascular complications

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Behzad, Molavi; Negah, Rassouli; Suveer, Bagwe; Neda, Rasouli

2007-01-01

The rising incidence of obesity and insulin resistance to epidemic proportions has closely paralleled the surge in the prevalence of diabetes and outpaced therapeutic advances in diabetes prevention and treatment. Current evidence points to obesity induced oxidative stress and chronic inflammation as the common denominators in the evolution of insulin resistance and diabetes. Of all the hypoglycemic agents in the pharmacological arsenal against diabetes, thiazolidinediones, in particular pioglitazone, as well as metformin appear to have additional effects in ameliorating oxidative stress and inflammation; rendering them attractive tools for prevention of insulin resistance and diabetes. In addition to their hypoglycemic and lipid modifying properties, pioglitazone and metformin have been shown to exert anti-oxidative and anti-inflammatory effects in vascular beds, potentially slowing the accelerated atherosclerosis in diabetes, which is the major cause of morbidity and mortality in the affected population. The combination of pioglitazone and metformin would thus appear to be an effective pharmacological intervention in prevention and treatment of diabetes. Finally, this review will address the currently available evidence on diabetic cardiomyopathy and the potential role of combination therapy with pioglitazone and metformin. PMID:18200815

Mitochondrial dysfunction contribute to diabetic neurotoxicity induced by streptozocin in mice: protective effect of Urtica dioica and pioglitazone.

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Shokrzadeh, Mohammad; Mirshafa, Atefeh; Yekta Moghaddam, Niusha; Birjandian, Behnoosh; Shaki, Fatemeh

2018-04-18

Uncontrolled chronic hyperglycemia in diabetic patients could result in various complications, including neurotoxicity. Urtica dioica L. (UD) is known for its hypoglycemic and antioxidant effects. In this study, we evaluated the efficacy of UD and pioglitazone (PIO) in reduction of neurotoxicity and oxidative stress in streptozocin-induced diabetic mice. Male mice were divided into seven groups: control, diabetic, dimethyl sulfoxide-treated control, PIO-treated, UD-treated, UD-PIO-treated, and vitamin E-treated. For induction of diabetes, streptozocin was injected in a single dose (65 mg/kg, i.p.). All treatments were performed for 5 weeks. Neurotoxicity was evaluated through hot plate and formalin test. Then, animals were killed, brain tissue was separated and the mitochondrial fraction was isolated with different centrifuge technique. Also, oxidative stress markers (reactive oxygen species, lipid peroxidation, protein carbonyl, glutathione) were measured in brain. Mitochondrial function was evaluated by MTT test in brain isolated mitochondria. Elevation of oxidative stress markers and mitochondrial damage were observed in diabetic mice compared to control group. Administration of PIO and UD ameliorated the oxidative stress and mitochondrial damage (p < 0.05) in diabetic mice. Also increase in pain score was shown in diabetic mice that treatment with UD and PIO diminished elevation of pain score in diabetic mice. Interestingly, simultaneous administration of PIO and UD showed synergism effect in attenuation of oxidative stress and hyperglycemia. UD showed a therapeutic potential for the attenuation of oxidative stress and diabetes-induced hyperglycemia that can be considered as co-treatment in treatment of diabetic neurotoxicity.

Lithium, phenserine, memantine and pioglitazone reverse memory deficit and restore phospho-GSK3β decreased in hippocampus in intracerebroventricular streptozotocin induced memory deficit model.

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Ponce-Lopez, Teresa; Liy-Salmeron, Gustavo; Hong, Enrique; Meneses, Alfredo

2011-12-02

Intracerebroventricular (ICV) streptozotocin (STZ) treated rat has been described as a suitable model for sporadic Alzheimer's disease (AD). Central application of STZ has demonstrated behavioral and neurochemical features that resembled those found in human AD. Chronic treatments with antioxidants, acetylcholinesterase (AChE) inhibitors, or improving glucose utilization drugs have reported a beneficial effect in ICV STZ-treated rats. In the present study the post-training administration of a glycogen synthase kinase (GSK3) inhibitor, lithium; antidementia drugs: phenserine and memantine, and insulin sensitizer, pioglitazone on memory function of ICV STZ-rats was assessed. In these same animals the phosphorylated GSK3β (p-GSK3β) and total GSK3β levels were determined, and importantly GSK3β regulates the tau phosphorylation responsible for neurofibrillary tangle formation in AD. Wistar rats received ICV STZ application (3mg/kg twice) and 2 weeks later short- (STM) and long-term memories (LTM) were assessed in an autoshaping learning task. Animals were sacrificed immediately following the last autoshaping session, their brains removed and dissected. The enzymes were measured in the hippocampus and prefrontal cortex (PFC) by western blot. ICV STZ-treated rats showed a memory deficit and significantly decreased p-GSK3β levels, while total GSK3β did not change, in both the hippocampus and PFC. Memory impairment was reversed by lithium (100mg/kg), phenserine (1mg/kg), memantine (5mg/kg) and pioglitazone (30 mg/kg). The p-GSK3β levels were restored by lithium, phenserine and pioglitazone in the hippocampus, and restored by lithium in the PFC. Memantine produced no changes in p-GSK3β levels in neither the hippocampus nor PFC. Total GSK3β levels did not change with either drug. Altogether these results show the beneficial effects of drugs with different mechanisms of actions on memory impairment induced by ICV STZ, and restored p-GSK3β levels, a kinase key of

Neuroprotective Effect and Mechanism of Thiazolidinedione on Dopaminergic Neurons In Vivo and In Vitro in Parkinson’s Disease

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Yanqin Wang

2017-01-01

Full Text Available The aim of the present study was to gain insight into the neuroprotection effects and mechanism of thiazolidinedione pioglitazone in both in vitro and in vivo MPP+/MPTP induced PD models. In vivo experimental results showed that oral treatment of pioglitazone resulted in significant improvements in behavior symptoms damaged by MPTP and increase in the survival of TH positive neurons in the pioglitazone intervention groups. In addition, oral treatment of pioglitazone increased the expression of peroxisome proliferator-activated receptor-γ coactivator of 1α (PGC-1α and increased the number of mitochondria, along with an observed improvement in mitochondrial ultrastructure. From in vitro studies, 2,4-thiazolidinedione resulted in increased levels of molecules regulated function of mitochondria, including PGC-1α, nuclear respiratory factor 1 (NRF1, NRF2, and mitochondria fusion 2 (Mfn2, and inhibited mitochondria fission 1 (Fis1. We show that protein levels of Bcl-2 and ERK were reduced in the MPP+-treated group compared with the control group. This effect was observed to be reversed upon treatment with 2,4-thiazolidinedione, as Bcl-2 and ERK expression levels were increased. We also observed that levels of the apoptotic protein Bax showed opposite changes compared to Bcl-2 and ERK levels. The results from this study confirm that pioglitazone/2,4-thiazolidinedione is able to activate PGC-1α and prevent damage of dopaminergic neurons and restore mitochondria ultrastructure through the regulation of mitochondria function.

Pioglitazone improves insulin sensitivity, reduces visceral fat and stimulates lipolysis in non diabetic dialyzed patients

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Anne Zanchi

2012-06-01

Full Text Available Insulin resistance is common in dialyzed patients and is associated with increased mortality and protein-energy wasting. The aim of this study was to investigate the effect of pioglitazone (PIO, a powerful insulin sensitizer, on insulin sensitivity, body composition and adipose tissue metabolism, in dialyzed patients. A double blind randomized cross-over study was performed in non diabetic dialysis patients. Each patient followed 2 treatment phases of 16 weeks, starting either with oral PIO 45 mg/d or placebo (PL, and then switched to the other phase. At the end of each phase, patients underwent hyperinsulinemic euglycemic clamps, dual energy X-ray absorptiometry, an abdominal CT, and extensive plasma biochemical analysis. Twelve patients including 8 HD (59.6±4.4 y and 4 PD patients (43.5±3.6 y were recruited. Nine patients completed both phases and 3 patients dropped out (renal transplantation/2 HD and peritonitis/1 PD. PIO was safe and well tolerated. Under PIO, insulin sensitivity improved, as assessed by increased total glucose disposal rate (1.98±0.24 for PIO versus 1.58±0.12 umol/kg/min for PL, p<0.05, and reduced glucose endogenous hepatic production. PIO did not affect post-dialysis body weight, total fat and lean body mass, but significantly reduced visceral adipose tissue (VAT area and the VAT/SAT (subcutaneous adipose tissue ratio. HDL-cholesterol significantly increased. PIO decreased CRP (3.96±1.44 mg/l vs 7.88±2.56, p<0.05, plasma leptin, and dramatically reduced leptin/adiponectin ratio. Glycerol turnover, circulating glycerol and non esterified fatty acids were paradoxically increased. In conclusion, the improvement in insulin sensitivity by PIO, in non diabetic dialyzed patients, was associated with favorable metabolic effects, reduction in inflammation and body fat redistribution. The stimulation of systemic lipolysis was a surprising finding which may reflect adipose tissue remodeling and/or a paradoxical lypolitic

Treatment with Parkinsonia aculeata combats insulin resistance-induced oxidative stress through the increase in PPARγ/CuZn-SOD axis expression in diet-induced obesity mice.

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Araújo, Tiago Gomes; Oliveira, Alexandre Gabarra; Vecina, Juliana Falcato; Marin, Rodrigo Miguel; Franco, Eryvelton Souza; Abdalla Saad, Mario J; de Sousa Maia, Maria Bernadete

2016-08-01

Parkinsonia aculeata L. (Caesalpiniaceae) is a traditional ethnomedicine and has been used for the empiric treatment of hyperglycemia, without scientific background. Mechanistic analyses at molecular level from the antioxidant mechanism observed by P. aculeata are required. Herein the effects of the treatment by hydroethanolic extract partitioned with ethyl acetate of P. aculeata aerial parts (HEPa/EtOAc) in mice fed a high-fat diet that share many obesity phenotypes with humans were evaluated. The animals were treated orally with HEPa/EtOAc (125 and 250 mg/kg/day) and pioglitazone (5 mg/kg/day), for 16 days. After the treatment, HEPa/EtOAc reduced fasting serum glucose and insulin levels, as well as homeostasis model assessment for insulin resistance. In addition, an improvement in glucose intolerance was also observed. Indeed, a reduction in the circulating levels of TNF-α and IL-6 was also observed. Furthermore, at molecular level, it was demonstrated that the HEPa/EtOAc treatment was able to improve these physiological parameters, through the activation of peroxisome proliferator-activated receptor γ (PPARγ) per si, as well as the enhancement of antioxidant mechanism by an increase in PPARγ/Cu(2+), Zn(2+)-superoxide dismutase (CuZn-SOD) axis expression in liver and adipose tissue. In sum, P. aculeata is effective to improve insulin resistance in a mouse model of obesity and this effect seems to involve the antioxidant and anti-inflammatory mechanisms through the increase in PPARγ/CuZn-SOD axis expression.

Pioglitazone utilization, efficacy & safety in Indian type 2 diabetic patients: A systematic review & comparison with European Medicines Agency Assessment Report

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Sarayu A Pai

2016-01-01

Interpretation & conclusions: In India, probably due to lower dose, lower background incidence of bladder cancer and smaller sample size in epidemiological studies, association of bladder cancer with pioglitazone was not found to be significant. Reporting of CTs and adverse drug reactions to Clinical Trials Registry of India and Pharmacovigilance Programme of India, respectively, along with compliance studies with warning given in package insert and epidemiological studies with larger sample size are needed.

Effects of peroxisome proliferator activated receptors (PPAR-γ and -α agonists on cochlear protection from oxidative stress.

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Marijana Sekulic-Jablanovic

Full Text Available Various insults cause ototoxicity in mammals by increasing oxidative stress leading to apoptosis of auditory hair cells (HCs. The thiazolidinediones (TZDs; e.g., pioglitazone and fibrate (e.g., fenofibrate drugs are used for the treatment of diabetes and dyslipidemia. These agents target the peroxisome proliferator-activated receptors, PPARγ and PPARα, which are transcription factors that influence glucose and lipid metabolism, inflammation, and organ protection. In this study, we explored the effects of pioglitazone and other PPAR agonists to prevent gentamicin-induced oxidative stress and apoptosis in mouse organ of Corti (OC explants. Western blots showed high levels of PPARγ and PPARα proteins in mouse OC lysates. Immunofluorescence assays indicated that PPARγ and PPARα proteins are present in auditory HCs and other cell types in the mouse cochlea. Gentamicin treatment induced production of reactive oxygen species (ROS, lipid peroxidation, caspase activation, PARP-1 cleavage, and HC apoptosis in cultured OCs. Pioglitazone mediated its anti-apoptotic effects by opposing the increase in ROS induced by gentamicin, which inhibited the subsequent formation of 4-hydroxy-2-nonenal (4-HNE and activation of pro-apoptotic mediators. Pioglitazone mediated its effects by upregulating genes that control ROS production and detoxification pathways leading to restoration of the reduced:oxidized glutathione ratio. Structurally diverse PPAR agonists were protective of HCs. Pioglitazone (PPARγ-specific, tesaglitazar (PPARγ/α-specific, and fenofibric acid (PPARα-specific all provided >90% protection from gentamicin toxicity by regulation of overlapping subsets of genes controlling ROS detoxification. This study revealed that PPARs play important roles in the cochlea, and that PPAR-targeting drugs possess therapeutic potential as treatment for hearing loss.

A Computational Drug Metabolite Detection Using the Stable Isotopic Mass-Shift Filtering with High Resolution Mass Spectrometry in Pioglitazone and Flurbiprofen

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Yohei Miyamoto

2013-09-01

Full Text Available The identification of metabolites in drug discovery is important. At present, radioisotopes and mass spectrometry are both widely used. However, rapid and comprehensive identification is still laborious and difficult. In this study, we developed new analytical software and employed a stable isotope as a tool to identify drug metabolites using mass spectrometry. A deuterium-labeled compound and non-labeled compound were both metabolized in human liver microsomes and analyzed by liquid chromatography/time-of-flight mass spectrometry (LC-TOF-MS. We computationally aligned two different MS data sets and filtered ions having a specific mass-shift equal to masses of labeled isotopes between those data using our own software. For pioglitazone and flurbiprofen, eight and four metabolites, respectively, were identified with calculations of mass and formulas and chemical structural fragmentation analysis. With high resolution MS, the approach became more accurate. The approach detected two unexpected metabolites in pioglitazone, i.e., the hydroxypropanamide form and the aldehyde hydrolysis form, which other approaches such as metabolite-biotransformation list matching and mass defect filtering could not detect. We demonstrated that the approach using computational alignment and stable isotopic mass-shift filtering has the ability to identify drug metabolites and is useful in drug discovery.

Pioglitazone treatment increases spontaneous growth hormone (GH) secretion and stimulated GH levels in polycystic ovary syndrome

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Glintborg, Dorte; Støving, René Klinkby; Hagen, Claus

2005-01-01

BACKGROUND: Low GH levels, probably due to insulin resistance and increased abdominal fat mass, are well described in polycystic ovary syndrome (PCOS). GH acts as an important ovarian cogonadotropin, and GH disturbances may be an additional pathogenic factor in PCOS. Decreased abdominal fat mass...

Prevention of Diabetes With Pioglitazone in ACT NOW

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DeFronzo, Ralph A.; Tripathy, Devjit; Schwenke, Dawn C.; Banerji, MaryAnn; Bray, George A.; Buchanan, Thomas A.; Clement, Stephen C.; Gastaldelli, Amalia; Henry, Robert R.; Kitabchi, Abbas E.; Mudaliar, Sunder; Ratner, Robert E.; Stentz, Frankie B.; Musi, Nicolas; Reaven, Peter D.

2013-01-01

We examined the metabolic characteristics that attend the development of type 2 diabetes (T2DM) in 441 impaired glucose tolerance (IGT) subjects who participated in the ACT NOW Study and had complete end-of-study metabolic measurements. Subjects were randomized to receive pioglitazone (PGZ; 45 mg/day) or placebo and were observed for a median of 2.4 years. Indices of insulin sensitivity (Matsuda index [MI]), insulin secretion (IS)/insulin resistance (IR; ΔI0–120/ΔG0–120, ΔIS rate [ISR]0–120/ΔG0–120), and β-cell function (ΔI/ΔG × MI and ΔISR/ΔG × MI) were calculated from plasma glucose, insulin, and C-peptide concentrations during oral glucose tolerance tests at baseline and study end. Diabetes developed in 45 placebo-treated vs. 15 PGZ-treated subjects (odds ratio [OR] 0.28 [95% CI 0.15–0.49]; P IGT > T2DM) was associated with improvements in insulin sensitivity (OR 0.61 [95% CI 0.54–0.80]), IS (OR 0.61 [95% CI 0.50–0.75]), and β-cell function (ln IS/IR index and ln ISR/IR index) (OR 0.26 [95% CI 0.19–0.37]; all P < 0.0001). Of the factors measured, improved β-cell function was most closely associated with final glucose tolerance status. PMID:23863810

Administration of the peroxisomal proliferator-activated receptor γ agonist pioglitazone during fractionated brain irradiation prevents radiation-induced cognitive impairment

International Nuclear Information System (INIS)

Zhao Weiling; Payne, Valerie; Tommasi, Ellen; Diz, Debra I.; Hsu, F.-C.; Robbins, Mike E.

2007-01-01

Purpose: We hypothesized that administration of the anti-inflammatory peroxisomal proliferator-activated receptor γ (PPARγ) agonist pioglitazone (Pio) to adult male rats would inhibit radiation-induced cognitive impairment. Methods and Materials: Young adult male F344 rats received one of the following: (1) fractionated whole brain irradiation (WBI); 40 or 45 Gy γ-rays in 4 or 4.5 weeks, respectively, two fractions per week and normal diet; (2) sham-irradiation and normal diet; (3) WBI plus Pio (120 ppm) before, during, and for 4 or 54 weeks postirradiation; (4) sham-irradiation plus Pio; or (5) WBI plus Pio starting 24h after completion of WBI. Results: Administration of Pio before, during, and for 4 or 54 weeks after WBI prevented Radiation-induced cognitive impairment. Administration of Pio for 54 weeks starting after completion of fractionated WBI substantially but not significantly reduced Radiation-induced cognitive impairment. Conclusions: These findings offer the promise of improving the quality of life and increasing the therapeutic window for brain tumor patients

Effect of pioglitazone and ramipril on biomarkers of low-grade inflammation and vascular function in nondiabetic patients with increased cardiovascular risk and an activated inflammation: results from the PIOace study.

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Pfützner, Andreas; Hanefeld, Markolf; Dekordi, Lida A; Müller, Jürgen; Kleine, Iris; Fuchs, Winfried; Forst, Thomas

2011-07-01

This study investigated the effects of pioglitazone (PIO), ramipril (RAM), or their combination (PIRA) on low-grade inflammation in nondiabetic hypertensive patients with increased cardiovascular risk. Patients enrolled in this placebo-controlled, double-blind, randomized, parallel trial (72 male, 77 female, aged 60 ± 9 years, body mass index 30.4 ± 4.7 kg/m(2), duration of hypertension 9 ± 8 years) were treated with either 30/45 mg PIO (dose titration), 2.5/5 mg RAM, or their combination for 12 weeks. A reduction in high-sensitivity C-reactive protein was observed with PIO (-0.89 ± 1.98 mg/liter; -25%) and PIRA (-0.49 ± 2.11 mg/liter; -16%), while an increase was seen with RAM (0.58 ± 2.13 mg/liter; +20%, p PIRA). The 24-hour blood pressure profile showed a small increase with both monotherapies but a decrease with PIRA (p PIRA arms only [PIO/RAM/PIRA: homeostasis model of assessment of IR: -0.78 ± 1.39 (-29%)/0.15 ± 1.03 (+5%)/ -1.44 ± 2.83 (-40%); adiponectin: 8.51 ± 5.91 (+104%)/ 0.09 ± 2.63 (+1%)/ 8.86 ± 6.37 mg/liter (+107%); matrix metallo-proteinase-9: -48 ± 127 (-12%)/-1 ± 224 (0%)/-60 ± 210 ng/ml (-13%), p PIRA in all cases]. Our 3-month study in nondiabetic hypertensive patients showed a decrease in biomarkers of IR and chronic systemic inflammation with the PIO monotherapy and the PIRA combination only, which may help to explain some findings in other cardiovascular outcome trials. © 2011 Diabetes Technology Society.

Rationale, Design, and Baseline Characteristics of Beijing Prediabetes Reversion Program: A Randomized Controlled Clinical Trial to Evaluate the Efficacy of Lifestyle Intervention and/or Pioglitazone in Reversion to Normal Glucose Tolerance in Prediabetes.

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Luo, Yingying; Paul, Sanjoy K; Zhou, Xianghai; Chang, Cuiqing; Chen, Wei; Guo, Xiaohui; Yang, Jinkui; Ji, Linong; Wang, Hongyuan

2017-01-01

Background . Patients with prediabetes are at high risk for diabetes and cardiovascular disease (CVD). No study has explored whether intervention could revert prediabetes to normal glycemic status as the primary outcome. Beijing Prediabetes Reversion Program (BPRP) would evaluate whether intensive lifestyle modification and/or pioglitazone could revert prediabetic state to normoglycemia and improve the risk factors of CVD as well. Methods . BPRP is a randomized, multicenter, 2 × 2 factorial design study. Participants diagnosed as prediabetes were randomized into four groups (conventional/intensive lifestyle intervention and 30 mg pioglitazone/placebo) with a three-year follow-up. The primary endpoint was conversion into normal glucose tolerance. The trial would recruit 2000 participants (500 in each arm). Results . Between March 2007 and March 2011, 1945 participants were randomized. At baseline, the individuals were 53 ± 10 years old, with median BMI 26.0 (23.9, 28.2) kg/m 2 and HbA1c 5.8 (5.6, 6.1)%. 85% of the participants had IGT and 15% had IFG. Parameters relevant to glucose, lipids, blood pressure, lifestyle, and other metabolic markers were similar between conventional and intensive lifestyle intervention group at baseline. Conclusion . BPRP was the first study to determine if lifestyle modification and/or pioglitazone could revert prediabetic state to normoglycemia in Chinese population. Major baseline parameters were balanced between two lifestyle intervention groups. This trial is registered with www.chictr.org.cn: ChiCTR-PRC-06000005.

Spectrophotometric assay of pioglitazone hydrochloride using permanganate in acidic and basic media

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Kanakapura Basavaiah

2018-04-01

Full Text Available Pioglitazone hydrochloride (PGH is an oral anti-hyperglycemic agent used in the treatment of type-2 diabetes mellitus. Potassium permanganate was found to oxidize PGH both in acidic and basic conditions, based on which two simple and sensitive methods were developed for its determination in bulk sample and tablets, and validated. In the first method (indirect method, PGH was reacted with a measured excess of standard permanganate in H2SO4 medium, and the residual oxidant was determined by measuring its absorbance at 550 nm. The second method (Direct method entails treating PGH with permanganate in NaOH medium, followed by the measurement of the resulting bluish-green manganite at 610 nm. Experimental variables affecting the reactions were studied and optimized. Under optimum conditions, linear relationships with good correlation coefficients were found between absorbance and concentration in the ranges, 1.25 – 25 µg mL-1 (Indirect method and 1-12 µg mL-1 (Direct method with respective molar absorptivity values of 1.10 × 104 and 2.77 × 104 l mol-1 cm-1. The limits of detection (LOD and quantification (LOQ were 0.36 and 1.08 (Indirect method and 0.23 and 0.69 µg mL-1 (Direct method. Intra-day and inter-day precisions were satisfactory, with %RSD values of ≤2.11, and the respective accuracies were excellent with %RE values of ≤2. The methods were also validated for robustness, ruggedness and selectivity. The methods were applied to the determination of PGH in its tablets with good accuracy and precision, and no interference from the tablet additives was encountered. The results were also compared with those obtained by a reference method.

Pioglitazone, a PPARγ Agonist, Upregulates the Expression of Caveolin-1 and Catalase, Essential for Thyroid Cell Homeostasis: A Clue to the Pathogenesis of Hashimoto's Thyroiditis.

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Werion, Alexis; Joris, Virginie; Hepp, Michael; Papasokrati, Lida; Marique, Lancelot; de Ville de Goyet, Christine; Van Regemorter, Victoria; Mourad, Michel; Lengelé, Benoit; Daumerie, Chantal; Marbaix, Etienne; Brichard, Sonia; Many, Marie-Christine; Craps, Julie

2016-09-01

Peroxisome proliferator-activated receptor γ (PPARγ) is a transcription factor that regulates the expression of multiple target genes involved in several metabolic pathways as well as in inflammation. The expression and cell localization of caveolin-1 (Cav-1), thyroperoxidase (TPO), and dual oxidase (DUOX), involved in extracellular iodination, is modulated by Th1 cytokines in human normal thyroid cells and in Hashimoto's thyroiditis (HT). The objectives of this study were (i) to analyze the PPARγ protein and mRNA expression at the follicular level in HT versus controls in correlation with the one of Cav-1; (ii) to study the effects of Th1 cytokines on PPARγ and catalase expression in human thyrocyte primary cultures; and (iii) to study the effects of pioglitazone, a PPARγ agonist, on thyroxisome components (Cav-1, TPO, DUOX) and on catalase, involved in antioxidant defense. Although the global expression of PPARγ in the whole gland of patients with HT was not modified compared with controls, there was great heterogeneity among glands and among follicles within the same thyroid. Besides normal (type 1) follicles, there were around inflammatory zones, hyperactive (type 2) follicles with high PPARγ and Cav-1 expression, and inactive (type 3) follicles which were unable to form thyroxine and did not express PPARγ or Cav-1. In human thyrocytes in primary culture, Th1 cytokines decreased PPARγ and catalase expression; pioglitazone increased Cav-1, TPO, and catalase expression. PPARγ may play a central role in normal thyroid physiology by upregulating Cav-1, essential for the organization of the thyroxisome and extracellular iodination. By upregulating catalase, PPARγ may also contribute to cell homeostasis. The inhibitory effect of Th1 cytokines on PPARγ expression may be considered as a new pathogenetic mechanism for HT, and the use of PPARγ agonists could open a new therapeutic approach.

Prevention of diabetes with pioglitazone in ACT NOW: physiologic correlates.

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Defronzo, Ralph A; Tripathy, Devjit; Schwenke, Dawn C; Banerji, Maryann; Bray, George A; Buchanan, Thomas A; Clement, Stephen C; Gastaldelli, Amalia; Henry, Robert R; Kitabchi, Abbas E; Mudaliar, Sunder; Ratner, Robert E; Stentz, Frankie B; Musi, Nicolas; Reaven, Peter D

2013-11-01

We examined the metabolic characteristics that attend the development of type 2 diabetes (T2DM) in 441 impaired glucose tolerance (IGT) subjects who participated in the ACT NOW Study and had complete end-of-study metabolic measurements. Subjects were randomized to receive pioglitazone (PGZ; 45 mg/day) or placebo and were observed for a median of 2.4 years. Indices of insulin sensitivity (Matsuda index [MI]), insulin secretion (IS)/insulin resistance (IR; ΔI0-120/ΔG0-120, ΔIS rate [ISR]0-120/ΔG0-120), and β-cell function (ΔI/ΔG × MI and ΔISR/ΔG × MI) were calculated from plasma glucose, insulin, and C-peptide concentrations during oral glucose tolerance tests at baseline and study end. Diabetes developed in 45 placebo-treated vs. 15 PGZ-treated subjects (odds ratio [OR] 0.28 [95% CI 0.15-0.49]; P IGT > T2DM) was associated with improvements in insulin sensitivity (OR 0.61 [95% CI 0.54-0.80]), IS (OR 0.61 [95% CI 0.50-0.75]), and β-cell function (ln IS/IR index and ln ISR/IR index) (OR 0.26 [95% CI 0.19-0.37]; all P < 0.0001). Of the factors measured, improved β-cell function was most closely associated with final glucose tolerance status.

A patient with Werner syndrome and adiponectin gene mutation.

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Hashimoto, Naotake; Hatanaka, Sachiko; Yokote, Koutaro; Kurosawa, Hiroko; Yoshida, Tomohiko; Iwai, Rie; Takahashi, Hidenori; Yoshida, Katsuya; Horie, Atsuya; Sakurai, Kenichi; Yagui, Kazuo; Saito, Yasushi; Yoshida, Shouji

2007-01-01

Werner syndrome is a premature aging disease characterized by genomic instability and increased cancer risk. Here, we report a 45-year-old diabetic man as the first Werner syndrome patient found to have an adiponectin gene mutation. Showing graying and loss of hair, skin atrophy, and juvenile cataract, he was diagnosed with Werner syndrome type 4 by molecular analysis. His serum adiponectin concentration was low. In the globular domain of the adiponectin gene, I164T in exon 3 was detected. When we examined effects of pioglitazone (15 mg/day) on serum adiponectin multimer and monomer concentrations using selective assays, the patient's relative percentage increased in adiponectin concentration was almost same as that in the 18 diabetic patients without an adiponectin mutation, but the absolute adiponectin concentration was half of those seen in diabetic patients treated with the same pioglitazone dose who had no adiponectin mutation. The response suggested that pioglitazone treatment might help to prevent future Werner syndrome-related acceleration of atherosclerosis. Present and further clinical relevant to atherosclerosis in this patient should be imformative concerning the pathogenesis and treatment of atherosclerosis in the presence of hypoadiponectinemia and insulin resistance.

Inflammation in Depression and the Potential for Anti-Inflammatory Treatment

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Kohler, Ole; Krogh, Jesper; Mors, Ole

2016-01-01

Accumulating evidence supports an association between depression and inflammatory processes, a connection that seems to be bidirectional. Clinical trials have indicated antidepressant treatment effects for anti-inflammatory agents, both as add-on treatment and as monotherapy. In particular......, nonsteroidal anti-inflammatory drugs (NSAIDs) and cytokine-inhibitors have shown antidepressant treatment effects compared to placebo, but also statins, poly-unsaturated fatty acids, pioglitazone, minocycline, modafinil, and corticosteroids may yield antidepressant treatment effects. However, the complexity...... of the inflammatory cascade, limited clinical evidence, and the risk for side effects stress cautiousness before clinical application. Thus, despite proof-of-concept studies of anti-inflammatory treatment effects in depression, important challenges remain to be investigated. Within this paper, we review...

Anti-inflammatory agents in the treatment of bipolar depression

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Rosenblat, Joshua D; Kakar, Ron; Berk, Michael

2016-01-01

for qualitative review. Eight RCTs (n = 312) assessing adjunctive nonsteroidal anti-inflammatory drugs (n = 53), omega-3 polyunsaturated fatty acids (n = 140), N-acetylcysteine (n = 76), and pioglitazone (n = 44) in the treatment of BD met the inclusion criteria for quantitative analysis. The overall effect size...... sample sizes limited interpretation of the current analysis.......OBJECTIVE: Inflammation has been implicated in the risk, pathophysiology, and progression of mood disorders and, as such, has become a target of interest in the treatment of bipolar disorder (BD). Therefore, the objective of the current qualitative and quantitative review was to determine...

Geraniol, alone and in combination with pioglitazone, ameliorates fructose-induced metabolic syndrome in rats via the modulation of both inflammatory and oxidative stress status.

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Sherehan M Ibrahim

Full Text Available Geraniol (GO potent antitumor and chemopreventive effects are attributed to its antioxidant and anti-inflammatory properties. In the current study, the potential efficacy of GO (250 mg/kg in ameliorating metabolic syndrome (MetS induced by fructose in drinking water was elucidated. Moreover, the effect of pioglitazone (5 and 10 mg/kg; PIO and the possible interaction of the co-treatment of GO with PIO5 were studied in the MetS model. After 4 weeks of treatment, GO and/or PIO reduced the fasting blood glucose and the glycemic excursion in the intraperitoneal glucose tolerance test. GO and PIO5/10 restrained visceral adiposity and partly the body weight gain. The decreased level of peroxisome proliferator activated receptor (PPAR-γ transcriptional activity in the visceral adipose tissue of MetS rats was increased by single treatment regimens. Though GO did not affect MetS-induced hyperinsulinemia, PIO5/10 lowered it. Additionally, GO and PIO5/10 suppressed glycated hemoglobin and the receptor for advanced glycated end products (RAGE. These single regimens also ameliorated hyperuricemia, the disrupted lipid profile, and the elevated systolic blood pressure evoked by MetS. The rise in serum transaminases, interleukin-1β, and tumor necrosis factor-α, as well as hepatic lipid peroxides and nitric oxide (NO was lowered by the single treatments to different extents. Moreover, hepatic non-protein thiols, as well as serum NO and adiponectin were enhanced by single regimens. Similar effects were reached by the combination of GO with PIO5; however, a potentiative interaction was noted on fasting serum insulin level, while synergistic effects were reflected as improved insulin sensitivity, as well as reduced RAGE and triglycerides. Therefore, GO via the transcriptional activation of PPAR-γ reduces inflammation and free radical injury produced by MetS. Thereby, these effects provide novel mechanistic insights on GO management of MetS associated critical

Relationship Between Serum Adiponectin and Urinary Albumin Excretion Rate in Patients with Diabetes Nephropathy

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Duan Yongqiang; Yu Hui; Wang Zuobing

2010-01-01

To explore the relationship between the levels of serum adiponectin and urinary albumin excretion rate in patients with type 2 diabetes nephropathy, the serum levels of adiponectin and the levels of urinary albumin excretion rate in diabetes patients before and after treatment with pioglitazone were tested by ELISA and automatic biochemical analyzer respectively. The results showed that the serum levels of adiponectin in DM and DN group were lower than that of normal controls(P<0.01), but they gradually increased with progression (P<0.01). The serum adiponectin level was positively correlated with urinary albumin excretion rate (r= 0.284, P<0.05). The urinary albumin level decreased (P<0.01) and the serum levels of adiponectin increased after treatment with pioglitazone in DN group. The serum levels of adiponectin and urinary albumin excretion rate may play important role in the indication of treatment of diabetes. (authors)

Clomiphene citrate alone, in combination with metformin or in combination with pioglitazone as first line therapy in induction of ovulation in infertile women with polycystic ovary syndrome, a randomized controlled trial

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Wessam Magdi Abuelghar

2013-09-01

Conclusion: There is no potential benefit from adding pioglitazone or metformin to CC while inducing ovulation in overweight and obese women complaining of infertility due to PCOS. Further larger extended trials are needed to assess using insulin sensitizers for longer duration which could give a better chance to evaluate the cumulative effect of these drugs.

Investigation of pharmacological responses to anti-diabetic drugs in female Spontaneously Diabetic Torii (SDT) fatty rats, a new nonalcoholic steatohepatitis (NASH) model.

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Toriniwa, Yasufumi; Saito, Tomoyuki; Miyajima, Katsuhiro; Ishii, Yukihito; Uno, Kinuko; Maekawa, Tatsuya; Matsui, Tohru; Kume, Shinichi; Yamada, Takahisa; Ohta, Takeshi

2018-04-10

Nonalcoholic steatohepatitis (NASH) is a progressive liver disease, and some patients develop hepatic cirrhosis/carcinoma. Animal models play key roles in the development of new therapies for NASH. In this study, the pharmacological effects of metformin and pioglitazone were investigated in female Spontaneously Diabetic Torii (SDT) fatty rats to verify the utility of this model. The anti-diabetic drugs were administered to SDT fatty rats fed a cholesterol-enriched diet from 4 to 25 weeks, and changes in food intake, body weight, and blood chemistry parameters were evaluated every 4 weeks. The hepatic lipid content, mRNA expression in relation to lipid synthesis, inflammation, and fibrosis, and histopathological analyses were performed at 25 weeks. Pioglitazone improved hyperglycemia, hyperlipidemia, and abnormalities in hepatic parameters. The insulin levels were lower than those in the control rats before 16 weeks. Plasma glucose levels in the metformin-treated rats were lower than those in the control rats, and plasma triglyceride and alanine aminotransferase levels temporarily decreased. The lipid content and some mRNA expression in relation to fibrosis in the liver decreased with pioglitazone treatment, and the mRNA expression of microsomal triglyceride transfer protein increased. Hepatic fibrosis observed in the SDT fatty rats improved with pioglitazone treatment; however, the effect with metformin treatment was partial. These results in both drugs are in line with results in the human study, suggesting that the SDT fatty rat is useful for developing new anti-NASH drugs that show potential to regulate glucose/lipid metabolism.

Imaging of a glucose analog, calcium and NADH in neurons and astrocytes: dynamic responses to depolarization and sensitivity to pioglitazone

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Pancani, Tristano; Anderson, Katie L.; Porter, Nada M.; Thibault, Olivier

2011-01-01

Neuronal Ca2+ dyshomeostasis associated with cognitive impairment and mediated by changes in several Ca2+ sources has been seen in animal models of both aging and diabetes. In the periphery, dysregulation of intracellular Ca2+ signals may contribute to the development of insulin resistance. In the brain, while it is well-established that type 2 diabetes mellitus is a risk factor for the development of dementia in the elderly, it is not clear whether Ca2+ dysregulation might also affect insulin sensitivity and glucose utilization. Here we present a combination of imaging techniques testing the disappearance of the fluorescent glucose analog 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose (2-NBDG) as an indication of glycolytic activity in neurons and astrocytes. Our work shows that glucose utilization at rest is greater in neurons compared to astrocytes, and ceases upon activation in neurons with little change in astrocytes. Pretreatment of hippocampal cultures with pioglitazone, a drug used in the treatment of type 2 diabetes, significantly reduced glycolytic activity in neurons and enhanced it in astrocytes. This series of experiments, including FURA-2 and NADH imaging, provides results that are consistent with the idea that Ca2+ levels may rapidly alter glycolytic activity, and that downstream events beyond Ca2+ dysregulation with aging, may alter cellular metabolism in the brain. PMID:21978418

Treatment of Nonalcoholic Steatohepatitis in Adults: Present and Future

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S. Gitto

2015-01-01

Full Text Available Nonalcoholic steatohepatitis has become one of the most common liver-related health problems. This condition has been linked to an unhealthy diet and weight gain, but it can also be observed in nonobese people. The standard of care is represented by the lifestyle intervention. However, because this approach has several limitations, such as a lack of compliance, the use of many drugs has been proposed. The first-line pharmacological choices are vitamin E and pioglitazone, both showing a positive effect on transaminases, fat accumulation, and inflammation. Nevertheless, vitamin E has no proven effect on fibrosis and on long-term morbidity and mortality and pioglitazone has a negative impact on weight. Other drugs have been studied such as metformin, ursodeoxycholic acid, statins, pentoxiphylline, and orlistat with only partially positive results. Among the emerging treatments, telmisartan is particularly interesting as it seems to have an impact on insulin resistance, liver steatosis, inflammation, and fibrosis. However, the pathogenesis of steatohepatitis is highly complex and is determined by different parallel hits; indeed, the association of different drugs that act on various levels has been suggested. In conclusion, lifestyle intervention should be optimised and the associations of different drugs should be tested in large studies with long-term outcomes.

Down-regulation of vascular PPAR-γ contributes to endothelial dysfunction in high-fat diet-induced obese mice exposed to chronic intermittent hypoxia.

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Zhang, Yanan; Zhang, Chunlian; Li, Haiou; Hou, Jingdong

2017-10-14

Obstructive sleep apnea (OSA), characterized by chronic intermittent hypoxia (CIH), is associated with endothelial dysfunction. The prevalence of OSA is linked to an epidemic of obesity. CIH has recently been reported to cause endothelial dysfunction in diet-induced obese animals by exaggerating oxidative stress and inflammation, but the underlying mechanism remains unclear. PPAR-γ, a ligand-inducible transcription factor that exerts anti-oxidant and anti-inflammatory effects, is down-regulated in the peripheral tissues in diet-induce obesity. We tested the hypothesis that down-regulation of vascular PPAR-γ in diet-induced obesity enhances inflammation and oxidative stress in response to CIH, resulting in endothelial dysfunction. Male C57BL/6 mice were fed either a high-fat diet (HFD) or a low-fat diet (LFD) and simultaneously exposed to CIH or intermittent air for 6 weeks. An additional HFD group received a combination of CIH and PPAR-γ agonist pioglitazone for 6 weeks. Endothelial-dependent vasodilation was impaired only in HFD group exposed to CIH, compared with other groups, but was restored by concomitant pioglitazone treatment. Molecular studies revealed that vascular PPAR-γ expression and activity were reduced in HFD groups, compared with LFD groups, but were reversed by pioglitazone treatment. In addition, CIH elevated vascular expression of NADPH oxidase 4 and dihydroethidium fluorescence, and increased expression of proinflammatory cytokines TNF-α and IL-1β in both LFD and HFD groups, but these increases was significantly greater in HFD group, along with decreased vascular eNOS activity. Pioglitazone treatment of HFD group prevented CIH-induced changes in above molecular markers. The results suggest that HFD-induced obesity down-regulates vascular PPAR-γ, which results in exaggerated oxidative stress and inflammation in response to CIH, contributing to endothelial dysfunction. This finding may provide new insights into the mechanisms by which OSA

New Treatments for Hair Loss.

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Vañó-Galván, S; Camacho, F

2017-04-01

The treatment of hair loss is an important part of clinical dermatology given the prevalence of the problem and great impact on patients' quality of life. Many new treatments have been introduced in recent years. This review summarizes the main ones in 4 groups: a) For androgenetic alopecia, we discuss new excipients for oral minoxidil, dutasteride, and finasteride as well as new forms of topical application; prostaglandin agonists and antagonists; low-level laser therapy; and regenerative medicine with Wnt signaling activators and stem cell therapy. b) For alopecia areata, Janus kinase inhibitors are reviewed. c) For frontal fibrosing alopecia, we discuss the use of antiandrogens and, for some patients, pioglitazone. d) Finally, we mention new robotic devices for hair transplant procedures and techniques for optimal follicular unit extraction. Copyright © 2016 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.

Evaluation and Treatment of Hirsutism in Premenopausal Women

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... working well, the clinical guidelines suggest against the use of flutamide, topical anti-androgen creams, and insulin- lowering drugs such as rosiglitazone, pioglitazone, or metformin, as therapy for hirsutism. The clinical guidelines suggest ...

Positive interaction between prebiotics and thiazolidinedione treatment on adiposity in diet-induced obese mice.

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Alligier, Maud; Dewulf, Evelyne M; Salazar, Nuria; Mairal, Aline; Neyrinck, Audrey M; Cani, Patrice D; Langin, Dominique; Delzenne, Nathalie M

2014-07-01

To investigate whether inulin-type fructan (ITF) prebiotics could counteract the thiazolidinedione (TZD, PPARγ activator) induced-fat mass gain, without affecting its beneficial effect on glucose homeostasis, in high-fat (HF) diet fed mice. Male C57bl6/J mice were fed a HF diet alone or supplemented with ITF prebiotics (0.2 g/day × mouse) or TZD (30 mg pioglitazone (PIO)/kg body weight × day) or both during 4 weeks. An insulin tolerance test was performed after 3 weeks of treatment. As expected, PIO improved glucose homeostasis and increased adiponectinaemia. Furthermore, it induced an over-expression of several PPARγ target genes in white adipose tissues. ITF prebiotics modulated the PIO-induced PPARγ activation in a tissue-dependent manner. The co-treatment with ITF prebiotics and PIO maintained the beneficial impact of TZD on glucose homeostasis and adiponectinaemia. Moreover, the combination of both treatments reduced fat mass accumulation, circulating lipids and hepatic triglyceride content, suggesting an overall improvement of metabolism. Finally, the co-treatment favored induction of white-to-brown fat conversion in subcutaneous adipose tissue, thereby leading to the development of brite adipocytes that could increase the oxidative capacity of the tissue. ITF prebiotics decrease adiposity and improve the metabolic response in HF fed mice treated with TZD. © 2014 The Obesity Society.

[Limitations of insulin-dependent drugs in the treatment of type 2 diabetes mellitus].

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Valerón, Pino Fuente; de Pablos-Velasco, Pedro L

2013-09-01

In this study, we review the efficacy and safety limitations of insulin-dependent oral antidiabetic agents. In terms of efficiency, the main drawback of metformin, sulfonylureas, gliptins and -to a lesser extent-glitazones is durability. No drug per se is able to maintain stable blood glucose control for years. Metformin, sulfonylureas and gliptins have demonstrated safety. Experience with the first two drug groups is more extensive. The main adverse effect of metformin is gastrointestinal discomfort. Major concerns related to the use of sulfonylureas are hypoglycemia and weight gain. The use of pioglitazone has been associated with an increased risk of bladder cancer, edema, heart failure, weight gain, and distal bone fractures in postmenopausal women. The most common adverse reactions associated with glucagon-like peptide-1 agonists are gastrointestinal discomfort that sometimes leads to treatment discontinuation. Copyright © 2013 Elsevier España, S.L. All rights reserved.

PPARγ Ligand as a Promising Candidate for Colorectal Cancer Chemoprevention: A Pilot Study

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Hirokazu Takahashi

2010-01-01

Full Text Available Activating synthetic ligands for peroxisome proliferator-activated receptor gamma (PPARγ, such as pioglitazone, are commonly used to treat persons with diabetes mellitus with improvement of insulin resistance. Several reports have clearly demonstrated that PPARγ ligands could inhibit colorectal cancer cell growth and induce apoptosis. Meanwhile, aberrant crypt foci (ACF have come to be established as a biomarker of the risk of CRC in azoxymethane-treated mice and rats. In humans, ACF can be detected using magnifying colonoscopy. Previously, CRC and adenoma were used as a target for chemopreventive agents, but it needs a long time to evaluate, however, ACF can be a surrogate marker of CRC even for a brief period. In this clinical study, we investigated the chemopreventive effect of pioglitazone on the development of human ACF as a surrogate marker of CRC. Twenty-nine patients were divided into two groups, 20 were in the endoscopically normal control group and 9 were in the pioglitazone (15 mg/day group, and ACF and adenoma were examined before and after 1-month treatment. The number of ACF was significantly decreased (5.8±1.1 to 3.3±2.3 after 1 month of pioglitazone treatment, however, there was no significant change in the number of crypts/ACF or in the number and size of adenomas. Pioglitazone may have a clinical application as a cancer-preventive drug. This investigation is just a pilot study, therefore, further clinical studies are needed to show that the PPARγ ligand may be a promising candidate as a chemopreventive agent for colorectal carcinogenesis.

A novel insulin resistance index to monitor changes in insulin sensitivity and glucose tolerance: the ACT NOW study.

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Tripathy, Devjit; Cobb, Jeff E; Gall, Walter; Adam, Klaus-Peter; George, Tabitha; Schwenke, Dawn C; Banerji, MaryAnn; Bray, George A; Buchanan, Thomas A; Clement, Stephen C; Henry, Robert R; Kitabchi, Abbas E; Mudaliar, Sunder; Ratner, Robert E; Stentz, Frankie B; Reaven, Peter D; Musi, Nicolas; Ferrannini, Ele; DeFronzo, Ralph A

2015-05-01

The objective was to test the clinical utility of Quantose M(Q) to monitor changes in insulin sensitivity after pioglitazone therapy in prediabetic subjects. Quantose M(Q) is derived from fasting measurements of insulin, α-hydroxybutyrate, linoleoyl-glycerophosphocholine, and oleate, three nonglucose metabolites shown to correlate with insulin-stimulated glucose disposal. Participants were 428 of the total of 602 ACT NOW impaired glucose tolerance (IGT) subjects randomized to pioglitazone (45 mg/d) or placebo and followed for 2.4 years. At baseline and study end, fasting plasma metabolites required for determination of Quantose, glycated hemoglobin, and oral glucose tolerance test with frequent plasma insulin and glucose measurements to calculate the Matsuda index of insulin sensitivity were obtained. Pioglitazone treatment lowered IGT conversion to diabetes (hazard ratio = 0.25; 95% confidence interval = 0.13-0.50; P < .0001). Although glycated hemoglobin did not track with insulin sensitivity, Quantose M(Q) increased in pioglitazone-treated subjects (by 1.45 [3.45] mg·min(-1)·kgwbm(-1)) (median [interquartile range]) (P < .001 vs placebo), as did the Matsuda index (by 3.05 [4.77] units; P < .0001). Quantose M(Q) correlated with the Matsuda index at baseline and change in the Matsuda index from baseline (rho, 0.85 and 0.79, respectively; P < .0001) and was progressively higher across closeout glucose tolerance status (diabetes, IGT, normal glucose tolerance). In logistic models including only anthropometric and fasting measurements, Quantose M(Q) outperformed both Matsuda and fasting insulin in predicting incident diabetes. In IGT subjects, Quantose M(Q) parallels changes in insulin sensitivity and glucose tolerance with pioglitazone therapy. Due to its strong correlation with improved insulin sensitivity and its ease of use, Quantose M(Q) may serve as a useful clinical test to identify and monitor therapy in insulin-resistant patients.

Insulin resistance is not conserved in myotubes established from women with PCOS.

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Mette Eriksen

2010-12-01

Full Text Available Polycystic ovary syndrome (PCOS is the most common endocrine disorder among premenopausal women, who often develop insulin resistance. We tested the hypothesis that insulin resistance in skeletal muscle of patients with polycystic ovary syndrome (PCOS is an intrinsic defect, by investigating the metabolic characteristics and gene expression of in vitro differentiated myotubes established from well characterized PCOS subjects.Using radiotracer techniques, RT-PCR and enzyme kinetic analysis we examined myotubes established from PCOS subjects with or without pioglitazone treatment, versus healthy control subjects who had been extensively metabolically characterized in vivo. Results. Myotubes established from PCOS and matched control subjects comprehensively expressed all insulin-sensitive biomarkers; glucose uptake and oxidation, glycogen synthesis and lipid uptake. There were no significant differences between groups either at baseline or during acute insulin stimulation, although in vivo skeletal muscle was insulin resistant. In particular, we found no evidence for defects in insulin-stimulated glycogen synthase activity between groups. Myotubes established from PCOS patients with or without pioglitazone treatment also showed no significant differences between groups, neither at baseline nor during acute insulin stimulation, although in vivo pioglitazone treatment significantly improved insulin sensitivity. Consistently, the myotube cultures failed to show differences in mRNA levels of genes previously demonstrated to differ in PCOS patients with or without pioglitazone treatment (PLEK, SLC22A16, and TTBK.These results suggest that the mechanisms governing insulin resistance in skeletal muscle of PCOS patients in vivo are not primary, but rather adaptive.ClinicalTrials.gov NCT00145340.

Increasing nursing treatment for pediatric procedural pain.

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Bice, April A; Gunther, Mary; Wyatt, Tami

2014-03-01

Procedural pain management is an underused practice in children. Despite the availability of efficacious treatments, many nurses do not provide adequate analgesia for painful interventions. Complementary therapies and nonpharmacologic interventions are additionally essential to managing pain. Owing to the increasing awareness of inadequate nursing utilization of pharmacologic measures for procedural pain, this paper focuses only on analgesic treatments. The aim of this review was to examine how varying degrees of quality improvement affect nursing utilization of treatments for routine pediatric procedural pain. A comprehensive search of databases including Cinahl, Medline/Pubmed, Web of Science, Google Scholar, Psycinfo, and Cochrane Library was performed. Sixty-two peer-reviewed research articles were examined. Ten articles focusing on quality improvement in pediatric pain management published in English from 2001 to 2011 were included. Three themes emerged: 1) increasing nursing knowledge; 2) nursing empowerment; and 3) protocol implementation. Research critique was completed with the use of guidelines and recommendations from Creswell (2009) and Garrard (2011). The literature reveals that nurses still think that pediatric pain management is essential. Quality improvement increases nursing utilization of procedural pain treatments. Although increasing nursing knowledge improves pediatric pain management, it appears that nursing empowerment and protocol implementation increase nursing compliance more than just education alone. Nurses providing pain management can enhance their individual practice with quality improvement measures that may increase nursing adherence to institutional and nationally recommended pediatric procedural pain management guidelines. Copyright © 2014 American Society for Pain Management Nursing. Published by Elsevier Inc. All rights reserved.

Development and validation of a high throughput LC–MS/MS method for simultaneous quantitation of pioglitazone and telmisartan in rat plasma and its application to a pharmacokinetic study

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Pinaki Sengupta

2017-12-01

Full Text Available Management of cardiovascular risk factors in diabetes demands special attention due to their co-existence. Pioglitazone (PIO and telmisartan (TLM combination can be beneficial in effective control of cardiovascular complication in diabetes. In this research, we developed and validated a high throughput LC–MS/MS method for simultaneous quantitation of PIO and TLM in rat plasma. This developed method is more sensitive and can quantitate the analytes in relatively shorter period of time compared to the previously reported methods for their individual quantification. Moreover, till date, there is no bioanalytical method available to simultaneously quantitate PIO and TLM in a single run. The method was validated according to the USFDA guidelines for bioanalytical method validation. A linear response of the analytes was observed over the range of 0.005–10 µg/mL with satisfactory precision and accuracy. Accuracy at four quality control levels was within 94.27%–106.10%. The intra- and inter-day precision ranged from 2.32%–10.14 and 5.02%–8.12%, respectively. The method was reproducible and sensitive enough to quantitate PIO and TLM in rat plasma samples of a preclinical pharmacokinetic study. Due to the potential of PIO-TLM combination to be therapeutically explored, this method is expected to have significant usefulness in future. Keywords: LC–MS/MS, Rat plasma, Pharmacokinetic applicability, Telmisartan, Pioglitazone, Pharmacokinetic application

Effects of increasing age, dosage, and duration of PTH treatment on BMD increase--a meta-analysis

DEFF Research Database (Denmark)

Schwarz, Peter; Jorgensen, Niklas Rye; Mosekilde, Leif

2012-01-01

were included. By metaregression analysis, we found that the increase in spine BMD (Z-score) after PTH treatment was blunted by increasing age (R (2) = 0.27; 2p = 0.01, slope -0.023 Z-scores per year, 11 studies). By increasing PTH dosage (μg/d), spine BMD increased significantly (2p = 0.......002) with a slope of +0.011 Z-scores/μg/d of teriparatide. Furthermore, the duration of treatment was positively correlated to spine BMD (P ......We studied the effects of increasing age, dosage, and duration of parathyroid hormone (PTH) treatment on changes in bone mineral density (BMD). Randomized placebo controlled trials on PTH treatment in men or women were retrieved from PubMed (1951 to present), Web of Science (1945 to present...

Activation of Central PPAR-γ Attenuates Angiotensin II-Induced Hypertension

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Yu, Yang; Xue, Bao-Jian; Wei, Shun-Guang; Zhang, Zhi-Hua; Beltz, Terry G; Guo, Fang; Johnson, Alan Kim; Felder, Robert B

2015-01-01

Inflammation and renin-angiotensin system activity in the brain contribute to hypertension through effects on fluid intake, vasopressin release, and sympathetic nerve activity. We recently reported that activation of brain peroxisome proliferator-activated receptor (PPAR)-γ in heart failure rats reduced inflammation and renin-angiotensin system activity in the hypothalamic paraventricular nucleus and ameliorated the peripheral manifestations of heart failure. We hypothesized that activation of brain PPAR-γ might have beneficial effects in angiotensin II-induced hypertension. Sprague-Dawley rats received a 2-week subcutaneous infusion of angiotensin II (120 ng/kg/min) combined with a continuous intracerebroventricular infusion of vehicle, the PPAR-γ agonist pioglitazone (3 nmol/h) or the PPAR-γ antagonist GW9662 (7 nmol/h). Angiotensin II+vehicle rats had increased mean blood pressure, increased sympathetic drive as indicated by the mean blood pressure response to ganglionic blockade, and increased water consumption. PPAR-γ mRNA in subfornical organ and hypothalamic paraventricular nucleus was unchanged, but PPAR-γ DNA binding activity was reduced. mRNA for interleukin-1β, tumor necrosis factor-α, cyclooxygenase-2 and angiotensin II type-1 receptor was augmented in both nuclei, and hypothalamic paraventricular nucleus neuronal activity was increased. The plasma vasopressin response to a 6-hour water restriction also increased. These responses to angiotensin II were exacerbated by GW9662 and ameliorated by pioglitazone, which increased PPAR-γ mRNA and PPAR-γ DNA binding activity in subfornical organ and hypothalamic paraventricular nucleus. Pioglitazone and GW9662 had no effects on control rats. The results suggest that activating brain PPAR-γ to reduce central inflammation and brain renin-angiotensin system activity may be a useful adjunct in the treatment of angiotensin II-dependent hypertension. PMID:26101342

Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility.

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Morley, Lara C; Tang, Thomas; Yasmin, Ephia; Norman, Robert J; Balen, Adam H

2017-11-29

Polycystic ovary syndrome (PCOS) is characterised by infrequent or absent ovulation, and high levels of androgens and insulin (hyperinsulinaemia). Hyperinsulinaemia occurs secondary to insulin resistance and is associated with increased risk of cardiovascular disease and diabetes mellitus. Insulin-sensitising agents such as metformin may be effective in treating PCOS-related anovulation. To evaluate the effectiveness and safety of insulin-sensitising drugs in improving reproductive and metabolic outcomes for women with PCOS undergoing ovulation induction. We searched the following databases from inception to January 2017: Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO and CINAHL. We searched registers of ongoing trials and reference lists from relevant studies. We included randomised controlled trials of insulin-sensitising drugs compared with placebo, no treatment, or an ovulation-induction agent for women with oligo and anovulatory PCOS. Two review authors independently assessed studies for eligibility and bias. Primary outcomes were live birth rate and gastrointestinal adverse effects. Secondary outcomes included other pregnancy outcomes, menstrual frequency and metabolic effects. We combined data to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs). We assessed statistical heterogeneity using the I 2 statistic and reported quality of the evidence for primary outcomes using GRADE methodology. We assessed the interventions metformin, clomiphene citrate, metformin plus clomiphene citrate, D-chiro-inositol, rosiglitazone and pioglitazone. We compared these with each other, placebo or no treatment. We included 48 studies (4451 women), 42 of which investigated metformin (4024 women). Evidence quality ranged from very low to moderate. Limitations were risk of bias (poor reporting of methodology and incomplete outcome data), imprecision and inconsistency. Metformin versus placebo or no treatment

Diabetes Incidence and Glucose Tolerance after Termination of Pioglitazone Therapy: Results from ACT NOW.

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Tripathy, Devjit; Schwenke, Dawn C; Banerji, MaryAnn; Bray, George A; Buchanan, Thomas A; Clement, Stephen C; Henry, Robert R; Kitabchi, Abbas E; Mudaliar, Sunder; Ratner, Robert E; Stentz, Frankie B; Musi, Nicolas; Reaven, Peter D; DeFronzo, Ralph A

2016-05-01

Thiazolidinediones have proven efficacy in preventing diabetes in high-risk individuals. However, the effect of thiazolidinediones on glucose tolerance after cessation of therapy is unclear. To examine the effect of pioglitazone (PIO) on incidence of diabetes after discontinuing therapy in ACT NOW. Design, Settings and Patients: Two-hundred ninety-three subjects (placebo [PLAC], n = 138; PIO, n = 152) completed a median followup of 11.7 mo after study medication was stopped. Diabetes developed in 138 (12.3%) of PLAC vs 17 of 152 PIO patients (11.2%; P = not significant, PIO vs PLAC). However, the cumulative incidence of diabetes from start of study medication to end of washout period remained significantly lower in PIO vs PLAC (10.7 vs 22.3%; P < .005). After therapy was discontinued, 23.0% (35/152) of PIO-treated patients remained normal-glucose tolerant (NGT) vs 13.8% (19/138) of PLAC-treated patients (P = .04). Insulin secretion/insulin resistance index (I0-120/G0-120 × Matsuda index) was markedly lower in subjects with impaired glucose tolerance (IGT) who converted to diabetes during followup vs those who remained IGT or NGT. The decline in-cell function (insulin secretion/insulin resistance index) was similar in subjects with IGT who developed diabetes, irrespective of whether they were treated with PIO or PLAC. 1) The protective effect of PIO on incidence of diabetes attenuates after discontinuation of therapy, 2) cumulative incidence of diabetes in individuals exposed to PIO remained significantly (56%) lower than PLAC and a greater number of PIO-treated individuals maintained NGT after median followup of 11.4 mo, and 3) low insulin secretion/insulin resistance index is a strong predictor of future diabetes following PIO discontinuation.

Potential effects of vildagliptin on biomarkers associated with prothrombosis in diabetes mellitus.

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Khan, Sana; Khan, Saba; Panda, Bibhu Prasad; Akhtar, Mohd; Najmi, Abul Kalam

2015-01-01

Diabetes mellitus (DM) is one of the risks linked with susceptibility of thrombosis. We tried to inspect the effect of a novel oral antidiabetic agent, vildagliptin, in preventing prothrombosis associated with DM. DM was produced by a dose of streptozotocin (STZ) or in albino wistar rats. Rats were treated orally with pioglitazone, standard treatment and vildagliptin alone and in combination for 3 weeks. Finally, the varied levels of coagulation biomarkers, including activated partial thromboplastin time (aPTT), prothrombin time (PT) and fibrinogen and inflammatory parameters, nitric oxide (NO), C-reactive protein (CRP) and TNF-α and lipid profile were estimated along with platelet count and total leukocyte count (TLC). In vitro fibrinolytic activity of both the drugs was also determined. Vildagliptin significantly reduced cholesterol, triglycerides, TLC, CRP and TNF-α and increased aPTT and NO levels in STZ diabetic rats. However, pioglitazone was more successful in reducing fibrinogen and platelet count. Nevertheless, combination of the drugs was also effective than pioglitazone or vildagliptin alone in improvising hypercoagulation and inflammatory biomarkers. It is evident from the present study that vildagliptin has an influence on the biomarkers linked to the progression of thrombosis and may delay thrombogenesis linked to DM. Hence, vildagliptin alone and in combination might prove as an encouraging therapy for DM-linked thrombosis marked by inflammation and hypercoagulation.

S961, an insulin receptor antagonist causes hyperinsulinemia, insulin-resistance and depletion of energy stores in rats

Energy Technology Data Exchange (ETDEWEB)

Vikram, Ajit [Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar, Mohali, Punjab 160 062 (India); Jena, Gopabandhu, E-mail: gbjena@gmail.com [Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar, Mohali, Punjab 160 062 (India)

2010-07-23

Research highlights: {yields}Insulin receptor antagonist S961 causes hyperglycemia, hyperinsulinemia and insulin resistance in rats. {yields}Peroxysome-proliferator-activated-receptor-gamma agonist pioglitazone improves S961 induced hyperglycemia and glucose intolerance. {yields}Long term treatment with insulin receptor antagonist S961 results in the decreased adiposity and hepatic glycogen content. {yields}Improvement in the hyperglycemia and glucose intolerance by pioglitazone clearly demonstrates that S961 treated rats can be successfully used to screen the novel therapeutic interventions having potential to improve glucose disposal through receptor independent mechanisms. -- Abstract: Impairment in the insulin receptor signaling and insulin mediated effects are the key features of type 2 diabetes. Here we report that S961, a peptide insulin receptor antagonist induces hyperglycemia, hyperinsulinemia ({approx}18-fold), glucose intolerance and impairment in the insulin mediated glucose disposal in the Sprague-Dawley rats. Further, long-term S961 treatment (15 day, 10 nM/kg/day) depletes energy storage as evident from decrease in the adiposity and hepatic glycogen content. However, peroxysome-proliferator-activated-receptor-gamma (PPAR{gamma}) agonist pioglitazone significantly (P < 0.001) restored S961 induced hyperglycemia (196.73 {+-} 16.32 vs. 126.37 {+-} 27.07 mg/dl) and glucose intolerance ({approx}78%). Improvement in the hyperglycemia and glucose intolerance by pioglitazone clearly demonstrates that S961 treated rats can be successfully used to screen the novel therapeutic interventions having potential to improve glucose disposal through receptor independent mechanisms. Further, results of the present study reconfirms and provide direct evidence to the crucial role of insulin receptor signaling in the glucose homeostasis and fuel metabolism.

Rapid increase in the use of oral antidiabetic drugs in the United States, 1990-2001.

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Wysowski, Diane K; Armstrong, George; Governale, Laura

2003-06-01

To describe the use of oral antidiabetic drugs for management of type 2 diabetes in the U.S. from 1990 through 2001. Data on oral antidiabetic drugs were derived from two pharmaceutical marketing databases from IMS Health, the National Prescription Audit Plus and the National Disease and Therapeutic Index. In 1990, 23.4 million outpatient prescriptions of oral antidiabetic agents were dispensed. By 2001, this number had increased 3.9-fold, to 91.8 million prescriptions. Glipizide and glyburide, two sulfonylurea medications, accounted for approximately 77% of prescriptions of oral antidiabetic drugs in 1990 and 35.5% of prescriptions in 2001. By 2001, the biguanide metformin (approved in 1995) had captured approximately 33% of prescriptions, and the thiazolidinedione insulin sensitizers (rosiglitazone and pioglitazone marketed beginning in 1999) accounted for approximately 17% of market share. Compared with patients treated in 1990, those in 2001 were proportionately younger and they more often used oral antidiabetic drugs and insulin in combination. Internists and general and family practitioners were the primary prescribers of this class of drugs. Consistent with the reported increase in the prevalence of type 2 diabetes, the number of dispensed outpatient prescriptions of oral antidiabetic drugs increased rapidly between 1990 and 2001. This period was marked by an increase in the treatment of younger people and the use of oral antidiabetic drugs in combination. With the approval in the last decade of several new types of oral antidiabetic medications with different mechanisms of action, options for management of type 2 diabetes have expanded.

Antidiabetic therapy in real practice: indicators for adherence and treatment cost

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Colombo GL

2012-09-01

Full Text Available Giorgio L Colombo,1,2 Elisa Rossi,4 Marisa De Rosa,4 Danilo Benedetto,3 Antonio V Gaddi31School of Pharmacy, Department of Drug Sciences, University of Pavia, Pavia, 2S.A.V.E. Studi Analisi Valutazioni Economiche, Milan, 3CINECA – Bologna; 4Centro Aterosclerosi GC Descovich, Dipartimento di Medicina Interna e dell'Invecchiamento, University of Bologna, Bologna, ItalyBackground: Type 2 diabetes has become a disease with a high economic and social impact. The ARNO Observatory is a clinical data warehouse consisting of a network of local health care units (ASL scattered throughout the Italian territory which collects data on health care consumption for about 10.5 million people. The purpose of this study was to evaluate the use of antidiabetic drugs with particular reference to type of treatment. The analyses were carried out on a sample of 169,375 patients treated with oral blood glucose-lowering drugs in 2008 from a total population of 4,040,624 health care beneficiaries at 12 local health care units in the ARNO Observatory.Methods: Patients were considered “on treatment with oral blood glucose-lowering drugs” if they had received at least one prescription of an antidiabetic drug (Anatomical Therapeutic Chemical code A10B during 2008. The patients were divided into three treatment groups, ie, monotherapy, fixed-combination drugs, and dual therapy. The following indicators were assessed: number of patients treated with an oral antidiabetic drug, mean number of hospitalizations, mean number of specialist examinations, and mean expenditure per treated patient. Adherence was assessed using the medication possession ratio indicator (MPR.Results: Patients treated with oral blood glucose-lowering drugs comprised 4.2% of the investigated population, and had an average age of 68.9 years. The mean annual number of hospitalizations was lower in the dual therapy group (298 versus 328 per 1000 patients in the sample, while the average number of

Effects of valproic acid and pioglitazone on cell cycle progression and proliferation of T-cell acute lymphoblastic leukemia Jurkat cells

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Marie Saghaeian Jazi

2016-07-01

Full Text Available Objective(s: T-cell acute lymphoblastic leukemia (T-ALL is an aggressive hematologic malignant tumor. Administration of chemical compounds influencing apoptosis and T cell development has been discussed as promising novel therapeutic strategies. Valproic acid (VPA as a recently emerged anti-neoplastic histone deacetylase (HDAC inhibitor and pioglitazone (PGZ as a high-affinity peroxisome proliferator-activated receptor-gamma (PPARγ agonist have been shown to induce apoptosis and cell cycle arrest in different studies. Here, we aimed to investigate the underlying molecular mechanisms involved in anti-proliferative effects of these compounds on human Jurkat cells. Materials and Methods: Treated cells were evaluated for cell cycle progression and apoptosis using flowcytometry and MTT viability assay. Real-time RT-PCR was carried out to measure the alterations in key genes associated with cell death and cell cycle arrest. Results: Our findings illustrated that both VPA and PGZ can inhibit Jurkat E6.1 cells in vitro after   24 hr; however, PGZ 400 μM presents the most anti-proliferative effect. Interestingly, treated cells have been arrested in G2/M with deregulated cell division cycle 25A (Cdc25A phosphatase and cyclin-dependent kinase inhibitor 1B (CDKN1B or p27 expression. Expression of cyclin D1 gene was inhibited when DNA synthesis entry was declined. Cell cycle deregulation in PGZ and VPA-exposed cells generated an increase in the proportion of aneuploid cell population, which has not reported before. Conclusion: These findings define that anti-proliferative effects of PGZ and VPA on Jurkat cell line are mediated by cell cycle deregulation. Thus, we suggest PGZ and VPA may relieve potential therapeutic application against apoptosis-resistant malignancies.

Chinese medicine Jinlida (JLD) ameliorates high-fat-diet induced insulin resistance in rats by reducing lipid accumulation in skeletal muscle.

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Zang, Sha-Sha; Song, An; Liu, Yi-Xuan; Wang, Chao; Song, Guang-Yao; Li, Xiao-Ling; Zhu, Ya-Jun; Yu, Xian; Li, Ling; Liu, Chen-Xi; Kang, Jun-Cong; Ren, Lu-Ping

2015-01-01

The present paper reports the effects of Jinlida (JLD), a traditional Chinese medicine which has been given as a treatment for high-fat-diet (HFD)-induced insulin resistance. A randomized controlled experiment was conducted to provide evidence in support of the affects of JLD on insulin resistance induced by HFD. The affect of JLD on blood glucose, lipid, insulin, adiponectin, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBIL) in serum and lipid content in skeletal muscle was measured. Genes and proteins of the AMPK signaling pathway were analyzed by real time RT-PCR and Western blot. Adiponectin receptor 1 and 2 (ADIPOR1, ADIPOR2) and other genes involved in mitochondrial function and fat oxidation were analyzed by real time RT-PCR. Histological staining was also performed. JLD or pioglitazone administration ameliorated fasting plasma levels of glucose, insulin, triglyceride (TG), total cholesterol (TC), ALT, AST and non-esterified fatty acid (NEFA) (P < 0.05). Treatment with JLD or pioglitazone significantly reverted muscle lipid content (P < 0.05). JLD (1.5 g/kg) significantly increased plasma adiponectin concentration by 60.17% and increased AMPK and acetyl-CoA carboxylase (ACC) phosphorylation in skeletal muscle (P < 0.05). JLD administration increased levels of ADIPOR1 and ADIPOR2 by 1.48 and 1.29 respectively. Levels of genes involved in mitochondrial function and fat oxidation were increased. This study provides the molecular mechanism by which JLD ameliorates HFD-induced insulin resistance in rats.

S961, an insulin receptor antagonist causes hyperinsulinemia, insulin-resistance and depletion of energy stores in rats

International Nuclear Information System (INIS)

Vikram, Ajit; Jena, Gopabandhu

2010-01-01

Research highlights: →Insulin receptor antagonist S961 causes hyperglycemia, hyperinsulinemia and insulin resistance in rats. →Peroxysome-proliferator-activated-receptor-gamma agonist pioglitazone improves S961 induced hyperglycemia and glucose intolerance. →Long term treatment with insulin receptor antagonist S961 results in the decreased adiposity and hepatic glycogen content. →Improvement in the hyperglycemia and glucose intolerance by pioglitazone clearly demonstrates that S961 treated rats can be successfully used to screen the novel therapeutic interventions having potential to improve glucose disposal through receptor independent mechanisms. -- Abstract: Impairment in the insulin receptor signaling and insulin mediated effects are the key features of type 2 diabetes. Here we report that S961, a peptide insulin receptor antagonist induces hyperglycemia, hyperinsulinemia (∼18-fold), glucose intolerance and impairment in the insulin mediated glucose disposal in the Sprague-Dawley rats. Further, long-term S961 treatment (15 day, 10 nM/kg/day) depletes energy storage as evident from decrease in the adiposity and hepatic glycogen content. However, peroxysome-proliferator-activated-receptor-gamma (PPARγ) agonist pioglitazone significantly (P < 0.001) restored S961 induced hyperglycemia (196.73 ± 16.32 vs. 126.37 ± 27.07 mg/dl) and glucose intolerance (∼78%). Improvement in the hyperglycemia and glucose intolerance by pioglitazone clearly demonstrates that S961 treated rats can be successfully used to screen the novel therapeutic interventions having potential to improve glucose disposal through receptor independent mechanisms. Further, results of the present study reconfirms and provide direct evidence to the crucial role of insulin receptor signaling in the glucose homeostasis and fuel metabolism.

Epigenetic Activity of Peroxisome Proliferator-Activated Receptor Gamma Agonists Increases the Anticancer Effect of Histone Deacetylase Inhibitors on Multiple Myeloma Cells.

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Nassera Aouali

Full Text Available Epigenetic modifications play a major role in the development of multiple myeloma. We have previously reported that the PPARγ agonist pioglitazone (PIO enhances, in-vitro, the cytotoxic effect of the Histone deacetylase inhibitor (HDACi, valproic acid (VPA, on multiple myeloma cells. Here, we described the development of a new multiple myeloma mouse model using MOLP8 cells, in order to evaluate the effect of VPA/PIO combination on the progression of myeloma cells, by analyzing the proliferation of bone marrow plasma cells. We showed that VPA/PIO delays the progression of the disease and the invasion of myeloma cells in the bone marrow. Mechanistically, we demonstrated that VPA/PIO increases the cleavage of caspase 3 and PARP, and induces the acetylation of Histone 3 (H3. Furthermore, we provided evidence that PPARγ agonist is able to enhance the action of other HDACi such as Vorinostat or Mocetinostat. Using PPARγ antagonist or siPPARγ, we strongly suggest that, as described during adipogenesis, PIO behaves as an epigenetic regulator by improving the activity of HDACi. This study highlights the therapeutic benefit of PIO/VPA combination, compared to VPA treatment as a single-arm therapy on multiple myeloma and further highlights that such combination may constitute a new promising treatment strategy which should be supported by clinical trials.

Increase in extraction yields of coals by water treatment

Energy Technology Data Exchange (ETDEWEB)

Masashi Iino; Toshimasa Takanohashi; Chunqi Li; Haruo Kumagai [National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba (Japan). Institute for Energy Utilization

2004-10-01

The effect of water treatment at 500 and 600 K on solvent extractions of Pocahontas No. 3 (PO), Upper Freeport (UF), and Illinois No. 6 (IL) coals was investigated. All the coals used show that the water treatments at 600 K increased the extraction yields greatly in the extractions with a 1:1 carbon disulfide/N-methyl-2-pyrrolidinone (CS{sub 2}/NMP) mixed solvent, NMP, or 1-methylnaphthalene (1-MN). However, the water treatments at 500 K and the heat treatments at 600 K without water gave only a slight increase in the yields. Characterizations of the water-treated coals were performed using ultimate and proximate compositions, Fourier transform infrared analysis, solvent swelling, nuclear magnetic resonance relaxation time, and viscoelasticity behavior. The swelling degree in methanol and toluene was increased by the water treatment at 600 K, suggesting that crosslinks become loosened by the treatment. The results of infrared analysis and the extraction temperature dependency of the extraction yields with NMP and 1-MN suggest that the loosening of {pi} - interactions, and of both {pi} - interactions and hydrogen bonds, are responsible for the yield enhancements for PO and UF coals, respectively. However, for IL coal, which exhibited a decrease in oxygen content and the amount of hydrogen-bonded OH, suggesting the occurrence of some chemical reactions, the yield enhancements may be due to the relaxation of hydrogen bonds and the removal of oxygen functional groups, such as the breaking of ether bonds. 17 refs., 3 figs., 5 tabs.

Thyroid cancer risk is not increased in diabetic patients.

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Chin-Hsiao Tseng

Full Text Available OBJECTIVE: This study evaluated thyroid cancer risk with regards to diabetes status and diabetes duration, and with the use of anti-diabetic drugs including sulfonylurea, metformin, insulin, acarbose, pioglitazone and rosiglitazone, by using a population-based reimbursement database in Taiwan. METHODS: A random sample of 1,000,000 subjects covered by the National Health Insurance was recruited. After excluding patients with type 1 diabetes, 999730 subjects (495673 men and 504057 women were recruited into the analyses. Logistic regression estimated the odds ratios (OR and their 95% confidence intervals (CI for independent variables including age, sex, diabetes status/duration, anti-diabetic drugs, other medications, comorbidities, living regions, occupation and examinations that might potentially lead to the diagnosis of thyroid cancer in various models. RESULTS: The diabetic patients had a significantly higher probability of receiving potential detection examinations (6.38% vs. 5.83%, P<0.0001. After multivariable-adjustment, the OR (95% CI for diabetes status was 0.816 (0.652-1.021; and for diabetes duration <1 year, 1-3 years, 3-5 years and ≥ 5 years vs. non-diabetes was 0.071 (0.010-0.507, 0.450 (0.250-0.813, 0.374 (0.203-0.689 and 1.159 (0.914-1.470, respectively. Among the anti-diabetic agents, only sulfonylurea was significantly associated with thyroid cancer, OR (95% CI: 1.882 (1.202-2.947. The OR (95% CI for insulin, metformin, acarbose, pioglitazone and rosiglitazone was 1.701 (0.860-3.364, 0.696 (0.419-1.155, 0.581 (0.202-1.674, 0.522 (0.069-3.926 and 0.669 (0.230-1.948, respectively. Furthermore, patients with benign thyroid disease or other cancer, living in Kao-Ping/Eastern regions, or receiving potential detection examinations might have a significantly higher risk; and male sex, hypertension, dyslipidemia, chronic obstructive pulmonary disease, vascular complications or use of statin, aspirin or non-steroidal anti

Fetal programming of adrenal androgen excess: lessons from a nonhuman primate model of polycystic ovary syndrome.

Science.gov (United States)

Abbott, David H; Zhou, Rao; Bird, Ian M; Dumesic, Daniel A; Conley, Alan J

2008-01-01

Adrenal androgen excess is found in adult female rhesus monkeys previously exposed to androgen treatment during early gestation. In adulthood, such prenatally androgenized female monkeys exhibit elevated basal circulating levels of dehydroepiandrosterone sulfate (DHEAS), typical of polycystic ovary syndrome (PCOS) women with adrenal androgen excess. Further androgen and glucocorticoid abnormalities in PA female monkeys are revealed by acute ACTH stimulation: DHEA, androstenedione and corticosterone responses are all elevated compared to responses in controls. Pioglitazone treatment, however, diminishes circulating DHEAS responses to ACTH in both prenatally androgenized and control female monkeys, while increasing the 17-hydroxyprogesterone response and reducing the DHEA to 17-hydroxyprogesterone ratio. Since 60-min post-ACTH serum values for 17-hydroxyprogesterone correlate negatively with basal serum insulin levels (all female monkeys on pioglitazone and placebo treatment combined), while similar DHEAS values correlate positively with basal serum insulin levels, circulating insulin levels may preferentially support adrenal androgen biosynthesis in both prenatally androgenized and control female rhesus monkeys. Overall, our findings suggest that differentiation of the monkey adrenal cortex in a hyperandrogenic fetal environment may permanently upregulate adult adrenal androgen biosynthesis through specific elevation of 17,20-lyase activity in the zona fasciculata-reticularis. As adult prenatally androgenized female rhesus monkeys closely emulate PCOS-like symptoms, excess fetal androgen programming may contribute to adult adrenal androgen excess in women with PCOS.

Pathogenesis and Novel Treatment from the Mouse Model of Type 2 Diabetic Nephropathy

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Masako Furukawa

2013-01-01

Full Text Available Diabetic nephropathy (DN is the leading cause of end-stage kidney disease worldwide. However, current treatments remain suboptimal. Many factors, such as genetic and nongenetic promoters, hypertension, hyperglycemia, the accumulation of advanced glycation end products (AGEs, dyslipidemia, and albuminuria/proteinuria itself, influence the progression of this disease. It is important to determine the molecular mechanisms and treatment of this disease. The development of diabetes results in the formation of AGEs, oxidative stress, and the activation of the renin-angiotensin-aldosterone system (RAAS within the kidney, which promotes progressive inflammation and fibrosis, leading to DN and declining renal function. A number of novel therapies have also been tested in the experimental diabetic model, including exercise, inhibitors of the RAAS (angiotensin type 1 receptor blockers (ARB, angiotensin-converting enzyme (ACE inhibitors, inhibitors of AGE (pyridoxamine, peroxisome proliferator-activated receptor (PPAR γ agonists (pioglitazone, inhibitors of lipid accumulation (statins and eicosapentaenoic acid (EPA, and the vitamin D analogues. This review summarizes the advances in knowledge gained from our studies and therapeutic interventions that may prevent this disease.

Neurobehavioral response to increased treatment dosage in chronic, severe aphasia

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Jennifer L Mozeiko

2014-04-01

•\tIncreased activation in S2’s bilateral inferior frontal gyrus following the second treatment session indicates that a second Treatment Period can influence continued neuroplastic change in severe, chronic aphasia. •\tS1 appears to show the most activation following Treatment Period I. It is possible that his greater lesion volume or site did not allow for benefit from a second dose to the same degree as S2. •\tActivation changes (or lack thereof in both cases corresponded with performance on the naming task in the scanner, reflecting the effect of treatment. •\tFor S2, neuroimaging supported the behavioral results which favor a second dose of ILAT. For S1, behavioral results, particularly in his consistent increases on the BNT, are not supported by either the behavioral results in the scanner or the BOLD response.

Chronomodulation of topotecan or X-radiation treatment increases treatment efficacy without enhancing acute toxicity

International Nuclear Information System (INIS)

Mullins, Dana; Proulx, Denise; Saoudi, A.; Ng, Cheng E.

2005-01-01

Purpose: Topotecan (TPT), a camptothecin analog, is currently used to treat human ovarian and small-cell lung cancer and is in clinical trials for other tumor sites. However, it is unknown whether chronomodulation of TPT treatment is beneficial. We examined the effects of administering TPT or X-radiation (XR) alone at different times of the day or night. Methods: We treated mice bearing human colorectal tumor xenografts at four different times representing the early rest period (9 AM or 3 HALO [hours after light onset]), late rest period (3 PM or 9 HALO), early active period (9 PM or 15 HALO), and late active period (3 AM or 21 HALO) of the mice. We gave either TPT (12 mg/kg, injected i.p.) or XR (4 Gy, directed to the tumor) twice weekly on Days 0, 4, 7, 10 within 2 weeks. Results: Treatment with either TPT or XR at 3 AM demonstrated the greatest efficacy (measured by a tumor regrowth assay) without significantly increasing acute toxicity (assessed by a decrease in leukocyte counts or body weight). Conversely, treatment at 3 PM, in particular, showed increased toxicity without any enhanced efficacy. Conclusions: Our study provided the first evidence that chronomodulation of TPT treatments, consistent with the findings of other camptothecin analogs, is potentially clinically beneficial. Additionally, our findings suggest that chronomodulation of fractionated XR treatments is also potentially clinically beneficial

Chronomodulation of topotecan or X-radiation treatment increases treatment efficacy without enhancing acute toxicity.

Science.gov (United States)

Mullins, Dana; Proulx, Denise; Saoudi, A; Ng, Cheng E

2005-05-01

Topotecan (TPT), a camptothecin analog, is currently used to treat human ovarian and small-cell lung cancer and is in clinical trials for other tumor sites. However, it is unknown whether chronomodulation of TPT treatment is beneficial. We examined the effects of administering TPT or X-radiation (XR) alone at different times of the day or night. We treated mice bearing human colorectal tumor xenografts at four different times representing the early rest period (9 am or 3 HALO [hours after light onset]), late rest period (3 pm or 9 HALO), early active period (9 pm or 15 HALO), and late active period (3 am or 21 HALO) of the mice. We gave either TPT (12 mg/kg, injected i.p.) or XR (4 Gy, directed to the tumor) twice weekly on Days 0, 4, 7, 10 within 2 weeks. Treatment with either TPT or XR at 3 am demonstrated the greatest efficacy (measured by a tumor regrowth assay) without significantly increasing acute toxicity (assessed by a decrease in leukocyte counts or body weight). Conversely, treatment at 3 pm, in particular, showed increased toxicity without any enhanced efficacy. Our study provided the first evidence that chronomodulation of TPT treatments, consistent with the findings of other camptothecin analogs, is potentially clinically beneficial. Additionally, our findings suggest that chronomodulation of fractionated XR treatments is also potentially clinically beneficial.

Treatment options for nonalcoholic steatohepatitis - a safety evaluation.

Science.gov (United States)

Issa, Danny; Wattacheril, Julia; Sanyal, Arun J

2017-08-01

There is an urgent as yet unmet need to develop highly effective and safe therapeutics for nonalcoholic fatty liver disease (NAFLD). The remarkable progress in understanding NAFLD pathogenesis allowed the identification of injury pathways which may be recruited as therapy targets. Areas covered: This article reviews the safety and tolerability data of the NAFLD therapies and explains the mechanistic basis for each of the established and investigational drugs. Treatment targets include: weight loss, anti-metabolic agents such as lipid lowering and anti-diabetic drugs, inflammation, fibrosis and others such as targeting gut microbiota, immune modulation and apoptosis. Expert opinion: Current therapies continue to remain suboptimal. Weight loss is effective but hard to achieve. Traditional and endoscopic bariatric procedures are promising although more randomized trials are needed and the long-term safety remains to be established. Clinical trials have demonstrated the efficacy of several drugs for the treatment of NASH. Of these, there remains some uncertainty about the long-term safety of vitamin E. Pioglitazone is associated with osteopenia, fluid retention and weight gain. Obeticholic acid causes pruritus in a substantial proportion of subjects and elafibranor has been associated with transient rises in creatinine. Several exciting therapies are under development and results of clinical and post-marketing trials will help elucidate their safety.

Bed rest and increased diuretic treatment in chronic congestive heart failure

DEFF Research Database (Denmark)

Abildgaard, U; Aldershvile, J; Ring-Larsen, H

1985-01-01

To elucidate the effect of bed rest used as an adjunct to increased diuretic treatment, twelve patients with chronic congestive heart failure (CHF) had a 50% increase in loop diuretic dosage and were allocated to either continuous bed rest or bed rest during nights only. The 24-hour bed rest group...... is a reasonable adjunct to diuretic treatment in patients with CHF....

The increase in extraction yields of coals by water treatment

Energy Technology Data Exchange (ETDEWEB)

M. Iino; T. Takanohashi; C. Li; N. Kashimura; K. Masaki; T. Shishido; I. Saito; H. Kumagai [Institute for Energy Utilization, National Institute of Advanced Industrial Science and Technology (AIST), Ibaraki (Japan)

2005-07-01

We have reported that the water treatments of bituminous coals at 600 K for 1 h increased their extraction yields greatly (Energy Fuels, 2005, 18, 1414). In this paper the effect of coal rank on the extraction yields enhancement by the water treatment has been investigated using four Argonne Premium coals, i.e., Pocahontas No. 3 (PO), Upper Freeport (UF), Illinois No.6 (IL), and Beulah Zap (BZ) coals with C % (daf) in the range 67 - 90%. All the coals used show that the water treatments at 600 K increased the extraction yields greatly with a 1:1 carbon disulfide / N-methyl-2-pyrrolidinone mixed solvent (CS2 / NMP) at room temperature. While, the water treatments at 500 K or the heat treatments at 600 K without water gave little increase in the yields. Characterizations of the water-treated coals were carried out from ultimate and proximate compositions, FT-IR spectrum, solvent swelling, NMR relaxation time, and viscoelasticity behavior. The effect of extraction temperature on the extraction yield enhancement was also investigated using polar NMP or non-polar 1-MN solvent. From these results it is concluded that for high coal rank coals the loosening of non-covalent bonds is responsible for the extraction yields enhancement by the water treatment. The loosening non-covalent bonds may be {pi}-{pi} interactions between aromatic rings for PO, and both {pi}-{pi} interactions and hydrogen bonds for UF. While, for lower rank IL and BZ, which showed decrease in O% and hydrogen-bonded OH, the yield enhancements may be due to the loosening of hydrogen bonds and the removal of oxygen functional groups. 9 refs., 5 figs., 1 tab.

Potential role of insulin signaling on vascular smooth muscle cell migration, proliferation, and inflammation pathways.

Science.gov (United States)

Cersosimo, Eugenio; Xu, Xiaojing; Musi, Nicolas

2012-02-15

To investigate the role of insulin signaling pathways in migration, proliferation, and inflammation of vascular smooth muscle cells (VSMCs), we examined the expression of active components of the phosphatidyl inositol 3 (PI-3) kinase (p-Akt) and mitogen-activated protein kinase (MAPK) (p-Erk) in primary cultures of VSMCs from human coronary arteries. VSMCs were treated in a dose-response manner with insulin (0, 1, 10, and 100 nM) for 20 min, and Akt and Erk phosphorylation were measured by Western blot analysis. In separate experiments, we evaluated the effect of 200 μM palmitate, in the presence and absence of 8 μM pioglitazone, on insulin-stimulated (100 nM for 20 min) Akt and Erk phosphorylation. The phosphorylation of Akt and Erk in VSMCs exhibited a dose dependency with a three- to fourfold increase, respectively, at the highest dose (100 nM). In the presence of palmitate, insulin-induced Akt phosphorylation was completely abolished, and there was a threefold increase in p-Erk. With addition of pioglitazone, the phosphorylation of Akt by insulin remained unchanged, whereas insulin-stimulated Erk phosphorylation was reduced by pioglitazone. These data in VSMCs indicate that high palmitate decreases insulin-stimulated Akt phosphorylation and stimulates MAPK, whereas preexposure peroxisome proliferator-activated receptor-γ agonist pioglitazone preserves Akt phosphorylation and simultaneously attenuates MAPK signaling. Our results suggest that metabolic and mitogenic insulin signals have different sensitivity, are independently regulated, and may play a role in arterial smooth muscle cells migration, proliferation, and inflammation in conditions of acute hyperinsulinemia.

Attempts to increase storage stability of strawberry yoghurt by combination treatments

International Nuclear Information System (INIS)

Kiss, I.

1975-01-01

The aim of the experiments was to establish whether the microbiological stability of strawberry yoghurt might be improved by decreasing the microbial load of the fruit. The effect of heat treatment, freezing, irradiation and various combinations of these treatments upon cell count and sensory quality was investigated. It was established that none of the individual treatments was entirely satisfactory. Surfacial heat treatment at 55 0 C, freezing and irradiation with 0.4-0.6 Mrad substantially increased the storage life of strawberries or that of the yoghurt prepared with this fruit; when compared to yoghurt made with frozen strawberries by the dairy factory, the increase was 2.5 fold at 15 0 C and 3.5 fold at 2 0 C. The relative increase of storage life was lower at lower yeast-cell counts. The strawberries irradiated with doses above 0.2 Mrad showed aroma and flavour changes immediately upon treatment. This effect, however, was eliminated after some days. The yoghurt made with strawberries given a radiation treatment of 0.57 Mrad did not differ organoleptically from the yoghurt made with untreated strawberries. In the knowledge of the survival rate of yeasts after irradiation the D 10 values were established. These were found in the dose range between 0.043 and 0.087 Mrad. It was established that the applied heat treatment, freezing and irradiation at these dose levels and at 10 3 -10 4 cells per gram were not sufficient from the point of view of microbiological stability. (F.J.)

Vildagliptin: a new oral treatment for type 2 diabetes mellitus

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Chantal Mathieu

2008-12-01

Full Text Available Chantal Mathieu, Evy DegrandeDepartment of Endocrinology, Katholieke Universiteit Leuven, Leuven, BelgiumAbstract: Vildagliptin is a new oral antidiabetic agent that enhances pancreatic islet cell responsiveness to glucose. An extensive clinical program involving approximately 22,000 patients and 7000 patient-years of exposure to vildagliptin has shown that the agent is well tolerated and efficacious in improving glycemic control in patients with type 2 diabetes mellitus (T2DM. Monotherapy trials have shown that significant HbA1c lowering is accompanied by body weight-neutral and lipid-neutral effects, low risk of edema, and low risk of hypoglycemia. These characteristics make vildagliptin a favorable partner for combination therapy. Studies of vildagliptin as an add-on to metformin have shown significant improvements in glycemic control (comparable to that of thiazolidinedione add-on, with the combination being well tolerated and associated with low risks for hypoglycemia and adverse effects on weight or lipid levels. Good tolerability and clinically relevant improvements in glycemic control have also been observed with vildagliptin as an add-on treatment to sulfonylurea, thiazolidinedione, or insulin treatment or in initial combination treatment with pioglitazone. Improved β-cell function and glycemic control have been shown with vildagliptin in subjects with impaired glucose tolerance and in T2DM patients with mild hyperglycemia, with some evidence in the latter suggesting the potential for modifying disease course.Keywords: diabetes, vildagliptin, incretin, metformin, add-on treatment, hypoglycemia

Niacin treatment increases plasma homocyst(e)ine levels.

Science.gov (United States)

Garg, R; Malinow, M; Pettinger, M; Upson, B; Hunninghake, D

1999-12-01

Studies have reported high levels of plasma homocyst(e)ine as an independent risk factor for arterial occlusive disease. The Cholesterol Lowering Atherosclerosis Study reported an increase in plasma homocyst(e)ine levels in patients receiving both colestipol and niacin compared with placebo. Thus the objective of this study was to examine the effect of niacin treatment on plasma homocyst(e)ine levels. The Arterial Disease Multiple Intervention Trial, a multicenter randomized, placebo-controlled trial, examined the effect of niacin compared with placebo on homocyst(e)ine in a subset of 52 participants with peripheral arterial disease. During the screening phase, titration of niacin dose from 100 mg to 1000 mg daily resulted in a 17% increase in mean plasma homocyst(e)ine level from 13.1 +/- 4.4 micromol/L to 15.3 +/- 5.6 micromol/L (P ine levels in the niacin group and a 7% decrease in the placebo group (P =.0001). This difference remained statistically significant at the end of follow-up at 48 weeks. Niacin substantially increased plasma homocyst(e)ine levels, which could potentially reduce the expected benefits of niacin associated with lipoprotein modification. However, plasma homocyst(e)ine levels can be decreased by folic acid supplementation. Thus further studies are needed to determine whether B vitamin supplementation to patients undergoing long-term niacin treatment would be beneficial.

Peroxisome Proliferator-Activated Receptor-γ in Thyroid Autoimmunity

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Silvia Martina Ferrari

2015-01-01

Full Text Available Peroxisome proliferator-activated receptor- (PPAR- γ expression has been shown in thyroid tissue from patients with thyroiditis or Graves’ disease and furthermore in the orbital tissue of patients with Graves’ ophthalmopathy (GO, such as in extraocular muscle cells. An increasing body of evidence shows the importance of the (C-X-C motif receptor 3 (CXCR3 and cognate chemokines (C-X-C motif ligand (CXCL9, CXCL10, and CXCL11, in the T helper 1 immune response and in inflammatory diseases such as thyroid autoimmune disorders. PPAR-γ agonists show a strong inhibitory effect on the expression and release of CXCR3 chemokines, in vitro, in various kinds of cells, such as thyrocytes, and in orbital fibroblasts, preadipocytes, and myoblasts from patients with GO. Recently, it has been demonstrated that rosiglitazone is involved in a higher risk of heart failure, stroke, and all-cause mortality in old patients. On the contrary, pioglitazone has not shown these effects until now; this favors pioglitazone for a possible use in patients with thyroid autoimmunity. However, further studies are ongoing to explore the use of new PPAR-γ agonists in the treatment of thyroid autoimmune disorders.

Increased Mental Health Treatment Financing, Community-Based Organization's Treatment Programs, and Latino-White Children's Financing Disparities.

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Snowden, Lonnie R; Wallace, Neal; Cordell, Kate; Graaf, Genevieve

2017-09-01

Latino child populations are large and growing, and they present considerable unmet need for mental health treatment. Poverty, lack of health insurance, limited English proficiency, stigma, undocumented status, and inhospitable programming are among many factors that contribute to Latino-White mental health treatment disparities. Lower treatment expenditures serve as an important marker of Latino children's low rates of mental health treatment and limited participation once enrolled in services. We investigated whether total Latino-White expenditure disparities declined when autonomous, county-level mental health plans receive funds free of customary cost-sharing charges, especially when they capitalized on cultural and language-sensitive mental health treatment programs as vehicles to receive and spend treatment funds. Using Whites as benchmark, we considered expenditure pattern disparities favoring Whites over Latinos and, in a smaller number of counties, Latinos over Whites. Using segmented regression for interrupted time series on county level treatment systems observed over 64 quarters, we analyzed Medi-Cal paid claims for per-user total expenditures for mental health services delivered to children and youth (under 18 years of age) during a study period covering July 1, 1991 through June 30, 2007. Settlement-mandated Medicaid's Early Periodic Screening, Diagnosis and Treatment (EPSDT) expenditure increases began in the third quarter of 1995. Terms were introduced to assess immediate and long term inequality reduction as well as the role of culture and language-sensitive community-based programs. Settlement-mandated increased EPSDT treatment funding was associated with more spending on Whites relative to Latinos unless plans arranged for cultural and language-sensitive mental health treatment programs. However, having programs served more to prevent expenditure disparities from growing than to reduce disparities. EPSDT expanded funding increased proportional

Optimal treatment increased the seed germination of Salvia verticillata L.

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ALALEH KHAKPOOR

2015-12-01

Full Text Available Most seeds of the medicinal species are variable regarding their ecological compatibility with environmental conditions. Therefore, identifying the ecophysiological factors that affect dormancy and create optimal conditions for seed germination of medicinal plants is necessary for their culture and production. To evaluate the effect of different treatments on seed germination of medicinal species of Salvia verticillata, collected in the summer of 2010 in Eastern Azarbaijan, we have performed completely randomized experimental tests with 4 replications. The experimental design of treatment prior to growth included: scrape the skin with sandpaper, treatment with 500 ppm gibberellic acid for 24 and 48 h, treatment with citric acid for 10, 20 and 30 minutes, chilling for 2 and 4 weeks, treatment with warm water at 70°C and control treatment. Results showed that the effect of different treatments was significant on seed germination percent of the medicinal plant Salvia verticillata. Scrape the skin with sandpaper, citric acid treatment for 10, 20 and 30 minutes, and gibberellic acid treatment for 24 hours, increased the germination percentage compared to the control treatment. The most positive impact was observed on the dormancy breaking and germination of medicinal species Salvia verticillata.

Increasing trend of metronidazole resistance in the treatment of ...

African Journals Online (AJOL)

Helicobacter pylori are gram negative spiral bacteria that colonize the human stomach. Infection with H. pylori is associated with chronic gastritis, peptic ulcer, gastric adenocarcinoma and gastric mucosaassociated lymphoid tissue (MALT) lymphoma. Antibiotic resistance is an ever increasing problem with the treatment of ...

Chemotherapeutic treatment efficacy and sensitivity are increased by adjuvant alternating electric fields (TTFields)

International Nuclear Information System (INIS)

Kirson, Eilon D; Goldsher, Dorit; Wasserman, Yoram; Palti, Yoram; Schneiderman, Rosa S; Dbalý, Vladimír; Tovaryš, František; Vymazal, Josef; Itzhaki, Aviran; Mordechovich, Daniel; Gurvich, Zoya; Shmueli, Esther

2009-01-01

The present study explores the efficacy and toxicity of combining a new, non-toxic, cancer treatment modality, termed Tumor Treating Fields (TTFields), with chemotherapeutic treatment in-vitro, in-vivo and in a pilot clinical trial. Cell proliferation in culture was studied in human breast carcinoma (MDA-MB-231) and human glioma (U-118) cell lines, exposed to TTFields, paclitaxel, doxorubicin, cyclophosphamide and dacarbazine (DTIC) separately and in combinations. In addition, we studied the effects of combining chemotherapy with TTFields in an animal tumor model and in a pilot clinical trial in recurrent and newly diagnosed GBM patients. The efficacy of TTFields-chemotherapy combination in-vitro was found to be additive with a tendency towards synergism for all drugs and cell lines tested (combination index ≤ 1). The sensitivity to chemotherapeutic treatment was increased by 1–3 orders of magnitude by adjuvant TTFields therapy (dose reduction indexes 23 – 1316). Similar findings were seen in an animal tumor model. Finally, 20 GBM patients were treated with TTFields for a median duration of 1 year. No TTFields related systemic toxicity was observed in any of these patients, nor was an increase in Temozolomide toxicity seen in patients receiving combined treatment. In newly diagnosed GBM patients, combining TTFields with Temozolomide treatment led to a progression free survival of 155 weeks and overall survival of 39+ months. These results indicate that combining chemotherapeutic cancer treatment with TTFields may increase chemotherapeutic efficacy and sensitivity without increasing treatment related toxicity

Preharvest methyl jasmonate and postharvest UVC treatments: increasing stilbenes in wine.

Science.gov (United States)

Fernández-Marín, María Isabel; Puertas, Belén; Guerrero, Raúl F; García-Parrilla, María Carmen; Cantos-Villar, Emma

2014-03-01

Stilbene-enriched wine is considered to be an interesting new food product with added value due to its potential health-promoting properties. Stilbene concentration in grape is highly variable and rather scarce. However, it can be increased by stress treatments. For this reason, numerous pre- and postharvest grape treatments, and some combinations of them, have been tested to maximize stilbene content in grapes. In the present manuscript, Syrah grapes were treated with (i) methyl jasmonate (MEJA), (ii) ultraviolet light (UVC), and (iii) methyl jasmonate and ultraviolet light (MEJA-UVC) and compared with untreated grapes. Afterward, winemaking was developed. Wine achieved by combination of both treatments (MEJA-UVC) contained significantly higher stilbene concentration (trans-resveratrol and piceatannol) than its respective control (2.5-fold). Wine quality was improved in color-related parameters (color intensity, L*, a*, b*, ΔE*, anthocyanins, and tannin). Moreover, MEJA-UVC wines obtained the highest score in sensorial analysis. To the best of our knowledge, this is the first time that pre- and postharvest treatments are combined to increase stilbenes in wine. The effect of treatment combination (methyl jasmonate and UVC light) on grape and wine was evaluated. Our results highlight the positive effect of the treatments in stilbene content, color parameters, and sensorial analysis. Moreover, added-value by-products were achieved. © 2014 Institute of Food Technologists®

[Current options of insulin resistence correction in patients with metabolic syndrome].

Science.gov (United States)

Demidova, T Iu; Ametov, A S; Titova, O I

2006-01-01

To study thiasolidindion drug pioglitazone for efficacy in metabolic syndrome (MS). Twenty patients with MS were examined at baseline and after 12 week therapy with pioglitazone. The examination included estimation of fasting and postprandial glycemia, insulin resistance index, HOMA-IR index, HbAlc, lipid profile, microalbuminuria (MAU), blood pressure, endothelium-related vasodilation. Pioglitazone therapy for 12 weeks significantly reduced HbAlc, fasting and postprandial glycemia, insulinemia, HOMA-IR, improved blood lipid spectrum, reduced visceral obesity. Positive effects were also achieved on blood pressure, MAU and endothelium-related vasodilation.

Effect of Additives on the Physicochemical and Drug Release ...

African Journals Online (AJOL)

Purpose: To prepare and evaluate spherical agglomerates of pioglitazone hydrochloride (PGH) for direct compression with different additives. Method: Spherical agglomerates of pioglitazone hydrochloride were prepared by emulsion solvent diffusion method with and without additives (polyethylene glycol 6000, polyvinyl ...

A Systematic Review of Non-Invasive Pharmacologic Neuroprotective Treatments for Acute Spinal Cord Injury

Science.gov (United States)

Okon, Elena; Hillyer, Jessica; Mann, Cody; Baptiste, Darryl; Weaver, Lynne C.; Fehlings, Michael G.; Tetzlaff, Wolfram

2011-01-01

Abstract An increasing number of therapies for spinal cord injury (SCI) are emerging from the laboratory and seeking translation into human clinical trials. Many of these are administered as soon as possible after injury with the hope of attenuating secondary damage and maximizing the extent of spared neurologic tissue. In this article, we systematically review the available pre-clinical research on such neuroprotective therapies that are administered in a non-invasive manner for acute SCI. Specifically, we review treatments that have a relatively high potential for translation due to the fact that they are already used in human clinical applications, or are available in a form that could be administered to humans. These include: erythropoietin, NSAIDs, anti-CD11d antibodies, minocycline, progesterone, estrogen, magnesium, riluzole, polyethylene glycol, atorvastatin, inosine, and pioglitazone. The literature was systematically reviewed to examine studies in which an in-vivo animal model was utilized to assess the efficacy of the therapy in a traumatic SCI paradigm. Using these criteria, 122 studies were identified and reviewed in detail. Wide variations exist in the animal species, injury models, and experimental designs reported in the pre-clinical literature on the therapies reviewed. The review highlights the extent of investigation that has occurred in these specific therapies, and points out gaps in our knowledge that would be potentially valuable prior to human translation. PMID:20146558

Pioglitazone

Science.gov (United States)

... manage your diabetes and improve your health. This therapy may also decrease your chances of having a heart attack, stroke, or other diabetes-related complications such as kidney failure, nerve damage (numb, cold legs or feet; decreased sexual ability in men and women), eye ...

INCREASED OIL RECOVERY FROM MATURE OIL FIELDS USING GELLED POLYMER TREATMENTS

Energy Technology Data Exchange (ETDEWEB)

G.P. Willhite; D.W. Green; C.S. McCool

2003-05-01

Gelled polymer treatments are applied to oil reservoirs to increase oil production and to reduce water production by altering the fluid movement within the reservoir. This report describes the results of a three-year research program aimed at reducing barriers to the widespread use of gelled polymer treatments by (1) developing methods to predict gel behavior during placement in matrix rock and fractures, (2) determining the persistence of permeability reduction after gel placement, and (3) developing methods to design production well treatments to control water production. The work focused on the gel system composed of polyacrylamide and chromium acetate. The molar mass of the polymer was about six million. Chromium(III) acetate reacted and formed crosslinks between polymer molecules. The crosslinked polymer molecules, or pre-gel aggregates, combine and grow to eventually form a 3-dimensional gel. A fundamental study to characterize the formation and growth of pre-gel aggregates was conducted. Two methods, flow field-flow fractionation (FFFF) and multi-angle laser light scattering (MALLS) were used. Studies using FFFF were inconclusive. Data taken using MALLS showed that at the gel time the average molar mass of gel aggregates increased by a factor of about three while the average size increase was approximately 50%. Increased acetate concentration in the gelant increases the gel time. The in situ performance of an added-acetate system was investigated to determine the applicability for in-depth treatments. Increased acetate concentrations delayed the development of increased flow resistance during gelant injection in short sandpacks. The development of increased flow resistance (in situ gelation) was extended from 2 to 34 days by increasing the acetate-to-chromium ratio from 38 to 153. In situ gelation occurred at a time that was approximately 22% of the bulk gelation time. When carbonate rocks are treated with gel, chromium retention in the rock may limit in

Increased amygdala responses to emotional faces after psilocybin for treatment-resistant depression.

Science.gov (United States)

Roseman, Leor; Demetriou, Lysia; Wall, Matthew B; Nutt, David J; Carhart-Harris, Robin L

2017-12-27

Recent evidence indicates that psilocybin with psychological support may be effective for treating depression. Some studies have found that patients with depression show heightened amygdala responses to fearful faces and there is reliable evidence that treatment with SSRIs attenuates amygdala responses (Ma, 2015). We hypothesised that amygdala responses to emotional faces would be altered post-treatment with psilocybin. In this open-label study, 20 individuals diagnosed with moderate to severe, treatment-resistant depression, underwent two separate dosing sessions with psilocybin. Psychological support was provided before, during and after these sessions and 19 completed fMRI scans one week prior to the first session and one day after the second and last. Neutral, fearful and happy faces were presented in the scanner and analyses focused on the amygdala. Group results revealed rapid and enduring improvements in depressive symptoms post psilocybin. Increased responses to fearful and happy faces were observed in the right amygdala post-treatment, and right amygdala increases to fearful versus neutral faces were predictive of clinical improvements at 1-week. Psilocybin with psychological support was associated with increased amygdala responses to emotional stimuli, an opposite effect to previous findings with SSRIs. This suggests fundamental differences in these treatments' therapeutic actions, with SSRIs mitigating negative emotions and psilocybin allowing patients to confront and work through them. Based on the present results, we propose that psilocybin with psychological support is a treatment approach that potentially revives emotional responsiveness in depression, enabling patients to reconnect with their emotions. ISRCTN, number ISRCTN14426797. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Saroglitazar for the treatment of dyslipidemia in diabetic patients.

Science.gov (United States)

Joshi, Shashank R

2015-03-01

Diabetes and dyslipidemia are commonly associated modifiable risk factors for cardiovascular diseases. Majority of patients with diabetes also suffer from dyslipidemia (diabetic dyslipidemia). Diabetic dyslipidemia is more atherogenic as it is commonly associated with high triglyceride (TG) levels, high proportion of small dense low-density lipoprotein cholesterol and low high-density lipoprotein cholesterol (HDL-C) level (atherogenic dyslipidemia). Currently used pharmacotherapies for the management of diabetes and dyslipidemia like thiazolidinediones (PPAR-γ agonist; for insulin resistance) and fibrates (PPAR-α agonist; for hypertriglyceridemia) have many limitations and side effects. Saroglitazar , a dual PPAR-α/γ agonists, is an emerging therapeutic option with its dual benefit on glycemic and lipid parameters. This paper reviews the clinical development of saroglitazar for the management of diabetic dyslipidemia. The efficacy and safety profile of saroglitazar is reviewed in context to currently available therapy like pioglitazone for diabetes and fibrates for hypertriglyceridemia. In addition, this paper also reviews the association between diabetes and dyslipidemia and the role of TG in reducing cardiovascular events. Saroglitazar, a dual PPAR-α/γ agonist, is a potential therapeutic option for the management of diabetic dyslipidemia. It has dual benefit of significant improvement in glycemic parameters (glycated hemoglobin and fasting blood glucose) and significant improvement in dyslipidemia (TGs, apolipoprotein B, non-HDL-C). The results of Phase III clinical trials indicate that saroglitazar is devoid of conventional side effects of fibrates and pioglitazone. Future clinical trials of saroglitazar will further establish its place in the management of diabetes, dyslipidemia and associated cardiovascular risk.

[Dapagliflozin, the first SGLT-2 inhibitor in the treatment of type 2 diabetes].

Science.gov (United States)

Albarrán, Olga González; Ampudia-Blasco, F Javier

2013-09-01

Dapagliflozin is the first novel sodium-glucose co-transporter-2 (SGLT2) inhibitor approved by the European Medicines Agency (EMA) for the treatment of type 2 diabetes. By inhibiting SGLT2, dapagliflozin blocks reabsorption of filtered glucose in the kidney, increasing urinary glucose excretion and reducing blood glucose levels. Its mechanism of action is independent of pancreatic β cell function and modulation of insulin sensitivity. The results of phase III clinical trials showed that dapagliflozin, at a dose of 5 or 10mg/day for 24 weeks as monotherapy in previously untreated patients, or as add-on combination therapy with metformin, glimepiride, pioglitazone or insulin-based therapy, significantly reduced both HbA1c and fasting plasma glucose levels compared with placebo. In addition, dapagliflozin was noninferior to glipizide, in terms of glycemic control after 52 weeks, when used as add-on therapy in patients with type 2 diabetes inadequately controlled with metformin. In most clinical trials, dapagliflozin reduced body weight. The combination of both effects (improved glycemic control and weight loss) is achieved to a greater extent in treatments that include dapaglifozin. Longer-term extension studies indicated that the efficacy of dapagliflozin on the glycemic control and weight reducción is maintained for up to 2 and 4 years. Dapagliflozin was well tolerated. Genital infections and urinary tract infections were more frequent in patients who received dapagliflozin than in placebo recipients. Hypoglycemic episodes were scarce with dapagliflozin. In conclusion, dapagliflozin is a novel option for the management of type 2 diabetes, particularly when used as add-on therapy. Copyright © 2013 Elsevier España, S.L. All rights reserved.

Increase in extraction yields of coals by water treatment: Beulah-Zap lignite

Energy Technology Data Exchange (ETDEWEB)

Masashi Iino; Toshimasa Takanohashi; Takahiro Shishido; Ikuo Saito; Haruo Kumagai [National Institute of Advanced Industrial Science and Technology, Tsukuba (Japan)

2007-01-15

In a previous paper, we have reported that water pretreatments of Argonne premium coals, Pocahontas No. 3 (PO), Upper Freeport (UF), and Illinois No. 6 (IL) at 600 K increased greatly the room-temperature extraction yields with a 1:1 carbon disulfide/N-methyl-2-pyrrolidinone (CS{sub 2}/NMP) mixed solvent. In this paper, the water treatment of Beulah-Zap (BZ) lignite has been carried out and the results obtained were compared with those for the three bituminous coals above. The extraction yields of BZ with CS{sub 2}/NMP increased from 5.5% for the raw coal to 21.7% by the water treatment at 600 K. Similar to the other three coals, the water treatments at 500 K gave little increase in the yields. The larger decrease in oxygen content and hydrogen-bonded OH and the increase in the methanol swelling ratio by the water treatment suggest that the yield enhancements for BZ are attributed to the removal of oxygen functional groups and the breaking of hydrogen bonds to a greater extent than that for IL. From the characterizations of the treated coals and the extraction temperature dependency of their extraction yields, it is suggested that, for high-coal-rank coals, PO and UF, the breaking of noncovalent bonds such as {pi}-{pi} interactions between aromatic layers and hydrogen bonds is responsible for the extraction yield enhancements. 14 refs., 3 figs., 2 tabs.

Increased Oil Recovery from Mature Oil Fields Using Gelled Polymer Treatments

Energy Technology Data Exchange (ETDEWEB)

Willhite, G.P.; Green, D.W.; McCool, S.

2001-03-28

Gelled polymer treatments were applied to oil reservoirs to increase oil production and to reduce water production by altering the fluid movement within the reservoir. This report is aimed at reducing barriers to the widespread use of these treatments by developing methods to predict gel behavior during placement in matrix rock and fractures, determining the persistence of permeability reduction after gel placement, and by developing methods to design production well treatments to control water production. Procedures were developed to determine the weight-average molecular weight and average size of polyacrylamide samples in aqueous solutions. Sample preparation techniques were key to achieving reproducible results.

Alterations in the hypothalamic melanocortin pathway in amyotrophic lateral sclerosis.

Science.gov (United States)

Vercruysse, Pauline; Sinniger, Jérôme; El Oussini, Hajer; Scekic-Zahirovic, Jelena; Dieterlé, Stéphane; Dengler, Reinhard; Meyer, Thomas; Zierz, Stephan; Kassubek, Jan; Fischer, Wilhelm; Dreyhaupt, Jens; Grehl, Torsten; Hermann, Andreas; Grosskreutz, Julian; Witting, Anke; Van Den Bosch, Ludo; Spreux-Varoquaux, Odile; Ludolph, Albert C; Dupuis, Luc

2016-04-01

Amyotrophic lateral sclerosis, the most common adult-onset motor neuron disease, leads to death within 3 to 5 years after onset. Beyond progressive motor impairment, patients with amyotrophic lateral sclerosis suffer from major defects in energy metabolism, such as weight loss, which are well correlated with survival. Indeed, nutritional intervention targeting weight loss might improve survival of patients. However, the neural mechanisms underlying metabolic impairment in patients with amyotrophic lateral sclerosis remain elusive, in particular due to the lack of longitudinal studies. Here we took advantage of samples collected during the clinical trial of pioglitazone (GERP-ALS), and characterized longitudinally energy metabolism of patients with amyotrophic lateral sclerosis in response to pioglitazone, a drug with well-characterized metabolic effects. As expected, pioglitazone decreased glycaemia, decreased liver enzymes and increased circulating adiponectin in patients with amyotrophic lateral sclerosis, showing its efficacy in the periphery. However, pioglitazone did not increase body weight of patients with amyotrophic lateral sclerosis independently of bulbar involvement. As pioglitazone increases body weight through a direct inhibition of the hypothalamic melanocortin system, we studied hypothalamic neurons producing proopiomelanocortin (POMC) and the endogenous melanocortin inhibitor agouti-related peptide (AGRP), in mice expressing amyotrophic lateral sclerosis-linked mutant SOD1(G86R). We observed lower Pomc but higher Agrp mRNA levels in the hypothalamus of presymptomatic SOD1(G86R) mice. Consistently, numbers of POMC-positive neurons were decreased, whereas AGRP fibre density was elevated in the hypothalamic arcuate nucleus of SOD1(G86R) mice. Consistent with a defect in the hypothalamic melanocortin system, food intake after short term fasting was increased in SOD1(G86R) mice. Importantly, these findings were replicated in two other amyotrophic

Effects of Organic Acids Treatments with or without Ultra-Sonic Treatment on Increasing the Shelf Life of Fresh Cut Kiwifruit

Directory of Open Access Journals (Sweden)

A. Mansoory

2016-02-01

Full Text Available The market sales of ready to use fresh cut fruits have grown rapidly in recent decades. Kiwi fruit is an important fruit that its marketing as fresh cut has increased in recent years. The main limiting factors in shelf life of fresh cut fruits are microbial spoilage, drastic softening and browning. In this study, the effects of oxalic and citric acids, both at 0, 2, 4 and 6 mM concentrations, with or without ultra-sonic treatment were investigated on the increasing the shelf life of fresh cut kiwi fruit. After treatments, the fresh slices were stored at 2°C for 7 or 14 days and assessed for several traits and analyzed. Results showed that, oxalic and citric acid treated slices, in comparison to the control, had greater marketability, as well as higher flesh firmness, titrable acidity, ascorbic acid content, total phenol content and antioxidant capacity and smaller bacterial forming colony unit (CFU. Among the treatments, 2, 4 and 6 mM oxalic acid and 6 mM citric acid treatments were found more appropriate than the reaming treatments. Application of ultra-sonic treatment, despite the reduction of microbial load and maintaining antioxidant capacity, had no effects on marketability of fresh cut kiwi fruit. Hence, application of organic acid treatments as dipping can be used to increase the shelf life of fresh cut kiwi fruit.

In vivo analysis of supersaturation/precipitation/absorption behavior after oral administration of pioglitazone hydrochloride salt; determinant site of oral absorption.

Science.gov (United States)

Tanaka, Yusuke; Sugihara, Masahisa; Kawakami, Ayaka; Imai, So; Itou, Takafumi; Murase, Hirokazu; Saiki, Kazunori; Kasaoka, Satoshi; Yoshikawa, Hiroshi

2017-08-30

The purpose of this study was to evaluate in vivo supersaturation/precipitation/absorption behavior in the gastrointestinal (GI) tract based on the luminal concentration-time profiles after oral administration of pioglitazone (PG, a highly permeable lipophilic base) and its hydrochloride salt (PG-HCl) to rats. In the in vitro precipitation experiment in the classic closed system, while the supersaturation was stable in the simulated gastric condition, PG drastically precipitated in the simulated intestinal condition, particularly at a higher initial degree of supersaturation. Nonetheless, a drastic and moderate improvement in absorption was observed in vivo at a low and high dose of PG-HCl, respectively. Analysis based on the luminal concentration of PG after oral administration of PG-HCl at a low dose revealed that most of the dissolved PG emptied from the stomach was rapidly absorbed before its precipitation in the duodenum. At a high dose of PG-HCl, PG partly precipitated in the duodenum but was absorbed to some extent. Therefore, the extent of the absorption was mainly dependent on the duodenal precipitation behavior. Furthermore, a higher-than expected absorption after oral administration of PG-HCl from in vitro precipitation study may be due to the absorption process in the small intestine, which suppresses the precipitation by removal of the drug. This study successfully clarify the impact of the absorption process on the supersaturation/precipitation/absorption behavior and key absorption site for a salt formulation of a highly permeable lipophilic base based on the direct observation of in vivo luminal concentration. Our findings may be beneficial in developing an ideal physiologically based pharmacokinetic model and in vitro predictive dissolution tools and/or translating the in silico and in vitro data to the in vivo outcome. Copyright © 2017 Elsevier B.V. All rights reserved.

Effects of Lobeglitazone, a New Thiazolidinedione, on Osteoblastogenesis and Bone Mineral Density in Mice

Directory of Open Access Journals (Sweden)

Kyoung Min Kim

2017-09-01

Full Text Available BackgroundBone strength is impaired in patients with type 2 diabetes mellitus despite an increase in bone mineral density (BMD. Thiazolidinedione (TZD, a peroxisome proliferator activated receptor γ agonist, promotes adipogenesis, and suppresses osteoblastogenesis. Therefore, its use is associated with an increased risk of fracture. The aim of this study was to examine the in vitro and in vivo effects of lobeglitazone, a new TZD, on bone.MethodsMC3T3E1 and C3H10T1/2 cells were cultured in osteogenic medium and exposed to lobeglitazone (0.1 or 1 µM, rosiglitazone (0.4 µM, or pioglitazone (1 µM for 10 to 14 days. Alkaline phosphatase (ALP activity, Alizarin red staining, and osteoblast marker gene expression were analyzed. For in vivo experiments, 6-month-old C57BL/6 mice were treated with vehicle, one of two doses of lobeglitazone, rosiglitazone, or pioglitazone. BMD was assessed using a PIXImus2 instrument at the baseline and after 12 weeks of treatment.ResultsAs expected, in vitro experiments showed that ALP activity was suppressed and the mRNA expression of osteoblast marker genes RUNX2 (runt-related transcription factor 2 and osteocalcin was significantly attenuated after rosiglitazone treatment. By contrast, lobeglitazone at either dose did not inhibit these variables. Rosiglitazone-treated mice showed significantly accelerated bone loss for the whole bone and femur, but BMD did not differ significantly between the lobeglitazone-treated and vehicle-treated mice.ConclusionThese findings suggest that lobeglitazone has no detrimental effects on osteoblast biology and might not induce side effects in the skeletal system.

Resveratrol Ameliorates the Depressive-Like Behaviors and Metabolic Abnormalities Induced by Chronic Corticosterone Injection

Directory of Open Access Journals (Sweden)

Yu-Cheng Li

2016-10-01

Full Text Available Chronic glucocorticoid exposure is known to cause depression and metabolic disorders. It is critical to improve abnormal metabolic status as well as depressive-like behaviors in patients with long-term glucocorticoid therapy. This study aimed to investigate the effects of resveratrol on the depressive-like behaviors and metabolic abnormalities induced by chronic corticosterone injection. Male ICR mice were administrated corticosterone (40 mg/kg by subcutaneous injection for three weeks. Resveratrol (50 and 100 mg/kg, fluoxetine (20 mg/kg and pioglitazone (10 mg/kg were given by oral gavage 30 min prior to corticosterone administration. The behavioral tests showed that resveratrol significantly reversed the depressive-like behaviors induced by corticosterone, including the reduced sucrose preference and increased immobility time in the forced swimming test. Moreover, resveratrol also increased the secretion of insulin, reduced serum level of glucose and improved blood lipid profiles in corticosterone-treated mice without affecting normal mice. However, fluoxetine only reverse depressive-like behaviors, and pioglitazone only prevent the dyslipidemia induced by corticosterone. Furthermore, resveratrol and pioglitazone decreased serum level of glucagon and corticosterone. The present results indicated that resveratrol can ameliorate depressive-like behaviors and metabolic abnormalities induced by corticosterone, which suggested that the multiple effects of resveratrol could be beneficial for patients with depression and/or metabolic syndrome associated with long-term glucocorticoid therapy.

Aeration to degas CO{sub 2}, increase pH, and increase iron oxidation rates for efficient treatment of net alkaline mine drainage

Energy Technology Data Exchange (ETDEWEB)

Kirby, C.S.; Dennis, A.; Kahler, A. [Bucknell University, Lewisburg, PA (United States). Dept. of Geology

2009-07-15

Passive treatment systems for mine drainage use no energy other than gravity, but they require greater area than active treatment systems. Researchers are considering 'hybrid' systems that have passive and active components for increased efficiency, especially where space limitations render passive-only technology ineffective. Flow-through reactor field experiments were conducted at two large net-alkaline anthracite mine discharges in central Pennsylvania. Assuming an Fe removal rate of 20 g m{sup -2} day{sup -1} and Fe loading from field data, 3.6 x 10{sup 3} and 3.0 x 10{sup 4} m{sup 2} oxidation ponds would be required for the passive treatment of Site 21 and Packer 5 discharges, respectively. However, only a small area is available at each site. This paper demonstrates aeration to drive off CO{sub 2}, increase pH, and increase Fe(II) oxidation rates, enabling treatment within a small area compared to passive treatment methods, and introduces a geochemical model to accurately predict these rates as well as semi-passive treatment system sizing parameters. Iron(II) oxidation modeling of actively aerated systems predicted that a 1-m deep pond with 10 times less area than estimated for passive treatment would lower Fe(II) concentrations to less than 1 mg L-1 at summer and winter temperatures for both sites. The use of active aeration for treatment Of CO{sub 2}-rich, net-alkaline discharges (including partially treated effluent from anoxic limestone drains) can result in considerably reduced treatment area for oxidation and may lower treatment costs, but settling of Fe hydroxides was not considered in this study. The reduced capital cost for earthmoving will need to be compared to energy and maintenance costs for aeration.

Effect of Omega-3 Fatty Acids Treatment on Insulin Resistance

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Mogoş Tiberius

2014-12-01

Full Text Available Background and aims: Insulin resistance (IR is a common pathogenic factor of several diseases: diabetes mellitus, the metabolic syndrome, arterial hypertension, atherosclerosis, dyslipidemia, etc. There are many therapeutic factors involved in decreasing IR. Among them we mention metformin, pioglitazone, physical activity, weight loss, diet, etc. In the last decade, there are more observations of the influence of polyunsaturated fatty acids on IR. The most powerful seem to be omega-3 fatty acids. In our study, we wanted to asses if the administration of omega-3 fatty acids is involved in modifying IR. Materials and methods: We evaluated 126 diabetic patients with IR from January 2011 until July 2014. The study was open-label and non-randomized. For the determination of IR we used the HOMA-IR method. Results: For both males and females there was a regression of HOMA-IR during the 4 weeks of treatment with omega-3 and also after 2 weeks after stopping the administration of these fatty acids. The decrease of HOMA-IR was statistically significant (p<0.05. The statistic result observed in the next 2 weeks after stopping administration of omega-3 was also significant (p<0.05.

Treatment Resistant Epilepsy in Autism Spectrum Disorder: Increased Risk for Females.

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Blackmon, Karen; Bluvstein, Judith; MacAllister, William S; Avallone, Jennifer; Misajon, Jade; Hedlund, Julie; Goldberg, Rina; Bojko, Aviva; Mitra, Nirmala; Giridharan, Radha; Sultan, Richard; Keller, Seth; Devinsky, Orrin

2016-02-01

The male:female ratio in autism spectrum disorder (ASD) averages greater than 4:1 while the male:female ratio of ASD with epilepsy averages less than 3:1. This indicates an elevated risk of epilepsy in females with ASD; yet, it is unknown whether phenotypic features of epilepsy and ASD differ between males and females with this comorbidity. The goal of this study is to investigate sex differences in phenotypic features of epilepsy and ASD in a prospective sample of 130 children and young adults with an initial ASD diagnosis and subsequent epilepsy diagnosis. All participants were characterized by standardized diagnostic inventories, parent/caregiver completed questionnaires, and medical/academic record review. Diagnostic classifications of epilepsy, ASD, and intellectual disability were performed by board certified neurologists and a pediatric neuropsychologist. Results demonstrated a lower male:female ratio (1.8:1) in individuals with ASD and treatment-resistant epilepsy relative to those with ASD and treatment-responsive epilepsy (4.9:1), indicating a higher risk of treatment-resistant epilepsy in females. Mild neuroimaging abnormalities were more common in females than males and this was associated with increased risk of treatment-resistance. In contrast, ASD symptom severity was lower in females compared with males. Findings distinguish females with ASD and epilepsy as a distinct subgroup at higher risk for a more severe epilepsy phenotype in the context of a less severe ASD phenotype. Increased risk of anti-epileptic treatment resistance in females with ASD and epilepsy suggests that comprehensive genetic, imaging, and neurologic screening and enhanced treatment monitoring may be indicated for this subgroup. Autism Res 2016, 9: 311-320. © 2015 International Society for Autism Research, Wiley Periodicals, Inc. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.

DPP-4 inhibitor des-F-sitagliptin treatment increased insulin exocytosis from db/db mice {beta} cells

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Nagamatsu, Shinya, E-mail: shinya@ks.kyorin-u.ac.jp [Department of Biochemistry, Kyorin University School of Medicine, Mitaka, Tokyo 181-8611 (Japan); Ohara-Imaizumi, Mica; Nakamichi, Yoko; Aoyagi, Kyota; Nishiwaki, Chiyono [Department of Biochemistry, Kyorin University School of Medicine, Mitaka, Tokyo 181-8611 (Japan)

2011-09-09

Highlights: {yields} Anti-diabetic new drug, DPP-4 inhibitor, can affect the insulin exocytosis. {yields} DPP-4 inhibitor treatment altered syntaxin 1 expression. {yields} Treatment of db/db mice with DPP-4 inhibitor increased insulin release. -- Abstract: Incretin promotes insulin secretion acutely. Recently, orally-administered DPP-4 inhibitors represent a new class of anti-hyperglycemic agents. Indeed, inhibitors of dipeptidyl peptidase-IV (DPP-4), sitagliptin, has just begun to be widely used as therapeutics for type 2 diabetes. However, the effects of sitagliptin-treatment on insulin exocytosis from single {beta}-cells are yet unknown. We therefore investigated how sitagliptin-treatment in db/db mice affects insulin exocytosis by treating db/db mice with des-F-sitagliptin for 2 weeks. Perfusion studies showed that 2 weeks-sitagliptin treatment potentiated insulin secretion. We then analyzed insulin granule motion and SNARE protein, syntaxin 1, by TIRF imaging system. TIRF imaging of insulin exocytosis showed the increased number of docked insulin granules and increased fusion events from them during first-phase release. In accord with insulin exocytosis data, des-F-sitagliptin-treatment increased the number of syntaxin 1 clusters on the plasma membrane. Thus, our data demonstrated that 2-weeks des-F-sitagliptin-treatment increased the fusion events of insulin granules, probably via increased number of docked insulin granules and that of syntaxin 1 clusters.

Genetic Deletion of Neuronal PPARγ Enhances the Emotional Response to Acute Stress and Exacerbates Anxiety: An Effect Reversed by Rescue of Amygdala PPARγ Function.

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Domi, Esi; Uhrig, Stefanie; Soverchia, Laura; Spanagel, Rainer; Hansson, Anita C; Barbier, Estelle; Heilig, Markus; Ciccocioppo, Roberto; Ubaldi, Massimo

2016-12-14

PPARγ is one of the three isoforms of the Peroxisome Proliferator-Activated Receptors (PPARs). PPARγ is activated by thiazolidinediones such as pioglitazone and is targeted to treat insulin resistance. PPARγ is densely expressed in brain areas involved in regulation of motivational and emotional processes. Here, we investigated the role of PPARγ in the brain and explored its role in anxiety and stress responses in mice. The results show that stimulation of PPARγ by pioglitazone did not affect basal anxiety, but fully prevented the anxiogenic effect of acute stress. Using mice with genetic ablation of neuronal PPARγ (PPARγ NestinCre ), we demonstrated that a lack of receptors, specifically in neurons, exacerbated basal anxiety and enhanced stress sensitivity. The administration of GW9662, a selective PPARγ antagonist, elicited a marked anxiogenic response in PPARγ wild-type (WT), but not in PPARγ NestinCre knock-out (KO) mice. Using c-Fos immunohistochemistry, we observed that acute stress exposure resulted in a different pattern of neuronal activation in the amygdala (AMY) and the hippocampus (HIPP) of PPARγ NestinCre KO mice compared with WT mice. No differences were found between WT and KO mice in hypothalamic regions responsible for hormonal response to stress or in blood corticosterone levels. Microinjection of pioglitazone into the AMY, but not into the HIPP, abolished the anxiogenic response elicited by acute stress. Results also showed that, in both regions, PPARγ colocalizes with GABAergic cells. These findings demonstrate that neuronal PPARγ is involved the regulation of the stress response and that the AMY is a key substrate for the anxiolytic effect of PPARγ. Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) is a classical target for antidiabetic therapies with thiazolidinedione compounds. PPARγ agonists such as rosiglitazone and pioglitazone are in clinical use for the treatment of insulin resistance. PPARγ has recently attracted

Aeration to degas CO2, increase pH, and increase iron oxidation rates for efficient treatment of net alkaline mine drainage

International Nuclear Information System (INIS)

Kirby, C.S.; Dennis, A.; Kahler, A.

2009-01-01

Passive treatment systems for mine drainage use no energy other than gravity, but they require greater area than active treatment systems. Researchers are considering 'hybrid' systems that have passive and active components for increased efficiency, especially where space limitations render passive-only technology ineffective. Flow-through reactor field experiments were conducted at two large net-alkaline anthracite mine discharges in central Pennsylvania. Assuming an Fe removal rate of 20 g m -2 day -1 and Fe loading from field data, 3.6 x 10 3 and 3.0 x 10 4 m 2 oxidation ponds would be required for the passive treatment of Site 21 and Packer 5 discharges, respectively. However, only a small area is available at each site. This paper demonstrates aeration to drive off CO 2 , increase pH, and increase Fe(II) oxidation rates, enabling treatment within a small area compared to passive treatment methods, and introduces a geochemical model to accurately predict these rates as well as semi-passive treatment system sizing parameters. Both net-alkaline discharges were suboxic with a pH of ∼5.7, Fe(II) concentration of ∼16 mg L -1 , and low Mn and Al concentrations. Flow rates were ∼4000 L min -1 at Site 21 and 15,000 L min -1 at Packer 5. Three-h aeration experiments with flow rates scaled to a 14-L reactor resulted in pH increases from 5.7 to greater than 7, temperature increases from 12 to 22 deg. C, dissolved O 2 increases to saturation with respect to the atmosphere, and Fe(II) concentration decreases from 16 to -1 . A 17,000-L pilot-scale reactor at Site 21 produced similar results although aeration was not as complete as in the smaller reactor. Two non-aerated experiments at Site 21 with 13 and 25-h run times resulted in pH changes of ≤0.2 and Fe(II) concentration decreases of less than 3 mg L -1 . An Fe(II) oxidation model written in a differential equation solver matched the field experiments very well using field-measured pH, temperature, dissolved O 2

Treatment with cinacalcet increases plasma sclerostin concentration in hemodialysis patients with secondary hyperparathyroidism.

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Kuczera, Piotr; Adamczak, Marcin; Więcek, Andrzej

2016-11-15

Sclerostin is a paracrine acting factor, which is expressed in the osteocytes and articular chondrocytes. Sclerostin decreases the osteoblast-related bone formation through the inhibition of the Wnt/β-catenin pathway. Osteocytes also express the Calcium sensing receptor which is a target for cinacalcet. The aim of this study was to assess the influence of six-month cinacalcet treatment on plasma sclerostin concentration in hemodialysed patients with secondary hyperparathyroidism (sHPT). In 58 hemodialysed patients with sHPT (PTH > 300 pg/ml) plasma sclerostin and serum PTH, calcium and phosphate concentrations were assessed before the first dose of cinacalcet and after 3 and 6 months of treatment. Serum PTH concentration decreased after 3 and 6 month of treatment from 1138 (931-1345) pg/ml to 772 (551-992) pg/ml and to 635 (430-839) pg/ml, respectively. Mean serum calcium and phosphate concentrations remained stable. Plasma sclerostin concentration increased after 3 and 6 months of treatment from 1.66 (1.35-1.96) ng/ml, to 1.77 (1.43-2.12) ng/ml and to 1.87 (1.50-2.25) ng/ml, respectively. In 42 patients with cinacalcet induced serum PTH decrease plasma sclerostin concentration increased after 3 and 6 months of treatment from 1.51 (1.19-1.84) ng/ml to 1.59 (1.29-1.89) ng/ml and to 1.75 (1.42-2.01) ng/ml, respectively. Contrary, in the 16 patients without cinacalcet induced serum PTH decrease plasma sclerostin concentration was stable. Plasma sclerostin concentrations correlated inversely with serum PTH concentrations at the baseline and also after 6 months of treatment. 1. In hemodialysed patients with secondary hyperparathyroidism treatment with cinacalcet increases plasma sclerostin concentration 2. This effect seems to be related to decrease of serum PTH concentration.

IGF-1 levels may increase paradoxically with dopamine agonist treatment for prolactinomas.

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Akirov, Amit; Greenman, Yona; Glaser, Benjamin; S'chigol, Irena; Mansiterski, Yossi; Eizenberg, Yoav; Shraga-Slutzky, Ilana; Shimon, Ilan

2018-05-04

Hyperprolactinemia is common in acromegaly and in these patients, insulin-like growth factor (IGF)-1 level may decrease with dopamine agonist. We report a series of patients with prolactinoma and a paradoxical increase of IGF-1 levels during cabergoline treatment. Clinical characteristics and response to treatment of patients with prolactinomas, in whom normal or slightly elevated baseline IGF-1 levels increased with cabergoline. The cohort consisted of ten prolactinoma patients (nine males, mean age 48 ± 14 years). Mean adenoma size was 23.8 ± 16.2 mm, with cavernous sinus invasion in eight. In five patients baseline IGF-1 levels were normal and in four levels were 1.2-1.5-fold the upper limit of the normal (ULN). One patient had IGF-1 measured shortly after initiating cabergoline and it was 1.4 × ULN. During cabergoline treatment (dose range 0.5-2 mg/week) PRL normalization was achieved in all and tumor shrinkage occurred in seven patients. The mean IGF-1 increase on cabergoline was 1.7 ± 0.4 × ULN. Cabergoline dose reduction or interruption was attempted in five patients and resulted in decreased IGF-1 levels in all, including normalization in two patients. Three patients were eventually diagnosed with acromegaly, one was referred for pituitary surgery followed by complete remission, another patient was switched to somatostatin analogue, and the third was treated by combination of somatostatin analogues with pegvisomant, with reduction of IGF-1 in all these patients. IGF-1 levels may increase to clinically significant levels during cabergoline treatment for PRL-adenoma. We suggest IGF-1 monitoring in all patients treated with dopamine agonists and not only in those presenting symptoms of acromegaly.

Erythropoetin treatment can increase 2,3-diphosphoglycerate levels in red blood cells.

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Birgegård, G; Sandhagen, B

2001-01-01

Some patients experience an improved well-being during treatment with recombinant human erythropoietin even with an unchanged Hb level. We have hypothesized that this may not be only a placebo effect. 2,3-diphosphoglycerate (2,3-DPG) in red blood cells increases in response to anaemia/hypoxia and causes a shift of the oxygen dissociation curve, allowing a more effective oxygen delivery. We have investigated red cell 2,3-DPG concentrations during erythropoietin treatment in healthy volunteers as a mediator of a possible physiological explanation. Thirteen healthy subjects with no iron deficiency were recruited and randomly assigned to a treatment group comprising five males and three females and a control group including three males and two females. The treatment group was treated with erythropoietin (Recormon), 20 IE/kg subcutaneously three times/week for 4 weeks. Blood samples were collected at each injection day and 10 days after the last injection and at corresponding times in the control group. B-Hb, red cell 2,3-DPG and P50 were measured by standard techniques and oxygen-releasing capacity was calculated. due to the sampling (26 ml each time, three times/week) the mean Hb level was lowered from 140.5 +/- 5.9 to 128.6 +/- 10.4 g/L in the control group whereas the erythropoietin treatment group maintained a mean Hb level of about 142 g/L (plevel curve as well as that for oxygen releasing capacity also differed significantly between the two groups (p levels. treatment with erythropoietin causes an increase in red cell 2,3-DPG levels.

Pre- and Peri-/Post-Compaction Follistatin Treatment Increases In Vitro Production of Cattle Embryos.

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Guo Zhenhua

Full Text Available Our previous studies demonstrated that maternal (oocyte derived follistatin (FST expression is positively associated with bovine oocyte competence and exogenous follistatin treatment during the pre-compaction period of development (d 1-3 post insemination is stimulatory to bovine early embryogenesis in vitro [blastocyst rates and cell numbers/allocation to trophectoderm (TE]. In the present study, bovine embryos were treated with exogenous follistatin during d 1-3, d 4-7 and d 1-7 post insemination to test the hypothesis that embryotropic effects of exogenous follistatin are specific to the pre-compaction period (d 1-3 of early embryogenesis. Follistatin treatment during d 4-7 (peri-/post-compaction period of embryo culture increased proportion of embryos reaching blastocyst and expanded blastocyst stage and total cell numbers compared to controls, but blastocyst rates and total cell numbers were lower than observed following d 1-3 (pre-compaction follistatin treatment. Follistatin supplementation during d 1-7 of embryo culture increased development to blastocyst and expanded blastocyst stages and blastocyst total cell numbers compared to d 1-3 and d 4-7 follistatin treatment and untreated controls. A similar increase in blastocyst CDX2 mRNA and protein (TE cell marker was observed in response to d 1-3, d 4-7 and d 1-7 follistatin treatment. However, an elevation in blastocyst BMP4 protein (TE cell regulator was observed in response to d 1-3 and d 1-7, but not d 4-7 (peri-/post-compaction follistatin treatment. In summary, our study revealed the potential utility of follistatin treatment for increasing the success rate of in vitro embryo production in cattle. Such results also expand our understanding of the embryotropic actions of follistatin and demonstrate that follistatin actions on blastocyst development and cell allocation to the TE layer are not specific to the pre-compaction period.

Increasing the efficacy of cue exposure treatment in preventing relapse of addictive behavior.

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Havermans, Remco C; Jansen, Anita T M

2003-07-01

Theoretically, cue exposure treatment should be able to prevent relapse by extinguishing conditioned drug responding (e.g. cue-elicited craving). According to contemporary learning theory, though, extinction does not eliminate conditioned responding. Analogous cue exposure with response prevention (CERP) as a treatment of addictive behavior might not eliminate the learned relation between drug-related cues and drug use. This does not necessarily mean that cue exposure cannot successfully prevent relapse. Various suggestions for increasing the efficacy of cue exposure treatment are being discussed from a contemporary learning theory perspective. It is suggested that cue exposure treatment incorporating retrieval cues can be a beneficial treatment in preventing relapse of addictive behavior.

Increased incidence of bowel cancer after non-surgical treatment of appendicitis.

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Enblad, Malin; Birgisson, Helgi; Ekbom, Anders; Sandin, Fredrik; Graf, Wilhelm

2017-11-01

There is an ongoing debate on the use of antibiotics instead of appendectomy for treating appendicitis but diagnostic difficulties and longstanding inflammation might lead to increased incidence of bowel cancer in these patients. The aim of this population-based study was to investigate the incidence of bowel cancer after non-surgical treatment of appendicitis. Patients diagnosed with appendicitis but lacking the surgical procedure code for appendix removal were retrieved from the Swedish National Inpatient Register 1987-2013. The cohort was matched with the Swedish Cancer Registry and the standardised incidence ratios (SIR) with 95% confidence interval (95% CI) for appendiceal, colorectal and small bowel cancers were calculated. Of 13 595 patients with non-surgical treatment of appendicitis, 352 (2.6%) were diagnosed with appendiceal, colorectal or small bowel cancer (SIR 4.1, 95% CI 3.7-4.6). The largest incidence increase was found for appendiceal (SIR 35, 95% CI 26-46) and right-sided colon cancer (SIR 7.5, 95% CI 6.6-8.6). SIR was still elevated when excluding patients with less than 12 months since appendicitis and the incidence of right-sided colon cancer was elevated five years after appendicitis (SIR 3.5, 95% CI 2.1-5.4). An increased incidence of bowel cancer was found after appendicitis with abscess (SIR 4.6, 95% CI 4.0-5.2), and without abscess (SIR 3.5, 95% CI 2.9-4.1). Patients with non-surgical treatment of appendicitis have an increased short and long-term incidence of bowel cancer. This should be considered in the discussion about optimal management of patients with appendicitis. Copyright © 2017 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

[Rhein promotes the expression of SIRT1 in kidney tissues of type 2 diabetic rat].

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Chen, Weidong; Chang, Baochao; Zhang, Yan; Yang, Ping; Liu, Lei

2015-05-01

To observe the effect of rhein on the expression of SIRT1(Sirtuin 1) in kidney of diabetic rats, and to explore the role of rhein in protecting rat kidney against diabetic nephropathy and possible mechanism. The type 2 diabetic rats were induced by high-glucose and high-fat diet combined with streptozotocin (35 mg/kg body mass). Seventy-five eight-week-old male SD rats were randomly divided into 6 groups: normal group, diabetic group, low-, medium- and high-dose (50, 100, 150 mg/kg) rhein treatment groups and 10 mg/kg pioglitazone treatment group. The rats were given corresponding substances intragastrically once a day. At the end of the 16th week, the fasting plasma glucose (FPG), fasting insulin (FINS), triglycerides (TG), total cholesterol (TC), serum creatinine (Scr) and 24 hours urine protein (24 h U-PRO) were determined. The renal hypertrophy index (KM/BM), insulin resistance index (HOMA-IR) were calculated. The pathological changes in renal tissues were examined by PAS staining under a light microscopy. The mean glomerular area (MGA) and mean glomerular volume (MGV) were measured by pathological image analysis system. Western blotting and real-time quantitative PCR were used to determine the expression of SIRT1 in renal tissues at protein and mRNA levels, respectively. The expression of SIRT1 was down-regulated in the kidney of diabetic rats. The levels of FPG, FINS, HOMA-IR, TG, TC, Scr, 24 h U-PRO, KM/BM, MGA and MGV significantly decreased and the histopathology of renal tissues were significantly improved in all treatment groups compared with diabetic group. The expression of SIRT1 mRNA and protein markedly increased in rhein treatment groups and pioglitazone treatment group compared with diabetic group. The indicators in high-dose rhein treatment group were improved more significantly than those in the other groups. Correlation analysis showed that the expression of SIRT1 was negatively correlated with 24 h U-PRO and MGV. The expression of SIRT1 was

Increased Mindfulness Skills as Predictors of Reduced Trauma-Related Guilt in Treatment-Seeking Veterans.

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Held, Philip; Owens, Gina P; Monroe, J Richard; Chard, Kathleen M

2017-08-01

The present study examined the predictive role of increased self-reported mindfulness skills on reduced trauma-related guilt in a sample of veterans over the course of residential treatment for posttraumatic stress disorder (PTSD; N = 128). The residential treatment consisted of seven weeks of intensive cognitive processing therapy (CPT) for PTSD, as well as additional psychoeducational groups, including seven sessions on mindfulness skills. Increased mindfulness skills describing, acting with awareness, and accepting without judgment were significantly associated with reductions in trauma-related guilt over the course of treatment. Increases in the ability to act with awareness and accept without judgment were significantly associated with reductions in global guilt, R 2 = .26, guilt distress, R 2 = .23, guilt cognitions, R 2 = .23, and lack of justification, R 2 = .11. An increase in the ability to accept without judgment was the only self-reported mindfulness skill that was associated with reductions in hindsight bias, β = -.34 and wrongdoing, β = -.44. Increases in self-reported mindfulness skills explained 15.1 to 24.1% of the variance in reductions in trauma-related guilt, suggesting that mindfulness skills may play a key role in reducing the experience of trauma-related guilt during psychotherapy. Our results provide preliminary support for the use of mindfulness groups as an adjunct to traditional evidence-based treatments aimed at reducing trauma-related guilt, though this claim needs to be tested further using experimental designs. Copyright © 2017 International Society for Traumatic Stress Studies.

Increase of Long-chain Branching by Thermo-oxidative Treatment of LDPE

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Rolón-Garrido, Víctor H.; Luo, Jinji; Wagner, Manfred H.

2011-07-01

Low-density polyethylene (LDPE) was exposed to thermal and thermo-oxidative treatment at 170 °C, and subsequently characterized by linear-viscoelastic measurements and in uniaxial extension. The Molecular Stress Function (MSF) model was used to quantify the elongational viscosities measured. For the thermally treated samples, exposure times between 2 and 6 hours were applied. Formation of long-chain branching (LCB) was found to occur only during the first two hours of thermal treatment. At longer exposure times, no difference in the level of strain hardening was observed. This was quantified by use of the MSF model: the nonlinear parameter fmax2 increased from fmax2 = 14 for the virgin sample to fmax2 = 22 for the samples thermally treated between 2 and 6 hours. For the thermo-oxidatively treated samples, which were exposed to air during thermal treatment between 30 and 90 minutes, the level of strain hardening increases drastically up to fmax2 = 55 with increasing exposure times from 30 up to 75 min due to LCB formation, and then decreases for an exposure time of 90 minutes due to chain scission dominating LCB formation. The nonlinear parameter β of the MSF model was found to be β = 2 for all samples, indicating that the general type of the random branching structure remains the same under all thermal conditions. Consequently only the parameter fmax2 of the MSF model and the linear-viscoelastic spectra were required to describe quantitatively the experimental observations. The strain hardening index, which is sometimes used to quantify strain hardening, follows accurately the trend of the MSF model parameter fmax2.

Treatment with antidepressants and lithium is associated with increased risk of treatment with antiparkinson drugs: a pharmacoepidemiological study

DEFF Research Database (Denmark)

Brandt-Christensen, Anne Mette; Kvist, Tine Kajsa; Nielsen, F.M.

2006-01-01

OBJECTIVE: To estimate the risk for persons treated with antidepressants or lithium of subsequent treatment with antiparkinson drugs (APD). METHODS: The Danish national prescription database supplied data on all persons who received antidepressants, lithium, or antidiabetics (first control group......). A second control group was included comprising persons from the general population. Outcome was purchase of APD and the study period was 1995 to 1999. RESULTS: In total, 1 293 789 persons were included. The rate ratio of treatment with APD after treatment with antidepressants was 2.27 (95% CI 2.14 to 2.......42) for men and 1.50 (95% CI 1.43 to 1.58) for women. Figures for lithium were almost identical. CONCLUSION: Persons treated with antidepressants or lithium are at increased risk of subsequently treatment with APD, showing an association between anxiety/affective disorder and Parkinson's disease....

Free ammonia pre-treatment of secondary sludge significantly increases anaerobic methane production.

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Wei, Wei; Zhou, Xu; Wang, Dongbo; Sun, Jing; Wang, Qilin

2017-07-01

Energy recovery in the form of methane from sludge/wastewater is restricted by the poor and slow biodegradability of secondary sludge. An innovative pre-treatment technology using free ammonia (FA, i.e. NH 3 ) was proposed in this study to increase anaerobic methane production. The solubilisation of secondary sludge was significantly increased after FA pre-treatment at up to 680 mg NH 3 -N/L for 1 day, under which the solubilisation (i.e. 0.4 mg SCOD/mg VS; SCOD: soluble chemical oxygen demand; VS: volatile solids) was >10 times higher than that without FA pre-treatment (i.e. 0.03 mg SCOD/mg VS). Biochemical methane potential assays showed that FA pre-treatment at above 250 mg NH 3 -N/L is effective in improving anaerobic methane production. The highest improvement in biochemical methane potential (B 0 ) and hydrolysis rate (k) was achieved at FA concentrations of 420-680 mg NH 3 -N/L, and was determined as approximately 22% (from 160 to 195 L CH 4 /kg VS added) and 140% (from 0.22 to 0.53 d -1 ) compared to the secondary sludge without pre-treatment. More analysis revealed that the FA induced improvement in B 0 and k could be attributed to the rapidly biodegradable substances rather than the slowly biodegradable substances. Economic and environmental analyses showed that the FA-based technology is economically favourable and environmentally friendly. Since this FA technology aims to use the wastewater treatment plants (WWTPs) waste (i.e. anaerobic digestion liquor) to enhance methane production from the WWTPs, it will set an example for the paradigm shift of the WWTPs from 'linear economy' to 'circular economy'. Copyright © 2017 Elsevier Ltd. All rights reserved.

A Very Simple and Sensitive Spectrofluorimetric Method Based on the Oxidation with Cerium (IV for the Determination of Four Different Drugs in Their Pharmaceutical Formulations

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Ahad Bavili-Tabrizi, Farshad Bahrami, Hossein Badrouj

2017-03-01

Full Text Available Background: Methyldopa is a catecholamine widely used as an antihypertensive agent. Pioglitazone is an oral anti-hyperglycemic agent. It is used for the treatment of diabetes mellitus type 2. A survey of the literature reveals that only one spectrofluorimetric method has been reported for the determination of pioglitazone in pharmaceutical preparations. Atenolol and metoprolol are prescription drugs of the β-blocker class with hypotensive action to treat angina, MI, alcohol syndrome, hypertension, and arrhythmias. A survey of the literature reveals that several spectrofluorimetric methods have been reported for the determination of atenolol and metoprolol in pharmaceutical preparations. In continuing of our studies on the developing of simple and fast spectrofluorimetric methods for determination of drugs and active ingredients, in this work we have developed a spectrofluorimetric method based on the oxidation with cerium (IV for the determination of studied drugs in their pharmaceutical formulations. Methods: A simple, rapid and sensitive spectrofluorimetric method was developed for the determination of studied drugs in pharmaceutical formulations. Proposed method is based on the oxidation of these drugs with Ce (IV to produce Ce (III, and its fluorescence was monitored at 356 ± 3 nm after excitation at 254 ± 3 nm. Results: The variables affecting oxidation of each drug were studied and optimized. Under the experimental conditions used, the calibration graphs were linear over the range of 25-450, 50-550, 15-800 and 15-800 ng/mL in the case of atenolol, metoprolol, pioglitazone and methyldopa, respectively. The limit of detection was found to be 8.27, 16.5, 1.52 and 5.08 ng/mL in the case of atenolol, metoprolol, pioglitazone and methyldopa, respectively. Intra- and inter-day assay precisions, expressed as the relative standard deviation (RSD, were lower than 3% in all cases. Conclusion: The proposed method was applied to the determination of

Increasing consumer demand for tobacco treatments: Ten design recommendations for clinicians and healthcare systems.

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Woods, Susan Swartz; Jaén, Carlos Roberto

2010-03-01

Health professionals play an important role in addressing patient tobacco use in clinical settings. While there is clear evidence that identifying tobacco use and assisting smokers in quitting affects outcomes, challenges to improve routine, clinician-delivered tobacco intervention persist. The Consumer Demand Initiative has identified simple design principles to increase consumers' use of proven tobacco treatments. Applying these design strategies to activities across the healthcare system, we articulate ten recommendations that can be implemented in the context of most clinical systems where most clinicians work. The recommendations are: (1) reframe the definition of success, (2) portray proven treatments as the best care, (3) redesign the 5A's of tobacco intervention, (4) be ready to deliver the right treatment at the right time, (5) move tobacco from the social history to the problem list, (6) use words as therapy and language that makes sense, (7) fit tobacco treatment into clinical team workflows, (8) embed tobacco treatment into health information technology, (9) make every encounter an opportunity to intervene, and (10) end social disparities for tobacco users. Clinical systems need to change to improve tobacco treatment implementation. The consumer- and clinician-centered recommendations provide a roadmap that focuses on increasing clinician performance through greater understanding of the clinician's role in helping tobacco users, highlighting the value of evidence-based tobacco treatments, employing shared decision-making skills, and integrating routine tobacco treatment into clinical system routines. Published by Elsevier Inc.

Anti-inflammatory agents in the treatment of bipolar depression: a systematic review and meta-analysis.

Science.gov (United States)

Rosenblat, Joshua D; Kakar, Ron; Berk, Michael; Kessing, Lars V; Vinberg, Maj; Baune, Bernhard T; Mansur, Rodrigo B; Brietzke, Elisa; Goldstein, Benjamin I; McIntyre, Roger S

2016-03-01

Inflammation has been implicated in the risk, pathophysiology, and progression of mood disorders and, as such, has become a target of interest in the treatment of bipolar disorder (BD). Therefore, the objective of the current qualitative and quantitative review was to determine the overall antidepressant effect of adjunctive anti-inflammatory agents in the treatment of bipolar depression. Completed and ongoing clinical trials of anti-inflammatory agents for BD published prior to 15 May 15 2015 were identified through searching the PubMed, Embase, PsychINFO, and Clinicaltrials.gov databases. Data from randomized controlled trials (RCTs) assessing the antidepressant effect of adjunctive mechanistically diverse anti-inflammatory agents were pooled to determine standard mean differences (SMDs) compared with standard therapy alone. Ten RCTs were identified for qualitative review. Eight RCTs (n = 312) assessing adjunctive nonsteroidal anti-inflammatory drugs (n = 53), omega-3 polyunsaturated fatty acids (n = 140), N-acetylcysteine (n = 76), and pioglitazone (n = 44) in the treatment of BD met the inclusion criteria for quantitative analysis. The overall effect size of adjunctive anti-inflammatory agents on depressive symptoms was -0.40 (95% confidence interval -0.14 to -0.65, p = 0.002), indicative of a moderate and statistically significant antidepressant effect. The heterogeneity of the pooled sample was low (I² = 14%, p = 0.32). No manic/hypomanic induction or significant treatment-emergent adverse events were reported. Overall, a moderate antidepressant effect was observed for adjunctive anti-inflammatory agents compared with conventional therapy alone in the treatment of bipolar depression. The small number of studies, diversity of agents, and small sample sizes limited interpretation of the current analysis. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Rapamycin treatment is associated with an increased apoptosis rate in experimental vein grafts.

Science.gov (United States)

Schachner, Thomas; Oberhuber, Alexander; Zou, Yping; Tzankov, Alexandar; Ott, Harald; Laufer, Günther; Bonatti, Johannes

2005-02-01

Rapamycin is an immunosuppressive agent with marked antiproliferative properties and is effective in reducing in stent restenosis and vein graft neointimal hyperplasia. Apoptosis is one mechanism counterbalancing cellular proliferation. We therefore investigated the role of apoptosis in rapamycin treated vein grafts in a mouse model. C57BL6J mice underwent interposition of the inferior vena cava from isogenic donor mice into the common carotid artery using a cuff technique. In the treatment group 200 microg of rapamycin were applied locally in pluronic gel. The control group did not receive local treatment. Vein grafts were harvested at 4 weeks postoperatively and underwent morphometric analysis as well as immunohistochemical analysis for apoptosis (TUNEL). In grafted veins without treatment (controls) neointimal thickness was 50 (12-58) microm at 4 weeks postoperatively. In 200 microg rapamycin treated grafts the neointimal thickness was 17 (5-55) microm. Rapamycin treated vein grafts showed a significantly increased rate of apoptosis in the adventitia as compared with controls (P=0.032). In the neointima the apoptosis rate was lower in both groups with no significant difference between rapamycin treated grafts and controls. We conclude that treatment of experimental vein grafts with rapamycin is associated with an increased apoptosis rate in the vascular wall and a trend towards reduction of neointimal hyperplasia. These results suggest that apoptosis may be a beneficial antiproliferative component for the treatment of vein graft disease.

Antisense pre-treatment increases gene therapy efficacy in dystrophic muscles.

Science.gov (United States)

Peccate, Cécile; Mollard, Amédée; Le Hir, Maëva; Julien, Laura; McClorey, Graham; Jarmin, Susan; Le Heron, Anita; Dickson, George; Benkhelifa-Ziyyat, Sofia; Piétri-Rouxel, France; Wood, Matthew J; Voit, Thomas; Lorain, Stéphanie

2016-08-15

In preclinical models for Duchenne muscular dystrophy, dystrophin restoration during adeno-associated virus (AAV)-U7-mediated exon-skipping therapy was shown to decrease drastically after six months in treated muscles. This decline in efficacy is strongly correlated with the loss of the therapeutic AAV genomes, probably due to alterations of the dystrophic myofiber membranes. To improve the membrane integrity of the dystrophic myofibers at the time of AAV-U7 injection, mdx muscles were pre-treated with a single dose of the peptide-phosphorodiamidate morpholino (PPMO) antisense oligonucleotides that induced temporary dystrophin expression at the sarcolemma. The PPMO pre-treatment allowed efficient maintenance of AAV genomes in mdx muscles and enhanced the AAV-U7 therapy effect with a ten-fold increase of the protein level after 6 months. PPMO pre-treatment was also beneficial to AAV-mediated gene therapy with transfer of micro-dystrophin cDNA into muscles. Therefore, avoiding vector genome loss after AAV injection by PPMO pre-treatment would allow efficient long-term restoration of dystrophin and the use of lower and thus safer vector doses for Duchenne patients. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

SSRI treatment suppresses dream recall frequency but increases subjective dream intensity in normal subjects.

Science.gov (United States)

Pace-Schott, E F; Gersh, T; Silvestri, R; Stickgold, R; Salzman, C; Hobson, J A

2001-06-01

Clinical lore and a small number of published studies report that the selective serotonin reuptake inhibitors (SSRIs) intensify dreaming. This study examines the dream effects of paroxetine and fluvoxamine in order to both increase clinical knowledge of these agents and to test an important potential method for probing the relationship between REM sleep neurobiology and dreaming in humans. Fourteen normal, paid volunteers (4 males, 10 females; mean age 27.4 year, range 22--39) free of medical or neuropsychiatric symptoms as well as of psychotropic or sleep affecting drugs completed a 31-day home-based study consisting of: 7 days drug-free baseline; 19 days on either 100 mg fluvoxamine (7 Ss) or 20 mg paroxetine (7 Ss) in divided morning and evening doses; and 5 days acute discontinuation. Upon awakening, subjects wrote dream reports, self-scored specific emotions in their reports and rated seven general dream characteristics using 5-point Likert scales. Dream reports were independently scored for bizarreness, movement and number of visual nouns by three judges. REM sleep-related measures were obtained using the Nightcap ambulatory sleep monitor. Mean dream recall frequency decreased during treatment compared with baseline. Dream report length and judge-rated bizarreness were greater during acute discontinuation compared with both baseline and treatment and this effect was a result of the fluvoxamine-treated subjects. The subjective intensity of dreaming increased during both treatment and acute discontinuation compared with baseline. Propensity to enter REM sleep was decreased during treatment compared with baseline and acute discontinuation and the intensity of REM sleep increased during acute discontinuation compared with baseline and treatment. The decrease in dream frequency during SSRI treatment may reflect serotonergic REM suppression while the augmented report length and bizarreness during acute SSRI discontinuation may reflect cholinergic rebound from

Continuous positive airway pressure treatment increases bronchial reactivity in obstructive sleep apnea patients.

Science.gov (United States)

Korczynski, Piotr; Gorska, Katarzyna; Przybylowski, Tadeusz; Bielicki, Piotr; Zielinski, Jan; Chazan, Ryszarda

2009-01-01

The effects of continuous positive airway pressure (CPAP) treatment on the function of the lower airways are poorly understood. One of the methods used to determine the influence of positive pressure breathing on lower airways is the bronchial hyperreactivity test. Some authors report that CPAP increases bronchial hyperreactivity, while others report decreases. To assess the influence of CPAP treatment on bronchial reactivity and the effects of bronchial hyperreactivity on compliance to CPAP treatment. The study group consisted of 101 obstructive sleep apnea syndrome patients (88 men and 13 women) with a mean age of 51 ± 11 years, mean apnea-hypopnea index of 53 ± 20 and mean body mass index of 32.6 ± 5.4. Patients were randomly assigned to a treatment group that received 3 weeks of CPAP therapy (group 1) or to a nontreatment control group (group 2). Pulmonary function tests and the methacholine bronchial provocation test were performed at baseline and 3 weeks later. There were no statistically significant differences between treated and control groups in anthropometry and polysomnography variables. At baseline, bronchial hyperreactivity was found in 6 patients from group 1 and 5 patients from group 2. A significant increase in bronchial reactivity was observed after CPAP treatment. Log PC20M decreased from 1.38 ± 0.30 at baseline to 1.26 ± 0.50 (p bronchial hyperreactivity during CPAP treatment were characterized by significantly lower FEV1, FVC and MEF50 values. CPAP produces statistically significant bronchial hyperreactivity. However, there were no clinical symptoms and it is not necessary to withdraw previous therapies. Copyright © 2009 S. Karger AG, Basel.

Does fertility treatment increase the risk of uterine cancer? A meta-analysis.

Science.gov (United States)

Saso, Srdjan; Louis, Louay S; Doctor, Farah; Hamed, Ali Hassan; Chatterjee, Jayanta; Yazbek, Joseph; Bora, Shabana; Abdalla, Hossam; Ghaem-Maghami, Sadaf; Thum, Meen-Yau

2015-12-01

An ongoing debate over the last two decades has focused on whether fertility treatment in women may lead to an increased risk of developing uterine cancer over a period of time. Uterine cancer (including mainly endometrial carcinoma and the less common uterine sarcoma) is the commonest reproductive tract cancer and the fourth commonest cancer in women in the UK. Our objective was to assess the association between fertility drugs used in the treatment of female infertility (both as an independent therapy and during in vitro fertilization cycles) and the development of uterine cancer. A literature search was performed using Medline, Embase, Cochrane Library and Google Scholar databases for comparative studies until December 2014 to investigate a clinical significance of fertility treatment on the incidence of developing uterine cancer. General and MESH search headings, as well as the 'related articles' function were applied. All comparative studies of 'fertility treatment' versus 'non-fertility treatment' reporting the incidence of uterine cancer as an outcome were included. Uterine cancer incorporated the following terms: uterine cancer, uterine body tumours, uterine sarcomas and endometrial cancers. The primary outcome of interest was the uterine cancer incidence in all 'fertility treatment' versus 'non-fertility treatment' patient groups. Secondary outcomes of interest were: (a) uterine cancer incidence in 'IVF' versus 'non-IVF' patient groups; and (b) uterine cancer incidence according to type of fertility drug used. Odds ratio was the summary statistic. Random-effects modelling, graphical exploration and sensitivity analysis were used to evaluate the consistency of the calculated treatment effect. We included six studies in our final analysis, which comprised 776,224 patients in total. Of these, 103,758 had undergone fertility treatment and 672,466 had not. There was 100% agreement between the two reviewers regarding the data extraction. All the studies

Mood stabilizer treatment increases serotonin type 1A receptor binding in bipolar depression

Science.gov (United States)

Nugent, Allison C; Carlson, Paul J; Bain, Earle E; Eckelman, William; Herscovitch, Peter; Manji, Husseini; Zarate, Carlos A; Drevets, Wayne C

2013-01-01

Abnormal serotonin type 1A (5-HT1A) receptor function and binding have been implicated in the pathophysiology of mood disorders. Preclinical studies have consistently shown that stress decreases the gene expression of 5-HT1A receptors in experimental animals, and that the associated increase in hormone secretion plays a crucial role in mediating this effect. Chronic administration of the mood stabilizers lithium and divalproex (valproate semisodium) reduces glucocorticoid signaling and function in the hippocampus. Lithium has further been shown to enhance 5-HT1A receptor function. To assess whether these effects translate to human subject with bipolar disorder (BD), positron emission tomography (PET) and [18F]trans-4-fluoro-N-(2-[4-(2-methoxyphenyl) piperazino]-ethyl)-N-(2-pyridyl) cyclohexanecarboxamide ([18F]FCWAY) were used to acquire PET images of 5-HT1A receptor binding in 10 subjects with BD, before and after treatment with lithium or divalproex. Mean 5-HT1A binding potential (BPP) significantly increased following mood stabilizer treatment, most prominently in the mesiotemporal cortex (hippocampus plus amygdala). When mood state was also controlled for, treatment was associated with increases in BPP in widespread cortical areas. These preliminary findings are consistent with the hypothesis that these mood stabilizers enhance 5-HT1A receptor expression in BD, which may underscore an important component of these agents' mechanism of action. PMID:23926239

Risperidone treatment increases CB1 receptor binding in rat brain

DEFF Research Database (Denmark)

Secher, Anna; Husum, Henriette; Holst, Birgitte

2010-01-01

, the ghrelin receptor, neuropeptide Y, adiponectin and proopiomelanocortin. We investigated whether the expression of these factors was affected in rats chronically treated with the antipsychotic risperidone. METHODS: Male Sprague-Dawley rats were treated with risperidone (1.0 mg/kg/day) or vehicle (20...... showed that risperidone treatment altered CB(1) receptor binding in the rat brain. Risperidone-induced adiposity and metabolic dysfunction in the clinic may be explained by increased CB(1) receptor density in brain regions involved in appetite and regulation of metabolic function....

Patient education in groups increases knowledge of osteoporosis and adherence to treatment

DEFF Research Database (Denmark)

Nielsen, Dorthe; Ryg, Jesper; Nielsen, Winnie

2010-01-01

OBJECTIVE: Non-adherence to pharmacological treatment in osteoporosis is a well-recognized problem. We hypothesized that a group-based educational programme would increase patients' knowledge and level of adherence with medical treatment. METHODS: A total of 300 patients (32 men aged 65 ± 9 years...... and 268 women aged 63 ± 8 years), recently diagnosed with osteoporosis, were randomised to either an osteoporosis school programme (four classes of 8-12 participants over four weeks) or a control group. Teaching was multidisciplinary, based on patients' experiences and background and designed to encourage...... empowerment. Patients' knowledge about osteoporosis and adherence to treatment was assessed with self-completed questionnaires at baseline and after 3, 12, and 24 months. RESULTS: There were no significant differences at baseline between the two groups with respect to knowledge score or level of adherence...

No Increased Risk of Cancer after Coal Tar Treatment in Patients with Psoriasis or Eczema

NARCIS (Netherlands)

Roelofzen, Judith H. J.; Aben, Katja K. H.; Oldenhof, Ursula T. H.; Coenraads, Pieter-Jan; Alkemade, Hans A.; van de Kerkhof, Peter C. M.; van der Valk, Pieter G. M.; Kiemeney, Lambertus A. L. M.

Coal tar is an effective treatment for psoriasis and eczema, but it contains several carcinogenic compounds. Occupational and animal studies have shown an increased risk of cancer after exposure to coal tar. Many dermatologists have abandoned this treatment for safety reasons, although the risk of

A daily SMS reminder increases adherence to asthma treatment: a three-month follow-up study

DEFF Research Database (Denmark)

Strandbygaard, Ulla; Thomsen, Simon Francis; Backer, Vibeke

2010-01-01

Poor adherence to asthma treatment is a well-recognised challenge and is associated with increased morbidity, mortality and consumption of health care resources. This study examined the impact of receiving a daily text message reminder on one's cell phone on adherence to asthma treatment....

Healthcare financing systems for increasing the use of tobacco dependence treatment.

Science.gov (United States)

van den Brand, Floor A; Nagelhout, Gera E; Reda, Ayalu A; Winkens, Bjorn; Evers, Silvia M A A; Kotz, Daniel; van Schayck, Onno Cp

2017-09-12

Tobacco smoking is the leading preventable cause of death worldwide, which makes it essential to stimulate smoking cessation. The financial cost of smoking cessation treatment can act as a barrier to those seeking support. We hypothesised that provision of financial assistance for people trying to quit smoking, or reimbursement of their care providers, could lead to an increased rate of successful quit attempts. This is an update of the original 2005 review. The primary objective of this review was to assess the impact of reducing the costs for tobacco smokers or healthcare providers for using or providing smoking cessation treatment through healthcare financing interventions on abstinence from smoking. The secondary objectives were to examine the effects of different levels of financial support on the use or prescription of smoking cessation treatment, or both, and on the number of smokers making a quit attempt (quitting smoking for at least 24 hours). We also assessed the cost effectiveness of different financial interventions, and analysed the costs per additional quitter, or per quality-adjusted life year (QALY) gained. We searched the Cochrane Tobacco Addiction Group Specialised Register in September 2016. We considered randomised controlled trials (RCTs), controlled trials and interrupted time series studies involving financial benefit interventions to smokers or their healthcare providers, or both. Two reviewers independently extracted data and assessed the quality of the included studies. We calculated risk ratios (RR) for individual studies on an intention-to-treat basis and performed meta-analysis using a random-effects model. In the current update, we have added six new relevant studies, resulting in a total of 17 studies included in this review involving financial interventions directed at smokers or healthcare providers, or both.Full financial interventions directed at smokers had a favourable effect on abstinence at six months or longer when compared

Short-term dehydroepiandrosterone treatment increases platelet cGMP production in elderly male subjects.

Science.gov (United States)

Martina, Valentino; Benso, Andrea; Gigliardi, Valentina Ramella; Masha, Andi; Origlia, Carla; Granata, Riccarda; Ghigo, Ezio

2006-03-01

Several clinical and population-based studies suggest that dehydroepiandrosterone (DHEA) and its sulphate (DHEA-S) play a protective role against atherosclerosis and coronary artery disease in human. However, the mechanisms underlying this action are still unknown. It has recently been suggested that DHEA-S could delay atheroma formation through an increase in nitric oxide (NO) production. Twenty-four aged male subjects [age (mean +/- SEM): 65.4 +/- 0.7 year; range: 58.2-67.6 years] underwent a blinded placebo controlled study receiving DHEA (50 mg p.o. daily at bedtime) or placebo for 2 months. Platelet cyclic guanosine-monophosphate (cGMP) concentration (as marker of NO production) and serum levels of DHEA-S, DHEA, IGF-I, insulin, glucose, oestradiol (E(2)), testosterone, plasminogen activator inhibitor (PAI)-1 antigen (PAI-1 Ag), homocysteine and lipid profile were evaluated before and after the 2-month treatment with DHEA or placebo. At the baseline, all variables in the two groups were overlapping. All parameters were unchanged after treatment with placebo. Conversely, treatment with DHEA (a) increased (P < 0.001 vs. baseline) platelet cGMP (111.9 +/- 7.1 vs. 50.1 +/- 4.1 fmol/10(6) plts), DHEA-S (13.6 +/- 0.8 vs. 3.0 +/- 0.3 micromol/l), DHEA (23.6 +/- 1.7 vs. 15.3 +/- 1.4 nmol/l), testosterone (23.6 +/- 1.0 vs. 17.7 +/- 1.0 nmol/l) and E(2) (72.0 +/- 5.0 vs. 60.0 +/- 4.0 pmol/l); and (b) decreased (P < 0.05 vs. baseline) PAI-1 Ag (27.4 +/- 3.8 vs. 21.5 +/- 2.5 ng/ml) and low-density lipoprotein (LDL) cholesterol (3.4 +/- 0.2 vs. 3.0 +/- 0.2 mmol/l). IGF-I, insulin, glucose, triglycerides, total cholesterol, HDL cholesterol, HDL2 cholesterol, HDL3 cholesterol, apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB) and homocysteine levels were not modified by DHEA treatment. This study shows that short-term treatment with DHEA increased platelet cGMP production, a marker of NO production, in healthy elderly subjects. This effect is coupled with a decrease in PAI-1

Gas Plasma Pre-treatment Increases Antibiotic Sensitivity and Persister Eradication in Methicillin-Resistant Staphylococcus aureus

Science.gov (United States)

Guo, Li; Xu, Ruobing; Zhao, Yiming; Liu, Dingxin; Liu, Zhijie; Wang, Xiaohua; Chen, Hailan; Kong, Michael G.

2018-01-01

Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of serious nosocomial infections, and recurrent MRSA infections primarily result from the survival of persister cells after antibiotic treatment. Gas plasma, a novel source of ROS (reactive oxygen species) and RNS (reactive nitrogen species) generation, not only inactivates pathogenic microbes but also restore the sensitivity of MRSA to antibiotics. This study further found that sublethal treatment of MRSA with both plasma and plasma-activated saline increased the antibiotic sensitivity and promoted the eradication of persister cells by tetracycline, gentamycin, clindamycin, chloramphenicol, ciprofloxacin, rifampicin, and vancomycin. The short-lived ROS and RNS generated by plasma played a primary role in the process and induced the increase of many species of ROS and RNS in MRSA cells. Thus, our data indicated that the plasma treatment could promote the effects of many different classes of antibiotics and act as an antibiotic sensitizer for the treatment of antibiotic-resistant bacteria involved in infectious diseases. PMID:29628915

The potential impact of increased treatment rates for alcohol dependence in the United Kingdom in 2004.

Science.gov (United States)

Shield, Kevin D; Rehm, Jürgen; Rehm, Maximilien X; Gmel, Gerrit; Drummond, Colin

2014-02-05

Alcohol consumption has been linked to a considerable burden of disease in the United Kingdom (UK), with most of this burden due to heavy drinking and Alcohol Dependence (AD). However, AD is undertreated in the UK, with only 8% of those individuals with AD being treated in England and only 6% of those individuals with AD being treated in Scotland. Thus, the objective of this paper is to quantify the deaths that would have been avoided in the UK in 2004 if the treatment rate for AD had been increased. Data on the prevalence of AD, alcohol consumption, and mortality were obtained from the Adult Psychiatric Morbidity Survey, the Global Information System on Alcohol and Health, and the 2004 Global Burden of Disease study respectively. Data on the effectiveness of pharmacological treatment and Motivational Interviewing/Cognitive Behavioural Therapy were obtained from Cochrane reviews and meta-analyses. Simulations were used to model the number of deaths under different treatment scenarios. Sensitivity analyses were performed to model the effects of Brief Interventions and to examine the effect of using AD prevalence data obtained from the National Institute for Health and Clinical Excellence. In the UK, 320 female and 1,385 male deaths would have been avoided if treatment coverage of pharmacological treatment had been increased to 20%. This decrease in the number of deaths represents 7.9% of all alcohol-attributable deaths (7.0% of all alcohol-attributable deaths for women and 8.1% of all alcohol-attributable deaths for men). If we used lower AD prevalence rates obtained from the National Institute for Health and Clinical Excellence, then treatment coverage of pharmacological treatment in hospitals for 20% of the population with AD would have resulted in the avoidance of 529 deaths in 2004 (99 deaths avoided for women and 430 deaths avoided for men). Increasing AD treatment in the UK would have led to a large number of deaths being avoided in 2004. Increased AD

Treatment update: thiazolidinediones in combination with metformin for the treatment of type 2 diabetes

Directory of Open Access Journals (Sweden)

John M Stafford

2007-10-01

Full Text Available John M Stafford1, Tom Elasy21Division of Diabetes Endocrinology and Metabolism, Vanderbilt University; 2Vanderbilt Eskind Diabetes Clinic, Vanderbilt University Medical CenterAbstract: Type 2 diabetes mellitus (DM2 is characterized by excessive hepatic gluconeogenesis, increased insulin resistance and a progressive inability of pancreatic beta cells to produce sufficient insulin. DM2 evolves as a progression from normal glucose tolerance, to impaired glucose tolerance (IGT to frank diabetes mellitus, reflecting the establishment of insulin resistance and beta cell dysfunction. Insulin resistance not only contributes to impaired glycemic control in DM2, but to the development of hypertension, dyslipidemia and endothelial dysfunction. Cardiovascular disease is the primary morbidity for patients with DM2. The onset of insulin resistance and cardiovascular insult likely occurs well before the onset of IGT is detected clinically. Biguanides and thiazolidinediones (TZDs are two classes of oral agents for the management of DM2 that improve insulin resistance, and thus have potential cardiovascular benefits beyond glycemic control alone. Metformin additionally inhibits hepatic gluconeogenesis. The combined use of two of these agents targets key pathophysiologic defects in DM2. Single pill combinations of rosiglitazone/metformin and pioglitazone/metformin have recently been approved for use in the US and Europe. This article reviews the clinical data behind the use of metformin in combination with TZDs for the management of diabetes, its impact on vascular health, side effects and potential mechanisms of action for combined use.Keywords: thiazolidinediones; metformin; Type 2 diabetes

Treatment update: thiazolidinediones in combination with metformin for the treatment of type 2 diabetes

Directory of Open Access Journals (Sweden)

John M Stafford

2007-09-01

Full Text Available John M Stafford1, Tom Elasy21Division of Diabetes Endocrinology and Metabolism, Vanderbilt University; 2Vanderbilt Eskind Diabetes Clinic, Vanderbilt University Medical CenterAbstract: Type 2 diabetes mellitus (DM2 is characterized by excessive hepatic gluconeogenesis, increased insulin resistance and a progressive inability of pancreatic beta cells to produce sufficient insulin. DM2 evolves as a progression from normal glucose tolerance, to impaired glucose tolerance (IGT to frank diabetes mellitus, reflecting the establishment of insulin resistance and beta cell dysfunction. Insulin resistance not only contributes to impaired glycemic control in DM2, but to the development of hypertension, dyslipidemia and endothelial dysfunction. Cardiovascular disease is the primary morbidity for patients with DM2. The onset of insulin resistance and cardiovascular insult likely occurs well before the onset of IGT is detected clinically. Biguanides and thiazolidinediones (TZDs are two classes of oral agents for the management of DM2 that improve insulin resistance, and thus have potential cardiovascular benefits beyond glycemic control alone. Metformin additionally inhibits hepatic gluconeogenesis. The combined use of two of these agents targets key pathophysiologic defects in DM2. Single pill combinations of rosiglitazone/metformin and pioglitazone/metformin have recently been approved for use in the US and Europe. This article reviews the clinical data behind the use of metformin in combination with TZDs for the management of diabetes, its impact on vascular health, side effects and potential mechanisms of action for combined use.Keywords: thiazolidinediones; metformin; Type 2 diabetes

Increasing daily water intake and fluid adherence in children receiving treatment for retentive encopresis.

Science.gov (United States)

Kuhl, Elizabeth S; Hoodin, Flora; Rice, Jennifer; Felt, Barbara T; Rausch, Joseph R; Patton, Susana R

2010-11-01

To examine the efficacy of an enhanced intervention (EI) compared to standard care (SC) in increasing daily water intake and fluid goal adherence in children seeking treatment for retentive encopresis. Changes in beverage intake patterns and fluid adherence were examined by comparing 7-week diet diary data collected during participation in the EI to achieved data for families who had previously completed the SC. Compared to children in SC (n = 19), children in the EI (n = 18) demonstrated a significantly greater increase in daily water intake from baseline to the conclusion of treatment ( p ≤ .001), and were four and six times more likely to meet fluid targets in Phases 1 (Weeks 3-4) and 2 (Weeks 5-6) of fluid intervention, respectively (both p ≤ .001). Enhanced education and behavioral strategies were efficacious in increasing children's intake of water and improving fluid adherence. Future research should replicate the findings in a prospective randomized clinical trial to discern their effectiveness.

Methodology for Determining Increases in Radionuclide Inventories for the Effluent Treatment Facility Process

International Nuclear Information System (INIS)

Blanchard, A.

1998-01-01

A study is currently underway to determine if the Effluent Treatment Facility can be downgraded from a Hazard Category 3 facility to a Radiological Facility per DOE STD-1027-92. This technical report provides a methodology to determine and monitor increases in the radionuclide inventories of the ETF process columns. It also provides guidelines to ensure that other potential increases to the ETF radionuclide inventory are evaluated as required to ensure that the ETF remains a Radiological Facility

Quinapril treatment increases insulin-stimulated endothelial function and adiponectin gene expression in patients with type 2 diabetes

DEFF Research Database (Denmark)

Hermann, Thomas S; Li, Weijie; Dominguez, Helena

2005-01-01

OBJECTIVE: Angiotensin-converting enzyme inhibitors reduce cardiovascular mortality and improve endothelial function in type 2 diabetic patients. We hypothesized that 2 months of quinapril treatment would improve insulin-stimulated endothelial function and glucose uptake in type 2 diabetic subjects...... and simultaneously increase the expression of genes that are pertinent for endothelial function and metabolism. METHODS: Twenty-four type 2 diabetic subjects were randomized to receive 2 months of quinapril 20 mg daily or no treatment in an open parallel study. Endothelium-dependent and -independent vasodilation...... occlusion plethysmography. Gene expression was measured by real-time PCR. RESULTS: Quinapril treatment increased insulin-stimulated endothelial function in the type 2 diabetic subjects (P = 0.005), whereas forearm glucose uptake was unchanged. Endothelial function was also increased by quinapril (P = 0...

Once-weekly albiglutide in the management of type 2 diabetes: patient considerations.

Science.gov (United States)

Woodward, Heather N; Anderson, Sarah L

2014-01-01

This review describes the pharmacologic, pharmacokinetic, and pharmacodynamic properties of albiglutide, as well as its clinical efficacy and safety. Albiglutide is a novel, once-weekly, injectable glucagon-like peptide-1 receptor agonist for the treatment of type 2 diabetes. The European Commission recently granted marketing authorization for the drug in the European Union and on April 15, 2014, the US Food and Drug Administration approved albiglutide (Tanzeum™ [GlaxoSmithKline LLC, Wilmington, DE, USA]) to improve glycemic control in adults with type 2 diabetes. Albiglutide has been studied in Phase I, II, and III clinical trials. In the Phase III clinical trials, known as the Harmony series, weekly dosing of albiglutide demonstrated reductions in fasting plasma glucose, postprandial plasma glucose, and glycated hemoglobin, and was associated with weight loss. In all phases of the clinical trials, albiglutide administered once weekly showed a safety and tolerability profile similar to that of placebo, with mild gastrointestinal-related complaints and injection site erythema being the most commonly encountered adverse effects. Compared with pioglitazone and liraglutide, albiglutide has been shown to be clinically less effective. However, it offers the benefit of weight loss that pioglitazone does not, with fewer gastrointestinal side effects than liraglutide. As guidelines continue to advocate for patient-centered treatment strategies, once-weekly albiglutide will be an important addition to the growing armamentarium of treatment options for adults with type 2 diabetes needing target glycemic control.

Do hypertension and diuretic treatment in pregnancy increase the risk of schizophrenia in offspring?

DEFF Research Database (Denmark)

Sørensen, Holger J; Mortensen, Erik L; Reinisch, June M

2003-01-01

OBJECTIVE: Diuretics prescribed after the first trimester for treatment of hypertension in pregnant women may interfere with normal plasma volume expansion and cause volume depletion. The authors hypothesized that prenatal exposure to diuretics and maternal hypertension might disrupt fetal...... neurodevelopment and increase the risk of schizophrenia in offspring. METHOD: Using data from the Copenhagen Perinatal Cohort of individuals born between 1959 and 1961, the authors studied the relationship of maternal hypertension and diuretic treatment during pregnancy with the risk of schizophrenia (ICD-8 code...... treatment during pregnancy. RESULTS: In a risk set of 7,866 individuals, 84 cases of schizophrenia were found (1.1% prevalence). Logistic multiple regression analysis identified the following independent risk factors: maternal hypertension (odds ratio=1.69 [95% CI=1.02-2.80]), diuretic treatment...

Do hypertension and diuretic treatment in pregnancy increase the risk of schizophrenia in offspring?

DEFF Research Database (Denmark)

Sørensen, Holger J; Mortensen, Erik L; Reinisch, June M

2003-01-01

treatment during pregnancy. RESULTS: In a risk set of 7,866 individuals, 84 cases of schizophrenia were found (1.1% prevalence). Logistic multiple regression analysis identified the following independent risk factors: maternal hypertension (odds ratio=1.69 [95% CI=1.02-2.80]), diuretic treatment...... neurodevelopment and increase the risk of schizophrenia in offspring. METHOD: Using data from the Copenhagen Perinatal Cohort of individuals born between 1959 and 1961, the authors studied the relationship of maternal hypertension and diuretic treatment during pregnancy with the risk of schizophrenia (ICD-8 code...... 295) in the offspring. Prenatal medical information was linked to the Danish National Psychiatric Register. The effects of maternal hypertension and diuretic treatment were adjusted for the maternal history of schizophrenia, social status of the family breadwinner, mother's age, and concomitant drug...

The Effectiveness of Matrix Treatment to Relapse prevention and Increase Self-Efficacy in People Withdrawing Methamphetamine

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Siamak Ghasemnezhad

2016-08-01

Full Text Available Given the prevalence of narcotic substances and their effect on mental health of society people, it is important to pay attention the matter and adopt an approach for its treatment. The research objective is to examine the effectiveness of matrix treatment on prevent relapsing and increase self-efficacy in people withdrawing methamphetamine. In a quasi-experimental design, methamphetamine users who referred to addiction treatment centers on west of Gilanin 2015 and were eligible for involving criteria completed theself efficacy questionnaire. Then among those who got low scores on this questionnaire, there were randomly selected 30 patients that were divided into experimental and control groups (15 patients for each group. The experimental group was treated for 18 weeks and two sessions per week (36 sessions using matrix therapeutic model. The control group remained on waiting list. Both groups completed self-efficacy questionnaire at baseline, end and 90 days later (follow-up stage with urine test. The control group remained on waiting list and there were assigned only common drug treatment in the withdrawal centers. The research data was analyzed using covariance analysis and SPSS22 software. The results showed efficiency of matrix treatment method in preventing relapse and increasing self-efficacy for people withdrawal methamphetamine, which this difference was statistically significant (p<0.5. Matrix-based treatmentis effective for relapse prevention and increasing self-efficacy for people withdrawal methamphetamine.

Chronic lithium treatment increased intracellular S100ß levels in rat primary neuronal culture.

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Masoumeh Emamghoreishi

2015-02-01

Full Text Available S100ß a neurotrophic factor mainly released by astrocytes, has been implicated in the pathogenesis of bipolar disorder. Thus, lithium may exert its neuroprotective effects to some extent through S100ß. Furthermore, the possible effects of lithium on astrocytes as well as on interactions between neurons and astrocytes as a part of its mechanisms of actions are unknown. This study was undertaken to determine the effect of lithium on S100β in neurons, astrocytes and a mixture of neurons and astrocytes. Rat primary astrocyte, neuronal and mixed neuro-astroglia cultures were prepared from cortices of 18-day's embryos. Cell cultures were exposed to lithium (1mM or vehicle for 1day (acute or 7 days (chronic. RT-PCR and ELISA determined S100β mRNA and intra- and extracellular protein levels. Chronic lithium treatment significantly increased intracellular S100β in neuronal and neuro-astroglia cultures in comparison to control cultures (P<0.05. Acute and chronic lithium treatments exerted no significant effects on intracellular S100β protein levels in astrocytes, and extracellular S100β protein levels in three studied cultures as compared to control cultures. Acute and chronic lithium treatments did not significantly alter S100β mRNA levels in three studied cultures, compared to control cultures. Chronic lithium treatment increased intracellular S100ß protein levels in a cell-type specific manner which may favor its neuroprotective action. The findings of this study suggest that lithium may exert its neuroprotective action, at least partly, by increasing neuronal S100ß level, with no effect on astrocytes or interaction between neurons and astrocytes.

Differential activation of catalase expression and activity by PPAR agonists: Implications for astrocyte protection in anti-glioma therapy☆

Science.gov (United States)

Khoo, Nicholas K.H.; Hebbar, Sachin; Zhao, Weiling; Moore, Steven A.; Domann, Frederick E.; Robbins, Mike E.

2013-01-01

Glioma survival is dismal, in part, due to an imbalance in antioxidant expression and activity. Peroxisome proliferator-activated receptor (PPAR) agonists have antineoplastic properties which present new redox-dependent targets for glioma anticancer therapies. Herein, we demonstrate that treatment of primary cultures of normal rat astrocytes with PPAR agonists increased the expression of catalase mRNA protein, and enzymatic activity. In contrast, these same agonists had no effect on catalase expression and activity in malignant rat glioma cells. The increase in steady-state catalase mRNA observed in normal rat astrocytes was due, in part, to de novo mRNA synthesis as opposed to increased catalase mRNA stability. Moreover, pioglitazone-mediated induction of catalase activity in normal rat astrocytes was completely blocked by transfection with a PPARγ-dominant negative plasmid. These data suggest that defects in PPAR-mediated signaling and gene expression may represent a block to normal catalase expression and induction in malignant glioma. The ability of PPAR agonists to differentially increase catalase expression and activity in normal astrocytes but not glioma cells suggests that these compounds might represent novel adjuvant therapeutic agents for the treatment of gliomas. PMID:24024139

Increasing Neuroplasticity to Bolster Chronic Pain Treatment: A Role for Intermittent Fasting and Glucose Administration?

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Sibille, Kimberly T; Bartsch, Felix; Reddy, Divya; Fillingim, Roger B; Keil, Andreas

2016-03-01

Neuroplastic changes in brain structure and function are not only a consequence of chronic pain but are involved in the maintenance of pain symptoms. Thus, promotion of adaptive, treatment-responsive neuroplasticity represents a promising clinical target. Emerging evidence about the human brain's response to an array of behavioral and environmental interventions may assist in identifying targets to facilitate increased neurobiological receptivity, promoting healthy neuroplastic changes. Specifically, strategies to maximize neuroplastic responsiveness to chronic pain treatment could enhance treatment gains by optimization of learning and positive central nervous system adaptation. Periods of heightened plasticity have been traditionally identified with the early years of development. More recent research, however, has identified a wide spectrum of methods that can be used to "reopen" and enhance plasticity and learning in adults. In addition to transcranial direct current stimulation and transcranial magnetic stimulation, behavioral and pharmacological interventions have been investigated. Intermittent fasting and glucose administration are two propitious strategies, that are noninvasive, inexpensive to administer, implementable in numerous settings, and might be applicable across differing chronic pain treatments. Key findings and neurophysiological mechanisms are summarized, and evidence for the potential clinical contributions of these two strategies toward ameliorating chronic pain is presented. Neuroplastic changes are a defining feature of chronic pain and a complicating factor in treatment. Noninvasive strategies to optimize the brain's response to treatment interventions might improve learning and memory, increase the positive adaptability of the central nervous system, and enhance treatment outcomes. Copyright © 2016 American Pain Society. Published by Elsevier Inc. All rights reserved.

Increase in natural killer cell activity during diethylcarbamazine treatment of patients with filariasis

DEFF Research Database (Denmark)

Pedersen, B K; Bygbjerg, Ib Christian; Svenson, M

1987-01-01

Two patients, one with Bancroftian filariasis and the other with onchocerciasis, and two healthy controls were treated with diethylcarbamazine (DEC). The natural killer (NK) cell activity of the two patients increased during DEC treatment to 2.5 and 2.8 times, respectively, while that of the cont...

Using the internet to understand smokers' treatment preferences: informing strategies to increase demand.

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Westmaas, J Lee; Abroms, Lorien; Bontemps-Jones, Jeuneviette; Bauer, Joseph E; Bade, Jeanine

2011-08-26

Most smokers attempt to quit on their own even though cessation aids can substantially increase their chances of success. Millions of smokers seek cessation advice on the Internet, so using it to promote cessation products and services is one strategy for increasing demand for treatments. Little is known, however, about what cessation aids these smokers would find most appealing or what predicts their preferences (eg, age, level of dependence, or timing of quit date). The objective of our study was to gain insight into how Internet seekers of cessation information make judgments about their preferences for treatments, and to identify sociodemographic and other predictors of preferences. An online survey assessing interest in 9 evidence-based cessation products and services was voluntarily completed by 1196 smokers who visited the American Cancer Society's Great American Smokeout (GASO) webpage. Cluster analysis was conducted on ratings of interest. In total, 48% (572/1196) of respondents were "quite a bit" or "very much" interested in nicotine replacement therapy (NRT), 45% (534/1196) in a website that provides customized quitting advice, and 37% (447/1196) in prescription medications. Only 11.5% (138/1196) indicated similar interest in quitlines, and 17% (208/1196) in receiving customized text messages. Hierarchical agglomerative cluster analysis revealed that interest in treatments formed 3 clusters: interpersonal-supportive methods (eg, telephone counseling, Web-based peer support, and in-person group programs), nonsocial-informational methods (eg, Internet programs, tailored emails, and informational booklets), and pharmacotherapy (NRT, bupropion, and varenicline). Only 5% (60/1196) of smokers were "quite a bit" or "very much" interested in interpersonal-supportive methods compared with 25% (298/1196) for nonsocial-informational methods and 33% (399/1196) for pharmacotherapy. Multivariate analyses and follow-up comparisons indicated that level of interest in

Development of titanium alloys and surface treatments to increase the implants lifetime

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Joan Lario-Femenía

2016-12-01

Full Text Available The population aging together with increase of life expectancy forces the development of new prosthesis which may present a higher useful life. The clinical success of implants is based on the osseointegration achievement. Therefore, metal implants must have a mechanical compatibility with the substituted bone, which is achieved through a combination of low elastic modulus, high flexural and fatigue strength. The improvement, in the short and long term, of the osseointegration depends on several factors, where the macroscopic design and dimensional, material and implant surface topography are of great importance. This article is focused on summarizing the advantages that present the titanium and its alloys to be used as biomaterials, and the development that they have suffered in recent decades to improve their biocompatibility. Consequently, the implants evolution has been recapitulated and summarized through three generations. In the recent years the interest on the surface treatments for metallic prostheses has been increased, the main objective is achieve a lasting integration between implant and bone tissue, in the shortest time possible. On this article various surface treatments currently used to modify the surface roughness or to obtain coatings are described it; it is worthy to mention the electrochemical oxidation with post-heat treated to modify the titanium oxide crystalline structure. After the literature review conducted for prepare this article, the ? titanium alloys, with a nanotubes surface of obtained by electrochemical oxidation and a subsequent step of heat treatment to obtain a crystalline structure are the future option to improve long term biocompatibility of titanium prostheses.

Treatment of HeLa cells with Giloe (Tinospora cordifolia meirs) increases the radiosensitivity by increasing DNA damage

International Nuclear Information System (INIS)

Varma, Hari Krishna; Jagetia, Ganesh Chandra; Nayak, Vijayashree

2014-01-01

Radiotherapy is an important treatment modality and screening of phytoceuticals may enhance the clinical outcome of radiotherapy, therefore radiosensitizing activity of various guduchi (Tinospora cordifolia) extracts was studied in HeLa cells. Chromosomal aberrations were scored in HeLa cells treated with 10 μg/ml of aqueous, methanol, or methylene chloride guduchi extracts or doxorubicin before exposure to 0, 0.5, 1, 2 or 3 Gy of γ-radiation at 12, 24, 36 or 48 h post-irradiation. Irradiation of HeLa cells caused a dose dependent rise in the chromatid breaks, chromosome breaks, dicentric, centric rings, acentric fragments and total aberrations at all post-irradiation times and the dose response was linear quadratic for all types of aberrations scored. Chromatid breaks increased up to 12 h post-irradiation and declined steadily up to 48 h post-irradiation, whereas chromosome breaks, dicentric, acentric fragments and total aberrations elevated up to 24 h post-irradiation and declined thereafter. However, centric rings continued to rise steadily up to 48 h post-irradiation. Treatment of HeLa cells with aqueous, methanol or methylene chloride guduchi extract or doxorubicin before irradiation significantly enhanced various types of chromosomal aberrations and a maximum rise in the chromosome aberrations was observed in the HeLa cells treated with methylene chloride extract before irradiation when compared to other groups. Various guduchi extracts enhanced the effect of radiation in HeLa cells by increasing the molecular damage to cellular genome and their effect was similar to or even greater than doxorubicin (positive control) pretreatment, depending on the type of guduchi extract used. (author)

temporomandibular joint cartilage in rabbits affected by drug-induced osteoarthritis

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Krzysztof Kałużyński

2016-02-01

Full Text Available Background: The aims of this study were to assess the anti-degenerative effects of pioglitazone and to compare these effects with those of methylprednisolone and hyaluronic acid on drug-induced osteoarthritis in rabbits’ temporomandibular joint cartilage.Material and Methods: The experiment was conducted on 40 Californian white rabbits. Degenerative changes were induced by intra-articular injections of papain. Subsequently, all of the animals were randomly assigned to one of four groups:1 a control group that received no medications;2 a group treated with 4 intra-articular injections of 2 mg (0.2 ml of hyaluronic acid at weekly intervals;3 a group treated with 4 intra-articular injections of 2 mg (0.1 ml of methylprednisolone at weekly intervals;4 a group administered pioglitazone orally in daily doses of 2 mg/kg of body weight. Four weeks after the beginning of drug administration, the rabbits were sacrificed. Sagittal sections of the intra-articular cartilage (discs and mandibular condyles were stained with hematoxylin and eosin by the PAS technique and with van Gieson’s solution. Histologic examinations, as well as cartilage thickness and number of cell layers measurements, were performed.Results: Histologic assessment in cases of arthritis-associated pathologies revealed that changes occurred most frequently in the control group and least frequently in the pioglitazone group. There were no differences in the histological structures of the intra-articular discs. Cartilage thickness measurements demonstrated the thinnest cartilage in group 2 and the thickest in group 3. Analysis of cell layer numbers showed the most numerous layers in the pioglitazone group and the least in the control group.Conclusion: Pioglitazone and hyaluronic acid showed anti-degenerative properties compared to methylprednisolone in an animal model.

Characterizing the mechanism of thiazolidinedione-induced hepatotoxicity: An in vitro model in mitochondria

International Nuclear Information System (INIS)

Hu, Dan; Wu, Chun-qi; Li, Ze-jun; Liu, Yue; Fan, Xing; Wang, Quan-jun; Ding, Ri-gao

2015-01-01

Objective: To characterize the mechanism of action of thiazolidinedione (TZD)-induced liver mitochondrial toxicity caused by troglitazone, rosiglitazone, and pioglitazone in HepaRG cells. Methods: Human hepatoma cells (HepaRG) were treated with troglitazone, rosiglitazone, or pioglitazone (12.5, 25, and 50 μM) for 48 h. The Seahorse Biosciences XF24 Flux Analyzer was used to measure mitochondrial oxygen consumption. The effect of TZDs on reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were detected by flow cytometry. The mitochondrial ultrastructure of HepaRG cells was observed under a transmission electrical microscope (TEM). mtDNA content was evaluated by real-time PCR, and ATP content and mitochondrial respiratory chain (MRC) complex I, II, III, IV activity were measured via chemiluminescence. Results were considered statistically significant at p < 0.05. Results: Among the three drugs, troglitazone exhibited the highest potency, followed by rosiglitazone, and then pioglitazone. The TZDs caused varying degrees of mitochondrial respiratory function disorders including decreases in oxygen consumption, MRC activity, and ATP level, and an elevation in ROS level. TZD treatment resulted in mtDNA content decline, reduction in MMP, and alterations of mitochondrial structure. Conclusion: All investigated TZDs show a certain degree of mitochondrial toxicity, with troglitazone exhibiting the highest potency. The underlying mechanism of TZD-induced hepatotoxicity may be associated with alterations in mitochondrial respiratory function disorders, oxidative stress, and changes in membrane permeability. These parameters may be used early in drug development to further optimize risk:benefit profiles. - Highlights: • We compared three TZD mitochondrial toxicity characteristics in HepaRG cells. • TZD induced respiratory disorders and mitochondrial structural damage. • Mitochondrial toxicity evaluation presents guidance value for hepatotoxicity

Characterizing the mechanism of thiazolidinedione-induced hepatotoxicity: An in vitro model in mitochondria

Energy Technology Data Exchange (ETDEWEB)

Hu, Dan; Wu, Chun-qi [State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, 27 Taiping Road, Beijing 100850 (China); Li, Ze-jun [State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, 27 Taiping Road, Beijing 100850 (China); Guang Dong Pharmaceutical University, Guangzhou 510006 (China); Liu, Yue; Fan, Xing [State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, 27 Taiping Road, Beijing 100850 (China); Wang, Quan-jun, E-mail: wangquanjunbeijing@163.com [State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, 27 Taiping Road, Beijing 100850 (China); Ding, Ri-gao, E-mail: dingrigao@nic.bmi.ac.cn [State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, 27 Taiping Road, Beijing 100850 (China)

2015-04-15

Objective: To characterize the mechanism of action of thiazolidinedione (TZD)-induced liver mitochondrial toxicity caused by troglitazone, rosiglitazone, and pioglitazone in HepaRG cells. Methods: Human hepatoma cells (HepaRG) were treated with troglitazone, rosiglitazone, or pioglitazone (12.5, 25, and 50 μM) for 48 h. The Seahorse Biosciences XF24 Flux Analyzer was used to measure mitochondrial oxygen consumption. The effect of TZDs on reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were detected by flow cytometry. The mitochondrial ultrastructure of HepaRG cells was observed under a transmission electrical microscope (TEM). mtDNA content was evaluated by real-time PCR, and ATP content and mitochondrial respiratory chain (MRC) complex I, II, III, IV activity were measured via chemiluminescence. Results were considered statistically significant at p < 0.05. Results: Among the three drugs, troglitazone exhibited the highest potency, followed by rosiglitazone, and then pioglitazone. The TZDs caused varying degrees of mitochondrial respiratory function disorders including decreases in oxygen consumption, MRC activity, and ATP level, and an elevation in ROS level. TZD treatment resulted in mtDNA content decline, reduction in MMP, and alterations of mitochondrial structure. Conclusion: All investigated TZDs show a certain degree of mitochondrial toxicity, with troglitazone exhibiting the highest potency. The underlying mechanism of TZD-induced hepatotoxicity may be associated with alterations in mitochondrial respiratory function disorders, oxidative stress, and changes in membrane permeability. These parameters may be used early in drug development to further optimize risk:benefit profiles. - Highlights: • We compared three TZD mitochondrial toxicity characteristics in HepaRG cells. • TZD induced respiratory disorders and mitochondrial structural damage. • Mitochondrial toxicity evaluation presents guidance value for hepatotoxicity.

The Increased Content of Micronutrients in Celery, Carrot, Parsnip and Parsley Plants after Treatment with Sodium Naphthenate

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Grbović Ljubica

2016-08-01

Full Text Available Young plants of celery, parsley, parsnip and carrot, grown in nutrient solution, were treated with sodium naphthenate (10−7 mol dm−3, applying foliar and root treatments. Both treatments affected the root content of all investigated elements present in the nutrient solution, but in a different way, depending on the plant species. An average change (increase/decrease in the contents of investigated essential elements was about 35%. Our experiments with naphthenate showed that this treatment may enhance the efficiency of essential elements uptake and increase its content in plants without changing concentration of these elements in the nutrient solution. Especially interesting results were obtained in the case of carrot, as increased contents were observed in the elements that are usually deficient in nutrition (Fe, Zn, Mn, whereas the other remained unchanged.

Increased rate of treatment with antidepressants in patients with multiple sclerosis

DEFF Research Database (Denmark)

Kessing, Lars Vedel; Harhoff, Mette; Andersen, Per Kragh

2008-01-01

The prevalence of depression and anxiety is increased in patients with multiple sclerosis, but it has not been investigated whether these conditions are treated in clinical practice. The objective of this study was to investigate whether the rate of treatment with antidepressants is increased...... in patients with multiple sclerosis compared with patients with other chronic illnesses and compared with the general population. By linkage of nationwide case registers, all patients were identified, who had received a main diagnosis of multiple sclerosis or osteoarthritis at first admission or during...... outpatient contact in the period 1995-2000 in Denmark. Rates of subsequent purchase of antidepressants for these patients were calculated. In total, 417 patients with a main diagnosis of multiple sclerosis and 12 127 patients with a main diagnosis of osteoarthritis, at first discharge from hospital...

Irisin levels increase after treatment in patients with newly diagnosed Hashimoto thyroiditis.

Science.gov (United States)

Uc, Z A; Gorar, S; Mizrak, S; Gullu, S

2018-05-18

Irisin is a newly identified myokine secreted by skeletal muscle and has significant effects on body metabolism. Thyroidal functional state has a profound influence on the metabolism of human body. Therefore, the aim of this study was to investigate the possible changes in serum irisin concentrations before and after treatment in hypothyroid subjects. The study included 26 patients with overt hypothyroidism due to Hashimoto thyroiditis and 19 healthy subjects. Baseline serum thyroid function tests and presence of thyroid autoantibodies and levels of creatine kinase (CK) and irisin were measured in both groups. All measurements in the hypothyroid group were repeated after euthyroidism was achieved. Serum irisin levels were significantly lower in the hypothyroid groups than the control group (p treatment (p hypothyroid patients were treated to achieve euthyroidism. To the best of our knowledge, this is the first study providing insight that low serum irisin levels significantly increased following treatment to euthyroid state in overt hypothyroid patients with Hashimoto thyroiditis. Larger scale studies are needed to confirm these results and to ensure irisin as a possible biomarker of Hashimoto's thyroiditis.

Estimated Budget Impact of Increased Use of Mirabegron, A Novel Treatment for Overactive Bladder.

Science.gov (United States)

Perk, Sinem; Wielage, Ronald C; Campbell, Noll L; Klein, Timothy M; Perkins, Anthony; Posta, Linda M; Yuran, Thomas; Klein, Robert W; Ng, Daniel B

2016-09-01

Oral pharmacological treatment for overactive bladder (OAB) consists of antimuscarinics and the beta-3 adrenergic agonist mirabegron. Antimuscarinic adverse events (AEs) such as dry mouth, constipation, and blurry vision can result in frequent treatment discontinuation rates, leaving part of the OAB population untreated. Antimuscarinics also contribute to a patient's anticholinergic cognitive burden (ACB), so the Beers Criteria recommends cautious use of antimuscarinics in elderly patients who take multiple anticholinergic medications or have cognitive impairment. Since mirabegron does not affect the cholinergic pathways, it is unlikely to contribute to a patient's ACB. To estimate the health care costs associated with the pharmacological treatment of OAB with mirabegron and antimuscarinics from U.S. commercial payer and Medicare Advantage perspectives, using a budget impact model. For this budget impact model, 2 analyses were performed. The primary analysis estimated the budgetary impact of increasing the use of mirabegron in a closed patient cohort treated with oral pharmacological treatments. The secondary analysis modeled the economic impact in an open cohort by allowing untreated patients to begin treatment with mirabegron after potential contraindication, intolerance, or lack of effectiveness of antimuscarinics. The analyses were performed over a 3-year time horizon. The economic impact of increased mirabegron use was quantified using direct medical costs, including prescription costs and health resource utilization (HRU) costs. Costs of comorbidities included pharmacy and medical costs of treating OAB-related urinary tract infections (UTI), skin rashes, and depression. An analysis of a large single-site integrated health network database was commissioned to quantify ACB-related HRU in terms of the increases in yearly outpatient and emergency department visits. Based on this analysis, the model associated each unit increase in ACB score with increased HRU and

Pioglitazone improves the ability of learning and memory via activating ERK1/2 signaling pathway in the hippocampus of T2DM rats.

Science.gov (United States)

Gao, F; Zang, L; Wu, D Y; Li, Y J; Zhang, Q; Wang, H B; Tian, G L; Mu, Y M

2017-06-09

To explore the correlation between effect of PIO (pioglitazone, PIO) on learning as well as memory and ERK1/2 (extracellular signal regulated kinase 1/2, ERK1/2) pathway in T2DM (type 2 diabetes mellitus, T2DM) rats, further to elucidate the potential mechanism of PIO in improvement of learning and memory. 12-week-old male SD rats (number of 10 per group) were randomly divided into control group (CON), T2DM group (DM) and T2DM +PIO group (DM+PG). Rats in DM and DM+PG groups were given high fat diet for 20 weeks, then treated with Streptozotocin (27mg/kg) by intraperitoneal injection at 21week. After 72h, the FBG (fasting blood glucose, FBG) was greater than 7.0mmol/L can considered T2DM rats. DM+PG group was treated with PIO (10 mg·kg -1 ·d -1 ) by gavage daily. After Hyperinsulinemic-Euglycemic Clamp Study and Morris water maze test at 30-week, all of animals were sacrificed. The expressions of RKIP (Raf-1 kinase inhibitor protein, RKIP) and ERK1/2 in hippocampus were detected using Western Blot and real-time PCR. The FBG level: DM group (7.68±0.54mmol/L) was higher than CON group (5.35±0.63mmol/L) and DM+PG group (6.07±0.84mmol/L), the differences were considered statistically significant (P 0.05); The relative content of p-ERK1/2 protein in CON group and DM+PG group rats dorsal were higher than those in group DM, the difference was considered statistically significant (P0.05). Activation of ERK1/2 signal transduction pathway via reducing RKIP in the hippocampus may be one of the mechanisms of PIO to improve the learning and memory of the T2DM rats. Copyright © 2017 Elsevier B.V. All rights reserved.

Exogenous Methyl Jasmonate Treatment Increases Glucosinolate Biosynthesis and Quinone Reductase Activity in Kale Leaf Tissue

Science.gov (United States)

Ku, Kang-Mo; Jeffery, Elizabeth H.; Juvik, John A.

2014-01-01

Methyl jasmonate (MeJA) spray treatments were applied to the kale varieties ‘Dwarf Blue Curled Vates’ and ‘Red Winter’ in replicated field plantings in 2010 and 2011 to investigate alteration of glucosinolate (GS) composition in harvested leaf tissue. Aqueous solutions of 250 µM MeJA were sprayed to saturation on aerial plant tissues four days prior to harvest at commercial maturity. The MeJA treatment significantly increased gluconasturtiin (56%), glucobrassicin (98%), and neoglucobrassicin (150%) concentrations in the apical leaf tissue of these genotypes over two seasons. Induction of quinone reductase (QR) activity, a biomarker for anti-carcinogenesis, was significantly increased by the extracts from the leaf tissue of these two cultivars. Extracts of apical leaf tissues had greater MeJA mediated increases in phenolics, glucosinolate concentrations, GS hydrolysis products, and QR activity than extracts from basal leaf tissue samples. The concentration of the hydrolysis product of glucoraphanin, sulforphane was significantly increased in apical leaf tissue of the cultivar ‘Red Winter’ in both 2010 and 2011. There was interaction between exogenous MeJA treatment and environmental conditions to induce endogenous JA. Correlation analysis revealed that indole-3-carbanol (I3C) generated from the hydrolysis of glucobrassicin significantly correlated with QR activity (r = 0.800, Pkale leaf tissues of both cultivars in 2011. Correlation analysis of these results indicated that sulforaphane, NI3C, neoascorbigen, I3C, and diindolylmethane were all significantly correlated with QR activity. Thus, increased QR activity may be due to combined increases in phenolics (quercetin and kaempferol) and GS hydrolysis product concentrations rather than by individual products alone. PMID:25084454

Night-time restricted feeding normalises clock genes and Pai-1 gene expression in the db/db mouse liver.

Science.gov (United States)

Kudo, T; Akiyama, M; Kuriyama, K; Sudo, M; Moriya, T; Shibata, S

2004-08-01

An increase in PAI-1 activity is thought to be a key factor underlying myocardial infarction. Mouse Pai-1 (mPai-1) activity shows a daily rhythm in vivo, and its transcription seems to be controlled not only by clock genes but also by humoral factors such as insulin and triglycerides. Thus, we investigated daily clock genes and mPai-1 mRNA expression in the liver of db/db mice exhibiting high levels of glucose, insulin and triglycerides. Locomotor activity was measured using an infrared detection system. RT-PCR or in situ hybridisation methods were applied to measure gene expression. Humoral factors were measured using measurement kits. The db/ db mice showed attenuated locomotor activity rhythms. The rhythmic expression of mPer2 mRNA was severely diminished and the phase of mBmal1 oscillation was advanced in the db/db mouse liver, whereas mPai-1 mRNA was highly and constitutively expressed. Night-time restricted feeding led to a recovery not only from the diminished locomotor activity, but also from the diminished Per2 and advanced mBmal1 mRNA rhythms. Expression of mPai-1 mRNA in db/db mice was reduced to levels far below normal. Pioglitazone treatment slightly normalised glucose and insulin levels, with a slight reduction in mPai-1 gene expression. We demonstrated that Type 2 diabetes impairs the oscillation of the peripheral oscillator. Night-time restricted feeding rather than pioglitazone injection led to a recovery from the diminished locomotor activity, and altered oscillation of the peripheral clock and mPai-1 mRNA rhythm. Thus, we conclude that scheduled restricted food intake may be a useful form of treatment for diabetes.

Effects of PPARs agonists on cardiac metabolism in littermate and cardiomyocyte-specific PPAR-γ-knockout (CM-PGKO mice.

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Michelangela Barbieri

Full Text Available Understanding the molecular regulatory mechanisms controlling for myocardial lipid metabolism is of critical importance for the development of new therapeutic strategies for heart diseases. The role of PPARγ and thiazolidinediones in regulation of myocardial lipid metabolism is controversial. The aim of our study was to assess the role of PPARγ on myocardial lipid metabolism and function and differentiate local/from systemic actions of PPARs agonists using cardiomyocyte-specific PPARγ -knockout (CM-PGKO mice. To this aim, the effect of PPARγ, PPARγ/PPARα and PPARα agonists on cardiac function, intra-myocyte lipid accumulation and myocardial expression profile of genes and proteins, affecting lipid oxidation, uptake, synthesis, and storage (CD36, CPT1MIIA, AOX, FAS, SREBP1-c and ADPR was evaluated in cardiomyocyte-specific PPARγ-knockout (CM-PGKO and littermate control mice undergoing standard and high fat diet (HFD. At baseline, protein levels and mRNA expression of genes involved in lipid uptake, oxidation, synthesis, and accumulation of CM-PGKO mice were not significantly different from those of their littermate controls. At baseline, no difference in myocardial lipid content was found between CM-PGKO and littermate controls. In standard condition, pioglitazone and rosiglitazone do not affect myocardial metabolism while, fenofibrate treatment significantly increased CD36 and CPT1MIIA gene expression. In both CM-PGKO and control mice submitted to HFD, six weeks of treatment with rosiglitazone, fenofibrate and pioglitazone lowered myocardial lipid accumulation shifting myocardial substrate utilization towards greater contribution of glucose. In conclusion, at baseline, PPARγ does not play a crucial role in regulating cardiac metabolism in mice, probably due to its low myocardial expression. PPARs agonists, indirectly protect myocardium from lipotoxic damage likely reducing fatty acids delivery to the heart through the actions on adipose

Long-Term Treatment with Paroxetine Increases Verbal Declarative Memory and Hippocampal Volume in Posttraumatic Stress Disorder

Science.gov (United States)

Vermetten, Eric; Vythilingam, Meena; Southwick, Steven M.; Charney, Dennis S.; Bremner, J. Douglas

2011-01-01

Background Animal studies have shown that stress is associated with damage to the hippocampus, inhibition of neurogenesis, and deficits in hippocampal-based memory dysfunction. Studies in patients with posttraumatic stress disorder (PTSD) found deficits in hippocampal-based declarative verbal memory and smaller hippocampal volume, as measured with magnetic resonance imaging (MRI). Recent preclinical evidence has shown that selective serotonin reuptake inhibitors promote neurogenesis and reverse the effects of stress on hippocampal atrophy. This study assessed the effects of long-term treatment with paroxetine on hippocampal volume and declarative memory performance in PTSD. Methods Declarative memory was assessed with the Wechsler Memory Scale–Revised and Selective Reminding Test before and after 9–12 months of treatment with paroxetine in PTSD. Hippocampal volume was measured with MRI. Of the 28 patients who started the protocol, 23 completed the full course of treatment and neuropsychological testing. Twenty patients were able to complete MRI imaging. Results Patients with PTSD showed a significant improvement in PTSD symptoms with treatment. Treatment resulted in significant improvements in verbal declarative memory and a 4.6% increase in mean hippocampal volume. Conclusions These findings suggest that long-term treatment with paroxetine is associated with improvement of verbal declarative memory deficits and an increase in hippocampal volume in PTSD. PMID:14512209

Cancer prehabilitation: an opportunity to decrease treatment-related morbidity, increase cancer treatment options, and improve physical and psychological health outcomes.

Science.gov (United States)

Silver, Julie K; Baima, Jennifer

2013-08-01

Cancer prehabilitation, a process on the continuum of care that occurs between the time of cancer diagnosis and the beginning of acute treatment, includes physical and psychological assessments that establish a baseline functional level, identifies impairments, and provides targeted interventions that improve a patient's health to reduce the incidence and the severity of current and future impairments. There is a growing body of scientific evidence that supports preparing newly diagnosed cancer patients for and optimizing their health before starting acute treatments. This is the first review of cancer prehabilitation, and the purpose was to describe early studies in the noncancer population and then the historical focus in cancer patients on aerobic conditioning and building strength and stamina through an appropriate exercise regimen. More recent research shows that opportunities exist to use other unimodal or multimodal prehabilitation interventions to decrease morbidity, improve physical and psychological health outcomes, increase the number of potential treatment options, decrease hospital readmissions, and reduce both direct and indirect healthcare costs attributed to cancer. Future research may demonstrate increased compliance with acute cancer treatment protocols and, therefore, improved survival outcomes. New studies suggest that a multimodal approach that incorporates both physical and psychological prehabilitation interventions may be more effective than a unimodal approach that addresses just one or the other. In an impairment-driven cancer rehabilitation model, identifying current and anticipating future impairments are the critical first steps in improving healthcare outcomes and decreasing costs. More research is urgently needed to evaluate the most effective prehabilitation interventions, and combinations thereof, for survivors of all types of cancer.

Increased trends in the use of treatment-limiting decisions in a regional neurosurgical unit.

Science.gov (United States)

Wilson, William T; McMillan, Tristan; Young, Adam M H; White, Mark A J

2017-04-01

Treatment-limiting decisions (TLDs) are employed to actively withhold treatment from patients whom clinicians feel would derive no benefit or suffer detrimental effects from further intervention. The use of such decisions has been heavily discussed in the media and clinicians in the past have been reluctant to institute them, even though it is in the best interests of the patients. Their use is influenced by several ethical, religious and social factors all of which have changed significantly over time. This study reports the trends in use of TLDs in a regional neurosurgical unit over 23 years. Patient archives were reviewed to identify the number of admissions and procedures performed at the Institute of Neurological Sciences, Glasgow, in the years 1988, 1997 and 2011. Death certificate records were used to identify mortality in the unit in the year 2011. Patient records were used to obtain details of diagnosis, time from admission to death, and the presence and timing of a TLD. The results show an increase in the use of TLDs, with decisions made for 89% of those who died in 2011, compared to 68% in 1997 and 51% in 1988. The number of admissions has increased substantially since 1988 as has the percentage of patients undergoing surgery (46, 67 and 72% in 1988, 1997 and 2011, respectively). There is a trending increase in the number of patients who have a TLD in our regional neurosurgical unit. This demonstrates an increased willingness of clinicians to recognise poor prognosis and to withdraw or withhold treatment in these cases. Continued appropriate use of the TLD is recommended but it is to only ever reflect the best interests of the patient.

Increasing Water System Efficiency with Ultrafiltration Pre-treatment in Power Plants

International Nuclear Information System (INIS)

Majamaa, Katariina; Suarez, Javier; Gasia Eduard

2012-09-01

Water demineralization with reverse osmosis (RO) membranes has a long and successful history in water treatment for power plants. As the industry strives for more efficient, reliable and compact water systems, pressurized hollow-fiber ultrafiltration (UF) has become an increasingly appealing pre-treatment technology. Compared to conventional, non- membrane based pretreatments, ultrafiltration offers higher efficiency in the removal of suspended solids, microorganisms and colloidal matter, which are all common causes for operational challenges experienced in the RO systems. In addition, UF is more capable of handling varying feed water qualities and removes the risk of particle carry-over often seen with conventional filtration techniques. Ultrafiltration is a suitable treatment technology for various water types from surface waters to wastewater, and the more fluctuating or challenging the feed water source is, the better the benefits of UF are seen compared to conventional pretreatments. Regardless of the feed water type, ultrafiltration sustains a constant supply of high quality feed water to downstream RO, allowing a more compact and cost efficient RO system design with improved operational reliability. A detailed focus on the design and operational aspects and experiences of two plants is provided. These examples demonstrate both economical UF operation and tangible impact of RO process improvement. Experience from these plants can be leveraged to new projects. (authors)

Increased risk of treatment with antidepressants in stroke compared with other chronic illness

DEFF Research Database (Denmark)

Dam, Henrik; Harhoff, Mette; Andersen, Per Kragh

2007-01-01

The prevalence of depression and anxiety is higher in patients with stroke than in the general population but it is unclear whether patients with stroke are at an increased risk of being treated for depression and anxiety compared with patients with other chronic illness. The objective...... of the present study was to investigate whether the rate of treatment with antidepressants is increased in patients with stroke compared with patients with other chronic illness and compared with the general population. By linkage of nationwide case registers, all patients who received a main diagnosis of stroke...

Do hypertension and diuretic treatment in pregnancy increase the risk of schizophrenia in offspring?

DEFF Research Database (Denmark)

Sørensen, Holger J; Mortensen, Erik Lykke; Reinisch, June M

2003-01-01

OBJECTIVE: Diuretics prescribed after the first trimester for treatment of hypertension in pregnant women may interfere with normal plasma volume expansion and cause volume depletion. The authors hypothesized that prenatal exposure to diuretics and maternal hypertension might disrupt fetal...... neurodevelopment and increase the risk of schizophrenia in offspring. METHOD: Using data from the Copenhagen Perinatal Cohort of individuals born between 1959 and 1961, the authors studied the relationship of maternal hypertension and diuretic treatment during pregnancy with the risk of schizophrenia (ICD-8 code...... 295) in the offspring. Prenatal medical information was linked to the Danish National Psychiatric Register. The effects of maternal hypertension and diuretic treatment were adjusted for the maternal history of schizophrenia, social status of the family breadwinner, mother's age, and concomitant drug...

Repeated treatment with nitric oxide synthase inhibitor attenuates learned helplessness development in rats and increases hippocampal BDNF expression.

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Stanquini, Laura Alves; Biojone, Caroline; Guimarães, Francisco Silveira; Joca, Sâmia Regiane

2017-11-20

Nitric oxide synthase (NOS) inhibitors induce antidepressant-like effects in animal models sensitive to acute drug treatment such as the forced swimming test. However, it is not yet clear if repeated treatment with these drugs is required to induce antidepressant-like effects in preclinical models. The aim of this study was to test the effect induced by acute or repeated (7 days) treatment with 7-nitroindazole (7-NI), a preferential inhibitor of neuronal NOS, in rats submitted to the learned helplessness (LH) model. In addition, we aimed at investigating if 7-NI treatment would increase brain-derived neurotrophic factor (BDNF) protein levels in the hippocampus, similarly to the effect of prototype antidepressants. Animals were submitted to a pre-test (PT) session with inescapable footshocks or habituation (no shocks) to the experimental shuttle box. Six days later they were exposed to a test with escapable footshocks. Independent groups received acute (a single injection after PT or before test) or repeated (once a day for 7 days) treatment with vehicle or 7-NI (30 mg/kg). Repeated, but not acute, treatment with 7-NI attenuated LH development. The effect was similar to repeated imipramine treatment. Moreover, in an independent experimental group, only repeated treatment with 7-NI and imipramine increased BDNF protein levels in the hippocampus. The results suggest the nitrergic system could be a target for the treatment of depressive-like conditions. They also indicate that, similar to the positive control imipramine, the antidepressant-like effects of NOS inhibition could involve an increase in hippocampal BDNF levels.

Smoking increases the likelihood of Helicobacter pylori treatment failure.

Science.gov (United States)

Itskoviz, David; Boltin, Doron; Leibovitzh, Haim; Tsadok Perets, Tsachi; Comaneshter, Doron; Cohen, Arnon; Niv, Yaron; Levi, Zohar

2017-07-01

Data regarding the impact of smoking on the success of Helicobacter pylori (H. pylori) eradication are conflicting, partially due to the fact that sociodemographic status is associated with both smoking and H. pylori treatment success. We aimed to assess the effect of smoking on H. pylori eradication rates after controlling for sociodemographic confounders. Included were subjects aged 15 years or older, with a first time positive C 13 -urea breath test (C 13 -UBT) between 2007 to 2014, who underwent a second C 13 -UBT after receiving clarithromycin-based triple therapy. Data regarding age, gender, socioeconomic status (SES), smoking (current smokers or "never smoked"), and drug use were extracted from the Clalit health maintenance organization database. Out of 120,914 subjects with a positive first time C 13 -UBT, 50,836 (42.0%) underwent a second C 13 -UBT test. After excluding former smokers, 48,130 remained who were eligible for analysis. The mean age was 44.3±18.2years, 69.2% were females, 87.8% were Jewish and 12.2% Arabs, 25.5% were current smokers. The overall eradication failure rates were 33.3%: 34.8% in current smokers and 32.8% in subjects who never smoked. In a multivariate analysis, eradication failure was positively associated with current smoking (Odds Ratio {OR} 1.15, 95% CI 1.10-1.20, psmoking was found to significantly increase the likelihood of unsuccessful first-line treatment for H. pylori infection. Copyright © 2017 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

A decision support tool for appropriate glucose-lowering therapy in patients with type 2 diabetes.

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Ampudia-Blasco, F Javier; Benhamou, Pierre Yves; Charpentier, Guillaume; Consoli, Agostino; Diamant, Michaela; Gallwitz, Baptist; Khunti, Kamlesh; Mathieu, Chantal; Ridderstråle, Martin; Seufert, Jochen; Tack, Cees; Vilsbøll, Tina; Phan, Tra-Mi; Stoevelaar, Herman

2015-03-01

Optimal glucose-lowering therapy in type 2 diabetes mellitus requires a patient-specific approach. Although a good framework, current guidelines are insufficiently detailed to address the different phenotypes and individual needs of patients seen in daily practice. We developed a patient-specific decision support tool based on a systematic analysis of expert opinion. Based on the American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) 2012 position statement, a panel of 12 European experts rated the appropriateness (RAND/UCLA Appropriateness Method) of treatment strategies for 930 clinical scenarios, which were permutations of clinical variables considered relevant to treatment choice. These included current treatment, hemoglobin A1c difference from individualized target, risk of hypoglycemia, body mass index, life expectancy, and comorbidities. Treatment options included addition of a second or third agent, drug switches, and replacement by monotherapies if the patient was metformin-intolerant. Treatment costs were not considered. Appropriateness (appropriate, inappropriate, uncertain) was based on the median score and expert agreement. The panel recommendations were embedded in an online decision support tool (DiaScope(®); Novo Nordisk Health Care AG, Zürich, Switzerland). Treatment appropriateness was associated with (combinations of) the patient variables mentioned above. As second-line agents, dipeptidyl peptidase-4 inhibitors were considered appropriate in all scenarios, followed by glucagon-like peptide-1 receptor agonists (50%), insulins (33%), and sulfonylureas (25%), but not pioglitazone (0%). Ratings of third-line combinations followed a similar pattern. Disagreement was highest for regimens including pioglitazone, sulfonylureas, or insulins and was partly due to differences in panelists' opinions and in drug availability and reimbursement across European countries (although costs were disregarded in the rating process

Immobilisation increases yeast cells' resistance to dehydration-rehydration treatment.

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Borovikova, Diana; Rozenfelde, Linda; Pavlovska, Ilona; Rapoport, Alexander

2014-08-20

This study was performed with the goal of revealing if the dehydration procedure used in our new immobilisation method noticeably decreases the viability of yeast cells in immobilised preparations. Various yeasts were used in this research: Saccharomyces cerevisiae cells that were rather sensitive to dehydration and had been aerobically grown in an ethanol-containing medium, a recombinant strain of S. cerevisiae grown in aerobic conditions which were completely non-resistant to dehydration and an anaerobically grown bakers' yeast strain S. cerevisiae, as well as a fairly resistant Pichia pastoris strain. Experiments performed showed that immobilisation of all these strains essentially increased their resistance to a dehydration-rehydration treatment. The increase of cells' viability (compared with control cells dehydrated in similar conditions) was from 30 to 60%. It is concluded that a new immobilisation method, which includes a dehydration stage, does not lead to an essential loss of yeast cell viability. Correspondingly, there is no risk of losing the biotechnological activities of immobilised preparations. The possibility of producing dry, active yeast preparations is shown, for those strains that are very sensitive to dehydration and which can be used in biotechnology in an immobilised form. Finally, the immobilisation approach can be used for the development of efficient methods for the storage of recombinant yeast strains. Copyright © 2014 Elsevier B.V. All rights reserved.

Evaluation of increased milking frequency as an additional treatment for cows with clinical mastitis.

Science.gov (United States)

Krömker, Volker; Zinke, Claudia; Paduch, Jan-Hendrik; Klocke, Doris; Reimann, Anette; Eller, Georg

2010-02-01

This field study focused on the possible effects of increased milking frequency (milking four times a day in comparison with milking twice a day) on clinical and bacteriological cure rates of clinical, antibiotically treated mastitis cases. Parameters tested were clinical, microbiological and full (cytomicrobiological) cure as well as the development of milk yield after the clinical mastitis episode. Cows from a large dairy herd meeting the study criteria (n=93) were assigned to two treatment groups by a systematic randomization scheme (blocked by body temperature 39.5 degrees C). Both groups were randomly divided by experimental treatments: a) antibiotic intramammary treatment and milking 2-times a day; b) antibiotic intramammary treatment and milking 4-times a day. Treatments were initiated before the culture results were known. Cows were surveyed and evaluated on days 1-6, 24 and 31. No significant differences between treatment and control groups regarding clinical cure, microbiological cure, full cure and milk production could be established. Applying a 4-times a day milking regime did not lead to any significant effect, either positive or negative. Therefore, the results suggest that milking 4-times a day as a supporting therapy for mild, moderate and severe antimicrobially treated mastitis cases cannot be recommended.

Electrokinetic Treatment for Model Caissons with Increasing Dimensions

Directory of Open Access Journals (Sweden)

Eltayeb Mohamedelhassan

2012-01-01

Full Text Available Electrokinetic treatment has been known in geotechnical engineering for over six decades, yet, the technique is rarely used. This stems from the absence of design guidelines and specifications for electrokinetic treatment systems. An important issue that need to be investigated and understood in order to devise guidelines from experimental results is the effect of the foundation element size on the outcome of the treatment. Also important is determining the optimum distance between the electrodes and estimating the energy consumption prior to treatment. This experimental study is a preliminary step in understanding some of the issues critical for the guidelines and specifications. Four model caissons with surface areas between 16000 and 128000 mm2 were embedded in soft clayey soil under water and treated for 168 hr with a dc voltage of 6 V. From the results, a distance between the anode (model caisson and the cathode equal 0.25 times the outside diameter of the model caisson was identified as optimum. Relationships between the surface area and axial capacity of the model caisson and the surface area and energy consumption were presented. The equations can be used to preliminary estimate the load capacity and the energy consumption for full-scale applications.

Allergic contact dermatitis from ophthalmic products: can pre-treatment with sodium lauryl sulfate increase patch test sensitivity?

Science.gov (United States)

Corazza, Monica; Virgili, Annarosa

2005-05-01

In patients suspected of allergic contact dermatitis because of topical ophthalmic medicaments, patch tests performed with patients' own products are often negative. The irritant anionic surfactant sodium lauryl sulfate (SLS) may alter the stratum corneum and increase antigen penetration. Pre-treatment of the skin with SLS 0.5% for 24 h was performed in the sites of patch tests with patients' own products in 15 selected patients. In patients previously negative to their own products tested with conventional patch tests, SLS pre-treatment showed 6 new relevant positive reactions and induced a stronger positive reaction in 1 patient. SLS pre-treatment could be proposed as an alternative promising method, which may increase sensitivity of patch tests with patients' own products.

Surface modification of ultra thin PES-zeolite using thermal annealing to increase flux and rejection of produced water treatment

Energy Technology Data Exchange (ETDEWEB)

Kusworo, T. D., E-mail: tdkusworo@che.undip.ac.id; Widayat,; Pradini, A. W.; Armeli, Y. P. [Department of Chemical Engineering, University of Diponegoro Prof. Soedarto, Tembalang, Semarang, 50239, Phone/Fax : (024) 7460058 (Indonesia)

2015-12-29

Membrane technology is an alternative of water treatment based on filtration that is being developed. Surface Modification using heat treatment has been investigated to improve the performance of ultra thin PES-Zeolite nanocomposite membrane for produced water treatment from Pertamina Balongan. Two types of membranes with surface modification and without modification were prepared to study the effect of surface modification on its permeation properties. Asymmetric ultra thin PES-Zeolite nanocomposite membrane for produced water treatment was casted using the dry/wet phase inversion technique from dope solutions containing polyethersulfone, N-methyl-2-pyrrolidone (NMP) as a solvent and zeolite as a filler. Experimental results showed that the heat treatment at near glass transition temperature was increase the rejection of COD, Turbidity and ion Ca{sup 2+}. The better adherence of zeolite particles in the polymer matrix combined with formation of charge transfer complexes (CTCs) and cross-linking might be the main factors to enhance the percent of rejection. Field emission scanning electron microscopy (FESEM) micrographs showed that the selective layer and the substructure of PES-zeolite membrane became denser and more compact after the heat treatment. The FESEM micrographs also showed that the heat treatment was increased the adherence of zeolite particle and polymer. Membranes treated at 180 °C for 15 seconds indicated increase the rejection and small decrease in flux for produced water treatment.

Treatment with a JNK inhibitor increases, whereas treatment with a p38 inhibitor decreases, H2O2-induced calf pulmonary arterial endothelial cell death.

Science.gov (United States)

Park, Woo Hyun

2017-08-01

Oxidative stress induces apoptosis in endothelial cells (ECs). Reactive oxygen species (ROS) promote cell death by regulating the activity of various mitogen-activated protein kinases (MAPKs) in ECs. The present study investigated the effects of MAPK inhibitors on cell survival and glutathione (GSH) levels upon H 2 O 2 treatment in calf pulmonary artery ECs (CPAECs). H 2 O 2 treatment inhibited the growth and induced the death of CPAECs, as well as causing GSH depletion and the loss of mitochondrial membrane potential (MMP). While treatment with the MEK or JNK inhibitor impaired the growth of H 2 O 2 -treated CPAECs, treatment with the p38 inhibitor attenuated this inhibition of growth. Additionally, JNK inhibitor treatment increased the proportion of sub-G 1 phase cells in H 2 O 2 -treated CPAECs and further decreased the MMP. However, treatment with a p38 inhibitor reversed the effects of H 2 O 2 treatment on cell growth and the MMP. Similarly, JNK inhibitor treatment further increased, whereas p38 inhibitor treatment decreased, the proportion of GSH-depleted cells in H 2 O 2 -treated CPAECs. Each of the MAPK inhibitors affected cell survival, and ROS or GSH levels differently in H 2 O 2 -untreated, control CPAECs. The data suggest that the exposure of CPAECs to H 2 O 2 caused the cell growth inhibition and cell death through GSH depletion. Furthermore, JNK inhibitor treatment further enhanced, whereas p38 inhibitors attenuated, these effects. Thus, the results of the present study suggest a specific protective role for the p38 inhibitor, and not the JNK inhibitor, against H 2 O 2 -induced cell growth inhibition and cell death.

Limited but increasing use of treatment for hepatitis C across Europe in patients coinfected with HIV and hepatitis

DEFF Research Database (Denmark)

Mocroft, A; Rockstroh, J; Soriano, V

2006-01-01

Uptake of hepatitis C (HCV) treatment in HIV-coinfected patients is not well described. Of 2356 HCV-seropositive patients, 180 (7.6%) started HCV treatment with interferon-based therapies. In multivariate Poisson-regression models, there was a 38% increase per year in the incidence of starting HCV...... treatment (95% CI 26 - 51%, ppatients, it remains infrequent and variable...

Weekly intra-amniotic IGF-1 treatment increases growth of growth-restricted ovine fetuses and up-regulates placental amino acid transporters.

Directory of Open Access Journals (Sweden)

Jibran A Wali

Full Text Available Frequent treatment of the growth-restricted (IUGR ovine fetus with intra-amniotic IGF-1 increases fetal growth. We aimed to determine whether increased growth was maintained with an extended dosing interval and to examine possible mechanisms. Pregnant ewes were allocated to three groups: Control, and two IUGR groups (induced by placental embolization treated with weekly intra-amniotic injections of either saline (IUGR or 360 µg IGF-1 (IGF1. IUGR fetuses were hypoxic, hyperuremic, hypoglycemic, and grew more slowly than controls. Placental glucose uptake and SLC2A1 (GLUT2 mRNA levels decreased in IUGR fetuses, but SLC2A3 (GLUT3 and SLC2A4 (GLUT4 levels were unaffected. IGF-1 treatment increased fetal growth rate, did not alter uterine blood flow or placental glucose uptake, and increased placental SLC2A1 and SLC2A4 (but not SLC2A3 mRNA levels compared with saline-treated IUGR animals. Following IGF-1 treatment, placental mRNA levels of isoforms of the system A, y(+, and L amino acid transporters increased 1.3 to 5.0 fold, while the ratio of phosphorylated-mTOR to total mTOR also tended to increase. Weekly intra-amniotic IGF-1 treatment provides a promising avenue for intra-uterine treatment of IUGR babies, and may act via increased fetal substrate supply, up-regulating placental transporters for neutral, cationic, and branched-chain amino acids, possibly via increased activation of the mTOR pathway.

Limited but increasing use of treatment for hepatitis C across Europe in patients coinfected with HIV and hepatitis

DEFF Research Database (Denmark)

Mocroft, A; Rockstroh, J; Soriano, V

2006-01-01

Uptake of hepatitis C (HCV) treatment in HIV-coinfected patients is not well described. Of 2356 HCV-seropositive patients, 180 (7.6%) started HCV treatment with interferon-based therapies. In multivariate Poisson-regression models, there was a 38% increase per year in the incidence of starting HCV...... treatment (95% CI 26 - 51%, pHIV-coinfected patients, it remains infrequent and variable...

FOXO1 Content Is Reduced in Cystic Fibrosis and Increases with IGF-I Treatment

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Arianna Smerieri

2014-10-01

Full Text Available Cystic fibrosis-related diabetes is to date the most frequent complication in cystic fibrosis (CF. The mechanisms underlying this condition are not well understood, and a possible role of insulin resistance is debated. We investigated insulin signal transduction in CF. Total insulin receptor, IRS1, p85 PI3K, and AKT contents were substantially normal in CF cells (CFBE41o-, whereas winged helix forkhead (FOXO1 contents were reduced both in baseline conditions and after insulin stimulation. In addition, CF cells showed increased ERK1/2, and reduced β2 arrestin contents. No significant change in SOCS2 was observed. By using a CFTR inhibitor and siRNA, changes in FOXO1 were related to CFTR loss of function. In a CF-affected mouse model, FOXO1 content was reduced in the muscle while no significant difference was observed in liver and adipose tissue compared with wild-type. Insulin-like growth factor 1 (IGF-I increased FOXO1 content in vitro and in vivo in muscle and adipose tissue. In conclusion; we present the first description of reduced FOXO1 content in CF, which is compatible with reduced gluconeogenesis and increased adipogenesis, both features of insulin insensitivity. IGF-I treatment was effective in increasing FOXO1, thereby suggesting that it could be considered as a potential treatment in CF patients possibly to prevent and treat cystic fibrosis-related diabetes.

High-dose thalidomide increases the risk of peripheral neuropathy in the treatment of ankylosing spondylitis.

Science.gov (United States)

Xue, Hong-Xia; Fu, Wen-Yi; Cui, Hua-Dong; Yang, Li-Li; Zhang, Ning; Zhao, Li-Juan

2015-05-01

Thalidomide is an effective drug for the treatment of ankylosing spondylitis but might induce peripheral neuropathy. This major adverse reaction has attracted much concern. The current study aimed to observe the incidence of thalidomide-induced peripheral neuropathy among ankylosing spondylitis patients for 1 year after treatment. In this study, 207 ankylosing spondylitis cases received thalidomide treatment, while 116 ankylosing spondylitis cases received other treatments. Results showed that the incidence of thalidomide-induced peripheral neuropathy in the thalidomide group was higher than that in the non-thalidomide group. There was no significant difference in the incidence of neuropathy between the peripheral neuropathy among patients receiving 25, 50, 75, or 100 mg thalidomide per day was 4.6%, 8.5%, 17.1%, 21.7%, respectively. The incidence was significantly different between the groups receiving 25 mg and 100 mg thalidomide. In conclusion, thalidomide can induce peripheral neuropathy within 1 year after treatment of ankylosing spondylitis; however, age and gender have no obvious impact on the incidence of peripheral neuropathy. The incidence of peripheral neuropathy is associated with increasing daily doses of thalidomide.

Cost-effectiveness analysis of thiazolidinediones in uncontrolled type 2 diabetic patients receiving sulfonylureas and metformin in Thailand.

Science.gov (United States)

Chirakup, Suphachai; Chaiyakunapruk, Nathorn; Chaikledkeaw, Usa; Pongcharoensuk, Petcharat; Ongphiphadhanakul, Boonsong; Roze, Stephane; Valentine, William J; Palmer, Andrew J

2008-03-01

The national essential drug committee in Thailand suggested that only one of thiazolidinediones be included in hospital formulary but little was know about their cost-effectiveness values. This study aims to determine an incremental cost-effectiveness ratio of pioglitazone 45 mg compared with rosiglitazone 8 mg in uncontrolled type 2 diabetic patients receiving sulfonylureas and metformin in Thailand. A Markov diabetes model (Center for Outcome Research model) was used in this study. Baseline characteristics of patients were based on Thai diabetes registry project. Costs of diabetes were calculated mainly from Buddhachinaraj hospital. Nonspecific mortality rate and transition probabilities of death from renal replacement therapy were obtained from Thai sources. Clinical effectiveness of thiazolidinediones was retrieved from a meta-analysis. All analyses were based on the government hospital policymaker perspective. Both cost and outcomes were discounted with the rate of 3%. Base-case analyses were analyzed as incremental cost per quality-adjusted life year (QALY) gained. A series of sensitive analyses were performed. In base-case analysis, the pioglitazone group had a better clinical outcomes and higher lifetime costs. The incremental cost per QALY gained was 186,246 baht (US$ 5389). The acceptability curves showed that the probability of pioglitazone being cost-effective was 29% at the willingness to pay of one time of Thai gross domestic product per capita (GDP per capita). The effect of pioglitazone on %HbA1c decrease was the most sensitive to the final outcomes. Our findings showed that in type 2 diabetic patients who cannot control their blood glucose under the combination of sulfonylurea and metformin, the use of pioglitazone 45 mg fell in the cost-effective range recommended by World Health Organization (one to three times of GDP per capita) on average, compared to rosiglitazone 8 mg. Nevertheless, based on sensitivity analysis, its probability of being cost

Chronic fluoxetine treatment increases daytime melatonin synthesis in the rodent

Directory of Open Access Journals (Sweden)

Gillian W Reierson

2009-09-01

Full Text Available Gillian W Reierson, Claudio A Mastronardi, Julio Licinio, Ma-Li WongCenter on Pharmacogenomics, Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL, USAAbstract: Circadian rhythm disturbances can occur as part of the clinical symptoms of major depressive disorder and have been found to resolve with antidepressant therapy. The pineal gland is relevant to circadian rhythms as it secretes the hormone melatonin following activation of the cyclic adenosine monophosphate (cAMP signaling cascade and of arylalkylamine N-acetyltransferase (AA-NAT, the rate-limiting enzyme for its synthesis. Cyclic AMP is synthesized by adenylate cyclases (AC and degraded by phosphodiesterases (PDEs. Little is known about the contribution of the PDE system to antidepressant-induced alterations in pineal cAMP signaling and melatonin synthesis. In the present study we used enzyme immunoassay to measure plasma melatonin levels and pineal cAMP levels and as well as quantitative real-time polymerase chain reaction to measure pineal expression of PDE, AC, and AA-NAT genes in rats chronically treated with the prototypic antidepressant fluoxetine. We found elevated melatonin synthesis with increased pineal AA-NAT gene expression and daytime plasma melatonin levels and downregulated cAMP signaling with increased PDE and unchanged AC pineal gene expression, and decreased content of pineal cAMP. We conclude that chronic fluoxetine treatment increases daytime plasma melatonin and pineal AA-NAT gene expression despite downregulated pineal cAMP signaling in the rodent.Keywords: antidepressant, melatonin, pineal, nucleotides, cyclic, phosphodiesterase, rat

Long-term IGF-I treatment of children with Laron syndrome increases adiposity.

Science.gov (United States)

Laron, Zvi; Ginsberg, Shira; Lilos, Pnina; Arbiv, Mira; Vaisman, Nahum

2006-02-01

Laron syndrome (LS) is an autosomal recessive disease caused by deletions or mutations in the GH receptor gene leading to an inability of insulin-like growth factor I (IGF-I) generation. Among the major resulting body changes are dwarfism and obesity. The only effective treatment is daily administration of biosynthetic IGF-I. Body composition determination by DEXA (dual energy X-ray absorptiometry) of three girls with LS treated by IGF-I for 1, 3 and 11 1/2 years, respectively, revealed that concomitantly with the increase in growth there was a significant increase in body adipose tissue to double or triple the normal values. Due to the underdevelopment of the muscular and skeletal systems body mass index (BMI) did not accurately reflect the degree of obesity. In conclusion, IGF-I similar to insulin, exerts an adipogenic effect.

Increasing the treatment motivation of patients with somatic symptom disorder: applying the URICA-S scale.

Science.gov (United States)

Mander, Johannes; Schaller, Georg; Bents, Hinrich; Dinger, Ulrike; Zipfel, Stephan; Junne, Florian

2017-07-03

Therapeutic intervention programs for somatic symptom disorder (SSD) show only small-to-moderate effect sizes. These effects are partly explained by the motivational problems of SSD patients. Hence, fostering treatment motivation could increase treatment success. One central aspect in SSD patients might be damage to motivation because of symptomatic relapses. Consequently, the aim of the present study was to investigate associations between motivational relapse struggle and therapeutic outcome in SSD patients. We assessed 84 inpatients diagnosed with SSD in the early, middle and late stages of their inpatient treatment. The maintenance subscale of the University of Rhode Island Change Assessment-Short (URICA-S) was applied as a measure to assess motivational relapse struggle. Additionally, patients completed measures of treatment outcome that focus on clinical symptoms, stress levels and interpersonal functioning. The results from multiple regression analyses indicate that higher URICA-S maintenance scores assessed in early stages of inpatient treatment were related to more negative treatment outcomes in SSD patients. SSD patients with ambivalent treatment motivation may fail in their struggle against relapse over the course of therapy. The URICA-S maintenance score assessed at therapy admission facilitated early identification of SSD patients who are at greater risk of relapse. Future studies should incorporate randomized controlled trials to investigate whether this subgroup could benefit from motivational interventions that address relapse.

State-Targeted Funding and Technical Assistance to Increase Access to Medication Treatment for Opioid Use Disorder.

Science.gov (United States)

Abraham, Amanda J; Andrews, Christina M; Grogan, Colleen M; Pollack, Harold A; D'Aunno, Thomas; Humphreys, Keith; Friedmann, Peter D

2018-04-01

As the United States grapples with an opioid epidemic, expanding access to effective treatment for opioid use disorder is a major public health priority. Identifying effective policy tools that can be used to expand access to care is critically important. This article examines the relationship between state-targeted funding and technical assistance and adoption of three medications for treating opioid use disorder: oral naltrexone, injectable naltrexone, and buprenorphine. This study draws from the 2013-2014 wave of the National Drug Abuse Treatment System Survey, a nationally representative, longitudinal study of substance use disorder treatment programs. The sample includes data from 695 treatment programs (85.5% response rate) and representatives from single-state agencies in 49 states and Washington, D.C. (98% response rate). Logistic regression was used to examine the relationships of single-state agency targeted funding and technical assistance to availability of opioid use disorder medications among treatment programs. State-targeted funding was associated with increased program-level adoption of oral naltrexone (adjusted odds ratio [AOR]=3.14, 95% confidence interval [CI]=1.49-6.60, p=.004) and buprenorphine (AOR=2.47, 95% CI=1.31-4.67, p=.006). Buprenorphine adoption was also correlated with state technical assistance to support medication provision (AOR=1.18, 95% CI=1.00-1.39, p=.049). State-targeted funding for medications may be a viable policy lever for increasing access to opioid use disorder medications. Given the historically low rates of opioid use disorder medication adoption in treatment programs, single-state agency targeted funding is a potentially important tool to reduce mortality and morbidity associated with opioid disorders and misuse.

Increase in nitrite content and functionality of ethanolic extracts of Perilla frutescens following treatment with atmospheric pressure plasma.

Science.gov (United States)

Jung, Samooel; Lee, Chul Woo; Lee, Juri; Yong, Hae In; Yum, Su Jin; Jeong, Hee Gon; Jo, Cheorun

2017-12-15

This study investigated the effect of atmospheric pressure plasma (APP) treatment on nitrite content and functionality of plant extracts. Ethanolic extracts of Perilla frutescens (EEP) were prepared and treated with APP for 60min. Nitrite content increased from 0 to 45.8mg/l in EEP after APP treatment for 60min. Antimicrobial activity of EEP against Clostridium perfringens and Salmonella Typhimurium was increased by APP with no influence on antioxidative activity (p<0.05). Lyophilized EEP (LEEP) treated with APP for 60min contained 3.74mg/g nitrite. The control (LEEP without APP) contained no nitrite. The minimum inhibitory concentration (MIC) of LEEP for C. perfringens was 200µg/ml. The control did not inhibit C. perfringens growth between 25 and 1000µg/ml. MICs of LEEP and the control against S. Typhimurium were 25 and 50µg/ml, respectively. New nitrite sources with increased antimicrobial activity can be produced from natural plants by APP treatment. Copyright © 2017 Elsevier Ltd. All rights reserved.

Can treatment of nocturia increase testosterone level in men with late onset hypogonadism?

Science.gov (United States)

Kim, Jong Wook; Chae, Ji Yun; Kim, Jin Wook; Yoon, Cheol Yong; Oh, Mi Mi; Park, Hong Seok; Kim, Je Jong; Moon, Du Geon

2014-04-01

To assess the effect of desmopressin on serum testosterone level in men with nocturia and late onset hypogonadism. We prospectively enrolled men with nocturia and symptoms of late onset hypogonadism. Desmopressin (0.1 mg) was administered once daily to patients for 12 weeks, and we then compared serum testosterone levels, electrolytes, frequency volume chart indices, and changes in the International Prostate Symptom Score (IPSS), International Index of Erectile Function, and Aging Male's Symptom scales before and after treatment. Patients with a history of cardiovascular disease or hyponatremia, those using hypnotics, and those who had primary hypogonadism or hypogonadotrophic hypogonadism were excluded from the study. Sixty-two men (mean age, 68.4 years) completed pre- and post-treatment questionnaires and underwent laboratory testing. At the end of the study, the testosterone levels in men with low testosterone levels (treatment (2.85 ± 0.58 to 3.97 ± 1.44 ng/mL; P = .001). Mean scores had decreased from 17.7 to 13.9 (IPSS), 3.8 to 3.2 (IPSS-Quality of Life), and 33.7 to 31.1 (Aging Male's Symptom). On the frequency volume chart, nocturnal urine volume, nocturnal polyuria index, actual number of nocturia events, nocturia index, and nocturnal bladder capacity index were significantly decreased. Desmopressin improved nocturia and other urinary symptoms. Moreover, serum testosterone levels increased significantly in men with low testosterone levels after 12-week desmopressin treatment. Copyright © 2014 Elsevier Inc. All rights reserved.

Do drug treatment facilities increase clients' exposure to potential neighborhood-level triggers for relapse? A small-area assessment of a large, public treatment system.

Science.gov (United States)

Jacobson, Jerry O

2006-03-01

Research on drug treatment facility locations has focused narrowly on the issue of geographic proximity to clients. We argue that neighborhood conditions should also enter into the facility location decision and illustrate a formal assessment of neighborhood conditions at facilities in a large, metropolitan area, taking into account conditions clients already face at home. We discuss choice and construction of small-area measures relevant to the drug treatment context, including drug activity, disadvantage, and violence as well as statistical comparisons of clients' home and treatment locations with respect to these measures. Analysis of 22,707 clients discharged from 494 community-based outpatient and residential treatment facilities that received public funds during 1998-2000 in Los Angeles County revealed no significant mean differences between home and treatment neighborhoods. However, up to 20% of clients are exposed to markedly higher levels of disadvantage, violence, or drug activity where they attend treatment than where they live, suggesting that it is not uncommon for treatment locations to increase clients' exposure to potential environmental triggers for relapse. Whereas on average both home and treatment locations exhibit higher levels of these measures than the household locations of the general population, substantial variability in public treatment clients' home neighborhoods calls into question the notion that they hail exclusively from poor, high drug activity areas. Shortcomings of measures available for neighborhood assessment of treatment locations and implications of the findings for other areas of treatment research are also discussed.

Chemical treatments for increasing the efficiency of B7 ordered packings

International Nuclear Information System (INIS)

Titescu, Gh.; Predescu, S.

1997-01-01

Efforts to improve the contact elements, particularly, the isotopic and mass exchange elements, resulted in a new highly performing ordered packing made of metallic net. Research directed to improve the functional characteristics of these packings, destined to heavy water separation processes by vacuum isotopic distillations, continued. A special goal was deposing oxide layers on the metallic surface to increase the wettability and, implicitly, the separation efficiency of the packings. Surface treatments are based on the contact of the material in given conditions with oxidizers such as KMnO 4 , H 2 O 2 , K 2 Cr 2 O 7 . At present, the experiments aim at correlating the functional characteristics and the morphologic characteristics of the oxide layers formed on their surface

Fluoxetine increases suicide ideation less than placebo during treatment of adults with minor depressive disorder.

Science.gov (United States)

Garlow, Steven J; Kinkead, Becky; Thase, Michael E; Judd, Lewis L; Rush, A John; Yonkers, Kimberly A; Kupfer, David J; Frank, Ellen; Schettler, Pamela J; Rapaport, Mark Hyman

2013-09-01

Some reports suggest an increase in suicide ideations and behaviors in patients treated with antidepressants. This is an analysis of the impact of fluoxetine on suicide ideations in outpatients with minor depressive disorder. Research subjects were adult outpatients with minor depressive disorder (N = 162), who received fluoxetine or placebo in a prospective, 12-week, double-blind randomized trial. The research participants were evaluated weekly with standard rating scales that included four suicide-related items: item 3 of the Hamilton Rating Scale for Depression (HRSD), item 18 of Inventory of Depressive Symptomatology (IDS-C), and items 15 and 59 of the Hopkins Symptom Checklist (SCL-90). Clinically significant intensification of suicide ideation was defined as an increase of ≥2 points on any of these items. Overall 60/162 subjects (37%) had an increase of ≥1 point during treatment and 17/162 (10.5%) of ≥2 points on at least one suicide item, with 12/81 (14.8%) placebo and 5/81 (6.2%) fluoxetine-treated subjects having a ≥2 point gain. Of the study participants with baseline suicide ideation, 9/22 (40.9%) placebo and 3/24 (12.5%) fluoxetine treated had ≥2 point increase (p = 0.04). Survival analysis revealed that subjects on placebo were significantly more likely (p = 0.050) to experience a ≥2 point increase on one or more item, a difference that emerged early and continued throughout the 12-week trial. Compared to placebo, fluoxetine was not associated with a clinically significant increase in suicide ideation among adults with minor depressive disorder during 12 weeks of treatment. Copyright © 2013 Elsevier Ltd. All rights reserved.

The Brazilian policy of withholding treatment for ADHD is probably increasing health and social costs

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Carlos R. Maia

2015-03-01

Full Text Available Objective: To estimate the economic consequences of the current Brazilian government policy for attention-deficit/hyperactivity disorder (ADHD treatment and how much the country would save if treatment with immediate-release methylphenidate (MPH-IR, as suggested by the World Health Organization (WHO, was offered to patients with ADHD. Method: Based on conservative previous analyses, we assumed that 257,662 patients aged 5 to 19 years are not receiving ADHD treatment in Brazil. We estimated the direct costs and savings of treating and not treating ADHD on the basis of the following data: a spending on ADHD patients directly attributable to grade retention and emergency department visits; and b savings due to impact of ADHD treatment on these outcomes. Results: Considering outcomes for which data on the impact of MPH-IR treatment are available, Brazil is probably wasting approximately R$ 1.841 billion/year on the direct consequences of not treating ADHD in this age range alone. On the other hand, treating ADHD in accordance with WHO recommendations would save approximately R$ 1.163 billion/year. Conclusions: By increasing investments on MPH-IR treatment for ADHD to around R$ 377 million/year, the country would save approximately 3.1 times more than is currently spent on the consequences of not treating ADHD in patients aged 5 to 19 years.

Increasing the Fine Flaky Graphite Recovery in Flotation via a Combined MultipleTreatments Technique of Middlings

Directory of Open Access Journals (Sweden)

Weijun Peng

2017-11-01

Full Text Available As the residual flaky graphite ores become miscellaneous and fine, a single treatment technique for the middlings from the flotation process of graphite ore cannot efficiently recover the valuable graphite in the multistage grinding-flotation technology. In the study, the existence form of graphite and relationship of graphite with the associated gangue minerals were estimated by optical microscope analysis. The results indicated that the fine flaky graphite particles embedded with gangue minerals like a honeycomb, making it difficult to be beneficiated using the typical flotation technique. A combination technique of individual process and concentrated returning for the treatment of middlings was used to increase the graphite recovery based on the co-existing relationship between graphite and gangue minerals in the middlings. The graphite recovery of the final concentrate upgraded from 51.81% to 91.14% at a fixed carbon (FC content of 92.01% by a beneficiation process consisted of once coarse (94.41% passing 74 μm and rougher, five stages regrinding and six stages cleaning. The proposed treatment technique for middlings is of great significance to increase the recovery of fine flaky graphite.

High-dose thalidomide increases the risk of peripheral neuropathy in the treatment of ankylosing spondylitis

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Hong-xia Xue

2015-01-01

Full Text Available Thalidomide is an effective drug for the treatment of ankylosing spondylitis but might induce peripheral neuropathy. This major adverse reaction has attracted much concern. The current study aimed to observe the incidence of thalidomide-induced peripheral neuropathy among ankylosing spondylitis patients for 1 year after treatment. In this study, 207 ankylosing spondylitis cases received thalidomide treatment, while 116 ankylosing spondylitis cases received other treatments. Results showed that the incidence of thalidomide-induced peripheral neuropathy in the thalidomide group was higher than that in the non-thalidomide group. There was no significant difference in the incidence of neuropathy between the < 6 months medication and ≥ 6 months medication groups. There were no differences in the mean age, gender, or daily dose between the two groups. The incidence of peripheral neuropathy among patients receiving 25, 50, 75, or 100 mg thalidomide per day was 4.6%, 8.5%, 17.1%, 21.7%, respectively. The incidence was significantly different between the groups receiving 25 mg and 100 mg thalidomide. In conclusion, thalidomide can induce peripheral neuropathy within 1 year after treatment of ankylosing spondylitis; however, age and gender have no obvious impact on the incidence of peripheral neuropathy. The incidence of peripheral neuropathy is associated with increasing daily doses of thalidomide.

Post-fusion treatment with MG132 increases transcription factor expression in somatic cell nuclear transfer embryos in pigs.

Science.gov (United States)

You, Jinyoung; Lee, Joohyeong; Kim, Jinyoung; Park, Junhong; Lee, Eunsong

2010-02-01

The objective of this study was to examine the effect of post-fusion treatment of somatic cell nuclear transfer (SCNT) oocytes with the proteasomal inhibitor MG132 on maturation promoting factor (MPF) activity, nuclear remodeling, embryonic development, and gene expression of cloned pig embryos. Immediately after electrofusion, SCNT oocytes were treated with MG132 and/or caffeine for 2 hr, vanadate for 0.5 hr, or vanadate for 0.5 hr followed by MG132 for 1.5 hr. Of the MG132 concentrations tested (0-5 microM), the 1 microM concentration showed a higher rate of blastocyst formation (25.9%) than 0 (14.2%), 0.5 (16.9%), and 5 microM (16.9%). Post-fusion treatment with MG132, caffeine, and both MG132 and caffeine improved blastocyst formation (22.1%, 21.4%, and 24.4%, respectively), whereas vanadate treatment inhibited blastocyst formation (6.5%) compared to the control (11.1%). When examined 2 hr after fusion and 1 hr after activation, MPF activity remained at a higher (P fusion with caffeine and/or MG132, but it was decreased by vanadate. The rate of oocytes showing premature chromosome condensation was not altered by MG132 but was decreased by vanadate treatment. In addition, formation of single pronuclei was increased by MG132 compared to control and vanadate treatment. MG132-treated embryos showed increased expression of POU5F1, DPPA2, DPPA3, DPPA5, and NDP52l1 genes compared to control embryos. Our results demonstrate that post-fusion treatment of SCNT oocytes with MG132 prevents MPF degradation and increases expression of transcription factors in SCNT embryos, which are necessary for normal development of SCNT embryos. (c) 2009 Wiley-Liss, Inc.

Increased short-term risk of thrombo-embolism or death after interruption of warfarin treatment in patients with atrial fibrillation.

Science.gov (United States)

Raunsø, Jakob; Selmer, Christian; Olesen, Jonas Bjerring; Charlot, Mette Gitz; Olsen, Anne-Marie S; Bretler, Ditte-Marie; Nielsen, Jørn Dalsgaard; Dominguez, Helena; Gadsbøll, Niels; Køber, Lars; Gislason, Gunnar H; Torp-Pedersen, Christian; Hansen, Morten Lock

2012-08-01

It is presently unknown whether patients with atrial fibrillation (AF) are at increased risk of thrombo-embolic adverse events after interruption of warfarin treatment. The purpose of this study was to assess the risk and timing of thrombo-embolism after warfarin treatment interruption. A retrospective, nationwide cohort study of all patients in Denmark treated with warfarin after a first hospitalization with AF in the period 1997-2008. Incidence rate ratios (IRRs) of thrombo-embolic events and all-cause mortality were calculated using the Poisson regression analyses. In total, 48 989 AF patients receiving warfarin treatment were included. Of these, 35 396 patients had at least one episode of warfarin treatment interruption. In all, 8255 deaths or thrombo-embolic events occurred during treatment interruption showing an initial clustering of events with 2717, 835, 500, and 427 events occurring during 0-90, 91-180, 181-270, and 271-360 days after treatment interruption, respectively. Correspondingly, the crude incidence rates were 31.6, 17.7, 12.3, and 11.4 events per 100 patient-years. In a multivariable analysis, the first 90-day interval of treatment interruption was associated with a markedly higher risk of death or thrombo-embolism (IRR 2.5; 95% confidence interval 2.3-2.8) vs. the interval of 271-360 days. In patients with AF, an interruption of warfarin treatment is associated with a significantly increased short-term risk of death or thrombo-embolic events within the first 90 days of treatment interruption.

Comparative Efficacy and Acceptability of Anti-Diabetic Agents for Alzheimer's Disease and Mild Cognitive Impairment: A Systematic Review and Network Meta-analysis.

Science.gov (United States)

Cao, Bing; Rosenblat, Joshua D; Brietzke, Elisa; Park, Caroline; Lee, Yena; Musial, Natalie; Pan, Zihang; Mansur, Rodrigo B; McIntyre, Roger S

2018-05-23

The current meta-analysis compares the efficacy (i.e., pro-cognitive effects) and acceptability of anti-diabetic agents for Alzheimer's disease (AD) and mild cognitive impairment (MCI). Cochrane Library (CENTRAL), PubMed/MEDLINE, EMBASE and PsycINFO were searched from inception to January 15, 2018 for randomized controlled trials (RCTs) comparing anti-diabetic agents with placebo and/or another active anti-diabetic agent for the treatment of AD or MCI. Nineteen eligible studies (n = 4,855) evaluating the effects of six different anti-diabetic drugs (i.e., intranasal insulin, pioglitazone, rosiglitazone, metformin, sitagliptin and liraglutide) were included. The results of 29 pairwise comparisons indicated that cognition was significantly improved in subjects treated with anti-diabetic agents compared to placebo. Pioglitazone 15-30 mg demonstrated the greatest efficacy compared to placebo in network meta-analysis. No significant differences in acceptability were identified when comparing agents with each other and with placebo. The current findings indicate a pro-cognitive class effect of anti-diabetic agents in AD/MCI. Other anti-diabetic agents should also be investigated in future studies. This study is registered with PROSPERO (CRD42018085967). This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Increased short-term risk of thrombo-embolism or death after interruption of warfarin treatment in patients with atrial fibrillation

DEFF Research Database (Denmark)

Raunsø, Jakob; Selmer, Christian; Olesen, Jonas Bjerring

2012-01-01

AimsIt is presently unknown whether patients with atrial fibrillation (AF) are at increased risk of thrombo-embolic adverse events after interruption of warfarin treatment. The purpose of this study was to assess the risk and timing of thrombo-embolism after warfarin treatment interruption.Method...

Sequential treatment with basic fibroblast growth factor and PTH is more efficacious than treatment with PTH alone for increasing vertebral bone mass and strength in osteopenic ovariectomized rats

DEFF Research Database (Denmark)

Iwaniec, U.T.; Mosekilde, Li.; Mitova-Caneva, N.G.

2002-01-01

The study was designed 1) to determine whether treatment with basic fibroblast growth factor (bFGF) and PTH is more efficacious than treatment with PTH alone for increasing bone mass and strength and improving trabecular microarchitecture in osteopenic ovariectomized rats, and 2) to assess whethe...

Evaluation of medical treatments to increase survival of ebullism in guinea pigs

Science.gov (United States)

Stegmann, Barbara J.; Pilmanis, Andrew A.; Wolf, E. G.; Derion, Toniann; Fanton, J. W.; Davis, H.; Kemper, G. B.; Scoggins, Terrell E.

1993-01-01

Spaceflight carriers run a constant risk of exposure to vacuum. Above 63,000 ft (47 mmHg), the ambient pressure falls below the vapor pressure of water at 37 C, and tissue vaporization (ebullism) begins. Little is know about appropriate resuscitative protocols after such an ebullism exposure. This study identified injury patterns and mortality rates associated with ebullism while verifying effectiveness of traditional pulmonary resuscitative techniques. Male Hartley guinea pigs were exposed to 87,000 ft for periods of 40 to 115 sec. After descent, those animals that did not breathe spontaneously were given artificial ventilation by bag and mask for up to 15 minutes. Those animals surviving were randomly assigned to one of three treatment groups--hyperbaric oxygen (HBO), ground-level oxygen (GLO2), and ground-level air (GLAIR). The HBO group was treated on a standard treatment table 6A while the GLO2 animals received O2 for an equivalent length of time. Those animals in the GLAIR group were observed only. All surviving animals were humanely sacrified at 48 hours. Inflation of the animal's lungs after the exposure was found to be difficult and, at times, impossible. This may be due to surfactant disruption at the alveolar lining. Electron microscopy identified a disruption of the surfactant layer in animals that did not survive initial exposure. Mortality was found to increase with exposure time: 40 sec--0 percent; 60 sec--6 percent; 70 sec--40 percent; 80 sec--13 percent; 100 sec--38 percent; 110 sec--40 percent; and 115 sec--100 percent. There was no difference in the delayed mortality among the treatment groups (HBO--15 percent, GLO2--11 percent, GLAIR--11 percent). However, since resuscitation was ineffective, the effectiveness of any post-exposure treatment was severely limited. Preliminary results indicate that reuscitation of guinea pigs following ebullism exposure is difficult, and that current techniques (such as traditional CPR) may not be appropriate.

Socioeconomic disparities in access to ART treatment and the differential impact of a policy that increased consumer costs.

Science.gov (United States)

Chambers, G M; Hoang, V P; Illingworth, P J

2013-11-01

What was the impact on access to assisted reproductive technology (ART) treatment by different socioeconomic status (SES) groups after the introduction of a policy that increased patient out-of-pocket costs? After the introduction of a policy that increased out-of-pocket costs in Australia, all SES groups experienced a similar percentage reduction in fresh ART cycles per 1000 women of reproductive age. Higher SES groups experienced a progressively greater reduction in absolute numbers of fresh ART cycles due to existing higher levels of utilization. Australia has supportive public funding arrangements for ARTs. Policies that substantially increase out-of-pocket costs for ART treatment create financial barriers to access and an overall reduction in utilization. Data from the USA suggests that disparities exist in access to ART treatment based on ethnicity, education level and income. Time series analysis of utilization of ART, intrauterine insemination (IUI) and clomiphene citrate by women from varying SES groups before and after the introduction of a change in the level of public funding for ART. Women undertaking fertility treatment in Australia between 2007 and 2010. Women from higher SES quintiles use more ART treatment than those in lower SES quintiles, which likely reflects a greater ability to pay for treatment and a greater need for ART treatment as indicated by the trend to later childbearing. In 2009, 10.13 and 5.17 fresh ART cycles per 1000 women of reproductive age were performed in women in the highest and lowest SES quintiles respectively. In the 12 months after the introduction of a policy that increased out-of-pocket costs from ∼$1500 Australian dollars (€1000) to ∼$2500 (€1670) for a fresh IVF cycle, there was a 21-25% reduction in fresh ART cycles across all SES quintiles. The absolute reduction in fresh ART cycles in the highest SES quintile was double that in the lowest SES quintile. In this study, SES was based on the average relative

Latest data on metabolic diseases: Diabetes Mellitus

Directory of Open Access Journals (Sweden)

Panagiota Mitrou

2017-01-01

Full Text Available With such a high cost in money and human lives, diabetes mellitus (DM is a major challenge for health care systems and an obstacle to sustainable economic growth. The pathophysiological disorders of diabetes include, besides the defect in pancreatic insulin secretion and insulin resistance in peripheral tissues (liver, muscle and adipose tissue, increased lipolysis, increased glucagon secretion, impaired secretion and action of incretin hormones, increased glucose resorption by the kidney and defects in the central nervous system. The therapeutic intervention must be timely and personalized. Lifestyle interventions (diet, exercise, smoking cessation are the cornerstone of treatment. Treatment should begin with metformin unless there is a contraindication (eg renal failure or intolerance (eg, gastrointestinal disorders. If HbA1c remains off target a second or a third treatment may be added, orally (glitazone, DPP-4 inhibitors, SGLT-2 inhibitors, sulfonylurea or by injection (GLP-1 agonist or basal insulin. On failure to achieve glycemic target combinations of injectable treatments (combination of agonist GLP-1 with basal insulin, intensified insulin therapy or in some cases insulin mixtures are recommended. New treatments (weekly administered GLP-1 analogs, combination of a basal insulin / GLP-1 in one injection, SGLT-2 inhibitors, long acting basal insulins in combination with the old tried treatments (e.g. metformin, pioglitazone, inhibitors DPP-4 can contribute to human-centered and individualized management of patients with diabetes. The cardiovascular safety of antidiabetic treatment should be considered. There is a need for early diagnosis and treatment of glucose metabolism disorders during pregnancy (before 24 to 28 weeks of gestation in women at high risk for developing gestational diabetes.

Actos Now for the prevention of diabetes (ACT NOW study

Directory of Open Access Journals (Sweden)

Reaven Peter D

2009-07-01

Full Text Available Abstract Background Impaired glucose tolerance (IGT is a prediabetic state. If IGT can be prevented from progressing to overt diabetes, hyperglycemia-related complications can be avoided. The purpose of the present study was to examine whether pioglitazone (ACTOS® can prevent progression of IGT to type 2 diabetes mellitus (T2DM in a prospective randomized, double blind, placebo controlled trial. Methods/Design 602 IGT subjects were identified with OGTT (2-hour plasma glucose = 140–199 mg/dl. In addition, IGT subjects were required to have FPG = 95–125 mg/dl and at least one other high risk characteristic. Prior to randomization all subjects had measurement of ankle-arm blood pressure, systolic/diastolic blood pressure, HbA1C, lipid profile and a subset had frequently sampled intravenous glucose tolerance test (FSIVGTT, DEXA, and ultrasound determination of carotid intima-media thickness (IMT. Following this, subjects were randomized to receive pioglitazone (45 mg/day or placebo, and returned every 2–3 months for FPG determination and annually for OGTT. Repeat carotid IMT measurement was performed at 18 months and study end. Recruitment took place over 24 months, and subjects were followed for an additional 24 months. At study end (48 months or at time of diagnosis of diabetes the OGTT, FSIVGTT, DEXA, carotid IMT, and all other measurements were repeated. Primary endpoint is conversion of IGT to T2DM based upon FPG ≥ 126 or 2-hour PG ≥ 200 mg/dl. Secondary endpoints include whether pioglitazone can: (i improve glycemic control (ii enhance insulin sensitivity, (iii augment beta cell function, (iv improve risk factors for cardiovascular disease, (v cause regression/slow progression of carotid IMT, (vi revert newly diagnosed diabetes to normal glucose tolerance. Conclusion ACT NOW is designed to determine if pioglitazone can prevent/delay progression to diabetes in high risk IGT subjects, and to define the mechanisms (improved insulin

About a possibility of increasing the adhesion strength between mineral glass and polymeric binder under radio-frequency induction plasma treatment

International Nuclear Information System (INIS)

Miftakhov, I S; Trofimov, A V; Nagmutdinova, A I; Voznesensky, E F; Sharifullin, F S; Krasina, I V; Rakhmatullina, G R

2017-01-01

The paper investigated influences of radio-frequency induction plasma treatment on the surface of sheet mineral glasses for household purpose. Discussion for casting the most suitable treatment modes and theirs substantiation is shown. During the investigation the most productive plasma treatment modes for applied binders have been found. It is shown that the durability of adhesive joints between mineral glass and polymeric binder under low-temperature plasma treatment increase to 65%. (paper)

Treatment timing for an orthopedic approach to patients with increased vertical dimension.

Science.gov (United States)

Baccetti, Tiziano; Franchi, Lorenzo; Schulz, Scott O; McNamara, James A

2008-01-01

The aim of this study was to investigate the role of treatment timing on the effectiveness of vertical-pull chincup (V-PCC) therapy in conjunction with a bonded rapid maxillary expander (RME) in growing subjects with mild-to-severe hyperdivergent facial patterns. The records of 39 subjects treated with a bonded RME combined with a V-PCC were compared with 29 untreated subjects with similar vertical skeletal disharmonies. Lateral cephalograms were analyzed before (T1) and after treatment or observation (T2). Both the treated and the untreated samples were divided into prepubertal and pubertal groups on the basis of cervical vertebral maturation (prepubertal treated group, 21 subjects; pubertal treated group, 18 subjects; prepubertal control group, 15 subjects; pubertal control group, 14 subjects). Mean change differences from T2 to T1 were compared in the 2 prepubertal and the 2 pubertal groups with independent-sample t tests. No statistically significant differences between the 2 prepubertal groups were found for any cephalometric skeletal measures from T1 to T2. When compared with the untreated pubertal sample, the group treated with the RME and V-PCC at puberty showed a statistically significant reduction in the inclination of the mandibular plane to the Frankfort horizontal (-2.2 mm), a statistically significant reduction in the inclination of the condylar axis to the mandibular plane (-2.2 degrees), and statistically significant supplementary growth of the mandibular ramus (1.7 mm). Treatment of increased vertical dimension with the RME and V-PCC protocol appears to produce better results during the pubertal growth spurt than before puberty, although the absolute amount of correction in the vertical skeletal parameters is limited.

Waiting Time Increases Risk of Attrition in Gambling Disorder Treatment

DEFF Research Database (Denmark)

Linnet, Jakob; Pedersen, Anders Sune

2014-01-01

Attrition is a well known problem in psychotherapeutic treatment. Patients with addiction have high attrition rates, and it is therefore important to identify factors that can improve completion rates in addiction. Here, we investigated the influence of waiting time as a predictor of treatment...

Applying the technology of hydrodynamic cavitation treatment of high-viscosity oils to increase the efficiency of transportation

Science.gov (United States)

Brand, A. E.; Vershinina, S. V.; Vengerov, A. A.; Mostovaya, N. A.

2015-10-01

The article investigates the possibility of applying hydrodynamic cavitation treatment to reduce oil viscosity in Russian pipeline transportation system and increase its performance. The result of laboratory tests and suggestions on technology application are given

Acute and repeated ECS treatment increases CRF, POMC and PENK gene expression in selected regions of the rat hypothalamus.

Science.gov (United States)

Garcia-Garcia, L; Llewellyn-Jones, V; Fernandez Fernandez, I; Fuentes, J A; Manzanares, J

1998-01-05

The purpose of this study was to investigate the effects of acute and repeated electroconvulsive shock (ECS) on corticotropin releasing factor (CRF), proopiomelanocortin (POMC) and proenkephalin (PENK) gene expression in selected regions of the brain and pituitary of the rat. Acute ECS increased CRF gene expression in the paraventricular nucleus (PVN) by 20%, an effect that was further enhanced to 38% when rats received repeated ECS treatment. Acute and repeated ECS increased POMC gene expression in the arcuate nucleus (ARC) by 49-59% but failed to alter these mRNA levels in the anterior lobe (AL) of the pituitary gland. PENK gene expression was increased by 35% in the nucleus accumbens (NA) and by 180% the ventromedial nucleus (VMN) after acute or repeated ECS treatment but no significant changes were found in the PVN or striatum (ST). Taken together, these results indicate a differential CRF and opioid gene expression regulation after acute or repeated ECS treatment that may be relevant to their therapeutic or side effects in depression.

Women-focused treatment agencies and process improvement: Strategies to increase client engagement

Science.gov (United States)

Wisdom, Jennifer P.; Hoffman, Kim; Rechberger, Elke; Seim, Kay; Owens, Betta

2009-01-01

Behavioral health treatment agencies often struggle to keep clients engaged in treatment. Women clients often have additional factors such as family responsibilities, financial difficulties, or abuse histories that provide extra challenges to remaining in care. As part of a national initiative, four women-focused drug treatment agencies used process improvement to address treatment engagement. Interviews and focus groups with staff assessed the nature and extent of interventions. Women-focused drug treatment agencies selected relational-based interventions to engage clients in treatment and improved four-week treatment retention from 66% to 76%. Process improvement interventions in women-focused treatment may be useful to improve engagement. PMID:20046914

Increasing Age and Treatment Modality Are Predictors for Subsequent Diagnosis of Bladder Cancer Following Prostate Cancer Diagnosis

International Nuclear Information System (INIS)

Singh, Anurag K.; Mashtare, Terry L.; McCloskey, Susan A.; Seixas-Mikelus, Stefanie A.; Kim, Hyung L.; May, Kilian Salerno

2010-01-01

Purpose: To determine the effect of prostate cancer therapy (surgery or external beam irradiation, or both or none) on the actuarial incidence of subsequent bladder cancer. Methods and Materials: The Surveillance, Epidemiology, and End Results registry from 1973 to 2005 was analyzed. Treatment was stratified as radiotherapy, surgery, both surgery and adjuvant radiation, and neither modality. Brachytherapy was excluded. Results: In all, 555,337 prostate carcinoma patients were identified; 124,141 patients were irradiated; 235,341 patients were treated surgically; 32,744 patients had both surgery and radiation; and 163,111 patients received neither modality. Bladder cancers were diagnosed in: 1,836 (1.48%) men who were irradiated (mean age, 69.4 years), 2,753 (1.09%) men who were treated surgically (mean age, 66.9 years); 683 (2.09%) men who received both modalities (mean age, 67.4 years), and 1,603 (0.98%) men who were treated with neither modality (mean age, 71.8 years). In each treatment cohort, Kaplan-Meier analyses showed that increasing age (by decade) was a significant predictor of developing bladder cancer (p < 0.0001). Incidence of bladder cancer was significantly different for either radiation or surgery alone versus no treatment, radiation versus surgery alone, and both surgery and radiation versus either modality alone (p < 0.0001). On multivariate analysis, age and irradiation were highly significant predictors of being diagnosed with bladder cancer. Conclusions: Following prostate cancer, increasing age and irradiation were highly significant predictors of being diagnosed with bladder cancer. While use of radiation increased the risk of bladder cancer compared to surgery alone or no treatment, the overall incidence of subsequent bladder cancer remained low. Routine bladder cancer surveillance is not warranted.

Increasing Neuroplasticity to Bolster Chronic Pain Treatment: A Role for Intermittent Fasting and Glucose Administration?

Science.gov (United States)

Sibille, KT; Bartsch, F; Reddy, D; Fillingim, RB; Keil, A

2016-01-01

Neuroplastic changes in brain structure and function are not only a consequence of chronic pain but are involved in the maintenance of pain symptoms. Thus, promoting adaptive, treatment responsive neuroplasticity represents a promising clinical target. Emerging evidence about the human brain’s response to an array of behavioral and environmental interventions may assist in identifying targets to facilitate increased neurobiological receptivity, promoting healthy neuroplastic changes. Specifically, strategies to maximize neuroplastic responsiveness to chronic pain treatment could enhance treatment gains by optimizing learning and positive central nervous system (CNS) adaptation. Periods of heightened plasticity have been traditionally identified with the early years of development. More recent research however has identified a wide spectrum of methods that can be used to “re-open” and enhance plasticity and learning in adults. In addition to transcranial direct current stimulation and transcranial magnetic stimulation, behavioral and pharmacological interventions have been investigated. Intermittent fasting and glucose administration are two propitious strategies, which are non-invasive, inexpensive to administer, implementable in numerous settings, and may be applicable across differing chronic pain treatments. Key findings and neurophysiological mechanisms are summarized, providing evidence for the potential clinical contributions of these two strategies toward ameliorating chronic pain. PMID:26848123

The learning curve of laparoscopic treatment of rectal cancer does not increase morbidity.

Science.gov (United States)

Luján, Juan; Gonzalez, Antonio; Abrisqueta, Jesús; Hernandez, Quiteria; Valero, Graciela; Abellán, Israel; Frutos, María Dolores; Parrilla, Pascual

2014-01-01

The treatment of rectal cancer via laparoscopy is controversial due to its technical complexity. Several randomized prospective studies have demonstrated clear advantages for the patient with similar oncological results to those of open surgery, although during the learning of this surgical technique there may be an increase in complications and a worse prognosis. Our aim is to analyze how the learning curve for rectal cancer via laparoscopy influences intra- and postoperative results and oncological markers. A retrospective review was conducted of the first 120 patients undergoing laparoscopic surgery for rectal neoplasia. The operations were performed by the same surgical team with a wide experience in the treatment of open colorectal cancer and qualified to perform advanced laparoscopic surgery. We analyzed sex, ASA, tumour location, neoadjuvant treatment, surgical technique, operating time, conversion, postoperative complications, length of hospital stay, number of lymph nodes, stage and involvement of margins. Significant differences were observed with regard to surgical time (224 min in the first group, 204 min in the second group), with a higher rate of conversion in the first group (22.5%) than in the second (11.3%). No significant differences were noted for rate of conservative sphincter surgery, length of hospital stay, post-surgical complications, number of affected/isolated lymph nodes or affected circumferential and distal margins. It is possible to learn this complex surgical technique without compromising the patient's safety and oncological outcome. Copyright © 2013 AEC. Published by Elsevier Espana. All rights reserved.

PPARγ Ligands Regulate Noncontractile and Contractile Functions of Airway Smooth Muscle: Implications for Asthma Therapy

Directory of Open Access Journals (Sweden)

Chantal Donovan

2012-01-01

Full Text Available In asthma, the increase in airway smooth muscle (ASM can contribute to inflammation, airway wall remodeling and airway hyperresponsiveness (AHR. Targetting peroxisome proliferator-activated receptor γ (PPARγ, a receptor upregulated in ASM in asthmatic airways, may provide a novel approach to regulate these contributions. This review summarises experimental evidence that PPARγ ligands, such as rosiglitazone (RGZ and pioglitazone (PGZ, inhibit proliferation and inflammatory cytokine production from ASM in vitro. In addition, inhaled administration of these ligands reduces inflammatory cell infiltration and airway remodelling in mouse models of allergen-induced airways disease. PPARγ ligands can also regulate ASM contractility, with acute treatment eliciting relaxation of mouse trachea in vitro through a PPARγ-independent mechanism. Chronic treatment can protect against the loss of bronchodilator sensitivity to β2-adrenoceptor agonists and inhibit the development of AHR associated with exposure to nicotine in utero or following allergen challenge. Of particular interest, a small clinical trial has shown that oral RGZ treatment improves lung function in smokers with asthma, a group that is generally unresponsive to conventional steroid treatment. These combined findings support further investigation of the potential for PPARγ agonists to target the noncontractile and contractile functions of ASM to improve outcomes for patients with poorly controlled asthma.

Treatment with acarbose, an alpha-glucosidase inhibitor, reduces increased albumin excretion in streptozotocin-diabetic rats.

Science.gov (United States)

Cohen, M P; Vasselli, J R; Neuman, R G; Witt, J

1995-10-01

1. We examined the effect of the alpha-glucosidase inhibitor acarbose on urinary albumin excretion (UAE) in streptozotocin diabetic rats. 2. Treatment with acarbose for 8 weeks after induction of diabetes prevented the significant increase in UAE observed in untreated diabetic rats relative to nondiabetic controls. 3. Acarbose significantly reduced integrated glycemia, which correlated with albumin excretion rates, and exerts a salutary effect on diabetic renal dysfunction.

The mitochondrial outer membrane protein mitoNEET is a redox enzyme catalyzing electron transfer from FMNH2 to oxygen or ubiquinone.

Science.gov (United States)

Wang, Yiming; Landry, Aaron P; Ding, Huangen

2017-06-16

Increasing evidence suggests that mitoNEET, a target of the type II diabetes drug pioglitazone, is a key regulator of energy metabolism in mitochondria. MitoNEET is anchored to the mitochondrial outer membrane via its N-terminal α helix domain and hosts a redox-active [2Fe-2S] cluster in its C-terminal cytosolic region. The mechanism by which mitoNEET regulates energy metabolism in mitochondria, however, is not fully understood. Previous studies have shown that mitoNEET specifically interacts with the reduced flavin mononucleotide (FMNH 2 ) and that FMNH 2 can quickly reduce the mitoNEET [2Fe-2S] clusters. Here we report that the reduced mitoNEET [2Fe-2S] clusters can be readily oxidized by oxygen. In the presence of FMN, NADH, and flavin reductase, which reduces FMN to FMNH 2 using NADH as the electron donor, mitoNEET mediates oxidation of NADH with a concomitant reduction of oxygen. Ubiquinone-2, an analog of ubiquinone-10, can also oxidize the reduced mitoNEET [2Fe-2S] clusters under anaerobic or aerobic conditions. Compared with oxygen, ubiquinone-2 is more efficient in oxidizing the mitoNEET [2Fe-2S] clusters, suggesting that ubiquinone could be an intrinsic electron acceptor of the reduced mitoNEET [2Fe-2S] clusters in mitochondria. Pioglitazone or its analog NL-1 appears to inhibit the electron transfer activity of mitoNEET by forming a unique complex with mitoNEET and FMNH 2 The results suggest that mitoNEET is a redox enzyme that may promote oxidation of NADH to facilitate enhanced glycolysis in the cytosol and that pioglitazone may regulate energy metabolism in mitochondria by inhibiting the electron transfer activity of mitoNEET. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

The Effect of Pioglitazone and Resistance Training on Body Composition in Older Men and Women Undergoing Hypocaloric Weight Loss

OpenAIRE

Shea, M. Kyla; Nicklas, Barbara J.; Marsh, Anthony P.; Houston, Denise K.; Miller, Gary D.; Isom, Scott; Miller, Michael E.; Carr, J. Jeffrey; Lyles, Mary F.; Harris, Tamara B.; Kritchevsky, Stephen B.

2011-01-01

Age-related increases in ectopic fat accumulation are associated with greater risk for metabolic and cardiovascular diseases, and physical disability. Reducing skeletal muscle fat and preserving lean tissue are associated with improved physical function in older adults. PPARγ-agonist treatment decreases abdominal visceral adipose tissue (VAT) and resistance training preserves lean tissue, but their effect on ectopic fat depots in nondiabetic overweight adults is unclear. We examined the influ...

Increased viability and resilience of haemolymph cells in blue mussels following pre-treatment with acute high-dose gamma irradiation

Energy Technology Data Exchange (ETDEWEB)

Jaeschke, B. [Stockholm University (Sweden)

2014-07-01

In an initial experiment, blue mussels (Mytilus edulis) were exposed to a range of acute high doses of gamma radiation in the laboratory. Haemolymph was extracted and the haemocytes (blood cells) were scored for cell viability (% living cells) under a microscope, directly after irradiation (0.04, 0.4 or 4 Gy) and again after a subsequent treatment with hydrogen peroxide in vitro (final H{sub 2}O{sub 2} conc.: 0.2 μM). Cell viability in controls (0 Gy) was approximately 100% and no cell death was observable from radiation exposure alone. When treated with H{sub 2}O{sub 2} a decrease in cell viability was seen across all treatments, however this decrease in viability was reduced with increasing radiation pre-treatment (0 Gy = 53%; 0.04 Gy = 66%; 0.4 Gy = 75%; 4 Gy = 83%). To investigate the mechanism for this therapeutic effect observed, the experiment was repeated. Using mussels from a different location, the same, but more extensive method of irradiation (0[control], 0.04, 0.4 Gy, 5 or 40 Gy) and H{sub 2}O{sub 2} treatment was used. Additional haemolymph sub-samples were taken for analysis of catalase concentration. In this second experiment, viability of cells from controls was only 62%, indicating the mussels were in a poorer condition than those of the previous experiment. The lowest level of radiation exposure (0.04 Gy) further decreased the viability (56%). However, at higher doses the viability was increased compared to control, which then gradually declined with increasing dose (0.4 Gy = 75%; 5 Gy = 72%; 40 Gy = 65%). Catalase analysis demonstrated a complimentary pattern of activity of the antioxidant in the haemolymph, directly correlating with radiation dose (0 Gy = 0.2 U; 0.04 Gy = 0.1 U; 0.4 Gy = 1.3 U; 5 Gy = 0.9 U; 40 Gy = 0.1 Gy). Treatment with H{sub 2}O{sub 2} decreased cell viability across all treatments, but no pattern between radiation treatments was discernable. The results indicate that an acute dose of radiation not only has negligible

Opposite effects of pioglitazone and rosiglitazone on mitochondrial respiration in skeletal muscle of patients with type 2 diabetes

DEFF Research Database (Denmark)

Rabøl, R; Boushel, R; Almdal, T

2010-01-01

mitochondrial respiration per milligram muscle was measured in saponin-treated skinned muscle fibres using high-resolution respirometry. RESULTS: Mitochondrial respiration per milligram muscle was lower in T2DM compared to controls at baseline and decreased during ROSI treatment but increased during PIO...... of ROSI and PIO on mitochondrial respiration, and also show that insulin sensitivity can be improved independently of changes in mitochondrial respiration. We confirm that mitochondrial respiration is reduced in T2DM compared to age- and BMI-matched control subjects....

Marrying Step Feed with Secondary Clarifier Improvements to Significantly Increase Peak Wet Weather Treatment Capacity: An Integrated Methodology.

Science.gov (United States)

Daigger, Glen T; Siczka, John S; Smith, Thomas F; Frank, David A; McCorquodale, J A

2017-08-01

  The need to increase the peak wet weather secondary treatment capacity of the City of Akron, Ohio, Water Reclamation Facility (WRF) provided the opportunity to test an integrated methodology for maximizing the peak wet weather secondary treatment capacity of activated sludge systems. An initial investigation, consisting of process modeling of the secondary treatment system and computational fluid dynamics (CFD) analysis of the existing relatively shallow secondary clarifiers (3.3 and 3.7 m sidewater depth in 30.5 m diameter units), indicated that a significant increase in capacity from 416 000 to 684 000 m3/d or more was possible by adding step feed capabilities to the existing bioreactors and upgrading the existing secondary clarifiers. One of the six treatment units at the WRF was modified, and an extensive 2-year testing program was conducted to determine the total peak wet weather secondary treatment capacity achievable. The results demonstrated that a peak wet weather secondary treatment capacity approaching 974 000 m3/d is possible as long as secondary clarifier solids and hydraulic loadings could be separately controlled using the step feed capability provided. Excellent sludge settling characteristics are routinely experienced at the City of Akron WRF, raising concerns that the identified peak wet weather secondary treatment capacity could not be maintained should sludge settling characteristics deteriorate for some reason. Computational fluid dynamics analysis indicated that the impact of the deterioration of sludge settling characteristics could be mitigated and the identified peak wet weather secondary treatment capacity maintained by further use of the step feed capability provided to further reduce secondary clarifier solids loading rates at the identified high surface overflow rates. The results also demonstrated that effluent limits not only for total suspended solids (TSS) and five-day carbonaceous biochemical oxygen demand (cBOD5) could be

Long-term lithium treatment increases intracellular and extracellular brain-derived neurotrophic factor (BDNF) in cortical and hippocampal neurons at subtherapeutic concentrations.

Science.gov (United States)

De-Paula, Vanessa J; Gattaz, Wagner F; Forlenza, Orestes V

2016-12-01

The putative neuroprotective effects of lithium treatment rely on the fact that it modulates several homeostatic mechanisms involved in the neurotrophic response, autophagy, oxidative stress, inflammation, and mitochondrial function. Lithium is a well-established therapeutic option for the acute and long-term management of bipolar disorder and major depression. The aim of this study was to evaluate the effects of subtherapeutic and therapeutic concentrations of chronic lithium treatment on brain-derived neurotrophic factor (BDNF) synthesis and secretion. Primary cultures of cortical and hippocampal neurons were treated with different subtherapeutic (0.02 and 0.2 mM) and therapeutic (2 mM) concentrations of chronic lithium treatment in cortical and hippocampal cell culture. Lithium treatment increased the intracellular protein expression of cortical neurons (10% at 0.02 mM) and hippocampal neurons (28% and 14% at 0.02 mM and 0.2 mM, respectively). Extracellular BDNF of cortical neurons increased 30% and 428% at 0.02 and 0.2 mM, respectively and in hippocampal neurons increased 44% at 0.02 mM. The present study indicates that chronic, low-dose lithium treatment up-regulates BDNF production in primary neuronal cell culture. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Effectiveness of a clinical practice change intervention in increasing the provision of nicotine dependence treatment in inpatient psychiatric facilities: an implementation trial.

Science.gov (United States)

Wye, Paula M; Stockings, Emily A; Bowman, Jenny A; Oldmeadow, Chris; Wiggers, John H

2017-02-07

Despite clinical practice guidelines recommending the routine provision of nicotine dependence treatment to smokers in inpatient psychiatric facilities, the prevalence of such treatment provision is low. The aim of this study was to examine the effectiveness of a clinical practice change intervention in increasing clinician recorded provision of nicotine dependence treatment to patients in inpatient psychiatric facilities. We undertook an interrupted time series analysis of nicotine dependence treatment provision before, during and after a clinical practice change intervention to increase clinician recorded provision of nicotine dependence treatment for all hospital discharges (aged >18 years, N = 4175) over a 19 month period in two inpatient adult psychiatric facilities in New South Wales, Australia. The clinical practice change intervention comprised six key strategies: leadership and consensus, enabling systems and procedures, training and education, information and resources, audit and feedback and an on-site practice change support officer. Systematic medical record audit and segmented logistic regression was used to determine differences in proportions for each nicotine dependence treatment outcome measure between the 'pre', 'during' and 'post-intervention' periods. The prevalence of all five outcome measures increased significantly between the pre and post-intervention periods, including clinician recorded: assessment of patient smoking status (36.43 to 51.95%; adjusted odds ratio [AOR] = 2.39, 99% Confidence Interval [CI]: 1.23 to 4.66); assessment of patient nicotine dependence status (4.74 to 11.04%; AOR = 109.67, 99% CI: 35.35 to 340.22); provision of brief advice to quit (0.85 to 8.81%; AOR = 97.43, 99% CI: 31.03 to 306.30); provision of nicotine replacement therapy (8.06 to 26.25%; AOR = 19.59, 99% CI: 8.17 to 46.94); and provision of nicotine dependence treatment on discharge (8.82 to 13.45%, AOR = 12.36; 99% CI: 6.08 to 25

Potential role of pectate lyase and Ca(2+) in the increase in strawberry fruit firmness induced by short-term treatment with high-pressure CO2.

Science.gov (United States)

Wang, Mao Hua; Kim, Jin Gook; Ahn, Sun Eun; Lee, Ah Youn; Bae, Tae Min; Kim, Deu Re; Hwang, Yong Soo

2014-04-01

Postharvest treatment with high-pressure CO2 helps to control decay and increase firmness in strawberries. Increases in firmness occurred through modification of calcium binding to cell wall. However, the mechanism(s) involved in Ca(2+) migration to pectic polymers and other physiological events associated with the maintenance of increased firmness are not clearly understood. The focus of this study was to find potential mechanism(s) that are associated with calcium movement, increases in firmness, or maintenance of firmness in strawberry fruit after high-pressure CO2 treatment. An increase in firmness was induced by high-pressure CO2 treatment, but not by high-pressure N2 treatment. This indicates that CO2 stimulates a change in firmness. The increase in firmness induced by high-pressure CO2 seems to involve calcium efflux. Using membrane Ca(2+) -dependent ATPase inhibitors sodium vanadate (250 μM) and erythrosin B (100 μM) delayed both the increase in firmness and calcium binding to wall polymers. Exogenous application of CaCl2 (10 mM) enhanced the firmness increase of fruit slices only when they were exposed to high-pressure CO2 . The activity of pectate lyase was downregulated by CO2 treatment, but β-galactosidase activity was not affected. The increase in strawberry firmness induced by high-pressure CO2 treatment primarily involves the efflux of calcium ions and their binding to wall polymers. These physiological changes are not induced by an anaerobic environment. The downregulation of wall-modifying enzymes, such as pectate lyase, appeared to contribute to the maintenance of firmness that was induced by high-pressure CO2 treatment. © 2014 Institute of Food Technologists®

Effect of PPAR γ activators on hypertrophic cardiac myocytes in vitro

International Nuclear Information System (INIS)

Wu Shimin; Zhou Xin; Ye Ping; Wang Qiong; Gao Yue; Liu Yongxue

2004-01-01

Objective: To investigate the effects of peroxisome proliferator-activated receptor γ (PPAR γ) activators pioglitazone and 15-deoxy-Δ 12,14 prostaglandin J 2 (15d-PGJ 2 ) on hypertrophic cardiac myocytes (MC) of neonatal rats in vitro. Methods; With the stimulation of angiotensin II(Ang II), a model of hypertrophy of MC was established. With the method of reverse transcription-polymerase chain reaction (RT-PCR), mRNA expression of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) was amplified; with the aid of NIH Image J software the surface area of MC was analyzed and with 3 H-leucine incorporation, the synthesizing rate of protein in MC was measured. Results: Increases in surface area of MC, mRNA expression of ANP and BNP and 3 H-leucine incorporation in MC were observed in the model of cardiac hypertrophy. Pioglitazone and 15d-PGJ 2 , two kinds of PPAR γ activators, inhibited the above changes in a dose-dependent manner. Conclusion: It is suggested that PPAR γ activators inhibit hypertrophy of cardiac myocytes and PPAR γ-dependent pathway be involved in the inhibitory course

Treatment with native heterodimeric IL-15 increases cytotoxic lymphocytes and reduces SHIV RNA in lymph nodes.

Directory of Open Access Journals (Sweden)

Dionysios C Watson

2018-02-01

Full Text Available B cell follicles in secondary lymphoid tissues represent an immune privileged sanctuary for AIDS viruses, in part because cytotoxic CD8+ T cells are mostly excluded from entering the follicles that harbor infected T follicular helper (TFH cells. We studied the effects of native heterodimeric IL-15 (hetIL-15 treatment on uninfected rhesus macaques and on macaques that had spontaneously controlled SHIV infection to low levels of chronic viremia. hetIL-15 increased effector CD8+ T lymphocytes with high granzyme B content in blood, mucosal sites and lymph nodes, including virus-specific MHC-peptide tetramer+ CD8+ cells in LN. Following hetIL-15 treatment, multiplexed quantitative image analysis (histo-cytometry of LN revealed increased numbers of granzyme B+ T cells in B cell follicles and SHIV RNA was decreased in plasma and in LN. Based on these properties, hetIL-15 shows promise as a potential component in combination immunotherapy regimens to target AIDS virus sanctuaries and reduce long-term viral reservoirs in HIV-1 infected individuals.ClinicalTrials.gov NCT02452268.

Nonalcoholic fatty liver disease: Update on pathogenesis, diagnosis, treatment and the role of S-adenosylmethionine

Science.gov (United States)

Mato, José M; Lu, Shelly C

2015-01-01

Nonalcoholic fatty liver disease (NAFLD) is currently the most common liver disease worldwide affecting over one-third of the population in the U.S. It has been associated with obesity, type 2 diabetes, hyperlipidemia, and insulin resistance and is initiated by the accumulation of triglycerides in hepatocytes. Isolated hepatic steatosis (IHS) remains a benign process, while a subset develops superimposed inflammatory activity and progression to nonalcoholic steatohepatitis (NASH) with or without fibrosis. However, the molecular mechanisms underlying NAFLD progression are not completely understood. Liver biopsy is still required to differentiate IHS from NASH as easily accessible noninvasive biomarkers are lacking. In terms of treatments for NASH, pioglitazone, vitamin E, and obeticholic acid have shown some benefit. All of these agents have potential complications associated with long-term use. Nowadays, a complex hypothesis suggests that multiple parallel hits are involved in NASH development. However, the ‘key switch’ between IHS and NASH remains to be discovered. We have recently shown that knocking out enzymes involved in S-adenosylmethionine (SAMe) metabolism, the main biological methyl donor in humans that is abundant in the liver, will lead to NASH development in mice. This could be due to the fact that a normal SAMe level is required to establish the proper ratio of phosphatidylethanolamine to phosphatidylcholine that has been found to be important in NAFLD progression. New data from humans have also suggested that these enzymes play a role in the pathogenesis of NAFLD and that some of SAMe cycle metabolites may serve as noninvasive biomarkers of NASH. In this review, we discuss the evidence of the role of SAMe in animal models and humans with NAFLD and how studying this area may lead to the discovery of new noninvasive biomarkers and possibly personalized treatment for NASH. PMID:25873078

Antidepressant-like effect of atorvastatin in the forced swimming test in mice: the role of PPAR-gamma receptor and nitric oxide pathway.

Science.gov (United States)

Shahsavarian, Arash; Javadi, Shiva; Jahanabadi, Samane; Khoshnoodi, Mina; Shamsaee, Javad; Shafaroodi, Hamed; Mehr, Shahram Ejtemaei; Dehpour, Ahmadreza

2014-12-15

Atorvastatin is a synthetic and lipophilic statin which has been reported to have a positive role in reducing depression. The potential antidepressant-like effects of atorvastatin and the possible involvement of peroxisome proliferator-activated receptor gamma (PPAR_γ) and nitric oxide system were determined using forced swimming test (FST) in mice was studied. Atorvastatin (0.01, 0.1 and 1 mg/kg, p.o.) was administered 1 h before FST. To assess the involvement of PPAR_γ in the possible antidepressant effect of atorvastatin, pioglitazone, a PPAR_γ agonist (5 mg/kg), and GW-9662, a specific PPAR_γ antagonist (2 mg/kg), was co-administered with atorvastatin (0.01 mg/kg, p.o.) and then FST was performed. The possible role of nitric oxide pathway was determined by using co-administration of a non-specific NOS inhibitor, N-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg, i.p.), and a NO precursor, L-arginine (750 mg/kg, i.p.) with sub-effective doses of atorvastatin and pioglitazone. Immobility time was significantly decreased after atorvastatin administration (0.1 and 1 mg/kg, p.o.). Administration of pioglitazone or L-NAME in combination with the sub-effective dose of atorvastatin (0.01 mg/kg, p.o.) reduced the immobility time in the FST compared to drugs alone, showing the participation of these pathways; while co-administration of non-effective doses of atorvastatin and pioglitazone with GW9662 or L-arginine reversed antidepressant-like effect of atorvastatin in FST. Data from concurrent use of GW9662 and atorvastatin also demonstrated that the antidepressant effect of atorvastatin was significantly reversed by GW9662. The antidepressant-like effect of atorvastatin on mice in the FST is mediated at least in part through PPAR_γ receptors and NO pathway. Copyright © 2014 Elsevier B.V. All rights reserved.

Suicidal changes in patients with first episode psychosis: clinical predictors of increasing suicidal tendency in the early treatment phase

DEFF Research Database (Denmark)

Madsen, Trine; Nordentoft, Merete

2012-01-01

significantly predicted developing a higher suicidal tendency, whereas a one-point increase score on delusions was preventive of this. Feeling hopeless was highly associated with suicide attempt in those with earlier suicide attempt. Conclusion: The risk of suicide attempt did not differ between patient groups......Aim: To identify predictors for developing a higher suicidal tendency during treatment of first-episode psychosis. Methods: In a prospective follow-up study, we examined clinical factors collected at treatment initiation as predictors for developing a higher suicidal tendency among patients...... in the first year of treatment of psychosis. Patients were grouped and ranked according to their highest suicidal tendency in the year before treatment: not suicidal, suicidal thoughts, suicidal plans or suicide attempt(s). Predictors for becoming more suicidal in the first year of treatment were examined...

The potential use of genetics to increase the effectiveness of treatment programs for criminal offenders.

Science.gov (United States)

Beaver, Kevin M; Jackson, Dylan B; Flesher, Dillon

2014-01-01

During the past couple of decades, the amount of research examining the genetic underpinnings to antisocial behaviors, including crime, has exploded. Findings from this body of work have generated a great deal of information linking genetics to criminal involvement. As a partial result, there is now a considerable amount of interest in how these findings should be integrated into the criminal justice system. In the current paper, we outline the potential ways that genetic information can be used to increase the effectiveness of treatment programs designed to reduce recidivism among offenders. We conclude by drawing attention to how genetic information can be used by rehabilitation programs to increase program effectiveness, reduce offender recidivism rates, and enhance public safety.

Combining antiangiogenic therapy with neoadjuvant chemotherapy increases treatment efficacy in stage IIIA (N2) non-small cell lung cancer without increasing adverse effects.

Science.gov (United States)

Zhao, Xiaoliang; Su, Yanjun; You, Jian; Gong, Liqun; Zhang, Zhenfa; Wang, Meng; Zhao, Zhenqing; Zhang, Zhen; Li, Xiaolin; Wang, Changli

2016-09-20

To evaluate the safety and efficacy of combining Endostar antiangiogenic therapy with neoadjuvant chemotherapy for the treatment of stage IIIA (N2) NSCLC, we conducted a randomized, controlled, open-label clinical study of 30 NSCLC patients. Patients were randomly assigned to the test or control groups, which received either two cycles of an NP neoadjuvant chemotherapy regimen combined with Endostar or the NP regimen alone, respectively, at a 2:1 ratio. Efficacy was assessed after 3 weeks, and surgical resection occurred within 4 weeks, in the 26 patients who successfully completed treatment. While total response rates (RR) and clinical benefit rates (CBR) did not differ between the experimental groups, total tumor regression rates (TRR) were higher in the test group than in the control group. Median DFS and OS also did not differ between the test and control groups. Clinical perioperative indicators, including intraoperative blood loss, number of dissected lymph node groups, duration of postoperative indwelling catheter use, and time to postoperative discharge, were comparable in the test and control groups. Finally, hematological and non-hematological toxicities and postoperative pathological indicators, including down-staging ratio, complete resection ratio, and metastatic lymph node ratio, also did not differ between the groups. Overall, combining Endostar with NP neoadjuvant chemotherapy increased therapeutic efficacy without increasing adverse effects in stage IIIA-N2 NSCLC patients. This study is registered with ClinicalTrials.gov (number NCT02497118).

Statin treatment prevents increased cardiovascular and all-cause mortality associated with clarithromycin in patients with stable coronary heart disease

DEFF Research Database (Denmark)

Jensen, Gorm B; Hilden, Jørgen; Als-Nielsen, Bodil

2010-01-01

In the CLARICOR trial, significantly increased cardiovascular (CV) and all-cause mortality in stable patients with coronary heart disease were observed after a short course of clarithromycin. We report on the impact of statin treatment at entry on the CV and all-cause mortality. The multicenter...... CLARICOR trial randomized patients to oral clarithromycin (500 mg daily; n = 2172) versus matching placebo (daily; n = 2201) for 2 weeks. Patients were followed through public databases. In the 41% patients on statin treatment at entry, no significant effect of clarithromycin was observed on CV (hazard...... ratio [HR], 0.68, 95% confidence interval [CI], 0.38-1.22; P = 0.20) or all-cause mortality (HR, 1.08; 95% CI, 0.71-1.65; P = 0.72) at 2.6-year follow up. In the patients not on statin treatment at entry, clarithromycin was associated with a significant increase in CV (HR, 1.90; 95% CI, 1.34-2.67; P = 0...

Dynamic changes in dopamine neuron function after DNSP-11 treatment: effects in vivo and increased ERK 1/2 phosphorylation in vitro.

Science.gov (United States)

Fuqua, Joshua L; Littrell, Ofelia M; Lundblad, Martin; Turchan-Cholewo, Jadwiga; Abdelmoti, Lina G; Galperin, Emilia; Bradley, Luke H; Cass, Wayne A; Gash, Don M; Gerhardt, Greg A

2014-04-01

Glial cell-line derived neurotrophic factor (GDNF) has demonstrated robust effects on dopamine (DA) neuron function and survival. A post-translational processing model of the human GDNF proprotein theorizes the formation of smaller, amidated peptide(s) from the proregion that exhibit neurobiological function, including an 11-amino-acid peptide named dopamine neuron stimulating peptide-11 (DNSP-11). A single treatment of DNSP-11 was delivered to the substantia nigra in the rat to investigate effects on DA-neuron function. Four weeks after treatment, potassium (K+) and D-amphetamine evoked DA release were studied in the striatum using microdialysis. There were no significant changes in DA-release after DNSP-11 treatment determined by microdialysis. Dopamine release was further examined in discrete regions of the striatum using high-speed chronoamperometry at 1-, 2-, and 4-weeks after DNSP-11 treatment. Two weeks after DNSP-11 treatment, potassium-evoked DA release was increased in specific subregions of the striatum. However, spontaneous locomotor activity was unchanged by DNSP-11 treatment. In addition, we show that a single treatment of DNSP-11 in the MN9D dopaminergic neuronal cell line results in phosphorylation of ERK1/2, which suggests a novel cellular mechanism responsible for increases in DA function. Copyright © 2014 Elsevier Inc. All rights reserved.

Increased Resilience is Associated with Positive Treatment Outcomes for Veterans with Comorbid PTSD and Substance Use Disorders.

Science.gov (United States)

McGuire, Adam P; Mota, Natalie P; Sippel, Lauren M; Connolly, Kevin M; Lyons, Judith A

2018-04-18

Resilience has been associated with less severe psychiatric symptomatology and better treatment outcomes among individuals with posttraumatic stress disorder (PTSD) and substance use disorders. However, it remains unknown whether resilience increases during psychotherapy within the comorbid PTSD and substance use disorder population with unique features of dual diagnosis, including trauma cue-related cravings. We tested whether veterans seeking psychotherapy for comorbid PTSD and substance use disorder reported increased resilience from pre- to posttreatment. We also tested whether increased resilience was associated with greater decreases in posttreatment PTSD and substance use disorder symptoms. Participants were 29 male veterans (M age = 49.07 years, SD = 11.24 years) receiving six-week residential day treatment including cognitive processing therapy for PTSD and cognitive behavioral therapy for substance use disorder. Resilience, PTSD symptoms, and trauma cue-related cravings were assessed at pre- and posttreatment. Veterans reported a large, significant increase in resilience posttreatment (M diff = 14.24, t = -4.22, p resilience were significantly associated with fewer PTSD symptoms (β = -0.37, p = .049, sr = -.36) and trauma-cued cravings (β = -0.39, p = .006, sr = -.38) posttreatment when controlling for pretreatment scores and baseline depressive symptoms. Results suggest that evidence-based psychotherapy for comorbid PTSD and substance use disorder may facilitate strength-based psychological growth, which may further promote sustained recovery.

Temporary increase in serum beta 2-microglobulin during treatment with interferon-alpha for AIDS-associated Kaposi's sarcoma

NARCIS (Netherlands)

de Wit, R.; Bakker, P. J.; Reiss, P.; Hoek, F. J.; Lange, J. M.; Goudsmit, J.; Veenhof, K. H.

1990-01-01

Beta 2-microglobulin (beta 2-M) levels were determined in the serum of 24 patients treated with high-dose human recombinant interferon-alpha (IFN alpha) for AIDS-associated Kaposi's sarcoma. There was a significant increase in serum beta 2-M levels, irrespective of the response to treatment.

Increased extravasation and lymphatic return rate of albumin during diuretic treatment of ascites in patients with liver cirrhosis

DEFF Research Database (Denmark)

Henriksen, Jens Henrik Sahl; Schlichting, P

1981-01-01

During steady state the overall lymphatic return rate of albumin equals the transvascular escape rate of albumin [TERalb, i.e. the fraction of intravascular mass of albumin (IVMalb) passing to the extravascular space per unit time] provided local back-transport is negligible, as previously substa......), indicating a net transport of albumin from the peritoneal cavity to the plasma during diuretic treatment. The results suggest an increased lymphatic drainage of albumin during diuretic treatment, which may play a role in amelioration of cirrhotic ascites....

The novel 2Fe–2S outer mitochondrial protein mitoNEET displays conformational flexibility in its N-terminal cytoplasmic tethering domain

International Nuclear Information System (INIS)

Conlan, Andrea R.; Paddock, Mark L.; Axelrod, Herbert L.; Cohen, Aina E.; Abresch, Edward C.; Wiley, Sandra; Roy, Melinda; Nechushtai, Rachel; Jennings, Patricia A.

2009-01-01

The crystal structure of the anti-diabetic drug target mitoNEET obtained from a GFP fusion construct (1.4 Å resolution, R factor = 20.2%) shows that the CDGSH 2Fe–2S binding domains are superimposable with previously determined non-fused constructs. However, there is considerable flexibility in the position of the outer mitochondrial tethering arms resulting in two different conformations in the crystal structure. A primary role for mitochondrial dysfunction is indicated in the pathogenesis of insulin resistance. A widely used drug for the treatment of type 2 diabetes is pioglitazone, a member of the thiazolidinedione class of molecules. MitoNEET, a 2Fe–2S outer mitochondrial membrane protein, binds pioglitazone [Colca et al. (2004 ▶), Am. J. Physiol. Endocrinol. Metab.286, E252–E260]. The soluble domain of the human mitoNEET protein has been expressed C-terminal to the superfolder green fluorescent protein and the mitoNEET protein has been isolated. Comparison of the crystal structure of mitoNEET isolated from cleavage of the fusion protein (1.4 Å resolution, R factor = 20.2%) with other solved structures shows that the CDGSH domains are superimposable, indicating proper assembly of mitoNEET. Furthermore, there is considerable flexibility in the position of the cytoplasmic tethering arms, resulting in two different conformations in the crystal structure. This flexibility affords multiple orientations on the outer mitochondrial membrane

Use of thiazolidinediones and risk of bladder cancer

DEFF Research Database (Denmark)

Bazelier, Marloes T; de Vries, Frank; Vestergaard, Peter

2013-01-01

BACKGROUND: Pioglitazone, a drug for the treatment of type 2 diabetes mellitus has been associated with bladder cancer in observational studies. Diabetes mellitus itself has also been linked with bladder cancer. The objective was to estimate the risk of bladder cancer for diabetic patients using...... thialozidinediones (TZDs) compared with patients in other treatment stages of the disease. METHODS: We performed a population-based cohort study (1996-2007) in the Danish National Health Registers. Oral antidiabetic drug users (n=179,056) were matched 1:3 by sex and year of birth to non-users. Hazard ratios (HRs......) of bladder cancer were estimated using Cox proportional hazards models. Time-dependent adjustments were made for age, comorbidity, and drug use. Four different treatment stages were defined: current use of either a biguanide or a sulfonylureum (stage 1), current use of a biguanide and a sulfonylureum...

The potential of natural products for targeting PPARα

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Daniela Rigano

2017-07-01

Full Text Available Peroxisome proliferator activated receptors (PPARs α, -γ and -β/δ are ligand-activated transcription factors and members of the superfamily of nuclear hormone receptor. These receptors play key roles in maintaining glucose and lipid homeostasis by modulating gene expression. PPARs constitute a recognized druggable target and indeed several classes of drugs used in the treatment of metabolic disease symptoms, such as dyslipidemia (fibrates, e.g. fenofibrate and gemfibrozil and diabetes (thiazolidinediones, e.g. rosiglitazone and pioglitazone are ligands for the various PPAR isoforms. More precisely, antidiabetic thiazolidinediones act on PPARγ, while PPARα is the main molecular target of antidyslipidemic fibrates. Over the past few years, our understanding of the mechanism underlying the PPAR modulation of gene expression has greatly increased. This review presents a survey on terrestrial and marine natural products modulating the PPARα system with the objective of highlighting how the incredible chemodiversity of natural products can provide innovative leads for this “hot” target.

Increased risk of gastric adenocarcinoma after treatment of primary gastric diffuse large B-cell lymphoma

International Nuclear Information System (INIS)

Inaba, Koji; Morota, Madoka; Mayahara, Hiroshi; Ito, Yoshinori; Sumi, Minako; Uno, Takashi; Itami, Jun; Kushima, Ryoji; Murakami, Naoya; Kuroda, Yuuki; Harada, Ken; Kitaguchi, Mayuka; Yoshio, Kotaro; Sekii, Shuhei; Takahashi, Kana

2013-01-01

There have been sporadic reports about synchronous as well as metachronous gastric adenocarcinoma and primary gastric lymphoma. Many reports have dealt with metachronous gastric adenocarcinoma in mucosa-associated lymphoid tissue lymphoma of stomach. But to our knowledge, there have been no reports that document the increased incidence of metachronous gastric adenocarcinoma in patients with gastric diffuse large B-cell lymphoma. This retrospective study was conducted to estimate the incidence of metachronous gastric adenocarcinoma after primary gastric lymphoma treatment, especially in diffuse large B-cell lymphoma. The retrospective cohort study of 139 primary gastric lymphoma patients treated with radiotherapy at our hospital. Mean observation period was 61.5 months (range: 3.7-124.6 months). Patients profile, characteristics of primary gastric lymphoma and metachronous gastric adenocarcinoma were retrieved from medical records. The risk of metachronous gastric adenocarcinoma was compared with the risk of gastric adenocarcinoma in Japanese population. There were 10 (7.2%) metachronous gastric adenocarcinoma patients after treatment of primary gastric lymphomas. It was quite high risk compared with the risk of gastric carcinoma in Japanese population of 54.7/100,000. Seven patients of 10 were diffuse large B-cell lymphoma and other 3 patients were mixed type of diffuse large B-cell lymphoma and mucosa associated lymphoid tissue lymphoma. Four patients of 10 metachronous gastric adenocarcinomas were signet-ring cell carcinoma and two patients died of gastric adenocarcinoma. Metachronous gastric adenocarcinoma may have a more malignant potential than sporadic gastric adenocarcinoma. Old age, Helicobacter pylori infection and gastric mucosal change of chronic gastritis and intestinal metaplasia were possible risk factors for metachronous gastric adenocarcinoma. There was an increased risk of gastric adenocarcinoma after treatment of primary gastric lymphoma

Bodypacking - An increasing problem in the Netherlands: Conservative or surgical treatment?

NARCIS (Netherlands)

van Geloven, A. A. W.; van Lienden, K. P.; Gouma, D. J.

2002-01-01

Objective: Evaluation of diagnostic work-up and treatment of bodypackers. Identification of predictive factors for surgical treatment. Design: Retrospective descriptive study. Setting: Teaching hospital, The Netherlands. Patients: All 40 consecutive patients, admitted during the period 1995-99

Increased platelet expression of glycoprotein IIIa following aspirin treatment in aspirin-resistant but not aspirin-sensitive subjects

Science.gov (United States)

Floyd, Christopher N; Goodman, Timothy; Becker, Silke; Chen, Nan; Mustafa, Agnesa; Schofield, Emma; Campbell, James; Ward, Malcolm; Sharma, Pankaj; Ferro, Albert

2014-01-01

Aims Aspirin is widely used as an anti-platelet agent for cardiovascular prophylaxis. Despite aspirin treatment, many patients experience recurrent thrombotic events, and aspirin resistance may contribute to this. We examined the prevalence of aspirin resistance in a healthy population, and investigated whether the platelet proteome differed in aspirin-resistant subjects. Methods Ninety-three healthy subjects received aspirin 300 mg daily for 28 days. Before and at the end of treatment, urine was taken to determine 11-dehydrothromboxane B2, and blood was taken to measure arachidonic acid (AA)-induced aggregation of platelet-rich plasma and to interrogate the platelet proteome by mass spectrometric analysis with further confirmation of findings using Western blotting. Results In two of the 93 subjects, neither AA-induced aggregation nor urinary 11-dehydrothromboxane B2 was effectively suppressed by aspirin, despite measurable plasma salicylate concentrations, suggesting the presence of true aspirin resistance. Despite no detectable differences in the platelet proteome at baseline, following aspirin a marked increase was seen in platelet glycoprotein IIIa expression in the aspirin-resistant but not aspirin-sensitive subjects. An increase in platelet glycoprotein IIIa expression with aspirin resistance was confirmed in a separate cohort of 17 patients with stable coronary artery disease on long term aspirin treatment, four of whom exhibited aspirin resistance. Conclusions In a healthy population, true aspirin resistance is uncommon but exists. Resistance is associated with an increase in platelet glycoprotein IIIa expression in response to aspirin. These data shed new light on the mechanism of aspirin resistance, and provide the potential to identify aspirin-resistant subjects using a novel biomarker. PMID:25099258

Mung bean nuclease treatment increases capture specificity of microdroplet-PCR based targeted DNA enrichment.

Directory of Open Access Journals (Sweden)

Zhenming Yu

Full Text Available Targeted DNA enrichment coupled with next generation sequencing has been increasingly used for interrogation of select sub-genomic regions at high depth of coverage in a cost effective manner. Specificity measured by on-target efficiency is a key performance metric for target enrichment. Non-specific capture leads to off-target reads, resulting in waste of sequencing throughput on irrelevant regions. Microdroplet-PCR allows simultaneous amplification of up to thousands of regions in the genome and is among the most commonly used strategies for target enrichment. Here we show that carryover of single-stranded template genomic DNA from microdroplet-PCR constitutes a major contributing factor for off-target reads in the resultant libraries. Moreover, treatment of microdroplet-PCR enrichment products with a nuclease specific to single-stranded DNA alleviates off-target load and improves enrichment specificity. We propose that nuclease treatment of enrichment products should be incorporated in the workflow of targeted sequencing using microdroplet-PCR for target capture. These findings may have a broad impact on other PCR based applications for which removal of template DNA is beneficial.

Increasing Treatment Seeking Among At-Risk Service Members Returning from Warzones

Science.gov (United States)

2017-03-01

intervention improves attitudes toward behavioral health treatment and initiation of treatment. Advertisements are used to recruit service members...involve guns, cutting, car accidents, and carbon monoxide poisoning. We have had four participants die during the trial. One participant died from

TREATMENTS OF PLASMA CORONA RADIATION ON SEAWEED Gracilaria Verrucosa (HUDSON PAPENFUSS: Efforts to increase growth and biomass

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Filemon Jalu N Putra

2014-12-01

Full Text Available Gracilaria verrucosa (Hudson Papenfuss has great potential to be farmed in the water resources in Indonesia. As natural resource, the weed has a major contribution in the field of industry both for human food and health. Efforts have been done intensively to increase the production capacity to meet the market demand especially gelatin, both national and international market. One of them is the application of plasma corona irradiation treatments on the weed to improve developmental pathways. The concept of plasma irradiation performed at atmospheric conditions may impact on nitrogen intrusion pathway that is important element in the growth of the weed. The aims of this study are to assess the potential impact of plasma irradiation in improving the growth of G. verrucosa and thus increase their biomass production. The treatments were done using five different duration of plasma irradiation, which were 2, 4, 6, 8, and 10 minutes at a 0,5mA stable source of voltage and 8kV of electrical current. Observations of growth rate include thallus length and biomass of G. verrucosa , that was observed every week for 28 days. The result showed that the growth of weed exhibited better than those without radiation. The best growth was reached in the group of treatment of 8 minutes irradiation, exhibited 65,91g of biomass and 9.5515% growth rate and length of thallus reached 22,33 cm and daily growth rate of 2.9759%. The lowest growth of the weed occurred in the treatment of 10 minutes irradiation, which was 44,82 g biomass, 8.123% growth rate, 17,13 cm thallus length with a daily growth rate of 1.9942%

Increasing complexity: which drug class to choose for treatment of hypertension in the elderly?

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Kaiser EA

2014-03-01

Full Text Available Edelgard Anna Kaiser,1 Ulrich Lotze,2 Hans Hendrik Schäfer1,31Roche Diagnostics International AG, Rotkreuz, Switzerland; 2Department of Internal Medicine, DRK-Manniske-Krankenhaus Bad Frankenhausen, Bad Frankenhausen, Germany; 3Institute of Anatomy II, University Hospital Jena, Friedrich-Schiller University, Jena, GermanyAbstract: Treatment of hypertension in the elderly is expected to become more complex in the coming decades. Based on the current landscape of clinical trials, guideline recommendations remain inconclusive. The present review discusses the latest evidence derived from studies available in 2013 and investigates optimal blood pressure (BP and preferred treatment substances. Three common archetypes are discussed that hamper the treatment of hypertension in the very elderly. In addition, this paper presents the current recommendations of the NICE 2011, JNC7 2013-update, ESH/ESC 2013, CHEP 2013, JNC8 and ASH/ISH guidelines for elderly patients. Advantages of the six main substance classes, namely diuretics, beta-blockers (BBs, calcium channel blockers (CCBs, angiotensin-converting enzyme inhibitors (ACEIs, angiotensin receptor blockers (ARBs, and direct renin inhibitors (DRIs are discussed. Medical and economic implications of drug administration in the very elderly are presented. Avoidance of treatment-related adverse effects has become increasingly relevant. Current substance classes are equally effective, with similar effects on cardiovascular outcomes. Selection of substances should therefore also be based on collateral advantages of drugs that extend beyond BP reduction. The combination of ACEIs and diuretics appears to be favorable in managing systolic/diastolic hypertension. Diuretics are a preferred and cheap combination drug, and the combination with CCBs is recommended for patients with isolated systolic hypertension. ACEIs and CCBs are favorable for patients with dementia, while CCBs and ARBs imply substantial cost

Remediation of incomplete nitrification and capacity increase of biofilters at different drinking water treatment plants through copper dosing

DEFF Research Database (Denmark)

Wagner, Florian Benedikt; Borch Nielsen, Peter; Boe-Hansen, Rasmus

2018-01-01

Drinking water treatment plants based on groundwater may suffer from incomplete ammonium removal, which deteriorates drinking water quality and constrains water utilities in the operation of their plants. Ammonium is normally removed through nitrification in biological granular media filters...... groundwater treatment plants, all of which had displayed several years of incomplete nitrification. Plants exceeded the Danish national water quality standard of 0.05 mg NH4+/L by a factor of 2–12. Within only 2-3 weeks of dosing, ammonium removal rates increased significantly (up to 150%). Nitrification...... was fully established, with ammonium effluent concentrations of water chemistry, ammonium loading rates, filter design and operation, or treatment plant configuration. However, for filters without primary filtration, it took longer time...

Remediation of incomplete nitrification and capacity increase of biofilters at different drinking water treatment plants through copper dosing.

Science.gov (United States)

Wagner, Florian B; Nielsen, Peter Borch; Boe-Hansen, Rasmus; Albrechtsen, Hans-Jørgen

2018-04-01

Drinking water treatment plants based on groundwater may suffer from incomplete ammonium removal, which deteriorates drinking water quality and constrains water utilities in the operation of their plants. Ammonium is normally removed through nitrification in biological granular media filters, and recent studies have demonstrated that dosing of copper can stimulate the removal of ammonium. Here, we investigated if copper dosing could generically improve ammonium removal of biofilters, at treatment plants with different characteristics. Copper was dosed at ≤1.5 μg Cu/L to biofilters at 10 groundwater treatment plants, all of which had displayed several years of incomplete nitrification. Plants exceeded the Danish national water quality standard of 0.05 mg NH 4 + /L by a factor of 2-12. Within only 2-3 weeks of dosing, ammonium removal rates increased significantly (up to 150%). Nitrification was fully established, with ammonium effluent concentrations of plants, regardless of the differences in raw water chemistry, ammonium loading rates, filter design and operation, or treatment plant configuration. However, for filters without primary filtration, it took longer time to reach complete ammonium removal than for filters receiving prefiltered water, likely due to sorption of copper to iron oxides, at plants without prefiltration. With complete ammonium removal, we subjected two plants to short-term loading rate upshifts, to examine the filters' ability to cope with loading rate variations. After 2 months of dosing and an average loading rate of 1.0 g NH 4 + -N/m 3 filter material/h, the loading rate was upshifted by 50%. Yet, a filter managed to completely remove all the influent ammonium, showing that with copper dosing the filter had extra capacity to remove ammonium even beyond its normal loading rates. Depth sampling revealed that the ammonium removal rate of the filter's upper 10 cm increased more than 7-fold from 0.67 to 4.90 g NH 4 + -N/m 3 /h, and

Acute Stimulant Treatment and Reinforcement Increase the Speed of Information Accumulation in Children with ADHD.

Science.gov (United States)

Fosco, Whitney D; White, Corey N; Hawk, Larry W

2017-07-01

The current studies utilized drift diffusion modeling (DDM) to examine how reinforcement and stimulant medication affect cognitive task performance in children with ADHD. In Study 1, children with (n = 25; 88 % male) and without ADHD (n = 33; 82 % male) completed a 2-choice discrimination task at baseline (100 trials) and again a week later under alternating reinforcement and no-reinforcement contingencies (400 trials total). In Study 2, participants with ADHD (n = 29; 72 % male) completed a double-blind, placebo-controlled trial of 0.3 and 0.6 mg/kg methylphenidate and completed the same task utilized in Study 1 at baseline (100 trials). Children with ADHD accumulated information at a much slower rate than controls, as evidenced by a lower drift rate. Groups were similar in nondecision time and boundary separation. Both reinforcement and stimulant medication markedly improved drift rate in children with ADHD (ds = 0.70 and 0.95 for reinforcement and methylphenidate, respectively); both treatments also reduced boundary separation (ds = 0.70 and 0.39). Reinforcement, which emphasized speeded accuracy, reduced nondecision time (d = 0.37), whereas stimulant medication increased nondecision time (d = 0.38). These studies provide initial evidence that frontline treatments for ADHD primarily impact cognitive performance in youth with ADHD by improving the speed/efficiency of information accumulation. Treatment effects on other DDM parameters may vary between treatments or interact with task parameters (number of trials, task difficulty). DDM, in conjunction with other approaches, may be helpful in clarifying the specific cognitive processes that are disrupted in ADHD, as well as the basic mechanisms that underlie the efficacy of ADHD treatments.

The Hepatitis C Genotype 1 Paradox: Cost per Treatment Is Increasing, but Cost per Cure Is Decreasing

Directory of Open Access Journals (Sweden)

Stephen D Shafran

2015-01-01

Full Text Available Significant attention has been focused on the perceived increase in the cost of antiviral treatment for hepatitis C genotype 1 infection since the approval of the first direct-acting antiviral agents in 2011. Using Canadian list prices, the present analysis points out a paradox: while the cost per antiviral regimen is increasing, the cost per cure is decreasing, especially with interferon-free therapy. In a publicly funded health care system, the lowest cost per cure is a more valuable measure of value for public money than the cost per regimen.

The hepatitis C genotype 1 paradox: cost per treatment is increasing, but cost per cure is decreasing.

Science.gov (United States)

Shafran, Stephen D

2015-01-01

Significant attention has been focused on the perceived increase in the cost of antiviral treatment for hepatitis C genotype 1 infection since the approval of the first direct-acting antiviral agents in 2011. Using Canadian list prices, the present analysis points out a paradox: while the cost per antiviral regimen is increasing, the cost per cure is decreasing, especially with interferon-free therapy. In a publicly funded health care system, the lowest cost per cure is a more valuable measure of value for public money than the cost per regimen.

Increasing the Environmental Sustainability of Sewage Treatment by Mitigating Pollutant Pathways

NARCIS (Netherlands)

Rulkens, W.H.

2006-01-01

The current centralized systems for sewage treatment are highly efficient with respect to the removal of COD and nutrients and the production of an effluent that can be discharged on surface water. However, from an environmental point of view the sewage treatment process is still far from being

The treatment of type 2 diabetes in the presence of renal impairment: what we should know about newer therapies

Directory of Open Access Journals (Sweden)

Davies M

2016-06-01

Full Text Available Melanie Davies,1,2 Sudesna Chatterjee,1,2 Kamlesh Khunti1,2 1Diabetes Research Centre, University of Leicester, 2Leicester Diabetes Centre, University Hospitals of Leicester NHS Trust, Leicester, UK Abstract: Worldwide, an estimated 200 million people have chronic kidney disease (CKD, the most common causes of which include hypertension, arteriosclerosis, and diabetes. Importantly, ~40% of patients with diabetes develop CKD, yet evidence from major multicenter randomized controlled trials shows that intensive blood glucose control through pharmacological intervention can reduce the incidence and progression of CKD. Standard therapies for the treatment of type 2 diabetes include metformin, sulfonylureas, meglitinides, thiazolidinediones, and insulin. While these drugs have an important role in the management of type 2 diabetes, only the thiazolidinedione pioglitazone can be used across the spectrum of CKD (stages 2–5 and without dose adjustment; there are contraindications and dose adjustments required for the remaining standard therapies. Newer therapies, particularly dipeptidyl peptidase-IV inhibitors, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter-2 inhibitors, are increasingly being used in the treatment of type 2 diabetes; however, a major consideration is whether these newer therapies can also be used safely and effectively across the spectrum of renal impairment. Notably, reductions in albuminuria, a marker of CKD, are observed with many of the drug classes. Dipeptidyl peptidase-IV inhibitors can be used in all stages of renal impairment, with appropriate dose reduction, with the exception of linagliptin, which can be used without dose adjustment. No dose adjustment is required for liraglutide, albiglutide, and dulaglutide in CKD stages 2 and 3, although all glucagon-like peptide-1 receptor agonists are currently contraindicated in stages 4 and 5 CKD. At stage 3 CKD or greater, the sodium

Methadone dose increase and abstinence reinforcement for treatment of continued heroin use during methadone maintenance.

Science.gov (United States)

Preston, K L; Umbricht, A; Epstein, D H

2000-04-01

Although methadone maintenance is an effective therapy for heroin dependence, some patients continue to use heroin and may benefit from therapeutic modifications. This study evaluated a behavioral intervention, a pharmacological intervention, and a combination of both interventions. Throughout the study all patients received daily methadone hydrochloride maintenance (initially 50 mg/d orally) and weekly counseling. Following baseline treatment patients who continued to use heroin were randomly assigned to 1 of 4 interventions: (1) contingent vouchers for opiate-negative urine specimens (n = 29 patients); (2) methadone hydrochloride dose increase to 70 mg/d (n = 31 patients); (3) combined contingent vouchers and methadone dose increase (n = 32 patients); and (4) neither intervention (comparison standard; n = 28 patients). Methadone dose increases were double blind. Vouchers had monetary value and were exchangeable for goods and services. Groups not receiving contingent vouchers received matching vouchers independent of urine test results. Primary outcome measure was opiate-negative urine specimens (thrice weekly urinalysis). Contingent vouchers and a methadone dose increase each significantly increased the percentage of opiate-negative urine specimens during intervention. Contingent vouchers, with or without a methadone dose increase, increased the duration of sustained abstinence as assessed by urine screenings. Methadone dose increase, with or without contingent vouchers, reduced self-reported frequency of use and self-reported craving. In patients enrolled in a methadone-maintainence program who continued to use heroin, abstinence reinforcement and a methadone dose increase were each effective in reducing use. When combined, they did not dramatically enhance each other's effects on any 1 outcome measure, but they did seem to have complementary benefits.

Increasing spelling achievement: an analysis of treatment procedures utilizing an alternating treatments design.

OpenAIRE

Ollendick, T H; Matson, J L; Esveldt-Dawson, K; Shapiro, E S

1980-01-01

Two studies which examine the effectiveness of spelling remediation procedures are reported. In both studies, an alternating treatment design was employed. In the first study, positive practice overcorrection plus positive reinforcement was compared to positive practice alone and a no-remediation control condition. In the second study, positive practice plus positive reinforcement was compared to a traditional corrective procedure plus positive reinforcement and a traditional procedure when u...

Combination of aging and dimethylhydrazine treatment causes an increase in cancer-stem cell population of rat colonic crypts.

Science.gov (United States)

Levi, Edi; Misra, Sandhya; Du, Jianhua; Patel, Bhaumik B; Majumdar, Adhip P N

2009-07-31

Aging is associated with increased incidence of colon cancers. It is also becoming evident that cancer stem cells (CSC) play a vital role in the pathogenesis and prognosis of colon cancer. Recently, we reported the presence of colon cancer stem-like cells in macroscopically normal mucosa in patients with adenomatous polyps and that they increase with aging, suggesting that aging may predispose the colon to carcinogenesis. In the current study we have examined the combined effects of aging and carcinogen exposure on the status of colon CSCs in an experimental model. We used young (4-6 months) and aged (22-24 months) rats and exposed them to the carcinogen, dimethylhydroxide (DMH). We investigated the expression of colon cancer stem cell markers, CD44, CD166, EpCam, and ALDH1 as well as EGFR expression in normal colonic crypt epithelium following carcinogen treatment. Our results demonstrate that aging per se or carcinogen treatment alone causes an increase in the number of colon cancer stems cells, as evidenced by increased immunoreactive-CSC-markers positive cells in the colonic mucosa. In aged rats, carcinogen exposure results in a more pronounced increase in colon cancer stem cells. Our study shows that in aging colon the effects of carcinogens are more pronounced, and an increase in colon CSCs is one of the earliest changes preceding tumor development. Moreover, the current investigation of the use of a panel of immunohistochemical markers of colon CSC can potentially serve as a prognostic marker during screening for colon cancer.

Clinical effects of sirolimus treatment in patients with increased ...

African Journals Online (AJOL)

transplanted kidney function will be lost. However, the development of new immunosuppressors, such as sirolimus (SRL), make it possible to stop CNI treatment [6]. Treating renal transplant patients with immunosuppressive drugs other than CNIs has received more attention in recent years. SRL, a new generation of ...

Heat treatment of organics for increasing anaerobic biodegradability. Annual progress report, June 1, 1976-May 31, 1977. Civil engineering technical report No. 222

Energy Technology Data Exchange (ETDEWEB)

Healy, J.B. Jr.; Owen, W.F.; Stuckey, D.C.; Young, L.Y.; McCarty, P.L.

1977-06-30

This report represents the results of the first year of study on the heat treatment of organics to increase its biodegradability by anaerobic bacteria for the microbial production of methane. The purpose of this study is to develop a means for increasing the yield and reducing the cost of methane, a useful energy source. The procedures being evaluated are heat treatment at temperatures up to 250/sup 0/C, under pH ranges of 1 to 13. Included in this report are results on: (1) lignocellulose digestion and acclimation to its products from heat treatment; (2) the fate of waste activated sludge and its cellular nitrogenous compounds; and (3) the biodegradability of model compounds likely to be formed during heat treatment.

Non-alcoholic steatohepatitis: review of a growing medical problem.

Science.gov (United States)

Te Sligte, K.; Bourass, I.; Sels, J.P.; Driessen, A.; Stockbrugger, R.W.; Koek, G.H.

2004-02-01

Non-alcoholic steatohepatitis (NASH) is a metabolic liver disorder that is seen in 2-6% of the general population. It manifests itself by elevated liver enzymes, frequently without symptoms. The histological findings include steatosis, inflammation, fibrosis, and cirrhosis. Three case reports are presented to illustrate features of NASH. A two-hit model has been proposed in the pathogenesis of NASH. The first hit is hepatic steatosis. A hypercaloric diet with high levels of carbohydrates and saturated fatty acids results in elevated plasma free fatty acids (FFA) and expands the adipose tissue. Insulin resistance develops and augments steatosis. Oxidation of FFA yields toxic free radicals, resulting in lipid peroxidation. They cause the second hits: increased oxidative stress on hepatocytes and induction of pro-inflammatory cytokines. When the antioxidant capacities of the liver are insufficient, mitochondrial dysfunction and tumor necrosis factor alpha (TNF-alpha) cause inflammation and fibrosis. Treatment consists of life style modifications, particularly weight loss and exercise. Many drugs have been tried in the treatment of NASH. The insulin-sensitizing drugs metformin, rosiglitazone, and pioglitazone, and the antioxidant vitamin E show promising results. Further investigation of therapeutic options is needed to direct the choice of therapy in the future.

Foraging at wastewater treatment works increases the potential for ...

African Journals Online (AJOL)

Wastewater treatment works (WWTWs) are known to provide profitable foraging areas for insectivorous bats in Europe and the New World because of their association with high abundance of pollution-tolerant midges (Diptera). However, bats that feed on these insects may also accumulate metal pollutants such as cadmium ...

Therapeutic effects of the allosteric protein tyrosine phosphatase 1B inhibitor KY-226 on experimental diabetes and obesity via enhancements in insulin and leptin signaling in mice

Directory of Open Access Journals (Sweden)

Yuma Ito

2018-05-01

Full Text Available The anti-diabetic and anti-obesity effects of the allosteric protein tyrosine phosphatase 1B (PTP1B inhibitor 4-(biphenyl-4-ylmethylsulfanylmethyl-N-(hexane-1-sulfonylbenzoylamide (KY-226 were pharmacologically evaluated. KY-226 inhibited human PTP1B activity (IC50 = 0.28 μM, but did not exhibit peroxisome proliferator-activated receptor γ (PPARγ agonist activity. In rodent preadipocytes (3T3-L1, KY-226 up to 10 μM had no effects on adipocyte differentiation, whereas pioglitazone, a PPARγ agonist, markedly promoted it. In human hepatoma-derived cells (HepG2, KY-226 (0.3–10 μM increased the phosphorylated insulin receptor (pIR produced by insulin. In db/db mice, the oral administration of KY-226 (10 and 30 mg/kg/day, 4 weeks significantly reduced plasma glucose and triglyceride levels as well as hemoglobin A1c values without increasing body weight gain, while pioglitazone exerted similar effects with increases in body weight gain. KY-226 attenuated plasma glucose elevations in the oral glucose tolerance test. KY-226 also increased pIR and phosphorylated Akt in the liver and femoral muscle. In high-fat diet-induced obese mice, the oral administration of KY-226 (30 and 60 mg/kg/day, 4 weeks decreased body weight gain, food consumption, and fat volume gain with increases in phosphorylated STAT3 in the hypothalamus. In conclusion, KY-226 exerted anti-diabetic and anti-obesity effects by enhancing insulin and leptin signaling, respectively. Keywords: PTP1B inhibitor, Diabetes, Obesity, Allosteric inhibitor, db/db mouse

Do Increasing Rates of Loss to Follow-up in Antiretroviral Treatment Programs Imply Deteriorating Patient Retention?

Science.gov (United States)

Johnson, Leigh F.; Estill, Janne; Keiser, Olivia; Cornell, Morna; Moolla, Haroon; Schomaker, Michael; Grimsrud, Anna; Davies, Mary-Ann; Boulle, Andrew

2014-01-01

In several studies of antiretroviral treatment (ART) programs for persons with human immunodeficiency virus infection, investigators have reported that there has been a higher rate of loss to follow-up (LTFU) among patients initiating ART in recent years than among patients who initiated ART during earlier time periods. This finding is frequently interpreted as reflecting deterioration of patient retention in the face of increasing patient loads. However, in this paper we demonstrate by simulation that transient gaps in follow-up could lead to bias when standard survival analysis techniques are applied. We created a simulated cohort of patients with different dates of ART initiation. Rates of ART interruption, ART resumption, and mortality were assumed to remain constant over time, but when we applied a standard definition of LTFU, the simulated probability of being classified LTFU at a particular ART duration was substantially higher in recently enrolled cohorts. This suggests that much of the apparent trend towards increased LTFU may be attributed to bias caused by transient interruptions in care. Alternative statistical techniques need to be used when analyzing predictors of LTFU—for example, using “prospective” definitions of LTFU in place of “retrospective” definitions. Similar considerations may apply when analyzing predictors of LTFU from treatment programs for other chronic diseases. PMID:25399412

The increasing roles of epigenetics in breast cancer: Implications for pathogenicity, biomarkers, prevention and treatment.

Science.gov (United States)

Basse, Clémence; Arock, Michel

2015-12-15

Nowadays, the mechanisms governing the occurrence of cancer are thought to be the consequence not only of genetic defects but also of epigenetic modifications. Therefore, epigenetic has become a very attractive and increasingly investigated field of research in order to find new ways of prevention and treatment of neoplasia, and this is particularly the case for breast cancer (BC). Thus, this review will first develop the main known epigenetic modifications that can occur in cancer and then expose the future role that control of epigenetic modifications might play in prevention, prognostication, follow-up and treatment of BC. Indeed, epigenetic biomarkers found in peripheral blood might become new tools to detect BC, to define its prognostic and to predict its outcome, whereas epi-drugs might have an increasing potential of development in the next future. However, if DNA methyltransferase inhibitors and histone desacetylase inhibitors have shown encouraging results in BC, their action remains nonspecific. Thus, additional clinical studies are needed to evaluate more precisely the effects of these molecules, even if they have provided encouraging results in cotreatment and combined therapies. This review will also deal with the potential of RNA interference (RNAi) as epi-drugs. Finally, we will focus on the potential prevention of BC through epigenetic based on diet and we will particularly develop the possible place of isothiocyanates from cruciferous vegetables or of Genistein from soybean in a dietary program that might potentially reduce the risk of BC in large populations. © 2014 UICC.

Antiretroviral treatment is associated with increased attentional load-dependent brain activation in HIV patients.

Science.gov (United States)

Chang, L; Yakupov, R; Nakama, H; Stokes, B; Ernst, T

2008-06-01

The purpose of this paper was to determine whether antiretroviral medications, especially the nucleoside analogue reverse transcriptase inhibitors, lead to altered brain activation due to their potential neurotoxic effects in patients with human immunodeficiency virus (HIV) infection. Forty-two right-handed men were enrolled in three groups: seronegative controls (SN, n = 18), HIV subjects treated with antiretroviral medications (HIV+ARV, n = 12), or not treated with antiretroviral medications (HIV+NARV, n = 12). Each subject performed a set of visual attention tasks with increasing difficulty or load (tracking two, three or four balls) during functional magnetic resonance imaging. HIV subjects, both groups combined, showed greater load-dependent increases in brain activation in the right frontal regions compared to SN (p-corrected = 0.006). HIV+ARV additionally showed greater load-dependent increases in activation compared to SN in bilateral superior frontal regions (p-corrected = 0.032) and a lower percent accuracy on the performance of the most difficult task (tracking four balls). Region of interest analyses further demonstrated that SN showed load-dependent decreases (with repeated trials despite increasing difficulty), while HIV subjects showed load-dependent increases in activation with the more difficult tasks, especially those on ARVs. These findings suggest that chronic ARV treatments may lead to greater requirement of the attentional network reserve and hence less efficient usage of the network and less practice effects in these HIV patients. As the brain has a limited reserve capacity, exhausting the reserve capacity in HIV+ARV would lead to declined performance with more difficult tasks that require more attention.

The presence of comorbidity in Tourette syndrome increases the need for pharmacological treatment

DEFF Research Database (Denmark)

Debes, Nanette M M M; Hjalgrim, Helle; Skov, Liselotte

2009-01-01

to a better insight into the common practice in Scandinavia. Furthermore, we wanted to elaborate the influence of the presence of comorbidities and of the severity of tics on pharmacological treatment. We have examined the frequency, art, and reason for pharmacological treatment in a Danish clinical cohort...... of 314 children with Tourette syndrome. In total, 60.5% of the children once had received pharmacological treatment. Mostly, the treatment was started because of tics or ADHD. If ADHD or obsessive-compulsive disorder were present, more children received pharmacological treatment and more different agents...... were tried. The children who received pharmacological treatment had more severe tics than those without medication....

Temperature increases on the external root surface during endodontic treatment using single file systems.

Science.gov (United States)

Özkocak, I; Taşkan, M M; Gökt Rk, H; Aytac, F; Karaarslan, E Şirin

2015-01-01

The aim of this study is to evaluate increases in temperature on the external root surface during endodontic treatment with different rotary systems. Fifty human mandibular incisors with a single root canal were selected. All root canals were instrumented using a size 20 Hedstrom file, and the canals were irrigated with 5% sodium hypochlorite solution. The samples were randomly divided into the following three groups of 15 teeth: Group 1: The OneShape Endodontic File no.: 25; Group 2: The Reciproc Endodontic File no.: 25; Group 3: The WaveOne Endodontic File no.: 25. During the preparation, the temperature changes were measured in the middle third of the roots using a noncontact infrared thermometer. The temperature data were transferred from the thermometer to the computer and were observed graphically. Statistical analysis was performed using the Kruskal-Wallis analysis of variance at a significance level of 0.05. The increases in temperature caused by the OneShape file system were lower than those of the other files (P file showed the highest temperature increases. However, there were no significant differences between the Reciproc and WaveOne files. The single file rotary systems used in this study may be recommended for clinical use.

Effects of a multifaceted implementation intervention to increase utilization of pharmacological treatments for alcohol use disorders in the US Veterans Health Administration.

Science.gov (United States)

Harris, Alex H S; Brown, Randall; Dawes, Michael; Dieperink, Eric; Myrick, Donald Hugh; Gerould, Heather; Wagner, Todd H; Wisdom, Jennifer P; Hagedorn, Hildi J

2017-11-01

Over 16 million Americans meet diagnostic criteria for alcohol use disorder (AUD), but only 7.8% of them receive formal treatment each year. Safe and effective pharmacological treatments for AUD exist; however, they are rarely prescribed. Therefore, we developed and pilot tested a multifaceted implementation intervention to improve consideration and receipt of effective pharmacologic treatments for AUD, focusing on primary care settings where patients have the most frequent contact with healthcare systems. The intervention included training of local providers to serve as champions and a website for primary care providers that included educational materials, a case-finding dashboard, and contact information for local and national clinical experts. We also mailed patients educational material about treatment options. The intervention was implemented at three large facilities of the Veterans Health Administration (VHA). An interrupted time series design, analyzed with segmented logistic regression, was used to evaluate the intervention's effects. The odds of a patient with AUD receiving one of the AUD medications was increasing throughout the pre-implementation period, and the rate of change (slope) increased significantly in the implementation period. Translating these numbers into percentages, at baseline 2.9% of patients filled a prescription for an AUD medication within 30days of a primary care visit. This increased to 3.8% by the end of the pre-implementation period (increasing 0.037% per month), and increased to 5.2% by the end of the implementation period (increasing 0.142% per month). However, the intervention effect was not significant when control sites were added, suggesting that improvement may have been driven by secular trends rather than solely by this intervention. Although the intervention was feasible, it was not effective. Continued analysis of process and implementation data including qualitative interviews with key stakeholders, may elucidate the

Increased Oil Recovery from Mature Oil Fields Using Gelled Polymer Treatments

Energy Technology Data Exchange (ETDEWEB)

Willhite, G.P.; Green, D.W.; McCool, C.S.

2001-01-22

This report describes the progress of the first year of a three-year research program. This program is aimed at reducing barriers to the widespread use of gelled polymer treatments by (1) developing methods to predict gel behavior during placement in matrix rock and fractures, (2) determining the persistence of permeability reduction after gel placement, and (3) developing methods to design production well treatments to control water production.

Hydrothermal treatment coupled with mechanical expression at increased temperature for excess sludge dewatering: the dewatering performance and the characteristics of products.

Science.gov (United States)

Wang, Liping; Li, Aimin

2015-01-01

Hydrothermal treatment coupled with mechanical expression at increased temperature in two separate cells respectively is effective for the dewatering of excess sludge with low energy consumption. The objectives of this study were to evaluate the dewatering performance and the characteristics of obtained products (hydrothermal sludge, hydrochar and filtrate). The results showed that harsher hydrothermal treatment (temperature from 120 to 210 °C and residence time from 10 to 90 min) led to greater water removal (from 7.44 to 96.64% reduction of total water) and mechanical pressure became less significant as it increased. The whole expression stage was completely described by the modified Terzaghi-Voigt rheological model. The role of tertiary consolidation stage in the water removal was reduced with hydrothermal treatment being stronger. The hydrothermal treatment is mainly a devolatilization process. The observed changes in H/C and O/C for hydrothermal sludge suggested dehydration was the major reaction mechanism and decarboxylation only occurred significantly at higher temperature. The higher heating value correlated well with carbon content of sludge, which was increased by 4.8% for hydrothermal sludge at 210 °C for 60 min and significantly decreased by 15.4% for hydrochar after 6.0 MPa for 20 min. The solubilization and decomposition of proteins, polysaccharides and DNA were determined to be temperature and residence time dependent. The improvement of dewaterability was closely correlated to the variation of these biopolymers. The filtrates collected above 150 °C were found to be acidic. The increase of humic substances and the melanoidins formed by Maillard reaction were largely responsible for the filtrate color.

Subchronic treatment with fluoxetine and ketanserin increases hippocampal brain-derived neurotrophic factor, β-catenin and antidepressant-like effects.

Science.gov (United States)

Pilar-Cuéllar, F; Vidal, R; Pazos, A

2012-02-01

5-HT(2A) receptor antagonists improve antidepressant responses when added to 5-HT-selective reuptake inhibitors (SSRIs) or tricyclic antidepressants. Here, we have studied the involvement of neuroplasticity pathways and/or the 5-hydroxytryptaminergic system in the antidepressant-like effect of this combined treatment, given subchronically. Expression of brain-derived neurotrophic factor (BDNF) and its receptor (TrkB), 5-bromo-2'-deoxyuridine (BrdU) incorporation, and β-catenin protein expression in different cellular fractions, as well as 5-HT(1A) receptor function were measured in the hippocampus of rats treated with fluoxetine, ketanserin and fluoxetine + ketanserin for 7 days, followed by a forced swimming test (FST) to analyse antidepressant efficacy. mRNA for BDNF was increased in the CA3 field and dentate gyrus of the hippocampus by combined treatment with fluoxetine + ketanserin. Expression of β-catenin was increased in total hippocampal homogenate and in the membrane fraction, but unchanged in the nuclear fraction after combined treatment with fluoxetine + ketanserin. These effects were paralleled by a decreased immobility time in the FST. There were no changes in BrdU incorporation, TrkB expression and 5-HT(1A) receptor function in any of the groups studied. The antidepressant-like effect induced by subchronic co-treatment with a SSRI and a 5-HT(2A) receptor antagonist may mainly be because of modifications in hippocampal neuroplasticity (BDNF and membrane-associated β-catenin), without a significant role for other mechanisms involved in chronic antidepressant response, such as hippocampal neuroproliferation or 5-HT(1A) receptor desensitization in the dorsal raphe nucleus. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Global demethylation of rat chondrosarcoma cells after treatment with 5-aza-2'-deoxycytidine results in increased tumorigenicity.

Directory of Open Access Journals (Sweden)

Christopher A Hamm

Full Text Available Abnormal patterns of DNA methylation are observed in several types of human cancer. While localized DNA methylation of CpG islands has been associated with gene silencing, the effect that genome-wide loss of methylation has on tumorigenesis is not completely known. To examine its effect on tumorigenesis, we induced DNA demethylation in a rat model of human chondrosarcoma using 5-aza-2-deoxycytidine. Rat specific pyrosequencing assays were utilized to assess the methylation levels in both LINEs and satellite DNA sequences following 5-aza-2-deoxycytidine treatment. Loss of DNA methylation was accompanied by an increase in invasiveness of the rat chondrosarcoma cells, in vitro, as well as by an increase in tumor growth in vivo. Subsequent microarray analysis provided insight into the gene expression changes that result from 5-aza-2-deoxycytidine induced DNA demethylation. In particular, two genes that may function in tumorigenesis, sox-2 and midkine, were expressed at low levels in control cells but upon 5-aza-2-deoxycytidine treatment these genes became overexpressed. Promoter region DNA analysis revealed that these genes were methylated in control cells but became demethylated following 5-aza-2-deoxycytidine treatment. Following withdrawal of 5-aza-2-deoxycytidine, the rat chondrosarcoma cells reestablished global DNA methylation levels that were comparable to that of control cells. Concurrently, invasiveness of the rat chondrosarcoma cells, in vitro, decreased to a level indistinguishable to that of control cells. Taken together these experiments demonstrate that global DNA hypomethylation induced by 5-aza-2-deoxycytidine may promote specific aspects of tumorigenesis in rat chondrosarcoma cells.

Salicylic Acid Treatment Increases the Levels of Triterpene Glycosides in Black Cohosh (Actaea Racemosa) Rhizomes.

Science.gov (United States)

De Capite, Annette; Lancaster, Tyler; Puthoff, David

2016-01-01

Black cohosh (Actaea racemosa) serves as the host plant for the Appalachian azure butterfly, Celastrina neglectamajor. Overharvesting of Black cohosh for the dietary supplement industry may result in its extirpation, and may also cause the elimination of the dependent butterfly. One way to increase or maintain the number of host plants in forested environments would be to reduce the number harvested, for example by increasing the levels of the desired metabolites in Black cohosh rhizomes. The secondary metabolites actein and deoxyactein are triterpene glycosides and are among the compounds associated with the putative activity of Black cohosh extracts. Acetein and deoxyacetein are used to standardize Black cohosh supplements. To gain an understanding of mechanisms that may control actein and deoxyactein accumulation, Black cohosh rhizomes were treated with exogenous salicylic acid, jasmonic acid, or ethylene, or were mechanically wounded. Salicylic acid treatment significantly increased the levels of actein and deoxyactein in the rhizome of Black cohosh, suggesting that the synthesis of triterpene glycosides is controlled in part by salicylic acid. Using salicylic acid or related chemicals to increase the levels of actein and deoxyactein in rhizomes may help supply the supplement industry and, simultaneously, help conserve Black cohosh and species dependent upon it.

Increased adhesion of polydimethylsiloxane (PDMS) to acrylic adhesive tape for medical use by surface treatment with an atmospheric pressure rotating plasma jet

International Nuclear Information System (INIS)

Jofre-Reche, José Antonio; Martín-Martínez, José Miguel; Pulpytel, Jérôme; Arefi-Khonsari, Farzaneh

2016-01-01

The surface properties of polydimethylsiloxane (PDMS) were modified by treatment with an atmospheric pressure rotating plasma jet (APPJ) and the surface modifications were studied to assess its hydrophilicity and adhesion to acrylic adhesive tape intended for medical applications. Furthermore, the extent of hydrophobic recovery under different storage conditions was studied. The surface treatment of PDMS with the APPJ under optimal conditions noticeably increased the oxygen content and most of the surface silicon species were fully oxidized. A brittle silica-like layer on the outermost surface was created showing changes in topography due to the formation of grooves and cracks. A huge improvement in T-peel and the shear adhesive strength of the APPJ-treated PDMS surface/acrylic tape joints was obtained. On the other hand, the hydrophilicity of the PDMS surface increased noticeably after the APPJ treatment, but 24 h after treatment almost 80% hydrophobicity was recovered and the adhesive strength was markedly reduced with time after the APPJ treatment. However, the application of an acrylic adhesive layer on the just-APPJ-treated PDMS surface retained the adhesive strength, limiting the extent of hydrophobic recovery. (paper)

Increased burden of treatment of cervical intraepithelial neoplasia: Denmark 1991 to 2007

DEFF Research Database (Denmark)

Barken, Sidsel Svennekjær; Rebolj, M; Lynge, Elsebeth

2011-01-01

Introduction: Since the introduction of cytological screening in Denmark in the late 1960s, the incidence of cervical cancer decreased from 40 to 14 per 100,000 due to treatment of screen-detected cervical intraepithelial neoplasia (CIN). However, some overtreatment is inevitable and its side...... on conisations, destructive therapies, excisions, hysterectomies and cervical treatments NOS from: The Pathology, Hospital Discharge, Health Insurance and Danish Cancer Register, for all female Danish residents aged 15 to 84 between 1991 and 2007. After linking the data using the unique Danish identification...... numbers, we excluded all duplicates and all destructive therapies and hysterectomies for which no cervical diagnosis was found in the period around the treatment. The total number of treatments was age-standardized using the Danish female population in 2007 as the standard population. Results...

Dewatering treatments to increase dry matter content of the brown seaweed, kelp (Laminaria digitata ((Hudson) JV Lamouroux)).

Science.gov (United States)

Gallagher, Joe A; Turner, Lesley B; Adams, Jessica M M; Dyer, Philip W; Theodorou, Michael K

2017-01-01

Macroalgal water content is an on-going problem for the use of readily accessible seaweeds in sustainable biorefining, including fuel production. Silage is a reduced-water, compactable, easily stored, transportable material. Ensiling could establish a non-seasonal supply of preserved algal biomass, but requires high initial dry matter content to mitigate environmental pollution risks from effluent. This study investigated potential dewatering methods for kelp harvested throughout the year. Treatments included air-drying, osmotic media and acids. Significant interactions between treatment and harvest-time were observed for traits of interest. Fresh weight loss during treatment was composed of changes in water and dry matter content. Air-drying gave reliable increase in final dry matter content; in summer and autumn 30% dry matter content was reached after 24h. Dilute hydrochloric acid reduced stickiness and rendered material suitable for dewatering by screw-pressing; it may be possible to use the consequent pH reduction to promote efficient preservation. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

How can we increase the involvement of primary health care in the treatment of tobacco dependence? A meta-analysis.

NARCIS (Netherlands)

Anderson, P.D.; Jané Llopis, E.

2004-01-01

AIMS: A systematic review of studies testing the effectiveness of educational and practice base strategies to increase the involvement of primary health-care practitioners in the treatment of tobacco dependence. DATA SOURCES: MEDLINE, EMBASE, CINAHL and the Cochrane Library (1966-2001). Selection

Fentanyl Nasal Spray

Science.gov (United States)

... medication, and who are tolerant (used to the effects of the medication) to narcotic pain medications. Fentanyl ... Afrin, Neo-Synephrine, Vicks Sinex, others); nevirapine (Viramune); oxcarbazepine (Trileptal); pentazocine (Talwin); phenytoin (Dilantin, Phenytek); pioglitazone (Actos, ...

NEW IN THE TREATMENT OF TYPE 2 DIABETES

Directory of Open Access Journals (Sweden)

V. G. Kadzharyan

2014-02-01

Full Text Available Diabetes mellitus (DM is a major medical and social problem almost in all countries of the world. Currently, there are more and more various pharmacological agents that make management of the glycaemia in patients with type 2 diabetes extremely difficult. Therefore, when the physician is faced with the choice of glucose-lowering therapy, he should be clearly aware of all the options in contemporary treatment. 11 groups of hypoglycemic agents are used for the treatment of type 2 diabetes The biguanides. According to modern concepts, biguanides inhibit the oxidation of glucose by stimulating anaerobic glycolysis. Both in the consensus of ADA / EASD, and in the IDF recommendations metformin may be the drug of the choice for hypoglycemic therapy of diabetes type 2. Sulfonylurea derivatives: glibenclamide, glimepiride, gliquidone, Glipizide. They belong to a group of secretagogues, as their action is based on the ability to stimulate the secretion of insulin by ß-cells of the pancreas. Prandial glucose regulators. Meglitinides (repaglinide and nateglinide stimulate insulin secretion by ß-cells. Due to the rapid normalization of stimulated insulin level after taking the drugs the risk of hypoglycaemia between meals is minimized. Insulin sensitayzers. Thiazolidinediones (rosiglitazone, pioglitazone reduce insulin resistance of peripheral tissues by binding to receptors, activating peroxisome proliferation (PPARg in the nuclear membrane. Alpha-glucosidase inhibitors (acarbose, miglitol, voglibose competitively inhibits intestinal enzymes (α-glucosidase. It consequently slows carbohydrate absorption from foods and supply of glucose into the blood. Incretin mimetics. Analogues of glucagon-like peptide 1 (GLP-1 stimulate the biosynthesis and secretion of insulin, regulate food consumption, support ß-cells in a healthy state, suppress glucagon secretion, depending on the glucose levels, affect the rate of gastric emptying, stimulat proliferation of �

Increased cortisol awakening response after completing the summer treatment program in children with ADHD.

Science.gov (United States)

Okabe, Rumiko; Okamura, Hisayoshi; Egami, Chiyomi; Tada, Yasuhiro; Anai, Chizuru; Mukasa, Akiko; Iemura, Akiko; Nagamitsu, Shinichiro; Furusho, Junichi; Matsuishi, Toyojiro; Yamashita, Yushiro

2017-08-01

Little is known about the cortisol awakening response (CAR) in children with attention deficit hyperactivity disorder (ADHD). Here, we examined the CAR in children with ADHD and their mothers before, immediately after, and 4months after an intensive summer treatment program (STP). Participants were 37 children aged 7-12years who completed the STP in 2009 and 2010, and their mothers. Daily saliva samples for cortisol measurement were collected twice daily at awakening and 30min afterwards at pre-STP, post-STP, and during a follow-up measurement period. ADHD symptom scores were evaluated by parents, and participants completed the Kid-KINDL R QOL questionnaire. CAR was low in children with ADHD before the STP, and increased to the control range 4months after STP. Maternal CAR also tended to increase after STP. Changes in the CAR in children tended to correlate with an improved ADHD inattention scores (p=0.091), physical health (p=0.070), and school life subscales scores in the Kid-KINDL R (p=0.079). We demonstrated that STP improved the behavior and QOL of children with ADHD. Our results indicate that STP could lead to improvements in HPA axis function, as reflected by increased CAR after STP. Copyright © 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Access to hepatitis C virus treatment: Lessons from implementation of strategies for increasing access to antiretroviral treatment.

Science.gov (United States)

Assefa, Yibeltal; Hill, Peter S; Williams, Owain D

2018-05-01

At September's 2017 United Nations General Assembly, a state-of-the-art HIV medicine was announced to be made available at just $75 per person per year. There have been a number of strategies that the global AIDS community and countries have utilized to reduce prices and make antiretrovirals (ARVs) accessible for people living with HIV/AIDS. There appears to be an opportunity for the treatment of hepatitis C virus infection using direct-acting antivirals (DAAs) to benefit from the often painful and laboured history of driving down the prices of ARVs. In general, the success of lowering prices for ARVs has stemmed from the politics needed to initially support generic entry into the on-patent market. The use of flexibilities present in the World Trade Organization's Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS) have been used to overcome patent barriers, with the use of compulsory licenses and/or the threat of their use as instruments for strengthening the bargaining power in price negotiations. These strategies have been combined with new financing mechanisms that have promoted more effective procurement and price negotiations. Partnership among the different stakeholders has also been critical in this regard. Countries have also invested in their health systems and implemented several strategies to reduce stigma and discrimination to increase access to and improve utilization of ARVs. This article suggests that any future international initiatives to increase access to DAAs can learn from these lessons surrounding price reduction, improved financing, advocacy, as well as health systems strengthening and stigma reduction. Adopting and reconfiguring these strategies will also incur substantial savings in time, money and lives. Crown Copyright © 2018. Published by Elsevier Ltd. All rights reserved.

Access to hepatitis C virus treatment: Lessons from implementation of strategies for increasing access to antiretroviral treatment

Directory of Open Access Journals (Sweden)

Yibeltal Assefa

2018-05-01

Full Text Available At September’s 2017 United Nations General Assembly, a state-of-the-art HIV medicine was announced to be made available at just $75 per person per year. There have been a number of strategies that the global AIDS community and countries have utilized to reduce prices and make antiretrovirals (ARVs accessible for people living with HIV/AIDS. There appears to be an opportunity for the treatment of hepatitis C virus infection using direct-acting antivirals (DAAs to benefit from the often painful and laboured history of driving down the prices of ARVs. In general, the success of lowering prices for ARVs has stemmed from the politics needed to initially support generic entry into the on-patent market. The use of flexibilities present in the World Trade Organization’s Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS have been used to overcome patent barriers, with the use of compulsory licenses and/or the threat of their use as instruments for strengthening the bargaining power in price negotiations.These strategies have been combined with new financing mechanisms that have promoted more effective procurement and price negotiations. Partnership among the different stakeholders has also been critical in this regard. Countries have also invested in their health systems and implemented several strategies to reduce stigma and discrimination to increase access to and improve utilization of ARVs. This article suggests that any future international initiatives to increase access to DAAs can learn from these lessons surrounding price reduction, improved financing, advocacy, as well as health systems strengthening and stigma reduction. Adopting and reconfiguring these strategies will also incur substantial savings in time, money and lives. Keywords: Acces to medicines, Hepatitis C virus, HIV, Antiretrovirals, Direct-acting antivirals

Interventions for Increasing Alcohol Treatment Utilization Among Patients with Alcohol Use Disorders from Emergency Departments: A Systematic Review.

Science.gov (United States)

Simioni, Nicolas; Rolland, Benjamin; Cottencin, Olivier

2015-11-01

Alcohol use disorders (AUDs) are characterized by low treatment coverage. Emergency departments (EDs) have great potential to increase alcohol treatment coverage. While ED-based brief interventions (BIs) are rarely effective for reducing alcohol use and related consequences in people with AUDs, utilization of formal alcohol treatment has been demonstrated to be useful. Thus we conducted a systematic review to determine efficacious interventions for increasing subsequent alcohol treatment from EDs. A systematic search of the literature up to 31 December 2013 was undertaken in three electronic databases: PubMed, PsycINFO and The Cochrane Library. Only randomized controlled trials (RCTs), controlled clinical trials (CCTs) and non-randomized controlled trials (NRCTs) were included. A meta-analysis was judged inappropriate because of substantial discrepancies in term of interventions' characteristics across studies. From the 2182 identified records, 7 studies (4RCTs, 2 CCTs, 1NRCT) met inclusion criteria. Onsite brief advice (BA) was found efficacious in comparison to no active control condition, but no evidence of efficacy was found when compared to active control conditions. Referral to post-discharge BIs was not found efficacious either used alone or in addition to onsite BA. There is evidence, albeit limited, suggesting that more intensive interventions, such as referral to extended post-discharge interventions and onsite extended BI, might be useful. Based on the available evidence, onsite BA with leaflets appears to be the minimum level of intervention since it enables to actively intervene while fitting in the time concerns experienced in EDs. Further research is needed to confirm these findings given the limited quantity and quality of existing data and to determine whether more intensive interventions could actually be useful. Copyright © 2015 Elsevier Inc. All rights reserved.

Raspberry Ketone

Science.gov (United States)

... a pounding heart beat (palpitations). Special precautions & warnings: Pregnancy and breast-feeding: There is not enough reliable ... glimepiride (Amaryl), glyburide (Diabeta, Glynase PresTab, Micronase), insulin, metformin (Glumetza, Fortamet, Glucophage, Riomet), pioglitazone (Actos), rosiglitazone (Avandia), ...

Transvenous stimulation of the renal sympathetic nerves increases systemic blood pressure: a potential new treatment option for neurocardiogenic syncope.

Science.gov (United States)

Madhavan, Malini; Desimone, Christopher V; Ebrille, Elisa; Mulpuru, Siva K; Mikell, Susan B; Johnson, Susan B; Suddendorf, Scott H; Ladewig, Dorothy J; Gilles, Emily J; Danielsen, Andrew J; Asirvatham, Samuel J

2014-10-01

Neurocardiogenic syncope (NCS) is a common and sometimes debilitating disorder, with no consistently effective treatment. NCS is due to a combination of bradycardia and vasodilation leading to syncope. Although pacemaker devices have been tried in treating the bradycardic aspect of NCS, no device-based therapy exists to treat the coexistent vasodilation that occurs. The renal sympathetic innervation has been the target of denervation to treat hypertension. We hypothesized that stimulation of the renal sympathetic nerves can increase blood pressure and counteract vasodilation in NCS. High-frequency stimulation (800-900 pps, 10 V, 30-200 seconds) was performed using a quadripolar catheter in the renal vein of 7 dogs and 1 baboon. A significant increase in blood pressure (BP; mean [SD] systolic BP 117 [±28] vs. 128 [±33], diastolic BP 75 [±19] vs. 87 [±29] mmHg) was noted during the stimulation, which returned to baseline after cessation of stimulation. The mean increase in systolic and diastolic BP was 13.0 (±3.3) (P = 0.006) and 10.2 (±4.6) (P = 0.08), respectively. We report the first ever study of feasibility and safety of high-frequency electrical stimulation of the renal sympathetic innervation to increase BP in animal models. This has potential applications in the treatment of hypotensive states such as NCS. © 2014 Wiley Periodicals, Inc.

Examining the safety of PPAR agonists - current trends and future prospects.

Science.gov (United States)

Bortolini, Michele; Wright, Matthew B; Bopst, Martin; Balas, Bogdana

2013-01-01

The peroxisome proliferator-activated receptor (PPAR)-α and -γ agonists, fibrates and glitazones, are effective treatments for dyslipidemia and type 2 diabetes mellitus, respectively, but exhibit class-related, as well as compound-specific safety characteristics. This article reviews the profiles of PPAR-α, PPAR-γ, and dual PPAR-α/γ agonists with regard to class-related and compound-specific efficacy and adverse effects. We explore how learnings from first-generation drugs are being applied to develop safer PPAR-targeted therapies. The finding that rosiglitazone may increase risk for cardiovascular events has led to regulatory guidelines requiring demonstration of cardiovascular safety in appropriate outcome trials for new type 2 diabetes mellitus drugs. The emerging data on the possibly increased risk of bladder cancer with pioglitazone may prompt the need for post-approval safety studies for new drugs. Since PPAR-α and -γ affect key cardiometabolic risk factors (diabetic dyslipidemia, insulin resistance, hyperglycemia, and inflammation) in a complementary fashion, combining their benefits has emerged as a particularly attractive option. New PPAR-targeted therapies that balance the relative potency and/or activity toward PPAR-α and -γ have shown promise in retaining efficacy while reducing potential side effects.

Patient-specific prescriber feedback can increase the rate of osteoporosis screening and treatment: results from two national interventions.

Science.gov (United States)

Kalisch Ellett, Lisa M; Pratt, N L; Sluggett, J K; Ramsay, E N; Kerr, M; LeBlanc, V T; Barratt, J D; Roughead, E E

2017-12-01

Osteoporosis interventions targeting older Australians and clinicians were conducted in 2008 and 2011 as part of a national quality improvement program underpinned by behavioural theory and stakeholder engagement. Uptake of bone mineral density (BMD) tests among targeted men and women increased after both interventions and sustained increases in osteoporosis treatment were observed among men targeted in 2008. Educational interventions incorporating patient-specific prescriber feedback have improved osteoporosis screening and treatment among at-risk patients in clinical trials but have not been evaluated nationally. This study assessed uptake of BMD testing and osteoporosis medicines following two national Australian quality improvement initiatives targeting women (70-79 years) and men (75-85 years) at risk of osteoporosis. Administrative health claims data were used to determine monthly rates of BMD testing and initiation of osteoporosis medicines in the 9-months post-intervention among targeted men and women compared to older cohorts of men and women. Log binomial regression models were used to assess differences between groups. In 2008 91,794 patients were targeted and 52,427 were targeted in 2011. There was a twofold increase in BMD testing after each intervention among targeted patients compared to controls (p theory and stakeholder engagement that target both primary care clinicians and patients can improve osteoporosis screening and management at the national level.

Does increased nerve length within the treatment volume improve trigeminal neuralgia radiosurgery? a prospective double-blind, randomized study

International Nuclear Information System (INIS)

Flickinger, John C.; Pollock, Bruce E.; Kondziolka, Douglas; Phuong, Loi K.; Foote, Robert L.; Stafford, Scott L.; Lunsford, L. Dade

2001-01-01

Purpose: To test the hypothesis that increasing the nerve length within the treatment volume for trigeminal neuralgia radiosurgery would improve pain relief. Methods and Materials: Eighty-seven patients with typical trigeminal neuralgia were randomized to undergo retrogasserian gamma knife radiosurgery (75 Gy maximal dose with 4-mm diameter collimators) using either one (n=44) or two (n=43) isocenters. The median follow-up was 26 months (range 1-36). Results: Pain relief was complete in 57 patients (45 without medication and 12 with low-dose medication), partial in 15, and minimal in another 15 patients. The actuarial rate of obtaining complete pain relief (with or without medication) was 67.7%±5.1%. The pain relief was identical for one- and two-isocenter radiosurgery. Pain relapsed in 30 of 72 responding patients. Facial numbness and mild and severe paresthesias developed in 8, 5, and 1 two-isocenter patients vs. 3, 4, and 0 one-isocenter patients, respectively (p=0.23). Improved pain relief correlated with younger age (p=0.025) and fewer prior procedures (p=0.039) and complications (numbness or paresthesias) correlated with the nerve length irradiated (p=0.018). Conclusions: Increasing the treatment volume to include a longer nerve length for trigeminal neuralgia radiosurgery does not significantly improve pain relief but may increase complications

Folic acid treatment increases homocysteine remethylation and methionine transmethylation in healthy subjects

NARCIS (Netherlands)

Stam, F.; Smulders, Y.M.; van Guldener, C.; Jakobs, C.A.J.M.; Stehouwer, C.D.A.; van der Meer, K.

2005-01-01

Folic acid treatment decreases plasma total homocysteine concentrations in healthy subjects, but the effects on homocysteine metabolism are unknown. In the present study, we investigated the effect of 3 weeks of oral treatment with 5 mg of folic acid on one-carbon flux rates in 12 healthy subjects,

Parallel increases in sister chromatid exchanges at base level and with UV treatment in human opiate users

International Nuclear Information System (INIS)

Shafer, D.A.; Falek, A.; Madden, J.J.; Tadayon, F.; Pline, M.; Kuehnle, J.C.; Mendelson, J.

1983-01-01

The SCE base level frequency and SCE levels induced by far-UV (254 nm) treatment of cells in early G 1 and early S phases of the cell cycle were significantly higher in leukocytes from heroin addicts as compared to controls. The increased SCE levels in addicts was greatest at base level and smallest after UV irradiation of cells in S phase. These results corrobate and extend our previous findings of increased chromosome damage and reduced DNA-repair synthesis in heroin users. Since opiates do not directly damage DNA, the elevated cytogenetic effects associated with opiate use probably arise from secondary promotional effects related to opiate-mediated alterations in leukocyte metabolism. (orig.)

Lifetime ATS use and increased HIV risk among not-in-treatment opiate injectors in Malaysia.

Science.gov (United States)

Chawarski, Marek C; Vicknasingam, Balasingam; Mazlan, Mahmud; Schottenfeld, Richard S

2012-07-01

Malaysia has been experiencing significant drug abuse problems since the 1970s, and drug abuse is the major driver of HIV transmission in Malaysia. We investigated risk factors for HIV associated with use of amphetamine type stimulants (ATS) among not-in-treatment opiate injectors in Malaysia. Between October of 2006 and May of 2008, we conducted a series of surveys in three major urban areas of Malaysia. A total of 732 opiate IDUs (679 males and 53 females) were enrolled in the three surveys. The survey instruments consisted of a structured interview on demographic characteristics, drug use history (including year of first use, and past month history of use of illicit drugs; lifetime and past month history of IDU or needle or equipment sharing), and HIV status. There were 194/704 (27.6%) HIV positive participants in the sample. Two factors were significantly associated with HIV infection in this sample: lifetime history of ATS use (OR [95%CI]: 2.3 [1.5-3.6]) and lifetime history of sharing of injection equipment (OR [95% CI]: 4.2 [1.8-9.8]). Both HIV-positive and HIV-negative participants reported high levels of current needle/equipment sharing practices: 82% vs. 75%, respectively. ATS use spread rapidly in the study sample after 1997 and is associated with an increased risk of HIV infection in this population already at high risk because of opiate IDU. Out-of-treatment IDUs in Malaysia engage in high risk behaviors regardless of their HIV status. Increased education and public health prevention measures are needed to reduce HIV transmission risks in this population. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Marine mud and manure treatment in Ultisols increase pH and phosphate availability and affectCapsicum annum L. grows and production

Directory of Open Access Journals (Sweden)

F. Matulessy

2015-07-01

Full Text Available Marine mud and manure has potentially to improve ultisol soil condition, especially in soil acidity, CEC, base saturation, neutralizing organic acid, improving soil structure, soil nutrient retention, aeration, soil humidity, capacity of water holding capacity and infiltration and enhance the rapid supply of phosphate for plant grows and development. Two treatments, namely planting media with 200 ton.ha-1 marine mud and 30 ton.ha-1 manure and 400 ton.ha-1 marine mud and 30 ton.ha-1 manure were able to increase pH from 4.6 to 5.6.Significant decrease of Alexcsolubility about 0.03 meq.100 g-1 was found in M1O3; M2O1; M2O3 and M3O1 treatment about. Increase of phosphate about 5.02 ppm was found at treatment 200 ton.ha-1 marine mud and 30 ton.ha-1 manure. There are significant interaction in plant high about 62.42 cm in the media without marine mud and 30 ton.ha-1manure treatments. The amount of 30 ton,ha-1manure produce plant with leaf size about 95,52 cm2.tan-1and produce fresh fruit about 9.81 ton.ha-1.

Patient-centered feedback on the results of personality testing increases early engagement in residential substance use disorder treatment: a pilot randomized controlled trial.

Science.gov (United States)

Blonigen, Daniel M; Timko, Christine; Jacob, Theodore; Moos, Rudolf H

2015-03-14

Patient-centered models of assessment have shown considerable promise for increasing patients' readiness for mental health treatment in general, but have not been used to facilitate patients' engagement in substance use disorder (SUD) treatment. We developed a brief patient-centered intervention using assessment and feedback of personality data and examined its acceptability and efficacy to increase early engagement in residential SUD treatment. Thirty patients entering a 90-day residential SUD treatment program were randomly assigned to a feedback (n = 17) or control (n = 13; assessment-only) condition. Normal-range personality was assessed with the NEO Personality Inventory-Revised (NEO PI-R). Patients were re-interviewed one month after treatment entry to obtain information on their satisfaction with the intervention, as well as their adjustment to the residential milieu. Electronic medical records were reviewed to obtain information on patients' length of stay in the program and discharge status. Univariate ANOVAs and chi-square tests were conducted to examine group differences on outcomes. Patients' ratings indicated strong satisfaction with the feedback intervention and expectations that it would have a positive impact on their treatment experiences. Among patients who had not previously been treated in the residential program, the feedback intervention was associated with more positive relationships with other residents in treatment and a stronger alliance with the treatment program one month after treatment entry. The feedback intervention was also associated with a longer length of stay in treatment, although this effect did not reach statistical significance. The findings highlight the clinical utility of providing SUD patients with patient-centered feedback based on the results of personality testing, and provide preliminary support for the acceptability and efficacy of this intervention to facilitate early engagement in residential SUD treatment.

Seroma indicates increased risk of lymphedema following breast cancer treatment

DEFF Research Database (Denmark)

Toyserkani, Navid Mohamadpour; Jørgensen, Mads Gustaf; Haugaard, Karen

2017-01-01

in one of the largest retrospective cohort studies. Material and methods We included all patients with unilateral breast cancer treated in the period of 2008-2014. Data regarding treatment and breast cancer characteristics were retrieved from the national breast cancer registry. Data regarding lymphedema...

Female Sexual Dysfunction Among Muslim Women: Increasing Awareness to Improve Overall Evaluation and Treatment.

Science.gov (United States)

Rahman, Sameena

2018-04-17

Muslim women are an increasingly underserved population in the United States and worldwide. Diagnosis and treatment of female sexual dysfunction bring unique challenges because of the conservative nature of those practicing the religion. Several cultural and religious codes of conduct affect sexual behavior and the dysfunction that can ensue. To assess and describe the types of sexual dysfunction that have been found in Muslim women internationally and encourage a better understanding of their issues to enhance health care delivery. A comprehensive review of the literature through Ovid and PubMed was performed in search of articles reviewing female sexual dysfunction, Muslim women, and Islam. A brief explanation and review of the interpretations of sexuality within Islam are discussed. The link is made between conservative sexual relations and interpretations and the types of sexual dysfunction experienced. Female sexual dysfunction is explored in relation to how female chastity is extolled and how cultural procedures continue despite the ethical and health concerns related to them. Most Muslim women experience sexual dysfunction similar to other women, including arousal, desire, and orgasmic disorders related to organic and psychologic factors. Sexual pain disorders might be more prevalent in this population, particularly concerning unconsummated marriage. There are special concerns related to maintaining virginity and preserving the hymen until marriage. Female genital cutting, practiced by some Muslim countries, has potential sexual consequences. Understanding Islamic views on sexuality and how they can affect sexual dysfunction in Muslim women is critical in opening lines of communication with patients and approaching female sexual dysfunction impartially. Although some issues that arise might introduce ethical dilemmas for the provider, having the cultural competence to address these issues will facilitate improved health care delivery. Rahman S. Female Sexual

Increasing the brittle fracture resistance in manual arc welding and heat treatment of type 12KhM steels

International Nuclear Information System (INIS)

Tikhonov, V.P.; Bychenkova, G.A.; Gordeev, Y.V.; Ilyuhov, C.V.

1984-01-01

The extensive application of heat-resisting steels is delayed by their poor weldability. Optimum technology has been developed for manual arc welding and heat treatment of structures of type 12KhM steels resulting in high cracking resistance. Trials were conducted to evaluate the efficiency of removing the structural stresses in tempering the structures. On the basis of the experimental results, it may be assumed that the toughness properties of the welded joints produced by manual arc welding can be improved by optimizing the alloying system of the weld metal, with the parent metal treated in the optimum heat treatment conditions. The aim of subsequent investigations was to assess the properties of the weld metal made with vanadium-free electrodes. It was found that the impact toughness increased two to three times; the mean hardness and the maximum hardness were both less than 220. The reduction in hardness and increase of the toughness properties of the metal are caused by the lower degree of hardening of the bulk of the grain and, consequently, by the lower concentration of plastic strain at the grain boundaries

Effectiveness of the Treatment Readiness and Induction Program for increasing adolescent motivation for change.

Science.gov (United States)

Becan, Jennifer E; Knight, Danica K; Crawley, Rachel D; Joe, George W; Flynn, Patrick M

2015-03-01

Success in substance abuse treatment is improved by problem recognition, desire to seek help, and readiness to engage in treatment, all of which are important aspects of motivation. Interventions that facilitate these at treatment induction for adolescents are especially needed. The purpose of this study is to assess the effectiveness of TRIP (Treatment Readiness and Induction Program) in promoting treatment motivation. Data represent 519 adolescents from 6 residential programs who completed assessments at treatment intake (time 1) and 35 days after admission (time 2). The design consisted of a comparison sample (n=281) that had enrolled in treatment prior to implementation of TRIP (standard operating practice) and a sample of clients that had entered treatment after TRIP began and received standard operating practice enhanced by TRIP (n=238). Repeated measures ANCOVAs were conducted using each time 2 motivation scale as a dependent measure. Motivation scales were conceptualized as representing sequential stages of change. LISREL was used to test a structural model involving TRIP participation, gender, drug use severity, juvenile justice involvement, age, race-ethnicity, prior treatment, and urgency as predictors of the stages of treatment motivation. Compared to standard practice, adolescents receiving TRIP demonstrated greater gains in problem recognition, even after controlling for the other variables in the model. The model fit was adequate, with TRIP directly affecting problem recognition and indirectly affecting later stages of change (desire for help and treatment readiness). Future studies should examine which specific components of TRIP affect change in motivation. Copyright © 2015 Elsevier Inc. All rights reserved.

Treatment of infertility does not increase the risk of ovarian cancer among women with a BRCA1 or BRCA2 mutation.

Science.gov (United States)

Gronwald, Jacek; Glass, Karen; Rosen, Barry; Karlan, Beth; Tung, Nadine; Neuhausen, Susan L; Moller, Pal; Ainsworth, Peter; Sun, Ping; Narod, Steven A; Lubinski, Jan; Kotsopoulos, Joanne

2016-03-01

To evaluate the relationship between use of fertility medication (i.e., selective estrogen receptor [ER] modulator, gonadotropin, or other) or infertility treatment (i.e., IVF or IUI) and the risk of ovarian cancer among women with a BRCA1 or BRCA2 mutation. A matched case-control study of 941 pairs of BRCA1 or BRCA2 mutation carriers with and without a diagnosis of ovarian cancer. Genetic clinics. Detailed information regarding treatment of infertility was collected from a routinely administered questionnaire. None. Conditional logistic regression was used to estimate odds ratios and 95% confidence intervals associated with fertility treatment. There was no significant relationship between the use of any fertility medication or IVF treatment (odds ratio, 0.66; 95% confidence interval 0.18-2.33) and the subsequent risk of ovarian cancer. Our findings suggest that treatment for infertility does not significantly increase the risk of ovarian cancer among women with a BRCA mutation. Copyright © 2016 American Society for Reproductive Medicine. All rights reserved.

Testosterone treatment increases androgen receptor and aromatase gene expression in myotubes from patients with PCOS and controls, but does not induce insulin resistance.

Science.gov (United States)

Eriksen, Mette Brandt; Glintborg, Dorte; Nielsen, Michael Friberg Bruun; Jakobsen, Marianne Antonius; Brusgaard, Klaus; Tan, Qihua; Gaster, Michael

2014-09-05

Polycystic ovary syndrome (PCOS) is associated with insulin resistance and increased risk of type 2 diabetes. Skeletal muscle is the major site of insulin mediated glucose disposal and the skeletal muscle tissue is capable to synthesize, convert and degrade androgens. Insulin sensitivity is conserved in cultured myotubes (in vitro) from patients with PCOS, but the effect of testosterone on this insulin sensitivity is unknown. We investigated the effect of 7days testosterone treatment (100nmol/l) on glucose transport and gene expression levels of hormone receptors and enzymes involved in the synthesis and conversion of testosterone (HSD17B1, HSD17B2, CYP19A1, SRD5A1-2, AR, ER-α, HSD17B6 and AKR1-3) in myotubes from ten patients with PCOS and ten matched controls. Testosterone treatment significantly increased aromatase and androgen receptor gene expression levels in patients and controls. Glucose transport in myotubes was comparable in patients with PCOS vs. controls and was unchanged by testosterone treatment (p=0.21 PCOS vs. controls). These results suggest that testosterone treatment of myotubes increases the aromatase and androgen receptor gene expression without affecting insulin sensitivity and if testosterone is implicated in muscular insulin resistance in PCOS, this is by and indirect mechanism. Copyright © 2014 Elsevier Inc. All rights reserved.

Increasing use of artemisinin-based combination therapy for treatment of malaria infection in Nigerian hospitals

Directory of Open Access Journals (Sweden)

Igboeli NU

2010-12-01

Full Text Available Objectives: This study aimed at describing the pattern of outpatient antimalarial drug prescribing in a secondary and a tertiary hospital, and to assess adherence to the National Antimalarial Treatment Guideline (ATG. Methods: An audit of antimalarial prescription files from the two health facilities for a period of six months in 2008 was conducted. Semi structured questionnaires were used to collect information from the doctors and pharmacists on their awareness and knowledge of the National Antimalarial Treatment Guideline. Results: Artemisinin-based combination therapies (ACTs were the most prescribed antimalarials. Overall, 81.4% of the total prescriptions contained ACTs, out of which 56.8% were artemether-lumefantrine. However, adherence to the drugs indicated by national guideline within the DU90% was 38.5% for the tertiary and 66.7 % for the secondary hospital. The standard practice of prescribing with generic name was still not adhered to as evidenced in the understudied hospitals. The percentage of health care providers that were aware of the ATG was 88.2% for doctors and 85.1% for pharmacists. However, 13.3% and 52.2% of doctors and pharmacists respectively could not properly list the drugs specified in the guideline. Amodiaquine was the most commonly preferred option for managing children aged 0 – 3 months with malaria infection against the indicated oral quinine.Conclusion: This study showed an increased use of artemisinin-based combination therapy for the treatment of uncomplicated malaria compared previous reports in Nigeria. This study also highlights the need for periodic in-service quality assurance among health professionals with monitoring of adherence to and assessment of knowledge of clinical guidelines to ensure the practice of evidence based medicine.

Serum NT-proCNP levels increased after initiation of GH treatment in patients with achondroplasia/hypochondroplasia.

Science.gov (United States)

Kubota, Takuo; Wang, Wei; Miura, Kohji; Nakayama, Hirofumi; Yamamoto, Keiko; Fujiwara, Makoto; Ohata, Yasuhisa; Tachibana, Makiko; Kitaoka, Taichi; Takakuwa, Satoshi; Miyoshi, Yoko; Namba, Noriyuki; Ozono, Keiichi

2016-06-01

Serum amino-terminal propeptide of C-type natriuretic peptide (NT-proCNP) levels have been proposed as a biomarker of linear growth in healthy children. The usefulness of NT-proCNP in patients with achondroplasia (ACH)/hypochondroplasia (HCH) remains to be elucidated. The objective was to study whether serum NT-proCNP level is a good biomarker for growth in ACH/HCH and other patients of short stature. This was a longitudinal cohort study. Sixteen children with ACH (aged 0·4-4·3 years), six children with HCH (2·7-6·3 years), 23 children with idiopathic short stature (ISS) (2·2-9·0 years), eight short children with GH deficiency (GHD) (2·9-6·8 years) and five short children born small for gestational age (SGA) (2·0-6·6 years). Patients with ACH/HCH received GH treatment for 1 year. Serum NT-proCNP levels and height were measured. NT-proCNP levels positively correlated with height velocity in these short children (P < 0·05, r = 0·27). NT-proCNP levels inversely correlated with age in children with ISS alone (P < 0·01, r = -0·55). Serum NT-proCNP levels in patients with ACH/HCH were increased 3 months following the initiation of GH treatment (P < 0·05). Height SDS gain during GH treatment for 1 year was positively correlated with the changes in NT-proCNP levels after the initiation of GH (P < 0·01, r = 0·72). Serum NT-proCNP levels may be a good biomarker to indicate the effect of GH treatment on growth in patients with ACH/HCH at least in the first year and height velocity in short stature patients. © 2016 John Wiley & Sons Ltd.

Physical-chemical pretreatment as an option for increased sustainability of municipal wastewater treatment plants

NARCIS (Netherlands)

Mels, A.

2001-01-01

Keywords : municipal wastewater treatment, physical-chemical pretreatment, chemically enhanced primary treatment, organic polymers, environmental sustainability

Most of the currently applied municipal wastewater treatment plants in The Netherlands are

Roux-en-Y gastric bypass in the treatment of non-classic congenital adrenal hyperplasia due to 11-hydroxylase deficiency.

Science.gov (United States)

Kalani, Amir; Thomas, Nithin; Sacerdote, Alan; Bahtiyar, Gül

2013-03-18

Non-classic adrenal hyperplasia (NCAH) has been associated with insulin resistance (IR). Therapies such as metformin, thiazolidinediones and lifestyle alterations improve IR and also ameliorate the biochemical and clinical abnormalities of NCAH, much as they do in polycystic ovarian syndrome (PCOS). More recently, bariatric surgery, such as Roux-en-Y gastric bypass (RYGBP), has also been associated with improvement in IR and amelioration of PCOS and may, therefore, be beneficial in NCAH. We report a case of a 39-year-old, deaf-mute, obese woman with NCAH due to 11-hydroxylase deficiency who underwent RYGBP followed by improvement of NCAH manifestations. She was initially treated with metformin and pioglitazone, which lowered serum 11-deoxycortisol from 198 ng/dl (irregular menses normalised as well. We conclude that RYGBP, like other interventions that reduce IR, may be another way of treating non-classic 11-hydroxylase deficiency in selected patients.

Can written information material help to increase treatment motivation in patients with erectile dysfunction? A survey of 1188 men.

Science.gov (United States)

Günzler, C; Kriston, L; Stodden, V; Leiber, C; Berner, M M

2007-01-01

Although erectile dysfunction (ED) prevalence is high, patients and physicians often have problems discussing this issue. This study examines whether written information material increases motivation to seek treatment in patients with ED. For the study, persons were able to order information material about sexual problems within the context of a public campaign. From a total of 70,000 responders, 8000 persons were asked to fill out an epidemiological questionnaire. The response rate yielded 18.4%, the data of 1188 men with ED were analyzed. As a result of the information material, 28.3% of the untreated men intended to seek treatment and 38.5% of the men who had not spoken with their physician about their problem, planned to do so now. Nearly all responders were satisfied with the information material. These data reflect the usefulness of written information for men with ED. It not only serves as an informational source for patients but may also encourage them to seek treatment.

Increased use of antipsychotic long-acting injections with community treatment orders.

Science.gov (United States)

Patel, Maxine X; Matonhodze, Jane; Baig, Mirza K; Gilleen, James; Boydell, Jane; Holloway, Frank; Taylor, David; Szmukler, George; Lambert, Tim; David, Anthony S

2011-04-01

Community treatment orders (CTOs) are increasingly being used, despite a weak evidence base, and problems continue regarding Second Opinion Appointed Doctor (SOAD) certification of medication. The aim of the current study was to describe current CTO usage regarding patient characteristics, prescribed medication and CTO conditions. A 1-year prospective cohort study with consecutive sampling was conducted for all patients whose CTO was registered in a large mental health trust. Only the first CTO for each patient was included. Measures included sociodemographic variables, psychiatric diagnosis, CTO date of initiation and conditions, psychotropic medication and date of SOAD certification for medication. This study was conducted in the first year of CTO legislation in England and Wales. A total of195 patients were sampled (mean age 40.6 years, 65% male, 52% black ethnic origin). There was significant geographical variability in rates of CTO use (χ(2) = 11.3, p = 0.012). A total of 53% had their place of residence specified as a condition and 29% were required to allow access into their homes. Of those with schizophrenia, 64% were prescribed an antipsychotic long-acting injection (LAI). Of the total group, 7% received high-dose antipsychotics, 10% were prescribed two antipsychotics and only 15% received SOAD certification in time. There was geographical and ethnic variation in CTO use but higher rates of hospital detention in minority ethnic groups may be contributory. Most patients were prescribed antipsychotic LAIs and CTO conditions may not follow the least restrictive principle.

Inhibition of rotavirus ECwt infection in ICR suckling mice by N-acetylcysteine, peroxisome proliferator-activated receptor gamma agonists and cyclooxygenase-2 inhibitors

Directory of Open Access Journals (Sweden)

Carlos Arturo Guerrero

2013-09-01

Full Text Available Live attenuated vaccines have recently been introduced for preventing rotavirus disease in children. However, alternative strategies for prevention and treatment of rotavirus infection are needed mainly in developing countries where low vaccine coverage occurs. In the present work, N-acetylcysteine (NAC, ascorbic acid (AA, some nonsteroidal anti-inflammatory drugs (NSAIDs and peroxisome proliferator-activated receptor gamma (PPARγ agonists were tested for their ability to interfere with rotavirus ECwt infectivity as detected by the percentage of viral antigen-positive cells of small intestinal villi isolated from ECwt-infected ICR mice. Administration of 6 mg NAC/kg every 8 h for three days following the first diarrhoeal episode reduced viral infectivity by about 90%. Administration of AA, ibuprofen, diclofenac, pioglitazone or rosiglitazone decreased viral infectivity by about 55%, 90%, 35%, 32% and 25%, respectively. ECwt infection of mice increased expression of cyclooxygenase-2, ERp57, Hsc70, NF-κB, Hsp70, protein disulphide isomerase (PDI and PPARγ in intestinal villus cells. NAC treatment of ECwt-infected mice reduced Hsc70 and PDI expression to levels similar to those observed in villi from uninfected control mice. The present results suggest that the drugs tested in the present work could be assayed in preventing or treating rotaviral diarrhoea in children and young animals.

Current Concepts and Management Approaches in Nonalcoholic Fatty Liver Disease

Directory of Open Access Journals (Sweden)

Bashar M. Attar

2013-01-01

Full Text Available Nonalcoholic fatty liver disease (NAFLD is the most common cause of liver dysfunction worldwide. NAFLD may progress to nonalcoholic steatohepatitis (NASH and in turn cirrhosis. Importantly, hepatic cancer can occur in NASH in the absence of cirrhosis. The cardinal histologic feature of NAFLD is the presence of an excessive accumulation of triacylglycerols and diacylglycerols in hepatocytes. The presence of obesity and insulin resistance lead to an increased hepatic-free fatty acid (FFA flux creating an environment appropriate for the development of NAFLD. The generation of toxic reactive oxygen species with the production of hepatic injury and inflammation as a consequence of FFA oxidation will ultimately lead to the initiation and progression of fibrosis. Lifestyle modifications specifically weight loss, physical exercise, and cognitive behavior therapy have been recommended as treatments for NASH. Dietary fructose is an independent risk factor for the development of NAFLD. Pioglitazone can be used to treat biopsy-proven NASH; however, its safety risks should be considered carefully. Greater consumption for coffee, independent of its caffeine component, has been associated with a significant reduced risk of advanced fibrosis in NASH. Additional data are needed before recommending bariatric surgery as an established option for the specific treatment of NASH.

Chronic treatment with tadalafil improves endothelial function in men with increased cardiovascular risk.

Science.gov (United States)

Rosano, Giuseppe M C; Aversa, Antonio; Vitale, Cristiana; Fabbri, Andrea; Fini, Massimo; Spera, Giovanni

2005-02-01

Erectile dysfunction (ED) is often associated with a cluster of risk factors for coronary artery disease and reduced endothelial function. Acute and chronic administration of oral sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, improves endothelial function in patients with ED. Tadalafil (TAD) is a new PDE5 inhibitor with a long half life that allows alternate day administration. Aim of the study was to evaluate whether chronic therapy (4 weeks) with TAD improves endothelial function in patients with increased cardiovascular risk and whether this effect is sustained after discontinuation of therapy. We randomized 32 patients with increased cardiovascular risk to receive either TAD 20 mg on alternate days or matching placebo (PLB) for 4 weeks. Patients underwent evaluation of brachial artery flow-mediated dilation (FMD), nitrite/nitrate and endothelin-1 plasma levels at baseline, at the end of treatment period and after two-weeks follow-up. At 4 weeks, FMD was significantly improved by TAD (from 4.2+/-3.2 to 9.3+/-3.7%, p<0.01 vs. baseline), but was not modified by PLB (from 4.1+/-2.8 to 4.0+/-3.4%, p=NS). At 6 weeks the benefit in FMD was sustained in patients that received TAD (9.1+/-3.9% vs. 4.2+/-3.2%, p=0.01 vs. baseline; 9.1+/-3.9% vs. 9.3+/-3.7%, vs. 4 weeks, p=NS) while no changes in FMD were observed in patients randomized to PLB. Also, compared to baseline, a net increase in nitrite/nitrate levels (38.2+/-12.3 vs. 52.6+/-11.7 and 51.1+/-3.1, p<0.05) and a decrease in endothelin-1 levels (3.3+/-0.9 vs. 2.9.+/-0.7 and 2.9+/-0.9, p<0.05) was found both at four and six-weeks after TAD; these changes were inversely correlated as shown by regression analysis (adjusted R2=0.81, p<0.0001). Chronic therapy with TAD improves endothelial function in patients with increased cardiovascular risk regardless their degree of ED. The benefit of this therapy is sustained for at least two weeks after the discontinuation of therapy. Larger studies are needed in order

Provision of fertility services for women at increased risk of complications during fertility treatment or pregnancy: an Ethics Committee opinion.

Science.gov (United States)

2016-11-01

This opinion addresses the ethics of providing fertility treatment to women at elevated risk from fertility treatment or pregnancy. Providers ethically may treat women at elevated risk provided that they are carefully assessed; that specialists in their medical condition are consulted as appropriate; and that patients are fully informed about risks, benefits, and alternatives, including oocyte and embryo donation, use of a gestational surrogate, not undergoing fertility care, and adoption. Providers also may conclude that the risks are too high for them to treat particular patients ethically; such determinations must be made in a medically objective and unbiased manner and patients must be fully informed of the decision. Counseling of women who wish to initiate fertility treatment with underlying medical conditions that confer increased risk during treatment or pregnancy should incorporate the most current knowledge available, being cognizant of the woman's personal determinants in relation to her reproductive desires. In such a way, both physician and patient will optimize decision making in an ethically sound, patient-supportive context. Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Adult Brtl/+ mouse model of osteogenesis imperfecta demonstrates anabolic response to sclerostin antibody treatment with increased bone mass and strength.

Science.gov (United States)

Sinder, B P; White, L E; Salemi, J D; Ominsky, M S; Caird, M S; Marini, J C; Kozloff, K M

2014-08-01

Treatments to reduce fracture rates in adults with osteogenesis imperfecta are limited. Sclerostin antibody, developed for treating osteoporosis, has not been explored in adults with OI. This study demonstrates that treatment of adult OI mice respond favorably to sclerostin antibody therapy despite retention of the OI-causing defect. Osteogenesis imperfecta (OI) is a heritable collagen-related bone dysplasia, characterized by brittle bones with increased fracture risk. Although OI fracture risk is greatest before puberty, adults with OI remain at risk of fracture. Antiresorptive bisphosphonates are commonly used to treat adult OI, but have shown mixed efficacy. New treatments which consistently improve bone mass throughout the skeleton may improve patient outcomes. Neutralizing antibodies to sclerostin (Scl-Ab) are a novel anabolic therapy that have shown efficacy in preclinical studies by stimulating bone formation via the canonical wnt signaling pathway. The purpose of this study was to evaluate Scl-Ab in an adult 6 month old Brtl/+ model of OI that harbors a typical heterozygous OI-causing Gly > Cys substitution on Col1a1. Six-month-old WT and Brtl/+ mice were treated with Scl-Ab (25 mg/kg, 2×/week) or Veh for 5 weeks. OCN and TRACP5b serum assays, dynamic histomorphometry, microCT and mechanical testing were performed. Adult Brtl/+ mice demonstrated a strong anabolic response to Scl-Ab with increased serum osteocalcin and bone formation rate. This anabolic response led to improved trabecular and cortical bone mass in the femur. Mechanical testing revealed Scl-Ab increased Brtl/+ femoral stiffness and strength. Scl-Ab was successfully anabolic in an adult Brtl/+ model of OI.

[Open-wedge osteotomy of the glenoid for treatment of posterior shoulder instability with increased glenoid retroversion].

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Pogorzelski, J; Braun, S; Imhoff, A B; Beitzel, K

2016-12-01

Treatment of posterior shoulder instability with increased retroversion of the glenoid using open-wedge osteotomy of the glenoid neck stabilized with an autologous bone block. Symptomatic, atraumatic posterior shoulder instability with increased retroversion (>20°) of the glenoid and previously failed conservative or surgical treatment. General contraindications against surgery. Relative contraindications: osteoporosis, nicotine abuse, or suspected patient noncompliance. Posterior approach with a 7 cm long incision starting medial of the posterolateral corner of the acromion heading to the posterior axillary fold and subsequent preparation of the deltoid muscle and the infraspinatus muscle. The posterior glenohumeral capsule is incised by performing a capsular T‑shift. The osteotomy is performed intracapsulary medial to the genoid rim. The wedge bone graft, harvested from spina scapulae or iliac spine, is placed "press fit" in position. Additional fixation of the graft is not necessary if the anterior cortex is intact. For reinforcing the posterior capsule, a posterior capsule shift should be performed. Insertion of extracapsular wound drainage. Successive wound closure. Postoperative immobilization in a 0° shoulder orthesis for 6 weeks; avoidance of horizontal abduction for 8 weeks. After removing the wound drainage, start of limited active-assisted range of motion. Over-head sports after 6 months. From 2009-2015, 6 posterior open wedge glenoid osteotomies were performed. Postoperative retroversion of the glenoid was 11.2 ± 9.4° compared to 26.0 ± 8.6° before surgery. Of 6 shoulders, 2 showed postoperative signs of persistent posterior instability; the other 4 shoulders were free of complaints. No revision surgery was needed.

Treatment of β-Thalassemia/Hemoglobin E with Antioxidant Cocktails Results in Decreased Oxidative Stress, Increased Hemoglobin Concentration, and Improvement of the Hypercoagulable State

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Orn-uma Yanpanitch

2015-01-01

Full Text Available Studies on the antioxidant treatment for thalassemia have reported variable outcomes. However, treatment of thalassemia with a combination of hydrophobic and hydrophilic antioxidants and an iron chelator has not been studied. This study investigated the effects of antioxidant cocktails for the treatment of β-thalassemia/hemoglobin E (HbE, which is the most common form of β-thalassemia in Southeast Asia. Sixty patients were divided into two groups receiving N-acetylcysteine, deferiprone, and either curcuminoids (CUR or vitamin E (Vit-E, and their hematological parameters, iron load, oxidative stress, and blood coagulation potential were evaluated. Patients were classified as responders if they showed the improvements of the markers of iron load and oxidative stress, otherwise as nonresponders. During treatment, the responders in both groups had significantly decreased iron load, oxidative stress, and coagulation potential and significantly increased antioxidant capacity and hemoglobin concentration. The significantly maximum increase (P<0.01 in hemoglobin concentration was 11% at month 4 in CUR group responders and 10% at month 10 in Vit-E group responders. In conclusion, the two antioxidant cocktails can improve anemia, iron overload, oxidative stress, and hypercoagulable state in β-thalassemia/HbE.

Methylphenidate treatment beyond adolescence maintains increased cocaine self-administration in the spontaneously hypertensive rat model of attention deficit/hyperactivity disorder.

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Baskin, Britahny M; Dwoskin, Linda P; Kantak, Kathleen M

2015-04-01

extending methylphenidate treatment beyond adolescence does not ameliorate explicitly the long-term consequences of adolescent methylphenidate treatment. Pre-session methylphenidate may mask temporarily the detection of an increase in cocaine self-administration following chronic methylphenidate treatment. Copyright © 2015 Elsevier Inc. All rights reserved.

Paradoxical response with increased tumor necrosis factor-α levels to anti-tuberculosis treatment in a patient with disseminated tuberculosis

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Sho Watanabe

2017-01-01

Full Text Available It has been reported that tuberculosis (TB worsens after cessation of tumor necrosis factor-α inhibitors and starting anti-TB treatment. Little is known about the immunological pathogenesis of this paradoxical response (PR. We report the first case of a TB patient in whom PR occurred concurrently with elevation of circulating tumor necrosis factor-α (TNFα levels. A 75-year-old woman, who had been treated with adalimumab for SAPHO syndrome, developed disseminated TB. Soon after administration of anti-TB treatment (isoniazid, rifampicin, pyrazinamide, and ethambutol, and after discontinuation of adalimumab, a PR occurred. Serial testing of serum cytokine levels revealed a marked increase in TNFα, and a decline in interferon-γ levels. Despite intensive treatment with antibiotics, prednisolone, noradrenaline, and mechanical ventilation, acute respiratory distress syndrome developed and she died. Thus, overproduction of TNFα after cessation of TNFα inhibitors may partially account for the pathogenesis of a PR. This supports preventative or therapeutic reinitiation of TNFα inhibitors when PR occurs. Serial monitoring of circulating inflammatory cytokine levels could lead to earlier identification of a PR.