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Otolaryngol Head Neck Surg. 2008 Jul; 139(1): 124-30
Jeon EJ, Lee SK, Park YS, Kim DH, Yum JH, Park CS
OBJECTIVES: To investigate the effect of rosiglitazone, a synthetic selective peroxisome proliferator-activated receptor (PPAR)-gamma agonist, for cytokine production and PPAR-gamma expression in nasal mucosa. METHODS: Mice in allergic rhinitis group received ovalbumin sensitization followed by ovalbumin intranasal challenge. Mice in the rosiglitazone group received rosiglitazone treatment additionally. Various allergic responses were then assessed. RESULTS: The frequency of nasal rubs and ovalbumin-specific immunoglobulin E decreased significantly in the rosiglitazone group compared with the allergic rhinitis group. The rosiglitazone group also showed that inflammation was markedly reduced by rosiglitazone administration. Immunohistochemistry showed that PPAR-gamma protein expression in nasal mucosa was enhanced in the allergic rhinitis group and the rosiglitazone group compared with control mice. CONCLUSION: PPAR-gamma activation with rosiglitazone effectively inhibited allergic symptom development, nasal mucosal inflammation, and production of ovoalbumin-specific immunoglobulin E and Th2-type cytokine. Our results provide evidence of the therapeutic potential of PPAR-gamma agonist for the treatment of allergic rhinitis.
Am Heart J. 2008 Jul; 156(1): 23-30
Hernandez AV, Walker E, Ioannidis JP, Kattan MW
Rare cardiovascular events of commonly used drugs are important to document and investigate, but single trials are notoriously underpowered to provide conclusive evidence. Recently, meta-analyses have been used to improve on the power. A recent rosiglitazone meta-analysis heightened the debate about the usefulness and limitations of meta-analysis in this setting. In this review, we examined the methods used in previous published meta-analyses for harmful cardiovascular events, with special attention to the rosiglitazone meta-analyses, and give suggestions for the improvement of methods and interpretation of such meta-analyses. The conduct of meta-analysis in this context is particularly difficult and requires timely investigation, availability of high-quality data on harms, and statistical expertise. There are important decisions that need to be made about selecting the appropriate analytical methods and performing sensitivity analyses to evaluate whether the results are robust to different analytical choices.
Rosiglitazone Treatment Reduces Diabetic Neuropathy in STZ Treated DBA/2J Mice.
Endocrinology. 2008 Jun 26;
Wiggin TD, Kretzler M, Pennathur S, Sullivan KA, Brosius FC, Feldman EL
Diabetic Neuropathy (DN) is a common complication of diabetes. Currently, there is no drug treatment to prevent or slow the development of DN. Rosiglitazone (Rosi) is a potent insulin sensitizer and may also slow the development of DN by a mechanism independent of its effect on hyperglycemia. A two by two design was used to test the effect of Rosi treatment on the development of DN. Streptozotocin-induced diabetic DBA/2J mice were treated with Rosi. DN and oxidative stress were quantified, and gene expression was profiled using the Affymetrix Mouse Genome 430 2.0 microarray platform. An informatics approach identified key regulatory elements activated by Rosi. Diabetic DBA/2J mice developed severe hyperglycemia, DN and elevated oxidative stress. Rosi treatment did not affect hyperglycemia but did reduce oxidative stress and prevented development of thermal hypoalgesia. Two novel transcription factor binding modules were identified that may control genes correlated to changes in DN following Rosi treatment: SP1F_ZBPF and EGRF_EGRF. These targets may be useful in designing drugs with the same efficacy as Rosi in treating DN but with fewer undesirable effects.
Eur J Endocrinol. 2008 Jun 26;
Antonelli A, Ferrari SM, Fallahi P, Berti P, Materazzi G, Marchetti I, Ugolini C, Basolo F, Miccoli P, Ferrannini E
Objective: Anaplastic thyroid cancer (ATC) is often unoperable and chemotherapy and radiotherapy are the main treatments. Until now primary ATC cell cultures (ANA) have been developed from surgical biopsies. The possibility to obtain ANA from fine-needle aspiration (FNA-ANA) and to test their sensitivity to different drugs could increase the effectiveness of treatments and avoid unnecessary surgical procedures. Design: To obtain FNA-ANA from 6 ATC patients before undergoing surgery and to evaluate the chemosensitivity of FNA-ANA to chemotherapeutic agents and thiazolidinediones. Methods and Results: FNA-ANA from the 6 ATC patients were cultured in RPMI 1640 and propagated in DMEM medium. Chemosensitivity was evaluated by inhibiting the proliferation with increasing concentrations of five different chemotherapeutic agents (bleomycin, cisplatin, gemcitabine, etoposide and carboplatin), or thiazolidinediones (rosiglitazone). Chemotherapeutic agents significantly inhibited (p
Nan Fang Yi Ke Da Xue Xue Bao. 2008 Jun; 28(6): 1056-60
Zhu XX, Niu XL, Chen DZ, Zhou XD, Pei JM, Zhu MZ, Guo J, Zhu XL, Wang WQ
OBJECTIVE: To investigate the mechanism of rosiglitazone (RSG, the activator of peroxisome proliferators activated receptor lambda) for inhibiting endothelin-1 (ET-1)-induced neonatal rat cardiac myocyte hypertrophy and the role of protein kinase C (PKC) and c-fos. METHODS: In vitro cultured neonatal rat cardiac myocytes were treated with ET-1, phorbol ester (PMA, the PKC activator), ET-1+RSG, ET-1+chelerythrine (che, the PKC inhibitor), PMA+RSG, or without treatment (control), respectively. The effects of RSG on the protein content, (3)H-leucine incorporation, PKC activity and C-fos protein expression were observed in the cardiac myocytes stimulated with ET-1 or PMA. RESULTS: After two days of culture, the intracellular protein content in ET-1 group and PMA group were increased by 15% (339-/+15 microg/ml) and 13% (329-/+14 microg/ml) as compared with the control cells (290-/+13 microg/ml), respectively (P
Nan Fang Yi Ke Da Xue Xue Bao. 2008 Jun; 28(6): 1050-1
Zhu HL, Yu RM, Huang XZ, Huang W
OBJECTIVE: To study the effect of rosiglitazone on serum high-sensitivity C-reactive protein (hs-CRP), interleukin-1beta (IL-1beta), IL-6, tumor necrosis factor-alpha (TNF-alpha) and insulin resistance in obese patients with newly diagnosed type 2 diabetes. METHODS: This study involved 118 patients with newly diagnosed type 2 diabetes and obesity, who were randomly assigned into two groups for a 12-week treatment with rosiglitazone (4 mg/day, group A) or sulfonylureas (group B). Serum hs-CRP, IL-1beta, IL-6, TNF-alpha, fasting plasma glucose (FPG) and fasting insulin (FINS) were measured before and after the treatment. Insulin resistance index was calculated according to the HOMA Model. RESULTS: In group A, rosiglitazone treatment resulted in significantly reduced serum hs-CRP, IL-1beta, IL-6, TNF-alpha, FPG and insulin resistance index (P0.05), but serum hs-CRP, IL-1beta, IL-6, TNF-alpha and insulin resistance index were significantly lower in group A than in group B (P
Nan Fang Yi Ke Da Xue Xue Bao. 2008 Jun; 28(6): 1025-7
Pei HH, Qiao WH, Liu ML, Bai L, Miao F
OBJECTIVE: To observe the effects of peroxisome proliferators-activated receptor-gamma (PPARgamma) on the function of the vital organs in rats with pancreatitis. METHODS: Acute pancreatitis (AP) was induced in 30 male SD rats by ductal injection of 4% sodium taurocholate at 1.0 ml/kg. The rats received subsequent intravenously injection of 0.3 mg/kg of PPARgamma ligand (rosiglitazone, n=10), PPARgamma antagonist (GW9662, n=10) followed 10 min later by rosiglitazone administration at 0.3 mg/kg, or left untreated (AP model group, n=10). Another 10 male SD rats receiving no particular treatment served as the control group. The rats were sacrificed 6 h after the operation, and blood samples were collected for measurement of the biochemical indices of the vital organs. The histological changes of the pancreas and portal vein blood endotoxin content were examined. RESULTS: The rats in AP group and GW9662 group showed significantly higher level of the biochemical indices for the vital organs, pathological scores of the pancreas and portal vein blood endotoxin content were significantly higher in the control group and roglitazone-treated groups (P
Reducing global cardiovascular risk in patients with type 2 diabetes mellitus.
J Am Osteopath Assoc. 2008 May; 108(5 Suppl 3): S14-9
Gavin JR
Type 2 diabetes mellitus (T2DM) and its complications must be managed by using a comprehensive, or global, approach to treatment. The author describes the case of a white man, aged 51 years, with T2DM that was diagnosed 3 years earlier. The patient was obese and had a history of chronic low back pain. He also had diagnosed hypertension, decreased vibratory sensation in the feet, an S4 atrial gallop, trace ankle edema, degenerative joint disease in the knees, and decreased range of motion in the lumbar spine. Other findings at the patient's initial visit included hyperglycemia, microalbuminuria, and lipid abnormalities. Initial treatment included metformin; a nonsteroidal anti-inflammatory drug (naproxen); a thiazolidinedione (rosiglitazone maleate); a thiazide diuretic (hydrochlorothiazide); an angiotensin-converting enzyme inhibitor (enalapril); and low-dose aspirin. At 6-month follow-up, the patient continued to have elevated glycosylated hemoglobin, hypertension, dyslipidemia, and excess weight. Additional treatment strategies consisted of pioglitazone hydrochloride; metformin in combination with the dipeptidyl peptidase IV inhibitor sitagliptin phosphate; a statin (atorvastatin hydrochloride); and enrollment in a diet and exercise program. Results at 12-month follow-up included a substantial decrease in glycosylated hemoglobin and improved hypertension and dyslipidemia. The patient was successfully treated across the full range of global cardiovascular risk reduction.
Antidepressant-like effect of the novel thiadiazolidinone NP031115 in mice.
Prog Neuropsychopharmacol Biol Psychiatry. 2008 Jun 24;
Rosa AO, Kaster MP, Binfaré RW, Morales S, Martín-Aparicio E, Navarro-Rico ML, Martinez A, Medina M, García AG, López MG, Rodrigues AL
Glycogen synthase kinase-3beta (GSK-3beta) is an enzyme that phosphorylates glycogen synthase, thereby inhibiting glycogen synthesis. Besides this role, it is now believed that this enzyme plays an important role in the pathophysiology of many brain diseases including depression. Some inhibitors of this enzyme have shown antidepressant effects in animal models. This study investigated the effects of a novel thiadiazolidinone NP031115, a putative GSK-3beta inhibitor, and the well-established GSK-3beta inhibitor AR-A014418 in the mouse forced swimming test (FST), a model widely used to evaluate antidepressant activity. We found that NP031115 had an IC(50) of 1.23 and 6.5 muM for GSK-3beta and GSK-3alpha, respectively. NP031115 (0.5 and 5 mg/kg, i.p.), in a way similar to imipramine (15 mg/kg, i.p), fluoxetine (32 mg/kg, i.p), AR-A014418 (9 mg/kg, i.p.), and rosiglitazone (5 mug/site, i.c.v.), significantly reduced immobility time in the FST. NP031115 at the higher dose and AR-A014418 (9 mg/kg, i.p.) reduced locomotion in the open-field test. Rosiglitazone (30 muM), AR-A014418 (1 muM), PG(J2) (10 muM), and NP031115 (1, 10 and 25 muM) activate PPARgamma in CHO transfected cells. GW-9662 (10 mug/site, i.c.v, a PPARgamma antagonist) administered 15 min before NP03115 (5 mg/kg, i.p.) or co-administered with rosiglitazone (5 mug/site, i.c.v.) prevented the antidepressant-like effect of these drugs in the FST. The results of this study show that NP031115 can exhibit an antidepressant effect, likely by inhibiting GSK-3beta and enhancing PPARgamma activity.
Br J Nutr. 2008 Jun 25; 1-9
Kwon DY, Kim YS, Hong SM, Park S
Crude saponins derived from Chinese Platycodi radix have been reported to prevent increases in body weight and liver TAG in mice fed a high-fat diet. We investigated the effects of an extract (PR) taken from Korean Platycodi radix, which is cultivated for 22 years in the ground (Jangsaeng doraji), and its saponins (PRS) on insulin resistance and glucose-stimulated insulin secretion in 90 % pancreatectomized diabetic rats fed high-fat diets. Four groups were orally supplemented with 2 g PR, 0.2 g PRS, 20 mg rosiglitazone (positive control) or 0.5 g cellulose (negative control) per kg body weight on a daily basis for 8 weeks. We found that PRS lowered body weight, visceral fat mass and serum leptin levels in pancreatectomized rats in comparison to the control. PR enhanced first- and second-phase insulin secretion while PRS stimulated only first-phase insulin secretion. Glucose infusion rates to maintain euglycaemia at hyperinsulinaemic states decreased in a descending order of rosiglitazone, PRS, PR and control, but they increased hepatic glucose output in the same order. This reduction was associated with the storage of decreased TAG and increased glycogen, which was a result of enhanced tyrosine phosphorylation of anti-insulin receptor substrate-2 and serine473 phosphporylation of protein kinase B (PKB, Akt). Improved hepatic insulin signalling led to decreased phosphoenolpyruvate carboxykinase expression and reduced hepatic glucose output accordingly. In conclusion, PRS principally improves glucose homeostasis by enhancing hepatic insulin sensitivity as a consequence of reducing fat storage and stimulating insulin signalling in diabetic rats. In addition, PR contains components that promote glucose-stimulated insulin secretion.