Commercialization of rosiglitazone, an oral blood glucose-lowering drug of the thiazolidinedione class, was recently suspended in Europe and significantly restricted in the United States due to a possibly increased risk of ischemic heart disease; the drug is still being marketed in Mexico. This study was aimed to analyze the post-marketing occurrence of adverse drug reactions (ADRs) with rosiglitazone when used in combination therapy in Mexican Type 2 Diabetes patients.A prospective observational study was conducted at a primary health-care clinic in Mexico City. Eligible subjects were adult patients with Type 2 diabetes inadequately controlled with maximal doses of oral monotherapy, in which one of two combined therapeutic schemes was prescribed: rosiglitazone/glibenclamide (R/G), or rosiglitazone/metformin (R/M). Patients' blood pressure, weight, treatment adherence and occurrence of ADRs were monitored during a 6-month follow-up period.174 patients received treatment with R/M or R/G (112 and 62 patients, respectively). At least one ADR was observed in about 75%, of patients. Prior to the end of the follow-up period, moderate ADRs leading to discontinuation of the treatment occurred in 29.5% and 14.5% of patients treated with R/M and R/G, respectively. The ADRs most frequently observed were peripheral edema and moderate weight gain.The use of rosiglitazone in combination with other oral anti-diabetic drugs was associated with a high frequency of ADRs in Mexican patients with Type 2 diabetes. Post-marketing studies are relevant to identify drug-associated risks to patients in clinical practice.

Alanine aminotransferase (ALT) predicts incident type 2 diabetes (T2DM), possibly reflecting early fatty liver and hepatic insulin resistance. Thiazolidinediones and metformin can improve fatty liver and hepatic insulin resistance, respectively. In the Canadian Normoglycemia Outcome Evaluation trial, rosiglitazone/metformin (Rosi/Met, 4/1000 mg) reduced incident T2DM by 66% in subjects with impaired glucose tolerance. For insight on the hepatic effects of this therapy in relation to T2DM, we evaluated the temporal changes in waist, hepatic insulin sensitivity (1/Homeostasis Model Assessment of Insulin Resistance) and ALT in the Rosi/Met (n = 103) and placebo (n = 104) arms over median of 3.9 years. Waist did not differ between the arms. Hepatic insulin sensitivity improved in the Rosi/Met arm in year 1, but deteriorated thereafter as in the placebo arm. In contrast, Rosi/Met lowered ALT in year 1 and maintained this effect throughout the trial. Thus, low-dose Rosi/Met had no effect on central obesity, a transient effect on hepatic insulin sensitivity, and a sustained effect on ALT.

The purpose of this study was to evaluate if superior glycaemic control could be achieved with Avandamet® (rosiglitazone/metformin/AVM) compared with metformin (MET) monotherapy, and if glycaemic effects attained with AVM are durable over 18 months of treatment. Bone mineral density (BMD) and bone biomarkers were evaluated in a subgroup of patients.This was a phase IV, randomized, double-blind, multi-centre study in 688, drug naÏve, male and female patients who had an established clinical diagnosis of type 2 diabetes mellitus (T2DM). Patients were randomized in a 1 : 1 ratio either to AVM or MET.As initial therapy in patients with T2DM, AVM was superior to MET in achieving statistically significant reductions in glycated haemoglobin (HbA1c) (p < 0.0001) and fasting plasma glucose (FPG) (p < 0.001), with more patients reaching recommended HbA1c and FPG targets for intensive glycaemic control. The glycaemic effects attained with AVM compared to MET monotherapy were durable over 18 months of treatment. In the bone substudy, AVM was associated with a significantly lower BMD in comparison with MET at week 80 in the lumbar spine and total hip (p < 0.0012 and p = 0.0005, respectively). Between-treatment differences were not statistically significant for distal one-third of radius BMD, femoral neck BMD or total BMD.Superior glycaemic control was achieved with AVM compared with MET monotherapy. The superior glycaemic effects were shown to be durable over 18 months of treatment. AVM was associated with a significantly reduced BMD in comparison with MET at week 80 in the lumbar spine and total hip.

Vaspin, adiponectin and interleukin-6 (IL-6) constitute novel adipose-tissue derivatives, known as adipokines, which mediate insulin resistance. The aim of the present study was to evaluate the effects of metformin and rosiglitazone on serum levels of those novel adipokines in drug-naïve patients with type 2 diabetes mellitus (T2DM).140 patients with T2DM, already treated with diet, but without adequate glycemic control (HbA1c > 7%), were randomly assigned to: RSG+MET group, (n = 70): Combination therapy with fixed dose of 4 mg rosiglitazone plus 500 mg metformin. MET group, (n = 70): Half-maximum dose of metformin monotherapy (1 700 mg/day). Before and after 6-month treatment, body-mass index (BMI), blood pressure (BP), fat-mass, fasting plasma glucose (FPG), HbA1c, insulin resistance indexes (HOMA-IR, insulin), lipids, high-sensitivity CRP (hsCRP), vaspin, adiponectin, and interleukin-6 (IL-6) were measured.Glucose regulation and insulin resistance were equivalently improved from baseline within both groups (p < 0.05). There was a considerable amelioration of hsCRP, WBC, adiponectin, IL-6, systolic and diastolic BP with rosiglitazone/metformin combined treatment as compared to baseline (p < 0.05) and MET group (p < 0.05). In contrast, metformin monotherapy significantly reduced BMI (p < 0.001), total-cholesterol (p = 0.012) and LDL (p = 0.020) levels compared to RSG+MET group. Importantly, serum vaspin concentration was equivalently decreased from baseline in both RSG+MET (-0.96 ± 0.75 ng/ml, p < 0.001) and MET (-0.92 ± 0.57 ng/ml, p=0.001) group. The aforementioned vaspin changes correlated with changes in WHR, HbA1c, FPG, HOMA-IR, insulin, IL-6 (only in the RSG+MET group) and fat-mass. In standard multiple regression analysis, FPG, HbA1c, HOMA-IR and insulin remained independent determinants of serum vaspin levels changes (R² = 0.836, p = 0.004).Both rosiglitazone/metformin combination therapy and metformin monotherapy decreased serum vaspin levels through glucose and insulin sensitivity regulation, while they exerted differential effects on adiponectin, IL-6 and other cardiovascular risk factors in drug-naïve patients with T2DM.

Complex diseases, such as Type 2 Diabetes, are generally caused by multiple factors, which hamper effective drug discovery. To combat these diseases, combination regimens or combination drugs provide an alternative way, and are becoming the standard of treatment for complex diseases. However, most of existing combination drugs are developed based on clinical experience or test-and-trial strategy, which are not only time consuming but also expensive.In this paper, we presented a novel network-based systems biology approach to identify effective drug combinations by exploiting high throughput data. We assumed that a subnetwork or pathway will be affected in the networked cellular system after a drug is administrated. Therefore, the affected subnetwork can be used to assess the drug's overall effect, and thereby help to identify effective drug combinations by comparing the subnetworks affected by individual drugs with that by the combination drug. In this work, we first constructed a molecular interaction network by integrating protein interactions, protein-DNA interactions, and signaling pathways. A new model was then developed to detect subnetworks affected by drugs. Furthermore, we proposed a new score to evaluate the overall effect of one drug by taking into account both efficacy and side-effects. As a pilot study we applied the proposed method to identify effective combinations of drugs used to treat Type 2 Diabetes. Our method detected the combination of Metformin and Rosiglitazone, which is actually Avandamet, a drug that has been successfully used to treat Type 2 Diabetes.The results on real biological data demonstrate the effectiveness and efficiency of the proposed method, which can not only detect effective cocktail combination of drugs in an accurate manner but also significantly reduce expensive and tedious trial-and-error experiments.

Thiazolidinediones (TZD) can cause adipose tissue accumulation and myocardial hypertrophy. This study aimed to determine if combined Metformin (Glucophage) and Rosiglitazone (Avandia) could reduce the risk of heart failure caused by Rosiglitazone in BALB/c mice. BALB/c mice were treated with oral Rosiglitazone/Metformin twice daily for four weeks. Metformin or Rosiglitazone alone and non-treated mice acted as double control. Myocardial hypertrophy and associated side effects of the combined therapy were determined through isolated heart and body weights. Reverse transcription-polymerase chain reaction (RT-PCR) and Western blot were applied to evaluate expression of sulfonylurea receptor 2A (SUR2A) and Kir 6.2. The activities of peroxisome proliferator activated receptor alpha (PPARalpha) in the myocardium were also observed. Rosiglitazone/Metformin decreased body weight gain and food intake, and inhibited an increasing adipose ratio but did not reduce myocardial hypertrophy. Rosiglitazone increased Kir6.2/SUR2A, Kir6.2/SUR2B, and PPARalpha gene expression. The Rosiglitazone/Metformin combination further increased these gene expressions, especially PPARalpha. Metformin inhibits obesity but has no effect in reducing myocardial hypertrophy caused by Rosiglitazone. Whether Metformin can reduce side effects of TZDs in humans warrants further study.

In this study, three spectrophotometric methods and one HPLC method were developed for analysis of anti-diabetic drugs in tablets. The two spectrophotometric methods were based on the reaction of rosiglitazone (RSG) with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and bromocresol green (BCG). Linear relationship between the absorbance at lambda(max) and the drug concentration was found to be in the ranges 6.0-50.0 and 1.5-12 microg ml(-1) for DDQ and BCG methods, respectively. The third spectrophotometric method consists of a zero-crossing first-derivative spectrophotometric method for simultaneous analysis of RSG and metformin (MTF) in tablets. The calibration curves were linear within the concentration ranges of 5.0-50 microg ml(-1) for RSG and 1.0-10.0 microg ml(-1) for MTF. The fourth method is a rapid stability-indicating HPLC method developed for the determination of RSG. A linear response was observed within the concentration range of 0.25-2.5 microg ml(-1). The proposed methods have been successfully applied to the tablet analysis.

Clinical practice guidelines from around the world have continued to highlight the importance of glycemic control in the prevention of diabetes complications. Despite the many tools available to achieve these targets, it remains a constant challenge for healthcare providers and patients alike. Rosiglitazone maleate + metformin hydrochloride extend is a new compound that has the advantage of the clinical experience and knowledge about the current version and the added benefit of being a once daily, single pill option. The existing version of rosiglitazone + metformin has been shown to effectively lower hemoglobin A1C, improve insulin sensitivity and minimize weight gain. It is expected that the new compound will also have similar features, with the added benefit of improved patient adherence given its once daily formulation.