Novartis

About: Novartis is a company organization based out in Basel, Switzerland. It is known for research contribution in the topics: Alkyl & Population. The organization has 41930 authors who have published 50566 publications receiving 1978996 citations. The organization is also known as: Novartis International AG.

Clinical pharmacology and pharmacogenetics of thiopurines.

Abstract: The thiopurine drugs—azathioprine (AZA), 6-mercaptopurine (6-MP), and thioguanine—are widely used to treat malignancies, rheumatic diseases, dermatologic conditions, inflammatory bowel disease, and solid organ transplant rejection. However, thiopurine drugs have a relatively narrow therapeutic index and are capable of causing life-threatening toxicity, most often myelosuppression. Thiopurine S-methyltransferase (TPMT; EC 2.1.1.67), an enzyme that catalyzes S-methylation of these drugs, exhibits a genetic polymorphism in 10% of Caucasians, with 1/300 individuals having complete deficiency. Patients with intermediate or deficient TPMT activity are at risk for excessive toxicity after receiving standard doses of thiopurine medications. This report reviews the recent advances in the knowledge of the mechanism of action as well as the molecular basis and interethnic variations of TPMT and inosine triphosphate pyrophosphatase (ITPase; EC 3.6.1.19), another enzyme implicated in thiopurine toxicity. In addition, an update on pharmacokinetics, metabolism, drug-drug interactions, safety, and tolerability of thiopurine drugs is provided.

The comparative prognostic value of plasma neurohormones at baseline in patients with heart failure enrolled in Val-HeFT

Abstract: Aims Plasma levels of individual neurohormones (NH) have been proposed as reliable indicators for risk stratification of patients with heart failure (HF). Mainly because of small sample size, the predictive value of different NH has never been compared, while taking into account demographic, clinical and echocardiographic markers of risk in HF. Methods and results Plasma brain natriuretic peptide (BNP), norepinephrine (NE), renin activity (PRA), aldosterone (aldo) and endothelin were measured in 4300 patients before randomization in Val-HeFT. Univariate and multivariate Cox proportional hazard analyses were performed to investigate the relationship between NH and two primary study outcomes, mortality and combined mortality and morbidity (M/M). Higher baseline values for all NH were related to mortality and M/M, with univariate hazard ratios ranging from 1.13 \[95% CI 0.99–1.30\] (aldo) to 2.47 \[2.13–2.87\] (BNP) for mortality, and from 1.24 \[1.11–1.39\] (aldo) to 2.56 \[2.28–2.89\] (BNP) for M/M. In multivariate analyses, BNP had the strongest association with outcome, followed by NE and PRA. Patients with more activation of renin-angiotensin-aldosterone system tended to show greater benefit from valsartan; but the trend was not statistically significant. Conclusion All the NHs evaluated in 4300 patients with stable moderate to severe HF were found to be significant markers of outcome, despite therapy with ACEi, BB and randomization to an angiotensin receptor blocker or placebo. Several of these markers have been implicated as contributors to progression of HF, but BNP, which is thought to be protective, was the most powerful indicator for poor outcome.

Once-daily bronchodilators for chronic obstructive pulmonary disease: indacaterol versus tiotropium.

Abstract: Rationale: Indacaterol is the first once-daily, long-acting inhaled β2-agonist bronchodilator studied in patients with chronic obstructive pulmonary disease (COPD).Objectives: To demonstrate greater efficacy of indacaterol versus placebo on FEV1 at 24 hours post dose (trough) after 12 weeks, to compare efficacy with placebo and tiotropium, and to evaluate safety and tolerability over 26 weeks.Measurements: Patients with moderate-to-severe COPD were randomized to double-blind indacaterol 150 or 300 μg or placebo, or open-label tiotropium 18 μg, all once daily, for 26 weeks. The primary efficacy outcome was trough FEV1 at 12 weeks. Additional analyses (not adjusted for multiplicity) included transition dyspnea index (TDI), health status (St George's Respiratory Questionnaire [SGRQ]), and exacerbations. Serum potassium, blood glucose, and QTc interval were measured.Results: A total of 1,683 patients (age, 63.3 yr; post-bronchodilator FEV1, 56% predicted; FEV1/FVC, 0.53) were randomized to the four treatment ...

Development of Ewing's Sarcoma from Primary Bone Marrow–Derived Mesenchymal Progenitor Cells

Abstract: Ewing's sarcoma is a member of Ewing's family tumors (EFTs) and the second most common solid bone and soft tissue malignancy of children and young adults. It is associated in 85% of cases with the t(11;22)(q24:q12) chromosomal translocation that generates fusion of the 5' segment of the EWS gene with the 3' segment of the ETS family gene FLI-1. The EWS-FLI-1 fusion protein behaves as an aberrant transcriptional activator and is believed to contribute to EFT development. However, EWS-FLI-1 induces growth arrest and apoptosis in normal fibroblasts, and primary cells that are permissive for its putative oncogenic properties have not been discovered, hampering basic understanding of EFT biology. Here, we show that EWS-FLI-1 alone can transform primary bone marrow-derived mesenchymal progenitor cells and generate tumors that display hallmarks of Ewing's sarcoma, including a small round cell phenotype, expression of EFT-associated markers, insulin like growth factor-I dependence, and induction or repression of numerous EWS-FLI-1 target genes. These observations provide the first identification of candidate primary cells from which EFTs originate and suggest that EWS-FLI-1 expression may constitute the initiating event in EFT pathogenesis.

Effects of pioglitazone on adipose tissue remodeling within the setting of obesity and insulin resistance.

Abstract: Obesity and dysfunctional energy partitioning can lead to the development of insulin resistance and type 2 diabetes. The antidiabetic thiazolidinediones shift the energy balance toward storage, leading to an increase in whole-body adiposity. These studies examine the effects of pioglitazone (Pio) on adipose tissue physiology, accumulation, and distribution in female Zucker (fa/fa) rats. Pio treatment (up to 28 days) decreased the insulin-resistant and hyperlipidemic states and increased food consumption and whole-body adiposity. Magnetic resonance imaging (MRI) analysis and weights of fat pads demonstrated that the increase in adiposity was not only limited to the major fat depots but also to fat deposition throughout the body. Adipocyte sizing profiles, fat pad histology, and DNA content show that Pio treatment increased the number of small adipocytes because of both the appearance of new adipocytes and the shrinkage and/or disappearance of existing mature adipocytes. The remodeling was time dependent, with new small adipocytes appearing in clusters throughout the fat pad, and accompanied by a three- to fourfold increase in citrate synthase and fatty acid synthase activity. The appearance of new fat cells and the increase in fat mass were depot specific, with a rank order of responsiveness of ovarian > retroperitoneal > subcutaneous. This differential depot effect resulted in a redistribution of the fat mass in the abdominal region such that there was an increase in the visceral:subcutaneous ratio, as confirmed by MRI analysis. Although the increased adiposity is paradoxical to an improvement in insulin sensitivity, the quantitative increase of adipose mass should be viewed in context of the qualitative changes in adipose tissue, including the remodeling of adipocytes to a smaller size with higher lipid storage potential. This shift in energy balance is likely to result in lower circulating free fatty acid levels, ultimately improving insulin sensitivity and the metabolic state.