Genomic Profiling Reveals the Potential Role of TCL1A and MDR1 Deficiency in Chemotherapy-Induced Cardiotoxicity.

Genomic Profiling Reveals the Potential Role of TCL1A and MDR1 Deficiency in Chemotherapy-Induced Cardiotoxicity.

Int J Biol Sci. 2013; 9(4): 350-60
McCaffrey TA, Tziros C, Lewis J, Katz R, Siegel R, Weglicki W, Kramer J, Mak IT, Toma I, Chen L, Benas E, Lowitt A, Rao S, Witkin L, Lian Y, Lai Y, Yang Z, Fu SW

Background: Anthracyclines, such as doxorubicin (Adriamycin), are highly effective chemotherapeutic agents, but are well known to cause myocardial dysfunction and life-threatening congestive heart failure (CHF) in some patients. Methods: To generate new hypotheses about its etiology, genome-wide transcript analysis was performed on whole blood RNA from women that received doxorubicin-based chemotherapy and either did, or did not develop CHF, as defined by ejection fractions (EF)?40%. Women with non-ischemic cardiomyopathy unrelated to chemotherapy were compared to breast cancer patients prior to chemo with normal EF to identify heart failure-related transcripts in women not receiving chemotherapy. Byproducts of oxidative stress in plasma were measured in a subset of patients. Results: The results indicate that patients treated with doxorubicin showed sustained elevations in oxidative byproducts in plasma. At the RNA level, women who exhibited low EFs after chemotherapy had 260 transcripts that differed >2-fold (p<0.05) compared to women who received chemo but maintained normal EFs. Most of these transcripts (201) were not altered in non-chemotherapy patients with low EFs. Pathway analysis of the differentially expressed genes indicated enrichment in apoptosis-related transcripts. Notably, women with chemo-induced low EFs had a 4.8-fold decrease in T-cell leukemia/lymphoma 1A (TCL1A) transcripts. TCL1A is expressed in both cardiac and skeletal muscle, and is a known co-activator for AKT, one of the major pro-survival factors for cardiomyocytes. Further, women who developed low EFs had a 2-fold lower level of ABCB1 transcript, encoding the multidrug resistance protein 1 (MDR1), which is an efflux pump for doxorubicin, potentially leading to higher cardiac levels of drug. In vitro studies confirmed that inhibition of MDR1 by verapamil in rat H9C2 cardiomyocytes increased their susceptibility to doxorubicin-induced toxicity. Conclusions: It is proposed that chemo-induced cardiomyopathy may be due to a reduction in TCL1A levels, thereby causing increased apoptotic sensitivity, and leading to reduced cardiac MDR1 levels, causing higher cardiac levels of doxorubicin and intracellular free radicals. If so, screening for TCL1A and MDR1 SNPs or expression level in blood, might identify women at greatest risk of chemo-induced heart failure. HubMed – drug


An observational study of acarbose treatment in patients with type 2 diabetes from the Middle East and Morocco.

Diabetes Metab Syndr Obes. 2013; 6: 141-50
Shihabi AR, Moussa EM, Sobierajska H, Schmidt B

The prevalence of type 2 diabetes is increasing dramatically in the Middle East and North Africa region. However, there are few trials that have determined the effect of antidiabetic treatment in an observational setting in these countries.This was a noninterventional study performed in Morocco in 2006-2007 and in the Middle East in 2005-2006 to observe the efficacy and safety of acarbose in patients with pretreated or untreated type 2 diabetes. Glycemic parameters (fasting blood glucose, one-hour postprandial blood glucose, and HbA1c) were recorded within a 3-month period. The observation period included an initial visit at the start of acarbose therapy and up to three follow-ups.Acarbose was effective in reducing glycemic parameters in patients from Morocco (n = 1082) and the Middle East (n = 1737). The mean one-hour postprandial blood glucose decreased by 35.5% to 165.4 ± 47.9 mg/dL in the Middle East and by 35.5% to 179.0 ± 49.9 mg/dL in Morocco. Mean fasting blood glucose decreased by 30.8% to 126.6 ± 34.2 mg/dL (Middle East) and by 34.5% to 150.6 ± 47.1 mg/dL (Morocco). The absolute reduction in HbA1c was 1.3% in the Middle East (final value 7.4%) and 1.0% in Morocco (final value 7.5%). Overall, 107 patients (Middle East) and 26 patients (Morocco) experienced minor drug-related adverse events, which were mainly gastrointestinal. The tolerability of acarbose was rated as very good/good by 80.8% in the Middle East and by 68.6% in Morocco.This study illustrates the efficacy and safety of acarbose in the treatment of type 2 diabetic patients in an observational setting. HubMed – drug


Clinical utility of phentermine/topiramate (Qsymia™) combination for the treatment of obesity.

Diabetes Metab Syndr Obes. 2013; 6: 131-9
Shin JH, Gadde KM

Qsymia™ (Vivus Inc, Mountain View, CA, USA), a combination of phentermine and delayed-release topiramate, has been available in the US since September 2012 for the treatment of obesity. Phentermine is an anorexigenic agent, which is approved for the short-term treatment of obesity, while topiramate is approved for nonweight loss indications – seizure disorders and migraine prophylaxis. The amount of weight loss achieved with combination therapy is of a greater magnitude than what could be achieved with either agent alone. Adverse events that occur with the combination therapy are in line with the known side effect profiles of the constituent drugs; teratogenicity, a slight increase in heart rate, psychiatric and cognitive adverse effects, and metabolic acidosis are concerns. HubMed – drug