Drug and Alcohol Rehabilitation: Levosimendan in Acute Heart Failure Following Primary Percutaneous Coronary Intervention-Treated Acute ST-Elevation Myocardial Infarction. Results From the LEAF Trial: A Randomized, Placebo-Controlled Study.
Levosimendan in acute heart failure following primary percutaneous coronary intervention-treated acute ST-elevation myocardial infarction. Results from the LEAF trial: a randomized, placebo-controlled study.
Filed under: Drug and Alcohol Rehabilitation
Eur J Heart Fail. 2013 Jan 2;
Husebye T, Eritsland J, Müller C, Sandvik L, Arnesen H, Seljeflot I, Mangschau A, Bjørnerheim R, Andersen GO
AIMS: The calcium sensitizer levosimendan may counteract stunning after reperfusion of ischaemic myocardium, but no randomized placebo-controlled trials exist regarding its use in PCI-treated ST-segment elevation infarction (STEMI). We evaluated the efficacy and safety of levosimendan in patients with a primary PCI-treated STEMI complicated by symptomatic heart failure (HF). METHODS AND RESULTS: A total of 61 patients developing clinical signs of HF within 48 h after a primary PCI-treated STEMI (including cardiogenic shock) were randomized double-blind to a 25 h infusion of levosimendan or placebo. The primary endpoint was change in wall motion score index (WMSI) from baseline to day 5 measured by echocardiography. There was a significantly larger improvement in WMSI from baseline to day 5 in the levosimendan group compared with placebo (from 1.94 ± 0.20 to 1.66 ± 0.31 vs. 1.99 ± 0.22 to 1.83 ± 0.26, respectively, P = 0.031). There were significantly more episodes of hypotension during study drug infusion in the levosimendan group (67% vs. 36%, P = 0.029), but no significant difference in blood pressure at the end of infusion or in use of vasopressors. No significant between-group differences in changes in NT-proBNP levels, clinical composite score, frequency of atrial fibrillation or ventricular arrhythmia, infarct size at 6 weeks, or new clinical events up to 6 months were found. One and four patients died in the levosimendan and placebo group, respectively. CONCLUSIONS: Levosimendan treatment improved contractility in post-ischaemic myocardium in patients with PCI-treated STEMI complicated by HF. The treatment was well tolerated, without any increase in arrhythmias.Trial registration: NCT00324766.
HubMed – drug
STAT3 suppresses transcription of proapoptotic genes in cancer cells with the involvement of its N-terminal domain.
Filed under: Drug and Alcohol Rehabilitation
Proc Natl Acad Sci U S A. 2013 Jan 3;
Timofeeva OA, Tarasova NI, Zhang X, Chasovskikh S, Cheema AK, Wang H, Brown ML, Dritschilo A
Activation of STAT3 in cancers leads to gene expression promoting cell proliferation and resistance to apoptosis, as well as tumor angiogenesis, invasion, and migration. In the characterization of effects of ST3-H2A2, a selective inhibitor of the STAT3 N-terminal domain (ND), we observed that the compound induced apoptotic death in cancer cells associated with robust activation of proapoptotic genes. Using ChIP and tiling human promoter arrays, we found that activation of gene expression in response to ST3-H2A2 is accompanied by altered STAT3 chromatin binding. Using inhibitors of STAT3 phosphorylation and a dominant-negative STAT3 mutant, we found that the unphosphorylated form of STAT3 binds to regulatory regions of proapoptotic genes and prevents their expression in tumor cells but not normal cells. siRNA knockdown confirmed the effects of ST3-HA2A on gene expression and chromatin binding to be STAT3 dependent. The STAT3-binding region of the C/EBP-homologous protein (CHOP) promoter was found to be localized in DNaseI hypersensitive site of chromatin in cancer cells but not in nontransformed cells, suggesting that STAT3 binding and suppressive action can be chromatin structure dependent. These data demonstrate a suppressive role for the STAT3 ND in the regulation of proapoptotic gene expression in cancer cells, providing further support for targeting STAT3 ND for cancer therapy.
HubMed – drug
Race Moderates the Effect of Menthol Cigarette Use on Short-Term Smoking Abstinence.
Filed under: Drug and Alcohol Rehabilitation
Nicotine Tob Res. 2013 Jan 3;
Reitzel LR, Li Y, Stewart DW, Cao Y, Wetter DW, Waters AJ, Vidrine JI
INTRODUCTION: The Food and Drug Administration is in the process of reviewing evidence of the impact of mentholated cigarettes on smoking behaviors and smoking cessation in order to determine if these products should be removed from the market. More empirical research is needed to inform those decisions. The goal of this study was to examine associations of menthol cigarette use with biochemically verified continuous short-term smoking abstinence, and potential moderation by race, among adult current smokers enrolled in a cohort study (N = 183; 57.4% female; 48.1% non-Hispanic Black, 51.9% non-Hispanic White). METHODS: Continuation ratio logit models, adjusted for age, race, gender, total annual household income, educational level, employment status, and partner status, were used to examine associations of menthol use with smoking abstinence with and without an interaction term for race. RESULTS: Menthol cigarette use was not significantly associated with smoking abstinence in the sample as a whole; however, there was a significant interaction of menthol use with race (p = .03). Follow-up analyses stratified by race indicated that among White participants, menthol users had significantly lower odds of maintaining continuous abstinence than nonmenthol users (p = .05). Exploratory analyses suggested that tobacco dependence may lie along the causal pathway and partially explain this effect. CONCLUSIONS: White menthol smokers in this sample were at increased risk of smoking relapse relative to White nonmenthol smokers, at least partially due to greater tobacco dependence. Results should be replicated among other treatment-seeking samples with a greater representation of White menthol and Black nonmenthol smokers.
HubMed – drug
Binding of a Cyano- and Fluoro-Containing Drug Bicalutamide to Cytochrome P450 46A1: Unusual Features and Spectral Response.
Filed under: Drug and Alcohol Rehabilitation
J Biol Chem. 2013 Jan 3;
Mast N, Zheng W, Stout CD, Pikuleva IA
Cytochrome P450 46A1 (CYP46A1) is the cholesterol 24-hydroxylase initiating the major pathways of cholesterol removal from the brain, and bicalutamide (BIC) is a drug of choice for the treatment of progressive androgen-dependent prostate cancer. We evaluated the interactions of BIC with CYP46A1 by X-ray crystallography and by conducting solution and mutagenesis studies. Since BIC is administered to patients as a racemic mixture of the S- and R-isomers, we studied all three, racemic BIC as well as the S- and R-isomers. Co-crystallization of CYP46A1 with racemic BIC led to structure determinations at 2.1 Å resolution with the drug complexes exhibiting novel properties. Both BIC isomers bind to the CYP46A1 active site in very similar single orientation and adopt an energetically unfavorable folded conformation. This folded BIC conformation is correlated with drug-induced localized shifts of amino acid side chains in CYP46A1 and unusual interactions in the CYP46A1-BIC complex. One of these interactions involves a water molecule that is coordinated to the P450 heme iron and also hydrogen bonded to the BIC nitrile. Due to polarization of the water in this environment, the heme elicits previously unreported types of P450 spectral responses. We also observed that access to the P450 active site was affected by differential recognition of S- vs. R-isomers at the CYP46A1 surface arising from BIC conformational polymorphism.
HubMed – drug
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