N-terminal pro-B-type natriuretic peptide for prediction of ventricular arrhythmias: Data from the SMASH study.

BACKGROUND: Elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations predict heart failure (HF) and mortality, but whether NT-proBNP predicts ventricular arrhythmias (VA) is not clear. HYPOTHESIS: We hypothesize that high NT-proBNP concentrations associate with the risk of incident VA, defined as adjudicated ventricular fibrillation or sustained ventricular tachycardia. METHODS: In a prospective, observational study of patients treated with implantable cardioverter defibrillator (ICD), we analyzed NT-proBNP concentrations at baseline and after mean 1.4 years in association to incident VA. RESULTS: We included 490 patients (age 66 ± 12 years, 83% men) out of whom 51% had a primary prevention ICD indication. The median NT-proBNP concentration was 567 (25-75 percentile 203-1480) ng/L and patients with higher concentrations were older with more HF and ICD for primary prevention. During mean 3.1 ± 0.7 years, 137 patients (28%) had ≥1 VA. Baseline NT-proBNP concentrations were associated with the risk of incident VA (hazard ratio [HR]: 1.39, 95% confidence interval [95% CI]: 1.22-1.58, p < .001), HF hospitalizations (HR: 3.11, 95% CI: 2.53-3.82, p < .001), and all-cause mortality (HR: 2.49, 95% CI: 2.04-3.03, p < .001), which persisted after adjusting for age, sex, body mass index, coronary artery disease, HF, renal function, and left ventricular ejection fraction. The association with VA was stronger in secondary versus primary prevention ICD indication: HR: 1.59 (95% CI: 1.34-1.88 C-statistics 0.71) versus HR: 1.24, 95% CI: 1.02-1.51, C-statistics 0.55), p-for-interaction = 0.06. Changes in NT-proBNP during the first 1.4 years did not associate with subsequent VA. CONCLUSIONS: NT-proBNP concentrations are associated with the risk of incident VA after adjustment for established risk factors, with the strongest association in patients with a secondary prevention ICD indication.

Galectin-3, a marker of cardiac remodeling, is inversely related to serum levels of marine omega-3 fatty acids. A cross-sectional study.

OBJECTIVE: Marine polyunsaturated n-3 fatty acids (n-3 PUFA) may have cardioprotective effects and beneficial influence on the fibrotic process. We evaluated the associations between serum marine n-3 PUFA and selected biomarkers of fibrosis and cardiac remodeling in elderly patients with acute myocardial infarction. SETTING: From the ongoing OMega-3 fatty acids in Elderly patients with Myocardial Infarction (OMEMI) trial, 299 patients were investigated. Soluble ST2 (sST2), Galectin-3 (Gal-3) and the serum content of major marine n-3 and n-6 PUFA were analyzed 2-8 weeks after the index acute myocardial infarction. RESULTS: Gal-3 was inversely correlated to eicosapentaenoic acid (r = -.120, p = .039) and docosahexaenoic acid (r = -.125, p = .031) and positively correlated to the n-6/n-3 ratio (r = .131, p = .023). Gal-3 levels were significantly higher in diabetics vs non-diabetics (12.00 vs 9.61 ng/mL, p = .007) and in patients with NYHA class ≥III for dyspnea at inclusion (11.33 vs 9.75 ng/mL, p = .006). CONCLUSIONS: The associations between the marine n-3 PUFA and levels of Gal-3 indicate beneficial effects of n-3 PUFA on cardiac remodeling in an elderly population with acute myocardial infarction.

A Neutral Control Condition for Hypnosis Experiments: "Wiki" Text.

A new control condition called Wiki is introduced. Key themes of each test suggestion of the Stanford Hypnotic Susceptibility Scale, Form C, were matched by a corresponding extract from Wikipedia.org. The authors compared phenomenological reports of participants across 4 conditions: hypnosis split into high and low hypnotizable subgroups, music, and Wiki condition, using the Phenomenology of Consciousness Inventory. High hypnotizables undergoing hypnosis reported higher altered experience and altered states of awareness than individuals in the Wiki condition, supporting the authors' hypothesis that the Wiki condition does not evoke an altered state of consciousness (internal dialogue, volitional control, and self-awareness did not differ). Wiki might be a viable control condition in hypnosis research given further examination.

Effect of food on the pharmacokinetics and bioavailability of oral imiquimod relative to a subcutaneous dose.

OBJECTIVES: The present study, the first clinical pharmacokinetic report of the immune response modifier imiquimod, was conducted to assess the effect of food on the oral absorption of imiquimod, to characterize its pharmacokinetics, and to estimate its oral bioavailability. SUBJECTS AND METHODS: Sixteen healthy male volunteers completed this open-label, randomized, three-period crossover study. Subjects received a 100 mg oral dose of imiquimod after fasting in one period, after a standarized, high fat meal in another, and a 30 mg subcutaneous dose in the third period. RESULTS: The oral bioavailability of imiquimod was on average 47%, and independent of whether imiquimod was administered with or without food. Oral imiquimod was absorbed in both fasted and non-fasted states with an absorption half-life of approximately 1 hour. However, there seemed to be a delay in the initiation of the absorption process when food was administered, which translated in to a Tmax of approximately 2.6 hours while fasting and one hour later in the non-fasted state. Imiquimod was rapidly eliminated with a half-life of approximately 2.5 hours and a total body clearance of approximately 970 ml/hxkg. Although equivalence could not be established due to the large intersubject variability, no significant differences in rate (Cmax) and extent (AUC) of oral absorption were observed between the fasted and non-fasted states. In addition, the Cmax, AUC and bioavailability values for individual subjects were consistent between both oral treatments. CONCLUSION: This study suggests that food does not have a major effect on the rate, extent of absorption or bioavailability of oral imiquimod, and thus, it is suitable to administer imiquimod orally in either the fasted or non-fasted states.

Induction of cytokines in cynomolgus monkeys by the immune response modifiers, imiquimod, S-27609 and S-28463.

Imiquimod, S-27609 and S-28463 are imidazoquinolines known to have antiviral and antitumour properties mediated by the induction of cytokines, in particular interferon alpha (IFN-alpha). This study evaluated these compounds for their ability to induce cytokines and cytokine specific messenger RNAs (mRNA) in cynomologus monkeys (Macaca fascicularis). Peripheral blood mononuclear cell (PBMC) cultures from monkeys produced IFN, interleukin 1beta (IL-1beta), IL-6 and IL-8 after treatment with imiquimod, S-27609 and S-28463. Tumour necrosis factor alpha (TNF-alpha) was also increased in cultures stimulated with S-27609 or S-28463. Monkey PBMCs stimulated with imiquimod, S-27609 and S-28463 showed increased mRNA levels of IFN-alpha, IL-1alpha, IL-6 and the IFN inducible protein, MxA above those seen in untreated cultures. S-27609 and S-28463 also had higher TNF-alpha mRNA expression than cultures not receiving drugs. When compared to lipopolysaccharide (LPS), S-27609 was less effective at inducing IL-1beta, IL-6, IL-8 and TNF-alpha but induced higher concentrations of IFN. Similar results were seen when evaluating cytokine mRNA levels. Upon oral administration to monkeys, S-28463 stimulated a dose-dependent increase in serum concentrations of IFN, TNF-alpha, IL-1 receptor antagonist (IL-1Ra) and IL-6, while imiquimod induced increases in IFN and IL-1Ra concentrations. Finally, skin biopsies from monkeys treated topically with S-28463 had increases over baseline in mRNA for IFN-alpha, IL-1alpha, IL-6 and MxA protein. The data show that imidazoquinolines induce cytokines and cytokine specific mRNA in cynomolgus monkeys. These results demonstrate the usefulness of human amplimers and human ELISAs in the detection of cytokine specific mRNAs and proteins in cynomolgus monkeys.

Immunomodulating and antiviral activities of the imidazoquinoline S-28463.

Recently, a new class of immunomodulating agents, represented by the molecules imiquimod and R-842, has demonstrated potent antiviral and antitumor activities in animal models. In this study, another representative of this class, S-28463 (4-amino-2-ethoxymethyl-alpha,alpha-dimethyl-1H-imidazo[4,5-c]quinoline- 1- ethanol) was evaluated for its immunomodulating and antiviral activities. S-28463 induced IFN and other cytokines in vivo in mice, rats, monkeys and in vitro in human peripheral blood mononuclear cell cultures. S-28463 showed potent antiviral activity against herpes simplex virus-challenged guinea pigs when given subcutaneously, dermally, or intravaginally 24 h before infection. Antiviral activity in guinea pigs correlated with the induction of serum 2',5'-oligoadenylate synthetase activity. Thus, S-28463, like the other imidazoquinolines, demonstrates potent antiviral and immunomodulating effects in a number of models.