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Modulating deposition of Aβ-containing plaques in the brain may be beneficial in treating Alzheimer's disease. β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors have been shown to reduce Aβ in plasma and CSF in healthy volunteers. In this study safety, pharmacokinetics and pharmacodynamics that is reduction of the plasma biomarkers Aβ40 and Aβ42, of the BACE1 inhibitor AZD3839 were evaluated. Single oral ascending doses (1-300 mg) of AZD3839 were administered to 54 young healthy volunteers in a randomized, double-blind, placebo-controlled study. The data was analyzed using non-linear mixed effects modeling. AZD3839 reduced Aβ40 and Aβ42 in plasma with estimated potencies (EC50) of 46 and 59 nM, respectively, and a maximum effect of approximately 55%. This was in excellent agreement with the concentration-response relationships obtained in mouse and guinea pig. AZD3839 exposure displayed non-linear kinetics, described by a three-compartment model with a saturated binding compartment and an increase in bioavailability with dose. AZD3839 was safe, although, a dose-dependent QTcF prolongation was observed (mean 20 milliseconds at 300 mg). In conclusion, AZD3839 reduced plasma Aβ40 and Aβ42, demonstrating clinical peripheral proof of mechanism. Pre-clinical models were predictive for the effect of AZD3839 on the human plasma biomarker in a strictly quantitative manner. [ABSTRACT FROM AUTHOR]

Eur J Clin Invest 2012; 42 (10): 1079-1086 Abstract Objectives The goal of this study was designed to assess prognostic values of simultaneous measurement of adipocytokines in systolic heart failure (HF) patients. Methods Patients with HF manifestations and left ventricular ejection fraction (LVEF) ≤ 50% were selected in this study. Gender, age, medications and serum biochemical data were recorded upon admissions. Adipocytokines including adiponectin, leptin, resistin, visfatin and retinol binding protein-4 were measured. Results A total of 108 (83 males and 25 females) patients were enroled. The age was 62 ± 15 years and mean LVEF was 35%. Twenty patients died during 776 ± 323 days follow-up. In univariate analysis, mortality was found to be associated with the log-transformed values of serum resistin (β = 5·616, P = 0·04), log-transformed values of serum adiponectin (β = 4·377, P = 0·038), age (β = 1·071, P < 0·001), NTHA functional status (β = 3·752, P = 0·001) and body mass index (β = 0·858, P = 0·012). Patients with higher level of serum resistin were associated with higher mortality ( P = 0·012). In multivariate analysis, mortality is associated with log-transformed values of serum resistin (β = 3·666, P = 0·045), age (β = 1·044, P = 0·017) and NTHA functional status (β = 2·541, P = 0·025). Conclusions Serum resistin level was associated with higher mortality in systolic HF patients even after adjusting clinical parameters. Resistin may be an informative risk marker for systolic HF patients. [ABSTRACT FROM AUTHOR]

Neuronal nicotinic acetylcholine receptor (nAChR) agonists active at the alpha-7 (α-7) receptor subtype are potential therapeutics for cognitive deficits in schizophrenia, Alzheimer's disease, and other mental disorders. SSR180711, an α-7 selective partial agonist, has been shown to improve preclinical cognition. A novel positron emission tomography (PET) radioligand, 11C-Chiba1001, is a close analog of SSR180711. We labeled Chiba-1001 with tritium in order to evaluate its utility as a preclinical radioligand tool. In vitro, the binding affinity of [3H]Chiba-1001 at the α-7 receptor was low ( Kd = 120-180 nM) in both HEK239 cell membranes expressing human α-7 receptor and in native rat hippocampus membranes. The α-7 selective ligands AZD0328, ARR17779, and MLA did not inhibit [3H]Chiba-1001 binding ( Ki > 10,000 nM). In rat hippocampal membranes, Chiba-1001 and SSR180711 inhibited [3H]Chiba-1001 binding ( Ki = 220 and 230 nM, respectively), consistent with the literature reports. The in vivo binding profile of the radioligand was examined in normal rat, wild type mouse, and α-7 knockout mouse brain. We found that [3H]Chiba-1001 lacks adequate and specific brain regional uptake in rat and mouse brain. No significant inhibition of the radioligand binding was obtained following pretreatment of the animal with AZ11637326, AZD0328, or MLA. Our results indicate that [3H]Chiba-1001 has low affinity for α-7 nAChRs in vitro and poor α-7 regional and pharmacological selectivity in the rodent brain. Synapse, 2012. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The objective of this paper is to present a genetic algorithm-based stochastic dynamic programming (GA-based SDP) to cope with the dimensionality problem of a multiple-reservoir system. The joint long-term operation of a parallel reservoir system in the Feitsui and Shihmen reservoirs in northern Taiwan demonstrates the successful application of the proposed GA-based SDP model. Within the case study system it is believed that GA is a useful technique in supporting optimization. Though the employment of GA-based SDP may be time consuming as it proceeds through generation by generation, the model can overcome the 'dimensionality curse' in searching solutions. Simulation results show Feitsui's surplus water can be utilized efficiently to fill Shihmen's deficit water without affecting Feitsui's main purpose as Taipei city's water supply. The optimal joint operation suggests that Feitsui, on average, can provide 650,000 m3/day and 920,000 m3/day to Shihmen during the wet season and dry season, respectively. [ABSTRACT FROM AUTHOR]