This work describes a microdosing study with an investigational, carbon 11-labeled antiamyloid drug, 1,1'-methylene-di-(2-naphthol) (ST1859), and positron emission tomography (PET) in healthy volunteers (n = 3) and patients with Alzheimer's disease (n = 6). The study aimed to assess the distribution and local tissue pharmacokinetics of the study drug in its target organ, the human brain. Before PET studies were performed in humans, the toxicologic characteristics of ST1859 were investigated by an extended single-dose toxicity study according to guidelines of the Food and Drug Administration and European Medicines Agency, which are relevant for clinical trials with a single microdose. After intravenous bolus injection of 341 +/- 21 MBq [(11)C]ST1859 (containing <11.4 nmol of unlabeled ST1859), peripheral metabolism was rapid, with less than 20% of total plasma radioactivity being in the form of unchanged parent drug at 10 minutes after administration. In both the control and patient groups, uptake of radioactivity into the brain was relatively fast (time to reach maximum concentration, 9-17 minutes) and pronounced (maximum concentration [standardized uptake value], 1.3-2.2). In both healthy volunteers and patients, there was a rather uniform distribution of radioactivity in the brain, including both amyloid-beta-rich and -poor regions, with slow washout of radioactivity (half-life, 82-185 minutes). In conclusion, these data provide important information on the blood-brain barrier penetration and metabolism of an investigational antiamyloid drug and suggest that the PET microdosing approach is a useful method to describe the target-organ pharmacokinetics of radiolabeled drugs in humans.

The duration and magnitude of the effect of inhaled formoterol (12 micrograms) against exercise-induced bronchoconstriction (EIB) was compared with that of inhaled salbutamol (200 micrograms) and that of placebo in 15 children with asthma and EIB in a double-blind, double-dummy, within-patient, placebo-controlled study. The treatments were given by metered dose aerosol on three different days. The exercise test was performed at the 3rd and the 12th hour after dosing. The magnitude of the blocking effect was assessed both by evaluating the lowest FEV1 reading obtained within an hour after each exercise test and by considering the percent decrease below the baseline FEV1 measured before drug administration. Comparison of the lowest values obtained during the hour after each exercise test shows that formoterol was significantly better than both salbutamol (p = 0.022), and placebo (p = 0.001) in limiting exercise-induced bronchoconstriction after the first exercise test (3 h after dosing), while no difference was observed between salbutamol and placebo (p = 0.198). After the second exercise test (12 h after dosing), formoterol again proved to be more effective than both salbutamol (p = 0.008) and placebo (p = 0.001), and no significant difference was observed between salbutamol and placebo (p = 0.391). The evaluation of the mean percentage decrease in FEV1 confirmed the results in favor of formoterol in both the exercise tests. No adverse effects were reported in any treatment group. The protection against EIB is significantly more prolonged after formoterol than after salbutamol, and persists for 12 h after dosing.

LVSI is a frequent occurrence in patients with early stage cervical cancer. It represents an unfavorable prognostic factor in univariate and multivariate analyses. Such results suggest that improvement is needed in the treatment of patients with a small tumor and LVS invasion.

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Dyes like CR are able to inhibit the aggregation of Aβ fibrils. Thus, a screening of a series of dyes including ABBB (1) was performed. Its main component 2 tested in an in vitro assay (i.e., ThT assay) showed good potency at inhibiting fibrils association. Congeners 4-9 have been designed and synthesized as inhibitors of Aβ aggregation. A number of these newly synthesized compounds have been found to be active in the ThT assay with IC(50) of 1-57.4 μM. The most potent compound of this series, 4k, showed micromolar activity in this test. Another potent derivative 4q (IC(50) = 5.6 μM) rapidly crossed the blood-brain barrier, achieving whole brain concentrations higher than in plasma. So 4q could be developed to find novel potent antiaggregating βA agents useful in Alzheimer disease as well as other neurological diseases characterized by deposits of amyloid aggregates.