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Background and purpose: Racemic (R,S) AM1241 is a cannabinoid receptor 2 (CB 2 )-selective aminoalkylindole with antinociceptive efficacy in animal pain models. The purpose of our studies was to provide a characterization of R,S-AM1241 and its resolved enantiomers in vitro and in vivo. Experimental approach: Competition binding assays were performed using membranes from cell lines expressing recombinant human, rat, and mouse CB 2 receptors. Inhibition of cAMP was assayed using intact CB 2 -expressing cells. A mouse model of visceral pain (para-phenylquinone, PPQ) and a rat model of acute inflammatory pain (carrageenan) were employed to characterize the compounds in vivo. Key results: In cAMP inhibition assays, R,S-AM1241 was found to be an agonist at human CB 2 , but an inverse agonist at rat and mouse CB 2 receptors. R-AM1241 bound with more than 40-fold higher affinity than S-AM1241, to all three CB 2 receptors and displayed a functional profile similar to that of the racemate. In contrast, S-AM1241 was an agonist at all three CB 2 receptors. In pain models, S-AM1241 was more efficacious than either R-AM1241 or the racemate. Antagonist blockade demonstrated that the in vivo effects of S-AM1241 were mediated by CB 2 receptors. Conclusions and implications: These findings constitute the first in vitro functional assessment of R,S-AM1241 at rodent CB 2 receptors and the first characterization of the AM1241 enantiomers in recombinant cell systems and in vivo. The greater antinociceptive efficacy of S-AM1241, the functional CB 2 agonist enantiomer of AM1241, is consistent with previous observations that CB 2 agonists are effective in relief of pain.

Thirteen low-tannin faba bean genotypes grown at two locations in north central Alberta in 2009 were evaluated to investigate the variation in seed characteristics, phenolic and phytate contents, and phytase and antioxidant activities and to elucidate the relationship of these components as a breeding strategy. Seed characteristics including color were predominantly genotype dependent. The faba bean genotypes with total phenolic content ranging from 5.5 to 41.8 mg of catechin equiv/g of sample was linearly related to tannin content and the best predictor of antioxidant activity. Phytic acid content and phytase activity varied significantly among genotypes and between locations, ranging from 5.9 to 15.1 g/kg and from 1606 to 2154 FTU/kg sample, respectively. Multivariate data analysis performed on 19 components analyzed in this study using principal component analysis (PCA) and cluster analysis demonstrate that differences in seed characteristics, phenolic components, phytic acid, and phytase are major factors in segregating faba bean genotypes. The relatively low phytic acid content and high phytase activity of these low-tannin faba bean genotypes are beneficial/essential traits for their use in human and animal nutrition.

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A new formulation of mometasone furoate (MF) for administration by dry powder inhaler (DPI) was evaluated for the treatment of asthma. A 12-week, double-blind, placebo-controlled dose-ranging study compared the efficacy and safety of three doses of MF DPI (100, 200 and 400 mcg b.i.d) with beclomethasone dipropionate (BDP) 168 mcg b.i.d. administered by metered dose inhaler in 365 adult or adolescent patients being treated with inhaled glucocorticoids. The mean change from baseline to endpoint (last treatment visit) for forced expiratory volume in 1 sec (FEV1) was the primary efficacy variable. Secondary efficacy variables included other objective measures of pulmonary function [forced vital capacity (FVC), forced expiratory flow 25-75% (FEV25-75%.) and peak expiratory flow rate (PEFR)] as well as subjective measures of therapeutic response (patients' daily evaluation of asthma symptoms and physicians' evaluation). At endpoint, all four active treatments were significantly more effective than placebo (P < 0.01) in improving FEV1 (MF DPI 5 to 7%, BDP 3%, placebo -6.6%) and all other measures of pulmonary function (FVC: MF DPI 4 to 5%, BDP 2%, placebo -4.7%; FEF25-75%: MF DPI 6 to 18%, BDP 7.5%, placebo -9.5%; PEFR (AM): MF DPI 5 to 10%, BDP 5.7%, placebo -7%). A consistent trend was observed for better improvement in patients treated with MF DPI 200 mcg b.i.d. than with MF DPI 100 mcg b.i.d., with no apparent additional benefit of MF DPI 400 mcg b.i.d. Results for the MF DPI 100 mcg b.i.d. and BDP 168 mcg b.i.d. treatment groups were similar. Patients' and physicians' subjective evaluations of symptoms found similar improvement in the MF DPI 200 and 400 mcg b.i.d. treatment groups, which were slightly better than that in the MF DPI 100 mcg b.i.d. group. Symptoms tended to worsen in the placebo group. MF DPI was well tolerated at all dose levels and the most frequently reported treatment-related adverse effects were headache, pharyngitis and oral candidiasis. No evidence of HPA-axis suppression was detected in any treatment group. In summary, all doses of MF DPI were well tolerated and significantly improved lung function and MF DPI 400 mcg (200 mcg b.i.d.) was the optimal dose in this study of patients with moderate persistent asthma.