Metabolites of PPI-2458, a selective, irreversible inhibitor of methionine aminopeptidase-2: structure determination and In vivo activity

The natural product fumagillin exhibits potent antiproliferative and antiangiogenic properties. The semisynthetic analog PPI-2458, (3R,4S,5S,6R)-5-methoxy-4-(2R,3R)-2-methyl-3-(3-methylbut-2-enyl) oxiran-2-yl]-1-oxaspiro2.5]octan-6-yl] N-(2R)-1-amino-3-methyl-1-oxobutan-2-yl]carbamate, demonstrates rapid inactivation of its molecular target, methionine aminopeptidase-2 (MetAP2), and good efficacy in several rodent models of cancer and inflammation with oral dosing despite low apparent oral bioavailability. To probe the basis of its in vivo efficacy, the metabolism of PPI-2458 was studied in detail. Reaction phenotyping identified CYP3A4/5 as the major source of metabolism in humans. Six metabolites were isolated from liver microsomes and characterized by mass spectrometry and nuclear resonance spectroscopy, and their structures were confirmed by chemical synthesis. The synthetic metabolites showed correlated inhibition of MetAP2 enzymatic activity and vascular endothelial cell growth. In an ex vivo experiment, MetAP2 inhibition in white blood cells, thymus, and lymph nodes in rats after single dosing with PPI-2458 and the isolated metabolites was found to correlate with the in vitro activity of the individual species. In a phase 1 clinical study, PPI-2458 was administered to patients with non-Hodgkin lymphoma. At 15 mg administered orally every other day, MetAP2 in whole blood was 80% inactivated for up to 48 hours, although the exposure of the parent compound was only similar to 10% that of the summed cytochrome P450 metabolites. Taken together, the data confirm the participation of active metabolites in the in vivo efficacy of PPI-2458. The structures define a metabolic pathway for PPI-2458 that is distinct from that of TNP-470 ((3R, 4S, 5S, 6R)-5-methoxy-4-(2R, 3R)-2-methyl-3-(3-methylbut-2-enyl)oxiran-2-yl]-1-oxaspiro2.5]octan-6 -yl] N-(2-chloroacetyl)carbamate). The high level of MetAP2 inhibition achieved in vivo supports the value of fumagillin-derived therapeutics for angiogenic diseases.

含砂率计

本实用新型涉及一种含砂率计，该砂率计是在砂浆管壁的径向对称位置分别通过射线发生器固定架和探测器固定架设有射线发生器和探测器，在射线发生器和探测器前均设有光栏，在射线发生器的光栏前还设有射线发生器防护活塞阀，在射线发生器的两侧分别设有前屏蔽块和后屏蔽；探测器的输出信号与探测器辅助电路相连；本实用新型为外卡式非接触γ射线测量，其测量精度高、测量范围大，可连续在线测量。

La competencia comunicativa : producción de textos escritos : orientaciones para la corrección : evaluación diagnóstica, Educación Secundaria Obligatoria.

Resumen tomado de la web del Departamento de Educación

Can Children Distinguish Between Thoughts and Behaviours?

Abstract. The extent to which cognitive behaviour therapy can be used with children is unclear. In meta analyses older children and teenagers seem to derive greater benefit than young children. This may be because the cognitive immaturity of young children means that they cannot manage the cognitive demands of cognitive behaviour therapy. This paper seeks to establish how well children aged 7–8 and aged 10–11 can complete a task requiring them to distinguish between thoughts and behaviours (based on Greenberger & Padesky, 1995). Half of the children were provided with a visual cue and half were not. The effects of age, the visual cue, and verbal IQ on performance were examined. Seventy-two children were randomized to the cue and no-cue condition and individually tested during school time. Both age groups performed well and there was a significant difference between older and younger children, with the older children performing better. Visual cues did not aid performance. Verbal IQ was significantly associated with performance in the younger but not the older children. The implications of these results for the delivery of cognitive behaviour therapy with children and future research are discussed. Keywords: Children, thoughts, behaviours, cognitive, development

Ms. lat. oct. 113 (mit Ausst. 88) - Rituale exorcismorum

Vorbesitzer: Oswaldus, Pleban in Ostheim (Vorbesitzer?), Karmeliterkloster Frankfurt am Main

1,2-Functionalized Imidazoles as Palladium Ligands: An Efficient and Robust Catalytic System for the Fluorine-Free Hiyama Reaction

A variety of hydroxy- and amino-functionalized imidazoles were prepared from 1-methyl- and 1-(diethoxymethyl)imidazole by means of isoprene-mediated lithiation followed by reaction with an electrophile. These compounds in combination with palladium acetate were screened as catalyst systems for the Hiyama reaction under fluorine-free conditions using microwave irradiation. The systematic study of the catalytic system showed 1-methyl-2-aminoalkylimidazole derivative L1 to be the best ligand, which was employed under solvent-free conditions with a 1:2 Pd/ligand ratio and TBAB (20 mol-%) as additive. The study has revealed an interaction between the Pd/ligand ratio and the amount of TBAB. The established catalytic system presented a certain degree of robustness, and it has been successfully employed in the coupling of a range of aryl bromides and chlorides with different aryl siloxanes. Furthermore, both reagents were employed in an equimolecular amount, without an excess of organosilane.