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In a screening of natural products for allosteric modulators of GABA A receptors (γ-aminobutyric acid type A receptor), piperine was identified as a compound targeting a benzodiazepine-independent binding site. Given that piperine is also an activator of TRPV1 (transient receptor potential vanilloid type 1) receptors involved in pain signaling and thermoregulation, a series of piperine analogs were prepared in several cycles of structural optimization, with the aim of separating GABA A and TRPV1 activating properties. We here investigated the metabolism of piperine and selected analogs in view of further cycles of lead optimization. Metabolic stability of the compounds was evaluated by incubation with pooled human liver microsomes, and metabolites were analyzed by UHPLC-Q-TOF-MS. CYP450 isoenzymes involved in metabolism of compounds were identified by reaction phenotyping with Silensomes™. Unbound fraction in whole blood was determined by rapid equilibrium dialysis. Piperine was the metabolically most stable compound. Aliphatic hydroxylation, and N- and O-dealkylation were the major routes of oxidative metabolism. Piperine was exclusively metabolized by CYP1A2, whereas CYP2C9 contributed significantly in the oxidative metabolism of all analogs. Extensive binding to blood constituents was observed for all compounds., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Purpose: If several studies analyse the working abilities of cancer survivors two years after the diagnosis, few of them analyse the long term becoming at work of these patients. Here we study a cohort of 153 workers, 6 years after they returned to work after experiencing a cancer in 2005 or 2006. All these workers participated in a previous study realised in 2008, two years after the diagnosis., Material and Methods: Fourty occupational physicians included 153 workers out of the 319 particpating in a first study conducted in 2008. Two questionnaires were completed by both the worker and the occupationnal physician. Twenty four patients' interviews and nine physician's interviews were also realized for qualitative analysis., Results: Six years after they returned to work, 46% were still working in the same company. Among patients aged less than 55 years (113 out of 153), they were 20% to leave the company (a 4% annual rate). Concerning the 83 salaries still at work, sequelaes of the disease are often still present: fatigue (57%), sleep disorders (56% vs 34% at 2 years), memory and concentration disorders (34%) and chronic pain (16%). Thirty one percent reported serious anxious disorders vs 29% in 2008. Difficulties are still present in 71% of the responders. Fourty percent of the nonexecutive workers feeled penalized. Qualitative study shows that a successfull return to work is associated with a friendly environement, the support of the company, and a long term accompagnying policy., Conclusions: Six years after returning to work, one employee out of two is still working in the same company. Far to disappear, the identified difficulties two years after the diagnosis are still present, long time after stopping the treatments. A successfull return to work needs an important support from both the company and the co-workers., (Copyright © 2015 Société Françise du Cancer. Publié par Elsevier Masson SAS. Tous droits réservés. Published by Elsevier Masson SAS. All rights reserved.)

Ten midly hirsute women with normal serum levels of testosterone were treated with spironolactone (100 mg die), and the effectiveness of this dose-schedule regimen was evaluated after six months of therapy. Hirsutism subsided partly in all women. We estimated however, that in 6 of the 10 women, the clinical benefit was out weighed by the side effects and other drawbacks of a long term therapy and their medication was then stopped 6 months after its initiation. The changes induced on the pituitary function were evaluated by measuring basal serum T3 T4 and basal and stimulated (TRH-LHRH) TSH, PRL, FSH and LH, prior to and after one month of therapy. Spironolactone induced a greater response of TSH to TRH (p less than .025) but no change in T3 T4, PRL, FSH and LH. These data suggest that changes in TSH response are not explained by the speculated intrinsic oestrogenic activity of spironolactone but rather by a selective interaction with TSH secreting cells. We conclude that spironolactone therapy should not be recommended for the large category of normal women complaining of slight increase of facial hair.