Enjeux de la prise en charge des troubles dépressifs en période périnatale

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synthetic strategies to 2'-hydroxy-4'-methylsulfonylacetophenone, a key compound for the preparation of flavonoid derivatives

International audienceDifferent strategies for the synthesis of 2′-hydroxy-4′- methylsulfonylacetophenone are reported in the present paper. This compound is considered as a key synthon for the synthesis of new flavonoid derivatives designed as potential cyclooxygenase-2 inhibitors. The retrosynthetic approach via 3′-methylsulfonylacetophenone, which included three synthetic pathways, did not allow us to obtain the expected compound. However, a synthesis from 3-mercaptophenol led to the desired acetophenone in three steps: thiophenol methylation, Friedel-Crafts acetylation and oxidation of the sulphide to the corresponding sulfone. The desired compound, 2′-hydroxy-4′- methylsulfonylacetophenone, will be used as a synthon for the preparation of novel flavonoid derivatives, such as 2′-hydroxychalcones, flavanones, flavones, and flavonols

Exploring the Use of the Suzuki Coupling Reaction in the Synthesis of 4′-Alkyl-2′-hydroxyacetophenones

International audienceA series of 4′-alkyl-2′-hydroxyacetophenones were prepared by Suzuki cross-coupling reactions of 4′-bromo-2′-hydroxyacetophenone. In these reactions, alkyl(trifluoro)borates were found to be better reactants than alkylboronic acids. 4′-Alkyl-2′-hydroxyacetophenones are key intermediates for the further synthesis of -lipoflavonoids that are more readily incorporated into lipid bilayer membranes than flavonoids and should, therefore, have superior -biological effects through increased bioavailability

Intérêt d’une séance éducative « flash » coordonnée par des pharmaciens d’officine pour des patients âgés diabétiques de type 2 en milieu rural

International audienceThe number of elderly people with type 2 diabetes (T2D) is increasing worldwide. Community pharmacies, thanks to their proximity, provide more easy access to therapeutic education for rural patients. Populations living in isolated areas require specific educational resources related to their condition. The aim of this project was to perform a short (FLASH) educational intervention, coordinated by community pharmacists, and then evaluate the impact of this intervention on patient knowledge of their disease. The study was performed in Issoudun, a rural French town of approximately 10,000 inhabitants. Educational priorities were defined and the project was presented to health authorities and local health professionals. Pharmacies in Issoudun recruited patients, either alone or accompanied by their caregivers. The educational intervention lasted 2h and focused on 4 teaching objectives: knowledge concerning diabetes, diabetic complications and how to monitor them; how to react to hypoglycemia; understanding treatments; and understanding glycated hemoglobin. The impact of this educational intervention was assessed using a questionnaire delivered before the intervention, immediately after, and after 6months. Forty-five patients aged 71±6years with T2D duration of 14±6years were recruited over 6months. Some false beliefs were identified before the intervention. The educational session led to a significant improvement in the percentage of correct answers (before: 60.3%±7.5, after: 99%±0.4, P=0.0002) and at 6months (99.5%±0.3, P=0.0002) compared with the patients' initial knowledge. Almost all false beliefs were corrected by the intervention and patients were able to recall the mechanism of action of their drugs, with the help of a "key and lock" schematic. This short FLASH educational intervention, coordinated by community pharmacists, showed that the model was both interesting to patients and effective. This method could be expanded to other rural communities and medical deserts.Les pharmacies d’officine représentent un service de proximité, idéal pour un accès à l’éducation thérapeutique en milieu rural. Les personnes âgées, peu mobiles, diabétiques de type 2, sont de plus en plus nombreuses et nécessitent un accompagnement éducatif relatif à leur pathologie. L’objectif de ce travail était de mettre en place une intervention éducative courte, dite « flash », coordonnée par des pharmaciens d’officine et de l’évaluer à Issoudun dans l’Indre, ville rurale française d’environ 10 000 habitants. Une fois les priorités éducatives établies, le projet a été présenté aux diverses instances de santé ainsi qu’aux professionnels de santé locaux. Les officines d’Issoudun ont recruté les patients accompagnés ou non d’un aidant. L’intervention éducative de 2 h portait sur 4 objectifs pédagogiques : connaître le diabète, ses complications et leur surveillance, comment réagir face à une hypoglycémie, comprendre ses traitements et l’hémoglobine glyquée. L’impact de la séance éducative a été évalué par un questionnaire de connaissances avant la réunion, après et à 6 mois. Quarante-cinq patients de 71 ± 6 ans avec 14 ± 6 ans de diabète ont été recrutés sur 6 mois. De fausses croyances ont été mises en évidence avant l’intervention. La séance a permis une amélioration significative du taux de bonnes réponses (avant : 60,3 % ± 7,5, après : 99 % ± 0,4, p = 0,0002) et à 6 mois (99,5 % ± 0,3, p = 0,0002) par rapport à l’état des connaissances initiales des participants. Les fausses croyances ont été rectifiées en quasi-totalité par l’intervention et les participants ont su replacer le mécanisme d’action de leur médicament à l’aide d’un schéma « clé-serrure ». Ce modèle d’intervention éducative « flash » coordonnée par les pharmaciens d’officine a démontré son efficacité et son intérêt auprès des patients. Il pourrait être étendu à d’autres communes rurales et déserts médicaux

Contributions of a blended learning based on peer evaluation for teaching drug-drug interactions to undergraduate pharmacy students

International audienceBACKGROUND:Numerous studies have pointed out the need for better training of healthcare professionals in drug-drug interactions management in order to minimize adverse drugs reactions impacts on patients. The aim of this study was to evaluate the benefits of a blended learning strategy based on peer evaluation (PE) for teaching drug-drug interactions to undergraduate pharmacy students.METHODS:Third-year pharmacy students (n = 72) from the University of Limoges were involved in a hybrid teaching using the Moodle platform (2.9 version). After the theoretical lectures, an online activity was proposed to students. Each student submitted a report addressing a clinical case for peer evaluation. Students evaluated the pedagogical approach using an online survey. Quantitative benefits were assessed from students randomly assigned into two groups: PE in pharmacodynamics items (PE-PD) or PE in pharmacokinetics items (PE-PK). During this activity, three marks were given: one from peers for their evaluation work and two from teachers for oral group presentation of the clinical cases and for the final written examination. Statistics were performed using two-tailed unpaired t-test and significance was set for p < 0.05.RESULTS:Only a few students (n = 14, 20.6%) were aware of the peer evaluation principle and even less, only one student (n = 1, 1.5%), had already encountered it. Students considered that they benefited from this evaluation (n = 65, 95.6%); from their work being reviewed (n = 62, 91.2%) and that they participated in improving their classmates understanding (n = 59, 86.8%). Peers' allocated marks were similar in the two PE groups (PE-PD = 17.4 ± 1.4; PE-PK = 17.3 ± 1.4). Teachers' marks for oral presentation were significantly lower for pharmacodynamics than for pharmacokinetics items (PE-PD = 15.2 ± 1.2; PE-PK = 16.1 ± 2.1; p < 0.05). The final examination marks were equivalent in both groups (PE-PD = 11.0 ± 2.1; PE-PK = 11.2 ± 1.9).CONCLUSIONS:Besides the fact that a major short-term quantitative improvement was not detected, our teaching approach was qualified as being a positive and stimulating learning tool by students

Enhancement of hydrosolubility and in vitro antiproliferative properties of chalcones following encapsulation into β-cyclodextrin/cellulose-nanocrystal complexes

International audienceThis paper describes the preparation of two chalcone/β-cyclodextrin/cellulose-nanocrystals complexes and thestudy of their antiproliferative activities against two colorectal and two prostatic cancer cell lines. The aim of thiswork was to enhance hydrosolubility of chalcones thanks to the hydrophilic character of cellulose nanocrystals.These latter were linked, through ionic interactions, to a cationic derivative of β-cyclodextrins whose lipophiliccavity allowed the encapsulation of hydrophobic chalcones: 3-hydroxy-3′,4,4′,5′-tetramethoxychalcone (1) and3′,4,4′,5′-tetramethoxychalcone (2). First, we showed that encapsulation allowed hydrosolubilization of chalcones.Then, chalcone/β-cyclodextrin/cellulose-nanocrystals complexes demonstrated enhanced in vitro antiproliferativeactivities, compared to the corresponding free-chalcones

2′-Hydroxy-4-methylsulfonylchalcone enhances TRAIL-induced apoptosis in prostate cancer cells

International audienceProstate cancer is the most common malignant cancer in men and the second leading cause of cancer deaths. Previously, we have shown that 2′-hydroxy-4-methylsulfonylchalcone (RG003) induced apoptosis in prostate cancer cell lines PC-3 and DU145. Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent, some cancer cells are resistant to TRAIL treatment. PC-3 and LNCaP prostatic cancer cell lines have been reported to be resistant to TRAIL-induced apoptosis. Here, we show for the first time that RG003 overcomes TRAIL resistance in prostate cancer cells. RG003 can enhance TRAIL-induced apoptosis through DR5 upregulation and downregulation of Bcl-2, PI3K/Akt, NF-?B, and cyclooxygenase-2 (COX-2) survival pathways. When used in combined treatment, RG003 and TRAIL amplified TRAIL-induced activation of apoptosis effectors and particularly activation of caspase-8 and the executioner caspase-3, leading to increased poly-ADP-ribose polymerase cleavage and DNA fragmentation in prostate cancer cells. Furthermore, we showed that RG003 reduced COX-2 expression in cells. Previously, we showed that COX-2 was involved in resistance to an apoptosis mechanism; then, its inhibition by RG003 could render cells more sensitive to TRAIL treatment. We showed that nuclear factor-?B activation was inhibited after RG003 treatment. This inhibition was correlated with reduction in COX-2 expression and induction of apoptosis. Overall, we conclude, for the first time, that RG003 can enhance TRAIL-induced apoptosis in human prostate cancer cells. The significance of our in-vitro study with RG003 and TRAIL combined is very encouraging, suggesting the relevance of testing this combined treatment in xenograft animal models

Novel methylsulfonyl chalcones as potential antiproliferative drugs for human prostate cancer: Involvement of the intrinsic pathway of apoptosis

International audienceLimited success has been achieved in extending the survival of patients with metastatic and hormone-refractory prostate cancer (HRPC). There is a strong need for novel agents in the treatment and prevention of HRPC. In the present study, the apoptotic mechanism of action of RG003 (2'-hydroxy-4- methylsulfonylchalcone) and RG005 (4'-chloro-2'-hydroxy-4- methylsulfonylchalcone) in association with intracellular signalling pathways was investigated in the hormone-independent prostate carcinoma cells PC-3 and DU145. We showed that these compounds induced apoptosis through the intrinsic pathway but not through the extrinsic one. We showed that synthetic chalcones induced an activation of caspase-9 but not caspase-8 in PC-3 cells. Even if both chalcones induced apoptosis in PC-3 cells, a dominant effect of RG003 treatment was observed resulting in a disruption of δm, caspase-9 and caspase-3 activation, PARP cleavage and DNA fragmentation. Furthermore, in regard to our results, it is clear that the simultaneous inhibition of Akt and NF-κB signalling can significantly contribute to the anticancer effects of RG003 and RG005 in PC-3 prostate cancer cells. NF-κB inhibition was correlated with the reduction of COX-2 expression and induction of apoptosis. Our results clearly indicate for the first time that RG003 and RG005 exert their potent anti proliferative and pro-apoptotic effects through the modulation of Akt/NF-κB/COX-2 signal transduction pathways in PC-3 prostate cancer cells with a dominant effect for RG00

Design and multi-step synthesis of chalcone-polyamine conjugates as potent antiproliferative agents

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