Développement et utilisation de modèles in vitro et de données précliniques pour augmenter la prédictibilité de la perméabilité et du métabolisme intestinal chez l'humain

Tout médicament administré par la voie orale doit être absorbé sans être métabolisé par l’intestin et le foie pour atteindre la circulation systémique. Malgré son impact majeur sur l’effet de premier passage de plusieurs médicaments, le métabolisme intestinal est souvent négligé comparativement au métabolisme hépatique. L’objectif de ces travaux de maîtrise est donc d’utiliser, caractériser et développer différents outils in vitro et in vivo pour mieux comprendre et prédire l’impact du métabolisme intestinal sur l’effet de premier passage des médicaments comparé au métabolisme hépatique. Pour se faire, différents substrats d’enzymes du métabolisme ont été incubés dans des microsomes intestinaux et hépatiques et des différences entre la vitesse de métabolisme et les métabolites produits ont été démontrés. Afin de mieux comprendre l’impact de ces différences in vivo, des études mécanistiques chez des animaux canulés et traités avec des inhibiteurs enzymatiques ont été conduites avec le substrat métoprolol. Ces études ont démontré l’impact du métabolisme intestinal sur le premier passage du métoprolol. De plus, elles ont révélé l’effet sur la vidange gastrique du 1-aminobenzotriazole, un inhibiteur des cytochromes p450, évitant ainsi une mauvaise utilisation de cet outil dans le futur. Ces travaux de maîtrise ont permis d’améliorer les connaissances des différents outils in vitro et in vivo pour étudier le métabolisme intestinal tout en permettant de mieux comprendre les différences entre le rôle de l’intestin et du foie sur l’effet de premier passage.To reach the systemic circulation, orally administered drugs have to be absorbed and not metabolized by the intestine and the liver. Even though it has a major impact on the first pass effect of many xenobiotics, the intestinal metabolism is often neglect compare to the hepatic metabolism. The objective of this work is to use, characterize and develop multiple in vitro and in vivo tools to better understand and predict the impact of intestinal metabolism on the first pass effect of xenobiotics compared to the liver. To do so, multiple substrates of metabolic enzymes were incubated in intestinal and hepatic microsomes and differences between the rate of metabolism and the production of metabolites were demonstrated. To better understand the impact of these differences in vivo, mechanistic studies were undergone in rats cannulated or treated with enzymatic inhibitors with the substrate metoprolol. These studies demonstrated the impact of intestinal metabolism on the first pass of metoprolol. Moreover, they exposed the effect on gastric emptying of 1-aminobenzotriazole, a cytochrome p450 inhibitor, avoiding its wrong utilisation in future studies. This work helped increase the knowledge about the different in vitro and in vivo tools to study intestinal metabolism and to better understand the differences between the role of the intestine and the liver on the first pass effect

Laser-induced dewetting of silver-doped chalcogenide glasses

We report the observation of laser-induced dewetting responsible for the formation of periodic relief structures in silver-based chalcogenide thin-films. By varying the concentration of silver in the Agx(As20S80)100-x system (with x = 0, 4, 9 and 36), different surface relief structures are formed. The evolution of the surface changes as a function of laser parameters (power density, duration of exposure, and polarisation) as well as film thickness and silver concentration has been investigated. The scanning electron microscopy and atomic force microscopy images of irradiated spots show periodic ripples aligned perpendicularly to the electric field of incident light. Our results show that addition of silver into sulphur-rich chalcogenide thin-films improves the dewetting when compared to pure As20S80 thinfilms. The changes in surface morphology were attributable to photo-induced chemical modifications and a laser-driven molecular rearrangement

Santé mentale et population universitaire : un laboratoire-vivant au service de la communauté : rapport de recherche

Cette étude a trois objectifs : 1) Identifier les principaux enjeux de santé des étudiant·es et des employé·es de l’UQAC en contexte pandémique, 2) Répertorier l’ensemble des mesures de soutien à la santé mises à la disposition des étudiant·es et des employé·es de l’UQAC, et 3) Identifier de nouvelles solutions à mettre en place afin de pallier les manques et de soutenir les étudiant·es et les employé·es de l’UQAC

Willingness to use and distribute HIV self-test kits to clients and partners: a qualitative analysis of female sex workers' collective opinion and attitude in Cote d'Ivoire, Mali, and Senegal

Background: In West Africa, female sex workers are at increased risk of HIV acquisition and transmission. HIV self-testing could be an effective tool to improve access to and frequency of HIV testing to female sex workers, their clients and partners. This article explores their perceptions regarding HIV self-testing use and the redistribution of HIV self-testing kits to their partners and clients. Methods: Embedded within ATLAS, a qualitative study was conducted in Côte-d’Ivoire, Mali, and Senegal in 2020. Nine focus group discussions were conducted. A thematic analysis was performed. Results: A total of 87 participants expressed both positive attitudes toward HIV self-testing and their willingness to use or reuse HIV self-testing. HIV self-testing was perceived to be discreet, confidential, and convenient. HIV self-testing provides autonomy from testing by providers and reduces stigma. Some perceived HIV self-testing as a valuable tool for testing their clients who are willing to offer a premium for condomless sex. While highlighting some potential issues, overall, female sex workers were optimistic about linkage to confirmatory testing following a reactive HIV self-testing. Female sex workers expressed positive attitudes toward secondary distribution to their partners and clients, although it depended on relationship types. They seemed more enthusiastic about secondary distribution to their regular/emotional partners and regular clients with whom they had difficulty using condoms, and whom they knew enough to discuss HIV self-testing. However, they expressed that it could be more difficult with casual clients; the duration of the interaction being too short to discuss HIV self-testing, and they fear violence and/or losing them. Conclusion: Overall, female sex workers have positive attitudes toward HIV self-testing use and are willing to redistribute to their regular partners and clients. However, they are reluctant to promote such use with their casual clients. HIV self-testing can improve access to HIV testing for female sex workers and the members of their sexual and social network

In vitro and in vivo mechanistic studies toward understanding the role of 1- aminobenzotriazole in rat drug-drug interactions DMD #66357 2 Running title: Effect of ABT on pharmacokinetics of metoprolol in rats

were conducted prior to the oral administration of metoprolol, a permeable P450 probe that undergoes extensive intestinal and hepatic metabolism. The pharmacokinetic profile of metoprolol was affected differently by the two ABT pretreatments. An increase in AUC of 16-fold with ABT p.o. and 6.5-fold with ABT i.v. was observed compared to control. Based on in vitro studies, this difference could not be attributed to a differential inhibition of intestinal and hepatic metabolism. In the ABT i.v. pretreatment, the increase in AUC was also associated with a prolonged Tmax (24-fold versus control) suggesting a delay in absorption. This was further confirmed by the administration of a charcoal meal which resulted in a 7-fold increase in stomach weights in the 1 h ABT pretreated groups compared to untreated or 16 h ABT pretreated rats. Based on these results, we recommend pretreating rats with ABT p.o. 16 h before the administration of a test compound to preserve the inhibitory effect on intestinal and hepatic metabolism and to avoid the confounding effect on drug absorption. DMD #66357

Identifying population-specific HIV diagnosis gaps in Western Africa and assessing their impact on new infections: a modelling analysis for Côte d'Ivoire, Mali and Senegal

International audienceBACKGROUND: Progress towards HIV elimination in Western Africa may be hindered by diagnosis gaps among people living with HIV (PLHIV), especially among key populations (KP) such as female sex workers (FSW), their clients, and men who have sex with men (MSM). We aimed to identify largest gaps in diagnosis by risk group in Mali, Côte d'Ivoire, and Senegal, and project their contribution to new HIV infections.METHODS: Deterministic models of HIV transmission/diagnosis/treatment that incorporate HIV transmission among KP were parameterized following comprehensive country-specific reviews of demographic, behavioural, HIV and intervention data. The model was calibrated to country- and group-specific empirical outcomes such as HIV incidence/prevalence, the fractions of PLHIV ever tested, diagnosed, and on treatment. We estimated the distribution of undiagnosed PLHIV by risk group in 2020 and the population-attributable-fractions (tPAFs) (i.e. fraction of new primary and secondary HIV infections 2020-2029 originating from risk groups of undiagnosed PLHIV).RESULTS: From 46% (95% UI: 38-58) to 69% (59-79) of undiagnosed PLHIV in 2020 were males, with the lowest proportion in Mali and the highest proportion in Senegal, where 41% (28-59) of undiagnosed PLHIV were MSM. Undiagnosed men are estimated to contribute most new HIV infections occurring over 2020-2029 (Table). Undiagnosed FSW and their clients contribute substantial proportions of new HIV infections in Mali, with tPAF=20% (10-36) and tPAF=43% (26-56), respectively, while undiagnosed MSM in Senegal are estimated to contribute half of new infections. A lower proportion of new HIV infections are transmitted by undiagnosed KP in Côte d'Ivoire (tPAF=21%(10-38)).CONCLUSIONS: Current HIV testing services and approaches are leaving members of KP behind. Increasing the availability of confidential HIV testing modalities in addition to traditional tests may substantially reduce gaps in HIV diagnosis and accelerate the decrease of new HIV infections in Western Africa since half of them could be transmitted by undiagnosed KP

Identifying population-specific HIV diagnosis gaps in Western Africa and assessing their impact on new infections: a modelling analysis for Côte d'Ivoire, Mali and Senegal

International audienceBACKGROUND: Progress towards HIV elimination in Western Africa may be hindered by diagnosis gaps among people living with HIV (PLHIV), especially among key populations (KP) such as female sex workers (FSW), their clients, and men who have sex with men (MSM). We aimed to identify largest gaps in diagnosis by risk group in Mali, Côte d'Ivoire, and Senegal, and project their contribution to new HIV infections.METHODS: Deterministic models of HIV transmission/diagnosis/treatment that incorporate HIV transmission among KP were parameterized following comprehensive country-specific reviews of demographic, behavioural, HIV and intervention data. The model was calibrated to country- and group-specific empirical outcomes such as HIV incidence/prevalence, the fractions of PLHIV ever tested, diagnosed, and on treatment. We estimated the distribution of undiagnosed PLHIV by risk group in 2020 and the population-attributable-fractions (tPAFs) (i.e. fraction of new primary and secondary HIV infections 2020-2029 originating from risk groups of undiagnosed PLHIV).RESULTS: From 46% (95% UI: 38-58) to 69% (59-79) of undiagnosed PLHIV in 2020 were males, with the lowest proportion in Mali and the highest proportion in Senegal, where 41% (28-59) of undiagnosed PLHIV were MSM. Undiagnosed men are estimated to contribute most new HIV infections occurring over 2020-2029 (Table). Undiagnosed FSW and their clients contribute substantial proportions of new HIV infections in Mali, with tPAF=20% (10-36) and tPAF=43% (26-56), respectively, while undiagnosed MSM in Senegal are estimated to contribute half of new infections. A lower proportion of new HIV infections are transmitted by undiagnosed KP in Côte d'Ivoire (tPAF=21%(10-38)).CONCLUSIONS: Current HIV testing services and approaches are leaving members of KP behind. Increasing the availability of confidential HIV testing modalities in addition to traditional tests may substantially reduce gaps in HIV diagnosis and accelerate the decrease of new HIV infections in Western Africa since half of them could be transmitted by undiagnosed KP