Influence de l'inflammation sur le métabolisme catalysé par les cytochromes P450 chez le rat : approches in vitro et implications sur la pharmacocinétique d'agonistes delta

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal

A psychological intervention aimed towards homeless men: the example of a proximity service

Une recherche qualitative de type descriptive sur les retombées d’un service de soutien psychologique auprès des personnes en situation d’itinérance Introduction : Une recherche sur les retombées perçues par les personnes suivies dans le cadre d’un service de psychologie de proximité offert dans un organisme communautaire aux personnes en situation d’itinérance à Montréal. Objectifs et méthodologie : L’objectif était de comprendre comment une pratique de proximité, soit le service de soutien psychologique offert par l’organisme sans but lucratif Médecins du Monde, s’inscrivait dans la trajectoire de vie et agissait sur le bien-être des personnes recevant ce service. Les personnes suivies étaient des personnes en situation d’itinérance ou en processus de réinsertion après avoir connu un épisode d’itinérance. Les objectifs spécifiques étaient d’explorer les perceptions des personnes en situation d’itinérance concernant le soutien psychologique reçu et de décrire les retombées que le soutien a eues sur leur bien-être. Un partenariat a été mis sur pied avec Médecins du Monde Canada et des rencontres d’équipe ont été menées afin d’établir le protocole et de suivre l’avancement des travaux. Douze entrevues ont été réalisées auprès des personnes suivies par les psychologues dans une approche qualitative descriptive. Résultats et conclusions : La majorité des participants ont retiré des bénéfices durables du suivi psychologique sur leur bien-être qui se sont manifestés par des changements dans leurs relations à eux-mêmes et avec autrui.Abstract: A qualitative descriptive study on the outcomes of a psychological service offered to the homeless individuals. Introduction : A research on the perceived outcomes by the patients of a proximity psychologica l service offered in a community context for homeless individuals. Objectives and methodology: To understand the intake of a proximity service, the psychology service of Doctors of the World, on the well-being of people receiving the service from the perspective of homeless people and/or on in a process of reinsertion after being homeless. The secondary objectives were to explore the perceptions of the homeless individuals towards the psychological support received and to describe the outcomes that the support brought on their well-being. A partnership was established with Doctors of The World Canada and team meetings were held to establish the protocol and follow-up on the work. Twelve interviews were held with the participants in a qualitative and descriptive way. Results and conclusions: The majority of the participants benefitted from the follow-up with the psychologist, which manifested on their wellbeing in changes with their relationships with others and with themselves

Evaluation of P-glycoprotein expression in pain relevant tissues: understanding translation of efflux from preclinical species to human

Various efflux transporters, such as P-glycoprotein (P-gp) are now widely accepted to have profound influence on the disposition of substrates. Nevertheless, there is paucity of information about their expression and functionality in the pain relevant tissues (such as brain, spinal cord and dorsal root ganglia (DRG)) across various species. Therefore, our attempts were directed at evaluating P-gp expression in these tissues to understand its effect on the central nervous system (CNS) disposition. As a means of characterizing the normal tissue distribution of P-gp, immunohistochemistry was performed with two antibodies (C219 and H241) directed against different epitopes of MDR1 gene. Notable expression of P-gp was detected in the DRG of Sprague Dawley rat, Beagle Dog, Cynomolgous monkey as well as human. The expression of P-gp was observed in the CNS tissues with evident species differences, the expression of P-gp in human brain and spinal cord was lower than in rats and dogs but relatively comparable to that in monkeys. However, no species related differences were seen in the expression at the DRG level. Double-labelling using an antibody against a marker of endothelial cells confirmed that P-gp was exclusively localized in capillary endothelial cells. This study highlights the cross species similarities and differences in the expression of P-gp and thus serves as a vital step in understanding the translation of exposure of P-gp substrates to human

Randomized Dose-Ranging Controlled Trial of AQ-13, a Candidate Antimalarial, and Chloroquine in Healthy Volunteers

OBJECTIVES: To determine: (1) the pharmacokinetics and safety of an investigational aminoquinoline active against multidrug–resistant malaria parasites (AQ-13), including its effects on the QT interval, and (2) whether it has pharmacokinetic and safety profiles similar to chloroquine (CQ) in humans. DESIGN: Phase I double-blind, randomized controlled trials to compare AQ-13 and CQ in healthy volunteers. Randomizations were performed at each step after completion of the previous dose. SETTING: Tulane–Louisiana State University–Charity Hospital General Clinical Research Center in New Orleans. PARTICIPANTS: 126 healthy adults 21–45 years of age. INTERVENTIONS: 10, 100, 300, 600, and 1,500 mg oral doses of CQ base in comparison with equivalent doses of AQ-13. OUTCOME MEASURES: Clinical and laboratory adverse events (AEs), pharmacokinetic parameters, and QT prolongation. RESULTS: No hematologic, hepatic, renal, or other organ toxicity was observed with AQ-13 or CQ at any dose tested. Headache, lightheadedness/dizziness, and gastrointestinal (GI) tract–related symptoms were the most common AEs. Although symptoms were more frequent with AQ-13, the numbers of volunteers who experienced symptoms with AQ-13 and CQ were similar (for AQ-13 and CQ, respectively: headache, 17/63 and 10/63, p = 0.2; lightheadedness/dizziness, 11/63 and 8/63, p = 0.6; GI symptoms, 14/63 and 13/63; p = 0.9). Both AQ-13 and CQ exhibited linear pharmacokinetics. However, AQ-13 was cleared more rapidly than CQ (respectively, median oral clearance 14.0–14.7 l/h versus 9.5–11.3 l/h; p ≤ 0.03). QTc prolongation was greater with CQ than AQ-13 (CQ: mean increase of 28 ms; 95% confidence interval [CI], 18 to 38 ms, versus AQ-13: mean increase of 10 ms; 95% CI, 2 to 17 ms; p = 0.01). There were no arrhythmias or other cardiac AEs with either AQ-13 or CQ. CONCLUSIONS: These studies revealed minimal differences in toxicity between AQ-13 and CQ, and similar linear pharmacokinetics

How can natural products serve as a viable source of lead compounds for the development of new/novel anti-malarials?

Malaria continues to be an enormous global health challenge, with millions of new infections and deaths reported annually. This is partly due to the development of resistance by the malaria parasite to the majority of established anti-malarial drugs, a situation that continues to hamper attempts at controlling the disease. This has spurred intensive drug discovery endeavours geared towards identifying novel, highly active anti-malarial drugs, and the identification of quality leads from natural sources would greatly augment these efforts. The current reality is that other than compounds that have their foundation in historic natural products, there are no other compounds in drug discovery as part of lead optimization projects and preclinical development or further that have originated from a natural product start-point in recent years. This paper briefly presents both classical as well as some more modern, but underutilized, approaches that have been applied outside the field of malaria, and which could be considered in enhancing the potential of natural products to provide or inspire the development of anti-malarial lead compounds

Unexpected removal of the most neutral cationic pharmaceutical in river waters

Contamination of surface waters by pharmaceuticals is now widespread. There are few data on their environmental behaviour, particularly for those which are cationic at typical surface water pH. As the external surfaces of bacterio-plankton cells are hydrophilic with a net negative charge, it was anticipated that bacterio-plankton in surface-waters would preferentially remove the most extensively-ionised cation at a given pH. To test this hypothesis, the persistence of four, widely-used, cationic pharmaceuticals, chloroquine, quinine, fluphenazine and levamisole, was assessed in batch microcosms, comprising water and bacterio-plankton, to which pharmaceuticals were added and incubated for 21 days. Results show that levamisole concentrations decreased by 19 % in microcosms containing bacterio-plankton, and by 13 % in a parallel microcosm containing tripeptide as a priming agent. In contrast to levamisole, concentrations of quinine, chloroquine and fluphenazine were unchanged over 21 days in microcosms containing bacterio-plankton. At the river-water pH, levamisole is 28 % cationic, while quinine is 91–98 % cationic, chloroquine 99 % cationic and fluphenazine 72–86 % cationic. Thus, the most neutral compound, levamisole, showed greatest removal, contradicting the expected bacterio-plankton preference for ionised molecules. However, levamisole was the most hydrophilic molecule, based on its octanol–water solubility coefficient (K ow). Overall, the pattern of pharmaceutical behaviour within the incubations did not reflect the relative hydrophilicity of the pharmaceuticals predicted by the octanol–water distribution coefficient, D ow, suggesting that improved predictive power, with respect to modelling bioaccumulation, may be needed to develop robust environmental risk assessments for cationic pharmaceuticals

A psychological intervention aimed towards homeless men: the example of a proximity service

Une recherche qualitative de type descriptive sur les retombées d’un service de soutien psychologique auprès des personnes en situation d’itinérance Introduction : Une recherche sur les retombées perçues par les personnes suivies dans le cadre d’un service de psychologie de proximité offert dans un organisme communautaire aux personnes en situation d’itinérance à Montréal. Objectifs et méthodologie : L’objectif était de comprendre comment une pratique de proximité, soit le service de soutien psychologique offert par l’organisme sans but lucratif Médecins du Monde, s’inscrivait dans la trajectoire de vie et agissait sur le bien-être des personnes recevant ce service. Les personnes suivies étaient des personnes en situation d’itinérance ou en processus de réinsertion après avoir connu un épisode d’itinérance. Les objectifs spécifiques étaient d’explorer les perceptions des personnes en situation d’itinérance concernant le soutien psychologique reçu et de décrire les retombées que le soutien a eues sur leur bien-être. Un partenariat a été mis sur pied avec Médecins du Monde Canada et des rencontres d’équipe ont été menées afin d’établir le protocole et de suivre l’avancement des travaux. Douze entrevues ont été réalisées auprès des personnes suivies par les psychologues dans une approche qualitative descriptive. Résultats et conclusions : La majorité des participants ont retiré des bénéfices durables du suivi psychologique sur leur bien-être qui se sont manifestés par des changements dans leurs relations à eux-mêmes et avec autrui.Abstract: A qualitative descriptive study on the outcomes of a psychological service offered to the homeless individuals. Introduction : A research on the perceived outcomes by the patients of a proximity psychologica l service offered in a community context for homeless individuals. Objectives and methodology: To understand the intake of a proximity service, the psychology service of Doctors of the World, on the well-being of people receiving the service from the perspective of homeless people and/or on in a process of reinsertion after being homeless. The secondary objectives were to explore the perceptions of the homeless individuals towards the psychological support received and to describe the outcomes that the support brought on their well-being. A partnership was established with Doctors of The World Canada and team meetings were held to establish the protocol and follow-up on the work. Twelve interviews were held with the participants in a qualitative and descriptive way. Results and conclusions: The majority of the participants benefitted from the follow-up with the psychologist, which manifested on their wellbeing in changes with their relationships with others and with themselves