9 research outputs found
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
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
Study of the bioaccumulation of tinzaparin in renally impaired patients when given at prophylactic doses : The STRIP study
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
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
IN VITRO METABOLISM OF CHLOROQUINE: IDENTIFICATION OF CYP2C8, CYP3A4, AND CYP2D6 AS THE MAIN ISOFORMS CATALYZING N
A randomized double-blind feasibility study comparing cetirizine and diphenhydramine in the prevention of paclitaxel-associated infusion-related reactions : the PREMED-F1 study
Purpose. Cetirizine is a less sedative alternative to diphenhydramine for the prevention
of infusion-related reactions (IRR) to paclitaxel. However, its use remains controversial. In this
study, we assessed feasibility for a future definitive non-inferiority trial comparing cetirizine to
diphenhydramine as premedication to prevent paclitaxel-related IRR. Methods. This was a single
center randomized prospective feasibility study. Participants were paclitaxel-naive cancer
patients scheduled to start paclitaxel chemotherapy. They were randomly assigned to receive
either intravenous diphenhydramine 50 mg + oral placebo (control) or intravenous placebo + oral
cetirizine 10 mg (intervention) for their first two paclitaxel treatments. The percentage of eligible
patients completing a first paclitaxel treatment and the recruitment rate were assessed (feasibility
outcomes). Drowsiness was measured at baseline and at selected time points using the Stanford
Sleepiness Scale (SSS) (safety outcome). IRR events were also documented (efficacy
outcome). Results. Among 37 eligible patients, 27 were recruited and randomized (control 13;
intervention 14) and 25 completed the study. The recruitment rate was 4.8 participants/month,
meeting the primary feasibility target. Drowsiness was the main adverse effect associated with
the premedication. The increase in drowsiness compared to baseline (ΔSSS) was greater in the
diphenhydramine group compared to the cetirizine group (median ΔSSS 2 (IQR 3.25) vs median
ΔSSS 0 (IQR 1), p < 0.01) when measured one hour after the premedication administration. One
participant had an IRR and no unexpected serious adverse event occurred. Conclusion. The trial
methods were feasible in terms of recruitment, retention and safety. Cetirizine was significantly
less sedating than diphenhydramine. IRR were infrequent and a larger trial is warranted to confirm
non-inferiority for IRR prevention