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Modulation de la P-glycoproteine et ...

Morissette, Pierre.

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Modulation de la P-glycoproteine et evaluation des repercussions electrophysiologiques cardiaques.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Modulation de la P-glycoproteine et evaluation des repercussions electrophysiologiques cardiaques./
Author:	Morissette, Pierre.
Description:	261 p.
Notes:	Source: Dissertation Abstracts International, Volume: 67-09, Section: B, page: 5015.
Contained By:	Dissertation Abstracts International67-09B.
Subject:	Health Sciences, Pharmacology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=NR18041
ISBN:	9780494180419

Modulation de la P-glycoproteine et evaluation des repercussions electrophysiologiques cardiaques.
Morissette, Pierre.

Modulation de la P-glycoproteine et evaluation des repercussions electrophysiologiques cardiaques. - 261 p.

Source: Dissertation Abstracts International, Volume: 67-09, Section: B, page: 5015.

Thesis (Ph.D.)--Universite de Montreal (Canada), 2006.

Over the last decade many cases of prolonged QT, torsades de pointes and/or sudden death were reported with many non-cardiac medications. The predictive value of most phenotypic traits of torsades de pointes remains low for a particular patient and there exists much interindividual variability that have pharmacodynamic and pharmacokinetic consequences on the effect of agents that prolong cardiac repolarization. QT prolongation greatly occurs during drug-drug interactions involving the cytochrome P450 3A4. In fact, many drugs that prolong cardiac repolarization are substrates of this cytochrome. Moreover, many substrates of the CYP3A4/5 are also substrates of the P-glycoprotein membrane transporter and of IKr potassium channels. Since IKr blockers bind to potassium channels intracellularly, the modulation of P-glycoproteins could affect intra-myocyte concentrations of medications and potentiate the effects of medications on potassium channels. In order to better understand the role of P-glycoprotein in the heart, we studied the effect of modulating this membrane transporter. In chapter III, we determined that intracellular concentrations and electrophysiological effects of an IKr blocker, cisapride, are potentiated after modulating P-glycoprotein. Moreover, women are more susceptible to drug induced torsades de pointes than men. It was shown that p-glycoprotein activity can be modulated by gender. In fact, P-glycoprotein activity seems to be less in women. In chapter IV we studied P-glycoprotein implication in the mechanisms involved in sex-related drug-induced long QT syndrome. We observed that females are more susceptible to P-glycoprotein modulation by showing that intracellular concentrations and electrophysiological effects of cisapride were greater in female animals. Finally, in chapter V, we evaluated if non CYP3A4 substrates could also inhibit IKr and prolong the QT interval. We determined that olanzapine, which is not a CYP3A4/5 substrate, can prolong cardiac repolarization by blocking the rapid component of the delayed rectifier potassium current (IKr).

ISBN: 9780494180419Subjects--Topical Terms:

1017717
Health Sciences, Pharmacology.

Modulation de la P-glycoproteine et evaluation des repercussions electrophysiologiques cardiaques.
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100 1 $a Morissette, Pierre. $3 1287138
245 1 0 $a Modulation de la P-glycoproteine et evaluation des repercussions electrophysiologiques cardiaques.
300 $a 261 p.
500 $a Source: Dissertation Abstracts International, Volume: 67-09, Section: B, page: 5015.
502 $a Thesis (Ph.D.)--Universite de Montreal (Canada), 2006.
520 $a Over the last decade many cases of prolonged QT, torsades de pointes and/or sudden death were reported with many non-cardiac medications. The predictive value of most phenotypic traits of torsades de pointes remains low for a particular patient and there exists much interindividual variability that have pharmacodynamic and pharmacokinetic consequences on the effect of agents that prolong cardiac repolarization. QT prolongation greatly occurs during drug-drug interactions involving the cytochrome P450 3A4. In fact, many drugs that prolong cardiac repolarization are substrates of this cytochrome. Moreover, many substrates of the CYP3A4/5 are also substrates of the P-glycoprotein membrane transporter and of IKr potassium channels. Since IKr blockers bind to potassium channels intracellularly, the modulation of P-glycoproteins could affect intra-myocyte concentrations of medications and potentiate the effects of medications on potassium channels. In order to better understand the role of P-glycoprotein in the heart, we studied the effect of modulating this membrane transporter. In chapter III, we determined that intracellular concentrations and electrophysiological effects of an IKr blocker, cisapride, are potentiated after modulating P-glycoprotein. Moreover, women are more susceptible to drug induced torsades de pointes than men. It was shown that p-glycoprotein activity can be modulated by gender. In fact, P-glycoprotein activity seems to be less in women. In chapter IV we studied P-glycoprotein implication in the mechanisms involved in sex-related drug-induced long QT syndrome. We observed that females are more susceptible to P-glycoprotein modulation by showing that intracellular concentrations and electrophysiological effects of cisapride were greater in female animals. Finally, in chapter V, we evaluated if non CYP3A4 substrates could also inhibit IKr and prolong the QT interval. We determined that olanzapine, which is not a CYP3A4/5 substrate, can prolong cardiac repolarization by blocking the rapid component of the delayed rectifier potassium current (IKr).
520 $a These results lead to a better understanding of interindividual variabilities and gender-related differences observed during drug-induced torsades de pointes. Moreover, these results will help to better predict drug-drug interactions that cause the long QT syndrome.
590 $a School code: 0992.
650 4 $a Health Sciences, Pharmacology. $3 1017717
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710 2 0 $a Universite de Montreal (Canada). $3 1018132
773 0 $t Dissertation Abstracts International $g 67-09B.
790 $a 0992
791 $a Ph.D.
792 $a 2006
793 $a French
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=NR18041