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Elodie Drouet - One of the best experts on this subject based on the ideXlab platform.
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clinical events as a function of proton pump inhibitor use clopidogrel use and Cytochrome P450 2C19 genotype in a large nationwide cohort of acute myocardial infarction
Circulation, 2011Co-Authors: Tabassome Simon, Philippe Gabriel Steg, Martine Gilard, Didier Blanchard, Laurent Bonello, M Hanssen, Herve Lardoux, Pierre Coste, Thierry Lefevre, Elodie DrouetAbstract:Background—Clopidogrel requires metabolic activation by Cytochrome P450 2C19 (CYP2C19). Proton pump inhibitors (PPIs) that inhibit CYP2C19 are commonly coadministered with clopidogrel to reduce the risk of gastrointestinal bleeding. This analysis compares treatment outcomes for patients in the French Registry of Acute ST-Elevation and Non–ST-Elevation Myocardial Infarction (FAST-MI) who did or did not receive clopidogrel and/or PPIs. Methods and Results—The FAST-MI registry included 3670 patients (2744 clopidogrel- and PPI-naive patients) presenting with definite MI. Patients were categorized according to use of clopidogrel and/or PPI within 48 hours after hospital admission. PPI use was not associated with an increased risk for any of the main in-hospital events (in-hospital survival, reinfarction, stroke, bleeding, and transfusion). Likewise, PPI treatment was not an independent predictor of 1-year survival (hazard ratio, 0.97; 95% confidence interval [CI], 0.87 to 1.08; P=0.57) or 1-year MI, stroke, or...
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clinical events as a function of proton pump inhibitor use clopidogrel use and Cytochrome P450 2C19 genotype in a large nationwide cohort of acute myocardial infarctionclinical perspective
Circulation, 2011Co-Authors: Tabassome Simon, Philippe Gabriel Steg, Martine Gilard, Didier Blanchard, Laurent Bonello, M Hanssen, Herve Lardoux, Pierre Coste, Thierry Lefevre, Elodie DrouetAbstract:Background— Clopidogrel requires metabolic activation by Cytochrome P450 2C19 (CYP2C19). Proton pump inhibitors (PPIs) that inhibit CYP2C19 are commonly coadministered with clopidogrel to reduce the risk of gastrointestinal bleeding. This analysis compares treatment outcomes for patients in the French Registry of Acute ST-Elevation and Non–ST-Elevation Myocardial Infarction (FAST-MI) who did or did not receive clopidogrel and/or PPIs. Methods and Results— The FAST-MI registry included 3670 patients (2744 clopidogrel- and PPI-naive patients) presenting with definite MI. Patients were categorized according to use of clopidogrel and/or PPI within 48 hours after hospital admission. PPI use was not associated with an increased risk for any of the main in-hospital events (in-hospital survival, reinfarction, stroke, bleeding, and transfusion). Likewise, PPI treatment was not an independent predictor of 1-year survival (hazard ratio, 0.97; 95% confidence interval [CI], 0.87 to 1.08; P =0.57) or 1-year MI, stroke, or death (hazard ratio, 0.98; 95% CI, 0.90 to 1.08; P =0.72). No differences were seen when the type of PPI or CYP2C19 genotype was taken into account. In the propensity-matched cohorts, the odds ratios for major in-hospital events in PPI versus no PPI were 0.29 (95% CI, 0.06 to 1.44) and 1.70 (95% CI, 0.10 to 30.3) for patients with 1 and 2 variant alleles, respectively. Similarly, the hazard ratio for 1-year events in hospital survivors was 0.68 (95% CI, 0.26 to 1.79) and 0.55 (95% CI, 0.06 to 5.30), respectively. Conclusion— PPI use was not associated with an increased risk of cardiovascular events or mortality in patients administered clopidogrel for recent MI, whatever the CYP2C19 genotype, although harm could not be formally excluded in patients with 2 loss-of-function alleles. Clinical Trial Registration— URL: . Unique identifier: [NCT00673036][1]. # Clinical Perspective {#article-title-33} [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00673036&atom=%2Fcirculationaha%2F123%2F5%2F474.atom
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clinical events as a function of proton pump inhibitor use clopidogrel use and Cytochrome P450 2C19 genotype in a large nationwide cohort of acute myocardial infarction results from the french registry of acute st elevation and non st elevation myoca
Circulation, 2011Co-Authors: Tabassome Simon, Philippe Gabriel Steg, Martine Gilard, Didier Blanchard, Laurent Bonello, M Hanssen, Herve Lardoux, Pierre Coste, Thierry Lefevre, Elodie DrouetAbstract:Background— Clopidogrel requires metabolic activation by Cytochrome P450 2C19 (CYP2C19). Proton pump inhibitors (PPIs) that inhibit CYP2C19 are commonly coadministered with clopidogrel to reduce the risk of gastrointestinal bleeding. This analysis compares treatment outcomes for patients in the French Registry of Acute ST-Elevation and Non–ST-Elevation Myocardial Infarction (FAST-MI) who did or did not receive clopidogrel and/or PPIs. Methods and Results— The FAST-MI registry included 3670 patients (2744 clopidogrel- and PPI-naive patients) presenting with definite MI. Patients were categorized according to use of clopidogrel and/or PPI within 48 hours after hospital admission. PPI use was not associated with an increased risk for any of the main in-hospital events (in-hospital survival, reinfarction, stroke, bleeding, and transfusion). Likewise, PPI treatment was not an independent predictor of 1-year survival (hazard ratio, 0.97; 95% confidence interval [CI], 0.87 to 1.08; P =0.57) or 1-year MI, stroke, or death (hazard ratio, 0.98; 95% CI, 0.90 to 1.08; P =0.72). No differences were seen when the type of PPI or CYP2C19 genotype was taken into account. In the propensity-matched cohorts, the odds ratios for major in-hospital events in PPI versus no PPI were 0.29 (95% CI, 0.06 to 1.44) and 1.70 (95% CI, 0.10 to 30.3) for patients with 1 and 2 variant alleles, respectively. Similarly, the hazard ratio for 1-year events in hospital survivors was 0.68 (95% CI, 0.26 to 1.79) and 0.55 (95% CI, 0.06 to 5.30), respectively. Conclusion— PPI use was not associated with an increased risk of cardiovascular events or mortality in patients administered clopidogrel for recent MI, whatever the CYP2C19 genotype, although harm could not be formally excluded in patients with 2 loss-of-function alleles. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00673036.
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Clinical events as a function of proton pump inhibitor use, clopidogrel use, and Cytochrome P450 2C19 genotype in a large nationwide cohort of acute myocardial infarction: results from the French Registry of Acute ST-Elevation and Non-ST-Elevation My
Circulation, 2011Co-Authors: Tabassome Simon, Philippe Gabriel Steg, Martine Gilard, Didier Blanchard, Laurent Bonello, M Hanssen, Herve Lardoux, Pierre Coste, Thierry Lefevre, Elodie DrouetAbstract:BACKGROUND: Clopidogrel requires metabolic activation by Cytochrome P450 2C19 (CYP2C19). Proton pump inhibitors (PPIs) that inhibit CYP2C19 are commonly coadministered with clopidogrel to reduce the risk of gastrointestinal bleeding. This analysis compares treatment outcomes for patients in the French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) who did or did not receive clopidogrel and/or PPIs. METHODS AND RESULTS: The FAST-MI registry included 3670 patients (2744 clopidogrel- and PPI-naïve patients) presenting with definite MI. Patients were categorized according to use of clopidogrel and/or PPI within 48 hours after hospital admission. PPI use was not associated with an increased risk for any of the main in-hospital events (in-hospital survival, reinfarction, stroke, bleeding, and transfusion). Likewise, PPI treatment was not an independent predictor of 1-year survival (hazard ratio, 0.97; 95% confidence interval [CI], 0.87 to 1.08; P=0.57) or 1-year MI, stroke, or death (hazard ratio, 0.98; 95% CI, 0.90 to 1.08; P=0.72). No differences were seen when the type of PPI or CYP2C19 genotype was taken into account. In the propensity-matched cohorts, the odds ratios for major in-hospital events in PPI versus no PPI were 0.29 (95% CI, 0.06 to 1.44) and 1.70 (95% CI, 0.10 to 30.3) for patients with 1 and 2 variant alleles, respectively. Similarly, the hazard ratio for 1-year events in hospital survivors was 0.68 (95% CI, 0.26 to 1.79) and 0.55 (95% CI, 0.06 to 5.30), respectively. CONCLUSION: PPI use was not associated with an increased risk of cardiovascular events or mortality in patients administered clopidogrel for recent MI, whatever the CYP2C19 genotype, although harm could not be formally excluded in patients with 2 loss-of-function alleles.
Hiroshi Yamazaki - One of the best experts on this subject based on the ideXlab platform.
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association with polymorphic marmoset Cytochrome P450 2C19 of in vivo hepatic clearances of chirally separated r omeprazole and s warfarin using individual marmoset physiologically based pharmacokinetic models
Xenobiotica, 2018Co-Authors: Takashi Kusama, Masahiro Utoh, Makiko Shimizu, Yasuhiro Uno, Akiko Toda, Shotaro Uehara, Takashi Inoue, Erika Sasaki, Hiroshi YamazakiAbstract:1. Simulated clearances of R-warfarin and efavirenz were recently reported for individual cynomolgus monkeys genotyped for Cytochrome P450 2C19 and 2C9, respectively. To expand and verify this modeling procedure, simulations of R/S-omeprazole and R/S-warfarin clearances after oral administrations in individual marmosets were performed using individual simplified physiologically based pharmacokinetic (PBPK) modeling consisting of gut, liver and central compartments.2. Pharmacokinetics of R/S-omeprazole were chirally determined using the previously reported plasma microsamples in this study. The areas under the plasma concentration/time curves (AUC) of R-omeprazole and S-warfarin, but not S-omeprazole and R-warfarin, after oral administrations in the P450 2C19 homozygous mutant group were significantly higher than those in the wild-type group. These modeled hepatic intrinsic clearances were also significantly associated with the marmoset P450 2C19 genotypes. Other parameter values, e.g. absorption r...
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effects of aging and rifampicin pretreatment on the pharmacokinetics of human Cytochrome P450 probes caffeine warfarin omeprazole metoprolol and midazolam in common marmosets genotyped for Cytochrome P450 2C19
Xenobiotica, 2018Co-Authors: Akiko Toda, Masahiro Utoh, Takashi Kusama, Makiko Shimizu, Yasuhiro Uno, Shotaro Uehara, Takashi Inoue, Erika Sasaki, Masayuki Mogi, Hiroshi YamazakiAbstract:Abstract1. The pharmacokinetics were investigated for human Cytochrome P450 probes after single intravenous and oral administrations of 0.20 and 1.0 mg/kg, respectively, of caffeine, warfarin, omeprazole, metoprolol and midazolam to aged (10–14 years old, n = 4) or rifampicin-treated/young (3 years old, n = 3) male common marmosets all genotyped as heterozygous for a Cytochrome P450 2C19 variant.2. Slopes of the plasma concentration–time curves after intravenous administration of warfarin and midazolam were slightly, but significantly (two-way analysis of variance), decreased in aged marmosets compared with young marmosets. The mean hepatic clearances determined by in silico fitting for individual pharmacokinetic models of warfarin and midazolam in the aged group were, respectively, 23% and 56% smaller than those for the young group.3. Significantly enhanced plasma clearances of caffeine, warfarin, omeprazole and midazolam were evident in young marmosets pretreated with rifampicin (25 mg/kg daily for 4 da...
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r warfarin clearances from plasma associated with polymorphic Cytochrome P450 2C19 and simulated by individual physiologically based pharmacokinetic models for 11 cynomolgus monkeys
Xenobiotica, 2018Co-Authors: Masahiro Utoh, Takashi Kusama, Tomonori Miura, Marina Mitsui, Mirai Kawano, Takahiro Hirano, Makiko Shimizu, Yasuhiro Uno, Hiroshi YamazakiAbstract:1. Cynomolgus monkey Cytochrome P450 2C19 (formerly known as P450 2C75), homologous to human P450 2C19, has been identified as R-warfarin 7-hydroxylase. In this study, simulations of R-warfarin cle...
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individual differences in metabolic clearance of s warfarin efficiently mediated by polymorphic marmoset Cytochrome P450 2C19 in livers
Drug Metabolism and Disposition, 2016Co-Authors: Shotaro Uehara, Masahiro Utoh, Mirai Kawano, Makiko Shimizu, Yasuhiro Uno, Akiko Toda, Takashi Inoue, Erika Sasaki, Hiroshi YamazakiAbstract:Marmoset Cytochrome P450 2C19, highly homologous to human P450 2C9 and 2C19, has been identified in common marmosets (Callithrix jacchus), a nonhuman primate species used in drug metabolism studies. Although genetic variants in human and macaque P450 2C genes account for the interindividual variability in drug metabolism, genetic variants have not been investigated in the marmoset P450 2C19. In this study, sequencing of P450 2C19 in 24 marmosets identified three variants p.[(Phe7Leu; Ser254Leu; Thr469Ile)], which showed substantially reduced metabolic capacity of S-warfarin compared with the wild-type group in vivo and in vitro. Although mean plasma concentrations of R-warfarin in marmosets determined after chiral separation were similar between the homozygous mutant and wild-type groups up to 24 hours after the intravenous and oral administrations of racemic warfarin, S-warfarin depletion from plasma was significantly faster in the three wild-type marmosets compared with the three homozygous mutant marmosets. These variants, cosegregating in the marmosets analyzed, influenced metabolic activities in 18 marmoset liver microsomes because the homozygotes and heterozygotes showed significantly reduced catalytic activities in liver microsomes toward S-warfarin 7-hydroxylation compared with the wild-type group. Kinetic analysis for S-warfarin 7-hydroxylation indicated that the recombinant P450 2C19 Ser254Leu variant would change the metabolic capacity. These results indicated that the interindividual variability of P450 2C–dependent drug metabolism such as S-warfarin clearance is at least partly accounted for by P450 2C19 variants in marmosets, suggesting that polymorphic P450 2C–dependent catalytic functions are relatively similar between marmosets and humans.
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voriconazole metabolism toxicity and the effect of Cytochrome P450 2C19 genotype
The Journal of Infectious Diseases, 2014Co-Authors: Dimitrios I Zonios, Hiroshi Yamazaki, Norie Murayama, Ven Natarajan, Tara N Palmore, Richard Childs, Jeff Skinner, John E BennettAbstract:Background. Prospective evaluation of the antifungal drug, voriconazole, is needed to determine whether drug toxicity correlates with CYP2C19 genotype or serum concentrations of voriconazole or its metabolites. Methods. We conducted a prospective study of 95 patients to determine voriconazole toxicity and its relationship to genotype and serum levels of voriconazole and its two metabolites. Efficacy was not evaluated because, in most cases, the drug was given for empirical or prophylactic therapy. Results. Hallucinations occurred in 16 patients (16.8%), visual changes in 17 (17.9%), photosensitivity in 10 (10.5%), and hepatotoxicity in 6 (6.3%). There was no correlation between photosensitivity or hepatotoxicity and levels of voriconazole or metabolites. Patients with hallucinations had higher average voriconazole levels (4.5 vs 2.5 μg/mL) but with extensive overlap. The recommended oral dose of 200 mg did not provide consistently detectable serum voriconazole levels in adults. CYP2C19 and CYP2C9 genotypes had a minor influence over levels, though the 4 patients homozygous for the 2C19*2 genotype had higher average levels for voriconazole (4.3 vs 2.5 μg/mL) and lower N-oxide levels (1.6 vs 2.5 μg/mL). Conclusions. CYP2C19 and 2C9 genotypes were not major determinants of voriconazole metabolism. No toxic serum level of voriconazole or its metabolites could be identified.
Laurent Bonello - One of the best experts on this subject based on the ideXlab platform.
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Personalized Antiplatelet Therapy: Review of the Latest Clinical Evidence
Current Cardiology Reports, 2011Co-Authors: Elise Camilleri, Laurent Jacquin, Franck Paganelli, Laurent BonelloAbstract:P2Y12-ADP receptor antagonist use has been critical in the development of percutaneous coronary intervention, dramatically reducing the rate of early stent thrombosis. However, it recently was observed that a significant proportion of patients do not achieve optimal platelet reactivity inhibition after clopidogrel loading dose. The large interindividual variability in clopidogrel responsiveness is related to several factors, including the genetic polymorphism of hepatic Cytochrome P450 2C19 ( CYP2C19*2 ), which recently has been highlighted by a warning from the U.S. Food and Drug Administration. Of importance, patients exhibiting reduced clopidogrel metabolism and/or low clopidogrel responsiveness (ie, high on-treatment platelet reactivity) have an increased rate of thrombotic events after percutaneous coronary intervention. This review summarizes the current knowledge on this important clinical issue. While the future of genetic testing remains undetermined, several trials are underway to demonstrate the potential utility of platelet reactivity testing with P2Y12-ADP receptor antagonists.
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clinical events as a function of proton pump inhibitor use clopidogrel use and Cytochrome P450 2C19 genotype in a large nationwide cohort of acute myocardial infarction
Circulation, 2011Co-Authors: Tabassome Simon, Philippe Gabriel Steg, Martine Gilard, Didier Blanchard, Laurent Bonello, M Hanssen, Herve Lardoux, Pierre Coste, Thierry Lefevre, Elodie DrouetAbstract:Background—Clopidogrel requires metabolic activation by Cytochrome P450 2C19 (CYP2C19). Proton pump inhibitors (PPIs) that inhibit CYP2C19 are commonly coadministered with clopidogrel to reduce the risk of gastrointestinal bleeding. This analysis compares treatment outcomes for patients in the French Registry of Acute ST-Elevation and Non–ST-Elevation Myocardial Infarction (FAST-MI) who did or did not receive clopidogrel and/or PPIs. Methods and Results—The FAST-MI registry included 3670 patients (2744 clopidogrel- and PPI-naive patients) presenting with definite MI. Patients were categorized according to use of clopidogrel and/or PPI within 48 hours after hospital admission. PPI use was not associated with an increased risk for any of the main in-hospital events (in-hospital survival, reinfarction, stroke, bleeding, and transfusion). Likewise, PPI treatment was not an independent predictor of 1-year survival (hazard ratio, 0.97; 95% confidence interval [CI], 0.87 to 1.08; P=0.57) or 1-year MI, stroke, or...
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clinical events as a function of proton pump inhibitor use clopidogrel use and Cytochrome P450 2C19 genotype in a large nationwide cohort of acute myocardial infarctionclinical perspective
Circulation, 2011Co-Authors: Tabassome Simon, Philippe Gabriel Steg, Martine Gilard, Didier Blanchard, Laurent Bonello, M Hanssen, Herve Lardoux, Pierre Coste, Thierry Lefevre, Elodie DrouetAbstract:Background— Clopidogrel requires metabolic activation by Cytochrome P450 2C19 (CYP2C19). Proton pump inhibitors (PPIs) that inhibit CYP2C19 are commonly coadministered with clopidogrel to reduce the risk of gastrointestinal bleeding. This analysis compares treatment outcomes for patients in the French Registry of Acute ST-Elevation and Non–ST-Elevation Myocardial Infarction (FAST-MI) who did or did not receive clopidogrel and/or PPIs. Methods and Results— The FAST-MI registry included 3670 patients (2744 clopidogrel- and PPI-naive patients) presenting with definite MI. Patients were categorized according to use of clopidogrel and/or PPI within 48 hours after hospital admission. PPI use was not associated with an increased risk for any of the main in-hospital events (in-hospital survival, reinfarction, stroke, bleeding, and transfusion). Likewise, PPI treatment was not an independent predictor of 1-year survival (hazard ratio, 0.97; 95% confidence interval [CI], 0.87 to 1.08; P =0.57) or 1-year MI, stroke, or death (hazard ratio, 0.98; 95% CI, 0.90 to 1.08; P =0.72). No differences were seen when the type of PPI or CYP2C19 genotype was taken into account. In the propensity-matched cohorts, the odds ratios for major in-hospital events in PPI versus no PPI were 0.29 (95% CI, 0.06 to 1.44) and 1.70 (95% CI, 0.10 to 30.3) for patients with 1 and 2 variant alleles, respectively. Similarly, the hazard ratio for 1-year events in hospital survivors was 0.68 (95% CI, 0.26 to 1.79) and 0.55 (95% CI, 0.06 to 5.30), respectively. Conclusion— PPI use was not associated with an increased risk of cardiovascular events or mortality in patients administered clopidogrel for recent MI, whatever the CYP2C19 genotype, although harm could not be formally excluded in patients with 2 loss-of-function alleles. Clinical Trial Registration— URL: . Unique identifier: [NCT00673036][1]. # Clinical Perspective {#article-title-33} [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00673036&atom=%2Fcirculationaha%2F123%2F5%2F474.atom
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clinical events as a function of proton pump inhibitor use clopidogrel use and Cytochrome P450 2C19 genotype in a large nationwide cohort of acute myocardial infarction results from the french registry of acute st elevation and non st elevation myoca
Circulation, 2011Co-Authors: Tabassome Simon, Philippe Gabriel Steg, Martine Gilard, Didier Blanchard, Laurent Bonello, M Hanssen, Herve Lardoux, Pierre Coste, Thierry Lefevre, Elodie DrouetAbstract:Background— Clopidogrel requires metabolic activation by Cytochrome P450 2C19 (CYP2C19). Proton pump inhibitors (PPIs) that inhibit CYP2C19 are commonly coadministered with clopidogrel to reduce the risk of gastrointestinal bleeding. This analysis compares treatment outcomes for patients in the French Registry of Acute ST-Elevation and Non–ST-Elevation Myocardial Infarction (FAST-MI) who did or did not receive clopidogrel and/or PPIs. Methods and Results— The FAST-MI registry included 3670 patients (2744 clopidogrel- and PPI-naive patients) presenting with definite MI. Patients were categorized according to use of clopidogrel and/or PPI within 48 hours after hospital admission. PPI use was not associated with an increased risk for any of the main in-hospital events (in-hospital survival, reinfarction, stroke, bleeding, and transfusion). Likewise, PPI treatment was not an independent predictor of 1-year survival (hazard ratio, 0.97; 95% confidence interval [CI], 0.87 to 1.08; P =0.57) or 1-year MI, stroke, or death (hazard ratio, 0.98; 95% CI, 0.90 to 1.08; P =0.72). No differences were seen when the type of PPI or CYP2C19 genotype was taken into account. In the propensity-matched cohorts, the odds ratios for major in-hospital events in PPI versus no PPI were 0.29 (95% CI, 0.06 to 1.44) and 1.70 (95% CI, 0.10 to 30.3) for patients with 1 and 2 variant alleles, respectively. Similarly, the hazard ratio for 1-year events in hospital survivors was 0.68 (95% CI, 0.26 to 1.79) and 0.55 (95% CI, 0.06 to 5.30), respectively. Conclusion— PPI use was not associated with an increased risk of cardiovascular events or mortality in patients administered clopidogrel for recent MI, whatever the CYP2C19 genotype, although harm could not be formally excluded in patients with 2 loss-of-function alleles. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00673036.
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Clinical events as a function of proton pump inhibitor use, clopidogrel use, and Cytochrome P450 2C19 genotype in a large nationwide cohort of acute myocardial infarction: results from the French Registry of Acute ST-Elevation and Non-ST-Elevation My
Circulation, 2011Co-Authors: Tabassome Simon, Philippe Gabriel Steg, Martine Gilard, Didier Blanchard, Laurent Bonello, M Hanssen, Herve Lardoux, Pierre Coste, Thierry Lefevre, Elodie DrouetAbstract:BACKGROUND: Clopidogrel requires metabolic activation by Cytochrome P450 2C19 (CYP2C19). Proton pump inhibitors (PPIs) that inhibit CYP2C19 are commonly coadministered with clopidogrel to reduce the risk of gastrointestinal bleeding. This analysis compares treatment outcomes for patients in the French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) who did or did not receive clopidogrel and/or PPIs. METHODS AND RESULTS: The FAST-MI registry included 3670 patients (2744 clopidogrel- and PPI-naïve patients) presenting with definite MI. Patients were categorized according to use of clopidogrel and/or PPI within 48 hours after hospital admission. PPI use was not associated with an increased risk for any of the main in-hospital events (in-hospital survival, reinfarction, stroke, bleeding, and transfusion). Likewise, PPI treatment was not an independent predictor of 1-year survival (hazard ratio, 0.97; 95% confidence interval [CI], 0.87 to 1.08; P=0.57) or 1-year MI, stroke, or death (hazard ratio, 0.98; 95% CI, 0.90 to 1.08; P=0.72). No differences were seen when the type of PPI or CYP2C19 genotype was taken into account. In the propensity-matched cohorts, the odds ratios for major in-hospital events in PPI versus no PPI were 0.29 (95% CI, 0.06 to 1.44) and 1.70 (95% CI, 0.10 to 30.3) for patients with 1 and 2 variant alleles, respectively. Similarly, the hazard ratio for 1-year events in hospital survivors was 0.68 (95% CI, 0.26 to 1.79) and 0.55 (95% CI, 0.06 to 5.30), respectively. CONCLUSION: PPI use was not associated with an increased risk of cardiovascular events or mortality in patients administered clopidogrel for recent MI, whatever the CYP2C19 genotype, although harm could not be formally excluded in patients with 2 loss-of-function alleles.
Tabassome Simon - One of the best experts on this subject based on the ideXlab platform.
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Derivation, Validation, and Prognostic Utility of a Prediction Rule for Nonresponse to Clopidogrel
JACC: Cardiovascular Interventions, 2020Co-Authors: Dominick Angiolillo, Tabassome Simon, Davide Capodanno, Nicolas Danchin, Thomas Bergmeijer, Jurrien Ten Berg, Dirk Sibbing, Matthew PriceAbstract:The aim of this study was to develop a risk score integrating Cytochrome P450 2C19 loss-of-function genotypes with clinical risk factors influencing clopidogrel response that would allow the identification with more precision of subjects at risk for high platelet reactivity (HPR) and adverse clinical outcomes.
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clinical events as a function of proton pump inhibitor use clopidogrel use and Cytochrome P450 2C19 genotype in a large nationwide cohort of acute myocardial infarction
Circulation, 2011Co-Authors: Tabassome Simon, Philippe Gabriel Steg, Martine Gilard, Didier Blanchard, Laurent Bonello, M Hanssen, Herve Lardoux, Pierre Coste, Thierry Lefevre, Elodie DrouetAbstract:Background—Clopidogrel requires metabolic activation by Cytochrome P450 2C19 (CYP2C19). Proton pump inhibitors (PPIs) that inhibit CYP2C19 are commonly coadministered with clopidogrel to reduce the risk of gastrointestinal bleeding. This analysis compares treatment outcomes for patients in the French Registry of Acute ST-Elevation and Non–ST-Elevation Myocardial Infarction (FAST-MI) who did or did not receive clopidogrel and/or PPIs. Methods and Results—The FAST-MI registry included 3670 patients (2744 clopidogrel- and PPI-naive patients) presenting with definite MI. Patients were categorized according to use of clopidogrel and/or PPI within 48 hours after hospital admission. PPI use was not associated with an increased risk for any of the main in-hospital events (in-hospital survival, reinfarction, stroke, bleeding, and transfusion). Likewise, PPI treatment was not an independent predictor of 1-year survival (hazard ratio, 0.97; 95% confidence interval [CI], 0.87 to 1.08; P=0.57) or 1-year MI, stroke, or...
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clinical events as a function of proton pump inhibitor use clopidogrel use and Cytochrome P450 2C19 genotype in a large nationwide cohort of acute myocardial infarctionclinical perspective
Circulation, 2011Co-Authors: Tabassome Simon, Philippe Gabriel Steg, Martine Gilard, Didier Blanchard, Laurent Bonello, M Hanssen, Herve Lardoux, Pierre Coste, Thierry Lefevre, Elodie DrouetAbstract:Background— Clopidogrel requires metabolic activation by Cytochrome P450 2C19 (CYP2C19). Proton pump inhibitors (PPIs) that inhibit CYP2C19 are commonly coadministered with clopidogrel to reduce the risk of gastrointestinal bleeding. This analysis compares treatment outcomes for patients in the French Registry of Acute ST-Elevation and Non–ST-Elevation Myocardial Infarction (FAST-MI) who did or did not receive clopidogrel and/or PPIs. Methods and Results— The FAST-MI registry included 3670 patients (2744 clopidogrel- and PPI-naive patients) presenting with definite MI. Patients were categorized according to use of clopidogrel and/or PPI within 48 hours after hospital admission. PPI use was not associated with an increased risk for any of the main in-hospital events (in-hospital survival, reinfarction, stroke, bleeding, and transfusion). Likewise, PPI treatment was not an independent predictor of 1-year survival (hazard ratio, 0.97; 95% confidence interval [CI], 0.87 to 1.08; P =0.57) or 1-year MI, stroke, or death (hazard ratio, 0.98; 95% CI, 0.90 to 1.08; P =0.72). No differences were seen when the type of PPI or CYP2C19 genotype was taken into account. In the propensity-matched cohorts, the odds ratios for major in-hospital events in PPI versus no PPI were 0.29 (95% CI, 0.06 to 1.44) and 1.70 (95% CI, 0.10 to 30.3) for patients with 1 and 2 variant alleles, respectively. Similarly, the hazard ratio for 1-year events in hospital survivors was 0.68 (95% CI, 0.26 to 1.79) and 0.55 (95% CI, 0.06 to 5.30), respectively. Conclusion— PPI use was not associated with an increased risk of cardiovascular events or mortality in patients administered clopidogrel for recent MI, whatever the CYP2C19 genotype, although harm could not be formally excluded in patients with 2 loss-of-function alleles. Clinical Trial Registration— URL: . Unique identifier: [NCT00673036][1]. # Clinical Perspective {#article-title-33} [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00673036&atom=%2Fcirculationaha%2F123%2F5%2F474.atom
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clinical events as a function of proton pump inhibitor use clopidogrel use and Cytochrome P450 2C19 genotype in a large nationwide cohort of acute myocardial infarction results from the french registry of acute st elevation and non st elevation myoca
Circulation, 2011Co-Authors: Tabassome Simon, Philippe Gabriel Steg, Martine Gilard, Didier Blanchard, Laurent Bonello, M Hanssen, Herve Lardoux, Pierre Coste, Thierry Lefevre, Elodie DrouetAbstract:Background— Clopidogrel requires metabolic activation by Cytochrome P450 2C19 (CYP2C19). Proton pump inhibitors (PPIs) that inhibit CYP2C19 are commonly coadministered with clopidogrel to reduce the risk of gastrointestinal bleeding. This analysis compares treatment outcomes for patients in the French Registry of Acute ST-Elevation and Non–ST-Elevation Myocardial Infarction (FAST-MI) who did or did not receive clopidogrel and/or PPIs. Methods and Results— The FAST-MI registry included 3670 patients (2744 clopidogrel- and PPI-naive patients) presenting with definite MI. Patients were categorized according to use of clopidogrel and/or PPI within 48 hours after hospital admission. PPI use was not associated with an increased risk for any of the main in-hospital events (in-hospital survival, reinfarction, stroke, bleeding, and transfusion). Likewise, PPI treatment was not an independent predictor of 1-year survival (hazard ratio, 0.97; 95% confidence interval [CI], 0.87 to 1.08; P =0.57) or 1-year MI, stroke, or death (hazard ratio, 0.98; 95% CI, 0.90 to 1.08; P =0.72). No differences were seen when the type of PPI or CYP2C19 genotype was taken into account. In the propensity-matched cohorts, the odds ratios for major in-hospital events in PPI versus no PPI were 0.29 (95% CI, 0.06 to 1.44) and 1.70 (95% CI, 0.10 to 30.3) for patients with 1 and 2 variant alleles, respectively. Similarly, the hazard ratio for 1-year events in hospital survivors was 0.68 (95% CI, 0.26 to 1.79) and 0.55 (95% CI, 0.06 to 5.30), respectively. Conclusion— PPI use was not associated with an increased risk of cardiovascular events or mortality in patients administered clopidogrel for recent MI, whatever the CYP2C19 genotype, although harm could not be formally excluded in patients with 2 loss-of-function alleles. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00673036.
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Clinical events as a function of proton pump inhibitor use, clopidogrel use, and Cytochrome P450 2C19 genotype in a large nationwide cohort of acute myocardial infarction: results from the French Registry of Acute ST-Elevation and Non-ST-Elevation My
Circulation, 2011Co-Authors: Tabassome Simon, Philippe Gabriel Steg, Martine Gilard, Didier Blanchard, Laurent Bonello, M Hanssen, Herve Lardoux, Pierre Coste, Thierry Lefevre, Elodie DrouetAbstract:BACKGROUND: Clopidogrel requires metabolic activation by Cytochrome P450 2C19 (CYP2C19). Proton pump inhibitors (PPIs) that inhibit CYP2C19 are commonly coadministered with clopidogrel to reduce the risk of gastrointestinal bleeding. This analysis compares treatment outcomes for patients in the French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) who did or did not receive clopidogrel and/or PPIs. METHODS AND RESULTS: The FAST-MI registry included 3670 patients (2744 clopidogrel- and PPI-naïve patients) presenting with definite MI. Patients were categorized according to use of clopidogrel and/or PPI within 48 hours after hospital admission. PPI use was not associated with an increased risk for any of the main in-hospital events (in-hospital survival, reinfarction, stroke, bleeding, and transfusion). Likewise, PPI treatment was not an independent predictor of 1-year survival (hazard ratio, 0.97; 95% confidence interval [CI], 0.87 to 1.08; P=0.57) or 1-year MI, stroke, or death (hazard ratio, 0.98; 95% CI, 0.90 to 1.08; P=0.72). No differences were seen when the type of PPI or CYP2C19 genotype was taken into account. In the propensity-matched cohorts, the odds ratios for major in-hospital events in PPI versus no PPI were 0.29 (95% CI, 0.06 to 1.44) and 1.70 (95% CI, 0.10 to 30.3) for patients with 1 and 2 variant alleles, respectively. Similarly, the hazard ratio for 1-year events in hospital survivors was 0.68 (95% CI, 0.26 to 1.79) and 0.55 (95% CI, 0.06 to 5.30), respectively. CONCLUSION: PPI use was not associated with an increased risk of cardiovascular events or mortality in patients administered clopidogrel for recent MI, whatever the CYP2C19 genotype, although harm could not be formally excluded in patients with 2 loss-of-function alleles.
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ticlopidine as a selective mechanism based inhibitor of human Cytochrome P450 2C19
Biochemistry, 2001Co-Authors: Nguyetthanh Haduong, Sylvie Dijols, Annechristine Macherey, Joyce A Goldstein, Patrick M Dansette, Daniel MansuyAbstract:Experiments using recombinant yeast-expressed human liver Cytochromes P450 confirmed previous literature data indicating that ticlopidine is an inhibitor of CYP 2C19. The present studies demonstrat...
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ticlopidine as a selective mechanism based inhibitor of human Cytochrome P450 2C19
Biochemistry, 2001Co-Authors: Nguyetthanh Haduong, Sylvie Dijols, Annechristine Macherey, Joyce A Goldstein, Patrick M Dansette, Daniel MansuyAbstract:Experiments using recombinant yeast-expressed human liver Cytochromes P450 confirmed previous literature data indicating that ticlopidine is an inhibitor of CYP 2C19. The present studies demonstrat...
