501 results on '"Funck Brentano, C"'
Search Results
302. [Cardiac tolerance of moxifloxacin: Clinical experience from a large observational French study in usual medical practice (IMMEDIAT study)].
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Veyssier P, Voirot P, Begaud B, and Funck-Brentano C
- Subjects
- Anti-Infective Agents adverse effects, Aza Compounds adverse effects, Fluoroquinolones, Humans, Moxifloxacin, Quinolines adverse effects, Anti-Infective Agents therapeutic use, Aza Compounds therapeutic use, Drug Tolerance, Heart drug effects, Myocarditis drug therapy, Quinolines therapeutic use, Respiratory Tract Infections drug therapy
- Abstract
Background: Moxifloxacin (Izilox) is prescribed for bacterial respiratory tract infections. ECG analysis done in clinical trials showed a mean QT prolongation at 6 ms that could lead to Torsades de Pointe. However, Izilox was well tolerated during clinical trials. To confirm the correct safety profile of Izilox in a large sample of patients, a French PMS study - MMEDIAT - was carried out in usual medical practice., Methods: This prospective observational uncontrolled and monitored study was conducted in 13,578 patients with respiratory tract infection and treated with moxifloxacin 400 mg daily (duration: 5 to 10 days in accordance to the Market Authorization). Any clinical event being potentially a surrogate of a ventricular rhythm disorder ("critical event") were collected and analyzed by a Scientific Committee in charge to determine the potential cardiac origin of the reported event and to establish a causal relationship with the treatment., Results: Among 13,578 patients, 1046 adverse events (678 patients [5%]) were reported, including 854 drug related events (564 patients [4.15%]). Of these 1046 adverse events, 95 (62 patients [0.46%]) were serious. A total of 189 critical adverse events (159 patients [1.2%]) were reviewed by the Scientific Committee. After analysis, 34 adverse events (28 patients [0.21%]) were assessed from potential cardiac origin. Of these 34 adverse events, 25 (19 patients [0.14%]) were assessed as drug-related: palpitations [13 patients], tachycardia [4 patients], malaise [4 patients], vertigo [3 patients] and pallor [1 patient]. All adverse events were transient and had favourable outcome., Conclusion: This PMS study confirmed that Izilox is well-tolerated in usual medical practice, in adequation with the safety data obtained in clinical trials.
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- 2006
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303. Effects of type of smoking (pipe, cigars or cigarettes) on biological indices of tobacco exposure and toxicity.
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Funck-Brentano C, Raphaël M, Lafontaine M, Arnould JP, Verstuyft C, Lebot M, Costagliola D, and Roussel R
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- Adult, Benzo(a)pyrene metabolism, Chromatography, High Pressure Liquid, Cotinine urine, Creatinine urine, Humans, Male, Middle Aged, Nitrosamines blood, Pyrenes metabolism, Statistics, Nonparametric, Biomarkers metabolism, Cytochrome P-450 CYP1A2 metabolism, Plants, Toxic, Smoking adverse effects, Nicotiana toxicity
- Abstract
Although all forms of smoking are harmful, smoking pipes or cigars is associated with lower exposure to the lethal products of tobacco products and lower levels of morbidity and mortality than smoking cigarettes. Cytochrome P-450-1A (CYP1A) is a major pathway activating carcinogens from tobacco smoke. Our primary aim was to compare CYP1A2 activity in individuals smoking pipes or cigars only, cigarettes only and in non-smokers. We studied 30 smokers of pipes or cigars only, 28 smokers of cigarettes only, and 30 non-smokers male subjects matched for age. CYP1A2 activity was assessed as the caffeine metabolic ratio in plasma. One-day urine collection was used for determining exposure to products of tobacco metabolism. Nitrosamine and benzo[a]pyrene DNA adducts were measured in lymphocytes. CYP1A2 activity was greater (p<0.0001) in cigarette smokers (median: 0.61; interquartile range: 0.52-0.76) than in pipe or cigar smokers (0.27; 0.21-0.37) and non-smokers (0.34; 0.25-0.42) who did not differ significantly. Urinary cotinine and 1-hydroxypyrene levels were higher in cigarette smokers than in pipe or cigar smokers and higher in the later than in non-smokers. DNA adducts levels were significantly lower in pipe or cigar smokers than in cigarette smokers. In multivariate analysis, cigarette smoking was the only independent predictor of CYP1A2 activity (p<0.0001) and of 1-hydroxypyrene excretion in urine (p=0.0012). In this study, pipe or cigar smoking was associated with lower exposure to products of tobacco metabolism than cigarette smoking and to an absence of CYP1A2 induction. Cigarette smoking was the only independent predictor of CYP1A2 activity in smokers. However, inhalation behaviour, rather than the type of tobacco smoked, may be the key factor linked to the extent of tobacco exposure and CYP1A2 induction. Our results provide a reasonable explanation for the results of epidemiological studies showing pipe or cigar smoking to present fewer health hazards than cigarette smoking.
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- 2006
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304. Poor ex vivo induction of T-cell responses to idiotype or tumor cell lysate-pulsed autologous dendritic cells in advanced pre-treated multiple myeloma.
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Garderet L, Mazurier C, Pellat-Deceunynck C, Karim A, Baudin B, Funck-Brentano C, Bouchet S, Geffroy A, Bataille R, Gorin NC, and Lopez M
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- Adult, Aged, Blood Component Removal, CD8-Positive T-Lymphocytes metabolism, Cell Differentiation, Chromium metabolism, Coculture Techniques, Female, Humans, Male, Middle Aged, Monocytes metabolism, Multiple Myeloma immunology, Tumor Necrosis Factor-alpha biosynthesis, Cell Transplantation methods, Dendritic Cells cytology, Immunoglobulin Idiotypes, Multiple Myeloma therapy, T-Lymphocytes metabolism
- Abstract
This study evaluated the feasibility of using dendritic cells (DCs) to generate, ex vivo, anti-tumor cytotoxic T lymphocytes (CTL) in patients with stage III multiple myeloma (MM). Nucleated cells from eight patients who had received chemotherapy (three of whom had undergone autologous hemopoeitic stem cell transplantation) were collected by apheresis. Their monocytes were enriched using counter-current centrifugation, differentiated into DCs which were further co-cultured with autologous CD8 lymphocytes to induce CTL. The DCs were pulsed either with the idiotypic paraprotein (regarded as a tumor-specific antigen) or with autologous MM cell lysate before co-culture. Specific T-cell responses were measured in IFNgamma enzyme-linked immunospot and chromium release assays of autologous plasmocyte targets. A slight increase in IFNgamma secretion by T-cells was observed for two patients (DCs pulsed with idiotypic paraprotein for one, MM cell lysate for the other). No or weak specific lysis of plasmocyte targets was observed in the chromium release assays. In conclusion, the T-cell response to pulsed DCs was very weak or absent. There are clinical and technical reasons that could explain, in part, this lack of response.
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- 2006
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305. 3-Hydroxybenzo[a]pyrene in the urine of smokers and non-smokers.
- Author
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Lafontaine M, Champmartin C, Simon P, Delsaut P, and Funck-Brentano C
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- Adult, Biomarkers urine, Environmental Monitoring, Humans, Male, Middle Aged, Occupational Exposure, Pyrenes metabolism, Benzopyrenes metabolism, Smoking urine
- Abstract
The people studied were male volunteers without occupational and dietary exposure to PAH: 27 smokers (10 cigarettes or more) and 27 non-smokers matched for age and socio-professional category. For each person, all the 24h voided urine samples were reassembled in a single sample. 1-Hydroxypyrene (1-OHPy) and 3-hydroxybenzo[a]pyrene (3-OHBaP) were then determined by automated column-switching high-performance liquid chromatography. Urinary 1-OHPy ranged from 0.041 to 0.530 micromol/molCreatinine (arithmetic mean 0.144, median 0.115) for smokers and from 0.01 to 0.148 mmol/molCreatinine (arithmetic mean 0.044, median 0.032) for non-smokers. These values are close to those of some other studies. Urinary 3-OHBaP ranged from <0.01 to 0.084 nmol/molCreatinine (arithmetic mean 0.030, median 0.023) for smokers and from <0.01 to 0.045 nmol/molCreatinine (arithmetic mean 0.014, median 0.011) for non-smokers. Considering more particularly the urinary 3-OHBaP values, the influence of smoking could be important among workers exposed to low levels of BaP (<100 ng/m(3)) and the concentrations for smokers were equivalent to most of the preshift values of exposed workers. The dietary BaP intake was slightly lower than the BaP intake for an average smoker. From the present study, temporary basic reference levels may be proposed for urinary 3-OHBaP.
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- 2006
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306. Comment on "Clinical trials update from the European Society of Cardiology meeting 2005: CIBIS-III, by JGF Cleland and others".
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Willenheimer R, Krum H, van Veldhuisen DJ, Funck-Brentano C, Erdmann E, and Meyer WR
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- Adrenergic beta-Antagonists administration & dosage, Angiotensin-Converting Enzyme Inhibitors administration & dosage, Bisoprolol administration & dosage, Enalapril administration & dosage, Heart Failure mortality, Hospitalization, Humans, Randomized Controlled Trials as Topic, Research Design standards, Treatment Outcome, Heart Failure drug therapy
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- 2006
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307. QT interval measurement: evaluation of automatic QTc measurement and new simple method to calculate and interpret corrected QT interval.
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Charbit B, Samain E, Merckx P, and Funck-Brentano C
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- Adult, Aged, Algorithms, Anesthesia, General, Female, Humans, Long QT Syndrome physiopathology, Male, Middle Aged, Monitoring, Intraoperative, Observer Variation, Postoperative Complications physiopathology, Electrocardiography statistics & numerical data, Heart Rate physiology, Long QT Syndrome chemically induced, Long QT Syndrome diagnosis, Postoperative Complications chemically induced, Postoperative Complications diagnosis
- Abstract
Background: Assessment of repolarization duration is often recommended to avoid administration of QT-prolonging drugs in patients with prolonged QTc interval, a frequent situation in the postoperative period. Bazett QT correction inappropriately increases QTc when heart rate is increased, and the use of the Fridericia formula may avoid a falsely prolonged QTc interval. The authors assessed automatic QT interval measurement to detect prolonged QTc interval (women >450 ms; men >440 ms) in the postoperative setting., Methods: Automatic and manual electrocardiograms were performed in 108 patients after anesthesia. Automatic electrocardiographic measurement used the Bazett formula. Manual measurements were made from each electrocardiogram and used as the reference. Agreement between the two methods was analyzed. Bazett and Fridericia QT corrections were compared in this population., Results: Agreement between automatic and manual measurements was low. The Fridericia correction, but not the Bazett correction, was independent from heart rate and allowed adequate QT correction. Sensitivity of automatic measurements to detect prolonged QTc-Bazett interval was 54%. Automatic QTc-Bazett interval less than 430 ms ruled out a manual prolonged QTc interval. When automatic QTc-Bazett was greater than 430 ms, this value was converted according to Fridericia. Automatic QTc-Fridericia greater than 430 ms identified all patients with prolonged manual QTc with a negative predictive error of 0% (95% confidence interval, 0-7%). QTc-Fridericia can be approximated by respectively adding or subtracting 5% to the uncorrected QT for each increase or decrease by 10 beats/min in heart rate from 60 beats/min., Conclusions: Automatic QTc-Bazett measurement, if abnormal, associated with calculation of QTc-Fridericia reliably identifies patients in whom manual QTc measurement must be performed to confirm postoperative prolonged QTc interval.
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- 2006
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308. Measurement of CYP2D6 and CYP3A4 activity in vivo with dextromethorphan: sources of variability and predictors of adverse effects in 419 healthy subjects.
- Author
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Funck-Brentano C, Boëlle PY, Verstuyft C, Bornert C, Becquemont L, and Poirier JM
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- Adult, Analgesics, Opioid metabolism, Cytochrome P-450 CYP2D6 metabolism, Cytochrome P-450 CYP3A, Cytochrome P-450 Enzyme System metabolism, Dextromethorphan metabolism, Female, Genotype, Humans, Logistic Models, Male, Retrospective Studies, Analgesics, Opioid adverse effects, Cytochrome P-450 CYP2D6 genetics, Cytochrome P-450 Enzyme System genetics, Dextromethorphan adverse effects
- Abstract
Objective: Dextromethorphan (DEM) shares part of the adverse event profile of opioids and is widely used as a probe drug for CYP2D6 phenotyping and for the assessment of CYP2D6 activity. It has also been used to assess CYP3A4 activity. This study examined the influence of anthropometric variables, oral contraceptives, smoking habits, mu-opioid receptor and MDR1 genetic polymorphisms and components of the DEM ratios on the variability of CYP2D6 and CYP3A4 metabolic ratios and on the occurrence of adverse events following DEM administration., Methods: This was a retrospective analysis of a database in 419 healthy subjects. CYP2D6 and CYP3A4 metabolic ratios were measured as the log of the ratios of the amount of DEM to the amount of dextrorphan (DOR) and of the amount of DEM to the amount of 3-methoxy-morphinan (MET) excreted in urine during a 12-h time period, respectively, following the oral administration of 80 mg of dextromethorphan hydrobromide. Logistic regression was performed to examine the factors associated with changes in metabolic ratios and with the occurrence of adverse events., Results: The CYP2D6 metabolic ratio allowed identification of extensive and poor metabolizers of DEM. The CYP2D6 and CYP3A4 metabolic ratios were not strictly independent one from each other. Based on multivariate analysis, the CYP2D6 metabolic ratio was a stronger independent predictor of adverse events (p<0.0001) than the CYP2D6 phenotype (p=0.05). Anthropometric variables, oral contraceptives, smoking habits, mu-opioid receptor and MDR1 genetic polymorphisms did not significantly contribute to changes in metabolic ratios or to the occurrence of adverse events., Conclusions: Dextromethorphan can be used for CYP2D6 phenotyping, but the CYP2D6 and CYP3A4 metabolic ratios are not strictly independent one from each other. The CYP2D6 metabolic ratio predicts adverse events to DEM as does CYP2D6 phenotype, and extensive metabolizer subjects are not protected against adverse events.
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- 2005
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309. Assessment of the effect of a single oral dose of telithromycin on sotalol-induced qt interval prolongation in healthy women.
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Démolis JL, Strabach S, Vacheron F, and Funck-Brentano C
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- Administration, Oral, Adult, Anti-Arrhythmia Agents adverse effects, Anti-Arrhythmia Agents pharmacokinetics, Anti-Bacterial Agents adverse effects, Anti-Bacterial Agents pharmacokinetics, Double-Blind Method, Drug Interactions, Electrocardiography methods, Female, Humans, Ketolides adverse effects, Ketolides pharmacokinetics, Sotalol adverse effects, Sotalol pharmacokinetics, Anti-Arrhythmia Agents administration & dosage, Anti-Bacterial Agents administration & dosage, Ketolides administration & dosage, Long QT Syndrome chemically induced, Sotalol administration & dosage, Ventricular Function drug effects
- Abstract
Aims: Telithromycin belongs to ketolides, a new class of macrolide antibiotics. Macrolides are known to have the potential to prolong QT interval duration. Previous studies have shown that telithromycin did not induce significant QT interval prolongation in healthy subjects compared with placebo. The main objective of this study was to demonstrate the absence of amplification of QT interval prolongation induced by sotalol, when telithromycin and sotalol were co-administered. The secondary objective was to correlate the QT interval changes induced by the study drugs to plasma concentrations during the elimination phase., Methods: Twenty-four women received sotalol (160 mg) together with placebo or telithromycin (800 mg) in a two-period, double-blind, randomized study. Electrocardiograms were recorded at rest. Comparison of maximal corrected QT interval (QTc(max)) with sotalol in the presence or absence of telithromycin was performed. The relation between sotalol concentration and QTc was studied using linear regression., Results: Mean difference (95% CI) between QTc(max) with sotalol-placebo and QTc(max) with sotalol-telithromycin was -15.5 ms (-27.7 to -3.2 ms). QTc(max) interval prolongation was lower (P < 0.05) with sotalol-telithromycin than with sotalol-placebo, in relation to decreased sotalol plasma concentrations. Regression analysis showed that the relationship between sotalol plasma concentration and QTc interval duration was not modified by telithromycin co-administration., Conclusion: Our results do not support a potential synergistic effect on QT interval prolongation between sotalol and telithromycin. The decrease of mean QTc interval in subjects taking telithromycin and sotalol may be explained by a decrease of sotalol concentration.
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- 2005
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310. Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) genotypes as determinants of acenocoumarol sensitivity.
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Bodin L, Verstuyft C, Tregouet DA, Robert A, Dubert L, Funck-Brentano C, Jaillon P, Beaune P, Laurent-Puig P, Becquemont L, and Loriot MA
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- Administration, Oral, Adolescent, Adult, Aged, Carcinoma, Hepatocellular, Cell Line, Tumor, Cytochrome P-450 CYP2C9, Female, Gene Frequency, Genes, Reporter, Haplotypes, Humans, Linear Models, Liver Neoplasms, Luciferases genetics, Male, Middle Aged, Predictive Value of Tests, Vitamin K Epoxide Reductases, Acenocoumarol administration & dosage, Anticoagulants administration & dosage, Aryl Hydrocarbon Hydroxylases genetics, Drug Resistance genetics, Mixed Function Oxygenases genetics
- Abstract
The aim of the study is to explore the contribution of genetic factors related either to drug metabolism (cytochrome P450 2C9) or to drug target (vitamin K epoxide reductase) to variability in the response to acenocoumarol among 222 healthy volunteers after a single oral dose. Associations between a pharmacodynamic index (reduction in factor VII activity and international normalized ratio [INR] change) and several genetic polymorphisms (VKORC1: -4931T>C, -4451C>A, -2659G>C, -1877A>G, -1639G>A, 497C>G, 1173C>T, and CYP2C9*3) were investigated using haplotype and univariate analyses. VKORC1 haplotypes were associated with the pharmacologic response, and this association can be explained only by the effect of the -1639G>A polymorphism (or alternatively by 1173C>T, which is in complete association with it). Indeed, it explains about one third of the variability of the pharmacologic response (37% of factor VII decrease and 30% of INR change). Moreover, the previously observed effect of the CYP2C9*3 allele is independent of the VKORC1 gene effect. These 2 polymorphisms account for up to 50% of the interindividual variability. The simple genotyping of 2 single-nucleotide polymorphisms (SNPs), VKORC1 -1639G>A or 1173C>T and the CYP2C9*3 polymorphisms, could thus predict a high risk of overdose before initiation of anticoagulation with acenocoumarol, and provide a safer and more individualized anticoagulant therapy.
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- 2005
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311. Prolongation of QTc interval after postoperative nausea and vomiting treatment by droperidol or ondansetron.
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Charbit B, Albaladejo P, Funck-Brentano C, Legrand M, Samain E, and Marty J
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- Adult, Droperidol pharmacology, Droperidol therapeutic use, Electrocardiography drug effects, Electrocardiography methods, Female, Humans, Long QT Syndrome physiopathology, Male, Middle Aged, Ondansetron pharmacology, Ondansetron therapeutic use, Postoperative Nausea and Vomiting physiopathology, Prospective Studies, Single-Blind Method, Droperidol adverse effects, Long QT Syndrome chemically induced, Ondansetron adverse effects, Postoperative Nausea and Vomiting drug therapy
- Abstract
Background: At dosages above 0.1 mg/kg, droperidol induces a dose-dependent QTc interval prolongation. Although subject to controversy, low-dose droperidol has recently been suspected to induce cardiac arrhythmias. Hence, 5-hydroxytryptamine type 3 antagonists have become the first-line drug for management of postoperative nausea and vomiting. These drugs are also known to prolong the QTc interval at high dosages. This study describes QTc interval changes associated with postoperative nausea and vomiting treatment by droperidol or ondansetron at low doses., Methods: Eighty-five patients with postoperative nausea and vomiting were included in this prospective, single-blind study. Patients received either 0.75 mg intravenous droperidol (n = 43) or 4 mg intravenous ondansetron (n = 42). Electrocardiographic recordings were obtained before administration of antiemetic drug and then 1, 2, 3, 5, 10, and 15 min after. Electrocardiographic monitoring was maintained for 3 h in eight patients in each group., Results: The QTc interval was prolonged (> 450 ms in men, > 470 ms in women) in 21% of the patients before antiemetic drug administration. This was significantly correlated with lower body temperature and longer duration of anesthesia. Compared with predrug QTc measurement, both antiemetics were associated with a significant QTc interval prolongation (P < 0.0001). The mean maximal QTc interval prolongation was 17 +/- 9 ms after droperidol occurring at the second minute and 20 +/- 13 ms after ondansetron at the third minute (both P < 0.0001). Compared with predrug measurement, the QTc interval was significantly lower after the 90th minute in both groups., Conclusions: Droperidol and ondansetron induced similar clinically relevant QTc interval prolongations. When used in treatment of postoperative nausea and vomiting, a situation where prolongation of the QTc interval seems to occur, the safety of 5-hydroxytryptamine type 3 antagonists may not be superior to that of low-dose droperidol.
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- 2005
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312. Corrected QT interval in anti-SSA-positive adults with connective tissue disease: comment on the article by Lazzerini et al.
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Costedoat-Chalumeau N, Amoura Z, Hulot JS, Ghillani P, Lechat P, Funck-Brentano C, and Piette JC
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- Adult, Female, Humans, Long QT Syndrome physiopathology, Male, Antibodies, Antinuclear analysis, Connective Tissue Diseases physiopathology, Electrocardiography
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- 2005
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313. QT interval prolongation after oxytocin bolus during surgical induced abortion.
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Charbit B, Funck-Brentano C, Samain E, Jannier-Guillou V, Albaladejo P, and Marty J
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- Adult, Electrocardiography, Female, Humans, Infusions, Intravenous, Oxytocics administration & dosage, Oxytocin administration & dosage, Pregnancy, Vacuum Curettage, Abortion, Induced, Long QT Syndrome chemically induced, Oxytocics adverse effects, Oxytocin adverse effects
- Abstract
Background: Although oxytocin, a uterotonic agent, may cause short-term vasodilation that results in severe hypotension, it is still routinely given as an intravenous bolus injection during surgical suction curettage. Two reported cases of ventricular tachycardia after oxytocin bolus in patients with long QT interval syndrome led us to assess the effect of oxytocin on QT interval., Method: Thirty-eight healthy women scheduled for a surgical suction curettage with general anesthesia were enrolled. General anesthesia was induced by propofol and maintained by either propofol (n = 18) or sevoflurane (n = 20). Electrocardiographic recordings were obtained before and at 1, 2, 3, and 5 minutes after a 10-U intravenous bolus of oxytocin., Results: Intravenous oxytocin induced a pronounced QTc interval prolongation of 41 +/- 21 ms ( P < .0001), which was maximal 1 minute after administration. The QTc interval returned to control values 3 minutes after oxytocin bolus. Oxytocin bolus also induced an increase in heart rate of 19 +/- 10 beats/min and a significant decrease in systolic arterial pressure of 11 +/- 9 mm Hg (both P < .0001). The drug used to maintain anesthesia was not an independent factor of QT interval prolongation in ANOVA analysis., Conclusions: Oxytocin intravenous bolus induced a large and transient QTc interval prolongation, suggesting that it may lead to proarrhythmia in circumstances favoring QTc interval increase.
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- 2004
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314. Pharmacogenetics of acenocoumarol pharmacodynamics.
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Morin S, Bodin L, Loriot MA, Thijssen HH, Robert A, Strabach S, Verstuyft C, Tregouet DA, Dubert L, Laurent-Puig P, Funck-Brentano C, Jaillon P, Beaune PH, and Becquemont L
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- Acenocoumarol administration & dosage, Acenocoumarol pharmacology, Administration, Oral, Adolescent, Adult, Aged, Alleles, Anticoagulants administration & dosage, Anticoagulants pharmacology, Area Under Curve, Cytochrome P-450 CYP2C9, DNA Primers, Factor VII drug effects, Female, France, Genotype, Humans, International Normalized Ratio, Male, Middle Aged, Pharmacogenetics, Polymerase Chain Reaction, Polymorphism, Genetic, Acenocoumarol pharmacokinetics, Anticoagulants pharmacokinetics, Aryl Hydrocarbon Hydroxylases genetics, NAD(P)H Dehydrogenase (Quinone) genetics
- Abstract
Objective: The aim of this study was to investigate the respective contribution of the different cytochrome P450 (CYP) 2C9 genetic polymorphisms to the interindividual variability of acenocoumarol pharmacodynamic response., Methods: A total of 263 healthy volunteers were genotyped for CYP2C9*2, CYP2C9*3, CYP2C9*4, and CYP2C9*5 alleles, as well as for the nicotinamide adenine dinucleotide phosphate, reduced, quinone oxidoreductase 1 genetic polymorphism (NQO1*2). Moreover, the 5'-flanking region of the CYP2C9 gene was investigated for new polymorphisms, and haplotype analysis was then performed. Finally, CYP2C9 phenotype was evaluated after a single oral dose of 4 mg of acenocoumarol. Factor VII coagulant activity was measured before and 24 hours after acenocoumarol intake., Results: The CYP2C9*3 allele was the only nonsynonymous single nucleotide polymorphism (SNP) influencing acenocoumarol pharmacodynamics; the percentages of remaining factor VII were 60% +/- 19%, 39% +/- 17%, and 17% for CYP2C9*1/CYP2C9*1, CYP2C9*1/CYP2C9*3, and CYP2C9*3/CYP2C9*3 subjects, respectively (P =.001). Among the white subjects, the CYP2C9 promoter showed the existence of 6 SNPs at positions G-1538A, T-1189C, G-1097A, G-982A, T-640 del, and G-620T with allelic frequencies of 0.085, 0.0398, 0.136, 0.086, 0.005, and 0.0138, respectively. Four major haplotypes could be inferred among white subjects. The haplotype that contains the CYP2C9*3 allele was the only one influencing acenocoumarol pharmacodynamics, explaining 14.3% of its interindividual variability. Body weight explained 5% of acenocoumarol pharmacodynamic variability, whereas the NQO1*2 allele had no significant effect., Conclusion: Overall, CYP2C9-related genetic variability accounts for 14% of the interindividual variability in acenocoumarol pharmacodynamic response. The information found by haplotype analysis is mainly related to the CYP2C9*3 SNP.
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- 2004
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315. Influence of endogenous oestrogens on QT interval duration.
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Hulot JS, Démolis JL, Rivière R, Strabach S, Christin-Maitre S, and Funck-Brentano C
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- Adolescent, Adult, Electrocardiography, Estradiol blood, Female, Humans, Menstrual Cycle physiology, Sex Factors, Ventricular Function physiology, Estradiol physiology, Heart Conduction System physiology, Heart Rate physiology
- Abstract
Aims: Women have a longer QT interval and a greater incidence of torsades de pointes than men. It has been suggested that oestrogens may influence the duration of cardiac repolarization. We thus investigated the influence of oestradiol (E2) on ventricular repolarization within the physiological concentration range of this hormone., Methods and Results: We studied QT interval duration in 21 healthy women aged 18 to 35 years with regular menstrual cycle (mean duration: 29+/-1 days) during two periods associated with a wide range of oestradiol plasma levels: low level during menses (105+/-34 pmol/l) and high level during the pre-ovulatory phase (750+/-277 pmol/l). We used heart rate-independent assessment of QT. QT-RR pairs were measured over a wide range of RR intervals obtained at rest and during a sub-maximal exercise test. Using a monoexponential nonlinear curve fitting for the QT-RR relation, the QT(1000 ms)during nadir and peak oestradiol periods was then determined for each subject. QT(1000 ms)interval was not different between both study periods: 382.1+/-18.4 ms at peak versus 382.2+/-19.4 ms at nadir oestradiol level (P=0.98)., Conclusion: No significant change in QT interval duration was observed within the large range of physiological E2 variations found during the menstrual cycle.
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- 2003
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316. Frequency of cytochrome P450 2C9 allelic variants in the Chinese and French populations.
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Yang JQ, Morin S, Verstuyft C, Fan LA, Zhang Y, Xu CD, Barbu V, Funck-Brentano C, Jaillon P, and Becquemont L
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- Adolescent, Adult, Aged, Child, China, Cytochrome P-450 CYP2C9, Female, France, Gene Frequency, Humans, Male, Middle Aged, Aryl Hydrocarbon Hydroxylases genetics, Asian People genetics, Polymorphism, Single Nucleotide, White People genetics
- Abstract
Cytochrome P450 2C9 (CYP2C9) is a polymorphic enzyme responsible for the metabolism of different drugs with low therapeutic index such as oral anticoagulants. CYP2C9*2 and CYP2C9*3 are two single nucleotide polymorphic allelic variants. The frequency of these alleles in different ethnic populations is extremely variable. In this study, we compared the frequencies of CYP2C9 allelic variants among 394 Chinese living in Shanghai to 151 French Caucasians living in Paris. The allelic frequencies of CYP2C9 variants of the Chinese and the French subjects were 0.963, 0.001, 0.036 and 0.77, 0.15, 0.08 for CYP2C9*1, CYP2C9*2, CYP2C9*3, respectively. Chinese CYP2C9*3 allelic frequency was twice as lower as the French subjects, but three times higher than Korean (0.036 vs. 0.011). The CYP2C9*2 allele could be detected in only one Chinese subject, whereas it represented the major allelic variant in French Caucasians. The low frequency of the CYP2C9*2 and CYP2C9*3 allelic variants in Chinese subjects does not justify their detection in clinical practice, unlike French Caucasians.
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- 2003
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317. Cardiovascular safety of salmeterol in COPD.
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Ferguson GT, Funck-Brentano C, Fischer T, Darken P, and Reisner C
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- Adrenergic beta-Agonists administration & dosage, Aged, Albuterol administration & dosage, Bronchodilator Agents administration & dosage, Cardiovascular Diseases chemically induced, Double-Blind Method, Electrocardiography, Electrocardiography, Ambulatory, Female, Humans, Male, Pulmonary Disease, Chronic Obstructive physiopathology, Salmeterol Xinafoate, Tachycardia chemically induced, Adrenergic beta-Agonists adverse effects, Albuterol adverse effects, Albuterol analogs & derivatives, Bronchodilator Agents adverse effects, Cardiovascular System drug effects, Pulmonary Disease, Chronic Obstructive drug therapy
- Abstract
Background: Patients with COPD have an increased risk of cardiovascular disease. Despite the clinical benefits of long-acting beta-agonist agents in the treatment of COPD, patients may be at an increased risk of cardiovascular toxicity, including tachyarrhythmia due to beta-adrenergic stimulation., Objective: To evaluate the cardiovascular safety of salmeterol in COPD patients by conducting a pooled analysis of cardiovascular safety data., Design: Randomized, double-blind, parallel group, multiple-dose studies, which included salmeterol, 50 micro g bid, and placebo arms., Study Selection: Seven of a total of 17 studies met the predefined inclusion requirements and were pooled. A total of 1,443 patients received placebo, while 1,410 patients received salmeterol, 50 micro g bid. The median duration of treatment was 24 weeks (range, 12 to 52 weeks)., Results: Treatment with salmeterol, 50 micro g bid, showed no increased risk of cardiovascular adverse events (AEs) compared with placebo (relative risk, 1.03; 95% confidence interval, 0.8 to 1.3; p = 0.838). Both groups had a similar incidence of cardiovascular events (8%), including cardiovascular deaths. The incidence of cardiovascular AEs increased with age, concurrent cardiovascular conditions, and treatment with antiarrhythmic/bradycardic agents, although increases were comparable in both treatment groups. There were no episodes of sustained ventricular tachycardia, and no clinically significant differences were observed in 24-h heart rate, ventricular and supraventricular ectopic events, qualitative ECGs, QT intervals, or vital signs between the salmeterol, 50 micro g bid, group and the placebo group. Similar findings were observed when patients were stratified for age of > 65 years or the known presence of cardiovascular disease., Conclusions: Treatment with salmeterol, 50 micro g bid, does not increase the risk of cardiovascular AEs in this population of COPD patients compared with placebo.
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- 2003
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318. Digoxin pharmacokinetics and MDR1 genetic polymorphisms.
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Verstuyft C, Schwab M, Schaeffeler E, Kerb R, Brinkmann U, Jaillon P, Funck-Brentano C, and Becquemont L
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 1 genetics, ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism, Adult, Area Under Curve, Digoxin administration & dosage, Digoxin blood, Female, Genotype, Homozygote, Humans, Male, Digoxin pharmacokinetics, Genes, MDR genetics, Polymorphism, Single Nucleotide
- Abstract
Background: The effect of MDR1 C3435T single nucleotide polymorphism (SNP) in exon 26 on digoxin pharmacokinetics has recently been challenged. OBJECTIVE. To clarify the relationships between MDR1 genetic polymorphisms in exon 26 (C3435T) and 21 (G2677T/A) and digoxin pharmacokinetics., Materials and Methods: MDR1 genotypes for C3435T and G2677T/A SNPs were determined in 32 healthy subjects whose single oral dose digoxin pharmacokinetics had been measured over 48 h., Results: A significant relationship was observed between C3435T SNP and digoxin AUCs ( p<0,05). Homozygous TT subjects had 20% higher digoxin plasma concentrations than CT and CC subjects and a trend for higher 48 h digoxin urinary recoveries (TT>CT>CC). Similar results, although not statistically significant, were observed from the MDR1 G2677T/A SNP., Conclusions: Our results confirm that the MDR1 C3435T single nucleotide polymorphism (SNP) significantly affects digoxin disposition kinetics, with homozygous TT subjects presenting the highest plasma concentrations.
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- 2003
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319. Bisoprolol dose-response relationship in patients with congestive heart failure: a subgroup analysis in the cardiac insufficiency bisoprolol study(CIBIS II).
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Simon T, Mary-Krause M, Funck-Brentano C, Lechat P, and Jaillon P
- Subjects
- Death, Sudden, Cardiac, Dose-Response Relationship, Drug, Double-Blind Method, Female, Follow-Up Studies, Humans, Male, Middle Aged, Risk Factors, Survival Analysis, Treatment Outcome, Treatment Refusal, Adrenergic beta-Antagonists administration & dosage, Bisoprolol administration & dosage, Heart Failure drug therapy
- Abstract
Aims: Whether all patients with congestive heart failure (CHF) need to reach the target dose of beta-blocker to obtain a benefit in terms of survival remains uncertain., Methods and Results: We classified by tertile the 2647 patients enrolled in CIBIS II according to the last tolerated dose: low dose (LD: 1.25, 2.5 or 3.75mg/day, n=434), moderate dose (MD: 5 or 7.5mg/day, n=328) and high dose (HD: 10mg/day, n=565) of bisoprolol or placebo (LD=234, MD=278 and HD=808). In both groups, patients tolerating only low doses were significantly older with more severe New York Heart Association (NYHA) functional class and higher frequency of co-morbidities. Treatment withdrawal was associated with a significant increase of mortality in the bisoprolol group (relative hazard (RH)=2.13, 95% confidence interval (CI)=1.43-3.17, p=0.0002). After adjustment, all-cause mortality was significantly reduced in the bisoprolol group compared to placebo regardless of the dose level considered: LD (RH=0.66, 95% CI=0.48-0.92), MD (RH=0.33, 95% CI=0.21-0.51) or HD (RH=0.59, 95% CI=0.40-0.89)., Conclusions: Bisoprolol reduces mortality in CHF patients at all tolerated dose levels and its withdrawal increases the risk of mortality. Efforts should be made to maintain bisoprolol therapy based on the individual patient's tolerability.
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- 2003
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320. Genetic and environmental risk factors for oral anticoagulant overdose.
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Verstuyft C, Robert A, Morin S, Loriot MA, Flahault A, Beaune P, Funck-Brentano C, Jaillon P, and Becquemont L
- Subjects
- Administration, Oral, Aged, Anticoagulants pharmacokinetics, Aryl Hydrocarbon Hydroxylases genetics, Case-Control Studies, Cytochrome P-450 CYP2C9, Dose-Response Relationship, Drug, Drug Interactions, Drug Overdose, Female, Food-Drug Interactions, Genotype, Hemorrhage chemically induced, Humans, Inpatients, International Normalized Ratio, Male, Mutation, Polymorphism, Genetic, Prospective Studies, Risk Factors, Vitamin K administration & dosage, Anticoagulants administration & dosage, Anticoagulants adverse effects
- Abstract
Background: Cytochrome P450 2C9 (CYP2C9) allelic variant carriers have been shown to experience hyper-responsiveness to small doses of oral anticoagulants (OAs) (warfarin or acenocoumarol) and a higher bleeding rate., Objectives: To determine the relative frequencies of different risk factors for OA overdose including diet, concomitant diseases, drug interactions, recent increment of OA dose and CYP2C9 genetic polymorphism among hospitalised patients., Materials and Methods: Frequencies of the different risk factors for OA overdose were determined in a prospective case-control study. Seventy-five consecutive patients with an International normalised ratio (INR) greater than 4 were matched with seventy-five control patients with an INR greater than 2 but less than 3.5 with respect to age, prescribed OA and daily dose. Genotyping of CYP2C9*2 and CYP2C9*3 allelic variants was detected by the TaqMan allelic discrimination assay., Results: Drug interactions and a recent increment of OA dose were the only significant independent risk factors identified in the first analysis with odds ratio 2.13 (95% CI: 1.06-4.28) and 3.38 (95%CI: 1.51-7.57), respectively. A recent increment of OA dose was the only significant independent risk factor identified among the patients treated with coumarin derivatives (acenocoumarol or warfarin), excluding those treated with fluindione; the odds ratio was 4.3 (95% CI: 1.5-12.3). CYP2C9 genetic polymorphism did not significantly predict the increased risk of OA overanticoagulation in this study. However three homozygous CYP2C9*3/CYP2C9*3 genotype patients were found among the cases, whereas no such patients could be identified among controls., Conclusion: This is the first observational study investigating the role of CYP2C9 genetic polymorphism together with other environmental OA overdose risk factors. Our results support the view that although the CYP2C9*3/CYP2C9*3 genotype is associated soon after the introduction of OA with dramatic overanticoagulation, OA overdose is mostly related to environmental factors.
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- 2003
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321. Effect of single and repeated oral doses of telithromycin on cardiac QT interval in healthy subjects.
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Démolis JL, Vacheron F, Cardus S, and Funck-Brentano C
- Subjects
- Administration, Oral, Adult, Analysis of Variance, Anti-Bacterial Agents administration & dosage, Clarithromycin administration & dosage, Clarithromycin pharmacology, Cross-Over Studies, Dose-Response Relationship, Drug, Double-Blind Method, Drug Administration Schedule, Electrocardiography drug effects, Exercise Test, Female, Humans, Male, Reference Values, Rest, Anti-Bacterial Agents pharmacology, Heart Conduction System drug effects, Ketolides, Macrolides
- Abstract
Background: Telithromycin is the first member of a new class of antimicrobials-the ketolides. The main objective of this study was to assess the effect of various oral doses of telithromycin on QT interval during single and repeated administrations., Methods: Seventeen men and 17 women participated in double-blind, placebo-controlled, crossover studies. Of these subjects, 18 (9 men and 9 women) received single and repeated oral doses of telithromycin (800 mg daily), clarithromycin (500 mg twice daily), or placebo (protocol 1). The other 16 subjects received a single oral dose (800 mg, 1600 mg, and 2400 mg) of telithromycin or placebo (protocol 2). At the time of expected telithromycin maximum concentration, several electrocardiographic recordings were obtained at rest and during the course of a submaximal exercise test. QT intervals were measured within a wide range of R-R intervals in each subject., Results: ANOVA showed that telithromycin did not increase QT interval at any dose compared with placebo. The greatest effect observed during any study period was a mean (+/-SD) change in QT-interval duration of 4.2 +/- 15.2 ms (ie, +1.2% +/- 4.0%, P not significant) at R-R = 1000 ms after repeated doses of 800 mg telithromycin. Outlier values (change in Bazett QTc from baseline >60 ms) from resting 12-lead electrocardiograms did not differ across treatment groups, including placebo., Conclusions: Telithromycin administered as repeated doses of 800 mg (recommended doses) or as single doses of up to 3 times this recommended dose did not increase the QT interval at any heart rate at rest and during effort. Telithromycin did not prolong QT-interval duration when administered to healthy young male and female subjects.
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- 2003
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322. Dipyridamole enhances digoxin bioavailability via P-glycoprotein inhibition.
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Verstuyft C, Strabach S, El-Morabet H, Kerb R, Brinkmann U, Dubert L, Jaillon P, Funck-Brentano C, Trugnan G, and Becquemont L
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 1 genetics, Adult, Area Under Curve, Biological Availability, Cross-Over Studies, Cysteine genetics, Female, Genotype, Humans, Male, Reference Values, Threonine genetics, ATP Binding Cassette Transporter, Subfamily B, Member 1 antagonists & inhibitors, Cardiotonic Agents pharmacokinetics, Digoxin pharmacokinetics, Dipyridamole pharmacology, Enzyme Inhibitors pharmacokinetics, Genes, MDR, Phosphodiesterase Inhibitors pharmacology, Platelet Aggregation Inhibitors pharmacology, Polymorphism, Genetic
- Abstract
Background: On the basis of in vitro studies indicating that dipyridamole is an inhibitor for the MDR1 efflux membrane transporter P-glycoprotein, we postulated that dipyridamole could increase the bioavailability of digoxin, a P-glycoprotein substrate., Objectives: The main objective was to determine whether dipyridamole alters the bioavailability of digoxin. The secondary objective was to determine whether the magnitude of the pharmacokinetic interaction was influenced by MDR1 genetic polymorphism in exon 26 (C3435T)., Material and Methods: (1) The effect of dipyridamole on in vitro P-glycoprotein-mediated, polarized transport of tritium-labeled digoxin was investigated in Caco-2 cell monolayers. (2) Twelve healthy volunteers participated in this open, randomized, 2-period crossover study, in which the effects of dipyridamole (300 mg/d for 3 days) versus placebo on the pharmacokinetics of a single oral dose of digoxin (0.5 mg) were compared. MDR1 genotyping (exon 26, C3435T) was determined before the study to include 6 homozygous CC and 6 homozygous TT subjects., Results: Dipyridamole inhibited [(3)H]digoxin transport in Caco-2 cells with a 50% inhibitory concentration value of 1.5 +/- 1.5 micromol/L. We observed a 20% and 13% increase in digoxin area under the plasma concentration-time curve (AUC) from 0 to 4 hours and AUC from 0 to 24 hours (P <.05), respectively, during dipyridamole administration, which was consecutive to an increase in digoxin absorption. Digoxin AUC from 0 to 4 hours and AUC from 0 to 24 hours were significantly higher among subjects harboring the TT compared with the CC MDR1 genotype: 7.5 +/- 1.2 ng x h x mL(-1) versus 6.1 +/- 0.8 ng x h x mL(-1) and 20.2 +/- 2.1 ng x h x mL(-1) versus 16.8 +/- 1.7 ng x h x mL(-1), respectively (P <.05). Digoxin pharmacokinetic modifications during the dipyridamole period were similar in both genotypes., Conclusion: Dipyridamole is an in vitro and in vivo P-glycoprotein inhibitor that increases intestinal digoxin absorption and digoxin plasma concentrations. In light of the modest changes in digoxin pharmacokinetics in the presence of dipyridamole, this drug interaction is probably clinically irrelevant.
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- 2003
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323. Pharmacokinetic and pharmacodynamic interaction between grapefruit juice and halofantrine.
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Charbit B, Becquemont L, Lepère B, Peytavin G, and Funck-Brentano C
- Subjects
- Adult, Area Under Curve, Cross-Over Studies, Dose-Response Relationship, Drug, Electrocardiography drug effects, Female, Humans, Male, Beverages, Citrus, Food-Drug Interactions, Phenanthrenes pharmacokinetics, Phenanthrenes pharmacology
- Abstract
Background: Halofantrine, an antimalarial drug that prolongs the QT interval, is metabolized into N-debutyl-halofantrine by cytochrome P450 (CYP) 3A4. Grapefruit juice increases the bioavailability of several orally administered CYP3A4 substrates by inhibiting CYP3A4 at the enterocyte level and could therefore increase the risk of halofantrine-induced QT interval prolongation. We studied the effect of grapefruit juice on halofantrine bioavailability and on QT interval prolongation associated with its oral administration., Methods: Twelve healthy male and female volunteers received 500 mg of halofantrine with 250 mL of water, orange juice, or grapefruit juice (250 mL once a day of regular strength for 3 days and once at 12 hours before halofantrine administration), in a random order, during a crossover study. Plasma pharmacokinetics of halofantrine and N-debutyl-halofantrine and QTc interval duration were studied during the following 168 hours., Results: Compared with water, grapefruit juice increased halofantrine area under the plasma concentration versus time curve (AUC) and peak plasma concentration by 2.8-fold +/- 1.5-fold (P <.0001) and 3.2-fold +/- 1.3-fold (P <.0001), respectively. There was a concomitant 2.4-fold +/- 1.6-fold decrease in N-debutyl-halofantrine AUC (P <.01) but no significant change in halofantrine elimination half-life. Maximum QTc interval prolongation increased from 17 +/- 6 ms when halofantrine was administered with water to 31 +/- 12 ms when it was administered with grapefruit juice (P <.0005). Multiple regression analysis showed that QTc interval prolongation was better correlated with halofantrine (partial r = 0.432; P <.0001) than with N-debutyl-halofantrine (partial r = 0.117; P <.01) concentrations. There was no significant difference between the water and orange juice study periods., Conclusions: Grapefruit juice increases halofantrine bioavailability and halofantrine-induced QT interval prolongation. Grapefruit juice should be contraindicated during administration of halofantrine.
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- 2002
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324. Pharmacokinetics and electrocardiographic effects of a new controlled-release form of flecainide acetate: comparison with the standard form and influence of the CYP2D6 polymorphism.
- Author
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Tennezé L, Tarral E, Ducloux N, and Funck-Brentano C
- Subjects
- Adult, Anti-Arrhythmia Agents administration & dosage, Anti-Arrhythmia Agents blood, Biological Availability, Cross-Over Studies, Cytochrome P-450 CYP2D6 genetics, Delayed-Action Preparations, Drug Administration Schedule, Electrocardiography drug effects, Female, Flecainide administration & dosage, Flecainide blood, Humans, Male, Reference Values, Anti-Arrhythmia Agents pharmacokinetics, Cytochrome P-450 CYP2D6 metabolism, Flecainide pharmacokinetics, Heart Conduction System drug effects, Polymorphism, Genetic
- Abstract
Objectives: Our objectives were study the single- and repeated-dose pharmacokinetics and electrocardiographic effects (QRS duration) of a new controlled-release form of flecainide acetate compared with the immediate-release form and to examine the influence of CYP2D6 activity., Methods: Twenty-four healthy subjects (6 men and 6 women at both dosages) received single and repeated doses of 100 or 200 mg immediate-release and controlled-release flecainide in a randomized crossover design. Electrocardiograms were recorded and flecainide plasma concentrations were measured before administration and up to 96 hours after administration., Results: The controlled-release formulation had sustained-release properties, with a significantly lower maximum concentration (C(max)) and delayed time to reach C(max). Compared with the immediate-release formulation, the relative bioavailability of the controlled-release formulation at steady state was 0.85 +/- 0.17 and 0.89 +/- 0.17 for the 100-mg/day and 200-mg/day doses, respectively. Trough flecainide plasma concentration at steady state was bioequivalent for both formulations. Maximum and minimum QRS increases were not significantly different for either the immediate-release or the controlled-release form of flecainide after administration of both single and repeated doses. Mean QRS duration during a dosing interval at steady state correlated with mean plasma concentration for both forms (pooled data; P <.001). The 95% confidence interval for this regression was 26% narrower for the controlled-release form than for the immediate-release form. Flecainide-induced QRS prolongation and pharmacokinetics were not significantly influenced by CYP2D6 activity., Conclusions: Flecainide-induced QRS prolongation did not differ between the new controlled-release form and the immediate-release form. Flecainide plasma concentrations associated with the new controlled-release form predicted QRS prolongation with less variability compared with the immediate-release form. The CYP2D6 polymorphism did not appear to influence flecainide disposition kinetics or electrocardiographic effects at steady state.
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- 2002
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325. [Efficacy and tolerance of propafenone after correction of atrial fibrillation: PEPS pharmaco-epidemiologic study].
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Simon T, Mary-Krause M, Funck-Brentano C, Davy JM, Weingrod M, and Jaillon P
- Subjects
- Aged, Cohort Studies, Female, Humans, Male, Middle Aged, Prospective Studies, Recurrence, Sex Factors, Treatment Outcome, Anti-Arrhythmia Agents pharmacology, Atrial Fibrillation drug therapy, Propafenone pharmacology
- Abstract
The PEPS study had the objective of documenting the acceptability and efficacy of propafenone in 1366 treated patients, after correction of chronic or paroxysmal AF, and followed up over one year. All the cases were validated by quality controls performed by the 196 participating cardiologists. All the events during follow up were validated by a committee of independent experts. The patients, aged 67 +/- 11 years, were in sinus rhythm on inclusion. Propafenone was prescribed at the initial dose of 600 mg/day in 65% of patients. The proportion of patients without relapse of AF was 64 +/- 1% at 12 months. After adjustment, the significant predictors of AF relapse were male sex, previous history of chronic AF and prescription of associated drugs. Neither patient age nor propafenone dose significantly influenced AF relapse. Seven deaths (0.5%) occurred during the study of which 3 were of unknown cause. A pro-arrhythmic effect was observed in 8 patients (0.59%) of which 6 had underlying heart disease. The overall frequency of pro-arrhythmic effects, including the 3 deaths of unknown cause, was therefore 0.81%. Tolerance of treatment with propafenone after correction of AF is therefore satisfactory and the frequency of pro-arrhythmic effects is less than 1%. The efficacy of the treatment for the maintenance of sinus rhythm is in accordance with previously published results.
- Published
- 2002
326. Renal and vascular effects of S21402, a dual inhibitor of angiotensin-converting enzyme and neutral endopeptidase, in healthy subjects with hypovolemia.
- Author
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Chodjania Y, Tharaux PL, Ragueneau I, Dussaule JC, Picker JL, Funck-Brentano C, and Jaillon P
- Subjects
- Adult, Cross-Over Studies, Double-Blind Method, Humans, Hypovolemia blood, Male, Reference Values, Angiotensin-Converting Enzyme Inhibitors pharmacology, Blood Pressure drug effects, Enzyme Inhibitors pharmacology, Hormones metabolism, Hypovolemia physiopathology, Kidney drug effects, Propionates pharmacology, Sulfhydryl Compounds pharmacology
- Abstract
Objective: To examine the mechanism of action of dual inhibitors of angiotensin-converting enzyme (ACE) and neutral endopeptidase, also called vasopeptidase inhibitors, we compared the effects of S21402 [(2S)-2-[(2S,3R)-2-thiomethyl-3-phenylbutanamido]propionic acid], which belongs to this pharmacologic class, with those of captopril, an ACE inhibitor, on blood pressure, endocrine parameters, and renal in healthy subjects with hypovolemia., Methods: Ten subjects participated to this double-blind, 2-period, randomized, crossover study. Hypovolemia was induced in these subjects with a 7-day treatment of hydrochlorothiazide. They received a single oral dose of 50 mg captopril or 250 mg S21402 on the last day of diuretic treatment. Blood pressure was measured, and urine and blood samples were collected before and during a 12-hour period after drug administration., Results: The plasma angiotensin II/angiotensin I ratio and aldosterone concentration decreased to the same degree with both drugs, 3 hours after dosing. Compared with captopril, S21402 increased levels of plasma atrial natriuretic peptide (P <.05) and urinary cyclic guanosine monophosphate (P <.001); these increases were the result of inhibition of neutral endopeptidase activity (P <.001). The increase in plasma renin concentration related to ACE inhibition was less marked (P <.001) after S21402 than after captopril. S21402, but not captopril, increased urinary sodium excretion (P <.05), without modifying blood pressure and creatinine clearance, whereas blood pressure transiently fell after captopril administration (P <.05)., Conclusions: In healthy hypovolemic subjects, the vasopeptidase inhibitor S21402 exhibits a natriuretic effect and does not affect blood pressure or glomerular filtration rate. In these conditions, the acute endocrine, vascular, and renal effects of vasopeptidase inhibition differ from those of ACE inhibition.
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- 2002
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327. Effect of interferon alpha-ribavirin bitherapy on cytochrome P450 1A2 and 2D6 and N-acetyltransferase-2 activities in patients with chronic active hepatitis C.
- Author
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Becquemont L, Chazouilleres O, Serfaty L, Poirier JM, Broly F, Jaillon P, Poupon R, and Funck-Brentano C
- Subjects
- Acute Disease, Adult, Aged, Antimetabolites therapeutic use, Antiviral Agents therapeutic use, Drug Therapy, Combination, Female, Humans, Interferon-alpha therapeutic use, Male, Middle Aged, Ribavirin therapeutic use, Treatment Outcome, Acyltransferases metabolism, Antimetabolites pharmacology, Antiviral Agents pharmacology, Cytochrome P-450 CYP1A2 metabolism, Cytochrome P-450 CYP2D6 metabolism, Hepatitis C, Chronic drug therapy, Hepatitis C, Chronic enzymology, Interferon-alpha pharmacology, Ribavirin pharmacology
- Abstract
Background: Interferon alpha (IFN-alpha) is thought to be responsible for cytochrome P450 (CYP)-dependent drug interactions mediated by a decrease in CYP activities., Objectives: The objectives are to determine whether IFN-alpha and ribavirin can alter pretreatment CYP1A2, CYP2D6, CYP3A4 and N-acetyltransferase-2 activities after 1 month of treatment., Methods: Enzymatic activities were determined among 14 patients with chronic active hepatitis C before IFN-alpha (3. 10(6) U, 3 times a week) and ribavirin introduction and after 1 month of treatment. During both study periods, subjects received 80 mg dextromethorphan and 140 mg caffeine (1,3,7-trimethylxanthine [137X]). CYP3A4, CYP2D6, and NAT2 activities were assessed by use of urinary metabolic ratios of 3-methoxymorphinan/dextromethorphan, dextrorphan/dextromethorphan, and 5-acetylamino-6-formylamino-3-methyluracil (AFMU)/1-methylxanthine(1X). The plasma paraxanthine/caffeine ratio was used to measure CYP1A2 activity., Results: CYP3A4 and CYP2D6 activities tended to increase after 1 month of antiviral therapy, but the change did not reach statistical significance. CYP1A2 and NAT2 activities were not significantly modified after 1 month of antiviral treatment. Pretreatment activities were significantly lower than those previously observed in healthy volunteers for CYP2D6 (mean +/- SD, 148 +/- 139 versus 759 +/- 692; P =.0008) and CYP3A4 (0.18 +/- 0.06 versus 0.52 +/- 0.72; P =.0006). This difference was no longer statistically significant after 1 month of treatment, because CYP2D6 and CYP3A4 activities improved in 7 patients., Conclusion: In patients with chronic hepatitis C, pretreatment CYP3A4 and CYP2D6 activities were significantly lower than those observed in healthy volunteers. These differences disappeared after 1 month of antiviral treatment because of the restoration of these CYP activities in about half of the patients.
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- 2002
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328. The role of the critical event committee in a major cardiovascular outcome study.
- Author
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Heagerty A, Deverly A, Palmer C, Kaplinsky E, Salvetti A, Wahlgren NG, and Funck-Brentano C
- Subjects
- Calcium Channel Blockers therapeutic use, Cardiovascular Diseases complications, Cardiovascular Diseases mortality, Humans, Hypertension drug therapy, Nifedipine therapeutic use, Research Design, Treatment Outcome, Cardiovascular Diseases therapy, Clinical Trials as Topic, Sentinel Surveillance
- Abstract
Outcome studies in cardiovascular diseases such as hypertension are often based in a number of countries recruiting from multiple centres. This can lead to difficulties in end-point evaluation and classification. The INSIGHT study provided the unique opportunity to examine the role and usefulness of a Critical Event Committee (CEC) established to examine all events occurring in a cohort of 6321 patients and classifying them according to pre-determined criteria. More than 28% of investigator-coded primary events and more than 41% of secondary events were re-classified by the CEC. Particularly difficult diagnoses included myocardial infarction, angina and heart failure, and the database finally analysed was substantially altered after CEC Committee evaluation. Post hoc analysis of the INSIGHT database demonstrated that the primary events compared would have been reduced from 6.3% vs 5.8% of those randomized on nifedipine vs co-amilozide to 5.1% vs 4.7%--an overall reduction of 72 events of 382, a fall of 18.8%. We conclude that a CEC should be a crucial component of any large outcome study and that if all events are subjected to scrutiny, the quality of the database is greatly enhanced.
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- 2002
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329. Predictors of medical events and of their competitive interactions in the Cardiac Insufficiency Bisoprolol Study 2 (CIBIS-2).
- Author
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Funck-Brentano C, Lancar R, Hansen S, Hohnloser SH, and Vanoli E
- Subjects
- Aged, Drug Administration Schedule, Female, Follow-Up Studies, Heart Failure mortality, Humans, Male, Middle Aged, Multivariate Analysis, Patient Compliance, Prognosis, Proportional Hazards Models, Randomized Controlled Trials as Topic, Risk Assessment, Survival Rate, Treatment Outcome, Adrenergic beta-Antagonists administration & dosage, Bisoprolol administration & dosage, Heart Failure drug therapy, Hospitalization statistics & numerical data
- Abstract
Aims: Predictive factors for medical events and interactions between events were not reported in the Cardiac Insufficiency Bisoprolol Study 2 (CIBIS-2). We examined the interactions among death, permanent treatment withdrawals, nonlethal cardiovascular hospitalizations and their own occurrence in a given patient, the treatment received, and baseline variables during CIBIS-2., Methods and Results: A Cox model for censored data was used to analyze the relations among baseline variables, medical events, and their interactions with treatment. We used competitive risk analysis to examine the interactions between successive events in a given patient during follow-up. No baseline variable predicted the reduction of mortality with bisoprolol. Withdrawal from bisoprolol therapy was more frequent in patients whose baseline heart rate was in the lower tertile of the distribution (P =.0002) but otherwise was not different between patients randomized to bisoprolol and to placebo. Event history analysis revealed that bisoprolol reduced mortality (P =.0006) and hospitalizations for nonlethal cardiovascular events (P =.003) in patients in whom treatment was not permanently withdrawn. Analysis of survival curves in patients who permanently discontinued treatment showed that bisoprolol did not reduce mortality compared with placebo in this population (relative risk 1.03, 95% CI 0.67-1.59; P =.88). Recurrent nonlethal events were reduced by bisoprolol., Conclusion: In CIBIS-2, medical events were significantly influenced by treatment withdrawal. Patients who derive benefit from bisoprolol therapy are those in whom treatment is not permanently withdrawn.
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- 2001
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330. Variability of cytochrome P450 1A2 activity over time in young and elderly healthy volunteers.
- Author
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Simon T, Becquemont L, Hamon B, Nouyrigat E, Chodjania Y, Poirier JM, Funck-Brentano C, and Jaillon P
- Subjects
- Adult, Age Factors, Aged, Caffeine pharmacokinetics, Central Nervous System Stimulants pharmacokinetics, Cytochrome P-450 CYP1A2 blood, Female, Humans, Male, Theophylline pharmacokinetics, Time Factors, Caffeine blood, Central Nervous System Stimulants blood, Cytochrome P-450 CYP1A2 metabolism, Theophylline blood
- Abstract
Aims: To assess the age-associated changes over time of plasma paraxanthine/caffeine (PAX/CAF) ratios used as a probe for CYP1A2 activity., Methods: Intraindividual and interindividual variabilities in PAX/CAF ratio were compared by phenotyping with caffeine, 16 young and 16 elderly healthy subjects on five occasions., Results: PAX/CAF ratio variability was comparable regardless of age (intraindividual CV: 17.6 +/- 6% and 16.2 +/- 5.9%, interindividual CV: 48.1 +/- 2.9% and 42.7 +/- 3.6% in young and elderly, respectively). The PAX/CAF ratio was lower in elderly than in young subjects (95% CI for the difference: 0.004, 0.32) but the difference was not significant in nonsmokers compared separately., Conclusions: The variability over time of the PAX/CAF ratio is not influenced by age.
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- 2001
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331. Effect of grapefruit juice on digoxin pharmacokinetics in humans.
- Author
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Becquemont L, Verstuyft C, Kerb R, Brinkmann U, Lebot M, Jaillon P, and Funck-Brentano C
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 1 genetics, ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism, Area Under Curve, Cross-Over Studies, Genotype, Humans, Polymorphism, Genetic, Beverages, Citrus, Digoxin pharmacokinetics, Food-Drug Interactions
- Abstract
Objectives: Grapefruit juice is responsible for drug interactions mediated by intestinal cytochrome P4503A4 inhibition and possibly P-glycoprotein inhibition in enterocytes. Our main objective was to determine whether grapefruit juice alters the bioavailability of digoxin, a P-glycoprotein substrate. The secondary objective was to determine whether the magnitude of the pharmacokinetic interaction was influenced by P-glycoprotein genetic polymorphism., Methods: Twelve healthy volunteers participated in this open randomized crossover study comparing the effect of grapefruit juice consumption (versus water) on the pharmacokinetics of a single oral dose of digoxin (0.5 mg). The P-glycoprotein genotype was determined according to MDR1 genetic polymorphism in exon 26 (C3435T)., Results: Grapefruit juice had no significant effect on the maximum plasma drug concentration (C(max)) of digoxin or the area under the plasma concentration-time curve (AUC) from time zero to 48 hours. However, there was a 9% increase in the digoxin AUC from time zero to 4 hours and from time zero to 24 hours (P =.01) during grapefruit juice administration. The digoxin renal clearance remained unchanged during both periods. No relationship between MDR1 C3435T genotype and early digoxin pharmacokinetic changes could be detected., Conclusion: The modest changes in digoxin pharmacokinetics observed during grapefruit juice ingestion do not support an important P-glycoprotein inhibition. Under our experimental conditions, grapefruit juice-mediated P-glycoprotein inhibition does not appear to play a relevant role in drug interactions, at least when assessed by use of digoxin disposition kinetics.
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- 2001
332. Comparison of sympathetic modulation induced by single oral doses of mibefradil, amlodipine, and nifedipine in healthy volunteers.
- Author
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Ragueneau I, Sao AB, Démolis JL, Darné B, Funck-Brentano C, and Jaillon P
- Subjects
- Administration, Oral, Adult, Aldosterone blood, Cross-Over Studies, Double-Blind Method, Electrocardiography drug effects, Epinephrine blood, Humans, Male, Amlodipine pharmacology, Calcium Channel Blockers pharmacology, Hemodynamics drug effects, Mibefradil pharmacology, Nifedipine pharmacology, Sympathetic Nervous System drug effects
- Abstract
Objective: Our objective was to compare the sympathetic modulation induced by oral administration of a single dose of 20 mg of standard nifedipine, of 10 mg of amlodipine, and of 100 mg of mibefradil., Methods: Sixteen healthy male volunteers participated in this double-blind, randomized, placebo-controlled, crossover four-period study. The sympathetic modulation induced by treatments was evaluated during 24 hours after drug administration by neurohormonal dosages, hemodynamic parameter measurements, and spectral analysis of heart rate and blood pressure., Results: We observed a significant (P <.05) decrease in diastolic blood pressure 1 hour after the administration of nifedipine (62 +/- 9 to 59 +/- 5 mm Hg) with concomitant increases in heart rate (59 +/- 5 to 74 +/- 8 bpm) and neurohormones (53 +/- 18 to 83 +/- 50 pg/mL for aldosterone, 157 +/- 56 to 282 +/- 119 pg/mL for norepinephrine, and 9.8 +/- 5.5 to 40.2 +/- 97.1 pg/mL for active renin). No significant modification of these parameters was observed with amlodipine and mibefradil, except an isolated increase of norepinephrine plasma level 2 hours after the administration of mibefradil (133.1 +/- 67.1 to 210.9 +/- 92.5 pg/mL). The spectral analysis over 24 hours of Mayer waves of systolic blood pressure did not show any significant change over time in the different groups. When the analysis was performed during the first 4 hours after treatment administration, we observed a decrease of Mayer waves of systolic blood pressure with nifedipine (2.21 +/- 1.45 mm Hg(2) versus 3.53 +/- 1.85 mm Hg(2) with placebo). These results indicate that oral single doses of mibefradil and amlodipine do not induce baroreflex-mediated clinical changes in healthy volunteers. The single oral dose of nifedipine resulted in a marked increase in sympathetic tone and a decrease in systolic blood pressure variability early after oral administration., Conclusion: Mibefradil, the nondihydropyridine calcium antagonist, exerts much less sympathetic stimulation than nifedipine.
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- 2001
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333. Sex differences in the prognosis of congestive heart failure: results from the Cardiac Insufficiency Bisoprolol Study (CIBIS II).
- Author
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Simon T, Mary-Krause M, Funck-Brentano C, and Jaillon P
- Subjects
- Aged, Female, Heart Failure mortality, Heart Failure physiopathology, Humans, Male, Middle Aged, Multivariate Analysis, Prognosis, Sex Factors, Survival Analysis, Adrenergic beta-Antagonists therapeutic use, Antihypertensive Agents therapeutic use, Bisoprolol therapeutic use, Heart Failure drug therapy
- Abstract
Background: Whether female sex is associated with a better prognosis in patients with congestive heart failure (CHF) remains uncertain. The Cardiac Insufficiency Bisoprolol Study (CIBIS) II showed that bisoprolol reduced all-cause mortality and morbidity rates in CHF patients treated with diuretics and ACE inhibitors. We examined whether survival was different in men (n=2132) and women (n=515) enrolled in CIBIS II., Methods and Results: Women differed from men with regard to age, NYHA functional classification, primary cause of CHF, and risk factors such as left bundle-branch block. After adjustment for baseline differences, the probability of all-cause mortality was significantly reduced by 36% in women compared with that in men (hazard ratio 0.64, 95% CI 0.47 to 0.86, P:=0.003). Women also had a 39% reduction in cardiovascular deaths (hazard ratio 0.64, 95% CI 0.45 to 0.91, P:=0.01) and a 70% reduction in deaths from pump failure (hazard ratio 0.30, 95% CI 0.13 to 0.70, P:=0.005) compared with men. Kaplan-Meier survival analysis revealed a significant reduction in all-cause mortality among women treated with bisoprolol compared with men (6% versus 12% P:=0.01) but not among women treated with placebo (13% versus 18%, P:=0.10). However, this sex/ss-blocker effect was not significant in multivariate analysis., Conclusions: These results indicate that regardless of ss-blocker treatment and baseline clinical profile, female sex is a significant independent predictor of survival in patients with CHF.
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- 2001
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334. Is diclofenac a valuable CYP2C9 probe in humans?
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Morin S, Loriot MA, Poirier JM, Tenneze L, Beaune PH, Funck-Brentano C, Jaillon P, and Becquemont L
- Subjects
- Adult, Alleles, Area Under Curve, Cytochrome P-450 CYP2C9, Cytochrome P-450 Enzyme System metabolism, Female, Genotype, Humans, Male, Middle Aged, Steroid Hydroxylases metabolism, Tablets, Enteric-Coated, Anti-Inflammatory Agents, Non-Steroidal pharmacokinetics, Aryl Hydrocarbon Hydroxylases, Cytochrome P-450 Enzyme System genetics, Diclofenac pharmacokinetics, Steroid 16-alpha-Hydroxylase, Steroid Hydroxylases genetics
- Abstract
Introduction: Besides the low therapeutic index drug tolbutamide, there is no validated in vivo probe to assess the genetically determined CYP2C9 activity in humans. The in vitro CYP2C9-specific substrate diclofenac might be a valuable, well-tolerated probe candidate. In order to validate diclofenac as an in vivo CYP2C9 probe, we planned to show that urinary 4'-hydroxydiclofenac/diclofenac metabolic ratio (MR) would correlate to the apparent partial metabolic clearance of diclofenac into 4'-hydroxydiclofenac (Clmet)., Patients and Methods: Eighteen healthy volunteers received a single oral dose of 50 mg diclofenac in its enteric-coated form. Blood and urinary pharmacokinetics of diclofenac were studied over 48 h. Identification of the CYP2C9 alleles (CYP2C9*1, CYP2C9*2, and CYP2C9*3) was performed with genomic DNA sequencing., Results: We observed a dramatic inter-individual variability in the delay of diclofenac intestinal absorption since its first detectable blood concentration ranged from 0.5 h to more than 12 h after drug intake. The Clmet of diclofenac could not be determined in two subjects who started to absorb the drug after 12 h. No correlation could be observed between Clmet of diclofenac and the different MRs calculated at 0-4 h, 0-8 h, 0-12 h, 0-24 h and 0-48 h urinary collections. The Clmet of diclofenac in heterozygous subjects tended to be lower than among wild-type homozygous subjects, but this difference did not reach statistical significance due to an insufficient number of subjects studied., Conclusion: Diclofenac, in its enteric-coated form, is not a useful in vivo CYP2C9 probe probably because of its highly variable intestinal absorption rate. However, since we found a lower metabolic clearance of diclofenac in heterozygous CYP2C9 subjects, as observed with other CYP2C9 substrates, diclofenac, in another galenic form, might be a potential probe to quantify CYP2C9 activity in humans.
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- 2001
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335. Effect of a single oral dose of moxifloxacin (400 mg and 800 mg) on ventricular repolarization in healthy subjects.
- Author
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Démolis JL, Kubitza D, Tennezé L, and Funck-Brentano C
- Subjects
- Administration, Oral, Adult, Anti-Infective Agents blood, Anti-Infective Agents pharmacokinetics, Cross-Over Studies, Dose-Response Relationship, Drug, Double-Blind Method, Electrocardiography drug effects, Exercise Test drug effects, Female, Heart Conduction System drug effects, Heart Conduction System physiology, Humans, Infusions, Intravenous, Male, Moxifloxacin, Placebos, Ventricular Function physiology, Anti-Infective Agents adverse effects, Aza Compounds, Fluoroquinolones, Quinolines, Ventricular Function drug effects
- Abstract
Background: Moxifloxacin is a new fluoroquinolone. In vitro studies have suggested that it could prolong ventricular repolarization. The main objective of this study was to measure the actual effect of single oral doses of moxifloxacin on QT interval duration in healthy volunteers., Methods: Nine men and 9 women participated in a double-blind, randomized, placebo-controlled, crossover study. Each participant received single oral doses (400 mg and 800 mg) of moxifloxacin or placebo. At the time of expected moxifloxacin maximum concentration, several electrocardiographic recordings were obtained at rest and during the course of a submaximal exercise test. QT interval and the corresponding RR interval value were measured within a wide range of RR intervals in each subject., Results: ANOVA showed that both moxifloxacin doses increased mean QT intervals compared with placebo. The mean QT interval duration at RR = 1000 ms was 379 +/- 24 ms during placebo, 394 +/- 33 ms during moxifloxacin 400 mg (P < .05), and 396 +/- 28 ms during moxifloxacin 800 mg (P < .05). Moxifloxacin-induced QT interval prolongation remained significant at all tested heart rates. The increase in QT interval duration relative to placebo remained between 2.3% +/- 2.8% and 4.5% + 3.8% across the range of RR intervals tested., Conclusion: Moxifloxacin prolongs QT interval duration. The amplitude of this effect is small, and the risk of moxifloxacin-induced torsades de pointes is expected to be minimal when the drug is administered at the recommended dose of 400 mg/d. However, moxifloxacin should not be used in patients with predisposing factors of torsades de pointes such as electrolyte disturbances and bradycardia or during coadministration of proarrhythmic drugs.
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- 2000
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336. Lymphocyte P-glycoprotein expression and activity before and after rifampicin in man.
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Becquemont L, Camus M, Eschwege V, Barbu V, Rey E, Funck-Brentano C, and Jaillon P
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 1 genetics, ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism, Adult, Female, Gene Expression drug effects, Genetic Variation, Humans, Lymphocytes metabolism, Male, RNA, Messenger biosynthesis, RNA, Messenger drug effects, ATP Binding Cassette Transporter, Subfamily B, Member 1 biosynthesis, Antibiotics, Antitubercular pharmacology, Lymphocytes drug effects, Rifampin pharmacology
- Abstract
It has recently been shown that P-glycoprotein (P-gp) is inducible by rifampicin in the human gut as shown in intestinal biopsies. The present study was performed in order to test the hypothesis that human peripheral lymphocytes can be used to assess such an inducibility. We also assessed inter- and intra-individual variability of P-gp expression and activity in peripheral lymphocytes. Blood samples from 13 healthy volunteers were collected 1.7, 14 and 19 days after inclusion. Rifampicin treatment (600 mg/day) was administered from day 15 to day 18. Lymphocyte P-gp expression was measured at the messenger RNA level by semi-quantitative RT-PCR and at the protein level by immunostaining flow cytometry. P-gp activity was determined by flow cytometry with rhodamine 123 efflux. Cytochrome P4503A4 (CYP3A4) inducibility was measured by comparing the urinary metabolic ratio of 6beta-hydroxycortisol/cortisol on day 14 and 19, Lymphocyte P-gp expression and activity was not induced by rifampicin, while it increased CYP3A4 activity from 5.0 +/- 4.0 to 22.9 +/- 16.6 (P < 0.001). There was a 3 - 4-fold inter-individual variability and a 3 - 44 % intra-individual variability of lymphocyte P-gp expression and activity. Peripheral lymphocytes are not an appropriate material to assess P-gp inducibility in humans. P-gp shows significant inter- and intra-individual variability in human lymphocytes.
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- 2000
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337. Combined glutathione-S-transferase M1 and T1 genetic polymorphism and tacrine hepatotoxicity.
- Author
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Simon T, Becquemont L, Mary-Krause M, de Waziers I, Beaune P, Funck-Brentano C, and Jaillon P
- Subjects
- Aged, Alleles, Female, Genetic Predisposition to Disease, Genotype, Glutathione Transferase drug effects, Humans, Isoenzymes drug effects, Isoenzymes genetics, Liver enzymology, Liver Function Tests, Male, Pharmacogenetics, Polymorphism, Genetic, Proportional Hazards Models, Alzheimer Disease drug therapy, Glutathione Transferase genetics, Liver drug effects, Parasympathomimetics adverse effects, Tacrine adverse effects
- Abstract
Background: Glutathione conjugation of tacrine reactive metabolites depends in part on the activity of glutathione-S-transferases (GST), of which two isozymes (GST M1 and GST T1) are polymorphically expressed., Objective and Methods: To determine whether GST M1, GST T1, and the combined GST M1 and GST T1 null genotypes predict individual susceptibility to tacrine hepatotoxicity, 141 patients with mild to moderate Alzheimer's disease treated with tacrine were genotyped., Results: During the treatment period, 52 patients had elevated alanine aminotransferase (ALT) levels at least three times the upper limit of normal, whereas 89 patients had normal ALT values (< or = upper limit of normal). Both groups were comparable in demographic and clinical characteristics. Twenty-eight patients were found to be GST T1-negative (20%; with a 95% confidence interval [95% CI] from 13% to 27%), and 68 patients (48%; 95% CI from 40% to 57%) were GST M1-negative. The combined GST M1-T1 null genotype was observed in 18 patients (13%; 95% CI from 7% to 18%) of whom 13 had an elevated plasma ALT at least three times the upper limit of normal during the study period. Although the cumulative percentage of elevated plasma ALT tended to be higher in the GST M1 null genotype, neither GST M1 nor GST T1 alone could predict individual susceptibility to tacrine hepatotoxicity. Multivariate Cox hazards model showed that the association of the GST M1-T1 null genotype was an independent risk factor of hepatotoxicity., Conclusions: The presence of combined alleles M1 and T1 deficiencies in glutathione-S-transferase genes increases the susceptibility to tacrine hepatotoxicity.
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- 2000
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338. Steady-state versus non-steady-state QT-RR relationships in 24-hour Holter recordings.
- Author
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Lande G, Funck-Brentano C, Ghadanfar M, and Escande D
- Subjects
- Adolescent, Adult, Circadian Rhythm, Humans, Male, Electrocardiography, Ambulatory
- Abstract
The aim of the present study was to investigate the QT-RR interval relationship in ambulatory ECG recordings with special emphasis on the physiological circumstances under which the QT-RR intervals follow a linear relation. Continuous ECG recordings make it possible to automatically measure QT duration in individual subjects under various physiological circumstances. However, identification of QT prolongation in Holter recordings is hampered by the rate dependence of QT duration. Comparison of QT duration and QT interval rate dependence between different individuals implies that the nature of the QT-RR relationship is defined in ambulatory ECG. Holter recordings were performed in healthy volunteers at baseline and after administration of dofetilide, a Class III antiarrhythmic drug. After dofetilide, beat-to-beat automated QT measurements on Holter tapes were compared with manually measured QT intervals on standard ECGs matched by time. The QT-RR relationship was analyzed at baseline in individual and group data during three different periods: 24-hour, daytime, and nighttime. Data were collected under steady-state or non-steady-state conditions of cycle length and fitted with various correction formulae. Our study demonstrated an excellent agreement between manually and automated measurements. The classic Bazett correction formula did not fit the QT-RR data points in individual or group data. When heart beats were selected for a steady rhythm during the preceding minute, QT-RR intervals fit a linear relationship during the day and night periods, but not during the 24-hour period in both individual and group data. In contrast, in the absence of beat selection, data fit a more complex curvilinear relationship irrespective of the period. Our study provides the basis for comparison of QT interval durations and QT-RR relationships between individuals and between groups of subjects.
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- 2000
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339. Predictors of medical events in patients enrolled in the cardiac insufficiency bisoprolol study (CIBIS): a study of the interactions between beta-blocker therapy and occurrence of critical events using analysis of competitive risks.
- Author
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Funck-Brentano C, Lancar R, Le Heuzey JY, Lardoux H, Soubrié C, and Lechat P
- Subjects
- Aged, Female, Heart Failure physiopathology, Humans, Male, Middle Aged, Prognosis, Randomized Controlled Trials as Topic, Risk Assessment, Survival Analysis, Adrenergic beta-Antagonists therapeutic use, Bisoprolol therapeutic use, Heart Failure drug therapy, Heart Failure mortality
- Abstract
Background: The risk of occurrence of medical events in a clinical trial is competitive in nature; that is, in a given patient the risk of having a critical event depends on the amount of time elapsed since random assignment and on the previous events that may have occurred in the patient. The purpose of this study was to examine the relations between baseline variables, the interactions between treatment, bisoprolol, or placebo, and the occurrence of critical events during the CIBIS trial, a mortality and morbidity trial of beta-blockade in patients with heart failure., Methods and Results: A Cox model for censored data was used to analyze the relations between baseline variables, total deaths, permanent treatment withdrawals, nonlethal cardiovascular events, and their interactions with bisoprolol or placebo. We examined the influence of treatment on the occurrence of deaths, permanent treatment withdrawals, and nonlethal cardiovascular events by using the technique of event history analysis, which takes into account competitive risks between events. Compared with placebo, bisoprolol reduced mortality rates in patients with a left ventricular ejection fraction < or =20% (relative risk [RR] 0.49; 95% confidence interval [CI] 0.27 to 0.88; P =.02). In patients whose baseline heart rate was in the upper tertile of distribution, permanent treatment withdrawals were less frequent in patients randomly assigned to bisoprolol than in patients randomly assigned to placebo (RR 0.50; 95% CI 0.28 to 0.88; P =.02). Bisoprolol reduced the incidence of nonlethal cardiac events in patients in whom heart failure was present for at least 4 years (RR 0.44; 95% CI 0.27 to 0.71; P <.01). Event history analysis revealed that among patients who died under treatment after having at least 1 nonlethal cardiovascular event, 20 patients were treated with placebo but only 7 patients were treated with bisoprolol (RR 0.41; 95% CI 0.17 to 0.98; P <.05)., Conclusions: Some patients with heart failure derive more benefit from beta-blocker therapy than others. In the CIBIS trial, they are those patients with the lower left ventricular ejection fractions and those who have nonlethal cardiovascular events but in whom beta-blocker therapy is not permanently discontinued.
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- 2000
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340. [Survival analysis example based on an event history model from a clinical trial in cardiology].
- Author
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Lancar R and Funck-Brentano C
- Subjects
- Heart Diseases therapy, Humans, Proportional Hazards Models, Survival Analysis, Heart Diseases mortality, Models, Statistical
- Abstract
Background: The main purpose of this paper is to present a survival analysis example based on an event history model in a competitive risks framework. Our example is derived from a clinical trial designed for comparing survival of a beta-blocker therapy group and a placebo group., Methods: Competitive risks under study were non lethal cardiovascular events, permanent treatment withdrawals and deaths. The event history model was assumed to be semi-Markovian. The Cox proportional hazards model was used for modeling effects of treatments and regression variables on the transition rates., Results: After taking into account all covariables influencing survival, mortality in patients who had one non lethal cardiovascular event after randomization but remained treated was shown to be reduced in the beta-blocker therapy group (RR=0.41; CI 95%=[0.17-0.98], p=0.04)., Conclusions: Our analysis indicates that beta-blocker therapy should not necessarily be stopped in patients who experience a non lethal cardiovascular event under treatment. This finding requires confirmation in a separate setting.
- Published
- 1999
341. Assessment of CYP2D6 and CYP2C19 activity in vivo in humans: a cocktail study with dextromethorphan and chloroguanide alone and in combination.
- Author
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Tennezé L, Verstuyft C, Becquemont L, Poirier JM, Wilkinson GR, and Funck-Brentano C
- Subjects
- Administration, Oral, Adult, Antimalarials administration & dosage, Antimalarials blood, Antitussive Agents administration & dosage, Antitussive Agents blood, Antitussive Agents pharmacokinetics, Cytochrome P-450 CYP2C19, Dextromethorphan administration & dosage, Dextromethorphan blood, Humans, Male, Proguanil administration & dosage, Proguanil blood, Reference Values, Antimalarials pharmacokinetics, Aryl Hydrocarbon Hydroxylases, Cytochrome P-450 CYP2D6 metabolism, Cytochrome P-450 Enzyme System metabolism, Dextromethorphan pharmacokinetics, Mixed Function Oxygenases metabolism, Proguanil pharmacokinetics
- Abstract
Objectives: Dextromethorphan and chloroguanide (INN, proguanil) are used as prototypic phenotyping substrates of polymorphically expressed CYP2D6 and CYP2C19 in humans. We determined whether the dextromethorphan/dextrorphan and chloroguanide/cycloguanil metabolic ratios, obtained after administration of the parent drugs either alone or in combination, are equivalent., Methods: Thirty-six healthy male volunteers received single oral doses of 80 mg dextromethorphan and 200 mg chloroguanide during a three-period, randomized crossover study. Plasma and urine were collected to calculate metabolic ratios and analyze the disposition kinetics of the probe drugs., Results: All subjects were extensive metabolizers for both CYP2D6 and CYP2C19. Chloroguanide kinetics and urinary metabolic ratio were not altered after dextromethorphan administration. Dextromethorphan urinary metabolic ratio increased from -2.52 +/- 0.67 to -2.03 +/- 0.58 (P < .001) in the presence of chloroguanide. This was caused by an increase of dextromethorphan without a significant change of dextrorphan in both urine and plasma. Inhibition of CYP3A-dependent biotransformation of dextromethorphan to methoxymorphinan did not appear to be responsible for this change because the log(dextromethorphan/methoxymorphinan) urinary ratio, an index of CYP3A activity, did not significantly change during chloroguanide coadministration. The chloroguanide and dextromethorphan metabolic ratio determined from urine collection correlated with the corresponding metabolic ratio determined from plasma obtained 3 hours after oral administration., Conclusion: When CYP2D6 and CYP2C19 activity are assessed, dextromethorphan and chloroguanide cannot be associated in a cocktail because chloroguanide increases the dextromethorphan metabolic ratio. CYP2D6 and CYP2C19 activity can be determined from a blood sample drawn 3 hours after oral administration of dextromethorphan and chloroguanide, respectively.
- Published
- 1999
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342. Pharmacokinetic and pharmacodynamic drug interactions between digoxin and macrogol 4000, a laxative polymer, in healthy volunteers.
- Author
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Ragueneau I, Poirier JM, Radembino N, Sao AB, Funck-Brentano C, and Jaillon P
- Subjects
- Adult, Cardiotonic Agents blood, Cross-Over Studies, Digoxin blood, Double-Blind Method, Drug Interactions, Female, Humans, Male, Cardiotonic Agents pharmacokinetics, Cathartics pharmacology, Digoxin pharmacokinetics, Polyethylene Glycols pharmacology
- Abstract
Aims: The aim of this study was to examine the bioequivalence between a single oral dose of digoxin administered alone and with a coadministration of macrogol 4000 (a laxative polymer) in 18 healthy volunteers., Methods: This was an open, randomised, two-way cross-over study, with a single dose oral administration of 0.5 mg digoxin administered alone or in combination with macrogol 4000, 20 g day-1 during 8 days. Pharmacokinetics of digoxin, heart rate and PR ECG interval at rest were assessed., Results: Macrogol 4000 coadministration was associated with a 30% decrease of digoxin AUC and a 40% decrease in its Cmax (P<0.05). Digoxin tmax and t1/2,z were not significantly altered. Heart rate and PR interval did not differ during the two therapeutic sequences, digoxin alone and digoxin in combination., Conclusions: Macrogol 4000 coadministration interacts with single-dose digoxin pharmacokinetics. This is most likely due to a reduction of the intestinal absorption of digoxin. However, there was no consequence of this interaction on heart rate and AV conduction.
- Published
- 1999
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343. Cytochrome P-450 3A4 and 2C8 are involved in zopiclone metabolism.
- Author
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Becquemont L, Mouajjah S, Escaffre O, Beaune P, Funck-Brentano C, and Jaillon P
- Subjects
- Azabicyclo Compounds, Cytochrome P-450 CYP3A, Dealkylation, Humans, In Vitro Techniques, Indicators and Reagents, Kinetics, Oxidation-Reduction, Recombinant Proteins metabolism, Yeasts metabolism, Cytochrome P-450 Enzyme System metabolism, Hypnotics and Sedatives metabolism, Microsomes, Liver enzymology, Mixed Function Oxygenases metabolism, Piperazines metabolism
- Abstract
Zopiclone is a widely prescribed, nonbenzodiazepine hypnotic that is extensively metabolized by the liver in humans. The aim of the present study was to identify the human cytochrome P-450 (CYP) isoforms involved in zopiclone metabolism in vitro. Zopiclone metabolism was studied with different human liver microsomes and a panel of heterologously expressed human CYPs (CYP1A2, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, and 3A4). In human liver microsomes, zopiclone was metabolized into N-desmethyl-zopiclone (ND-Z) and N-oxide-zopiclone (NO-Z) with the following K(m) and V(m) of 78 +/- 5 and 84 +/- 19 microM, 45 +/- 1 and 54 +/- 5 pmol/min/mg for ND-Z and NO-Z generation, respectively. Ketoconazole (CYP3A inhibitor) inhibited approximately 40% of the generation of both metabolites, sulfaphenazole (CYP2C inhibitor) inhibited the formation of ND-Z, whereas alpha-naphtoflavone (CYP1A), quinidine (CYP2D6), and chlorzoxazone (CYP2E1) did not affect zopiclone metabolism. The generation of ND-Z and NO-Z were highly correlated to testosterone 6beta-hydroxylation (CYP3A activity, r = 0.95 and 0.92, respectively; p =.0001), and ND-Z was highly correlated to CYP2C8 activity (paclitaxel 6alpha-hydroxylase; r = 0.76, p =.004). Recombinant CYP2C8 had the highest enzymatic activity toward zopiclone metabolism into both its metabolites, followed by CYP2C9 and 3A4. CYP3A4 is the major enzyme involved in zopiclone metabolism in vitro, and CYP2C8 contributes significantly to ND-Z formation.
- Published
- 1999
344. [How can institutional structures make clinical research in France more operational?].
- Author
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Funck-Brentano C and Brouard R
- Subjects
- France, Goals, Internet, Research education, Research legislation & jurisprudence, Research Support as Topic, Research organization & administration
- Abstract
The laws regulating the practice of clinical research in France, in particular the law of 20 December 1988, the so-called Huriet's law, constitute a major advance for medical progress. However, their implementation by administrative offices generates practical difficulties which impair the development of applied research in human beings. Beyond the laws themselves, it appears that our institutions are unprepared to optimize the conduct of such research. This round table sought to list the existing problems and to propose constructive solutions or objectives to be reached to optimize clinical research in France, with a view to improving French participation in international collaborative programmes, notably European ones. Evaluation of projects and practices, financial support and accounting, and some aspects of existing laws have been identified as the major sources of our difficulties. Harmonization and clarification of our procedures as well as improvement of training should be our primary objectives to achieve a higher level of medical, scientific, financial and administrative quality in the conduct of clinical research. Creation of a referential Web site, designed and updated by a central public organization, is an imperative step towards reaching these objectives.
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- 1999
345. A study of the relative bioavailability of cysteamine hydrochloride, cysteamine bitartrate and phosphocysteamine in healthy adult male volunteers.
- Author
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Tennezé L, Daurat V, Tibi A, Chaumet-Riffaud P, and Funck-Brentano C
- Subjects
- Adult, Biological Availability, Cross-Over Studies, Cysteamine adverse effects, Double-Blind Method, Humans, Male, Vomiting chemically induced, Cystaphos pharmacokinetics, Cysteamine pharmacokinetics
- Abstract
Aims: Cysteamine, the only drug available for the treatment of cystinosis in paediatric patients, is available as the hydrochloride, the bitartrate and as sodium phosphocysteamine salts. It has been suggested that cysteamine bitartrate and phosphocysteamine are better tolerated and may have a better bioavailability than cysteamine hydrochloride. This has, however, never been demonstrated., Methods: We compared the pharmacokinetics and tolerance of these three formulations of cysteamine in 18 healthy adult male volunteers in a double-blind, latin-square, three-period, single oral dose cross-over relative bioavailability study., Results: No statistical difference was found between relative bioavailabilities, AUC (0, infinity) (geometric mean and s.d. in micromol l(-1) h: 169+/-51, 158+/-46, 173+/-49 with cysteamine hydrochloride, phosphocysteamine and cysteamine bitartrate respectively), Cmax (geometric mean and s.d. in micromol l(-1); 66+/-25.5, 59+/-12, 63+/-20) and tmax (median and range in h: 0.88 (0.25-2), 1.25 (0.25-2), 0.88 (0.25-2)) with each of the three forms of cysteamine tested. Bioequivalence statistics (90% confidence intervals) showed non equivalence of Cmax of cysteamine base as the only non equivalence of pharmacokinetics between the three formulations: 90% CI for Cmax relative ratios to cysteamine hydrochloride were [75.6-105.81 for phosphocysteamine and [74.2-124.2] for cysteamine bitartrate. The only significant adverse event was vomiting whose frequency was inversely correlated with body weight (Spearman's r=-0.76, P<0.001). The nature of the salt tested did not influence vomiting., Conclusions: While none of the three forms of cysteamine tested has a clear advantage over the others in terms of pharmacokinetics and tolerance profile, this should now however be addressed in patients treated for cystinosis during repeat administrations.
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- 1999
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346. Effects of cigarette smoking on short-term variability of blood pressure in smoking and non smoking healthy volunteers.
- Author
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Ragueneau I, Michaud P, Démolis JL, Moryusef A, Jaillon P, and Funck-Brentano C
- Subjects
- Adult, Heart Rate, Humans, Male, Nicotine blood, Smoking blood, Smoking Cessation, Blood Pressure, Smoking physiopathology
- Abstract
The present trial was planned to study the effects of smoking on short-term variability of blood pressure and on haemodynamic parameters after an overnight cessation and after one day of repeated smoking in healthy cigarette smoking volunteers, compared to a control group of non-smokers who were not asked to smoke. 40 healthy male volunteers, 20 smokers and 20 non-smokers, participated in an open study with two period of measurements over a single day (morning and afternoon). Blood pressure and heart rate were measured using standard and finger recordings over 6 min before and 10 min after smoking one cigarette (in smokers only). During the two periods, smokers were asked to smoke 4 cm of a cigarette containing 1 mg of nicotine in 2 min, and a blood sample was taken for a plasma nicotine assay. In the smoking group, smoking the first cigarette of the day caused a significant increase of systolic blood pressure (+7%), diastolic blood pressure (+10%) and heart rate (+25%). The blood pressure variability in the frequency range of the Mayer waves (66-129 mHz) was increased after an overnight cessation of smoking in the smoking group in comparison to the non-smokers, and decreased significantly after the first cigarette of the day (7.1 +/- 4.0 to 3.2 +/- 1.8 mmHg2; P < 0.01). The changes observed in the afternoon after continuous smoking were significantly less important (3.8 +/- 1.9 to 3.2 +/- 1.9 mmHg2; NS). In the non-smoking group, the different parameters remained stable between the different measurements. These results suggest that an overnight cessation of smoking in smoking subjects is associated with a increase in sympathetic activity to the vascular system in the morning, which is released by smoking the first cigarette. This effect of smoking is reduced in the afternoon after a continuous nicotinic impregnation.
- Published
- 1999
- Full Text
- View/download PDF
347. Mibefradil, a potent CYP3A inhibitor, does not alter pravastatin pharmacokinetics.
- Author
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Becquemont L, Funck-Brentano C, and Jaillon P
- Subjects
- Adult, Area Under Curve, Benzimidazoles blood, Benzimidazoles pharmacokinetics, Cytochrome P-450 CYP3A, Drug Interactions, Enzyme Inhibitors blood, Enzyme Inhibitors pharmacokinetics, Female, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors blood, Male, Mibefradil, Pravastatin blood, Tetrahydronaphthalenes blood, Tetrahydronaphthalenes pharmacokinetics, Vasodilator Agents blood, Vasodilator Agents pharmacokinetics, Aryl Hydrocarbon Hydroxylases, Benzimidazoles pharmacology, Cytochrome P-450 Enzyme Inhibitors, Enzyme Inhibitors pharmacology, Hydroxymethylglutaryl-CoA Reductase Inhibitors pharmacokinetics, Oxidoreductases, N-Demethylating antagonists & inhibitors, Pravastatin pharmacokinetics, Tetrahydronaphthalenes pharmacology, Vasodilator Agents pharmacology
- Abstract
Dramatic drug-drug interactions have been observed between several HMG-CoA reductase inhibitors and cytochrome P450 3A (CYP3A) inhibitors. The aim of the present study was to investigate the effects of mibefradil, a potent CYP3A inhibitor, on pravastatin pharmacokinetics. 12 healthy volunteers were included in this open-label one-period study. Pravastatin pharmacokinetics (following a single oral dose of 40 mg) was studied in the absence of mibefradil (day 1) and after repeated doses (100 mg/day) of mibefradil (day 8). Pravastatin pharmacokinetics after repeated doses of 40 mg/day was also studied in association with repeated doses (100 mg/day) of mibefradil (day 16). Pravastatin area under the plasma concentration vs. time curve (AUC0-infinity) and Cmax in the absence of mibefradil on day 1 (170 [117 to 395] ng h/mL and 91 [72 to 200] ng/mL respectively, geometric mean [95% confidence intervals]) were not significantly altered in the presence of mibefradil on day 8 (224 [174 to 381] ng h/mL and 124 [72 to 200] ng/mL) and on day 16 (200 [137 to 555] ng h/mL and 91 [74 to 184] ng/mL). Tmax of pravastatin in the absence of mibefradil (0.9 +/- 0.1 h, arithmetic mean +/- SD) was slightly delayed in the presence of mibefradil on day 8 and 16 (1.1 +/- 0.3 and 1.2 +/- 0.3 h respectively, p < 0.01 for both comparisons). The results of the present study confirm the lack of pharmacokinetic interactions between mibefradil and pravastatin and indicate that pravastatin may be safely prescribed in the presence of potent CYP3A inhibitors.
- Published
- 1999
- Full Text
- View/download PDF
348. Dynamic analysis of dofetilide-induced changes in ventricular repolarization.
- Author
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Lande G, Maison-Blanche P, Fayn J, Ghadanfar M, Coumel P, and Funck-Brentano C
- Subjects
- Administration, Oral, Adult, Anti-Arrhythmia Agents administration & dosage, Anti-Arrhythmia Agents pharmacokinetics, Electrocardiography drug effects, Humans, Male, Phenethylamines administration & dosage, Phenethylamines pharmacokinetics, Sulfonamides administration & dosage, Sulfonamides pharmacokinetics, Anti-Arrhythmia Agents pharmacology, Heart Conduction System drug effects, Heart Rate drug effects, Phenethylamines pharmacology, Potassium Channel Blockers, Sulfonamides pharmacology
- Abstract
Objective: To use dynamic electrocardiographic (ECG) techniques to study the influence of heart rate on dofetilide-induced QT prolongation among healthy volunteers., Background: The extent to which heart rate modulates QT prolongation induced by the new class III antiarrhythmic drug dofetilide is a matter of debate., Methods: Ten healthy volunteers underwent two 24-hour ECG recordings, one in the absence of dofetilide and the other after a single oral dose of 0.5 mg dofetilide. Two 4-hour periods were defined during the second recording: Dh, which corresponded to stable high concentration of the drug, and D1, which corresponded to low concentration of the drug. Corresponding baseline recording periods, Ch and C1, matched by time with Dh and D1 were selected from the control ECG recording in the absence of dofetilide. QT versus R-R relations were compared in the presence and absence of dofetilide. The QT versus R-R relation slope was used as an index of the rate dependence QT prolongation. Rate-independent changes in QT duration were also analyzed., Results: During Dh, dofetilide induced a mean 12% lengthening of ventricular repolarization. Dynamic ECG analysis showed that this prolongation increased as R-R cycles became longer, a phenomenon known as reverse rate dependence. However, QT prolongation persisted at the shortest (600 ms) R-R cycle length that could be analyzed. During D1, dynamic ECG analysis showed a persistent, although small, effect of dofetilide on both QT prolongation (3%) and reverse rate dependence of this effect., Conclusions: Dofetilide prolongs QT duration, and this class III effect is influenced by heart rate. Although dofetilide-induced QT prolongation decreases when the R-R cycle shortens, this reverse rate dependence is only partial because marked QT prolongation persists at an R-R cycle of 600 ms. The results of our study indicated that dynamic ECG techniques can be useful in detection of subtle, drug-induced changes in the duration of ventricular repolarization.
- Published
- 1998
- Full Text
- View/download PDF
349. Pharmacokinetic-pharmacodynamic modeling of the effects of ivabradine, a direct sinus node inhibitor, on heart rate in healthy volunteers.
- Author
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Ragueneau I, Laveille C, Jochemsen R, Resplandy G, Funck-Brentano C, and Jaillon P
- Subjects
- Adult, Benzazepines blood, Benzazepines pharmacokinetics, Cardiotonic Agents blood, Cardiotonic Agents pharmacokinetics, Dose-Response Relationship, Drug, Double-Blind Method, Exercise Test, Humans, Ivabradine, Male, Reference Values, Benzazepines pharmacology, Cardiotonic Agents pharmacology, Heart Rate drug effects
- Abstract
Objective: Ivabradine (S-16257) is a new bradycardic agent with a direct effect on the sinus node. Its N-dealkylated metabolite, S-18982, has shown a bradycardic activity in animals. The aim of this trial was to study the correlation between drug bradycardic activity and plasma levels of the parent compound and its metabolite in healthy volunteers., Methods: Eighteen healthy volunteers participated in three successive study periods: an oral double-blind period with two parallel groups of doses (10 or 20 mg, single and repeated); a 10 mg intravenous bolus open period; and a final control period. The effects of ivabradine on heart rate were studied at rest and during bicycle exercise tests (at 85% of maximum workload) during 24-hour postdosing, and ivabradine and S-18982 plasma levels were determined simultaneously., Results: The maximal reductions of exercise heart rate were 11% +/- 4% (10 mg) and 18% +/- 6% (20 mg) after single oral doses (p < 0.05) and 18% +/- 4% (10 mg) and 27% +/- 6% (20 mg) after repeated doses (p < 0.01). Maximum heart rate reduction after the intravenous bolus was 19% +/- 4%. After oral administrations an indirect relationship between the bradycardic effect and the plasma concentrations of the two compounds was found. A pharmacokinetic/pharmacodynamic population analysis done with the NONMEM computer program showed that S-18982 contributes in part to the overall activity of ivabradine: modeling suggested that the metabolite is responsible for the initial bradycardic effect, whereas the parent compound is responsible for the duration of action., Conclusion: This study shows that ivabradine exerts a dose-dependent bradycardic effect and that its N-dealkylated metabolite contributes to this bradycardic effect.
- Published
- 1998
- Full Text
- View/download PDF
350. Use of heterologously expressed human cytochrome P450 1A2 to predict tacrine-fluvoxamine drug interaction in man.
- Author
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Becquemont L, Le Bot MA, Riche C, Funck-Brentano C, Jaillon P, and Beaune P
- Subjects
- Antidepressive Agents, Second-Generation metabolism, Antidepressive Agents, Second-Generation pharmacology, Cytochrome P-450 CYP1A2 metabolism, Cytochrome P-450 CYP1A2 Inhibitors, Drug Interactions, Enzyme Inhibitors metabolism, Enzyme Inhibitors pharmacology, Fluvoxamine metabolism, Humans, Hydroxylation, Microsomes, Liver drug effects, Microsomes, Liver enzymology, Nootropic Agents metabolism, Nootropic Agents pharmacology, Recombinant Proteins genetics, Recombinant Proteins metabolism, Tacrine metabolism, Cytochrome P-450 CYP1A2 genetics, Fluvoxamine pharmacology, Tacrine pharmacology
- Abstract
The aim of the present study was to evaluate the use of recombinant human cytochrome P-450 1A2 (rH-CYP1A2) in studies performed in vitro in order to predict metabolic drug-drug interactions occurring in man. In vitro metabolism of tacrine (a CYP1A2 probe) in the presence and absence of fluvoxamine, a CYP1A2 inhibitor, was investigated in human liver mircrosomes and with different rH-CYP. Vmax, Km and Ki determined with human liver microsomes were compared with those observed using rH-CYP1A2, assuming that 1 mg of liver microsomes contains, on average, 69 pmol of CYP1A2. The extent of tacrine metabolism inhibition procured by fluvoxamine with rH-CYP1A2, was compared with previous results observed in man. The Vax and Km for 1-hydroxytacrine formation rates obtained with rH-CYP1A2 were in good agreement with those observed in human liver microsomes (175+/-9 versus 140+/-60 pmol/min/mg for Vmax and 14+/-2 versus 16+/-2 microM for Km, respectively. The Ki of fluvoxamine on 1-hydroxytacrine formation rate observed with rH-CYP1A2 was similar to that observed with human liver microsome (0.35+/-0.05 versus 0.20+/-0.20 microM, respectively). Using the Km, Vmax and Ki determined with rH-CYP1A2, we calculated that fluvoxamine produced an inhibition of 1-, 2- and 4-hydroxytacrine formation rate of 91, 87 and 88%, respectively, in the range of tacrine and fluvoxamine concentrations observed in man. These percentages of inhibition calculated in vitro were in agreement with the percentage of fluvoxamine-dependent decrease in tacrine apparent oral clearance previously observed in man (83+/-13%). We conclude that human CYP1A2 expressed in yeast is a powerful tool to predict and to quantify drug-drug interactions in man.
- Published
- 1998
- Full Text
- View/download PDF
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