RESUMO
OBJECTIVES: To describe the management of patients with atrial fibrillation (AF) and to study consistency with guidelines on management of AF. PATIENTS AND METHODS: Observational study on a random sample of cardiologists from a French national database. Each cardiologist had to recruit the first five patients meeting inclusion criteria (patients diagnosed with AF between January 2004 and one month before inclusion and accepting the collection of their medical data). RESULTS: Between December 2006 and January 2207, 1789 patients aged 71 on average have been recruited by 481 cardiologists. Fifty-one percent were diagnosed with paroxysmal, 15% with persistent and 33% with permanent AF. Restoration of sinus rhythm was preferred in forms considered as paroxysmal or persistent forms whereas control of the ventricular rate was more frequent in AF considered as permanent. Overall, therapeutic guidelines are applied in practice, despite a frequent use of amiodarone in patients with no associated heart disease. Prevention of thromboembolism was observed in 88% of the patients. CONCLUSIONS: FACTUEL is the biggest observational study on AF ever conducted in France. The therapeutic strategies used by the cardiologists are consistent with the objectives of preventing thromboembolism and controlling heart rhythm and/or rate. In most cases, the treatment used is consistent with the therapeutic guidelines.
Assuntos
Fibrilação Atrial/terapia , Fidelidade a Diretrizes , Padrões de Prática Médica , Idoso , Estudos Transversais , Feminino , França , Humanos , MasculinoRESUMO
AIMS: This study aimed at describing usual conditions of carvedilol use in heart failure (HF) patients. METHODS: KEOPS was a one-year, multi-centre, prospective pharmaco-epidemiological study in carvedilol treated HF patients recruited by private cardiologists. RESULTS: Two thousand nine patients (mean age: 68) with heart failure were included by 401 cardiologists. 64% of patients were in class II of NYHA and 27% in class III, 87% of patients presented stable heart failure for at least four weeks. Contraindication to beta blocking was observed in 24% of patients, mean left ventricular fraction of ejection was 39% and only 39% of patients had mean left ventricular fraction of ejection<35%. Co-medications included a diuretic agent, ACE inhibitor or ARB in 68% of cases. Eighty three percent of patients had a titration of carvedilol (median duration=1 20 days). Thirty percent reached the recommended maximal dose. The dose of carvedilol at the titration's visit for all the patients (patient in stop included) was on average 30.5 +/- 22.1 mg/day with a median on 25 [confidence interval: 23-27] During the year of follow-up, 10% of patients have stopped the treatment (3% of patients having reached the maximum recommended dose of carvedilol versus 13% for the others), for cardiovascular reasons in 50% of patients (aggravation of heart failure: 28%, symptomatic arterial hypotension: 9%, symptomatic bradycardia: 5%). Finally, symptomatology of patients has improved during the study (59% of patients in class mild to severe at inclusion, versus 36% at the end of the observation), especially for the 30% of patients followed at one year and having reached the maximum recommended dose of carvedilol. Only in univariate analysis, patients with an inclusion high weight (>85 kg) were likely less to reach recommended maximal dose (37.2 versus 8.7%, p-value<0.0001), the patients with systolic heart failure had more chance than the patients with diastolic heart failure to reach the recommended maximal dose (31 versus 17.4%, p-value=0.006), in the same way, the lack of auricular supported more the reach of recommended maximal dose (31.2 versus 24.1%, p-value=0.018) CONCLUSION: KEOPS study suggests an improvement of usual conditions of carvedilol compared to the last investigation but the persistence of prescription outside medical authorization and less dosage of this product compared with clinical studies.
Assuntos
Carbazóis/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Propanolaminas/uso terapêutico , Vasodilatadores/uso terapêutico , Idoso , Carvedilol , Feminino , França , Humanos , Masculino , Pessoa de Meia-Idade , Prática Privada/estatística & dados numéricos , Estudos Prospectivos , Sociedades MédicasRESUMO
The aim of this study was to determine the influence of amiodarone on the pharmacokinetics of simvastatin and pravastatin in humans. This was a prospective, crossover, randomized, open-label study performed in 12 healthy volunteers comparing the pharmacokinetics of a single oral dose of simvastatin (40 mg) or pravastatin (40 mg) taken alone and after 3 days of amiodarone (400 mg/day). Amiodarone increased simvastatin acid AUC (area under the plasma concentration-time curve)0-24 h, peak plasma concentration (Cmax), and t1/2 by 73% (P=0.02), 100% (P=0.02), and 48% (P=0.06), respectively, whereas it did not significantly alter pravastatin pharmacokinetics. Point estimates and 90% confidence intervals for simvastatin acid, simvastatin lactone, and pravastatin AUC0-24 h were 154% (109-216%), 155% (109-227%), and 86% (63-118%), respectively. If amiodarone and a statin have to be simultaneously prescribed, pravastatin should be preferred to simvastatin in order to avoid a drug interaction.
Assuntos
Amiodarona/farmacologia , Antiarrítmicos/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Pravastatina/farmacocinética , Sinvastatina/farmacocinética , Adulto , Área Sob a Curva , Biotransformação , Estudos Cross-Over , Interações Medicamentosas , Feminino , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado , Masculino , Transportadores de Ânions Orgânicos/biossíntese , Transportadores de Ânions Orgânicos/genética , Polimorfismo Genético/genética , Estudos Prospectivos , Distribuição TecidualRESUMO
A pharmacoepidemiological cross-sectional observational study was performed among a representative sample of French general practitioners and cardiologists. The aim of this study was to describe the prescription modalities of flecainide acetate, an Ic class antiarrhythmic, and how these modalities match the marketing authorization and the current summary of product characteristics. A total of 941 physicians participated in the study, 496 GPs and 445 cardiologists, and 1116 patients treated with flecainide for more than one month were included. On average, the patients were 68.7-years-old and 54% of them were women. Most of the initial flecainide prescriptions came from cardiologists (96%) and the check-up included an electrocardiogram (98%), a Holter monitoring (56%) and/or an echocardiography (71%). The preferred indication was supraventricular rhythm disorders (95%) and mostly atrial fibrillation (63%). A small proportion of coronary patients (7%) and of patient suffering from cardiac insufficiency (4%) was found. Flecainide was prescribed with a median posology of 150 mg per day, mostly as LP form (64%). Overall, the indications specified in the summary of product characteristics were respected in 90% of the cases, the contraindications in 91% of the cases and the patient follow-up was appropriate in 99% of the cases. In conclusion, the study showed that the prescription's conditions of flecainide in France complied with the summary of product characteristics data for most of the prescribing physicians with a respect of the indications, contraindications and management recommendations in 84% of the cases.
Assuntos
Antiarrítmicos/uso terapêutico , Cardiologia/estatística & dados numéricos , Medicina de Família e Comunidade/estatística & dados numéricos , Flecainida/uso terapêutico , Idoso , Fibrilação Atrial/tratamento farmacológico , Baixo Débito Cardíaco/tratamento farmacológico , Doença das Coronárias/tratamento farmacológico , Estudos Transversais , Prescrições de Medicamentos/estatística & dados numéricos , Uso de Medicamentos/estatística & dados numéricos , Ecocardiografia/estatística & dados numéricos , Eletrocardiografia/estatística & dados numéricos , Eletrocardiografia Ambulatorial/estatística & dados numéricos , Estudos Epidemiológicos , Feminino , França , Humanos , Masculino , Corpo Clínico Hospitalar/estatística & dados numéricos , Pessoa de Meia-Idade , Prática Privada/estatística & dados numéricos , Estudos Prospectivos , Taquicardia Supraventricular/tratamento farmacológicoRESUMO
UNLABELLED: Flecainide acetate instant release (LI) has been prescribed for years in the prevention of atrial fibrillation (AF) relapse after sinus rate conversion. A new controlled-release (LP) formulation of flecainide was recently introduced. The objectives of this observational study were to evaluate the benefit/risk ratio of LI or LP flecainide treatment for prevention of AF relapse. METHODS: EPIFLEC study was an open, prospective, observational study conducted by 151 cardiologists who had prescribed either flecainide LI (group 1) to 838 patients or flecainide LP (group 2) to 214 patients or flecainide LI before LP (group 3) to 242 patients. In these patients, AF was either paroxystic (35%) or persistant (65%). Concomitant pathologies were observed in 80% of these patients (mean age 68 years) with a high incidence (50%) of hypertension. The mean duration of treatment was 6.9 +/- 6.7 months in group 1 (LI), 6.2 +/- 3.1 months in group 2 (LP) and 12.7 +/- 5.4 months in group 3 (LI-LP). RESULTS: mean daily dosages of flecainide were similar among the 3 groups. Antithrombotic drugs were prescribed in 74% (group 1) to 83% (group 2) of the patients and another antiarrhythmic drug was associated to flecainide among 12 to 21% of the patients. AF relapse was observed in 171 patients in group 1 (LI), 38 patients in group 2 (LP) and 39 patients in group 3 (LI-LP). The incidence of AF relapse was compared in groups 1 and 2 at 10 months of follow-up and AF relapse probability was not significantly different between flecainide LI and LP :26 +/- 2% and 23 +/- 4% respectively (OR = 0.99, CI 95%:0.69-1.4; p = 0.96). A multivariate analysis showed that previous multiples episodes of AF, electrical shock rate conversion and history of flutter and hypertension were independent predictors of AF relapse. Among 11 deaths observed during follow-up, only 2 were cardiovascular. The most frequent non lethal cardiovascular adverse events were arrhythmias or cardiac conduction disorders and were limited to less than 5% of the patients. Only 5 supraventricular transient pro arrhythmias episodes were recorded. CONCLUSION: this pharmaco-epidemiological study in private practice confirms that flecainide is able to prevent AF relapse in 75% of patients at 10 months and that the tolerance of the treatment is acceptable in these patients.
Assuntos
Antiarrítmicos/uso terapêutico , Fibrilação Atrial/prevenção & controle , Flecainida/uso terapêutico , Idoso , Flutter Atrial/complicações , Preparações de Ação Retardada/uso terapêutico , Cardioversão Elétrica , Feminino , Humanos , Hipertensão/complicações , Masculino , Análise Multivariada , Estudos Prospectivos , Prevenção SecundáriaRESUMO
During these last years, several therapeutic strategies trials have been performed in atrial fibrillation: the goal was to compare the rhythm control strategy (restoration and maintenance of sinus rhythm) to the rate control strategy (slowing of heart rate in atrial fibrillation). The most important of these different trials is the AFFIRM study. The main conclusion of this trial is that rate control can be chosen in first intention and not only in case of failure of the rhythm control strategy. These results can not be applied to 2 categories of patients: on one hand patients with heart failure and on the other hand young patients without cardiopathy in whom the strategy of rhythm control and sinus rhythm maintenance, mainly by class I antiarrhythmic drugs, remains the better choice.
Assuntos
Antiarrítmicos/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/mortalidade , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Análise de SobrevidaRESUMO
The pharmacokinetics of immediate (IR) and modified release (MR) trimetazidine (TMZ) in dogs and pigs, have been compared under single dose conditions, then predicted at steady-state under conditions mimicking an actual human pharmacokinetic study. In both animal species, the MR tablet has demonstrated sustained release properties, as assessed by delayed time to peak and increased mean absorption times. Multiple dose simulations in dogs revealed a delayed time to peak (3.0 vs. 1.0 h), a decrease in peak plasma concentration (544 vs. 659 microg/L), an increase in trough concentrations (115 vs. 63 microg/L), a decrease in peak-trough fluctuation (141 vs. 193%), and an increase in plateau time (5.5 vs. 4.9 h). Qualitatively similar changes were simulated in pigs. These properties have then been verified in humans where a TMZ MR 35 mg b.i.d regimen did provide similar total exposure, increased plateau time (11 vs. 4 h), decreased peak-trough fluctuation (86 vs. 121%), a 31% increase in trough concentrations, and no increase in inter-individual variability as compared to a TMZ IR 20 mg t.i.d. regimen. Furthermore, the TMZ MR 35 mg b.i.d. regimen is likely to result in improved patient compliance and better patient anti-ischemic protection in the early morning.
Assuntos
Trimetazidina/administração & dosagem , Trimetazidina/farmacocinética , Administração Oral , Adulto , Animais , Química Farmacêutica , Estudos Cross-Over , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Cães , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Masculino , Especificidade da Espécie , SuínosRESUMO
Single nucleotide polymorphisms (SNPs) can significantly affect human phenotypes. Detection of allelic variant carriers has become a major goal for clinical pharmacologists in order to study phenotype-genotype relationships. However, there is a crucial need for rapid, and validated pharmacogenetic tests. The aim of the study was to validate a new fluorescence PCR strategy for cytochrome P450 2C9 (CYP2C9) and multidrug resistance gene (MDR1) genotyping. Results of CYP2C9 and MDR1 genotypes determined with reference techniques were compared to those obtained by allelic discrimination assays employing fluorescent TaqMan probes. Sixteen subjects carrying CYP2C9*2 and CYP2C9*3 allelic variants (heterozygous and homozygous) previously identified by sequencing and 55 subjects previously genotyped for MDR1 exon 26 (C3435T) SNP by conventional PCR-RFLP were genotyped with fluorescent PCR. Fluorescent PCR gave 100 % accuracy with the results obtained with reference genotyping strategies for each of the 3 SNPs. Genotyping results with fluorescent PCR repeated on three consecutive occasions remained constant over time for each of the 3 SNPs. Allelic discrimination assays based on fluorescent PCR gave entire satisfaction for CYP2C9 and MDR1 genotyping. This reliable genotyping strategy can be easily used in clinical practice and should be further developed for additional SNPs identification.
Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Genes MDR/genética , Genótipo , Hibridização in Situ Fluorescente/métodos , Reação em Cadeia da Polimerase/métodos , Polimorfismo de Nucleotídeo Único/genética , Alelos , Citocromo P-450 CYP2C9 , Análise Discriminante , Variação Genética/genética , Heterozigoto , Homozigoto , Humanos , Hibridização in Situ Fluorescente/normas , Fenótipo , Reação em Cadeia da Polimerase/normas , Polimorfismo de Fragmento de Restrição , Taq Polimerase , Fatores de TempoRESUMO
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.
Assuntos
Antagonistas Adrenérgicos beta/administração & dosagem , Bisoprolol/administração & dosagem , Insuficiência Cardíaca/tratamento farmacológico , Morte Súbita Cardíaca , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Análise de Sobrevida , Resultado do Tratamento , Recusa do Paciente ao TratamentoRESUMO
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.
Assuntos
Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Administração Oral , Idoso , Anticoagulantes/farmacocinética , Hidrocarboneto de Aril Hidroxilases/genética , Estudos de Casos e Controles , Citocromo P-450 CYP2C9 , Relação Dose-Resposta a Droga , Interações Medicamentosas , Overdose de Drogas , Feminino , Interações Alimento-Droga , Genótipo , Hemorragia/induzido quimicamente , Humanos , Pacientes Internados , Coeficiente Internacional Normatizado , Masculino , Mutação , Polimorfismo Genético , Estudos Prospectivos , Fatores de Risco , Vitamina K/administração & dosagemRESUMO
BACKGROUND: Intima-media thickness of the common carotid artery (IMT-CCA) is an early marker of atherosclerosis. Tamoxifen is a selective estrogen-receptor modulator with estrogen-like effects on cardiovascular risk factors but as-yet unexplored effects on carotid artery structure. The goal of this study was to determine the influence of tamoxifen on IMT-CCA in menopausal women. METHODS AND RESULTS: With a predefined calculation of the sample size, 67 menopausal women with cancer who were treated with tamoxifen for > or =1 year and 37 menopausal women with cancer who were never treated with tamoxifen were enrolled. IMT-CCA, internal diameter, and pulse pressure were determined with a high-definition echotracking device and applanation tonometry in a central core laboratory that was blinded to treatment. Both groups were similar for clinical characteristics, including cardiovascular risk factors. IMT and internal diameter were significantly lower in the tamoxifen group (mean duration of treatment, 2.4+/-0.9 years) than in the control group (609+/-117 microm versus 662+/-147 microm, P=0.04, and 4.89+/-0.60 mm versus 5.12+/-0.58 mm, P=0.03, respectively). Pulse pressure was not influenced by the use of tamoxifen. After adjustment for age, cardiovascular risk factors, carotid pulse pressure, duration of menopause, and previous use of hormone replacement therapy, IMT remained significantly lower among tamoxifen users (P<0.00001), with an impact on IMT (-70 microm) equivalent to spontaneous evolution with 12 years of aging (5 microm/y). CONCLUSION: The use of tamoxifen was associated with a significantly lower carotid IMT in menopausal women with cancer. Randomized trials are needed to confirm the cardioprotective effect of selective estrogen-receptor modulators in terms of prevention of atherosclerosis.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Artérias Carótidas/efeitos dos fármacos , Pós-Menopausa , Tamoxifeno/administração & dosagem , Túnica Íntima/efeitos dos fármacos , Túnica Média/efeitos dos fármacos , Antineoplásicos Hormonais/administração & dosagem , Artérias Carótidas/diagnóstico por imagem , Feminino , Humanos , Menopausa/efeitos dos fármacos , Pessoa de Meia-Idade , Fatores de Risco , Tamanho da Amostra , Moduladores Seletivos de Receptor Estrogênico/administração & dosagem , Túnica Íntima/diagnóstico por imagem , Túnica Média/diagnóstico por imagem , UltrassonografiaRESUMO
Fourteen years after the concept was created, it seemed important to assess how well investigators actually apply Good Clinical Practice. Various sources of information have revealed a general deficiency in their application: "investigation by the working group, Afssaps (French Agency for the Safety of Health-Care Products) inspections, industrial data". The deficiencies identified stem from different factors: lack of professionalization, lack of training, lack of motivation, the large numbers of poorly conducted studies. The working group drew up proposals intended to improve the training of investigators, to dissuade investigators from pursuing inadequate procedure and to verify the level of compliance. However in this respect, the investigator is not the only one at fault. Improved practice unavoidably requires better assistance on the part of the sponsors, more consistent supervision of monitoring, and greater vigilence by the authorities involved in the control and use of trials.
Assuntos
Ensaios Clínicos como Assunto/normas , Farmacologia Clínica/educação , Farmacologia Clínica/normas , França , Controle de QualidadeRESUMO
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.
Assuntos
Antiarrítmicos/farmacologia , Fibrilação Atrial/tratamento farmacológico , Propafenona/farmacologia , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Recidiva , Fatores Sexuais , Resultado do TratamentoRESUMO
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.
Assuntos
Cafeína/sangue , Estimulantes do Sistema Nervoso Central/sangue , Citocromo P-450 CYP1A2/metabolismo , Teofilina/sangue , Adulto , Fatores Etários , Idoso , Cafeína/farmacocinética , Estimulantes do Sistema Nervoso Central/farmacocinética , Citocromo P-450 CYP1A2/sangue , Feminino , Humanos , Masculino , Teofilina/farmacocinética , Fatores de TempoRESUMO
Cytochrome P450 2C9 (CYP2C9) is the enzyme that terminates the anticoagulant effect of warfarin. The heterozygous carriers of the two allelic variants CYP2C9*2 and CYP2C9*3 have been associated with impaired warfarin metabolism and a higher risk of haemorrhage. Only three CYP2C9 poor metabolizers (CYP2C9*3/CYP2C9*3) initiating warfarin treatment have so far been identified, all of them with a dramatic overdose occurring a few days after treatment initiation. Acenocoumarol, another coumarinic anticoagulant, has recently been shown to be metabolized by CYP2C9. We report, for the first time, two cases of dramatic overanticoagulation occurring in patients starting acenocoumarol treatment while taking recommended doses (4 mg/day). In both cases, the overdose was discovered at the first INR control with values above 9. Genotyping revealed that the two patients were homozygous for the CYP2C9*3 allele. Our report highlights the need for CYP2C9 genotyping before starting oral anticoagulants in order to prevent early overanticoagulation episodes.
Assuntos
Acenocumarol/efeitos adversos , Anticoagulantes/efeitos adversos , Hidrocarboneto de Aril Hidroxilases , Transtornos da Coagulação Sanguínea/enzimologia , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Esteroide 16-alfa-Hidroxilase , Esteroide Hidroxilases/genética , Esteroide Hidroxilases/metabolismo , Acenocumarol/uso terapêutico , Adolescente , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/uso terapêutico , Transtornos da Coagulação Sanguínea/induzido quimicamente , Transtornos da Coagulação Sanguínea/genética , Citocromo P-450 CYP2C9 , Feminino , Humanos , Coeficiente Internacional Normatizado , Mutação/efeitos dos fármacos , Mutação/genéticaRESUMO
Reference data on pathologies, their management, risk factors and the use of drugs in real life is necessary. In France, there are no existing databases of a set of systematically recorded data which associate information on drugs and morbidity/mortality. In contrast, there are a great number of studies focused on pathologies, their management or on drugs. A directory that could identify these databases and a means of accessing them would be desirable. Pharmaco-epidemiology studies must answer epidemiologically specific quality criteria, which must be planned at study conception. The protocol must be developed with a scientific committee on which there are epidemiologically experienced people. It is a prerequisite that a committee of experts with epidemiological competence should give advice on the 'acceptability' of the protocol, that is on the aim and the methodology. Data collection must be the subject of specific quality control of both the study and its aims. Cross-checking with other sources of data is recommended when possible. The coordinator of each study must send a final report to investigators and publish the results.
Assuntos
Bases de Dados Factuais , Avaliação de Medicamentos , Epidemiologia , Necessidades e Demandas de Serviços de Saúde , Farmacologia , Projetos de Pesquisa/normas , Protocolos Clínicos/normas , Avaliação de Medicamentos/métodos , Avaliação de Medicamentos/normas , Métodos Epidemiológicos , França , Humanos , Motivação , Garantia da Qualidade dos Cuidados de Saúde/métodos , Controle de Qualidade , Pesquisadores/psicologiaRESUMO
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.
Assuntos
Bebidas , Citrus , Digoxina/farmacocinética , Interações Alimento-Droga , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Área Sob a Curva , Estudos Cross-Over , Genótipo , Humanos , Polimorfismo GenéticoRESUMO
OBJECTIVE: Phase I clinical trials consist in studying tolerance to new drugs administered for the first time to humans, the pharmacodynamics of these drugs in order to describing as clearly as possible their pharmacological mechanism of action, and their pharmacokinetics in order to determine the metabolic and excretory pathways involved in the human organism. IMPLEMENTATION: Phase I trials are conducted in healthy volunteer men and women. An exception is made for drugs with predictable toxic effects, for example anti-cancer drugs, which cannot be tested in healthy subjects. These trials are controlled by legal regulations clearly defined in the French law of December 20, 1988. CONTRIBUTION: Data collected from Phase I trails in humans are crucial for initiating phase II and III drug development trials to be conducted in patients and designed to obtain a satisfactory assessment of the new drug's risk/benefit ratio.