A pharmacokinetic-pharmacodynamic model for predicting the impact of CYP2C9 and VKORC1 polymorphisms on fluindione and acenocoumarol during induction therapy.

BACKGROUND AND OBJECTIVE: Vitamin K epoxide reductase complex, subunit 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) polymorphisms are taken into account when predicting a safe oral dose of coumarin anticoagulant therapy, but little is known about the effects of genetic predictors on the response to fluindione and acenocoumarol. The aims of this study were to characterize the relationship between fluindione and acenocoumarol concentrations and the international normalized ratio (INR) response, and to identify genetic predictors that are important for dose individualization. METHODS: Fluindione concentrations, S- and R-acenocoumarol concentrations, the INR and genotype data from healthy subjects were used to develop a population pharmacokinetic-pharmacodynamic model in Monolix software. Twenty-four White healthy subjects were enrolled in the pharmacogenetic study. The study was an open-label, randomized, two-period cross-over study. The subjects received two doses of an oral anticoagulant: 20 mg of fluindione (period A) or 4 mg of acenocoumarol (period B). The pharmacokinetics and pharmacodynamics were studied from day 2 to day 3. RESULTS: A two-compartment model with a first-order input model was selected as the base model for the two drugs. The pharmacodynamic response was best described by an indirect action model with S-acenocoumarol concentrations and fluindione concentrations as the only exposure predictors of the INR response. Three covariates (CYP2C9 genotype, VKORC1 genotype and body weight) were identified as important predictors for the pharmacokinetic-pharmacodynamic model of S-acenocoumarol, and four covariates (CYP2C9 genotype, VKORC1 genotype, CYP1A2 phenotype and body weight) were identified as predictors for the pharmacokinetic-pharmacodynamic model of fluindione. Because some previous studies have shown a dose-response relationship between smoking exposure and the CYP1A2 phenotype, it was also noted that smokers have greater CYP1A2 activity. CONCLUSION: During initiation of therapy, CYP2C9 and VKORC1 genetic polymorphisms are important predictors of fluindione and acenocoumarol pharmacokinetic-pharmacodynamic responses. Our result suggests that it is important to take the CYP1A2 phenotype into account to improve individualization of fluindione therapy, in addition to genetic factors.

Association of menopause and hormone replacement therapy with large artery remodeling.

OBJECTIVE: To evaluate the remodeling of large arteries according to age at menopause, duration of menopause, and use of hormone therapy (HT). DESIGN: A cross-sectional study consisting of baseline measurements of a multicentric randomized trial were used to evaluate arterial parameters. SETTING: The study was conducted in France, Belgium, and the Netherlands in academic hospitals and private clinics. PATIENT(S): Postmenopausal women (n = 538) with mild hypercholesterolemia. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Common carotid artery intima-media thickness (CCA-IMT), central pulse pressure, and aortic stiffness (carotid-femoral pulse wave velocity) were measured and centrally controlled for quality. Multivariate regression analysis was used to assess the possible covariates associated with arterial parameters. RESULT(S): Women were 58 ± 6 (mean ± SD) years of age with an age of 50 ± 5 at menopause and a mean duration of menopause of 8 ± 7 years. Lower age at menopause, time since menopause, and absence of HT use were independently associated with worsening of the arterial parameters. After multivariate analysis, HT was associated with a lower CCA-IMT (-40 µm [range -64 to -1]), whereas lower age at menopause and menopause duration were respectively associated with a CCA-IMT increase (25 µm/5 y and 27 µm/5 y). Similarly, values of central pulse pressure and pulse wave velocity were lower in HT users (-3.1 mm Hg [-5.1 to -0.9] and -0.31 m/s [-0.63 to -0.02], respectively) but worsened with age at menopause and menopause duration. CONCLUSION(S): The age at menopause, the time since menopause, and the use of HT are independently associated with the thickening and stiffening of the large arteries. CLINICAL TRIAL REGISTRATION NUMBER: NCT00163163.

Impact of age and gender interaction on circulating endothelial progenitor cells in healthy subjects.

OBJECTIVE: To assess the level of circulating endothelial progenitor cells (CEPC) in cycling women compared with men and menopausal women. DESIGN: Controlled clinical study. SETTING: Healthy, nonsmoking volunteers. PATIENT(S): Twelve women, aged 18-40 years, with regular menstrual cycles, 12 menopausal women, and two groups of 12 age-matched men were recruited. Women did not receive any hormone therapy. INTERVENTION(S): Collection of 20 mL of peripheral blood. MAIN OUTCOME MEASURE(S): The number of CEPC, defined as (Lin-/7AAD-/CD34+/CD133+/KDR+) cells per 10(6) mononuclear cells (MNC), was measured by flow cytometry. RESULT(S): The number of CEPC was significantly higher in cycling women than in age-matched men and menopausal women (26.5 per 10(6) MNC vs. 10.5 per 10(6) MNC vs. 10 per 10(6) MNC, respectively). The number of CEPC was similar in menopausal women, age-matched, and young men. CONCLUSION(S): The number of CEPC is influenced by an age-gender interaction. This phenomenon may explain in part the better vascular repair and relative cardiovascular protection in younger women as compared with age-matched men.

Droperidol and ondansetron in vitro electrophysiological drug interaction study.

Droperidol and ondansetron are potent anti-emetic agents which are often administered together. Although both drugs prolong QT interval in man by inhibition of Human Ether-a-go-go Related Gene-coded potassium channels, only droperidol was tested using more integrated experimental models. Therefore, we studied the effects of both compounds and their combination on action potentials (AP) of rabbit Purkinje fibers using conventional intracellular glass microelectrode. Purkinje fibers, driven at 1 Hz, were exposed to increasing concentrations (from 0.001 to 10 microm) of droperidol (n = 7) or ondansetron (n = 8) at 30 min intervals at 36.5 degrees C. Other fibers were exposed to a constant droperidol concentration (0.1 microm) alone (n = 7) or together with the same increasing concentrations of ondansetron (n = 6). Droperidol increased AP duration measured at 90% repolarization (APD90) in a concentration-dependent manner from 4.4 +/- 0.8% (mean +/- SEM) after 1 nm to a maximum of 158 +/- 72% after 1 microm. Ondansetron significantly increased APD90 by 5.3 +/- 2.1% at 100 nm up to 76 +/- 14% after 10 microm. Early after-depolarization occurred in 6/7 fibers exposed to droperidol and 1/8 fibers exposed to ondansetron. When given together, pure additive effects were observed. The concentrations that increased APD90 by 50% were 0.25 +/- 0.25 microm droperidol, 3.8 +/- 2.4 microm ondansetron and 1.5 +/- 0.8 microm ondansetron when given together with droperidol. Both ondansetron and droperidol prolong AP duration in Purkinje fibers, droperidol being 10 times more potent than ondansetron. Combination of ondansetron and droperidol exhibits an additive effect on AP duration. However, within clinically relevant concentrations, ondansetron does not further increase the AP prolongation caused by droperidol alone.

Quantification of the HIV-integrase inhibitor raltegravir (MK-0518) in human plasma by high-performance liquid chromatography with fluorescence detection.

A simple and sensitive HLPC method with fluorescence detection was developed for the accurate determination of the first licensed HIV integrase inhibitor raltegravir in human plasma. A 500-microL plasma sample was spiked with delavirdine as internal standard and subjected to liquid-liquid extraction based on a previously described assay i.e. using hexane/methylene chloride (1:1, v/v%) at pH 4.0. HPLC was performed using a Symmetry Shield RP18 column (150 mm x 4.6 mm), a gradient elution of acetonitrile -0.01% (v/v) triethylamine in water adjusted to pH 3.0 at a flow rate of 1 mL/min and a fluorimetric detector set at 299 and 396 nm as excitation and emission wavelengths, respectively. The retention time was 5.0 min for internal standard and 6.4 min for raltegravir. Calibration curves were linear in the range 5-1000 ng/mL and the accuracy of quality control samples in the range 10-750 ng/mL varied from 98.3 to 99.1% and 98.3 to 101.0% of the nominal concentrations for intra-day and day-to-day analysis, respectively with a precision of 6.3% or less. Among the other antiretroviral drugs which can be given in association to HIV-infected patients, none was found to interfere with internal standard or raltegravir. The described assay was developed for the purpose of therapeutic drug of this HIV integrase inhibitor.

[Organisation of clinical research in France: the new missions of inter-regional delegations for clinical research]. / L'organisation de la recherche clinique en France: les nouvelles missions des délégations inter-régionales à la recherche clinique.

The organisation of clinical research in French teaching hospitals has been profoundly modified over the past 15 years. The first call for clinical research projects was made by the Ministry of Health in 1993. This Hospital Program for Clinical Research was created by the public welfare system, a situation unique in Europe and the USA at the time. Every year since 1993, new clinical research projects have been supported through this program. In 2007, more than 14 million euros was provided for clinical research in oncology more than 21 million euros for clinical research in other fields, and more than 11 million euros through interregional grants. Overall, more than 50 million euros will be provided in 2008 to support clinical research with public sponsorship in French teaching hospitals. Major organisational changes were made to support this unprecedented financial effort in favor of clinical research. In each of the 29 French teaching hospitals, a Delegation for Clinical Research (DRC) was created to promote public sponsorship of clinical trials, to monitor these trials, to guarantee that Good Clinical Practices are respected, and to control the financial aspects of research projects. Clinical Research Assistants were recruited by DRC to monitor clinical trials. Clinical Investigation Centers (CIC) were organized in conjunction with teaching hospitals and with the French biomedical research council (INSERM). Today, there are 54 CICs located in 23 teaching hospitals, conducting clinical trials and other research in epidemiology and biotechnology. In May 2005, seven interregional delegations for clinical research (DIRC) were created to coordinate these activities on a regional basis. The aim was to improve scientific collaboration between teaching hospitals in a given region, to organize the training of clinical investigators and technicians, and to support the development of clinical trial monitoring, quality assurance, and pharmacovigilance. A 2006 survey of clinical trials sponsored by the drug industry in France showed that, by comparison to 2004, the number of patients enrolled had fallen. The mean rate of enrolments per investigator was lower than the European average (1.4 patients per month versus 1.7 in Europe as a whole), and the time necessary to organize hospital-based clinical trials was excessive (140 days). Given the globalisation of clinical trials and the increasing competition among countries, these weaknesses could have had deleterious consequences for French investigators and patients. Thus, in 2007, a joint public-private working party created a public interest group called CENGEPS (Centre national de gestion des essais des produits de santé) to provide financial support for DIRC (10 million euros per year for 4 years), derived from a special tax on drugs industry revenue. The objectives were to promote the development of clinical trials of drugs with industrial sponsors in France, to help clinical investigators to participate in these trials, and to increase the patient accrual rate. After a call for projects from each DIRC, grants were distributed to regional offices charged with managing relations with drug companies. Funds were also provided for the recruitment of 150 clinical trial technicians responsible for speeding patient enrolment and for providing clinicians with logistic backup for patient follow-up. National networks of clinical investigators will be created to develop clinical trials in fields such as Alzheimer's disease, other mental illnesses, pediatric drugs, vaccines, AIDS, thromboembolism, etc. Thus, over the last 15 years, the organization of clinical research in France has been completely overhauled. The creation of DIRC will boost interregional cooperation among teaching hospitals and increase the number of clinical trials with both public and private sponsorship. Quality and efficiency will be improved by the increased professionalism of all those involved in clinical trials.

[GIP CeNGEPS, an agreement of clinical research operators to reinforce clinical trials' organisation in France]. / GIP CeNGEPS, un collectif des opérateurs de recherche clinique pour une organisation des essais cliniques industriels plus performante.

The "GIP CeNGEPS" (national center of industrial clinical trials' management), a new corporate body, relates the major French actors in clinical trials activity, belonging to public service or commercial sector. CeNGEPS is devoted to improving the French organisation of clinical trials with four headings: Economic with a strong common will of shaking up the organisation of clinical trials in France; Political with a decision taken to the highest level; Juridical with the choice of an unusual legal form to act; Methodological with the efforts to associate the most numerous operators (investigators; local managers...).

Modelling the influence of MDR1 polymorphism on digoxin pharmacokinetic parameters.

OBJECTIVES: Digoxin is a well-known probe for the activity of P-glycoprotein. The objective of this work was to apply different methods for covariate selection in non-linear mixed-effect models to study the relationship between the pharmacokinetic parameters of digoxin and the genotype for two major exons located on the multi-drug-resistance 1 (MDR1) gene coding for P-glycoprotein. METHODS: Thirty-two healthy volunteers were recruited in three pharmacokinetic drug interaction studies. The data after a single oral administration of digoxin alone were pooled. All subjects were genotyped for the MDR1 C3435T and G2677T/A genotypes. The concentration-time profile of digoxin was established using 12-16 blood samples taken between 15 min and 72 h after administration. We modelled the pharmacokinetics of digoxin using non-linear mixed-effect models. Parameter estimation was performed using the stochastic approximation EM method (SAEM). We used three methods to select the covariate model: selection from a full model using Wald tests, forward inclusion using the log-likelihood ratio test and model selection using the Bayesian Information Criterion. RESULTS: The three covariate inclusion methods led to the same final model. Carriers of two T alleles for the C3435T polymorphism in exon 26 of MDR1 had a lower apparent volume of distribution than carriers of a C allele. The only other covariate effect was a shorter absorption time-lag in women. CONCLUSION: The apparent volume of distribution of digoxin is lower in TT subjects, probably reflecting differences in bioavailability. Non-linear mixed-effect models can be useful for detecting the influence of covariates on pharmacokinetic parameters.

sigma(2)-receptor ligand-mediated inhibition of inwardly rectifying K(+) channels in the heart.

The sigma(2)-receptor agonist, ifenprodil, was suggested as an inhibitor of G protein-coupled inwardly rectifying potassium channels. Nevertheless, an analysis of the role of sigma(2) receptors in cardiac electrophysiology has never been done. This work aims i) to identify the roles of cardiac sigma(2) receptors in the regulation of cardiac K(+) channel conductances and ii) to check whether sigma(2)-receptor agonists exhibit class III antiarrhythmic properties. The sigma(2)-receptor agonists ifenprodil, threo-ifenprodil, LNP250A [threo-8-[1-(4-hydroxyphenyl)-1-hydroxy-propan-2-yl]-1-phenyl-1,3,8-triazaspiro[4,5]decane-4-one] (a derivative of ifenprodil devoid of alpha(1)-adrenergic and N-methyl-d-aspartate glutamate receptor-blocking properties), and 1,3-di(2-tolyl)guanidine were used to discriminate the effects linked to sigma(2) receptors from those of the sigma(1) subtype, induced by (+/-)-N-allylnormetazocine (SKF-10,047). The sigma(2)-receptor antagonist 3-alpha-tropanyl-2(pCl-phenoxy)butyrate (SM-21) was employed to characterize sigma(2)-mediated effects in patch-clamp experiments. In rabbits, all sigma(2)-receptor agonists reduced phenylephrine-induced cardiac arrhythmias. They prolonged action potential duration in rabbit Purkinje fibers and reduced human ether-a-go-go-related gene (HERG) K(+) currents. (+)-SKF-10,047 was completely inactive in the last two tests. The effects of threo-ifenprodil were not antagonized by SM-21. In HERG-transfected COS-7 cells, SM-21 potentiated the ifenprodil-induced blockade of the HERG current. These data suggest that sigma(2)-receptor ligands block I(Kr) and that this effect could explain part of the antiarrhythmic properties of this ligands family. Nevertheless, an interaction with HERG channels not involving sigma(2) receptors seems to share this pharmacological property. This work shows for the first time that particular caution has to be taken toward ligands with affinity for sigma(2) receptors. The repolarization prolongation and the early-afterdepolarization can be responsible for "torsades de pointe" and sudden cardiac death.

[Genetic polymorphism of beta-adrenergic receptors and mortality in ischemic heart disease]. / Polymorphisme génétique des récepteurs bêta-adrénergiques et mortalité dans l'ischémie myocardique.

The genetic polymorphism of beta-2 adrenergic receptors (B2AR) could play a major role in the prognostic of patients with a coronary heart disease. Two recent epidemiological studies could support this hypothesis. In 597 patients treated by a beta-blocker and followed for 3 years after a myocardial infarction or an acute coronary syndrome, the death rate was 5.4 times higher in homozygous Arg 16 and Gln 27 B2AR genotypes than in heterozygous or homozygous Gly 16 and Glu 27 B2AR genotypes. The beta-1 adrenergic receptor (B1AR) genetic polymorphism did not modify mortality. In a second study, in a prospective cohort of 5249 patients aged > or =65 years, the incidence of sudden cardiac death was 1.56 times higher in patients with homozygous Gln 27 B2AR than in heterozygous or homozygous Glu 27 B2AR genotype. This result was confirmed by a case-control study (155 cases of sudden cardiac death versus 144 control subjects). These data suggest that B2AR genetic polymorphism should be systematically studied in clinical trials in myocardial ischemia, with or without congestive heart failure.

[Controlled randomized clinical trials]. / L'essai clinique contrôlé randomisé.

It is generally agreed that the first comparative clinical trial in history was done by James Lind in 1747, in the treatment of scurvy. The general bases of modern experimental medicine were published by Claude Bernard in 1865. However, it is the development of new drugs and the evolution of methodological concepts that led to the first randomized controlled clinical trial, in 1948, which showed that the effects of streptomycin on pulmonary tuberculosis were significantly different from those of a placebo. Today, "evidence-based" medicine aims to rationalize the medical decision-making process by taking into account, first and foremost, the results of controlled randomized clinical trials, which provide the highest level of evidence. In the second half of the 20th century it became clear that different kinds of clinical trials might not provide the same level of evidence. Practitioners' intimate convictions must be challenged by the results of controlled clinical trials. Take the CAST trial for example, which, in 1989, tested antiarrhythmic drugs versus placebo in patients with myocardial infarction. It was well known that ventricular arrhythmias were a factor of poor prognosis in coronary heart disease, and it was therefore considered self-evident that drug suppression of these ventricular arrhythmias would reduce the mortality rate. In the event, the CAST trial showed the exact opposite, with an almost 3-fold increase in total mortality among patients with coronary heart disease who were treated with antiarrhythmic drugs. These results had a profound impact on the use of antiarrythmic drugs, which became contraindicated after myocardial infarction. A clinical trial has to fulfill certain methodological standards to be accepted as evidence-based medicine. First, a working hypothesis has to be formulated, and then the primary outcome measure must be chosen before beginning the study. An appropriate major endpoint for efficacy must be selected, in keeping with the primary outcome. One may choose either a single endpoint (for instance all-cause mortality; or a composite criterion taking into account various manifestations of the same health disorder (for instance cardiovascular mortality plus non lethal myocardial infarction plus non lethal ischemic stroke). The trial must be controlled, i.e. must compare the intervention with a standard or dummy treatment. A randomization process is used to ensure that the groups are comparable. The patients must be monitored and the results analyzed in double-blind manner The required number of patients is calculated based on the working hypothesis ("superiority" trial or "equivalence" trial), as well as the spontaneous variability of the main endpoint, and the alpha and beta statistical risks. The experimental design (cross-over or parallel groups) is chosen according to the primary outcome measure and the disease characteristics. Finally, the results must be analyzed in an intention-to-treat manner, taking into account all the patients who were initially randomized. The results of these methodologically sound trials form the basis for official therapeutic guidelines, which help physicians to choose the best treatments for their patients. However, extrapolating the results of randomized controlled clinical trials to the general patient population is not always straightforward. For instance, it is well known that patients who participate in clinical trials are highly selected and therefore somewhat unrepresentative. In addition, their numbers are limited and the treatment period is often much shorter than in routine management of a chronic disease. Finally, patients in clinical trials are monitored more closely than in routine practice. This is why we need post-marketing pharmacoepidemiological studies, in which cohorts of patients exposed to the treatment in question are monitored sufficiently long to determine the precise risk-benefit ratio. Controlled clinical trials are lacking in various fields of biomedical research, either because drug companies consider them unprofitable, or because they concern public health issues that are outside the scope of the private sector In such cases, controlled clinical trials must be undertaken and funded by the public sector Today, only North American institutions such as NIH and the National Heart Blood and Lung Institute are capable of sponsoring such trials. This creates a potential problem for extrapolation to European patient populations, which may be different. Large controlled clinical trials must start to be sponsored by public funding in Europe if European practitioners are to receive the evidence-based results they need to rationalize their medical practice.

[Pharmacogenetic testing: utility in drug development and in routine clinical practice]. / Tests pharmacogénétiques: leur place en pratique médicale courante et dans le développement des medicaments.

Pharmacogenetic tests can identify the role of genetic factors in the inter-individual variability of drug responsiveness. This variability can involve three systems, namely drug-metabolizing enzymes, transmembrane drug transporters, and drug effctor sites (receptors, enzymes, ion, channels, etc.). At present, pharmacogenetic testing is rarely used in clinical practice. A rapid survey of the four laboratories conducting such tests for Paris hospitals shows that about 750 tests were done during a 12-months period in 2004-2005, and that most focused on allelic variants of drug-metabolizing enzymes. Three other European laboratories perform between 25, and 7.000 tests per year. However, the number of pharmacogenetic tests is set to grow rapidely in the near future. The role of genetic factors in adverse drug reactions (ADR) has not yet been the subject of a systematic study. Drug-drug interactions that inhibit or induce certain enzyme activities are a major cause of adverse reactions, but they have not been exhaustively studied Pharmacogenetic and pharmacogenomic tools are increasingly used in the drug development process. This should result in the discovery of new therapeutic targets and in a better understanding of factors governing drug efficacy and tolerability. DNA samples are already collected systematically in many phase II and III clinical trials, and registration agencies such as the FDA are establishing guidelines for the submission of pharmacogenetic data on new drugs. These efforts, together with DNA samples collection during post-registration pharmacoepidemiological studies, should help to understand inter-individual variability in drug efficacy and tolerability. They may also result in the identification of new drug targets and will help to tailor therapy to the individual patient.

[Pharmacogenetics and interindividual variability in drug response: cytochrome P-450 2C9 and coumarin anticoagulants]. / Pharmacogénétique et variabilité inter individuelle de la réponse aux traitements: l'exemple du cytochrome P-450 2C9 et des anticoagulants coumariniques.

Pharmacogenetics, a discipline still in its infancy, is the study of genetically determined variations in how individuals respond to drugs. Mutations may affect drug metabolism, transmembrane transport into cells, or target receptors. Genetic polymorphisms affecting drug metabolism were the first to be identified. Genetic factors control the activity of phase I reactions involving cytochrome (CYP) P450 isoenzymes. Three CYP families catalyze drug metabolism in humans. Their genes have been identified and polymorphisms have been described in various populations, leading to either high activity ("extensive metabolizer" phenotype) or low activity ("poor metabolizer" phenotype). The CYP2C9 polymorphism illustrates the potential clinical importance of pharmacogenetics. This enzyme catalyzes the metabolism of the coumarinic oral anticoagulants acenocoumarol and warfarin. The homozygous mutant genotype CYP 2C9 *31*3, present in 0, 7% of Caucasians, leads to low enzyme activity and thus to the accumulation of these drugs in the body; this in turn increases the anticoagulant activity and induces a higher risk of bleeding. In three clinical studies of patients and healthy volunteers, we found that this CYP2C9 *3 mutant allele was responsible for 14% of the variability in the response to these drugs. Then, by studying the genetic polymorphism of the receptor site of oral anticoagulants--the vitamin K epoxide reductase multiprotein complex--we showed that a combination of the two genetic variants (CYP2C9 and the receptor site) was responsible for 50% of the variability. These data suggest that patients who have both genetic polymorphisms could be at an increased risk of bleeding during oral anticoagulant therapy.

Environmental and genetic factors associated with morphine response in the postoperative period.

OBJECTIVE: The aim of this study was to investigate the respective influence of genetic and nongenetic factors on morphine dose requirements and adverse effects after colorectal surgery. METHODS: Seventy-four patients who planned to undergo colorectal surgery were included in this pilot study. The cumulative 24-hour postoperative dose of morphine and postoperative nausea or vomiting requiring the antiemetic ondansetron were the 2 clinical end points. The association of patient characteristics, A118G mu-opioid receptor (OPRM1) single-nucleotide polymorphism (SNP); T802C uridine diphosphate-glucuronosyltransferase 2B7 (UGT2B7) SNP; and 2 adenosine triphosphate-binding cassette, subfamily B, member 1 (ABCB1) (multidrug resistance 1 [MDR1]) exonic SNPs (G2677T/A and C3435T) with study end points was investigated. RESULTS: Age, creatinine clearance, and the regular use of psychotropic agents were found to be significantly associated with postoperative morphine dose requirements by univariate analysis. Multivariate analysis identified that age (P = .01) and the use of psychotropic agents before surgery (P = .03) were positively associated with a higher rate of morphine consumption. A higher weight (P = .05) and the ABCB1 homozygous GG-CC diplotype (P = .03) were significantly associated with fewer morphine side effects by univariate analysis. The homozygous ABCB1 diplotype (GG-CC) conferred an odds ratio of 0.12 (95% confidence interval, 0.01-0.98) with regard to the use of ondansetron for postoperative nausea or vomiting. Multivariate analysis identified that the ABCB1 GG-CC diplotype was the only borderline-significant (P = .07) predictive factor of morphine side effects. CONCLUSION: Age and prior use of psychotropic agents are associated with postoperative morphine dose requirements. Whether ABCB1 polymorphisms might predict morphine side effects remains to be determined.

Medical pharmacology: from review to planning.

The mission of medical pharmacology in the CHU (University Medical Centres) is to contribute, through research, instruction and treatment, to the development and optimal utilization of drugs. With a progressive development, medical pharmacology is now present in all CHUs, where its responsibilities are both hospital-related and university-related. This progressive development also explains why medical pharmacologists, regardless of their initial training, are recognized as drug experts. Continued growth of the discipline, in the context of changes in the hospital and university environment, should reinforce its position in the evaluation and proper use of drugs.

Teaching basic and clinical pharmacology to medical students: a 2006 survey in French schools of medicine.

This survey was organized in 2006 in France in order to investigate the status of the core curriculum of basic and clinical pharmacology (BCP) teaching hours (TH) in the 6 years training of medical studies. An open questionnaire was sent to 37 pharmacological teams with a 100% response rate. The results of this survey showed that the national mean number of TH is 67.6 per student, i.e. a mean of 11.3 TH per year per student during the 6 year training program. There was a wide dispersion of TH between universities with extremes ranging from 141 to 24. BCP of major classes of drugs was the leading subject (mean 35% of total) followed by general principles of pharmacology (33%), pre-clinical and clinical pharmacology (15%), pharmacology of mediator systems (9%) and miscellaneous subjects (8%). The time allotted to BCP teaching program is considered as insufficient in most of medical schools where it is less than 100 TH. New methods of active learning for students should be developed in the near future (integrated problem-base learning), and students should be trained to construct their knowledge-base via an access to pharmacological data-bases. Major changes in teaching BCP represent an important challenge for pharmacologists.

The respective roles of controlled clinical trials and cohort monitoring studies in the pre- and postmarketing assessment of drugs.

The respective roles of controlled clinical trials and observational studies (cohort or case-control studies) in evaluating the efficacy, safety and usefulness of a drug were analysed. A randomised, controlled, double-blind study is the best method of estimating the efficacy of a treatment. It provides the least biased and most robust estimate of the causal relationship. In certain situations and on the basis of certain criteria, observational studies can have a proof-of-efficacy value. Randomised, controlled, pre- and postmarketing authorisation (MA) clinical studies identify the rarer adverse effects and compare them with those resulting from the reference treatment. Before the MA, the pooled safety data from different controlled trials can provide an estimation of relatively frequent adverse events and subjects at risk. However, an observational study is the most appropriate method of evaluating the safety of a drug in the currently used conditions. By definition, a drug influences the health of a population if it directly or indirectly improves its health. A drug would have a major role in public health if it reduced mortality or morbidity related to a particular disease or if it improved the quality of life of patients with this disease. Prior to marketing a product, modelling is the approach of choice to quantify the expected effect. Pragmatic, postmarketing trials and observational studies are the reference methods used to define the population affected, the efficacy and safety of the drug in a real situation and its usefulness for public health. In conclusion, randomised clinical trials remain the reference approach for evaluating efficacy, while observational studies have a confirmatory value. Observational studies are the most appropriate way of evaluating safety in the currently used conditions, as the clinical trial has limited indications. In the interests of public health, modelling is the pre-marketing approach of choice, while pragmatic trials and observational studies are the postmarketing reference approaches.