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Resume Cet article reprend les evenements principaux qui ont ecrit l’histoire de la pharmacovigilance jusqu’au debut du XXI e siecle et met en lumiere leurs impacts et les evolutions reglementaires qui en decoulent.

Resume Propos Les patients de medecine interne presentent souvent des tableaux cliniques inexpliques pour lesquels une origine medicamenteuse peut etre envisagee. La prevalence de patients hospitalises pour iatrogenie est estimee entre 4 a 22 %. Nous avons voulu evaluer l’apport diagnostique du centre regional de la pharmacovigilance pour identifier ou confirmer une iatrogenie dans le service de medecine interne de Lille et caracteriser les facteurs associes a l’iatrogenie. Methodes Il s’agit d’une etude diagnostique prospective monocentrique dans laquelle ont ete incluses toutes les demandes consecutives du service de medecine interne aupres du centre regional de pharmacovigilance du Nord-Pas-de-Calais entre 2010 et 2012. L’iatrogenie selon le centre regional de pharmacovigilance etait retenue sur l’enregistrement de l’effet indesirable medicamenteux dans la base nationale de pharmacovigilance, et analysee en fonction de la conclusion d’iatrogenie retenue par les cliniciens de medecine interne (diagnostic de reference) avec un suivi jusqu’a juin 2013. Les variables concernant le patient, les medicaments et l’evenement indesirable ont ete analysees en regression logistique binaire. Resultats Nous avons analyse 160 contacts, dont 118 cas concordants, 38 faux-positifs (iatrogenie retenue par le centre regional de pharmacovigilance seul), 4 faux-negatifs. L’enregistrement dans la base nationale de pharmacovigilance avait une sensibilite de 96 % (IC95 % [0,92–0,99]), une specificite de 46 % (IC95 % [0,38–0,53]), une valeur predictive positive de 69 % (IC95 % [0,62–0,76]), une valeur predictive negative de 89 % (IC95 % [0,84–0,94]) et un rapport de vraisemblance negatif de 0,1. Les faux-positifs avaient une imputabilite chronologique et semiologique douteuse (RR ajuste = 2,1, IC95 % [1,2,8]). Conclusion Dans notre etude, le centre regional de pharmacovigilance conforte le clinicien dans sa suspicion d’iatrogenie et aide a exclure l’origine medicamenteuse avec une forte valeur predictive negative.

Many elderly patients are routinely exposed to drugs that may prolong the cardiac QT interval and cause Torsades de pointes (TdP). However, predictors of TdP in patients with drug-associated long QT syndrome (LQTS) are not fully understood, especially in the geriatric population. The objective of this study was to identify risk factors of TdP in elderly patients with drug-associated LQTS. In this retrospective, case-control study, documented reports of drug-associated LQTS plus TdP (n = 125) and LQTS without TdP (n = 81) in patients ≥65 years of age were retrieved from the French Pharmacovigilance Database over a 10-year period. Available clinical, biological, and drug therapy data were compared in the two groups and logistic regression was performed to identify significant predictors of TdP. The uncorrected QT interval was significantly longer in patients with TdP than in patients without TdP (577 ± 79 vs. 519 ± 68 ms; p = 0.0001). The number of drugs with a known risk of TdP administered to each patient was not a predictor of arrhythmia, nor was female gender. Logistic regression analysis identified the uncorrected QT interval as the only significant predictor of TdP. The receiver operating characteristic curve analysis was characterized by an area under the curve of 0.77 (95 % confidence interval 0.64–0.88) and a QT cutoff of 550 ms. The uncorrected QT interval was significantly associated with the probability of TdP in elderly patients with acquired, drug-associated LQTS.

Objective During the 2009–2010 influenza A variant virus (A(H1N1)v) pandemic in France, a national pharmacovigilance program was set up to monitor vaccinated, pregnant women, especially the reactogenicity of the vaccine and its impact on the outcome of pregnancy and on the newborn. Here, we present the results for the cohort of pregnant women constituted in the Nord-Pas de Calais region of northern France. Study design Vaccinated pregnant women were included in the study by the region's vaccination centers between November 2009 and April 2010. Results Eight hundred and six pregnant women were included and 781 were followed up until delivery. The risk of adverse events after vaccination and the maternal, fetal and neonatal medical conditions in our cohort did not appear different from the risk observed in the general population. Conclusions Our results suggest that A(H1N1)v vaccination of pregnant women did not have an adverse impact on the pregnancies’ course and outcome.

We report two cases of torsade de pointes directly related to intracoronary contrast media injection in patients without previous history of neither arrhythmia nor syncope but chronically treated with a drug prolonging ventricular repolarization. We discussed the effects of the contrast medium used on repolarization and concluded that three suggestions may be highlighted from the case reports presented and from the literature: (i) a QT prolongation should be systematically searched before coronary angiography; (ii) it seems important to correct QT prolongation when it results from a reversible cause (such as drug-induced) before nonurgent coronary angiography; and (iii) if there is no reversible cause explaining QT prolongation, contrast media should be used cautiously in such patient and nonionic iso-osmolar contrast media should be preferred.

This article reviews the main historical events before the 21st century and explained their consequences in the current pharmacovigilance legislation.

Resume Contexte et methodes A la suite du retrait du marche de la cerivastatine en 2001, une enquete a ete realisee sur l’ensemble de cas d’atteintes musculaires severes associees a la prise de statines notifies en France au systeme national de pharmacovigilance et aux laboratoires pharmaceutiques jusqu’en fevrier 2002. Resultats Sur 238 observations retenues, 69 concernaient la cerivastatine, 86 la simvastatine, 49 la pravastatine, 23 l’atorvastatine et 9 la fluvastatine. L’incidence des cas notifies est apparue 6 a 10 fois plus elevee avec la cerivastatine qu’avec les autres statines. Un facteur de risque majeur etait l’association au gemfibrozil. Conclusion La surveillance apres mise sur le marche apparait determinante pour detecter precocement un risque d’effet indesirable excessif d’un nouveau medicament.

Resume La plupart des etudes sur les effets indesirables medicamenteux (EIM) montrent qu’un certain nombre sont « evitables ». Des methodes de mesure de l’evitabilite des EIM existent mais aucun auteur n’a clairement evalue la validite de telles methodes. Ainsi, a ce jour, aucune echelle de mesure de l’evitabilite ne represente un « gold standard ». Pour etre validee, une echelle doit posseder les qualites d’un bon instrument de mesure : la convenance (ou validite de contenu), la fiabilite, la validite contre critere et l’applicabilite. Ce travail presente les deux premieres etapes d’une etude de validation d’une echelle francaise d’evitabilite des EIM (convenance et fiabilite). La premiere etape a consiste a construire une echelle d’evitabilite (choix et formulation des items, choix d’un score global et de categories d’evitabilite, par consensus entre experts). Durant la seconde etape, plusieurs experts ont teste cette nouvelle echelle pour evaluer l’evitabilite d’un echantillon d’EIM. La comprehension de certains items et l’accord interjuges se sont reveles mediocres. Cette etude montre la faisabilite d’une etude de validation et surtout la necessite de poursuivre cette demarche afin de disposer d’une echelle de mesure fiable d’evaluation de l’evitabilite des EIM.

Resume A partir d’une revue de la litterature et des observations de la base de donnees nationale francaise de pharmacovigilance pour la periode de 1984 a avril 2003, sont presentes les principaux medicaments responsables ou revelateurs d’une insuffisance cardiaque. Plusieurs grandes classes pharmacologiques se distinguent : outre certains antimitotiques dont les anthracyclines, de nombreux medicaments tels que les immunomodulateurs, les anti-inflammatoires (y compris les coxibs), les antiarythmiques, les anesthesiques, les antipsychotiques, les medicaments antidiabetiques (dont les glitazones) sont impliques dans la survenue de decompensations cardiaques. Il est habituel de les classer en trois categories : (i) medicaments susceptibles de provoquer des insuffisances cardiaques de novo (tels que cyclophosphamide, paclitaxel, mitoxantrone, interferons, interleukine-2…) ; (ii) medicaments susceptibles d’aggraver une insuffisance cardiaque preexistante (tels que antiarythmiques, β-bloquants, antagonistes du calcium, anti-inflammatoires non steroidiens et steroidiens, sympathomimetiques…) ; et (iii) medicaments provoquant exceptionnellement une insuffisance cardiaque. Cette revue montre que cette classification est en fait artificielle et que si la preoccupation d’une toxicite cardiaque doit etre constante lors du maniement des anticancereux et de certains immunomodulateurs, il convient d’etre attentif au maniement de nombreux medicaments chez le sujet insuffisant cardiaque, y compris lorsque la situation clinique est bien equilibree, en tenant compte, en particulier, du terrain et des interactions medicamenteuses potentielles.

Adverse drug interactions increase morbidity and mortality. To prevent these, situations leading to adverse prescriptions must be clarified. This study quantifies and analyses prescriptions with potential adverse drug interactions in primary health care in the North of France over a 3-month period.All prescriptions administered between 1 January 1999 and 31 March 1999 were analysed to identify potential interactions amongst drugs appearing on the same prescription sheet. The regional French healthcare database was compiled to further classify contraindications.There were 5,358,374 prescriptions administered to 44% of the overall population of the Nord-Pas de Calais area (1,754,372 patients per 3,990,167 general population). There were 14,390 prescriptions classified as either absolute (26%) or relative contraindications (74%). Nine drug categories accounted for most of the absolute contraindications: dopaminergic antiparkinsonians, neuroleptic agents, migraine treatments (such as ergot alkaloids, sumatriptan and other triptan derivatives), prokinetic drugs (cisapride), antibacterial drugs (macrolides), antifungals (imidazoles), antiarrhythmics, beta-blockers and analgesics (opioids and floctafenine). In 54% of patients exposed, the incurred risk was either QT prolongation/Torsade de Pointes or antagonism of dopaminergic antiparkinson agents with dopamine receptor antagonists prescribed as antipsychotic agents.Among a non-selected population of ambulatory outpatients, the number of quarterly prescriptions with contraindications with potentially harmful drug interactions is 27 in 10,000 prescriptions. This would extrapolate to nearly 200,000 contraindications on same-prescription sheets in France in the first quarter of 1999.

Prolongation of QT interval by several antibacterial drugs is an unwanted side effect that may be associated with development of ventricular arrhythmias. The macrolide antibacterial agent clarithromycin has been shown to cause QT prolongation. To determine the electrophysiologic basis for this arrhythmogenic potential, we investigated clarithromycin effects on (i). action potentials recorded from rabbit Purkinje fibers and atrial and ventricular myocardium using conventional microelectrodes and (ii). potassium and calcium currents recorded from rabbit atrial and ventricular isolated myocytes using whole-cell patch clamp recordings. We found that (i). clarithromycin (3-100 microM) exerted concentration-dependent lengthening effects on action potential duration in all tissues, with higher efficacy and reverse frequency-dependence in Purkinje fibers. However, clarithromycin did not cause development of early afterdepolarizations, and the parameters other than action potential duration were almost unaffected; (ii). clarithromycin (10-100 microM) reduced the delayed rectifier current. Significant blockade (approximately 30%) was found at the concentration of 30 microM. At 100 microM, it decreased significantly the maximum peak of the calcium current amplitude but failed to alter the transient outward and inwardly rectifier currents. It was concluded that these effects might be an explanation for the QT prolongation observed in some patients treated with clarithromycin.

Resume Le probleme de la securite d’emploi des inhibiteurs de l’HMG-CoA reductase (statines) a ete recemment mis en avant a l’occasion du retrait mondial de la cerivastatine. La bonne tolerance des statines etait une notion unanimement admise a partir des donnees des essais cliniques. Il convient donc de re-preciser les circonstances dans lesquelles des effets indesirables peuvent survenir. Le probleme se pose essentiellement vis a vis des atteintes musculaires. Celles-ci peuvent etre de gravite variable. Les formes severes (myopathies et rhabdomyolyses) sont exceptionnelles avec une incidence de l’ordre de 1 cas pour 100 000 patients-annees. L’atteinte musculaire est dose-dependante et le plus souvent observee dans le cadre d’interactions medicamenteuses. Les autres effets indesirables sont peu frequents et sont surtout dans la grande majorite des cas sans gravite clinique : elevation des transaminases, atteintes tendineuses. La question reste ouverte pour ce qui concerne un eventuel risque de cancer ; en revanche, le risque oculaire semble ecarte.

Prolongation of QT interval by antipsychotic drugs is an unwanted side effect that may lead to ventricular arrhythmias. The antipsychotic agent risperidone has been shown to cause QT prolongation, especially in case of overdosage. We investigated risperidone effects on action potentials recorded from rabbit Purkinje fibers and ventricular myocardium and on potassium currents recorded from atrial and ventricular rabbit isolated myocytes. The results showed that (1) risperidone (0.1-3 microM) exerted potent lengthening effects on action potential duration in both tissues with higher potency in Purkinje fibers and caused the development of early afterdepolarizations at low stimulation rate; (2) risperidone (0.03-0.3 microM) reduced significantly the current density of the delayed rectifier current and at 30 microM decreased the transient outward and the inward rectifier currents. This study might explain QT prolongation observed in some patients treated with risperidone and gives enlightenment on the risk of cardiac adverse events.

Switching reactive components with a high voltage circuit breaker (CB) can generate transients on the electrical network that decrease power quality and produce excessive stresses on the power apparatus. While conventional solutions provide some degree of mitigation, a more effective and reliable solution has been successfully deployed and validated: Controlled Switching (CS). Furthermore, to extend the useful life of the existing CB and prevent its costly replacement, this solution has been retrofitted on more than 140 CBs over the last 20 years on the Hydro-Quebec network. The technology has evolved considerably in the last ten years. Initially used for shunt reactors, then for shunt capacitor banks, this proven technology is now often applied to the energization of unloaded power transformers, as well. No matter the application type, CS retrofitting has proven to be effective on CBs from a variety of manufacturers and technologies. From this long experience, many lessons have been learned and innovative ideas developed regarding optimal target specifications, switching strategies, commissioning procedures and the valorization of data recorded during switching events. Using acquisition functionalities that are intrinsic to the Controlled Switching Device (CSD), it is now possible to go beyond theoretical principles and optimize the simulation models through analysis of field measurements. The ongoing process of data collection offers the possibility of expanding the knowledge in this field and improving the diagnostics of related equipment. It also allows the industrial partners to apply these developments to new applications such as Flexible AC Transmission Systems (FACTS), power line energization, fast switching and wind farm connection to the distribution network.

The hospitalised patients in a cardiological hospital (Lille, France) over an 18-month period were subjected to a prospective high-intensity adverse drug reaction (ADR) monitoring in order to assess the additional financial resource utilisation associated with ADRs and analyse the distribution of excess of cost according to ADR nature and therapeutic classes. Over 18 months, among the 16,916 hospitalised patients, 371 verified ADRs detected by self-report stimulated by a special unit of nurses and pharmacologists occurred in 336 patients with an overall ADR rate of 2.2%. This rate increased with age. The most common reactions were cutaneous events (24%), cardiovascular events (21%), metabolic disorders (12%), coagulation disorders (10%) and nervous system impairment (10%). The most common drug classes involved were cardiovascular agents (36%), contrast media (20%), drugs affecting blood clotting (13%) and anti-infectives (14%). Increased ADR-induced costs result especially from prolongation of length of stay and cost increase was evaluated at Euro 4150 per ADR. Among the 371 ADRs, 134 ADRs, which were significantly more severe, induced a prolongation of length of stay. Renal insufficiency and cardiovascular events were significantly over-represented in this sub-group. The most common ADR-inducing drugs associated with a prolongation of length of stay are cardiovascular agents and drugs affecting blood clotting. In contrast, cutaneous ADRs were significantly over-represented in the group of ADRs without prolongation of length of stay. The severity and substantial costs of ADRs in hospital justify investments to prevent these events. Nevertheless, only a portion of ADRs induces cost increases, suggesting that prevention efforts should focus on this limited category of ADRs.

Aims Grapefruit juice increases blood concentrations of many drugs metabolized by CYP3A. Amiodarone is metabolized by CYP3A to N-desethylamiodarone (N-DEA). The aim of this study was to determine amiodarone kinetics when administrated with and without grapefruit juice. Methods Eleven healthy adult volunteers took part in a single sequence, repeated-measures design study. Each subject, who had been evaluated 6 months previously for amiodarone pharmacokinetics, was given a single oral dose of amiodarone (17 mg kg -1 ) with three glasses of 300 ml of grapefruit juice on the same day. Results Grapefruit juice completely inhibited the production of N-DEA, the major metabolite of amiodarone, in all subjects and increased the area-under-the-curve (AUC) and maximum concentration of amiodarone (C max ) by 50% and 84%, respectively, as compared with the control period during which water had been administrated instead of grapefruit juice (AUC: 35.9±14.3 vs 23.9±11.2 μg ml -1 h, P

Class I antiarrhythmic drugs are characterised by their ability to block the fast inward sodium current in cardiac muscle tissue. However, at the same time, they can be responsible for various effects involving other organs and systems. Although some of these effects can be helpful in specific situations, most of them, such as their pro-arrhythmic propensity, are deleterious. Some of the adverse effects of class I antiarrhythmic drugs are directly linked to sodium-channel blockade (conduction disorders haemodynamic perturbations, and digestive and neurological effects), while others are linked to other specific pharmacological properties (e.g. atropinic, or alpha- or beta-adrenergic blockade) or to nonspecific properties (idiosyncratic hypersensitivity, and haematological, dermatological or hepatic reactions). Other adverse effects are associated with complex interactions between class I antiarrhythmics and individual predisposing factors, trigger mechanisms and physiological factors (including concomitant drug treatment). These numerous variations and interactions within a specific environment and underlying disorder might be of pharmacological or/and pharmacokinetic origin, making analysis of the true liability of the class I drugs very difficult when adverse effects occur.

The aim of this study was to evaluate the effect of an angiotensin-converting enzyme (ACE) inhibitor, ramipril, on heart rate variability in patients with heart failure simultaneously treated with digitalis. This study was a multicentric, randomized, double-blind, placebo-controlled study including 50 patients with chronic heart failure (CHF). All patients were in NYHA functional class II and III. The etiology of CHF was mainly idiopathic dilated cardiomyopathy and ischemic heart disease. After a 4-week placebo run-in period with digoxin and diuretics, patients were randomized to receive additional ramipril or placebo. To assess heart rate variability (HRV) and arrhythmias, 24-hour ECGs were recorded at the end of the placebo run-in period, 8 and 24 weeks after randomization. Spectral analysis of HRV was performed during one diurnal and one nocturnal 5-minute time period. No statistically significant differences in HRV within low-, high-, and total-frequency bands were induced by ramipril in either the diurnal or nocturnal periods, both at 8 and 24 weeks after randomization. Ramipril produced a significant decrease in nonsustained ventricular tachycardia at 24 weeks of treatment (p = 0.01). These results run against previous observations showing an increase in parasympathetic tone with ACE inhibitors in heart failure. The present study thus suggests that the effects of ACE inhibitors in CHF are variable and depend on the patient and concomitant treatment that might influence HRV such as digoxin treatment.

Astemizole is a potent histamine H1-antagonist that has been associated with cases of life-threatening cardiac arrhythmias, including torsade de pointes and atrioventricular (AV) block. However, its effects on cardiac action potential (AP) has not been described. We examined the electrophysiological effects of astemizole on rabbit Purkinje fibers using conventional glass microelectrodes in parallel with the effects of the widely used histamine H2-antagonist cimetidine, selected because it has no known cardiac arrhythmic toxicity. Astemizole (0.01-3 microM) exerted a concentration-dependent prolonging effect on final repolarization that did not reach steady state after 3 h of exposure. This effect was more pronounced at low stimulation frequency and was less marked at high stimulation frequency. In addition, early afterdepolarizations (EADs) occurred in one third of the fibers. Increasing extracellular concentration of KCl (2.7-5.4 mM) or MgCl2 (1-5 mM) suppressed EADs and reversed the prolonging effect that was conversely exaggerated by decreasing KCl (4-2.7 mM) or MgCl2 (1-0.5 mM) concentration. At higher concentrations (3-30 microM), astemizole induced an increasing depressant effect on the maximal rate of depolarization (Vmax) that became more pronounced with high stimulation frequency. All parameters were strongly depressed at 10 microM astemizole, leading to cellular inexcitability in 5 of 12 fibers when exposed to 30 microM astemizole. In comparison, cimetidine induced minor changes on AP characteristics, i.e., a prolongation in plateau duration at high (30-100 microM) concentrations. These results provide evidence that astemizole exerts quinidine-like effects on cardiac APs that are compatible with the occurrence of the clinically observed arrhythmias.

We report two cases of torsade de pointes directly related to intracoronary contrast media injection in patients without previous history of neither arrhythmia nor syncope but chronically treated with a drug prolonging ventricular repolarization. We discussed the effects of the contrast medium used on repolarization and concluded that three suggestions may be highlighted from the case reports presented and from the literature: (i) a QT prolongation should be systematically searched before coronary angiography; (ii) it seems important to correct QT prolongation when it results from a reversible cause (such as drug-induced) before nonurgent coronary angiography; and (iii) if there is no reversible cause explaining QT prolongation, contrast media should be used cautiously in such patient and nonionic iso-osmolar contrast media should be preferred.

Background and purpose: Polymorphonuclear neutrophils (PMNs) contribute to the vascular damage caused by transient cerebral ischaemia. Here we have evaluated the role of PMNs in intracerebral haemorrhage (ICH) induced in a model of thrombolysis with recombinant tissue plasminogen activator (t-PA) during the acute phase of cerebral ischaemia. Experimental approach: The middle cerebral artery (MCA) of male spontaneously hypertensive rats was occluded for 1 h followed by reperfusion and, 5 h later, infusion of thrombolytic products (generated in vitro by t-PA on autologous clots). Effects of pretreatment (before the MCA occlusion) with vinblastine (4 days before; 0.5 mg·kg−1), monoclonal anti-neutrophil antibody (mAbRP3; 12 h, 0.3 mg·kg−1) or saline on ICH, neutrophil infiltration, MCA vascular reactivity and brain infarct volume were assessed, 24 h after the beginning of reperfusion. Key results: Depletion of circulating neutrophils significantly reduced t-PA-induced ICH (vinblastine, 4.6 ± 1.0; mAbRP3, 5.2 ± 1.0 vs. saline, 10.8 ± 2.7 haemorrhages; P

The reality of sinoatrial Wenckebach periods (WP) has been suggested, but not proven, in the literature. We report experimental and clinical data showing WP in sinoatrial blocks. Experimental sinoatrial blocks were induced by superfusion of bepridil (10(-5) M) in 15 preparations of isolated rabbit right atria. Different types of block were observed, including Blumberger I block, i.e., sinoatrial WP. The recordings showed that the typical pattern of Blumberger type IA block and sinoatrial WP may be due to transient acceleration of the sinus rate, without change in the increment. We also observed sinoatrial WP in a 72-year-old patient on direct recordings of the sinus node (SN) electrical activity. In this case, transient acceleration of the sinus rate also seemed to be involved in the genesis of sinoatrial WP. Analysis of these clinical and experimental data showed similarities that may explain the mechanism of the WP. Usually type IA Blumberger block is said to involve a decrease in the sinoatrial increment to explain the atrial sequence (decrease in PP interval followed by a pause shorter than twice the value of the preceding cycle, then a cycle longer than the one preceding the pause). In fact, this pattern can be observed when the acceleration of the higher structure, the SN, induces block within the lower structure, i.e., the atrium.

Urinary elimination of unchanged mexiletine, p-hydroxymexiletine (PHM), hydroxymethylmexiletine (HMM) and mexiletine N-glucuronide conjugate (MGC) was investigated before and after treatment with quinidine. All subjects were phenotyped as extensive metabolizers for debrisoquine oxidation. The total recovery of mexiletine and metabolites was significantly reduced after quinidine pretreatment. It is concluded that pretreatment with a very low dose of quinidine inhibits markedly the elimination of both major mexiletine metabolites (PHM and HMM) and likely decreases the overall elimination of mexiletine. That should lead to changes in mexiletine disposition and have clinical consequences during combination therapy with both drugs.

The intracellular electrophysiologic effects of encainide (E) and its main metabolite, O-desmethyl-encainide (ODE), were studied in guinea-pig papillary muscle preparations and related to the in-vivo electrophysiologic effects observed after intravenous (IV) infusion of E in 11 patients undergoing electrophysiologic study (EPS). At equipotent concentrations of E and ODE, frequency-dependent reductions in Vmax studied at pacing rates of 30-180 beats/min ranged from -11.5% to -53%, with maximum reductions of -53% and -47%, respectively at the highest frequency. The kinetics of onset of use-dependent Vmax reduction were slower for ODE than for E at each studied pacing rate. The kinetics of total recovery from use-dependent block were still slower (120 seconds for E and 300 seconds for ODE at a 90 beats/min pacing rate). These in-vitro electrophysiologic data could explain the marked alterations in intraventricular and atrioventricular conduction observed in humans 60 minutes after IV administration of 1 mg/kg of E over a 15-minute period. The QRS, PA, AH, and HV intervals were significantly increased (p less than 0.01) and the Wenckebach cycle length was increased by 8% (p less than 0.05). Blood pressure, RR, QT, CSNRT, ESACT, ERP, and FRP did not vary significantly. The HV interval was already increased 2 minutes after drug administration, while AH was not increased until 15 minutes after drug administration. There was a positive correlation between the increase of the AH interval and the blood level of ODE.

After the withdrawal of cerivastatin from the market, a survey was performed concerning severe muscular disorders associated with statin treatments that were notified to the French national and pharmaceutical industry pharmacovigilance systems up to February 2002.Among the 238 cases analysed, 69 were related to cerivastatin, 86 to simvastatin, 49 to pravastatin, 23 to atorvastatin and 9 to fluvastatin. The reporting rate was six- to ten-times higher for cerivastatin than for other statins. A major risk factor for rhabdomyolysis with cerivastatin was its association with gemfibrozil.Postmarketing surveillance appears to be a major tool for early detection of safety problems with a new drug.

Adverse drug reactions (ADRs) have been recognised as an important cause of hospital admission. Most of these drug-related admissions were expected ADRs and, thus, partly preventable. However, as far as we know, the assessment of the preventability of ADRs was addressed in only two studies performed in France. In contrast, several other studies have been performed, mainly in the USA, and using different methods of assessing preventability. None of these methods were clearly evaluated with regard to reproducibility, validity or relevance. The purpose of this study was to initiate the validation of a French preventability scale. Here, we propose the first two phases of validation: the content validity and reliability of the scale. A working group of pharmacovigilance experts has been specifically established for this purpose. The content validity was assessed by collecting items representative of preventability. The choice and the formulation of items and a proposal of a score (global and for each item) were adopted after the consensus of the experts. A definitive version of the ADR preventability scale was used for the assessment of reliability. During the second phase, experts independently tested the new scale from observations of ADRs (49 central nervous system haemorrhages with antivitamine K). The concordance of the experts' judgements was calculated using two statistical methods (Kappa statistic and correlation coefficient). The content validity phase was performed during several workshops where experts discussed the choice and formulation of the best items. We decided to construct a scale with a small number of items, allowing a rapid evaluation of the preventability of ADRs. On the basis of a global score, four categories of preventability of ADRs ("preventable", "potentially preventable", "unclassable", "not preventable" ADRs) were proposed. The agreement of experts regarding the global score was low, with a poor correlation coefficient value (coefficient interclass = 0.491). Classification of ADRs in the four categories by the experts showed discrepancies (Kappa = 0.1136). The preventability assessment using this scale was feasible, although poor concordance between the judges has raised some questions. Several experts found use of this scale difficult in terms of a clear understanding of the items, and found that two of them were redundant. We have oversimplified some items and revision of their formulation will be necessary. Moreover, most of ADR notifications were poorly documented, resulting in a frequent choice of an "unevaluable" item. This represented an important bias in the calculation of the global score. This experience suggests the need for further studies to improve this French ADR preventability scale and validate it in differing circumstances, in order to provide a useful tool to enhance the rational use of drugs.

The principal drugs implicated in or disclosing cardiac insufficiency are drawn from a review of the literature and observations by the French national pharmacovigilance database, from 1984 to April 2003. Several pharmacological classes are identified: in addition to antimitotic drugs, such as anthracyclines, many drugs are implicated in cardiac insufficiency, e.g. immunomodulators, anti-inflammatory drugs (including coxibs), antiarrhythmic drugs, anaesthetic drugs, antipsychotic drugs, and antidiabetic drugs (including glitazones). It is usual to classify these drugs according to three categories: (i) drugs likely to cause cardiac insufficiency de novo (such as cyclophosphamide, paclitaxel, mitoxantrone, interferons, interleukin-2 etc.); (ii) drugs likely to worsen preexisting cardiac insufficiency (such as antiarrhythmics, beta-blockers, calcium antagonists, nonsteroidal and steroidal anti-inflammatory drugs, sympathomimetic drugs etc.); and (iii) drugs only occasionally causing cardiac insufficiency. This review shows that this classification is, in fact, artificial. If cardiac toxicity is a constant concern when using antimitotic drugs or some immunomodulator drugs, it is advisable to exercise caution in the use of many other drugs when treating patients with cardiac insufficiency, even if the clinical situation is well controlled. In particular, drug-drug interactions and patient medical history must be taken into account.

Background and Purpose— In a model of mechanical focal ischemia, we investigated the involvement of thrombolysis products (TLP) in recombinant tissue plasminogen activator (rtPA)-induced intracerebral complications and the effects on infarct volume and postischemic endothelial function. Methods— Hemorrhage incidence and severity were evaluated by histomorphometric analysis in male spontaneously hypertensive rats (SHR) subjected to 60-minute intraluminal middle cerebral artery (MCA) occlusion and receiving intravenously 5 hours later either saline, rtPA (3, 10, or 30 mg/kg), or rtPA (10 mg/kg) associated with TLP (rtPA+TLP). In addition, MCA reactivity was assessed in rtPA- or rtPA+TLP-treated SHR versus control Wistar-Kyoto rats or SHR. Results— No hemorrhage was observed visually in SHR receiving saline. In contrast, rtPA administration induced hemorrhagic complications in infarcted areas in a dose-independent manner. Administration of rtPA+TLP solution, containing a high concentration of plasmin, did not affect hemorrhage incidence but significantly increased hemorrhage severity (8.8±2.3 petechiae versus 3.0±1.0 petechiae in rtPA group; P 3 in rtPA group; P P Conclusions— Treatment with rtPA led to intracerebral hemorrhages, in contrast to saline-treated animals, and the presence of TLP increased the severity of these hemorrhages, in parallel with increased infarct volume and worsened endothelial function.

In this retrospective study, performed on 16 HIV-infected patients with congenital coagulation disorders who were part of a French clinical cohort, the incidence rate of bleeding with a lopinavir-ritonavir-containing regimen was almost four times the rate with other protease inhibitor-containing regimens. Lopinavir-ritonavir also appeared to be associated with exceptionally severe haemorrhagic events. If these results are confirmed, they suggest that when other therapeutic options are available, we should reconsider lopinavir-ritonavir use in haemophilic patients.

In addition to their impact on human health, adverse drug reactions (ADRs) also have significant impact on healthcare costs. These costs are essentially hospital costs, in particular arising from an increase in length of stay caused by an ADR. Although it has been estimated that the occurrence of an ADR during hospitalisation or leading to hospitalisation is responsible for a cost of approximately EURO2800, several studies have also pointed out that the structure of ADR cost is heterogeneous, a factor which must be taken into account when developing preventive strategies. ADR cost evaluation remains difficult from a methodological point of view given that most studies have only evaluated the direct cost. Because of the substantial annual estimated cost of ADRs in industrialised countries, it is necessary to implement preventive programmes, with different strategies consisting of: educational programmes; identifying risk groups; implementing good drug practice; and clinical and laboratory monitoring for ADRs. Promoting pharmacoeconomic studies and co-operation between clinicians, medical pharmacologists and pharmacists remains the key factor for preventing ADRs and decreasing their costs.

beta-Adrenergic blocking drugs are effective in reducing sudden cardiac death after acute myocardial infarction but the precise mechanism of this effect is unclear. We investigated the acute and chronic effects of acebutolol, a beta-adrenergic blocker, on electrocardiographic parameters, diastolic excitability threshold (DET), and right ventricular effective refractory period (RVERP) in chronically instrumented conscious dogs. These parameters were determined during spontaneous sinus rhythm and at a fixed pacing rate (200 beats/min). Acebutolol (0.5, 1, and 5 mg/kg i.v.) decreased the heart rate (HR) (by 23, 26, and 24%, respectively) without effects on any electrocardiographic parameters or on the DET. The maximal increases in ERP were 4.7, 7, and 7.8%, respectively, during pacing and 8.5, 13.3, and 10.3%, respectively, during sinus rhythm. Acebutolol, 10 mg/kg/day P.O. for 6 weeks, reduced the HR from the third day onward without altering the PR, QRS, QT, or QTc intervals or the DET. The increase in ERP was significant from the third day (14%) during pacing and from the seventh day (15.5%) during sinus rhythm. The degree of prolongation of the ERP subsequently remained stable during the 6 weeks of treatment. The ERP returned to the baseline value 7 days after acebutolol withdrawal. This increase in ERP, which was more marked during chronic oral treatment, could contribute to the documented protective effect of the beta-blocking drugs against sudden cardiac death after myocardial infarction.

To evaluate whether the hydroxylated metabolites of quinidine (Q) and hydroquinidine (HQ): hydroxy-3S-quinidine (OH-Q) and hydroxy-3S-hydroquinidine (OH-HQ), exert electrophysiologic effects and participate in the therapeutic action of the parent drugs, we examined and compared the effects of the metabolites and the parent drugs on the electrical activity of guinea pig ventricular cells recorded by standard microelectrode technique. In addition, we investigated the potential arrhythmogenic properties of these compounds in rabbit Purkinje fibers in low K+ (2.7 mM) Tyrode's solution. The concentration [C]-, frequency-, and voltage-dependent effects of the drugs were investigated. Maximum upstroke velocity of phase 0 (Vmax) was [C]-dependently depressed by both OH-Q and OH-HQ but at a lesser degree than with Q and HQ, respectively: at the [C] of 50 microM, Vmax depression attained 26.7 +/- 2.6% with OH-Q versus 45.9 +/- 1.6% with Q and 32.3 +/- 1.9% with OH-HQ versus 54.6 +/- 1.4% with HQ. This effect was frequency and voltage dependent without significant differences between the four compounds. In the presence of equipotent [C], recovery kinetics of Vmax was significantly slower with metabolites than with respective parent drugs. In contrast, the effects of metabolites on action potential duration at 90% of repolarization (APD90) and effective refractory period (ERP) differed from those observed with parent drugs. With metabolites, APD90 and ERP were increased in a [C]-dependent manner, whereas the Q- and HQ-induced lengthening in APD90 and ERP was observed only at low concentration and low frequency. In addition, the OH-Q- and OH-HQ-induced APD90 lengthening was not altered by increasing pacing rate. In rabbit Purkinje fibers, increase in cycle length and prolonged exposure to either metabolites or parent drug caused early afterdepolarizations (EADs) and triggered activity. With all drugs tested, EADs arose more frequently at the plateau level than at the final repolarization of AP, but the incidence of EADs appeared to be much lower with metabolites than with parent drugs. The present results demonstrate that OH-Q and OH-HQ exert qualitatively similar but quantitatively less potent depressant effects on Vmax than Q and HQ, respectively, but differ in the lengthening effect on APD. We suggest that metabolites may participate in class I antiarrhythmic action of their respective parent drug and contribute to their arrhythmogenicity.

Clopidogrel, an inhibitor of platelet aggregation, was initially thought to be free of the side-effects of ticlopidine. We describe a man who developed aplastic anaemia after 5 months of treatment with clopidogrel. There were no other plausible causes. We suggest that his fatal aplastic anaemia might have been induced by clopidogrel.

Ten patients suffering from chronic premature ventricular complexes (>60/h) were treated orally in a double-blind crossover study with encainide (50 mg three times a day) and disopyramide (200 mg three times a day), with five 7 day study periods: survey, placebo, encainide or disopyramide, washout placebo and disopyramide or encainide. At the end of each 7 day period, a 12 lead electrocardiogram, a 48 hour ambulatory electrocardiogram and a treadmill exercise test were performed. Blood levels of encainide and its metabolites and of disopyramide were measured at the end of each treatment (steady state). Drug efficacy was assessed by: 1) more than 80% reduction in the number of premature ventricular complexes per 24 hours, and 2) absence of ventricular tachycardia.Encainide was effective in four patients (complete suppression of premature ventricular complexes) and ineffective in five. One patient who showed a 92% re- auction in the number of premature ventricular complexes developed sustained ventricular tachycardia after 24 hours of treatment. Disopyramide was effective in three patients (>80% reduction in the number of premature ventricular complexes) and ineffective in seven patients. With encainide, the percent increase in PR, QRS and QT interval duration was, respectively: 32.7 (p < 0.001), 30.8 (p < 0.001) and 10.6% (p < 0.01). With disopyramide this increase was not significant. Despite the variability of drug blood levels, a relation between blood levels and suppression of premature ventricular complexes on the 48 hour ambulatory electrocardiogram was found with encainide, but not with disopyramide. The side effects observed for encainide were visual disturbances and headache; for disopyramide, they were headache, dryness of mouth and dysuria.

In vitro and in vivo electrophysiological studies have shown that propafenone could be classified as a class I antiarrhythmic agent. The aim of this study was to investigate the short-term antiarrhythmic efficacy and safety of propafenone in 10 patients compared to disopyramide in a double-blind randomized protocol. Included patients suffered from ventricular arrhythmias with at least 60 ventricular premature beats (VPB) per hour refractory to at least two other antiarrhythmic agents. At the end of the control period and of the two treatment periods during which patients received either propafenone (300 mg three times a day) or disopyramide (200 mg three times a day), clinical examination, Holter recordings, electrocardiogram, and clinical laboratory tests were performed. The PR interval and the QRS interval were significantly increased with propafenone, but not with disopyramide. The cQT interval was not significantly changed by either propafenone or disopyramide. Heart rate was decreased with propafenone (p

Encainide is a new antiarrhythmic class IC agent. Eleven patients were given 1 mg/kg of encainide i.v. over a 15-min period. Electrophysiological studies were done before and l h after drug administration. Blood levels of encainide and its principle metabolites O-demethyl-encainide, 3 metoxy-O-demetyl-encainide and N-demethyl-encainide were measured serially after drug administration. Heart rate, blood pressure, and conduction intervals were monitored. Sixty minutes after drug administration there was a marked increase of the QRS, PA, AH, and HV intervals of 28.1% (p less than 0.01), 17.2% (p less than 0.01), 22.4% (p less than 0.01), and 32.2% (p less than 0.01), respectively, and a slight increase of the Wenckebach cycle length of 8% (p less than 0.05). BP, RR, QT, CSNRT, ESACT, ERP, and FRP did not vary significantly. The HV interval already was increased significantly 2 min after drug administration, while AH was not increased until 15 min after drug administration. The average blood levels of encainide and ODE 60 min after drug administration were 0.410 +/- 0.12 and 0.176 +/- 0.09 microgram/ml, respectively (mean +/- SE of the mean). There was a positive correlation between the increase of the AH and the blood level of ODE, which points out the importance of prolonged electrophysiological studies when testing drug with possibly active metabolites.

At the present time, there is no satisfactory pharmacological treatment for arrhythmia or conduction disorders induced by or aggravated by vagal hypertonia. The limited duration of action of the atropine derivatives currently available justifies the development of new compounds with expected longer acting duration. The aim of this study was to compare the effects of a single blind intravenous injection of ipratropium bromide to those of atropine sulfate in 22 patients. These patients were studied with continuous Holter recordings for three days. During the second and the third nights (patient sleeping), boluses of atropine (0.03 mg/kg) and of ipratropium bromide (0.03 mg/kg), respectively, were added to a continuous saline intravenous infusion. Accurate ECG analysis allowed determination of maximal heart rate peak, timing of maximal heart rate, variations in sinus cycle length, atrioventricular conduction, and durations of drug action. A nonsuggestive questionnaire was presented to patients to detect possible occurrence of side effects. The mean maximal heart rate rose significantly (p less than 0.001) for atropine (+46.2%) and for ipratropium bromide (+57.4%). The effects obtained with ipratropium bromide on the heart rate lasted nearly twice as long as those obtained with atropine (respectively, 120 +/- 38.4 min and 70 +/- 30 min- for the pharmacological half-life). Common minor muscarinic side effects (dryness of the mouth) were noted with the two drugs. In conclusion, this comparative intraindividual study confirmed the prolonged vagolytic effects of intravenous ipratropium bromide, which may be valuable in the treatment of patients with vagally mediated automaticity and conduction disturbances.

Propafenone (Pf) is a class I antiarrhythmic drug that can be given both orally and intravenously. In order to examine whether its two major metabolites [5-hydroxypropafenone (5-OH-Pf) and N-depropylpropafenone (N-DP-Pf)] possess pharmacodynamical properties, we compared their electrophysiological effects to those of the parent drug on papillary muscle fibers from guinea pig ventricular myocardium. After baseline action potential and refractory period characteristics were measured at different pacing rates, the tissue preparations were superfused with either Pf, 5-OH-Pf, or N-DP-Pf at five different concentrations and electrophysiological characteristics were studied again. The maximal rate of depolarization (Vmax) was depressed by the three compounds only at the highest concentration, although the effect of N-DP-Pf was slightly less than the other two. Refractory periods were altered only by the highest concentration of 5-OH-Pf. Propafenone and N-DP-Pf exhibited equally slow on-set/off-set kinetics of the sodium channel block, whereas those of 5-OH-Pf were twice as long, which seems to suggest a slower rate of dissociation of the latter from the inactivated sodium channels. Thus, 5-OH-Pf and N-DP-Pf comply with the definition of the class IC antiarrhythmic drugs. The cumulative in vivo effects of the two metabolites and of the parent drug could have far reaching clinical implications, especially in the genetically predisposed extensive metabolizing subject.