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Introduction L’association fixe d’antiviraux directs ledipasvir/sofosbuvir (LDV/SOF), disponible sous la forme d’un comprimé unique, n’a pas été étudiée spécifiquement chez les patients chroniquement infectés par un VHC de génotype 1 (G1), co-infectés par le VIH et en échec d’un traitement préalable incluant un inhibiteur de la protéase (IP) NS3/A4 du VHC. Nous avons évalué l’efficacité et la tolérance de cette combinaison dans cette population de patients, historiquement considérés comme très difficiles à traiter (étude ANRS HC31 SOFTRIH). Patients et méthodes Les patients infectés de manière chronique par un VHC G1, co-infectés par le VIH et sous traitement antirétroviral stable (ARV), en échec d’un traitement anti-VHC antérieur par interféron pégylé/ribavirine/IP NS3/A4 ou ayant interrompu précocement ce traitement pour intolérance, ont été inclus dans cette étude prospective. Tous les patients ont reçu la combinaison fixe LDV/SOF (90 mg/400 mg), une fois par jour pendant 12 semaines ou 24 semaines en cas cirrhose hépatique. Les patients pouvaient également recevoir les ARVs suivants : tenofovir, emtricitabine,lamivudine, raltegravir, efavirenz, rilpivirine, enfuvirtide. Les critères de jugement d’efficacité étaient l’obtention d’une réponse virologique soutenue, définie par un ARN VHC indétectable 4 semaines (RVS4) ou 12 semaines (RVS12, critère principal) après l’arrêt du traitement. La survenue d’effets indésirables (EIs) et les paramètres biologiques standards incluant la numération des lymphocytes CD4 et l’ARN VIH ont été étudiés. Résultats Soixante-huit patients avec un G1a (82,5 %), un G1b (13 %) ou un autre G1 (4,5 %) ont été inclus : hommes 79 % ; âge moyen 52 ans ; médiane de l’ARN VHC (6,2 Log UI/mL) et des lymphocytes CD4 (629/mm 3 ) à l’inclusion ; cirrhose compensée (40 %). Soixante-cinq patients étaient évaluables pour les critères virologiques. Soixante-deux patients (95,4 %) ont obtenu une RVS4 (prélèvement sanguin non disponible chez 1 patient, ARN VHC détectable inférieur au seuil de quantification chez 2 patients). Tous les patients (100 %) ont obtenu une RVS12. Deux patients ont présenté un rebond virologique VIH confirmé. Aucun patient n’a interrompu précocement le traitement de l’étude pour intolérance. Les EIs constatés chez plus de 10 % des patients étaient les suivants : fatigue (19,1 %), pression artérielle élevée (14,7 %), céphalées (11,8 %). Conclusion Si les études ERADICATE [1] et ION-4 [2] ont récemment montré une efficacité et une tolérance très bonnes de l’association LDV/SOF chez les patients co-infectés par le VIH, notre étude apporte des résultats supplémentaires chez les patients historiquement considérés comme très difficiles à traiter, incluant ceux présentant une cirrhose hépatique. [ABSTRACT FROM AUTHOR]

Good clinical practice (GCP) is an international ethical and scientific quality standard for the design, conduct, performance, monitoring, auditing, recording, analyses and reporting of clinical trials. Before the start of a clinical trial, investigators commit to perform the research in accordance with GCPs, regulatory dispositions and protocol. The sponsors are responsible for investigators' selection and for controlling their skills. Whereas industrial sponsors systematically require a certificate of GCP training, academic sponsors seem to be less demanding. We have carried out two surveys between April and June 2018. A first questionnaire was sent to the 40 French academic directions of clinical research and innovation in order to determine their requirements about the GCP training of the investigators participating in their trials. The second questionnaire was transmitted to physicians of the "Bretagne recherche clinique hospitalière network": Rennes, Saint-Malo, Saint-Brieuc, Vannes, Lorient and Pontivy hospitals, in order to determine the GCP certification rate, and their needs in terms of clinical research training. Twenty-eight (70%) directions of clinical research answered the first survey, among which 18 (64%) required systematically the investigators' GCP certification in case of category 1 interventional studies. This rate decreased for category 2 (50%) and non-interventional category 3 (18%) studies. A total of 345 physicians answered the second survey, among which 263 (76%) had already been clinical trial investigators. However, only 29% of all physicians and 54% of those who had been principal investigator were certified for GCP training. These results support the need for large campaigns of GCP training in public hospitals., (Copyright © 2020 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Pitch perception modifications are among the little-known adverse effects observed with antiepileptics, mainly affecting patients treated with carbamazepine (CBZ). Here, we describe an original French case of pitch perception modification due to CBZ resulting in perfect pitch loss. We also reviewed the literature as well as French and world health organisation global pharmacovigilance database. The case report concerns a 22-year-old patient with perfect pitch with untreated left temporal partial epilepsy. Following a generalized seizure, the introduction of CBZ prolonged release (200mg twice a day) is decided. As soon as CBZ is introduced, the patient notices a change in pitch perception, about a semitone lower. This adverse effect persisted despite a gradual decrease in doses. The patient reported a total recovery of his perfect pitch when CBZ stopped completely 11 years later. In the French pharmacovigilance database, only one other case of pitch perception modification under CBZ was recorded (no cases were found with oxcarbazepine, lacosamide, sodium valproate, lamotrigine, levetiracetam, phenobarbital, phenytoin, primidone, ethosuximide, vigabatrine, felbamate, gabapentin, tiagabine and topiramate). In the literature, 27 cases of pitch perception modification have been published with CBZ, 1 case with oxcarbazepine and 1 case with lacosamide. Pitch perception modification is a very rare adverse effect of CBZ, oxcarbazepine and lacosamide, identified in the literature mainly in the Japanese population, in experienced musicians. A rapid onset after the introduction of treatment, a complete resolution of symptoms, in most cases upon discontinuation of treatment, is observed, with no sequelae reported. Due to the impact on quality of life, especially in patients whose profession is related to music, knowledge of this adverse event seems important to evoke this diagnosis., (Copyright © 2020 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Beyond the application of legal requirements, clinical trials must have a permanent approach of quality control. The clinical investigation centers (CICs) are academic structures of clinical research certified by the French National institute of health and medical research (Inserm) and whose functioning relies on recommendations of good practice. It is important to accompany this standardization of practices by the implementation of a quality management system. This article presents the process that enabled the CIC of Rennes to become certified ISO 9001 by French standards association (Afnor) certification in May, 2016. The application of the fundamental principles of the standard ISO 9001 in the domain of clinical research is approached. The problem of the perimeter for the certification and the related process mapping are exposed. The activities of methodology, management and analysis of clinical studies were chosen for the initial certification of the CIC of Rennes. The perspectives for the extension of the perimeter of certification are also approached at the end of article., (Copyright © 2018 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Aim: To stimulate spontaneous reporting of adverse drug reactions and to enable information sharing on drug's safety between Rennes Pharmacovigilance Regional Center and hospitals of its territory., Methods: After having outlined objectives of the network to 11 major public institutions, the network was launched. It is coordinated by a dedicated pharmacist thanks to animation of monthly videoconference and diffusion of a quarterly newsletter. It relies on a local correspondent in each hospital who disseminates information to healthcare professionals and becomes their local contact for pharmacovigilance., Results: The quality and usefulness of information sharing are emphasized by every one. We observed an increase in notifications and information requests multiplied by 3.4 and 2.4 % respectively between 2008 and 2013., Conclusions: The existence of a dedicated coordinator and implication of the correspondents are key elements enabling the network to be efficient. The increase of spontaneous notifications is noteworthy. The next step is to officially enlarge the network to private hospitals., (© 2014 Société Française de Pharmacologie et de Thérapeutique.)

An important part of drug development relies on the analysis of the relationships between drug doses and therapeutic and/or side effects. This analysis implies an in-depth understanding of the pharmacokinetics (PK) and pharmacodynamics (PD) of the drug and of the relationship which links them (PK-PD relationship). The aim of this round table was to define the place of the study of PK-PD relationships in drug development. After reviewing the definitions of PK models, PD models, and of integrated PK-PD models, the article highlights the importance of studying the PK-PD relationship during the successive phases of drug development (pre-clinical, phase I/II, phase III) and in specific populations (children, elderly people). A number of examples taken from pharmaceutical development or international literature are given. They show the methodology used and the type of information which can be drawn at each step of drug development. The article also presents the difficulties which prevent a more systematic application of this kind of approach during drug development. Scientific limits, problems in relation with the misunderstanding of the approach both in academic institutions and in pharmaceutical companies, and difficulties related to the lack of specific guidelines are discussed. The conclusion emphasizes the importance of using PK-PD modeling all along drug development and presents a number of actions which could further broaden its use.

Although the decision to continue or to stop prematurely a clinical trial is not solely based on statistical tests, they bring useful objective arguments to the data monitoring board. However, the multiple use of statistical tests leads to increase the risk of false positive conclusions in favor of one of the treatments, and several methods have been developed to address this problem. This article presents the four major strategies that are being used for monitoring clinical trials, as well as the rationale for planning and using such statistical monitoring procedures.

In order to fulfil the ethical principles linked to the protection of patients randomized in a controlled clinical trial, monitoring procedures need to be set up. In this context, a committee of experts, called the data monitoring committee is in charge of reviewing regularly unblinded data to assess the quality and the relevance of the trial, to evaluate the evidence of an emerging treatment difference and to control the rate of occurrence of serious adverse events. After each meeting, the monitoring committee reports to the steering committee its recommendation to continue or to stop the trial prematurely. Protocol modifications might be proposed as well. Illustrated with several examples, this article reviews different situations a monitoring committee might have to tackle with.

In cancer, phase II clinical trials are most of the time non comparative trials, the purpose of which is to determine whether a new chemotherapy is effective enough to warrant further study in phase III. So, it is necessary, at this stage, to dispose of decision methods which allow, for ethical reasons, for early stopping when inefficacy or efficacy is evident. In a previous work, we have extended to these phase II trials two group sequential methods initially proposed in phase III, and we have demonstrated the advantages of these methods (type I error alpha and power close to the nominal values, reduction of the sample size) as compared to the main methods proposed in the literature. The aim of this paper is to present the method which appears to be the best suited to phase II clinical trials, the triangular test. After a first part, focused on its theoretical aspects, the second part, more practical, presents its use for the design of a cancer trial and its analysis.

Theoretically, there are two reasons for using the association of dobutamine and enoximone in patients with acute cardiac failure; the powerful vasodilator effect of enoximone and the different biochemical actions of the two drugs on the myocardial fibre affecting the production (dobutamine) or the degradation (enoximone) of cyclic AMP. The combined effects of beta adrenergic agonists and phosphodiesterase III inhibitors in vitro and in vivo have been previously reported. An increased contractile response to dobutamine has been demonstrated with enoximone on isolated human ventricle obtained during cardiac transplantation. We confirmed the additive effect of dobutamine (5 to 10 micrograms/kg/min) and enoximone (1 mg/kg/bolus IV) in 8 patients with acute cardiac failure with each molecule used alone. Mild changes in heart rate (+19 bpm) and in systolic blood pressure (-3 mmHg) were observed simultaneously. The absence of an increase in SvO2 compared to the use of each molecule in monotherapy is probably related to a tendency to increase myocardial oxygen consumption which may be potentially deleterious in terms of gas exchange. Having demonstrated the additive effects of the association of dobutamine and enoximone, there is probably a place for this therapeutic association in the management of acute cardiac failure. However, the potential risk of inducing an atrial and/or ventricular tachyarrhythmia and the consequences of lowering ventricular filling pressures and systemic vascular resistances should be born in mind; when using this therapeutic association, the authors suggest starting treatment with low doses of dobutamine (5/kg/min) and enoximone (0.5 - 1 mg/kg) with haemodynamic control and steadily increasing the doses, depending on the results obtained.

Unlabelled: The purpose of this study was to investigate the relationship between plasma concentration (Cp) of perindoprilat (P), the active metabolite of perindopril, and plasma converting enzyme activity (CEA) after a single oral administration of perindopril. CEA and Cp were investigated before, and, 1, 2, 3, 4, 6, 8, 10, 24 and 48 hours after a random administration of a placebo or 4, 8, 16 mg perindopril in a double-blind and crossover study performed in 6 healthy male volunteers. Effect on CEA was expressed as the percentage of inhibition of pretreatment value (CEA0): CEI = 100 (CEA0 = CEA)/CEA0. The CEI-Cp relationship was non linear and displayed an hysteresis loop. Following Sheiner et al. (Clin Pharmacol Ther, 1979; 25: 358-71), we used an effect compartment in which drug dissipation is governed by a first-order rate constant keo. Concentration of P in the effect compartment (Ce) was related to CEI by the Hill equation CEI = 100 Emax Cen/(EC50n + Cen), where Emax (expressed as a percentage) is the theoretical maximum effect, EC50 the Ce which produces 50 p. 100 of Emax, and n the Hill coefficient. Pharmacodynamic parameters were estimated by the non parametric approach proposed by Unadkat et al. (Clin Pharmacol Ther, 1986; 40: 86-93). The Hill equation was fitted to the data for 3 different values of n: 1, 2, and 3., Results: for all the 3 doses, the best curve fitting was achieved for n = 1 or 2. We obtained keo = 0.60 +/- 0.30 h-1 (mean +/- s.d.), Emax = 90 +/- 10 p. 100, EC50 = 1.30 +/- 0.95 ng/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of nifedipine (20 mg), propranolol (80 mg), the nifedipine (20 mg) + propranolol (80 mg) combination and a placebo on cardiac [heart rate (HR), cardiac output (CO, Doppler determination)] and systemic [mean arterial pressure (MAP), systemic vascular resistance (SVR)] and regional hemodynamic [brachial blood flow (BBF) and arterial diameter (BAD) (pulsed Doppler), forearm vascular resistance (FVR)] parameters were investigated during the 3 hours following their random administration in a double blind and cross over study performed in 6 healthy subjects. At their peak effects, (a) nifedipine decreased SVR (-17 p. 100, p less than 0.01), increased HR (+ 12p. 100, p less than 0.001) and CO (+ 18 p. 100, p less than 0.001), did not change MAP and increased BBF (+31 p. 100, p less than 0.001) with a vasodilating effect which affected both large and small arteries; (b) propranolol decreased HR (-14 p. 100, p less than 0.05) and CO (-25 p. 100, p less than 0.01), increased SVR (+25 p. 100, p less than 0.01), did not change MAP and decreased BBF (-28 p. 100, p less than 0.05) with a vasoconstrictor effect which affected both large and small arteries; (c) in the nifedipine-propranolol combination, nifedipine neutralized propranolol-induced systemic and regional vasoconstrictor effects while propranolol antagonized nifedipine-induced increases in HR and CO. Thus, the favorable synergistic effects of the nifedipine-propranolol combination in hypertensive patients could be demonstrated in healthy subjects inasmuch as MAP was decreased and peripheral vascular blood flows were preserved.(ABSTRACT TRUNCATED AT 250 WORDS)