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2. Piperacillin Population Pharmacokinetics and Dosing Regimen Optimization in Critically Ill Children Receiving Continuous Renal Replacement Therapy

Author

Michael Thy, Saïk Urien, Frantz Foissac, Naïm Bouazza, Inès Gana, Emmanuelle Bille, Agathe Béranger, Julie Toubiana, Romain Berthaud, Fabrice Lesage, Sylvain Renolleau, Jean-Marc Tréluyer, Sihem Benaboud, and Mehdi Oualha

Subjects
Pharmacology, Infectious Diseases, Pharmacology (medical)
Abstract

We aimed to develop a piperacillin population pharmacokinetic (PK) model in critically ill children receiving continuous renal replacement therapy (CRRT) and to optimize dosing regimens. The piperacillin plasma concentration was quantified by high-performance liquid chromatography. Piperacillin PK was investigated using a nonlinear mixed-effect modeling approach. Monte Carlo simulations were performed to compute the optimal scheme of administration according to the target of 100% interdose interval time in which concentration is one to four times above the MIC (100% fT > 1 to 4× MIC). A total of 32 children with a median (interquartile range [IQR]) postnatal age of 2 years (0 to 11), body weight (BW) of 15 kg (6 to 38), and receiving CRRT were included. Concentration-time courses were best described by a one-compartment model with first-order elimination. BW and residual diuresis (Q(u)) explained some between-subject variabilities on volume of distribution (V), where [Image: see text] , and clearance (CL), where [Image: see text] , where CL(pop) and V(pop) are 6.78 L/h and 55.0 L, respectively, normalized to a 70-kg subject and median residual diuresis of 0.06 mL/kg/h. Simulations with intermittent and continuous administrations for 4 typical patients with different rates of residual diuresis (0, 0.1, 0.25, and 0.5 mL/kg/h) showed that continuous infusions were appropriate to attain the PK target for patients with residual diuresis higher than 0.1 mL/kg/h according to BW and MIC, while for anuric patients, less frequent intermittent doses were mandatory to avoid accumulation. Optimal exposure to piperacillin in critically ill children on CRRT should be achieved by using continuous infusions with escalating doses for high-MIC bacteria, except for anuric patients who require less frequent intermittent doses.

Published
2022

3. Lopinavir-Ritonavir Impairs Adrenal Function in Infants

Author

Dulanjalee, Kariyawasam, Marianne, Peries, Frantz, Foissac, Sabrina, Eymard-Duvernay, Thorkild, Tylleskär, Mandisa, Singata-Madliki, Chipepo, Kankasa, Nicolas, Meda, James, Tumwine, Mwiya, Mwiya, Ingunn, Engebretsen, Christa E, Flück, Michaela F, Hartmann, Stefan A, Wudy, Deborah, Hirt, Jean Marc, Treluyer, Jean-Pierre, Molès, Stéphane, Blanche, Philippe, Van De Perre, Michel, Polak, Nicolas, Nagot, C, Rekacewicz, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Pathogénèse et contrôle des infections chroniques (PCCI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Evaluation thérapeutique et pharmacologie périnatale et pédiatrique (EA_7323), Université Paris Descartes - Paris 5 (UPD5), Nutrition, alimentation, sociétés (NALIS), Centre for International Health [Bergen, Norway], University of Bergen (UiB), Effective Care Research Unit, University of Fort Hare, Alice, South Africa, University of Zambia [Lusaka] (UNZA), SANTE/SIDA [Bobo-Dioulasso, Burkina Faso], Institut de Recherche en Sciences de la Santé (IRSS) / Centre Muraz, Department of Paediatrics and Child Health, Makerere University [Kampala, Ouganda] (MAK), Department of Paediatrics and Child Health [Lusaka, Zambia], University of Zambia, Centre for International Health, Pediatric Endocrinology and Diabetology, University Children's Hospital Bern, Justus-Liebig-Universität Gießen (JLU), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Bergen (UIB), Makerere University (MAK), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP]

Subjects
0301 basic medicine, Microbiology (medical), medicine.medical_specialty, Anti-HIV Agents, [SDV]Life Sciences [q-bio], 030106 microbiology, Lopinavir/ritonavir, Dehydroepiandrosterone, HIV Infections, 610 Medicine & health, Asymptomatic, Lopinavir, 03 medical and health sciences, South Africa, 0302 clinical medicine, Pregnancy, Internal medicine, Burkina Faso, medicine, Humans, 030212 general & internal medicine, Child, Testosterone, ComputingMilieux_MISCELLANEOUS, Ritonavir, business.industry, Lamivudine, Infant, 3. Good health, Infectious Diseases, Endocrinology, 570 Life sciences, biology, Female, Fresh frozen plasma, Steroid 21-Hydroxylase, medicine.symptom, business, medicine.drug
Abstract

BackgroundPerinatal treatment with lopinavir boosted by ritonavir (LPV/r) is associated with steroidogenic abnormalities. Long-term effects in infants have not been studied.MethodsAdrenal-hormone profiles were compared at weeks 6 and 26 between human immunodeficiency virus (HIV)-1–exposed but uninfected infants randomly assigned at 7 days of life to prophylaxis with LPV/r or lamivudine (3TC) to prevent transmission during breastfeeding. LPV/r in vitro effect on steroidogenesis was assessed in H295R cells.ResultsAt week 6, 159 frozen plasma samples from Burkina Faso and South Africa were assessed (LPV/r group: n = 92; 3TC group: n = 67) and at week 26, 95 samples from Burkina Faso (LPV/r group: n = 47; 3TC group: n = 48). At week 6, LPV/r-treated infants had a higher median dehydroepiandrosterone (DHEA) level than infants from the 3TC arm: 3.91 versus 1.48 ng/mL (P < .001). Higher DHEA levels (>5 ng/mL) at week 6 were associated with higher 17-OH-pregnenolone (7.78 vs 3.71 ng/mL, P = .0004) and lower testosterone (0.05 vs 1.34 ng/mL, P = .009) levels in LPV/r-exposed children. There was a significant correlation between the DHEA and LPV/r AUC levels (ρ = 0.40, P = .019) and Ctrough (ρ = 0.40, P = .017). At week 26, DHEA levels remained higher in the LPV/r arm: 0.45 versus 0.13 ng/mL (P = .002). Lopinavir, but not ritonavir, inhibited CYP17A1 and CYP21A2 activity in H295R cells.ConclusionsLopinavir was associated with dose-dependent adrenal dysfunction in infants. The impact of long-term exposure and potential clinical consequences require evaluation.Clinical Trials RegistrationNCT00640263

Published
2020
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4. Alendronate or Zoledronic acid do not impair wound healing after tooth extraction in postmenopausal women with osteoporosis

Author

Frantz Foissac, Philippe Lesclous, Sylvain Catros, Christian Roux, Alexandra Cloitre, Béatrice Louvet, Cécile Châtel, Laurent Devoize, Université de Nantes - UFR Odontologie (UFR Odonto), Université de Nantes (UN), Regenerative Medicine and Skeleton (RMeS), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Bioingénierie tissulaire (BIOTIS), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Service d'Odontologie [CHRU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de chirurgie plastique et maxillofaciale, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Hôpital Michallon, CIC - Mère Enfant Necker Cochin Paris Centre (CIC 1419), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Nantes - UFR Odontologie, Regenerative Medicine and Skeleton research lab (RMeS), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Jehan, Frederic

Subjects
0301 basic medicine, [SDV.MHEP.AHA] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Histology, Physiology, Tooth extraction, Endocrinology, Diabetes and Metabolism, Population, Osteoporosis, Dentistry, 030209 endocrinology & metabolism, Zoledronic Acid, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, Medicine, Antibiotic prophylaxis, education, Osteoporosis, Postmenopausal, Dental alveolus, Wound Healing, education.field_of_study, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Alendronate, Bone Density Conservation Agents, Diphosphonates, [SDV.MHEP.GEG] Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, Osteonecrosis of the jaw, business.industry, Incidence (epidemiology), [SDV.MHEP.GEG]Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, Wound healing, Bisphosphonates, medicine.disease, 3. Good health, Discontinuation, Postmenopause, 030104 developmental biology, Zoledronic acid, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Bisphosphonate-Associated Osteonecrosis of the Jaw, Female, business, medicine.drug
Abstract

International audience; Background: Bisphosphonates (BPs) are widely used for the prevention or treatment of osteoporosis. One of the most serious complications associated with BPs is medication-related osteonecrosis of the jaw (MRONJ) but its incidence in patients with osteoporosis is very low ranging from 0.001-0.15%. A major predisposing factor for MRONJ is tooth extraction (TE). Controversies persist about the influence of current BP therapy regarding socket healing after TE. The aims of this study were to investigate prospectively, (i) alveolar bone healing, i.e., filling of the bony socket by new bone and (ii) mucosal healing, i.e., closure of the overlying mucosa, after TE in women receiving current BP therapy for the prevention or the treatment of postmenopausal osteoporosis. Methods: Women with osteoporosis under current treatment with BPs (BP+ group) or other anti-osteoporotic medications (BP-group) undergoing single TE were included in this study. No antibiotic prophylaxis was prescribed solely for the BP therapy, but antibiotic treatment may have been required for local infectious conditions. Chlorohexidine mouthwashes were systematically prescribed in all study patients for one week after TE. New bone height (NBH) and rate of socket filling (RSF) were recorded using intraoral standardized radiographs one month and 3 months after TE (T30 and T90 respectively). The closure of the overlying mucosa was assessed by measuring the wound extent with an electronic caliper at 1 week and at 1 month after TE (T7 and T30 respectively). Results: At T30, NBH was not statistically different between the BP+ and BP-groups (p = .76). At T90, more than a twofold in NBH increase was recorded for both groups with no statistically significant difference between them (p = .76). At T30 and T90, RSF was similar in both groups (p = .58 and p = .32 respectively). More than a twofold RSF increase was founded between T30 and T90 in both groups. No demographic or BPs-related factors were correlated with the RSF at T90. At T7, the mucosa wound extent was reduced by more than twofold with no statistically significant difference between both groups (p = .80). At this time, mucosa healing was achieved in 11.9% of the BP+ group and 10% of the BP-group (p = .99). At T30, mucosal healing was achieved in all patients but two, and at T90 it was achieved in all patients. Conclusion: This study provides new insights into bone and mucosal healing in patients with osteoporosis taking BPs after TE. In this population, TE can be managed successfully with an appropriate surgical protocol and without discontinuation of BP treatment.

Published
2020
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5. HPLC-MS/MS method for the simultaneous quantification of dolutegravir, elvitegravir, rilpivirine, darunavir, ritonavir, raltegravir and raltegravir-β-d-glucuronide in human plasma

Author

Jean-Marc Tréluyer, Déborah Hirt, Radia Aboura, Gabrielle Lui, Sihem Benaboud, Naïm Bouazza, Frantz Foissac, Sana Boujaafar, Inès Gana, Yi Zheng, Evaluation thérapeutique et pharmacologie périnatale et pédiatrique (EA_7323), Université Paris Descartes - Paris 5 (UPD5), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Anti-HIV Agents, Clinical Biochemistry, Pharmaceutical Science, Integrase inhibitor, 01 natural sciences, Analytical Chemistry, chemistry.chemical_compound, Tandem Mass Spectrometry, Drug Discovery, medicine, Humans, [CHIM]Chemical Sciences, Chromatography, High Pressure Liquid, Spectroscopy, Darunavir, Randomized Controlled Trials as Topic, Chromatography, medicine.diagnostic_test, 010405 organic chemistry, Chemistry, Elvitegravir, 010401 analytical chemistry, Reproducibility of Results, Raltegravir, 3. Good health, 0104 chemical sciences, Therapeutic drug monitoring, Rilpivirine, Dolutegravir, Ritonavir, Drug Monitoring, medicine.drug
Abstract

Therapeutic drug monitoring (TDM) is essential in the optimization of antiretroviral (ARV) treatments. In this work, we describe a new method for the simultaneous quantification of six molecules: the three novel ARV agents dolutegravir (DTG), elvitegravir (ELV) and rilpivirine (RPV), the first integrase inhibitor raltegravir (RAL) and its major metabolite the raltegravir-β- d -glucuronide (RAL-GLU), an protease inhibitor darunavir (DRV) and its booster ritonavir (RTV) in human plasma. The drugs were extracted from 100 μL of plasma by a simple method of protein precipitation using acetonitrile. The separation was carried out on a Kinetex phehyl-hexyl column using a phase mobile composed of 55 % of water (0.05 % formic acid,v/v) and 45 % of methanol (0.05 % formic acid,v/v). The flow rate was set at 0.5 mL/min. The calibration ranged from 60 to 15000 ng/mL for DRV, from 20 to 5000 ng/mL for DTG and ELV, from 10 to 2500 ng/mL for RAL, RAL-GLU, RTV and RPV. The proposed method was validated with a good precision (inter- and intra-day CV% inferior to 12.3 %) and a good accuracy (inter- and intra-day bias between −9.9 % and 10 %) for all the analytes. The proposed method is simple, reliable and suitable for therapeutic drug monitoring (TDM) and for pharmacokinetics studies.

Published
2020
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6. Relationships between metabolic status, seminal adipokines, and reproductive functions in men from infertile couples

Author

Yaelle Elfassy, Alice Bongrani, Pierre Levy, Frantz Foissac, Soraya Fellahi, Céline Faure, Chloé McAvoy, Jacqueline Capeau, Joëlle Dupont, Bruno Fève, Rachel Levy, Jean-Philippe Bastard, Nathalie Sermondade, Florence Eustache, Myriam Benarroch, Charlotte Dupont, Isabelle Cedrin, Vanina De Larouzière, Emmanuelle Mathieu D’Argent, Angela Sutton, Jérôme Guechot, Sébastien Czernichow, Hôpital Tenon, Assistance Publique - Hôpitaux de Paris (AP-HP), Sorbonne Université, Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Université de Tours-Institut Français du Cheval et de l'Equitation [Saumur]-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Saint-Antoine [AP-HP], Pathologies biliaires, fibrose et cancer du foie (Inserm UMR_S 938), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
Infertility, Adult, Leptin, Male, [SDV.SA]Life Sciences [q-bio]/Agricultural sciences, medicine.medical_specialty, Adolescent, Endocrinology, Diabetes and Metabolism, Urology, MEDLINE, Adipokine, Physiology, 030209 endocrinology & metabolism, Semen, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Endocrinology, Adipokines, Internal medicine, Chemerin, Medicine, Humans, Nicotinamide Phosphoribosyltransferase, Infertility, Male, Adiponectin, biology, Sperm Count, business.industry, Interleukin-6, Reproduction, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, General Medicine, Middle Aged, medicine.disease, Sperm, Spermatozoa, 030220 oncology & carcinogenesis, biology.protein, Sperm Motility, Resistin, Female, Metabolic syndrome, Chemokines, business
Abstract

Objective Adipokines could be a link between metabolic syndrome (MS) and infertility. While the association between circulating adipokines and fertility has been extensively studied in females, this relationship in males was less investigated, although some adipokines are detectable in seminal plasma (SP). The aim of this study was to determine adipokine levels in blood and SP and to assess the relationships between adipokines, MS and semen parameters in men from infertile couples. Design Male partners of infertile couples referred to four medical French centers were enrolled in years 2013–2016. Methods Subjects (n = 160) aged 18–45 years were assessed for anthropometric, biochemical, sperm, and circulating hormonal parameters. Leptin, adiponectin, resistin, chemerin, visfatin, and IL-6 were measured in serum and SP. Results Infertility duration was higher in men with than without MS. Adipokine concentrations were higher in blood than in SP, except for IL-6 and visfatin. The most striking result was the significant correlation observed between seminal IL-6 and spermatozoid concentration, progressive motility, and sperm vitality. Moreover, while men with MS exhibited an expected lower adiponectinemia, they displayed 2.1-fold higher adiponectin levels in SP than men without MS. Finally, logistic regression analysis showed that BMI, infertility duration, and adiponectin serum/SP ratio were independently associated with MS. Conclusions These results suggest an involvement of seminal adipokines to modulate fertility in men with MS and that seminal IL-6 could play a beneficial role on sperm functionality. Further mechanistic studies are necessary to investigate the precise roles of these adipokines in male reproduction.

Published
2020
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7. Study characteristics impacted the pragmatism of randomized controlled trial published in nursing: a meta-epidemiological study

Author

Hélène Chappuy, Frantz Foissac, Naïm Bouazza, Jean-Marc Tréluyer, Flora Devos, Pierre-Yves Ancel, Evaluation thérapeutique et pharmacologie périnatale et pédiatrique (EA_7323), Université Paris Descartes - Paris 5 (UPD5), CIC - Mère Enfant Necker Cochin Paris Centre (CIC 1419), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service des Urgences Pédiatriques [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CCSD, Accord Elsevier, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
medicine.medical_specialty, Blinding, Epidemiology, [SDV]Life Sciences [q-bio], CINAHL, Placebo, law.invention, 03 medical and health sciences, Nursing care, 0302 clinical medicine, Randomized controlled trial, Nursing, law, Pragmatic Clinical Trials as Topic, medicine, Humans, 030212 general & internal medicine, Impact factor, business.industry, 3. Good health, [SDV] Life Sciences [q-bio], Epidemiologic Studies, Nursing Research, Sample size determination, Research Design, Periodicals as Topic, business, 030217 neurology & neurosurgery
Abstract

Objectives The objective of this study was to examine the impact of study characteristics on the score of the pragmatism/explanatory continuum of randomized controlled trials (RCTs) published in nursing journals using the PRagmatic Explanatory Continuum Indicator Summary (PRECIS)-2 tool. Study Design and Setting RCTs concerning five themes of nursing care indexed in the PubMed and CINAHL databases published from 2002 to 2005 and 2012 to 2015 were selected by title/abstract. A sample of 400 was randomly selected and evaluated with the PRECIS-2 tool and reading grid. Results The median PRECIS score was 32 of a possible 45 [28; 36] corresponding to a medium level of pragmatism. Studies with “medication” as an intervention had a more explanatory PRECIS score than studies with other intervention types (P = 0.015). Studies with “placebo” and “no usual care” as comparators had a more explanatory PRECIS score (P = 0.0027). The pragmatism/explanatory level was unaffected by impact factor (P = 0.42), h-index of the first and last author (P = 0.27 and P = 0.25, respectively), funding (P = 0.32), blinding (P = 0.41), sample size (P = 0.22), and time (P = 0.11). Conclusion This study highlights the pragmatism/explanatory level of nursing RCTs, the impact of the field of the article, and the comparator type on the pragmatism of these studies. Further studies are needed to confirm the astonishing result that blinding resulted in no significant difference in the PRECIS score.

Published
2019
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8. Is self-assessment by patients of disease activity acceptable over the long term in rheumatoid arthritis? A 3-year follow-up of 771 patients

Author

Sophie Pouplin, Nathalie Balandraud, Laure Gossec, Aleth Perdriger, Françoise Fayet, T. Marhadour, Frantz Foissac, Adeline Ruyssen-Witrand, Liana Euller-Ziegler, Emmanuelle Dernis, Christelle Sordet, Isabelle Chary-Valckenaere, Mélanie Gilson, Xavier Mariette, Maxime Dougados, Martin Soubrier, C. Beauvais, Pascal Richette, Anna Molto, Gaël Mouterde, René-Marc Flipo, Thierry Schaeverbeke, Service de Rhumatologie [CHU Pitié Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Rhumatologie [CHU Gabriel-Montpied], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Unité de Nutrition Humaine (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Service de Rhumatologie [CHU Clermont-Ferrand], Evaluation thérapeutique et pharmacologie périnatale et pédiatrique (EA_7323), Université Paris Descartes - Paris 5 (UPD5), CIC - Mère Enfant Necker Cochin Paris Centre (CIC 1419), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), PRES Sorbonne Paris Cité, Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie de l'Os et du Cartilage : Régulations et Ciblages Thérapeutiques (BIOSCAR (UMR_S_1132 / U1132)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université Paris Diderot - Paris 7 (UPD7), Service de rhumatologie [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], CHU Toulouse [Toulouse], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Service de rhumatologie [Rennes] = Rheumatology [Rennes], CHU Pontchaillou [Rennes], Service de Rhumatologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Hôpital Lapeyronie [Montpellier] (CHU), Aide à la Décision pour une Médecine Personnalisé - Laboratoire de Biostatistique, Epidémiologie et Recherche Clinique - EA 2415 (AIDMP), Université Montpellier 1 (UM1)-Université de Montpellier (UM), Service de Rhumatologie [CH Le Mans], Centre Hospitalier Le Mans (CH Le Mans), Service de rhumatologie, Centre Hospitalier Universitaire de Nice (CHU Nice)-Hôpital l'Archet, Service de rhumatologie[Lille], Hôpital Roger Salengro [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de Rhumatologie [CHU de Grenoble], Hôpital Sud de Grenoble, Groupe de Recherche et d'Etude du Processus Inflammatoire (GREPI), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Assistance Publique - Hôpitaux de Marseille (APHM), Arthrites autoimmunes (AA), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), CHU Rouen, Normandie Université (NU), Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de Hautepierre [Strasbourg], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Lariboisière, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes 1 - Faculté de Médecine (UR1 Médecine), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Département de Rhumatologie[Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Lapeyronie, Hôpital Pasteur [Nice] (CHU), Hôpital Roger Salengro [Lille], Centre Hospitalier Universitaire [Grenoble] (CHU), CHU Marseille, Immunologie des Maladies Virales et Autoimmunes (IMVA - U1184), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHRU Brest - Service de Rhumatologie (CHU - BREST - Rhumato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Lymphocytes B, Autoimmunité et Immunothérapies (LBAI), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), CHU Bordeaux [Bordeaux], Composantes innées de la réponse immunitaire et différenciation (CIRID), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Service de rhumatologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], CHU Pitié-Salpêtrière [APHP], CHU Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Lariboisière-Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Service de Rhumatologie [CHU Le Mans], CHU Le MAns, Hôpital Roger Salengro, Lymphocyte B et Auto-immunité (LBAI), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes - Faculté de Médecine (UR Médecine), Université de Rennes (UR), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Université Paris Diderot - Paris 7 (UPD7)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Jonchère, Laurent

Subjects
Self-assessment, musculoskeletal diseases, Adult, Male, medicine.medical_specialty, Self-Assessment, Time Factors, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, [SDV]Life Sciences [q-bio], education, MEDLINE, Aucun, Arthritis, Aftercare, Severity of Illness Index, law.invention, Disease activity, Arthritis, Rheumatoid, 03 medical and health sciences, 0302 clinical medicine, Rheumatology, Randomized controlled trial, law, Internal medicine, Severity of illness, Outcome Assessment, Health Care, medicine, Humans, Pharmacology (medical), 030212 general & internal medicine, skin and connective tissue diseases, health care economics and organizations, ComputingMilieux_MISCELLANEOUS, 030203 arthritis & rheumatology, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, business.industry, Reproducibility of Results, Middle Aged, medicine.disease, Term (time), [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Rheumatoid arthritis, Feasibility Studies, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Female, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Follow-Up Studies
Abstract

International audience; Self-assessment of disease activity is feasible in rheumatoid arthritis, but its frequency decreases over time.

Published
2019
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9. Fine Particulate Pollution and Asthma Exacerbations

Author

Frantz Foissac, Jean-Marc Tréluyer, Ricardo Carbajal, Naïm Bouazza, Saïk Urien, Romain Guedj, Hélène Chappuy, Evaluation thérapeutique et pharmacologie périnatale et pédiatrique (EA_7323), Université Paris Descartes - Paris 5 (UPD5), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Necker - Enfants Malades [AP-HP], Université Sorbonne Paris Cité (USPC), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), and CHU Cochin [AP-HP]

Subjects
Male, Databases, Factual, Meteorological Concepts, Fine particulate, Air pollution, 010501 environmental sciences, medicine.disease_cause, 01 natural sciences, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, chemistry.chemical_compound, 0302 clinical medicine, 11. Sustainability, Child, media_common, Air Pollutants, Asthma exacerbations, 3. Good health, Child, Preschool, Acute Disease, Female, Emergency Service, Hospital, Environmental Monitoring, Pollution, Paris, Emergency rooms, media_common.quotation_subject, 03 medical and health sciences, Air pollutants, Air Pollution, 030225 pediatrics, Environmental health, medicine, Humans, Nitrogen dioxide, 0105 earth and related environmental sciences, Asthma, [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, business.industry, Urban Health, Infant, Environmental Exposure, medicine.disease, chemistry, 13. Climate action, Pediatrics, Perinatology and Child Health, Particulate Matter, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business
Abstract

ObjectiveAs the results from epidemiological studies about the impact of outdoor air pollution on asthma in children are heterogeneous, our objective was to investigate the association between asthma exacerbation in children and exposure to air pollutants.MethodsA database of 1 264 585 paediatric visits during the 2010–2015 period to the emergency rooms from 20 emergency departments (EDs) of ‘Assistance Publique Hôpitaux de Paris (APHP)’, the largest hospital group in Europe, was used. A total of 47 107 visits were classified as asthma exacerbations. Concentration of air pollutants (nitrogen dioxide, ozone, fine particulate matter (PM) with an aerodynamic diameter smaller than 10 µm (PM10) and 2.5 µm (PM2.5)), as well as meteorological data, evolution of respiratory syncytial virus infection and pollen exposition, were collected on an hourly or daily basis for the same period using institutional databases. To assess the association between air pollution and asthma, mixed-effects quasi-Poisson regression modelling was performed.ResultsThe only compound independently associated with ED visits for asthma was PM2.5 (P−4). The association between asthma exacerbation and PM2.5 was not linear, and a sigmoid function described the relationshipsatisfactorily. PM2.5 concentration, which gives half the maximum effect, was estimated at 13.5 µg/m3.ConclusionsWe found an association between daily asthma exacerbation in paediatric visits to the ED and fine particulate air pollutants.

Published
2018
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10. Pharmacokinetics of Efavirenz at a High Dose of 25 Milligrams per Kilogram per Day in Children 2 to 3 Years Old

Author

Karen Malateste, Madeleine Amorissani-Folquet, Naïm Bouazza, Déborah Hirt, Stéphane Blanche, Gabrielle Lui, Jean-Marc Tréluyer, Caroline Yonaba, Sylvie Ouédraogo, François Tanoh Eboua, Frantz Foissac, Désiré Lucien Dahourou, Valériane Leroy, Claire Pressiat, and Véronique Mea-Assande

Subjects
0301 basic medicine, Cyclopropanes, Male, medicine.medical_specialty, Efavirenz, Anti-HIV Agents, Gastroenterology, Drug Administration Schedule, Lopinavir, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Therapeutic index, Pharmacokinetics, Internal medicine, medicine, Humans, Pharmacology (medical), 030212 general & internal medicine, Pharmacology, business.industry, Liter, Bayes Theorem, 030112 virology, NONMEM, Benzoxazines, Infectious Diseases, chemistry, Alkynes, Child, Preschool, Toxicity, Female, business, medicine.drug, Blood sampling
Abstract

The MONOD ANRS 12206 trial was designated to assess simplification of a successful lopinavir (LPV)-based antiretroviral treatment in HIV-infected children younger than 3 years of age using efavirenz (EFV; 25 mg/kg of body weight/day) to preserve the class of protease inhibitors for children in that age group. In this substudy, EFV concentrations were measured to check the consistency of an EFV dose of 25 mg/kg and to compare it with the 2016 FDA recommended dose. Fifty-two children underwent blood sampling for pharmacokinetic study at 6 months and 12 months after switching to EFV. We applied a Bayesian approach to derive EFV pharmacokinetic parameters using the nonlinear mixed-effect modeling (NONMEM) program. The proportion of midinterval concentrations 12 h after drug intake (C12 h) corresponding to the EFV therapeutic pharmacokinetic thresholds (1 to 4 mg/liter) was assessed according to different dose regimens (25 mg/kg in the MONOD study versus the 2016 FDA recommended dose). With both the 25 mg/kg/day dose and the 2016 FDA recommended EFV dose, simulations showed that the majority ofC12 hvalues were within the therapeutic range (62.6% versus 62.8%). However, there were more children underexposed with the 2016 FDA recommended dose (11.6% versus 1.2%). Conversely, there were more concentrations above the threshold of toxicity with the 25 mg/kg dose (36.2% versus 25.6%), withC12 hvalues of up to 15 mg/liter. Only 1 of 52 children was switched back to LPV because of persistent sleeping disorders, but hisC12 hvalue was within therapeutic ranges. A high EFV dose of 25 mg/kg per day in children under 3 years old achieved satisfactory therapeutic effective levels. However, the 2016 FDA recommended EFV dose appeared to provide more acceptable safe therapeutic profiles. (This study has been registered at ClinicalTrials.gov under identifier NCT01127204.)

Published
2017

11. Population Pharmacokinetic Modeling of Tenofovir in the Genital Tract of Male HIV-Infected Patients

Author

Saïk Urien, Déborah Hirt, Marie Suzan-Monti, Jade Ghosn, Christine Rouzioux, Elodie Valade, Lambert Assoumou, Sílvia M. Illamola, Frantz Foissac, Jean-Marc Tréluyer, Maïlys De Sousa Mendes, Sihem Benaboud, Gabrielle Lui, Naïm Bouazza, Jean-Paul Viard, Aurélie Cobat, Camille Chenevier-Gobeaux, Evaluation thérapeutique et pharmacologie périnatale et pédiatrique (EA_7323), Université Paris Descartes - Paris 5 (UPD5), CIC - Mère Enfant Necker Cochin Paris Centre (CIC 1419), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Département de Pharmacologie Clinique [CHU Cochin], Hôpital Cochin [AP-HP], CTG repeat instability and myotonic dystrophy (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U912 INSERM - Aix Marseille Univ - IRD), Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Observatoire régional de la santé Provence-Alpes-Côte d'Azur [Marseille] (ORS PACA), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Infection à VIH, réservoirs, diversité génétique et résistance aux antirétroviraux (ARV) (EA 7327), Laboratoire de Virologie [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Epidémiologie, stratégies thérapeutiques et virologie cliniques dans l'infection à VIH [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM), UF de Thérapeutique en Immuno‑Infectiologie [AP-HP Hôtel Dieu], Hôpital Hôtel-Dieu [Paris], Service de médecine interne et maladies infectieuses, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Infections à Vih, Réservoirs, Pharmacologie des Antirétroviraux et Prévention de la Transmission Mère Enfant, The French National Agency for Research on AIDS and Viral Hepatitis (ANRS) sponsored the Evarist study. This study also received financial support from SIDACTION., Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], and Lissalde, Claire

Subjects
0301 basic medicine, Male, Physiology, Gene Expression, HIV Infections, population pharmacokinetics, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Blood plasma, Medicine, Pharmacology (medical), Drug Dosage Calculations, education.field_of_study, Liter, Middle Aged, HIV Reverse Transcriptase, Markov Chains, Infectious Diseases, Area Under Curve, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Monte Carlo Method, medicine.drug, Adult, Tenofovir, Anti-HIV Agents, Population, Biological Availability, Single-nucleotide polymorphism, Semen, Microbial Sensitivity Tests, Genitalia, Male, Polymorphism, Single Nucleotide, Drug Administration Schedule, 03 medical and health sciences, Pharmacokinetics, Humans, education, Pharmacology, Models, Statistical, business.industry, Body Weight, Bayes Theorem, genital tract, 030112 virology, tenofovir, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, HIV-1, seminal plasma, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Pharmacogenetics
Abstract

The aims of this study were to describe the blood plasma (BP) and seminal plasma (SP) pharmacokinetics of tenofovir (TFV) in HIV-1-infected men, to assess the role of genetic polymorphism in the variability of TFV transfer into the male genital tract, and to evaluate the impact of TFV SP exposure on seminal plasma HIV load (spVL). Men from the Evarist-ANRS EP 49 study treated with TFV as part of their antiretroviral therapy were included in the study. A total of 248 and 217 TFV BP and SP concentrations from 129 men were available for the analysis. For pharmacogenetic assessment, a total of 121 single nucleotide polymorphisms (SNP) were genotyped. Data were analyzed using a nonlinear mixed-effects modeling approach. TFV pharmacokinetics were best described by a two-compartment model for BP and by an effect compartment with different input and output constants for SP. TFV exposures (area under the concentration-time curve from 0 to 24 h [AUC 0–24 ]) were higher in SP than in BP (median AUC 0–24 , 7.01 versus 2.97 mg · liter −1 · h, respectively). The median (range) SP-to-BP AUC 0–24 ratio was 2.24 (0.53 to 34.13). After correction for multiple testing, none of the SNPs were significantly associated with the TFV transfer rate constant. The impact of the TFV SP AUC 0–24 or TFV SP-to-BP AUC 0–24 ratio on spVL was not significant ( P = 0.808 and 0.768, respectively). This is the first population model describing TFV pharmacokinetics in the male genital tract. TFV SP concentrations were higher than BP concentrations. Despite TFV SP exposures being higher than BP exposures, an spVL was detectable for 12.2% of the men.

Published
2017
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12. Are Prophylactic and Therapeutic Target Concentrations Different? The Case of Lopinavir/ritonavir or Lamivudine Administered to Infants for the Prevention of Mother-to-Child HIV-1 Transmission during Breastfeeding

Author

Nicolas Nagot, Naïm Bouazza, Frantz Foissac, Sílvia M. Illamola, Thorkild Tylleskär, Déborah Hirt, Philippe Van de Perre, Stéphane Blanche, Jörn Blume, Kim Harper, Jean-Marc Tréluyer, Mandisa Singata-Madliki, James K Tumwine, Nicolas Meda, Chipepo Kankasa, Evaluation thérapeutique et pharmacologie périnatale et pédiatrique (EA_7323), Université Paris Descartes - Paris 5 (UPD5), Unité de Recherche Clinique, Hopital Tarnier, CIC - Mère Enfant Necker Cochin Paris Centre (CIC 1419), CHU Cochin [AP-HP]-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Cochin [AP-HP], Pathogénèse et contrôle des infections chroniques (PCCI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP]

Subjects
0301 basic medicine, medicine.medical_specialty, Anti-HIV Agents, breastfeeding, Population, preexposure prophylaxis, Mothers, Lopinavir/ritonavir, HIV Infections, Context (language use), Gastroenterology, Lopinavir, 03 medical and health sciences, Internal medicine, medicine, Humans, Pharmacology (medical), education, Pharmacology, education.field_of_study, Ritonavir, business.industry, Area under the curve, Infant, Lamivudine, Bayes Theorem, Liter, 030112 virology, Virology, Infectious Disease Transmission, Vertical, 3. Good health, Breast Feeding, Infectious Diseases, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, business, pharmacokinetics, medicine.drug, Blood sampling
Abstract

The ANRS 12174 trial assessed the efficacy and tolerance of lopinavir (LPV)-ritonavir (LPV/r) prophylaxis versus those of lamivudine (3TC) prophylaxis administered to breastfed infants whose HIV-infected mothers were not on antiretroviral therapy. In this substudy, we assessed LPV/r and 3TC pharmacokinetics to evaluate the percentage of infants with therapeutic plasma concentrations and to discuss these data in the context of a prophylactic treatment. Infants from the South African trial site underwent blood sampling for pharmacokinetic study at weeks 6, 26, and 38 of life. We applied a Bayesian approach to derive the 3TC and LPV pharmacokinetic parameters on the basis of previously published pharmacokinetic models for HIV-infected children. We analyzed 114 LPV and 180 3TC plasma concentrations from 69 infants and 92 infants, respectively. A total of 30 LPV and 20 3TC observations were considered missing doses and discarded from the Bayesian analysis. The overall population analysis showed that 30 to 40% of the infants did not reach therapeutic targets, regardless of treatment group. The median LPV trough concentrations at weeks 6, 26, and 38 were 2.8 mg/liter (interquartile range [IQR], 1.7 to 4.4 mg/liter), 5.6 mg/liter (IQR, 3.2 to 7.7 mg/liter), and 3.4 mg/liter (IQR, 2.3 to 7.3 mg/liter), respectively. The median 3TC area under the curve from 0 to 12 h after the last drug intake were 5.6 mg · h/liter (IQR, 4.1 to 7.8 mg · h/liter), 5.9 mg · h/liter (IQR, 5.1 to 7.5 mg · h/liter), and 7.3 mg · h/liter (IQR, 4.9 to 8.5 mg · h/liter) at weeks 6, 26, and 38, respectively. Use of the therapeutic doses recommended by the WHO would have resulted in a higher proportion of infants achieving the targets. However, no HIV-1 infection was reported among these infants. These results suggest that the prophylactic targets for both 3TC and LPV may be lower than the therapeutic ones. For treatment, the WHO dosing guidelines should be suitable to maintain values above the therapeutic pharmacokinetic targets in most infants. (This study has been registered at ClinicalTrials.gov under identifier NCT00640263.)

Published
2017
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13. Arterial Spin Labeling to Predict Brain Tumor Grading in Children: Correlations between Histopathologic Vascular Density and Perfusion MR Imaging

Author

Francis Brunelle, Thomas Blauwblomme, David Grevent, Christian Sainte-Rose, Pascale Varlet, Stéphanie Puget, Christelle Dufour, Mathilde Badoual, Nathalie Boddaert, Eimad Shotar, Mélanie Pagès, Volodia Dangouloff-Ros, Frantz Foissac, Raphael Calmon, Michel Zerah, Christophe Deroulers, Jacques Grill, Neuroimagerie en psychiatrie (U1000), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Sud - Paris 11 (UP11), Imagerie et Modélisation en Neurobiologie et Cancérologie (IMNC (UMR_8165)), Université Paris-Sud - Paris 11 (UP11)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Evaluation thérapeutique et pharmacologie périnatale et pédiatrique (EA_7323), Université Paris Descartes - Paris 5 (UPD5), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Service de pédiatrie générale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), PRES Sorbonne Paris Cité, Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy], Institut Gustave Roussy (IGR), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP]

Subjects
Male, medicine.medical_specialty, Adolescent, Brain tumor, Contrast Media, [PHYS.NEXP]Physics [physics]/Nuclear Experiment [nucl-ex], Sensitivity and Specificity, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Interquartile range, medicine, Humans, Radiology, Nuclear Medicine and imaging, Child, Grading (tumors), ComputingMilieux_MISCELLANEOUS, Retrospective Studies, medicine.diagnostic_test, Brain Neoplasms, business.industry, Microvascular Density, Infant, Magnetic resonance imaging, medicine.disease, Confidence interval, Cerebral blood flow, Cerebrovascular Circulation, Child, Preschool, Female, Spin Labels, Radiology, Neoplasm Grading, Nuclear medicine, business, Perfusion, Magnetic Resonance Angiography, 030217 neurology & neurosurgery
Abstract

Purpose To compare arterial spin labeling (ASL) data between low- and high-grade brain tumors in children to establish a cutoff to distinguish low- from high-grade neoplasms and to assess potential correlations between cerebral blood flow (CBF) and quantitative histologic microvascular data. Materials and Methods Approval was obtained from the regional review board. ASL data obtained in 129 children between 2011 and 2015 were retrospectively analyzed. CBF and relative CBF in the most perfused area of each neoplasm and contrast enhancement were quantified with a semiquantitative ratio. The correlation between CBF and microvascular density was analyzed in specimens stained with anti-CD34. Results were controlled in two validation cohorts with 1.5- and 3.0-T magnetic resonance (MR) imaging. Results Mean CBF was significantly higher for high-grade than for low-grade hemispheric (116 mL/min/100 g [interquartile range {IQR}, 73-131 mL/min/100 g] vs 29 mL/min/100 g [IQR, 23-35 29 mL/min/100 g], P < .001), thalamic (87 mL/min/100 g [IQR, 73-100 mL/min/100 g] vs 36 mL/min/100 g [IQR, 30-40 mL/min/100 g], P = .016), and posterior fossa (59 mL/min/100 g [IQR, 45-91 mL/min/100 g] vs 33 mL/min/100 g [IQR, 25-40 mL/min/100 g], P < .001) tumors. With a cutoff of 50 mL/min/100 g, sensitivity and specificity were 90% (95% confidence interval [CI]: 68, 100) and 93% (95% CI: 66, 100), respectively, for hemispheric tumors; 100% (95% CI: 48, 100) and 80% (95% CI: 28, 100), respectively, for thalamic tumors; and 65% (95% CI: 51, 78) and 94% (95% CI: 80, 99), respectively, for posterior fossa tumors. In posterior fossa tumors, additional use of the CBF-to-contrast enhancement ratio yielded sensitivity and specificity of 96% (95% CI: 87, 100) and 97% (95% CI: 84, 100), respectively. Use of a simple algorithm based on these values yielded an accuracy of 93% (95% CI: 87, 97). Validation sets yielded similar results, with grading accuracy of 88% (95% CI: 62, 98) with 1.5-T MR imaging and 77% (95% CI: 46, 95) with 3.0-T MR imaging. CBF was strongly correlated with microvascular density (R = 0.66, P < .001). Conclusion High-grade pediatric brain tumors display higher CBF than do low-grade tumors, and they may be accurately graded by using these values. CBF is correlated with tumor microvascular density. © RSNA, 2016 Online supplemental material is available for this article.

Published
2016
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14. Population Pharmacokinetics of Emtricitabine in HIV-1-Infected Adult Patients

Author

Jean-Marc Tréluyer, Jean-Paul Viard, Jade Ghosn, Naïm Bouazza, Saïk Urien, Déborah Hirt, Floris Fauchet, Elodie Valade, Sihem Benaboud, and Frantz Foissac

Subjects
Adult, Male, medicine.medical_specialty, Adolescent, Anti-HIV Agents, Population, Urology, Renal function, HIV Infections, Pharmacology, Emtricitabine, urologic and male genital diseases, Deoxycytidine, Young Adult, Pharmacokinetics, Blood plasma, medicine, Humans, Pharmacology (medical), Dosing, education, Aged, education.field_of_study, medicine.diagnostic_test, business.industry, Liter, Middle Aged, Infectious Diseases, Therapeutic drug monitoring, Female, business, medicine.drug
Abstract

The aims of this study were to describe emtricitabine concentration-time courses in a large population of HIV-1-infected adults, to evaluate the influence of renal function on emtricitabine disposition, and to assess current dosing adjustment recommendations. Emtricitabine blood plasma concentrations were determined from samples collected from 161 adult patients during therapeutic drug monitoring and measured by liquid chromatography coupled to tandem mass spectrometry. The data were analyzed by a population approach. Emtricitabine pharmacokinetics was best described by a two-compartment model in which the absorption and distribution rate constants were assumed to be equal. Typical population parameter estimates (interindividual variability) were apparent elimination and intercompartmental clearances of 15.1 liters/h (17.4%) and 5.75 liters/h, respectively, and apparent central and peripheral volumes of distribution of 42.3 liters and 55.4 liters, respectively. The apparent elimination clearance was significantly related to creatinine clearance (CL CR ), reflecting renal function. For 200 mg once a day (QD), the median area under the concentration-time curve over 24 h (AUC 0-24 ) was 12.5 mg · h/liter for patients with normal renal function (CL CR , >80 ml/min), 14.7 mg · h/liter for patients with mild renal impairment (CL CR , 79 to 50 ml/min), and 17.9 mg · h/liter for patients with moderate renal impairment (CL CR , 49 to 30 ml/min). Simulations of the recommended dosing schemes for the oral solid form of emtricitabine (i.e., 200 mg per 48 h according to renal function) led to lower emtricitabine exposures for patients with moderate renal impairment (median AUC 0-48 , 17.2 mg · h/liter) than for patients with normal renal function (median AUC 0-48 , 25.6 mg · h/liter). Administering 18 ml of emtricitabine oral solution (10 mg/ml) QD to patients with moderate renal impairment should yield emtricitabine exposures similar to those in patients with normal renal function.

Published
2014

15. Association of prenatal and postnatal exposure to lopinavir-ritonavir and adrenal dysfunction among uninfected infants of HIV-infected mothers

Author

Albane Simon, Josiane Warszawski, Dulanjalee Kariyawasam, Jerome Le Chenadec, Valerie Benhammou, Paul Czernichow, Frantz Foissac, Kathleen Laborde, Jean-Marc Tréluyer, Ghislaine Firtion, Inès Layouni, Martine Munzer, Françoise Bavoux, Michel Polak, Stéphane Blanche, and for the ANRS French Perinatal Cohort Study Group

Subjects
Male, medicine.medical_specialty, Lopinavir/ritonavir, Physiology, Context (language use), HIV Infections, Pyrimidinones, Lopinavir, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Dehydroepiandrosterone sulfate, immune system diseases, Interquartile range, Pregnancy, Internal medicine, medicine, Humans, Congenital adrenal hyperplasia, 030212 general & internal medicine, Pregnancy Complications, Infectious, Retrospective Studies, 0303 health sciences, Ritonavir, 030306 microbiology, business.industry, Dehydroepiandrosterone Sulfate, 17-alpha-Hydroxyprogesterone, Infant, Newborn, virus diseases, General Medicine, medicine.disease, Infectious Disease Transmission, Vertical, 3. Good health, Regimen, Endocrinology, Cross-Sectional Studies, chemistry, Case-Control Studies, HIV-1, Female, France, business, Zidovudine, medicine.drug, Adrenal Insufficiency
Abstract

Lopinavir-ritonavir is a human immunodeficiency virus 1 (HIV-1) protease inhibitor boosted by ritonavir, a cytochrome p450 inhibitor. A warning about its tolerance in premature newborns was recently released, and transient elevation of 17-hydroxyprogesterone (17OHP) was noted in 2 newborns treated with lopinavir-ritonavir in France.To evaluate adrenal function in newborns postnatally treated with lopinavir-ritonavir.Retrospective cross-sectional analysis of the database from the national screening for congenital adrenal hyperplasia (CAH) and the French Perinatal Cohort. Comparison of HIV-1-uninfected newborns postnatally treated with lopinavir-ritonavir and controls treated with standard zidovudine.Plasma 17OHP and dehydroepiandrosterone-sulfate (DHEA-S) concentrations during the first week of treatment. Clinical and biological symptoms compatible with adrenal deficiency.Of 50 HIV-1-uninfected newborns who received lopinavir-ritonavir at birth for a median of 30 days (interquartile range [IQR], 25-33), 7 (14%) had elevated 17OHP levels greater than 16.5 ng/mL for term infants (23.1 ng/mL for preterm) on days 1 to 6 vs 0 of 108 controls having elevated levels. The median 17OHP concentration for 42 term newborns treated with lopinavir-ritonavir was 9.9 ng/mL (IQR, 3.9-14.1 ng/mL) vs 3.7 ng/mL (IQR, 2.6-5.3 ng/mL) for 93 term controls (P.001). The difference observed in median 17OHP values between treated newborns and controls was higher in children also exposed in utero (11.5 ng/mL vs 3.7 ng/mL; P.001) than not exposed in utero (6.9 ng/mL vs 3.3 ng/mL; P = .03). The median DHEA-S concentration among 18 term newborns treated with lopinavir-ritonavir was 9242 ng/mL (IQR, 1347-25,986 ng/mL) compared with 484 ng/mL (IQR, 218-1308 ng/mL) among 17 term controls (P.001). The 17OHP and DHEA-S concentrations were positively correlated (r = 0.53; P = .001). All term newborns treated with lopinavir-ritonavir were asymptomatic, although 3 premature newborns experienced life-threatening symptoms compatible with adrenal insufficiency, including hyponatremia and hyperkalemia with, in 1 case, cardiogenic shock. All symptoms resolved following completion of the lopinavir-ritonavir treatment.Among newborn children of HIV-1-infected mothers exposed in utero to lopinavir-ritonavir, postnatal treatment with a lopinavir-ritonavir-based regimen, compared with a zidovudine-based regimen, was associated with transient adrenal dysfunction.

Published
2011
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