Youssef Bennis

ARA290, a Specific Agonist of Erythropoietin/CD131 Heteroreceptor, Improves Circulating Endothelial Progenitors' Angiogenic Potential and Homing Ability.

Background: Alternate erythropoietin (EPO)-mediated signaling via the EPOR/CD131 heteromeric receptor exerts the tissue-protective actions of EPO in a wide spectrum of injuries, especially ischemic diseases. Circulating endothelial progenitor cells contribute to endothelial repair and post-natal angiogenesis after chronic ischemic injury. This work aims to investigate the effects of ARA290, a specific agonist of EPOR/CD131 complex, on a subpopulation of endothelial progenitor cells named endothelial colony-forming cells (ECFCs) and to characterize its contribution to ECFCs-induced angiogenesis after peripheral ischemia. Methods: ARA290 effects on ECFCs properties were studied using cell cultures in vitro. We injected ARA290 to mice undergoing chronic hindlimb ischemia (CLI) in combination with ECFC transplantation. The homing of transplanted ECFC to ischemic tissue in vivo was assessed by SPECT/CT imaging. Results: In vitro, ARA290 enhanced the proliferation, migration, and resistance to H2O2-induced apoptosis of ECFCs. After ECFC transplantation to mice with CLI, a single ARA290 injection enhanced the ischemic/non-ischemic ratio of hindlimb blood flow and capillary density after 28 days and the homing of radiolabeled transplanted cells to the ischemic leg 4u200ah after transplantation. Prior neutralization of platelet-endothelial cell adhesion molecule-1 (CD31) expressed by the transplanted cells inhibited ARA290-induced improvement of homing. Discussion: ARA290 induces specific improvement of the biological activity of ECFCs. ARA290 administration in combination with ECFCs has a synergistic effect on post-ischemic angiogenesis in vivo. This potentiation appears to rely, at least in part, on a CD31-dependent increase in homing of the transplanted cells to the ischemic tissue.

Therapeutic benefit of a combined strategy using erythropoietin and endothelial progenitor cells after transient focal cerebral ischemia in rats

Abstract Objective: Many studies have demonstrated beneficial effects of either erythropoietin (EPO) or endothelial progenitor cell (EPC) treatment in cerebral ischemia. To improve post-ischemic tissue repair, we investigated the effect of systemic administration of endothelial colony-forming cells (ECFCs), considered as relevant endothelial progenitors due to their specific vasculogenic activity, in the presence or absence of EPO, on functional recovery, apoptosis, angiogenesis, and neurogenesis in a transient focal cerebral ischemia model in the adult rat. Design: Experimental study. Intervention: The rats were divided into four groups 24 hours after ischemia,, namely control, ECFCs, EPO, and ECFCs+EPO, and received a single intravenous injection of ECFCs (5×106 cells) and/or intraperitoneal administration of EPO (2500 UI/kg per day for 3 days). Measurement: Infarct volume, functional recovery, apoptosis, angiogenesis, and neurogenesis were assessed at different time points after ischemia. Main results: The combination of EPO and ECFCs was the only treatment that completely restored neurological function. The ECFCs+EPO treatment was also the most effective to decrease apoptosis and to increase angiogenesis and neurogenesis in the ischemic hemisphere compared to controls and to groups receiving ECFCs or EPO alone. Conclusion: These results suggest that EPO could act in a synergistic way with ECFCs to potentiate their therapeutic benefits.

Patients treated with first‐generation HCV protease inhibitors exhibit high ribavirin concentrations

Anemia is a well‐known RBV‐related event in HCV therapy which is exacerbated by the addition of telaprevir and boceprevir. This retrospective study evaluated and compared ribavirin exposure and parameters able to influence hemoglobin decrease in a large population of patients treated with dual or triple therapy. Patients on triple therapy had higher ribavirin concentrations at week 12 of treatment (3460u2009ng/mL vs. 1843u2009ng/mL; Pu2009<u2009.0001). An association was also observed between week 12 eGFR and ribavirin concentration only for patients on triple therapy (Pu2009=u2009.002). The proportion of patients with a u2009>20u2009mL/min/1.73u2009m2 decrease in eGFR at week 12 was higher among patients on triple therapy: 32%, 14%, and 5% for boceprevir, telaprevir, and dual therapy, respectively (Pu2009=u2009.025 and .026). No correlation was observed between boceprevir and telaprevir concentrations and hemoglobin or eGFR decrease. Exacerbation of anemia in patients on triple therapy is related to higher ribavirin concentrations. We provide an explanation for this increase in plasma RBV concentration. Triple therapy with PEG‐IFN, RBV, and telaprevir or boceprevir will remain the only HCV treatment option for many patients. Our data show that the RBV dose can be decreased while maintaining adequate plasma concentrations and reducing anemia.

High metabolic N‐oxidation of voriconazole in a patient with refractory aspergillosis and CYP2C19*17/*17 genotype

oratory of pharmacology and toxicology, CHU Amiens Picardie, UPJV, INSERM U1088, France,Laboratory of pharmacology and toxicology, Nantes ersity Hospital, France,Department of Pharmacology, EA 4123, Le Kremlin Bicêtre University Hospital, Universite Paris Sud, France,Department linical Hematology, CHU Amiens Picardie, France,Laboratory of pharmacology and toxicology, CHU Amiens Picardie, France and Laboratory of ology, CHU Amiens Picardie, France

Neurotoxic Concentration of Piperacillin during Continuous Infusion in Critically Ill Patients

ABSTRACT This retrospective cohort study included 53 patients admitted to the intensive care unit (ICU), with an average age of 69 years, without neurologic disorder before initiation of a continuous piperacillin infusion at the standard dose and who underwent piperacillin serum concentration monitoring. Among them, 23 developed a neurologic disorder for which the piperacillin causality was chronologically and semiologically suggestive. A concentration threshold of 157.2 mg/liter independently predicted neurotoxicity with 96.7% specificity and 52.2% sensitivity and may constitute a limitation when targeting less susceptible pathogens.

Aseptic simulation test for cytotoxic drug production in isolators

PURPOSEnThe results of a media-fill test (MFT) study to validate processes for cytotoxic drug preparation inside and outside aseptic compounding isolators are presented.nnnMETHODSnUsing an MFT protocol adapted to institution-specific production conditions, the pharmacy team at a hospital in France performed a series of tests to verify the efficacy of decontamination and sterile compounding procedures, as required by French compendial standards, while assessing the performance of its team of 12 isolator operators; all operators were tested on three occasions, producing 10 MFT samples per test for a total of 30 samples per operator. The team also tested alternative compounding systems (i.e., two closed-system transfer devices and a classic spike system) for use during power outages or other emergencies precluding drug preparation within isolators. MFTs were performed using a standard tryptone soy broth-based test kit under worst-case conditions.nnnRESULTSnThe hospitals facilities for cytotoxic drug preparation were found to be in conformance with applicable sterility standards. Bacterial growth was not detected in any of the MFT samples produced by isolator operators during the study (total n = 360). In one instance, an MFT sample prepared using a closed-system transfer device was found to be contaminated due to improper cleaning of the medication vial, highlighting the importance of strict adherence to proper decontamination procedures.nnnCONCLUSIONnA hospitals practices for preparation of sterile products according to applicable good manufacturing guidelines, as well as emergency procedures for cytotoxic drug preparation outside isolators, were validated by the results of an MFT study.

Tolerability and Plasma Drug Level Monitoring of Prolonged Subcutaneous Teicoplanin Treatment for Bone and Joint Infections

ABSTRACT Teicoplanin is a key drug for the treatment of multiresistant staphylococcal bone and joint infections (BJI), yet can only be administered via a parenteral route. The objective of this study was to evaluate the safety and tolerability of subcutaneous (s.c.) teicoplanin for that indication over 42 days. Thirty patients with Gram-positive cocci BJI were included. Once the target of 25 to 40 mg/liter trough serum concentration was achieved, treatment was switched from an intravenous to an s.c. route. No discontinuation of teicoplanin related to injection site reaction and no severe local adverse event were observed. On multivariate analysis, better tolerability was observed at the beginning of treatment, in patients over 70 years old, and for dosages less than 600 mg. In conclusion, we recommend s.c. administration of teicoplanin when needed.

La consommation chronique de cocaïne adultérée par du lévamisole peut-elle être impliquée dans l’aggravation d’un surdosage à l’aripiprazole ?

Objectif Discuter les differentes etiologies toxiques de lesions cerebrales survenues chez un patient. Description du cas Monsieur B., 31xa0ans, a ete pris en charge par le SAMU pour des troubles de la vigilance survenus dans un contexte de suspicion d’injection IV d’aripiprazole LP (ABILIFY MAINTENA®) destinee a l’injection 1xa0fois par mois par voie IM. Le patient avait debute depuis une dizaine de jours un traitement par neuroleptique LP pour sa schizophrenie et etait egalement suivi pour une toxicomanie au cannabis, a la cocaine et a l’heroine. A la prise en charge, le patient etait comateux sans deficit focal ni de signe en faveur d’un syndrome extrapyramidal. En revanche, un discret mouvement pendulaire des yeux etait observe. Il etait apyretique et ne presentait pas d’hypersudation. Sur le plan cardiaque, aucun trouble du rythme n’etait constate. Devant l’aggravation des troubles de la vigilance, le patient a ete intube/sedate puis transfere en reanimation pour surveillance et recherche etiologique. Methodes Un scanner cerebral sans injection et une IRM cerebrale avec injection ont ete realises a l’entree. Un bilan biologique comprenant un criblage toxicologique urinaire par LC-MS/MS et un dosage serique de l’aripiprazole par LC-MS/MS a ete realise dans des echantillons sanguins et urinaires preleves a l’admission. Ce bilan a ete complete par la recherche de NPS et metabolites par LC-HRMS et LC-MS/MS dans les memes echantillons. Une meche de cheveux prelevee 3xa0semaines plus tard a egalement ete analysee par LC-MS/MS. Resultats Le scanner cerebral montrait 2xa0hypodensites au niveau des noyaux lenticulaires. Le taux d’HbCO, determine d’emblee pour eliminer une intoxication au monoxyde de carbone, etait inferieur a 1xa0%. L’IRM en sequences diffusion et FLAIR montrait un hypersignal symetrique des globi pallidi avec preservation des putamens. Le bilan biologique etait evocateur d’une insuffisance renale compliquee d’une hyperkaliemie et d’une acidose metabolique, d’une rhabdomyolyse et d’une cytolyse hepatique. En dehors des medicaments administres au cours de la prise en charge, la presence d’aripiprazole et de ses metabolites, de 6-MAM, de morphine, de codeine et de noscapine, de tramadol, de paracetamol, de cocaine et de benzoylecgonine, de cyamemazine et de ses metabolites, de diazepam et de ses metabolites, de loprazolam et de THC-COOH ont ete identifies lors du criblage toxicologique urinaire. Aucun NPS ni metabolite n’a ete mis en evidence. La concentration d’aripiprazole mesuree environ 16xa0h apres l’injection presumee etait de 527xa0μg/L. L’analyse de cheveux a confirme une consommation chronique d’heroine et de cocaine et a revele la presence de levamisole, antiparasitaire frequemment utilise comme adulterant de la cocaine. Conclusion La concentration d’aripiprazole n’etait pas en faveur d’une injection par voie IV mais etait superieure aux concentrations habituellement mesurees a l’equilibre chez les patients traites par aripiprazole IM (100xa0a 350xa0μg/L). Des lesions cerebrales des noyaux gris n’ont pas ete decrites lors d’intoxication isolee a l’aripiprazole mais ont deja ete decrites dans des cas d’intoxication a la cocaine et a l’ecstasy. Dans ce contexte, les proprietes vasoconstrictrices puissantes de la cocaine et de ses metabolites associees au vasospasme dans les regions riches en recepteurs 5-HT, telles que les globi pallidi, ont ete impliques dans la genese de ces lesions. Dans le cas present, l’effet synergique de la cocaine, du levamisole et de l’aminorex, ayant un effet amphetamine-lik et de l’aripiprazole, agoniste/antagoniste serotoninergique, pourrait etre implique dans l’apparition des lesions cerebrales observees chez le patient.

Severe neurological disorders and refractory aspergillosis in an adolescent treated by vincristine and voriconazole

Voriconazole and vincristine are major therapeutics in paediatric haematology. However, the risk‐benefit ratio of the treatment of invasive aspergillosis with voriconazole in patients receiving vincristine‐based chemotherapy remains unclear.

Évaluation de la valeur prédictive neurotoxique de la concentration sérique de pipéracilline chez les patients de réanimation

Objectif La piperacilline associee au tazobactam est l’une des β-lactamines les plus utilisees dans les unites de soins intensifs. Sa neurotoxicite est marquee par des encephalopathies, une confusion, des myoclonies, des troubles cognitifs ou des hallucinations. Meme si la neurotoxicite en lien avec un phenomene d’accumulation est bien connue, aucune etude clinique publiee a ce jour n’a permis d’etablir un veritable seuil de toxicite. Nous avons donc mene une etude retrospective visant a determiner la valeur de la concentration serique de la piperacilline qui serait predictive de la neurotoxicite chez les patients recevant cet antibiotique par perfusion continue en reanimation. Methodes Cette etude a ete realisee sur 22xa0mois dans le service de reanimation medicale du CHU d’Amiens. Les patients inclus avaient recu depuis au moins 48xa0heures une perfusion IV continue de piperacilline/tazobactam a la posologie standard (12xa0g/1,5xa0g sur 24xa0h) ajustee a la clairance de la creatinine. Les donnees d’evaluation clinique tracees quotidiennement par les reanimateurs ont ete retrospectivement analysees. En cas de troubles neurologiques, l’imputabilite de la piperacilline pour l’evenement indesirable a ete jugee suggestive selon les criteres suivantsxa0: –xa0existence d’un symptome compatible avec la neurotoxicite de la piperacillinexa0; –xa0evenement survenu au moins 48xa0h apres l’instauration du traitementxa0; –xa0resolution ou amelioration dans les 2xa0jours apres l’arret ou la reduction de la posologie de la piperacilline. Les caracteristiques des patients ayant developpe des troubles neurologiques dont l’imputabilite de la piperacilline etait suggestive (groupe 1, lors du 1 er jour des manifestations neurologiques) ont ete comparees a celles des patients qui n’ont pas developpe de troubles neurologiques ou dont l’imputabilite de la piperacilline n’etait pas suggestive (groupe 2, lors du jour correspondant a la concentration de piperacilline mesuree la plus elevee). Les concentrations seriques de piperacilline etaient mesurees par HPLC-UV/BD. Resultats Cinquante-trois patients ont ete inclusxa0: 23xa0ont constitue le groupe 1 (39,1xa0% de femmes, âge median 65xa0ans, poids median 87xa0kg) et 30xa0patients le groupe 2 (23,3xa0% de femmes, âge median 71,5xa0ans, poids median 87,5xa0kg). Les patients des deux groupes ne presentaient pas de differences significatives en termes d’antecedents medicaux et de criteres de gravite (IGS II et score de Glasgow) lors de leur entree. En revanche, compares aux patients du groupe 2, les patients du groupe 1xa0avaient une concentration serique de piperacilline significativement plus elevee (156,9xa0mg/L contre 91,3xa0mg/L, p xa0=xa00,0016), un debit de filtration glomerulaire plus faible (18xa0mL/min/1,73xa0m 2 xa0vs 50xa0mL/min/1,73xa0m 2 , p xa0=xa00,0142) et presentaient les criteres du sepsis dans 65,2xa0% des cas contre 26,7xa0% ( p xa0=xa00,0006). L’analyse ROC a indique qu’une concentration seuil de 157,2xa0mg/L serait predictive d’une neurotoxicite de la piperacilline (specificite de 92,7xa0% et sensibilite de 50,5xa0%). L’analyse multivariee par regression logistique suggere qu’une concentration superieure a 157,2xa0mg/L serait en effet un facteur de troubles neurologiques independant en reanimation. Conclusion Bien qu’elle puisse tout de meme se manifester a plus faible concentration, la neurotoxicite induite par la piperacilline serait quasi systematique des le seuil de 157,2xa0mg/L. Cette valeur seuil permet de definir avec plus de precision la marge therapeutique de la piperacilline en tenant compte egalement des donnees microbiologiques indispensables a l’optimisation therapeutique.