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Ketoconazole (KTZ) is an antifungal agent; however, its bioavailability and therapeutic efficacy are reduced by the low aqueous solubility of the drug. Aiming at providing to improve the biopharmaceutical properties of KTZ, we studied the water-soluble different calix[n]arenes as carrier systems for KTZ. All calix[n]arene-KTZ tested showed in vitro antifungal activity superior or similar to free KTZ against Candida spp. The CX6Na/KTZ obtained by physical mixture and freeze-drying methods were the most active, decreasing KTZ concentrations required for growth inhibition against azole-resistant isolates (e.g., C. auris). Moreover, CX6Na/KTZ showed no toxic effect on Galleria mellonella larvae and the treatment of infected larvae with C. albicans and C. auris was effective at a lower dose compared with free KTZ. Thus, CX6Na/KTZ may have a potential approach to treat mycosis, especially by improvement of KTZ inhibitory activity against azole-resistant Candida.

Paracoccidioidomycosis (PCM) is a systemic mycosis with lymphatic dissemination that is caused by Paracoccidioides species. Treatment of PCM consists of chemotherapeutics such as itraconazole, trimethoprim, sulfamethoxazole or amphotericin B. However, several studies are aiming to develop therapeutic alternatives for the treatment of fungal infection using new molecules as adjuvants. The single-chain variable fragments (scFv) from an antibody that mimics the main fungal component incorporated within poly(lactide-co-glycolic) acid (PLGA) nanoparticles helped treat the fungal disease. After expressing the scFv in Picchia pastoris (P. pastoris), the recombinant molecules were coupled with PLGA, and the BALB/c mice were immunized before or after infection with yeast Paracoccidioides brasiliensis (P. brasiliensis). Our results showed decreased disease progression and decreased fungal burden. Taken together, our results showed an increased of IFN-γ and IL-12 cytokine production and an increased number of macrophages and dendritic cells in the pulmonary tissue of BALB/c mice treated with a high concentration of our molecule. Our data further confirm that the scFv plays an important role in the treatment of experimental PCM.

Cryptococcal meningitis is caused by Cryptococcus spp. and predominantly affects patients with acquired immunodeficiency syndrome. However, an increase in the number of nonHIV patients diagnosed with cryptococcosis raises concerns worldwide. The current antifungal therapy has some limitations such as being unavailable in some countries, high cost, toxicity, and the need for trained professionals for intravenous administration, which compromises patient compliance, resulting in treatment withdrawal and increased fungal resistance. In this regard, new alternative drugs, especially those administered orally and at affordable cost are desired. However, these drugs face challenges due to the gastrointestinal (GI) and blood-brain barriers (BBB). In this present work, we developed a new oil-in-water nanoemulsion containing flubendazole (FLZ) for oral administration using a unique low-energy process for treating cryptococcosis. The combination of D -phase emulsification (DPE) process and design of experiment (DoE) resulted in a stable FLZ-loaded nanoemulsion with 35-nm mean particle size, 60.0% oil phase with 3.0% surfactant phase (both % w/w), at 25 °C process temperature without using specific equipment. The careful selection of components for developing this nanoemulsion as a drug carrier is thoroughly discussed herein, including the interaction of lipid components with brain transporters, the type of surfactant as a permeability enhancer through BBB, as well as the choice of the drug. The use of statistical design combined with the DPE process, and selection of components, resulted in reducing approximately 30% of fungal burden in mice brain, and safety testing in an invertebrate model showed nontoxicity by this nanoemulsion. This work reports a step-by-step alternative process for designing a nanoemulsion with improved efficacy and safety, even containing a drug at a significantly reduced concentration compared to previously published works. This nanoemulsion provides multiple benefits - overcoming GI and BBB barriers, and affordable production cost - delivering a new antifungal alternative for treating cryptococcosis.

The aim of this retrospective study was to describe the use of simple interrupted suture pattern for the closure of the abdomen after ventral midline celiotomy in horses and to evaluate the prevalence of resulting incisional complications. Seventy horses undergoing abdominal surgery (2006–2015) and surviving at least 30 days were included in the study. Closure technique of the abdominal wall was performed on three layers. Linea alba was closed with a simple interrupted pattern using number two coated braided absorbable polyglycolic acid suture. Follow-up information was recovered at the 90th day postoperatively. Incisional complications considered included drainage, infection, dehiscence, and herniation. The complications observed in the present study using simple interrupted suture pattern were 4.29% (3 of 70), lower than reported in literature with different suture pattern. Simple interrupted suture pattern could be a valid option for the closure of linea alba after ventral midline celiotomy in horses.

Objectifs En raison de ses specificites pharmacologiques, le maniement de la methadone est complexe et les sujets sont plus exposes a un risque de surdosage. Dans ce contexte, les modalites d’acces de la methadone ete encadrees des sa commercialisation et un suivi national d’addictovigilance ete mis en place afin d’evaluer les risques lies a cette molecule. Dans un contexte d’augmentation de la consommation de methadone (+47 % entre 2009 et 2017) et d’augmentation de son obtention illegale (6 % des consommateurs de methadone l’ont obtenu illegalement en 2008 versus 12 % en 2018), une analyse des complications sanitaires graves a ete effectuee. Methode Une analyse medicale et pharmacologique des observations cliniques d’Addictovigilance « notifications spontanees ; NOTS » et des donnees du dispositif « Deces en Relation Avec les Medicaments Et les Substances ; DRAMES » a ete effectuee sur la periode avril 2008 a avril 2019. Resultats Parmi les 1322 observations cliniques d’addictovigilance recueillies sur 11 ans, 39 % ont ete notifiees ces deux dernieres annees. Le nombre d’observations cliniques graves ayant necessite une prise en charge hospitaliere a ete multipliee par 12 entre 2008 et 2019 et le nombre d’administration de naloxone par 11. Ces dernieres annees, on observe une augmentation des tableaux cliniques severes avec des cas de coma profond (representant un tiers des surdosages durant la 11eme annee de suivi), des cas d’arret cardio-respiratoire, de defaillance multiviscerale, quelques cas d’encephalopathie, d’allongement du QT et de torsade de pointe ; ces complications ayant entraine des sejours long en reanimation, voire des deces. Dans la majorite des surdosages, d’autres substances psychoactives etaient consommees en particulier d’autres depresseurs respiratoires comme des benzodiazepines (57 % des surdosages), l’alcool (41 %), d’autres opiaces (25 %) et egalement de la cocaine (38 %). D’apres le dispositif DRAMES, le nombre de deces impliquant la methadone est croissant avec un total de 1 111 deces sur 10 ans (versus 370 deces impliquant la buprenorphine) ; avec le nombre de deces le plus eleve en 2017 (n = 160). La methadone est toujours la substance la plus impliquee dans les deces. D’apres une modelisation lineaire sur 5 ans, le taux de progression annuelle de deces est estime a 14 deces en plus par an (versus 1 deces en moins par an pour la buprenorphine). Le nombre de deces lies a l’association cocaine et methadone a ete multiplie par 2. Les surdosages et les deces peuvent survenir dans differents contextes : chez des consommateurs occasionnels de methadone et egalement chez des sujets consommant la methadone dans le cadre d’un protocole de soins (contexte de surconsommation, polyconsommation, injection…). Conclusion Ces donnees mettent en avant le lien entre l’augmentation de l’accessibilite a la methadone et l’augmentation de son obtention illegale et des complications sanitaires graves associees. Cette tendance a egalement ete observee aux Etats-Unis dans les annees 2000 ou la methadone, utilisee dans la douleur, etait fortement impliquee dans les deces lies aux opioides. Dans ce contexte, il est urgent d’alerter la communaute medicale et les patients et rappeler les specificites pharmacologiques de la methadone, les facteurs de risque de surdosage et l’interet de diffuser la naloxone a tous les consommateurs de methadone. Il serait interessant de mieux connaitre en France les circonstances de deces liees a la methadone (sujet naif ? consommateur occasionnel ? si le sujet sous traitement : quel est le motif de prescription et a quel moment du traitement le deces est survenu ? quels sont les modalites de consommation ?). Le moyen le plus efficace serait de lever l’anonymat pour retracer le parcours de chaque sujet a partir des donnees de prescriptions et de delivrances disponibles via l’assurance maladie et les structures specialisees.

The aim of the present work was to isolate, cultivate, differentiate, and conduct cellular characterization of mesenchymal stem cells (MSCs) derived from equine adipose tissue (eAT) and bone marrow (eBM). Isolated and characterized cells were used in racehorses suffering from a superficial flexor tendon injury. Equine adipose tissue collection was performed at the base of the horse tail, whereas eBM was aspirated from iliac crest. Mononuclear cell fraction was isolated and cultured. In vitro differentiation and molecular characterization at P3 of culture were performed. No statistically significant differences in the number of cell doublings were found among different culture passages (P > .05). Doubling time was greater for eBM than eAT (3.2 1.5 vs. 1.3 0.7; P < .05). Positive von Kossa and Alizarin Red staining confirmed osteogenesis. Alcian Blue and Oil Red O staining illustrated chondrogenesis and adipogenesis, respectively. Isolated cells resulted positive for CD90, CD44, and CD105, whereas negative for hematopoietic markers, CD14, CD45, and CD34. Using isolated cells for injured tendon therapy, no adverse reactions were observed, and all inoculated horses returned to race competitions. In vitro results revealed the immunophenotypic characterization of isolated cells similar to that observed in human MSCs from the same sources; furthermore, in the present study, their clinical use proves the safety of eBM-derived and eAT-derived MSCs and a successful outcome for the treated animals that returned to their previous level of sport activity.

Poor data could be found in the literature on the effects of intra-articular (IA) administration of stanozolol in horses affected by osteoarthritis (OA). To verify the clinical effects of IA stanozolol in acute and chronic cases of OA in horses, a clinical double-blinded trial involving 60 client-owned horses was performed. Veterinary practitioners selected horses, all showing clinical signs of acute or chronic OA, diagnosed in a single joint. After lameness evaluation and synovial fluid collection, the clinicians administered one to four (acute cases) or one to six (chronic cases) weekly IA doses of 5 mg of stanozolol or placebo. Positive result was considered a grade 1 improvement in lameness scored according to the American Association of Equine Practitioner scale. The characteristics of the synovial fluid were also evaluated. Of the 60 horses included in the study, 31 were affected by acute OA and 29 by chronic OA. Horses were treated blindly with placebo. The overall outcomes were positive in 82.50% of cases. Lameness disappeared completely in 15 of 21 (acute) and 11 of 19 (chronic) animals, and there was a significant reduction after two and four treatments, in the acute and chronic cases, respectively. Improvement in the physical characteristics of the synovial fluid sampled was evident after the third treatment. Stanozolol injected IA at a dose of 5 mg significantly resolved lameness in affected joints. Stanozolol could be considered a safe option for the treatment of horses suffering from OA.

The study clinically evaluated the effectiveness of autologous platelet-rich plasma (PRP), obtained using a double transfusion bag after an ultrasound-guided intralesion injection into an acute lesion of proximal portion of suspensory ligament (SL). Twenty horses with acute proximal suspensory ligament desmitis were included in the study. An ultrasound evaluation of the proximal region of the SL was carried out, and the cross-sectional area (CSA) percentage and fiber score alignment were determined. Four hundred fifty milliliters of blood was collected, and PRP was obtained by means of the buffy coat method, using a double transfusion bag. The PRP was injected into the lesion using an ultrasound guide. A long-term follow-up was carried out by means of a telephonic interview with the owner. The median CSA of the SL lesion at the first examination was 30%. The median platelet count in the PRP was 1,045 × 10 3 platelets/μL; the final concentration ranged from six to 20 times higher than the platelet blood count. Sixteen horses returned to activity within a period ranging from 12 to 24 weeks from the last PRP injection, and four animals recidivated in different regions of suspensory ligament: midbody desmitis and medial branch. Clinical results confirm that the use of autologous PRP supports healing and reduces recurrence in acute SL lesions.

Introduction La consommation de nefopam est en constante augmentation en France. Les objectifs de cette etude sont de quantifier l’intensite du signal de pharmacodependance, d’identifier les populations a risque et les facteurs de risque de survenue. Methodes L’ensemble des cas graves et non graves d’abus, de pharmacodependance, d’usage detourne, de surdosage et de syndrome de sevrage rapportes en France depuis 1988, ont ete analyses, ainsi que des donnees de remboursement du nefopam (Echantillon Generaliste des Beneficiaires) sur la periode 2006-2017. Resultats Le profil de pharmacodependance du nefopam s’apparente a celui d’un psychostimulant. L’analyse de la litterature et des notifications spontanees confirme le risque d’abus et de dependance sous nefopam. En plus d’un terrain psychiatrique frequent (depression, psychose, anxiete), pres de la moitie des patients presente des antecedents de troubles addictifs, dont plus d’un tiers une dependance aux opioides. Pour pres de la moitie des 120 cas rapportes, l’effet indesirable principal est une dependance et la frequence des effets graves parmi les effets rapportes est superieure a 40 %. Pres de 70 % des cas d’abus ou de dependance rapportes, concernent la douleur chronique, ce qui explique, en partie, les prises prolongees. Par ailleurs, l’analyse des donnees de remboursement du nefopam en population generale, montre qu’un francais sur deux ayant une prescription de nefopam, presente une douleur chronique. Pourtant, le nefopam est uniquement indique dans le traitement des affections douloureuses aigues. La question de la limitation de la duree de traitement a 28 jours se pose donc. Bien qu’elle ne semble pas associee a un plus grand risque d’abus ou de dependance, la prise du produit par voie orale est un usage hors AMM, tres frequent, qui merite d’etre encadre. Discussion En France, la prescription hors AMM du nefopam est d’autant plus regrettable qu’elle contribue au developpement des cas d’abus et de dependance.

The aim of this pilot study was to test a new customized biomimetic composite scaffolds to restore bone defects using CAD–CAM technology. The new biomaterial was synthesized using biomimetic mineralized collagen, and poly (ɛ-caprolactone) (PCL). The mold used in scaffolding, the surgical guide, and the bony plate used during the surgery, were rapid prototyped (CAD–CAM technology). Our in vitro results showed that sheep mesenchymal stem cells (MSC) seeding efficiency was very high (>94%). Furthermore, cells can adhere, grow and maintain cell viability up to 7 days of in vitro cultivation on the scaffold as revealed by SEM and confocal laser scanning microscope analysis. These results are indicative of good scaffold biocompatibility. The use of the sheep experimental model allowed exploring the efficacy of the customized bony plate used to give extra mechanical support to the scaffold, the potential of CAD–CAM technology in customization of the scaffold, and the in vivo biomimetic properties of the composite biomaterial.

Methylenedioxymethamphetamine (MDMA), the active compound of ecstasy, has been used for several years, especially by young adults to benefit of psychostimulant properties. By raising the level of neuromodulators in the synapsis, MDMA can cause psychiatric and physical injuries. After reduced supplies in 2009 (number of ecstasy seizures equal to 10 percent of those recorded in 2002), judicial authorities now observed an increased availability (a half more part of seizures in 2012 than 2010). From its "Spontaneous Notifications" data base and "deaths in connection with the abuse of medicine and substances (DRAMES)", "observation of illegal drugs and misuse of psychotropic medications" (OPPIDUM), and "observation of drug dependencies in ambulatory medicine" (OPEMA) national inquiries, the French Addictovigilance network (CEIP-A) highlighted the increasing consumption of MDMA. The way of use appeared quite unchanged: users were mainly young men between 25 and 30 years; they favored an occasional use but mainly combined other products such as alcohol, cannabis and other stimulants. Severity of the clinical cases, based on hospital care and forensic data, could be consistent with the higher amounts of MDMA measured in pills.

Paracoccidioidomycosis is a systemic mycosis endemic to Latin America. The infection is initiated by inhalation of conidia into the lung and may develop as localized or disseminated disease depending on the depression of cellular immunity. In the present study, we observed that intratracheal infection with Paracoccidioides brasiliensis caused the percentage of resident B-1 cells to decrease. Using xid mice reconstituted with B-1 cells, we observed that B-1 cells migrate to the spleen and stimulate increases in the regulatory T cell subpopulation in response to P. brasiliensis infection. Collectively, these data demonstrate an active role for B-1 cells in susceptibility to paracoccidioidomycosis.

Drug addiction is a chronically relapsing disorder characterized by compulsion to seek and take the drug, loss of control in limiting intake and, eventually, the emergence of a negative emotional state when access to the drug is prevented. Both dopamine and corticotropin-releasing factor (CRF)-mediated systems seem to play important roles in the modulation of alcohol abuse and dependence. The present study investigated the effects of alcohol consumption on anxiety and locomotor parameters and on the activation of dopamine and CRF-innervated brain regions. Male Wistar rats were given a choice of two bottles for 31 days, one containing water and the other a solution of saccharin + alcohol. Control animals only received water and a solution of 0.2% saccharin. On the 31st day, animals were tested in the elevated plus-maze and open field, and euthanized immediately after the behavioral tests. An independent group of animals was treated with ethanol and used to measure blood ethanol concentration. Results showed that alcohol intake did not alter behavioral measurements in the plus-maze, but increased the number of crossings in the open field, an index of locomotor activity. Additionally, alcohol intake increased Fos-immunoreactivity (Fos-ir) in the prefrontal cortex, in the shell region of the nucleus accumbens, in the medial and central amygdala, in the bed nucleus of the stria terminalis, in the septal region, and in the paraventricular and dorsomedial hypothalamus, structures that have been linked to reward and to approach/withdrawal behavior. These observations might be relevant to a better understanding of the behavioral and physiological alterations that follow alcohol consumption.

A 2-year-old Quarter Horse filly was admitted to our facility with a two-day history of trauma caused by barbed wire on the front face of the right front limb fetlock joint. A septic arthritis was confirmed with the synovial fluid examination. The cytologic evaluation of synovial fluid showed 101,000 leukocytes/mm3, 90% neutrophils, and a total protein concentration of 4 g/dL. It was, therefore, decided to perform an arthroscopic lavage using an ultrasonic device with the tip inserted inside the synovial cavity to exploit the phenomenon of acoustic cavitation. After the removal of the synovial pannus, the probe was left to vibrate in the area near the visible penetrating wound inside the joint until three liters of saline was finished. Further studies are needed for understanding and applying this technology in different equine fields and with different bacterial species. However, these first results are promising for the efficacy of this innovative procedure.

Aim of the study was to verify the clinical and morphological effects of intra-articular stanozolol or placebo treatment, lasting 3 and 9months, in sheep in which a femoro-tibial osteo-arthritis (OA) were surgically induced (medial bilateral meniscectomy).Twenty healthy sheep divided into four groups and two control animals group, after surgical medial bilateral meniscectomy, were weekly injected in femoral-tibial joint (FTJ) with stanozolol or placebo. Lameness evaluation was performed and synovial fluid was collected from all sheep at each treatment time. Necropsies were performed after 3 or 9month as described in experimental design. Gross pathologies were described and specimen tissues collected from femoro-tibial articular joints were processed for routine histological examination.The gross anatomy of the FTJ was well-preserved in stanozolol-treated sheep; this also applied to the histological features of articular cartilage. Joint aseptic inflammation and fibrosis were observed in placebo-treated sheep, associated with a different degree of severity of condylar and tibial plate cartilage degeneration.Stanozolol intra-articular treatment reduces osteophytes formation and subchondral bone reaction and promotes articular cartilage regeneration.

Riassunto Obiettivi Analizzare l’accuratezza diagnostica della Cone Beam Computed Tomography (CBCT) rispetto ad altre metodiche d’immagine nel rilevare l’invasione ossea da carcinoma squamocellulare orale (Oral Squamous Cell Carcinoma, OSCC). Materiali e metodi La revisione della letteratura e stata condotta su studi in lingua inglese indicizzati in PubMed dal 1990 al 2014. Sensibilita, specificita e rapporto di verosimiglianza positivo (RV+) e negativo (RV–) sono stati calcolati per ogni studio. Dei 61 articoli raccolti, 7 soddisfacevano i criteri di inclusione. Risultati e conclusioni I dati analitici mostrano valori di RV+ e RV–, rispettivamente, di 14,4 e 0,35 per la CT (Computed Tomography); 37,9 e 0,24 per la MRI (Magnetic Resonance Imaging); 27,8 e 0,10 per la CBCT; 25,5 e 0,06 per la SPECT (Single- Photon Emission Computed Tomography); 37,0 e 0,31 per la MSCT (Multi- Slice Computed Tomography); 4,8 e 0,36 per l’ortopantomografia (OPT). Il grado di evidenza scientifica a oggi disponibile e debole. Ulteriori studi con impostazione metodologica uniforme sono necessari per definire meglio l’impatto della CBCT sul processo decisionale clinico.

Gastrointestinal stromal tumours (GISTs) represent a distinctive group of primary mesenchymal tumours of the gastrointestinal tract identified immunohistochemically by expression of CD117. A 10-year-old neutered female domestic shorthair cat with a history of recurrent vomiting was examined. The presence of a gastric mass was recognized and a laparotomy was performed. Cytological examination was consistent with a low-grade malignant mesenchymal tumour and histopathological investigation suggested myogenic differentiation of tumour cells. The diagnosis of GIST was confirmed by immunohistochemical expression of CD117. Sequence analysis of the KIT gene identified a deletion in exon 11. The same mutation is found often in human GISTs.

The development of antibacterial and antifungal drugs has been the target of several pharmaceutical and chemical industries mainly due to the lack of effective drugs with low or no side effect. In this work, studies were conducted both in vitro and in vivo with 8-oxyquinolinepropoxycalix[4]arene (A) and 5-Cl-8-oxyquinolinepropoxycalix[4]arene (B) ligands, showing fairly good results. Cytotoxicity and fungicidal actions of compounds A and B were determined in Wistar male rats and peritoneal macrophages of mice. A slight change in the total of leukocytes and erythrocytes was observed on the hematologic assays, showing almost no inflammation after using both compounds in Wistar male rats. We have also noted some, but not significant, alteration in liver enzymes representing modest hepatotoxicity. Cytotoxicity of peritoneal macrophages, in the presence of compound A or B, showed 50% of survival of macrophages. On the other hand, macrophages previously infected with Candida albicans and treated with substance A or B exhibited an increased cytokine IL-10 at 24 h incubation. By checking the effect of substance A or B on growing C. albicans , the results pointed that these substances revealed antifungal activity against C. albicans , in 24 h culture with a reduction of yeast cells.

Previous studies from our group have demonstrated the protective effect of S-nitroso-N-acetylcysteine (SNAC) on the cardiovascular system in dyslipidemic LDLr−/− mice that develop atheroma and left ventricular hypertrophy after 15days on a high fat diet. We have shown that SNAC treatment attenuates plaque development via the suppression of vascular oxidative stress and protects the heart from structural and functional myocardial alterations, such as heart arrhythmia, by reducing cardiomyocyte sensitivity to catecholamines. Here we investigate the ability of SNAC to modulate oxidative stress and cell survival in cardiomyocytes during remodeling and correlation with β2-AR signaling in mediating this protection. Ventricular superoxide (O2-) and hydrogen peroxide (H2O2) generation was measured by HPLC methods to allow quantification of dihydroethidium (DHE) products. Ventricular histological sections were stained using terminal dUTP nick-end labeling (TUNEL) to identify nuclei with DNA degradation (apoptosis) and this was confirmed by Western blot for cleaved caspase-3 and caspase-7 protein expression. The findings show that O2- and H2O2 production and also cell apoptosis were increased during left ventricular hypertrophy (LVH). SNAC treatment reduced oxidative stress during on cardiac remodeling, measured by decreased H2O2 and O2- production (65% and 52%, respectively), and a decrease in the ratio of p-Ser1177 eNOS/total eNOS. Left ventricle (LV) from SNAC-treated mice revealed a 4-fold increase in β2-AR expression associated with coupling change to Gi; β2-ARs-S-nitrosation (β2-AR-SNO) increased 61%, while apoptosis decreased by 70%. These results suggest that the cardio-protective effect of SNAC treatment is primarily through its anti-oxidant role and is associated with β2-ARs overexpression and β2-AR-SNO via an anti-apoptotic pathway.

Introduction Le Reseau francais d’addictovigilance a mis en evidence depuis de nombreuses annees l’augmentation de la consommation des medicaments opioides et de ses complications sanitaires [1] . Les demandes de prise en charge dans des contextes d’abus, de mesusage et de pharmacodependances sont frequentes. Le centre d’addictovigilance PACA-Corse a mene une synthese de ces consommations sur 17 mois. Methode Tous les cas d’abus, de dependance ou de mesusage concernant des medicaments opioides, notifies au centre d’addictovigilance (1er janvier 2017–31 mai 2018) et les modalites de prise en charge d’un sevrage eventuel ont ete recueillis et analyses. Resultats Cinquante cas concernent 21 specialites differentes : principaux resultats dans le Tableau 1 . Discussion Cette synthese montre un phenomene de « Purple drank » et une consommation de codeine a forte dose toujours d’actualite a fortiori dans le contexte de la prescription medicale obligatoire [2] . L’absence de recommandations sur la prise en charge de la pharmacodependance a ces medicaments (diminution de dose, switch ou TSO) au regard de la consommation croissante implique qu’un travail pluridisciplinaire sur le sevrage pourrait aider les professionnels de sante et leurs patients.

Objectif En France, la methadone, agoniste puissant et complet des recepteurs opioides de type mu, est indiquee comme traitement substitutif des pharmacodependances majeures aux opiaces. En avril 2008, la commercialisation de la methadone gelule a ete accompagnee de la mise en place d’un plan de gestion des risques visant a minimiser les risques de deces et de surdosage, d’intoxication accidentelle, en particulier chez l’enfant, d’abus, d’usage detourne et de trafic. Un suivi national d’addictovigilance, de pharmacovigilance et de toxicovigilance a ete mis en place. L’objectif de ce travail est de presenter les donnees medico-pharmacologiques d’addictovigilance analysees pour les 9 annees de suivi (15 avril 2008–15 avril 2017). Methodes Une approche multi-sources a partir des dispositifs de surveillance et de veille sanitaire du reseau francais d’addictovigilance (notifications spontanees « NOTS », OSIAP, OPPIDUM, DRAMES) a ete effectuee afin de decrire les caracteristiques de consommation de la methadone et les complications sanitaires associees. Resultats Les principaux faits marquants sont : – l’augmentation de la part de la methadone gelule ; – des prescriptions de methadone comme traitement substitutif des pharmacodependances aux antalgiques opioides et dans la douleur ; – l’augmentation de l’obtention illegale de methadone (88 NOTS sont en lien avec une obtention illegale la 9e annee de suivi versus 20 la 1re annee ; dans OPPIDUM, 10 % des consommateurs de methadone l’ont obtenu illegalement en 2016 versus 6 % en 2008) ; – une consommation associee d’autres opioides (dans OPPIDUM en 2016, 22 % des sujets sous protocole sirop et 15 % des sujets sous protocole gelule ont egalement consomme de l’heroine dans la semaine) ; – la consommation de la methadone sirop et gelule par voie intraveineuse ; – une augmentation de la consommation de methadone par des sujets naifs ou de facon occasionnelle (39 NOTS la 9e annee versus 7 NOTS la 1re annee) ; – une augmentation des NOTS en lien avec une necessite de prise en charge hospitaliere avec dans certains cas administration de naloxone (64 NOTS avec prise en charge hospitaliere et 13 avec administration de naloxone la 9e annee versus 10 et 5 la 1re annee) ; – d’apres DRAMES, en 2016, la methadone est toujours la premiere substance impliquee dans les deces (n = 148 deces) et on observe le nombre le plus eleve de deces ou la methadone est impliquee depuis 2008. Conclusion Dans le contexte de l’augmentation de l’utilisation de la methadone (+44 % du nombre moyen de sujets sous methadone entre 2008 et 2014), de ses caracteristiques pharmacologiques et de l’augmentation des indicateurs d’abus, des complications sanitaires graves et des deces, il est important d’alerter la communaute medicale et les patients et rappeler les specificites pharmacologiques de la methadone, les facteurs de risque de surdosage et l’interet de la naloxone [1] . Il serait interessant de mieux connaitre en France les circonstances de deces liees a la methadone (sujet naif ou sous traitement, modalites de consommation, consommations associees).

Structures used in rockfall protection are designed on the basis of the expected impact energy. This quantity is usually assessed using commercial lumped mass models that stochastically predict possible block trajectories on a given slope. In New South Wales, Australia, it is estimated that rockfall hazard involves values of energy which are much lower than those in Europe, Canada or the USA. However, this view has not been supported by any systematic study across the whole state. Such a study is presented in this paper. It applies to the five geological situations that are the most prone to rockfall in eastern Australia. Previous experimental findings, relating to block size distribution or restitution coefficients (reviewed herein), have been used to perform this statistical analysis. A newly formulated lumped mass program, which incorporates a relationship between the normal restitution coefficient and the impact angle, allows the adoption of normal restitution coefficients in excess of unity for impact angles lower than 30°. The results confirm that in three out of the five geological situations, the 95th percentile of impact energy is lower than 200 kJ, and less than 2000 kJ for the other two situations.