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Objective Several biological DMARDs (bDMARDs) have demonstrated anti-inflammatory effects in PsA. However, their comparative cardiovascular safety profiles remain unknown. We evaluated the risk of major adverse cardiovascular events (MACEs) in PsA patients on therapy with different classes of bDMARDs and apremilast. Methods This nationwide cohort study involved the administrative healthcare database of the French health insurance scheme linked to the hospital discharge database. All adults with PsA who were new users of bDMARDs/apremilast (neither in the year before the index date) during 2015–19 were included. Patients with previous cardiovascular diseases were excluded. End of follow-up was 31 December 2019. The primary endpoint was an occurrence of MACEs in a time-to-event analysis with propensity score-weighted Cox and Fine–Gray models. Results Between 2015 and 2019, we included 9510 bDMARD new users [mean age 48.5 (s.d. 12.7) years; 42% men], including 7289 starting a TNF inhibitor, 1058 an IL-12/23 inhibitor and 1163 an IL-17 inhibitor, with 1885 apremilast new users [mean age 54.0 (s.d. 12.5) years; 44% men]. MACEs occurred in 51 (0.4%) patients. After propensity score weighting, the risk of MACEs was significantly greater with IL-12/23 (weighted hazard ratio 2.0, 95% CI 1.3, 3.0) and IL-17 (weighted hazard ratio 1.9, 95% CI 1.2, 3.0) inhibitors than TNF inhibitors, with no significant increased risk with apremilast (weighted hazard ratio 1.3, 95% CI 0.8, 2.2). Similar results were observed with the Fine–Gray competing risks survival model. Conclusion Analysis of a large database revealed a small overall number of MACEs, and the risk of MACEs was greater for PsA new users of IL-12/23 and IL-17 vs TNF inhibitors.

Flavonoids have been considered as promising molecules for cancer treatment due to their pleiotropic properties such as anti-carcinogenic, anti-angiogenic or efflux proteins inhibition. However, due to their lipophilic properties and their chemical instability, vectorization seems compulsory to administer flavonoids. Flavonoids have been co-encapsulated with other anti-cancer agents in a broad range of nanocarriers aiming to i) achieve a synergistic/additive effect at the tumor site, ii) delay drug resistance apparition by combining agents with different action mechanisms or iii) administer a lower dose of the anti-cancer drug, reducing its toxicity. However, co-encapsulation could lead to a change in the nanoparticles' diameter and drug-loading, as well as a decrease in their stability during storage. The preparation process should also take into accounts the physico-chemical properties of both the flavonoid and the anti-cancer agent. Moreover, the co-encapsulation could affect the release and activity of each drug. This review aims to study the formulation, preparation and characterization strategies of these co-loaded nanomedicines, as well as their stability. The in vitro assays to predict the nanomedicines' behavior in biological fluids, as well as their in vivo efficacy, are also discussed. A special focus concerns the evaluation of their synergistic effect on tumor treatment.

There are limited data on the use of skin testing, other than patch testing, and challenges in the evaluation of epidermal necrolysis (EN), including Stevens-Johnson syndrome and toxic epidermal necrolysis.To report a French multicenter experience in skin testing and challenges in EN, and investigate the factors associated with tests' positivity.All patients who were evaluated by patch tests (PTs), skin prick tests, intradermal tests (IDTs), or drug provocation tests (DPTs) for EN between 2010 and 2020 were retrospectively included through 2 French drug reaction networks.In total, 113 patients were included from 8 centers. Median (interquartile range) time from EN to hypersensitivity workup was 7.9 months (5.1-15 months). All patients had PTs, 17 (15%) had skin prick tests or IDTs with delayed readings and 32 (28.3%) had DPTs. One mild reaction occurred after a DPT. Overall, 22 patients (19.5%) had positive PTs, and the only factors associated with positivity were Algorithm of Drug Causality for Epidermal Necrolysis (ALDEN) score and drug class. Only 1 IDT was positive but considered irrelevant. The DPTs were never performed to prove responsibility of a highly suspected drug but were used to confirm current tolerance of needed medications.Allergological workup in EN, performed by specialists involved in EN, seems safe. Skin tests, although of limited sensitivity, can be helpful for considering the reintroduction of essential drugs according to a benefit-to-risk decision. We propose an algorithm for approaching hypersensitivity testing in patients with EN, to be adapted to each patient.

Introduction The extended stability of the trastuzumab biosimilar Ogivri™ (MYL-1401O; trastuzumab-dkst) was studied under different storage conditions, including following reconstitution of the lyophilized powder (21 mg/mL) but undiluted and stored in vials at 4°C; after dilution at two concentrations (0.8 and 2.4 mg/mL) in polyolefin bags and stored at 4°C; and following a three-day thermal excursion to 25°C. Methods Several methods were utilized to assess the physical and chemical stability of the drug under different storage conditions. Results At all storage conditions tested, there was no change in the tertiary structure of MYL-1401O as assessed by second-derivative ultraviolet and fluorescence-derived spectral analysis, and no evidence of oligomer formation or fragmentation was observed as assessed by gel exclusion chromatography and dynamic light scattering, confirmed by assessment of quinary structures using size-exclusion chromatography. Ion-exchange chromatography showed no significant changes in the distribution of ionic variants, particularly deamidations. Thermal denaturation curves indicated no destabilization of the three-dimensional structure after 90 days at 4°C or after thermal excursion for 72 h at 25°C. Conclusion The trastuzumab biosimilar MYL-1401O maintained its physical and chemical stability for at least 90 days at 4°C or after thermal excursion to 25°C, supporting the safe use of MYL-1401O in several real-world settings, including advanced preparation for administration or when a break in the cold cycle occurs.

Resume Objectif Le parcours de soins du patient souffrant de troubles psychiques etant un parcours complexe et a risque d’interruption de traitement, nous avons mis en place la conciliation medicamenteuse a l’admission en psychiatrie en fevrier 2017. L’objectif de ce travail a ete de realiser un retour d’experience repondant a nos questionnements sur la faisabilite et la pertinence de cette demarche. Methode Une analyse prospective des conciliations sur les 7 premiers mois de mise en place a ete realisee selon 3 indicateurs d’activite et 6 indicateurs de performance. Resultats Au total, 39 patients ont ete concilies dont 56,4 % en secteur ferme. La totalite des patients ont ete rencontres lors d’un entretien pharmaceutique. Les informations issues de cet entretien etaient concordantes avec au moins l’une des autres sources dans 70,4 % des cas. 13 patients n’ont pu etre concilies dans les 72 h en raison de leur pathologie psychiatrique. Le nombre moyen de divergences non intentionnelles (DNI) par conciliation etait de 0,97. Le taux de DNI de gravite majeure etait de 23,7 %. Le nombre de DNI par patient etait significativement superieur en secteur ferme (p Conclusion Ces resultats montrent que la conciliation d’entree est realisable et pertinente en psychiatrie. Pour limiter les contraintes liees a la pathologie psychiatrique, nous proposons de concilier les patients au-dela de 72h apres leur admission, des que leur etat clinique le permet.

Aims The role of diuretics in patients with intermediate-risk pulmonary embolism (PE) is controversial. In this multicentre, double-blind trial, we randomly assigned normotensive patients with intermediate-risk PE to receive either a single 80 mg bolus of furosemide or a placebo. Methods and results Eligible patients had at least a simplified PE Severity Index (sPESI) ≥1 with right ventricular dysfunction. The primary efficacy endpoint assessed 24 h after randomization included (i) absence of oligo-anuria and (ii) normalization of all sPESI items. Safety outcomes were worsening renal function and major adverse outcomes at 48 hours defined by death, cardiac arrest, mechanical ventilation, or need of catecholamine. A total of 276 patients underwent randomization; 135 were assigned to receive the diuretic, and 141 to receive the placebo. The primary outcome occurred in 68/132 patients (51.5%) in the diuretic and in 49/132 (37.1%) in the placebo group (relative risk = 1.30, 95% confidence interval 1.04–1.61; P = 0.021). Major adverse outcome at 48 h occurred in 1 (0.8%) patients in the diuretic group and 4 patients (2.9%) in the placebo group (P = 0.19). Increase in serum creatinine level was greater in diuretic than placebo group [+4 µM/L (−2; 14) vs. −1 µM/L (−11; 6), P Conclusion In normotensive patients with intermediate-risk PE, a single bolus of furosemide improved the primary efficacy outcome at 24 h and maintained stable renal function. In the furosemide group, urine output increased, without a demonstrable improvement in heart rate, systolic blood pressure, or arterial oxygenation. ClinicalTrials.gov identifier NCT02268903.

BACKGROUND: Citrulline (CIT), is not extracted by the splanchnic area, can stimulate muscle protein synthesis and could potentially find clinical applications in conditions involving low amino acid (AA) intake, such as in malnourished older subjects. OBJECTIVE: Our purpose was to research the effects of CIT supplementation on protein metabolism in particular on non-oxidative leucine disposal (NOLD, primary endpoint), and splanchnic extraction of amino acids in malnourished older patients. DESIGN: This prospective randomized multicenter study determined whole-body and liver protein synthesis, splanchnic protein metabolism and appendicular skeletal muscle mass (ASMM) in 24 malnourished older patients [80-92 years; 18 women and 6 men] in inpatient rehabilitation units. All received an oral dose of 10 g of CIT or an equimolar mixture of six non-essential amino acids (NEAAs), as isonitrogenous placebo, for 3 weeks. RESULTS: NOLD and albumin fractional synthesis rates were not different between the NEAA and CIT groups. Splanchnic extraction of dietary amino acid tended to decrease (p = 0.09) in the CIT group (45.2%) compared with the NEAA group (60.3%). Total differences in AA and NEAA area under the curves between fed-state and postabsorptive-state were significantly higher in the CIT than in the NEAA group. There were no significant differences for body mass index, fat mass (FM), lean mass (LM) or ASMM in the whole population except for a tendential decrease in FM for the citrulline group (p = 0.089). Compared with Day 1, lean mass and ASMM significantly increased (respectively p = 0.016 and p = 0.018) at Day 20 in CIT-treated women (mean respective increase of 1.7 kg and 1.1 kg), and fat mass significantly decreased (p = 0.001) at Day 20 in CIT-group women (mean decrease of 1.3 kg). CONCLUSIONS: Our results demonstrate that CIT supplementation has no effect on whole-body protein synthesis or liver protein synthesis in malnourished older subjects. However, CIT supplementation was associated with a higher systemic AA availability. In the subgroup of women, CIT supplementation increased LM and ASMM, and decreased FM.

Injection-site pain (ISP) is a subjective side effect that is commonly reported with the subcutaneous administration of biological agents, yet it may only be a concern to some. Multiple factors related to the product formulation, such as pH, volume and excipients, and/or to the injection process have the potential to contribute to ISP, while patient-related factors, such as low body weight, gender and age, can make an individual more susceptible to experiencing ISP. While total elimination of ISP remains unlikely with any subcutaneously administered agent, it can be minimised by helping the patient to develop a confident and competent injection technique via robust and effective training. Careful management of patient expectations along with open discussion regarding the potential risk of ISP may serve to minimise treatment-related anxieties and, importantly, allow the patient to remain in control of his/her treatment. Other interventions to help minimise ISP include psychological interventions, allowing biologics to reach room temperature prior to injection, using the most suitable injection device for the individual patient and selecting an alternative drug formulation, when available. Productive patient-physician communication remains important in order to support and optimise treatment experience and adherence, while also providing the opportunity for patients to discuss any ISP-related issues.

Importance Erythema multiforme (EM) may become long term, with a recurrent or persistent course. First-line treatment for chronic EM is valaciclovir. There is no consensus for selection of second-line treatment of chronic EM. Objective The aim of this study was to assess the effectiveness of treatment with thalidomide for patients with chronic EM. Design, Setting, and Participants In this retrospective national multicenter cohort study, among 68 French hospital dermatology departments contacted by e-mail, 10 reported having eligible cases. All adults aged 18 years or older under dermatology care for chronic EM (including recurrent and persistent forms) who had received thalidomide between 2010 and 2018 were included. Analyses were conducted from June 24, 2019, to December 31, 2019. Main Outcomes and Measures The primary outcome was the proportion of patients who did not experience an EM flare within 6 months of initiating thalidomide treatment for recurrent EM or with complete clearance at 6 months for persistent EM (complete remission). Results Overall, 35 patients with chronic EM (median [range] age, 33 [15-65] years; 20 [57%] female) experienced failure of at least 1 previous treatment prior to initiating treatment with thalidomide. After 6 months of continuous thalidomide treatment, 23 (66%) were in complete remission, 5 (14%) had stopped the treatment, and 7 (20%) experienced at least 1 flare. The median (IQR) initial dose followed by remission was 50 (50-100) mg/d. Main adverse effects were asthenia (16 [46%]) and neuropathy (14 [40%]). Twenty-five (71%) of patients stopped thalidomide treatment after a median (IQR) of 12 (8-20) months owing to lack of effect (7/25 [28%]), neuropathy or another adverse effect (14/25 [56%]), or long-term complete remission (4/25 [16%]). Low-dose thalidomide, less than 50 mg every other day was sufficient in 9 of 23 (39%) of responders and was associated with less neuropathy and longer treatment duration. Conclusions and Relevance In this cohort study, second-line therapy with thalidomide was associated with complete remission in two-thirds of the 35 patients with chronic EM. However, adverse events were a common cause of thalidomide withdrawal. In the long term, dose reduction when possible may allow for continuation by improving tolerance.

Background:Psoriatic arthritis (PsA) is associated with other diseases of the spectrum of spondyloarthritis but also appears to be linked to an increased prevalence of numerous comorbidities and more specifically cardiovascular risk factors and events. Several biological disease-modifying anti-rheumatic drugs (bDMARDs) have demonstrated anti-inflammatory effects in PsA. However, their comparative cardiovascular safety profiles remain unknown.Objectives:Our objective was to assess the relative comparative risk of major adverse cardiovascular events (MACEs) of different classes of bDMARDs or apremilast for PsA.Methods:This nationwide cohort study involved the administrative healthcare database of the French health insurance scheme covering approximately 67 million individuals linked to the hospital discharge database. All adults with PsA who were new users of bDMARDs/apremilast (neither in the year before the index date) during 2015-2019 were included. Patients with previous cardiovascular diseases were excluded. End of follow-up was December 31, 2019. The primary end point was an occurrence of MACE (acute myocardial infarction and ischaemic stroke) in a time-to-event analysis with propensity score-weighted Cox and Fine-Gray models (including age, sex, inflammatory diseases associated, cardiovascular risk biomarkers and other comorbidities). To assess the sensitivity of the estimated weighted hazard ratio (HRw) with respect to several possible models, we performed a per-protocol analysis, a conventional multivariate Cox model, an analysis using a larger definition of MACE, an analysis modifying the new-user definition (as those who had not filled a prescription for a bDMARDs or apremilast for 5 years before the index date) and an analysis modifying the treatment discontinuation definition.Results:Between 2015 and 2019, we included 9,510 bDMARD new users (mean age 48.5±12.7 years; 42% men), including 7,289 starting a TNF inhibitor, 1,058 an IL12/23 inhibitor and 1,163 an IL17 inhibitor, with 1,885 apremilast new users (mean age 54.0±12.5 years; 44% men). MACEs occurred in 51 (0.4%) patients (Figure 1). After propensity score weighting, the risk of MACEs was significantly greater with IL12/23 (HRw 2.0, 95%CI 1.3-3.0) and IL17 (HRw 1.9, 95%CI 1.2-3.0) inhibitors than TNF inhibitors, with no significant increased risk with apremilast (HRw 1.3, 95%CI 0.8-2.2). Similar results were observed with the Fine-Gray competing-risks survival model. The sensitivity analyses results were consistent with those of the main analysis.Conclusion:Analysis of a large national database revealed an overall small number of MACEs. Using robust methodology from the causal inference field, the risk of MACEs was greater for PsA new users of IL12/23 and IL17 versus TNF inhibitors. The risk of MACEs did not significantly differ between new users of apremilast and new users of TNF inhibitors.Figure 1.Flowchart for analytic approach Data are n. bDMARD: biological disease-modifying antirheumatic drugs; CVD: cardiovascular disease; TNF: tumor necrosis factor; IL: interleukin; MACE: major adverse cardiac events.Acknowledgements:L Pina Vegas received a Master 2 grant from the French Society of Rheumatology (Bourse Master 2ème Année 2019)Disclosure of Interests:Laura Pina Vegas: None declared, Philippe Le Corvoisier: None declared, Laetitia Penso: None declared, Muriel Paul: None declared, Emilie Sbidian: None declared, Pascal Claudepierre Speakers bureau: AbbVie, Janssen, Lilly, MSD, Novartis, Pfizer, Consultant of: Abbvie, Pfizer, Roche-Chugai, Bristol-Myers Squibb, MSD, UCB, Novartis, Janssen, Lilly, Celgene (consulting fees, less than 10,000 $ each)., Employee of: Roche Chugai, Sanofi Aventis, Celgene, Pfizer, MSD, Novartis and BMS (investigator).

As drug delivery activity to outpatients in precarious situation is rising continuously, the goal of this work was to perform an assessment of the professional practices of the care pathway of these patients, called PASS in France (permanence d'acces aux soins de sante). At first, two pharmacists did an audit of this care pathway. Then, options for improvement were suggested and established after a multidisciplinary work with pharmacists, physicians and social workers of the relevant services. Finally, after six months, those actions and their impact were evaluated. Over a three-year period, the audit showed an increase by a factor of 1.77 of the average number of prescriptions provided per year. Over the same period, the number of dispensed lines was increased by 2.2 and the annual costs were multiplied per 1.82. The pharmacy department suggested several corrective actions: at first, initiating new schedules suited to the activity; then, making adjustments in the reception zone; but also, establishing two new specific prescriptions and 89 helps cards about the most frequently delivered medications. As a result, the time dedicated to drug delivery has been cut in half while the number of pharmaceutical actions remained constant. This assessment of the professional practices showed how hard it is to formalize a transversal circuit as the PASS in hospital. The actions established had improved the organization and the drug delivery activity in the pharmacy department.

There is currently only one monoclonal antibody for which there is a biosimilar: infliximab, which was released onto the French market in 2015. The SPC for the biosimilar (Remsima®) are superimposable on those of the original, including 24-hour stability at both 4 and 25°C. The aim of our study was to determine the stability of this biosimilar during one month at 4 and 25°C. Three different batches at two concentrations (0.7mg/mL or 1.6mg/mL) were used. Physicochemical stability was evaluated by the following methods: turbidity, UV spectrometry, DLS, ion chromatography (CEX), gel exclusion chromatography (SEC), and light microscopy. The analyses were performed in triplicate. All methods used have been demonstrated to be valid for measuring antibody stability. There were no signs of physicochemical instability after seven days (on D7) of storage at 4 or 25°C. From D15, we observed slight changes by ion (percentage distribution of the different isoforms) and gel exclusion chromatography (percentage distribution of different polymers, i.e. dimers, oligomers). However, the areas under the curves were unchanged, and the proportions of polymers remained lower than 0.5%. Tertiary structure analysis also showed a change from D15. All observed changes are consistent with progressive oligomerization by hydrophobic interactions. In conclusion, the reconstituted biosimilar is stable for seven days at 4 and 25°C. Gradual oligomerization is observed from D15 but appears to be less than 0.5%, suggesting instability, albeit very limited, in the longer term; the practical consequences of this remain to be evaluated.

Background In 2017 a patient’s death occurred in the psychiatry department of our establishment. After a morbidity-mortality review, the hypothesis of a cardiac arrest after intake of torsadogenic drugs has been suggested. Purpose The state of cardiac patient care in our psychiatry units was one of the strategic axes retained to define priority actions for improvement. Material and methods Records of the hospitalised psychiatry patients were analysed on a given day in April 2018. A literature review allowed selection of the factors to analyse: ionogram dates and results, thyroid function, arterial tension (AT), heart rhythm (HR), electrocardiogram realisation, corrected QT interval (QTc), torsadogenic risk factors (female ≥65 years, ischaemic heart disease, torsadogenic drug) and co-prescriptions of psychotropic drugs inducing QT prolongation (PDIQTP). Only the factors traced in the patients’ records during the first 30 days of hospitalisation were analysed. Results Ninety-six records were analysed (100% of inpatients). Found at admission were ionograms, thyroid function, AT, HR and electrocardiogram realisation, respectively for 94%, 70%, 95%, 96% and 90% of patients. Seven hypokalaemias were found and were all adjusted during the first month. No hypocalcaemia or hypothyroidism were found but one hyperthyroidism was revealed and explored. Seven hypertensions were explored. No bradycardia was recorded. Four patients had QTc prolongation (≥450 ms). Among them, two profited from an additional electrocardiogram. The percentage of patients with one risk factor was 19% and 2% of patients had more than one risk factor. Half of these patients underwent an additional electrocardiogram. During hospitalisation, 44 PDIQTP, 17 initiations and 12 raises of torsadogenic drug dosage were carried out. These modifications were monitored by an extra electrocardiogram in 13% of cases. Conclusion Admission cardiac check-up was mainly realised and its disturbances corrected or explored. However, the thyroid function was underestimated whereas its disturbance can cause not only cardiac disorders but also psychiatric disorders. Furthermore, in risk situations that need an extra electrocardiogram during hospitalisation (QTc prolongation for example), cardiac monitoring was insufficient. These two points will be spotlighted in a cardiac monitoring protocol for psychiatry inpatients, in order to prevent iatrogenic cardiac arrests throughout the hospitalisation. References and/or acknowledgements No conflict of interest.

Objectives In recent years, various formulations containing rapamycin, mainly petrolatum-based, have been tested on facial angiofibromas in tuberous sclerosis. They are often poorly tolerated due to irritation and bleeding. In addition, their effectiveness was insufficient in young adults. The objective of this study was to develop and characterise a hydro-alcoholic gel containing solubilised rapamycin. The stability of the product stored at 4°C was evaluated over 1 year. Methods Two different 0.1% rapamycin gels were formulated with or without α-tocopherol and urea. Different methods were used to characterise the gels: HPLC, gas chromatography, pH, visual observation and optical microscopy. A physico-chemical and microbiological stability study was also conducted for 1 year at 4°C. Results Gels were physically and microbiologically stable after 1 year at 4°C: organoleptic characteristics and pH unchanged, no significant decrease in rapamycin was observed, tocopherol droplet size was constant and rheological behaviour was not altered. Conclusions This study describes a new gel formulation to improve skin penetration using various excipients to promote skin tolerance. This study provides, for the first time, detailed stability data for a hydro-alcoholic rapamycin gel.

Introduction Le rhumatisme psoriasique (RhPso) semble associe a un sur-risque d’evenements cardiovasculaires graves (ECVG) comparativement a la population generale. La plupart des traitements de seconde intention ont montre dans la polyarthrite rhumatoide, outre leur effet anti-inflammatoire, un effet cardiovasculaire favorable ; cependant un tel effet dans le RhPso n’a pas ete etabli. Notre objectif etait d’estimer le risque d’ECVG selon le traitement prescrit dans une population de patients initiant un traitement de seconde intention pour un RhPso, en pratique courante. Materiels et methodes Nous avons mene une etude de cohorte a partir des donnees du Systeme National des Donnees de Sante (SNDS) rassemblant les informations de remboursement de 99 % des residents francais. Les adultes reperes RhPso (CIM-10 M07), nouveaux utilisateurs d’un bDMARD ou d’apremilast (n’ayant recu aucun de ces traitements dans l’annee precedant la date index) entre le 01/01/2015 et le 31/12/2019 ont ete inclus. Ceux ayant des antecedents cardiovasulaires ont ete exclus. L’association entre une classe therapeutique et la survenue d’un ECVG (syndrome coronarien aigu et accident vasculaire cerebral ischemique) a ete estimee par un modele de Cox et de Fine and Gray apres ponderation inverse par un score de propension (incluant notamment l’âge, le sexe, les pathologies inflammatoires associees, la consommation de soins, la consommation d’AINS et de prednisone et les facteurs de risque cardiovasculaires tels que l’hypertension arterielle, la dyslipidemie, le diabete, les maladies respiratoires chroniques et autres troubles lies au tabac, la prise d’antiagregant plaquettaire et l’obesite morbide ou compliquee). Des analyses de sensibilite ont ete realisees pour evaluer la robustesse de nos resultats. Resultats Au total, 66 456 patients ont ete identifies RhPso dans notre base. Parmi eux, 9510 (14 %) nouveaux utilisateurs d’un bDMARD (48,5 ± 12,7 ans ; 42 % d’hommes) dont 7289 (77 %) initiant un anti-TNF, 1058 (11 %) initiant un anti-IL12/23 et 1 163 (12 %) initiant un anti-IL17, et 1885 (3 %) initiant de l’apremilast (54,0 ± 12,5 ans ; 44 % d’hommes) ont ete inclus dans l’analyse principale. Un ECVG etait observe chez 51 (0,4 %) patients sur une duree mediane de suivi de 10 mois (ecart interquartile 4-22). Apres ponderation inverse par un score de propension, et comparativement aux anti-TNF, l’anti-IL12/23 (HRp 2,0, IC95 % 1,4-2,8) et l’anti-IL17 (HRp 2,2, IC95 % 1,5-3,2) etaient lies au risque d’ECVG de facon statistiquement significative (p global Conclusion En utilisant une grande base de donnees nationale, le risque global d’ECVG semblait moins important parmi les patients RhPso sous anti-TNF que sous anti-IL12/23 ou anti-IL17.

Rapamycin has been used topically to treat facial angiofibromas associated with tuberous sclerosis for more than a decade. In the absence of a commercial form, a large number of formulations have been clinically tested. However, given the great heterogeneity of these studies, particularly with regard to the response criteria, it was difficult to know the impact and thus to compare the relevance of the formulations used. The objective of this work was therefore to evaluate the link between the diffusion of rapamycin and the physico-chemical characteristics of these different formulations on Strat-M&reg, membranes as well as on human skin using Franz cells. Our results underline the importance of the type of vehicle used (hydrogel &gt, cream &gt, lipophilic ointment), the soluble state of rapamycin and its concentration close to saturation to ensure maximum thermodynamic activity. Thus, this is the first time that a comparative study of the different rapamycin formulations identified in the literature for the management of facial angiofibromas has been carried out using a pharmaceutical and biopharmaceutical approach. It highlights the important parameters to be considered in the development and optimization of topical rapamycin formulations with regard to cutaneous absorption for clinical efficacy.

Introduction La carbidopa (CDP) ameliore la biodisponibilite de la [18F]-Dopa utilisee en tomographie a emission de positons afin de detecter des pertes fonctionnelles des terminaisons des neurones dopaminergiques. Disponible uniquement en association fixe, une preparation hospitaliere a base de CDP seule et dosee a 100 mg a ete developpee. Son instabilite chimique requiert une etude de stabilite rigoureusement realisee au moyen de methodes indicatrices de stabilite. La recherche des substances apparentees dans la matiere premiere CDP est une exigence de la Pharmacopee Europeenne (Ph. Eur.). Elle est realisee par chromatographie liquide a haute performance (CLHP) conformement aux conditions decrites par la monographie 0755. Cette methode pourrait donc potentiellement śappliquer a l’etude de stabilite de cette preparation hospitaliere. L’objectif de cette etude etait donc d’evaluer ses criteres de performance requis pour permettre le suivi de la teneur de la substance active au cours de la conservation. Materiels et methode La methode CLHP etudiee met en œuvre un mecanisme de partage en phase inverse (0755, Ph. Eur.) : colonne silice greffee C18 (250 × 4,6 mm, 5 μm) en equilibre avec une phase mobile constituee initialement dun melange KH2PO4 0,103 mol/L - methanol (98/2). Apres optimisation, la phase mobile a base de KH2PO4 0,103 mol/L - acetonitrile (ACN) (95/5) est utilisee. La methode a ete validee sur un domaine de concentrations en CDP de 60 a 140 μg/mL. Resultats et discussion La methode decrite par la Ph. Eur. est instable. Le temps de retention (tR) de la CDP est fluctuant, diminuant au fur et a mesure de l’enchainement des analyses. Ce phenomene est inattendu dans la mesure ou ĺequilibre entre les phases stationnaire et mobile est dautant plus favorable que la duree de contact entre les deux systemes est grande. L’etude de ĺimpact du pH, de la temperature et de la nature du solvant organique a montre que la stabilisation du tR de la CDP est fortement conditionnee par la nature et la teneur en solvant organique de la phase mobile. En effet, le remplacement du methanol par ĺACN et l’augmentation de la fraction organique de la phase a 5 % ont cette fois permis de fixer le tR (4,87 ± 0,02 min). Presentant une plus faible affinite que l’ACN vis-a-vis des chaines alkyl, le methanol semble moins enclin a permettre leur solvatation, dautant que la fraction organique est faible. Ces nouvelles conditions ont ete testees sur des solutions soumises aux conditions de degradation forcee. La nouvelle methode separe efficacement la CDP de ses produits de degradation et repond aux criteres de validation. Conclusion Meme si la methode Ph. Eur. pour la CDP a fait l’objet de test d’aptitude inter-laboratoire, une adaptation et une optimisation ont ete necessaires car elle a ete jugee instable et donc peu adaptee pour des etudes de stabilite de la CDP dans nos gelules.

Background Automated dispensing cabinets (ADCs) have been tested and approved for medication management in hospitals. Objectives First, to evaluate the logistics and organisational effect of a similar system for management of sterile medical devices in a medical intensive care unit (ICU). Second, to assess the cost savings of this new organisation for the sterile medical devices budget of this department. Methods The organisational effect was evaluated by comparing (1) the workload of head nurse, nursing auxiliary and pharmacy technician and (2) sterile medical devices emergency orders, 1 year before and after implementation of three ADCs and 100 wireless open-access devices. The hospital9s costs (ADC, wireless devices and software) and benefits (stock value and resupplying value before and after implementation) were evaluated. Results Employment of ADCs led to organisational improvement: the total time saved by the pharmacy and ICU together was 34% of the time spent before introduction. The number of emergency orders decreased from 6% to 1% of total orders after 1 year. €55 000 were saved (stock value + resupplying value) 1 year after introduction of ADCs. These benefits were almost equal to the cost of introducing the system. Conclusions ADCs could provide an innovative and efficient solution for the management of sterile medical devices in hospitals. Further investigations are needed to complete the financial evaluation, and to develop this system to provide a secure a medical devices circuit.

The stability of the rituximab biosimilar CT-P10, in 50mL vials at a concentration of 10mg/mL, and after dilution to final concentrations of 1 and 4mg/mL and storage in polyolefin bags at 4°C and 25°C was studied by several orthogonal and complementary methods. No significant change (as defined by a magnitude greater than the inter-batch variability) was observed, for each of the parameters characterizing physical and chemical stability studied, for the two concentrations and temperatures tested, or for any of the three batches tested. This implies that cold-chain rupture and exposure to room temperature up to 15 days both for vials and diluted bags have no deleterious consequence on the quality of the product. Moreover, this extended stability permits safe in-advance preparation, dose-banding or flat-dose, that to avoid unnecessary delays in the management of the patient, improvement of the pharmacy and nurse workload and money saving by avoiding non justified losses of this expensive drug.

Summary Post-production analytic control of chemotherapies preparations remains a challenge for hospital pharmacists. Indeed, to be feasible, this control needs to be reliable, fast and easy to implement and to use on real life. This is particularly true for teams not familiar with analytic methods. The Multispec ® analyser has been specially manufactured for that purpose. After several years of daily use, we wanted to focus on its implementation, abilities and defects that should be corrected on the next analyser. Upon 24 months, 23,350 samples have been analysed. Four percent have been rejected on the first analysis, and finally only 0.37% with another sample after homogenization. Eighty-six preparations have been done another time for non-conformity purpose. Difficulties of implementation were in particular on anthracyclins, oxazophosphorins and monoclonal antibodies. However, compared to liquid chromatography for example, the ultraviolet and infrared combination allows a large number of drugs to be recognized and quantified fastly. As a conclusion this analyser is quite helpful and gives a serious alternative to post-production analytic control for chemotherapies preparations. Some points should however be improved, probably on the next analyser, for instance the sample volume necessary for analysis.

Introduction Dans le service de readaptation cardiaque de notre etablissement, 3 programmes d’education therapeutique du patient (ETP) sont actifs et destines aux patients hospitalises insuffisants cardiaques, traites par anti-vitamine K ou souffrant d’une maladie coronarienne. Chaque programme comprend 3 a 4 seances. Les objectifs sont communs aux 3 programmes : developper les connaissances et competences du patient sur sa pathologie, ses traitements, son alimentation, sa gestion du stress et l’aider a integrer l’activite physique a son quotidien tout en favorisant son autonomie. L’objectif etait de realiser une evaluation du sentiment d’efficacite personnelle (SEP) des patients avant et apres ces programmes. Le SEP est le sentiment du patient d’avoir atteint les objectifs fixes en debut de programme. Materiels et methode Il s’agissait d’une etude retrospective reprenant 10 % des dossiers d’education therapeutique, selectionnes au hasard sur l’annee 2017, soit 90 dossiers. Les scores obtenus avant et apres ont ete compares par un test des rangs signes de Wilcoxon. Cette etude comprenait 2 phases : une evaluation instauree a l’entree du programme au moment du bilan educatif partage (BEP) et une evaluation finale (EF) en fin de programme. Durant le BEP, l’infirmiere proposait au patient de s’autoevaluer en remplissant un diagramme en etoile constitue de 6 branches, reprenant les 6 objectifs communs aux 3 programmes. Chaque branche etait graduee de 0 a 10 (10 etant le meilleur score). En fin de programme, l’infirmiere proposait de nouveau au patient de remplir ce diagramme lors de l’EF. Les 2 diagrammes ont ete compares afin de discuter avec le patient de l’evolution de ses competences et de l’atteinte de ses objectifs avant et apres le programme d’ETP. Resultats et discussion La repartition des patients par programme etait de 30 % (insuffisance cardiaque), 47 % (anti-vitamine K) et 23 % (maladies coronariennes). Sur les 90 dossiers analyses, 86 patients ont suivi de facon complete au moins un des 3 programmes d’ETP proposes dans le service de readaptation cardiaque. Pour ces 86 patients, le sexe ratio homme/femme etait de 5,1 et l’âge median etait de 67,5 ans. La duree moyenne entre les 2 evaluations etait d’environ 1,5 semaine. Les moyennes des scores lors du BEP versus EF etaient de : 5,5 ± 2,4 vs 7,8 ± 1,7 1 concernant la pathologie, 4,7 ± 2,8 vs 7,4 ± 2,11 pour les traitements, 6,5 ± 2,1 vs 8,0 ± 1,41 pour l’alimentation, 6,6 ± 2,4 vs 8,2 ± 1,71 concernant la gestion du stress, 5,5 ± 2,5 vs 7,9 ± 1,71 pour l’activite physique et 6,9 ± 2,5 vs 8,5 ± 1,51 concernant l’autonomie. Le score global passait de 5,8 ± 1,3 a 8,0 ± 1,01. Conclusion Lors du BEP, les patients ont un score de 5,8 ± 1,3 en moyenne, laissant place a une marge de progression. Cette progression apparait plus forte (+ 2,7 points) pour les traitements. Durant nos programmes d’ETP en readaptation cardiaque, nos patients progressent et renforcent significativement leur SEP, quel que soit l’item evalue. Ceci temoigne de l’interet de nos seances d’ETP et particulierement celles axees sur les medicaments. Nos patients sortent donc de l’hopital avec une dynamique de prise en charge. Pour apprecier la persistance de cette dynamique au domicile, il serait interessant qu’une nouvelle evaluation soit realisee a distance de l’hospitalisation.

Resume Introduction Dans un but d’amelioration de la prise en charge des patients porteurs de stimulateurs ou de defibrillateurs, nous avons realise une enquete visant a evaluer l’appropriation de l’implant cardiaque par les patients. Patients et methode Un questionnaire a ete propose permettant d’evaluer le degre d’assimilation des informations donnees sur leur implant (indication de la pose, precautions et conduite a tenir…) par les patients se presentant dans le service de cardiologie pour une primo-implantation ou un changement de dispositif. Resultats Les resultats revelent que 84 % des patients connaissent l’indication de la pose de l’implant. Seulement 55 % avertissent l’equipe medicale qu’ils sont porteurs d’implant cardiaque, en cas de prescription d’IRM. Seuls 35 % des porteurs de defibrillateurs connaissent la conduite a tenir en cas de choc. La majeure partie des patients disent consulter lorsque des signes d’infections se manifestent ou lors de la reapparition de symptomes. Discussion Les resultats montrent que les patients sont generalement bien informes sur les principales precautions et connaissent l’implant en lui-meme. Cependant, les messages de conduite a tenir ne sont pas toujours assimiles. Les porteurs de defibrillateurs ont mieux assimile l’information que les porteurs de stimulateurs. Conclusion Notre demarche a permis de rendre compte du niveau d’information et du degre d’appropriation par les patients. Elle s’inscrit dans le developpement de plans d’education therapeutique du patient.

Introduction Les permissions de sortie, frequentes en psychiatrie, permettent de mesurer la capacite de reinsertion des patients hors de l’hopital. Elles sont a risque d’iatrogenie et d’inobservance. Pour limiter ce risque, des ateliers piluliers individuels sont realises la veille des permissions dans l’unite psychiatrique des jeunes adultes de notre etablissement depuis 2016. L’objectif est d’evaluer le savoir et le savoir-faire des patients a l’issue de ces ateliers. Materiels et methode Durant ces ateliers, l’infirmier remet le plan d’administration au patient et lui demande de preparer son pilulier. En parallele, l’infirmier lui delivre une information orale sur la gestion du traitement. En se basant sur l’echelle du reseau PIC, une fiche de recueil est creee par le pharmacien avec l’infirmier. Cette fiche est remplie par l’infirmier durant l’atelier afin d’evaluer le savoir et le savoir-faire par 9 questions ouvertes et une observation de la pratique. Le savoir est evalue par : le nom et dosage des medicaments, leurs indications, leurs effets indesirables (EI) et le risque lie a un arret de traitement. Le savoir-faire est evalue par : le niveau d’autonomie du patient lors de la preparation du pilulier, la conduite a tenir en cas d’oubli, la gestion des prises conditionnelles, la gestion et le signalement des EI. Chaque item est cote de 1 (insuffisant) a 4 (satisfaisant) pour obtenir 2 scores sur 20. Resultats et discussion De janvier a juillet 2017, 45 ateliers ont ete realises pour 280 permissions. Le nombre moyen de medicaments prescrits est de 6 [2 ; 12]. Le score moyen est de 15,4 [7 ; 20] pour le savoir et de 15,6 [8 ; 20] pour le savoir-faire. Dans 1 cas sur 2, les patients preparent leur pilulier seul. Les noms des medicaments et dosages sont memorises par les patients dans 49 % et 47 % des cas. L’indication des medicaments est connue dans 40 % des cas. La majorite des patients savent qu’ils vont rechuter s’ils arretent leur traitement (82 % de reponses satisfaisantes). Dans 9 cas sur 10, ils connaissent la conduite a tenir en cas d’oubli et dans 38 % des cas, savent gerer les prises conditionnelles. Ils mentionnent les EI dans 62 % des cas, mais ne savent pas les gerer et ne les signalent pas spontanement dans 36 % et 42 % des cas. Conclusion Malgre un score moyen eleve, des items essentiels restent non maitrises par les patients : gestion des prises conditionnelles et des EI. Des outils pedagogiques a destination des patients seront donc crees afin d’insister sur ces notions. En raison d’un manque de temps infirmier, le nombre d’ateliers est faible par rapport au nombre de permission. Ainsi, une selection des patients les plus a risque sera mise en place, en ciblant par exemple les patients ayant des antecedents de rechutes, un nombre eleve de medicaments ou vivant seul a domicile. Le partenariat pharmacien–infirmier deja existant est a accentuer par : une animation des ateliers en binome ou l’evaluation de l’impact des ateliers sur l’observance des patients par exemple. Cet etat des lieux est donc l’etape preliminaire d’un projet d’optimisation de ces ateliers afin d’ameliorer la securisation de la prise medicamenteuse au domicile.

Currently, severe erectile dysfunction can be treated by intracavernous injections of solutions containing three active ingredients: prostaglandin E1 (PGE1), papaverine and urapidil. Very few data exist on this mixture where phentolamine has been replaced by Urapidil because Phentolamine is not used for this indication in France. The aim of our study was to assess the stability of this formulation and to extend its expiration to permit preparation of batches. Three batches of the preparation containing 15μg/mL PGE1, 15mg/mL of papaverine and 2mg/mL urapidil were made aseptically and then packed in polypropylene syringes stored at 4°C. The physico-chemical stability has been tested as follows: HPLC stability-indicating method, visual observation, measurement of pH and osmolarity. We found that the limiting factor was PGE1 and we exceeded the threshold of 10% loss after 55 days. Replacement of Urapidil by Phentolamine seems to have a slight detrimental effect on stability. Nevertheless, these results allow us to consider the advance preparation of this formulation and provide quality treatment to these patients by avoiding too frequent visits to the hospital.

Using several complementary analytical methods, we demonstrated that the monoclonal antibody Trastuzumab (Tz), diluted in 0.9% sodium chloride can be stored in polyolefin infusion bags at 4°C or room temperature up to 6 months with no evidence of chemical or physical instability. No aggregation of Tz was observed and its three dimensional structure remains unaltered. Thus, the practical use of diluted Tz can be safely extended to optimize the workload of centralized preparation units and to minimize costs.

Resume Objectif Evaluer l’efficacite de l’abatacept chez les patients ayant une spondylarthropathie (SpA) axiale refractaire au traitement par anti-TNF-α. Methodes Les patients repondant aux criteres de SpA axiale active malgre le traitement par au moins deux agents anti-TNF-α ont ete inclus de maniere consecutive. Ils ont recu un traitement par abatacept (10 mg/kg) a j1, 15 et 29 puis tous les 28 jours jusqu’a 24 semaines. Les parametres cliniques et biologiques ont ete evalues a six mois. Resultats Sept patients ont ete inclus. Tous etaient des femmes (âge median : 39 ans ; duree mediane d’evolution de la maladie : 12 ans), cinq avaient une spondylarthrite ankylosante (SA) et deux une SpA indifferenciee. Apres six mois de traitement par abatacept, une reduction d’au moins 50 % du score BASDAI n’a ete atteinte chez aucune des patientes ; une reduction d’au moins deux points du score BASDAI n’a ete observee que chez une seule patiente (−3,8 points ; −49,3 %). Aucune variation significative des scores de douleur ou d’opinion globale du patient n’a ete observee. Des rachialgies inflammatoires ont persiste chez l’ensemble des patientes. Une amelioration des enthesites a ete notee chez la plupart d’entre elles et une amelioration de la mobilite rachidienne a ete observee chez deux patientes. Aucun evenement clinique indesirable significatif n’a ete rapporte. Conclusion Un traitement de six mois par abatacept n’a pas ameliore de maniere significative l’activite de la maladie, la fonction ou les autres parametres chez sept patientes presentant une SpA axiale. Ces resultats preliminaires suggerent un manque d’efficacite de l’abatacept dans les formes axiales de SpA.

Purpose Well-documented stability data of monoclonal antibodies are generally missing. That is why we studied the physicochemical and biological stability of undiluted ipilimumab (IPI) in glass vial (5 mg/ml) over 28 d after opening, stored at 4°C and 25°C. Method A stressed study (60°C) was performed to validate our analytical methods as ‘stability indicating’. The different methods used were turbidimetry, dynamic light scattering (DLS), second-derivative ultraviolet and chromatographic methods as size-exclusion chromatography (SEC) and cation-exchange (CEX). Biological characterisation was performed by an in vitro functional binding inhibition bioassay. Results We demonstrated that ipilimumab in opened vials stored at 4°C and 25°C remained stable for at least 28 d. No physical, chemical or structural instability was found. No aggregation was observed by turbidimetry, SEC and DLS. Hydrodynamic diameters remained unchanged, as chromatographic profiles in CEX and thermal aggregation curves. Functionally, the ability of IPI to antagonise CTLA-4/B7.2 binding remained stable over 1 month at 4°C. Conclusion These results indicate that unused residues of IPI in their original vials can be safely kept up to 28 d, following good manufacturing procedures, allowing re-use for another patient or in case of cold-chain rupture.

Summary Introduction The anti-angiogenic monoclonal antibody, bevacizumab, is currently used by intravitreal administration as off-label drug to treat age-related macular degeneration or other ophthalmologic diseases. For this purpose, commercial bevacizumab is repackaged in 1 mL polypropylene syringes under sterile conditions. However, no complete study on the stability of this hospital-based preparation is available. Methods Commercial bevacizumab (25 mg/mL; Avastin ® ) was aseptically repackaged in 1 mL polypropylene syringes, stored at 4 °C, and analyzed within the preparation day (D0), after 30 days (D30) and 90 days (D90). Some syringes were kept for up to 8 months to observe possible instability. Several complementary and stability-indicating analytical methods were used to assess in details the primary, secondary and tertiary structure of the antibody during its conservation: ionic chromatography, size-exclusion chromatography, peptide mapping, 2nd derivative UV and IR spectroscopy, turbidimetry, diffraction laser spectroscopy, thermal denaturation curves, microscopic examination and image analysis. Results We clearly demonstrate that the commercial solution of bevacizumab can be safely repackaged in polypropylene syringes and stored up to 3 months at 4 °C without alteration of its primary, secondary and tertiary structure. The only difference observed is the contamination of the syringe content by silicone oil microdroplets, which is quite immediate and does not change significantly during the storage in terms of number and size. Conclusion Our results support the off-label use of repackaged bevacizumab by intravitreal administration, at least from a pharmaceutical point of view, with a validated stability of 3 months. This stability period is largely enough to practical situations and support current practices, such as in advance or batch preparations, which present major advantages in terms of GMP respect, workload optimization and financial savings.

Objective To assess the efficacy of abatacept in patients with axial spondyloarthropathies who had failed TNFα antagonist therapy. Methods Consecutive patients fulfilling criteria for active axial spondyloarthropathy, despite at least two previous TNFα antagonists, were treated with abatacept (10 mg/kg) given on days 1, 15, and 29, then every 28 days until week 24. Clinical and laboratory outcome criteria were assessed monthly for 6 months. Results Seven patients were treated and followed, all women (median age, 39 years; median disease duration, 12 years), five with ankylosing spondylitis and two with undifferentiated spondyloarthropathy. After 6 months of abatacept therapy, no patient had an at least 50% decrease in the BASDAI; a single patient had an at least 2 cm decrease in the BASDAI (−3.8 cm; −49.3%). No significant changes were observed in pain or patient global assessment scores. Inflammatory back pain persisted in all seven patients. When present, enthesitis improved in most patients. Improvements in spinal mobility measures occurred in two patients. There were no clinically significant adverse events. Conclusion A 6-month regimen of abatacept did not meaningfully improve disease activity, function, or other disease parameters in seven patients with axial spondyloarthropathies. These preliminary results do not suggest a strong efficacy of abatacept in axial forms of spondyloarthropathies.

The aim of our study was the implementation of a systematic control for preparations based upon monoclonal antibodies. Multispec automaton combines ultraviolet (UV) with infrared spectroscopy. Validation of the analytical method was carried out, in terms of qualitative results (with a correct recognition) and quantitative ones. Our first tests tend to show that Multispec automaton is not reliable enough to manage every antibody currently sold on the French market because of a weak correct recognition percentage (around 35 %). When taking into consideration only its own spectra, the improvement is low (50 % recognition). Only a new spectral library with restricted zones in the infrared domain and furthermore with another correlation calculation mode will be able to produce fast and reliable results. In our final library, spectral recognition is correct for 100 % of samples. Quantification achieved thanks to UV is correct in terms of exactness and precision, respectively 6.0 and 8.1 %. To date, we have settled this routine control for every monoclonal antibody available in our institution used in chemotherapies regimens (alemtuzumab, bevacizumab, cetuximab, gemtuzumab ozogamycin, panitumumab, rituximab and trastuzumab). The reliability of our antibody-specific library was demonstrated, likewise the original library for classical chemotherapies.

International audience; Inclusion complexes of nefopam base (NEF) with various beta-cyclodextrins (betaCDs) were investigated. All tested betaCDs increased the apparent solubility of NEF according to a Higuchi AL type plot (except betaCD: AN type plot), which indicates the formation of 1:1 stoichiometry inclusion complexes. 1H-NMR and 13C-NMR experiments showed that complexation by CDs allowed an easy separation of the R and S enantiomers. Based on spectral data obtained from the two-dimensional rotating frame nuclear Overhauser effect spectroscopy (2D-ROESY), a reasonable geometry for the complexes could be proposed implicating the insertion of the benzoxazocine ring into the wide end of the torus cavity.

Introduction et but de l’etude Le vieillissement est associe a la sarcopenie qui peut etre aggravee par la denutrition. Il a ete demontre que la citrulline (Cit) a la propriete de stimuler la synthese proteique musculaire et de diminuer la masse grasse chez le rat âge. Notre hypothese est que la Cit pourrait stimuler la synthese proteique musculaire et augmenter la masse musculaire chez la personne âgee denutrie, qui presente une resistance a l’anabolisme musculaire. Materiel et methodes Cette etude prospective, randomisee, multicentrique a inclus 29 patients âges denutris hospitalises en soins de suite. Ils recevaient, pendant 20 j, par voie orale, soit 10 g de Cit, soit un melange equimolaire de six acides amines non essentiels (AANE) comme placebo isoazote. La composition corporelle des patients etait evaluee par DEXA a j1 et a j20 : masse maigre totale (MM), masse maigre squelettique appendiculaire (MMSA), masse grasse (MG). Resultats Vingt-quatre patients ont termine l’etude. Les MM et MMSA etaient significativement augmentees a j20 par rapport a j1 dans le groupe Cit. La MG etait significativement diminuee dans le groupe Cit chez les femmes. Les variations de la MMSA et de la MG etaient significativement differentes entre les deux groupes chez les femmes ( Tableau 1 ). Conclusion Cette etude demontre pour la premiere fois que la Cit augmente la masse maigre et reduit la masse grasse chez des patients âges denutris hospitalises.

The present study evaluated the influence of various vehicles on the in vitro percutaneous absorption of piroxicam across human skin under standard diffusion conditions to optimise the formulation of patch tests in dermatology. The transdermal permeation properties of piroxicam were evaluated from five vehicles (PEG 400, propylene glycol, transcutol P, petrolatum, and petrolatum + transcutol P 10%) using Franz diffusion cells. Piroxicam was applied as a saturated solution in vehicles to ensure equal thermodynamic activity of piroxicam in the vehicles. Concentrations of piroxicam were determined by high performance liquid chromatography in epidermis, dermis, and receptor liquid. The release of piroxicam from its vehicles and consequently its cutaneous absorption are influenced by the vehicle assayed and the solubility of piroxicam in each vehicle. The penetration of piroxicam through human skin was clearly enhanced by propylene glycol and petrolatum + transcutol P 10%, with cumulated amounts of piroxicam in the receptor fluid at 48 h of 116±32 and 159±28 μg/mg/cm2 respectively, whereas petrolatum alone did not allow the diffusion of piroxicam. Additional experiments should be conducted in vivo to correlate the results obtained in vitro and to provide clinicians with a more reliable diagnostic test. Drug Dev. Res. 58:283–290, 2003. © 2003 Wiley-Liss, Inc.

Nanocapsules with atovaquone concentration of 1000 mg/ml were prepared according to the interfacial deposition technique using different polymers: poly-o-caprolactone (PECL), poly(lactic acid) (PLA) and poly(lactic-co-glycolic acid) (PLAGA). The following characteristics of nanoparticles were determined: percentage of encapsulation of atovaquone, percentage of encapsulation of benzyl benzoate (BB), nanoparticle size, nanoparticle wall thickness, suspension pH, and in vitro stability. The different formulations showed similar characteristics: maximal percentage of encapsulation (100%), particle size of approximately 230 nm, neutral pH and wall thickness of approximately 20 nm. The type of polymer used was the main factor influencing stability, in decreasing order: PECL� /PLA � /PLAGA. No release of atovaquone or benzylbenzoate was noted with PECL nanoparticles over 4 months. Release of atovaquone (25.9%) was found with PLA nanoparticles at 4 months. Release of both atovaquone (18.9%) and benzylbenzoate (54.2%) was noted with PLAGA nanoparticles from the third month, indicating a disruption of the nanoparticle membrane. # 2002 Elsevier Science B.V. All rights reserved.

Atovaquone, an antiparasitic agent, could possibly represent an alternative therapy after relapse following classical treatment for visceral leishmaniasis. Atovaquone-resistant strains were selected in vitro by stepwise drug pressure to study the mechanism of resistance in Leishmania. Characteristics of a promastigote strain resistant to 250 microg/ml of atovaquone were compared with those of the wild type (WT) strain. Resistant strains were shown to have a high level of resistance (45 times). They were stable in drug-free medium for 6 months, and showed no cross-resistance with other antileishmanial drugs. Rhodamine uptake and efflux were studied. They were not modified in the resistant strain, indicating the absence of P-glycoprotein overexpession. The effect of atovaquone on membrane lipidic composition was determined in both WT and atovaquone-resistant promastigotes. Analysis of lipid composition of the atovaquone-resistant strain showed that sterol biosynthesis was decreased in atovaquone-resistant parasites. Cholesterol was found to be the major membrane sterol as opposed to the WT strain. Cholesterol, due to its ordering effect, could decrease membrane fluidity and subsequently block the passage of atovaquone through the membrane. Increased membrane cholesterol content and altered drug membrane fluidity resulted from possible decrease of ergosterol biosynthesis by atovaquone, incorporation of cholesterol by promastigotes in the culture medium, solubilisation of atovaquone by cholesterol and co-passage of the two compounds or influence of dimethylsulfoxide. These results indicate that different cellular alterations may participate in the resistant phenotype, by altering drug membrane permeability.