Impact of methylene blue and atorvastatin combination therapy on the apparition of cerebral malaria in a murine model

BACKGROUND: Proveblue®, a methylene blue dye that complies with European Pharmacopoeia and contains limited organic impurities and heavy metals of recognized toxicity, showed in vitro synergy against Plasmodium falciparum when combined with atorvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-Coenzyme A reductase. The objective of this study was to evaluate the in vivo efficacy of Proveblue® when combined with atorvastatin in a murine model of experimental cerebral malaria. METHODS: Forty female C57Bl6/N mice were divided into four groups (control, atorvastatin 40 mg/kg for seven days, Proveblue® 10 mg/kg for five days and atorvastatin combined with Proveblue®), infected with Plasmodium berghei ANKA parasites by intraperitoneal inoculation and observed for 45 days. RESULTS: Treatment with atorvastatin alone did not demonstrate an effect significantly different from no treatment (p = 0.0573). All the mice treated by atorvastatin alone died. Treatment with Proveblue® or a combination of Proveblue® and atorvastatin was significantly increased survival of cerebral malaria (p = 0.0011 and 0.0002, respectively). Although there was only one death in the atorvastatin and Proveblue® combination treatment group (10%) versus two deaths (22%) with Proveblue® treatment, the effect on cerebral malaria was not significant (p = 0.283). CONCLUSIONS: The present work demonstrated, for the first time, the high efficacy of Proveblue® in preventing cerebral malaria. Atorvastatin alone or in combination appears to possess limited use for preventing cerebral malaria. Combination of atorvastatin with lower doses of Proveblue® (<10 mg/kg/day) should be evaluated to show potential synergistic effects in cerebral malaria prevention

Differences in anti-malarial activity of 4-aminoalcohol quinoline enantiomers and investigation of the presumed underlying mechanism of action

International audienc

Antiplasmodial activity of cepharanthine isolated from Stephania rotunda Lour. : analytical, transcriptional and pharmacokinetic approaches

Ce doctorat porte sur l’étude de l’activité antipaludique de la cépharanthine. Deux méthodes écologiques d’extraction, utilisant des micro-ondes et ultrasons, ont été proposées. L'activité antiplasmodiale a été évaluée par le calcul de la concentration qui inhibe 50 % de la croissance parasitaire. Les cibles potentielles ont été évaluées par l’étude de la variation d’expression des gènes. Au niveau microscopique, la cépharanthine a semblé inhiber le développement parasitaire et bloquer les parasites au stade anneau. Au niveau transcriptomique, la cépharanthine semble avoir un impact sur le transport de protéines plasmodiales à la surface du globule rouge ; sur des organelles nécessaires à la survie du parasite, et sur les interactions entre le globule rouge parasité et l’endothélium ou les globules rouges sains. Des études de combinaisons thérapeutiques ont montré que la cépharanthine semble potentialiser certains antipaludiques. Une analyse quantitative de la cépharathine plasmatique a permis d’effectuer une étude pharmacocinétique. La cépharanthine pourrait être un chef de file intéressant pour le développement de nouveaux antipaludiques.This PhD focuses on the study of the antimalarial activity of cepharanthine. Two green extraction methods, using microwave and ultrasound, have been proposed. The antiplasmodial activity was evaluated by calculating the concentration inhibiting 50 % of parasite growth. Potential targets were evaluated by studying the variation of gene expression. At the microscopic level, cepharanthine seemed to inhibit the parasite growth and to block parasite at the ring stages. The transcriptomic assay showed that cepharanthine seems to have an impact on the transport of Plasmodium proteins to the red blood cell surface, on organellar functions necessary for the survival of the parasite, and on the interactions between infected red blood cells and the endothelium or healthy red blood cells. The study of combination therapies showed that cepharanthine appears to potentiate some antimalarial compounds. A quantitative analysis of cepharathine in mouse plasma allowed performing a pharmacokinetic study. Cepharanthine could be an interesting lead to the development of new antimalarial drugs

Inhaled antibiotics during mechanical ventilation—why it will work

International audienc

Evaluation de l'activité antipaludique de 4-aminoalcools quinoléines énantiomériquement pures

AIX-MARSEILLE2-BU Pharmacie (130552105) / SudocSudocFranceF

Comportement asymptotique de processus utilisés en fiabilité dynamique

En fiabilité dynamique, un système est représenté par un couple de variables aléatoires (It,Xt) où It représente les états discrets du système comme les différents états de marche et de panne, et Xt décrit des variables physiques ou environnementales influençant les changements d état discret. Entre deux changements d état, l évolution de la variable environnementale est déterminée par une équation différentielle. Ces processus se classent dans la famille des processus de Markov déterministes par morceaux (ou Piecewise Deterministic Markov Processes : PDMP). Cette thèse a pour objet l étude du comportement asymptotique (convergence, existence et unicité d une loi stationnaire) de ces processus. Pour réaliser ce travail, nous nous intéressons tout d abord aux théories existantes permettant d étudier le régime asymptotique, pour ensuite donner des résultats propres à la fiabilité dynamique en adaptant la théorie qui semble la plus appropriée. Nous nous intéressons dans un second temps au calcul de cette loi stationnaire. Nous voyons que dans de nombreux cas, il est difficile, voir impossible, de la déterminer explicitement. Pour approcher cette loi, nous proposons une méthode numérique déterministe basée sur une méthode de volumes finisIn dynamic reliability, a system is represented by a couple of random variables (It,Xt), where It stands for the discrete state of the system such as up or down state, and Xt stands for physical or environmental variables which influence jumps between discrete states. Between jumps, the evolution of the environmental variable is specified by a differential equation. Such processes (It,Xt) belong to the family of Piecewise Deterministic Markov Processes (PDMP). The aim of this thesis is the study of the asymptotic behaviour of these processes (convergence, existence and uniqueness of a stationary distribution). To carry out this work, we are first interested in existing theories which allow the study of the asymptotic behaviour and next, in providing specific results for dynamic reliability, by adapting the theory which seems the most appropriate. In a second time, we are interested in the computation of the stationary distribution. In a lot of cases, we can see that it is hard and even impossible to get an explicit expression for It. In order to get an approximation for this distribution, we propose a determinist numerical method based on a finite volume schemePARIS-EST Marne-la-Vallee-BU (774682101) / SudocSudocFranceF

Chanson sur l'air du "troubadour béarnais", dédiée aux gardes nationaux volontaires du département de l'Orne, allans sur les frontières ([Reprod.]) / par Desgrouas

Collection : Les archives de la Révolution française ; 11.1a.423Appartient à l’ensemble documentaire : BNormand

Differences in anti-malarial activity of 4-aminoalcohol quinoline enantiomers and investigation of the presumed underlying mechanism of action

Abstract Background A better anti-malarial efficiency and lower neurotoxicity have been reported for mefloquine (MQ) (+)- enantiomer. However, the importance of stereoselectivity remains poorly understood as the anti-malarial activity of pure enantiomer MQ analogues has never been described. Building on these observations, a series of enantiopure 4-aminoalcohol quinoline derivatives has previously been synthesized to optimize the efficiency and reduce possible adverse effects. Their in vitro activity on Plasmodium falciparum W2 and 3D7 strains is reported here along with their inhibition of β-haematin formation and peroxidative degradation of haemin, two possible mechanisms of action of anti-malarial drugs. Results The (S)-enantiomers of this series of 4-aminoalcohol quinoline derivatives were found to be at least as effective as both chloroquine (CQ) and MQ. The derivative with a 5-carbon side-chain length was the more efficient on both P. falciparum strains. (R )-enantiomers displayed an activity decreased by 2 to 15-fold as compared to their (S) counterparts. The inhibition of β-haematin formation was significantly stronger with all tested compounds than with MQ, irrespective of the stereochemistry. Similarly, the inhibition of haemin peroxidation was significantly higher for both (S) and (R)-enantiomers of derivatives with a side-chain length of five or six carbons than for MQ and CQ. Conclusions The prominence of stereochemistry in the anti-malarial activity of 4-aminoalcohol quinoline derivatives is confirmed. The inhibition of β-haematin formation and haemin peroxidation can be put forward as presumed mechanisms of action but do not account for the stereoselectivity of action witnessed in vitro.</p

Development and optimization of two processes for producing nanosized liposomes using supercritical CO2

International audienc

Supercritical millifluidic process for siRNA encapsulation in nanoliposomes for potential Progeria treatment (ex-vivo assays)

A millifluidic process working in continuous mode for the preparation of nanoliposomes using supercritical CO2 has been developed. Nanoliposomes with an average diameter ranging between 123.9 ± 3.0 and 165.7 ± 1.6 nm depending on the operating conditions were obtained. The effects of pressure (90–150 bar), temperature (35–45 °C) and phospholipid mass ratio (0.1–1.9 wt%) in feed solution on liposome sizes were investigated. The concentration of phospholipids was found to be the most significant parameter for controlling the mean diameter of nanoliposomes while pressure and temperature had a minor influence on liposomes’ properties. The encapsulation of siRNAs targeting the LMNA gene by nanoliposomes obtained with the millifluidic process was achieved at optimized operating conditions (150 bar, 35 °C and a phospholipid mass ratio in the feed solution of 0.1 wt%). The resulting formulations were compared with commercial transfection agents in ex vivo assays. These assays showed a decrease in the expression of the encoded protein lamin A for the formulations obtained with the process developed in this work. Therefore, the use of siRNAs targeting LMNA, encapsulated by nanoliposomes represents a potential new therapeutic approach for the treatment of progeria