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See detailEccentric training for tendon healing after lesion: a rat model
Kaux, Jean-François ULg; Libertiaux, Vincent ULg; Leprince, Pierre ULg et al

in American Journal of Sports Medicine (in press)

BACKGROUND:The tendon is a dynamic entity that remodels permanently. Platelet-rich plasma (PRP) injection has been shown to have a beneficial effect on tendon healing after lesion in rats. Furthermore ... [more ▼]

BACKGROUND:The tendon is a dynamic entity that remodels permanently. Platelet-rich plasma (PRP) injection has been shown to have a beneficial effect on tendon healing after lesion in rats. Furthermore, eccentric exercise seems to improve the mechanical quality of the tendon. HYPOTHESIS:A combination of PRP injection and eccentric training might be more effective than either treatment alone. STUDY DESIGN:Controlled laboratory study. METHODS:Adult male rats were anesthetized, an incision was performed in the middle of their left patellar tendon and an injection of physiological fluid (PF) or homologous PRP was randomly made at the lesion level. The rats were then divided into 2 groups: the eccentric group, undergoing eccentric training 3 times a week, and the untrained group, without any training. Thus, 4 groups were compared. After 5 weeks, the tendons were removed and their ultimate tensile strength and energy were measured. Tendons were frozen for proteomic analyses when all biomechanical tests were completed. Statistical analysis was performed with linear mixed effect models. RESULTS:No significant difference was found between the treatments using PF injection or PRP injection alone. However, the value of the ultimate tensile force at rupture was increased by 4.5 N (108% of control, P = .006) when eccentric training was performed. An intragroup analysis revealed that eccentric training significantly improved the ultimate force values for the PRP group. Proteomic analysis revealed that eccentric training led to an increase in abundance of several cytoskeletal proteins in the PF group, while a decrease in abundance of enzymes of the glycolytic pathway occurred in the PRP treated groups, indicating that this treatment might redirect the exercise-driven metabolic plasticity of the tendon. CONCLUSION: Eccentric training altered the metabolic plasticity of tendon and led to an improvement of injured tendon resistance regardless of the treatment injected (PF or PRP). CLINICAL RELEVANCE:This study demonstrates the necessity of eccentric rehabilitation and training in cases of tendon lesion regardless of the treatment carried out. [less ▲]

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See detailBioavailability enhancement of itraconazole-based solid dispersions produced by hot melt extrusion in the framework of the Three Rs rule
Thiry, Justine ULg; Kok, Miranda ULg; Collard, Laurence ULg et al

in European Journal of Pharmaceutical Sciences (2017), 99

Solid dispersion formulations made of itraconazole (ITZ) and Soluplus® (polyethylene glycol, polyvinyl acetate and polyvinylcaprolactame-based graft copolymer abbreviated SOL) were produced using hot melt ... [more ▼]

Solid dispersion formulations made of itraconazole (ITZ) and Soluplus® (polyethylene glycol, polyvinyl acetate and polyvinylcaprolactame-based graft copolymer abbreviated SOL) were produced using hot melt extrusion. Since ITZ possesses a water solubility of less than 1 ng/mL, the aim of this work was to enhance the aqueous solubility of ITZ, and thereby improve its bioavailability. The three formulations consisted of a simple SOL/ITZ amorphous solid dispersion (ASD), an optimized SOL/ITZ/AcDiSol® (super-disintegrant) ASD and an equimolar inclusion complex of ITZ in hydroxypropyl-β-cyclodextrin (substitution degree = 0.63, CD) with SOL. The three formulations were compared in vitro and in vivo to the marketed product Sporanox®. The in vitro enhancement of dissolution rate was evaluated using a biphasic dissolution test. In vitro dissolution results showed that all three formulations had a higher percentage of ITZ released than Sporanox® with the following ranking: SOL/ITZ/CD > SOL/ITZ/AcDiSol® > SOL/ITZ > Sporanox®. The bioavailability of these four formulations was evaluated in rats. The bioanalytical method was optimized so that only 10 μL of blood was withdrawn from the rats using specific volumetric absorptive microsampling devices. This enabled to keep the same rats during the whole study, which was in accordance with the Three Rs rules (reduction, refinement and replacement). Furthermore, this technique allowed the suppression of inter-individual variability. Higher Cmax and AUC were obtained after the administration of all three formulations compared to the levels after the use of Sporanox® as follows: SOL/ITZ/AcDiSol® > SOL/ITZ/CD > SOL/ITZ > Sporanox®. The inversion in the ranking between SOL/ITZ/CD and SOL/ITZ/AcDiSol® made impossible the establishment of an in vitro–vivo correlation. Indeed, very different release rates were obtained in vitro and in vivo for the two optimized formulations. These results suggest that ITZ would be protected inside the core of the SOL micelles even during the absorption step at the intestine, while some agents present in the intestinal fluids could displace ITZ from the hydrophobic cavity of CD by competition. [less ▲]

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See detailSampling only ten microliters of whole blood for the quantification of poorly soluble drugs: Itraconazole as case study
Thiry, Justine ULg; Evrard, Brigitte ULg; Nys, Gwenaël ULg et al

in Journal of Chromatography. A (2017), 1479

Nowadays in animal studies, it is important to comply with the so-called Three Rs rule by replacing or reducing the number of tested animals. Volumetric absorptive microsampling (VAMS) can be used to ... [more ▼]

Nowadays in animal studies, it is important to comply with the so-called Three Rs rule by replacing or reducing the number of tested animals. Volumetric absorptive microsampling (VAMS) can be used to collect small quantities (10 or 20 µL) of whole blood, thereby limiting the amount of animals needed. In this study, a quantitative method was developed and subsequently validated for the poorly soluble drug itraconazole (ITZ) using VAMS and ultra-high performance liquid chromatography (UHPLC) coupled to tandem mass spectrometry (MS). A proof of concept study showed that the optimized method is applicable to test the bioavailability of drug formulations containing ITZ. Using VAMS, smaller blood volumes can be taken per sampling point (10-20 µL instead of the conventional 0.2-0.5 mL) avoiding the sacrifice of animals. Moreover, the same rats can be used to compare different drug formulations which strengthens the validity of the results. In long-term bioavailability studies, it is necessary to guarantee the stability of the tested drugs supported on VAMS devices. In this study, we show that ITZ was only stable for 24 hours after collection with VAMS, but for at least two weeks by the storage of extracted samples at -80°C. [less ▲]

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See detailNEW INJECTABLE LIPOSOME AND DRUG-IN-CYCLODEXTRIN-IN LIPOSOME SYSTEMS ENCAPSULATING ESTETROL FOR THE TREATMENT OF ISCHEMIA DISEASES IN PREMATURE BABIES
Palazzo, Claudio ULg; Laloy, Julie; Delvigne, Anne-Sophie et al

Poster (2016, December)

Purpose: In 2010, almost 15 million of babies in the world are prematurely borned, 11.1 % of the total amount of alive children. Despite the better neonatology techniques, the number of preterm babies ... [more ▼]

Purpose: In 2010, almost 15 million of babies in the world are prematurely borned, 11.1 % of the total amount of alive children. Despite the better neonatology techniques, the number of preterm babies with motor, vision, hearing or mental deficiencies is still constant along the last twenty years. Moreover, no efficacy treatment is available to the present day. The estetrol (E4) has an important role in the brain development and protection. The aim of this study is to develop new injectable liposome and drug-in-cyclodextrin-in-liposome (DCL) formulations, encapsulating E4 in order to enhance its crossing through the blood-brain barrier (BBB). Methods: Cyclodextrins (CD) were used to increase E4 aqueous solubility. Liposome and DCL (E4-CD complex) formulations were prepared by thin-film hydration technique. The formulations were physicochemical characterized. LDH and MTS tests on endothelial, neuronal and BBB model cells were performed in vitro on the liposome formulation. Hemocompatibility of the formulations was evaluated on red blood cells, platelet aggregation and coagulation. BBB passage tests were performed using human BBB cell line (hCMEC/D3). Results: E4-CD complexes proportionally increased the solubility of the hormone. Liposomes and DCL encapsulating E4 were prepared. All the formulations had average particle size below 150 nm, polydispersity index below 0.10 and ζ potential around + 30 mV. The encapsulation efficacy for liposomes was between 3% and 10% while those of DCL are between 15% and 35%. Moreover, the formulations are capable to release 80 % (liposome) and 90 % (DCL) of encapsulated E4 after 3 h at 37°C. The effect of liposome and DCL formulations on cell viability and integrity was evaluated. The results showed no toxic effects on all the tested cell lines. Hemocompatibility tests showed no hemolysis, platelet aggregation or effects on coagulation, confirming the possibility of the formulations to be intravenously administrated. BBB passage tests highlighted the capability of the formulations to pass the BBB and reach the brain. Conclusions: New non-toxic, hemocompatible liposome and DCL formulations encapsulating E4 were prepared. The formulations are promising drug delivery system to target estrogens to the brain, due to their physiochemical characteristics. [less ▲]

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See detailOPTIMIZATION OF A FULLY AUTOMATED ELECTROPHORETICALLY MEDIATED MICROANALYSIS SYSTEM FOR CYP1A1 ACTIVITY MONITORING
Farcas, Elena ULg; Servais, Anne-Catherine ULg; Lamalle, Caroline et al

Conference (2016, October 01)

Objective of the study Since CYP1A1, a member of cytochrome P450 superfamily, has been described to be over expressed in various types of cancer, our study was focused on the optimization of a fully ... [more ▼]

Objective of the study Since CYP1A1, a member of cytochrome P450 superfamily, has been described to be over expressed in various types of cancer, our study was focused on the optimization of a fully automated system for the monitoring of this particularly interesting enzyme. Moreover, the potentiality of this approach to screen CYP1A1 inhibitors was investigated. Materials and methods The experiments were carried out on a HP3DCE system using an on-column DAD. The EMMA procedure was performed by injecting a plug containing the co-factor(NADPH) and the substrate(7-ethoxycoumarin) between two plugs of CYP1A1 supersomes. The reaction was triggered by the application of a voltage switch. The voltage was then turned off to allow the metabolic reaction to occur. The separation of the components was then performed. Results Satisfying results were obtained using CYP1A1 at a concentration of 200 pmol/mL, while the incubation time was settled to 15 min. A DoE was performed to find the best mixing conditions. The amount of metabolite obtained was comparable to the one detected after conventional off-line metabolization. The ability of our system to monitor CYP1A1 inhibition was then proven with apigenin, a well-known CYP1A1 inhibitor. Conclusions The present study describes the development of a fully automatized in-capillary method for CYP1A1 activity monitoring and proves the potentialy of our system to be used for the screening of CYP1A1 inhibitors. The advantages of performing inline metabolization assays are mainly the miniaturization and the automatization of the process. Besides, the reagents consumption is drastically reduced due to the injection of few tens of nanoliters. [less ▲]

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See detailINNOVATIVE INJECTABLE LIPOSOME AND DRUG-IN-CYCLODEXTRIN-IN LIPOSOME SYSTEMS ENCAPSULATING ESTETROL FOR THE TREATMENT OF ISCHEMIA DISEASES IN PREMATURE BABIES
Palazzo, Claudio ULg; Laloy, Julie; Delvigne, Anne-Sophie et al

Conference (2016, September 28)

Purpose: In 2010, almost 15 million of babies in the world are prematurely borned, 11.1 % of the total amount of alive children. Despite the better neonatology techniques, the number of preterm babies ... [more ▼]

Purpose: In 2010, almost 15 million of babies in the world are prematurely borned, 11.1 % of the total amount of alive children. Despite the better neonatology techniques, the number of preterm babies with motor, vision, hearing or mental deficiencies is still constant along the last twenty years. Moreover, no efficacy treatment is available to the present day. The estetrol (E4) has an important role in the brain development and protection. The aim of this study is to develop new injectable liposome and drug-in-cyclodextrin-in-liposome (DCL) formulations, encapsulating E4 in order to enhance its crossing through the blood-brain barrier (BBB). Methods: Hydroxypropyl-β-cyclodextrins (degrees of substitution 0.87 and 0.63) (HPβCD 0.87 and HPβCD 0.63) were used to increase E4 aqueous solubility. Liposome and DCL (E4-HPβCD 0.63 complex) formulations were prepared by thin-film hydration technique. The formulations were physicochemical characterized and stability in foetal bovine serum (FBS) was evaluated. LDH and MTS tests on endothelial, neuronal and BBB model cells were performed in vitro on the liposome formulation. Hemocompatibility of the formulations was evaluated on red blood cells, platelet aggregation and coagulation. BBB passage tests were performed using human BBB cell line (hCMEC/D3). Results: E4-HPβCD complexes proportionally increased the solubility of the hormone. Due to the lower solubility obtained with HPβCD ds 0.87, only HPβCD ds 0.63 was retained for future tests. Liposomes and DCL encapsulating E4 were prepared. All the formulations had average particle size below 150 nm, polydispersity index below 0.10 and ζ potential around + 30 mV. The encapsulation efficacy for liposomes was between 3% and 10% while those of DCL are between 15% and 35%. Moreover, the formulations are capable to release 80 % (liposome) and 90 % (DCL) of encapsulated E4 after 3 h at 37°C. The formulations, incubated in FBS at 37°C under gentle stirring, keep the same size and do not form protein corona up to 6 h. The effect of liposome and DCL formulations on cell viability and integrity was evaluated. The results showed no toxic effects on all the tested cell lines. Hemocompatibility tests showed no hemolysis, platelet aggregation or effects on coagulation, confirming the possibility of the formulations to be intravenously administrated. Preliminary BBB passage tests highlighted the capability of the formulations to pass the BBB and reach the brain. Conclusions: New non-toxic, hemocompatible liposome and DCL formulations encapsulating E4 were prepared. The formulations are promising drug delivery system to target estrogens to the brain, due to their physiochemical characteristics. Aknowledgment : The authors thank Estetra SPRL for providing Estetrol. [less ▲]

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See detailBiomarkers of inflammation and innate immunity in atrophic nonunion fracture
DE SENY, Dominique ULg; COBRAIVILLE, Gaël ULg; Leprince, Pierre ULg et al

in Journal of Translational Medicine (2016)

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See detailRelease of cardiac biomarkers during a cycling race
LE GOFF, Caroline ULg; Kaux, Jean-François ULg; D'OTREPPE DE BOUVETTE, Stéphanie ULg et al

in World Journal of Cardiovascular Diseases (2016), 6(8), 285-294

Objectives: Over the past two decades, a large interest in cardiac marker elevations has developed in endurance sports events. The intense effort is not without risk. We aim to see if the relatively ... [more ▼]

Objectives: Over the past two decades, a large interest in cardiac marker elevations has developed in endurance sports events. The intense effort is not without risk. We aim to see if the relatively cardiospecific biomarkers could show the damage on cardiac muscle cells. Methods: Fourteen cyclists were recruited for an international race (177km). We studied the release of injury related cardiac markers, risk related cardiac markers, renal function markers and blood cytology. The subjects were submitted to three blood test: one before (T0), one just after (T1) and the last one 3 hours after the race (T3). Results: Blood cytology markers, namely erythrocytes, hemoglobin, hematocrit, and average hemoglobin concentration, were found to evolve in a similar way. Renal function markers, such as creatinin, cystatin C and uric acid, showed a post effort increase that might be related to renal blood flow depletion during exercise. Cardiac and muscular markers were all increased at T1. Conclusions: Physiological stress induced by an international cycling race certainly has consequences on cardiac muscle cells. Fortunately, those blood concentration variations are more representative of a transitional state, due to an imbalance created by an intense aerobic effort maintained during several hours, rather than an irreversible injury. [less ▲]

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See detailCapillary electrophoresis method to determine siRNA complexation with cationic liposomes
Furst, Tania ULg; Bettonville, Virginie ULg; Farcas, Elena ULg et al

in Electrophoresis (2016)

Small interfering RNA (siRNA) inducing gene silencing has great potential to treat many human diseases. To ensure effective siRNA delivery, it must be complexed with an appropriate vector, generally ... [more ▼]

Small interfering RNA (siRNA) inducing gene silencing has great potential to treat many human diseases. To ensure effective siRNA delivery, it must be complexed with an appropriate vector, generally nanoparticles. The nanoparticulate complex requires an optimal physiochemical characterization and the complexation efficiency has to be precisely determined. The methods usually used to measure complexation are gel electrophoresis and RiboGreen® fluorescence-based assay. However, those approaches are not automated and present some drawbacks such as the low throughput and the use of carcinogenic reagents. The aim of this work is to develop a new simple and fast method to accurately quantify the complexation efficiency. In this research, capillary electrophoresis (CE) was used to determine the siRNA complexation with cationic liposomes. The short-end injection mode applied enabled siRNA detection in less than 5 min. Moreover, the CE technique offers many advantages compared to the other classical methods. It is automated, does not require sample preparation and expensive reagents. Moreover, no mutagenic risk is associated to CE approach since no carcinogenic product is used. Finally, this methodology can also be extended to the characterization of other types of nanoparticles encapsulating siRNA, such as cationic polymeric nanoparticles. [less ▲]

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See detailVolumetric Absorptive Microsampling for Hepcidin Peptide Extraction from Whole Blood
Houbart, Virginie ULg; COBRAIVILLE, Gaël ULg; Nys, Gwenaël ULg et al

in LCGC North America (2016), 34(5),

Whole blood analysis is an emerging trend in the field of bioanalysis. We developed a fast and simple protocol to extract and analyze a peptide, hepcidin, from whole blood. Sampling and extraction were ... [more ▼]

Whole blood analysis is an emerging trend in the field of bioanalysis. We developed a fast and simple protocol to extract and analyze a peptide, hepcidin, from whole blood. Sampling and extraction were carried out using volumetric absorptive microsampling (VAMS), a novel blood collection method that allows the sampling of a known blood volume independently from hematocrit. The composition of the extraction medium was optimized using an experimental design to get the most intense signal of hepcidin, considering different organic solvents and acidic additives. [less ▲]

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See detailAlpha-synuclein as biomarker in Parkinson’s disease: strategies for detection in CGE-LIF
Houbart, Virginie ULg; Napp, Aurore ULg; Rudaz, Serge et al

Poster (2016, April)

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See detailMetabolomics as a Challenging Approach for Medicinal Chemistry and Personalized Medicine.
Frederich, Michel ULg; Pirotte, Bernard ULg; Fillet, Marianne ULg et al

in Journal of Medicinal Chemistry (2016), 59(19), 86498666

"Omics" sciences have been developed to provide a holistic point of view of biology and to better understand the complexity of an organism as a whole. These systems biology approaches can be examined at ... [more ▼]

"Omics" sciences have been developed to provide a holistic point of view of biology and to better understand the complexity of an organism as a whole. These systems biology approaches can be examined at different levels, starting from the most fundamental, i.e., the genome, and finishing with the most functional, i.e., the metabolome. Similar to how genomics is applied to the exploration of DNA, metabolomics is the qualitative and quantitative study of metabolites. This emerging field is clearly linked to genomics, transcriptomics, and proteomics. In addition, metabolomics provides a unique and direct vision of the functional outcome of an organism's activities that are required for it to survive, grow, and respond to internal and external stimuli or stress, e.g., pathologies and drugs. The links between metabolic changes, patient phenotype, physiological and/or pathological status, and treatment are now well established and have opened a new area for the application of metabolomics in the drug discovery process and in personalized medicine. [less ▲]

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See detailLiquid chromatography separation of the chiral prodrug eslicarbazepine acetate and its main metabolites in polar organic mode. Application to their analysis after in vitro metabolism.
Servais, Anne-Catherine ULg; Janicot, Bertrand; Takam, Arnold et al

in Journal of Chromatography. A (2016), 1467

A LC method using a chiral stationary phase (CSP) with cellulose tris(3-chloro-4-methylphenylcarbamate) as chiral selector in polar organic mode (POM) was developed for the separation of the ... [more ▼]

A LC method using a chiral stationary phase (CSP) with cellulose tris(3-chloro-4-methylphenylcarbamate) as chiral selector in polar organic mode (POM) was developed for the separation of the biopharmaceutic classification system (BCS) class II chiral prodrug eslicarbazepine acetate (ESL) and its main metabolites, namely eslicarbazepine, its optical antipode, (R)-licarbazepine, and the achiral oxcarbazepine (OXC). The percentage of methanol (MeOH) in the mobile phase containing acetonitrile (ACN) as the main solvent was found to significantly influence analyte retention and resolution. A reversal of elution order of OXC and (R)-licarbazepine was observed, depending on the MeOH percentage in the mobile phase. The optimized mobile phase consisted of ACN/MeOH/acetic acid/diethylamine (95/5/0.2/0.07; v/v/v/v). The potential of this chemo- and enantioselective LC method combined with solid-phase extraction (SPE) was then evaluated for in vitro metabolism studies using ESL as a model case. Only eslicarbazepine could be detected after incubation of ESL in human liver microsome systems. [less ▲]

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See detailFully automated electrophoretically mediated microanalysis for CYP1A1 activity monitoring optimized by multivariate approach
Farcas, Elena ULg; Servais, Anne-Catherine ULg; Lamalle, Caroline ULg et al

in Electrophoresis (2016), 37(2), 248-255

In this study, a fully automatized in-capillary system was developed to monitor the activity of CYP1A1 in physiological conditions. Ethoxycoumarin, the selected substrate, undergoes an in-line bioreaction ... [more ▼]

In this study, a fully automatized in-capillary system was developed to monitor the activity of CYP1A1 in physiological conditions. Ethoxycoumarin, the selected substrate, undergoes an in-line bioreaction in the presence of CYP1A1 supersomes and NADPH as co-factor, giving rise to hydroxycoumarin, the product that was assayed. The optimization of the experimental conditions was supported by the application of a design of experiment, providing a better understanding of electrophoretic mixing parameters that influence the metabolic reactions. The results obtained in optimal conditions were compared not only to those achieved after off-line metabolization but also with liver microsomes. Finally, inhibition studies were conducted showing an important decrease of hydroxycoumarin formation using apigenin as CYP1A1 potent inhibitor. This study demonstrates the usefulness of our in-line system for the fully automated in vitro metabolism studies and the screening of new CYP1A1 inhibitors. [less ▲]

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