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See detailWhole blood microsampling for the quantitation of estetrol without derivatization by liquid chromatography-tandem mass spectrometry
Nys, Gwenaël ULg; Gallez, Anne ULg; Kok, Miranda ULg et al

in Journal of Pharmaceutical & Biomedical Analysis (2017), 140

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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 (2017), 45(6), 1440-1446

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 detailCapillary electrophoresis in the context of drug discovery.
Farcas, Elena ULg; Pochet, Lionel; Crommen, Jacques ULg et al

in Journal of Pharmaceutical & Biomedical Analysis (2017)

Capillary Electrophoresis is a very efficient and resolutive separation technique used for many years in the analytical field. Despite all its assets, CE remains poorly used in drug discovery. This can be ... [more ▼]

Capillary Electrophoresis is a very efficient and resolutive separation technique used for many years in the analytical field. Despite all its assets, CE remains poorly used in drug discovery. This can be explained by the relatively low number of experienced CE practitioners, the maturity of HPLC in the pharmaceutical industry and some intrinsic limitations of the technique. The objective of this review is to focus our attention on recent developments of this technique in three different drug discovery areas: bioassays, drug-plasma interactions and drug metabolism studies. These developments were based on two important abilities of CE: the capacity to measure non-covalent interactions in solution and the ability to use a portion of the capillary as a reactor while the rest of the capillary is used for the separation of the product of the reaction. [less ▲]

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See detailSingle and dual cyclodextrins systems for the enantiomeric and diastereoisomeric separations of structurally related dihydropyridone analogues.
Delplanques, Thibaut; Boulahjar, Rajaa; Charton, Julie et al

in Electrophoresis (2017)

Cyclodextrin capillary electrophoresis methods (CD-CZE) were developed for complete enantiomeric and diastereoisomeric separations of a series of ten dihydropyridone analogues, of which eight were neutral ... [more ▼]

Cyclodextrin capillary electrophoresis methods (CD-CZE) were developed for complete enantiomeric and diastereoisomeric separations of a series of ten dihydropyridone analogues, of which eight were neutral, one was anionic and one was cationic. Ten different systems comprising one or two cyclodextrins were found to successfully separate the isomers thanks to a screening approach. Among the tested cyclodextrins, HS-gamma-CD, either in a single or in a dual system, in a phosphate buffer using capillaries dynamically coated with polyethylene oxide (PEO), and SBE-beta-CD, either in a single or in a dual system, in a borate buffer using uncoated capillaries, were the most selective selectors. The effects of different parameters such as the nature and concentration of the cyclodextrins, nature and concentration of the buffer, and voltage were examined. The precision and limits of detection and quantification were evaluated for the optimized methods. This article is protected by copyright. All rights reserved. [less ▲]

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See detailStudy of virus-like particles of human papillomavirus in capillary electrophoresis
Bettonville, Virginie ULg; Nicol, Jérôme; Furst, Tania et al

Poster (2017)

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See detailRIP3 antagonizes a TSC2-mediated pro-survival pathway in glioblastoma cell death.
Fettweis, Grégory ULg; Di Valentin, Emmanuel ULg; L'homme, Laurent et al

in Biochimica et Biophysica Acta (2017)

Glioblastomas are the deadliest type of brain cancer and are frequently associated with poor prognosis and a high degree of recurrence despite removal by surgical resection and treatment by chemo- and ... [more ▼]

Glioblastomas are the deadliest type of brain cancer and are frequently associated with poor prognosis and a high degree of recurrence despite removal by surgical resection and treatment by chemo- and radio-therapy. Photodynamic therapy (PDT) is a treatment well known to induce mainly necrotic and apoptotic cell death in solid tumors. 5-Aminolevulinic acid (5-ALA)-based PDT was recently shown to sensitize human glioblastoma cells (LN-18) to a RIP3 (Receptor Interacting Protein 3)-dependent cell death which is counter-acted by activation of autophagy. These promising results led us to investigate the pathways involved in cell death and survival mechanisms occurring in glioblastoma following PDT. In the present study, we describe a new TSC2 (Tuberous Sclerosis 2)-dependent survival pathway implicating MK2 (MAPKAPK2) kinase and 14-3-3 proteins which conducts to the activation of a pro-survival autophagy. Moreover, we characterized a new RIP3/TSC2 complex where RIP3 is suggested to promote cell death by targeting TSC2-dependent survival pathway. These results highlight (i) a new role of TSC2 to protect glioblastoma against PDT-induced cell death and (ii) TSC2 and 14-3-3 as new RIP3 partners. [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)

Detailed reference viewed: 23 (3 ULg)