Publications of Brigitte Evrard
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See detailControlled release of drugs from multi-component biomaterials
Zalfen, Alina ULiege; Nizet, D.; Jérôme, Christine ULiege et al

in Acta Biomaterialia (2008), 4(6), 1788-1796

In order to control their release, drugs are encapsulated into systems which are expected to provide a certain site with a predetermined amount of drug over a well-defined period of time. Here we report ... [more ▼]

In order to control their release, drugs are encapsulated into systems which are expected to provide a certain site with a predetermined amount of drug over a well-defined period of time. Here we report on a multi-component drug delivery biomaterial that consists of a hydrogel matrix in which drug-loaded biodegradable microcarriers are dispersed, and whose potential applications could be found in the design of implantable devices with long-term activity, as required by contraceptive and hormone replacement treatments. The release profile of the drug can actually be tuned by the complex interplay of several release mechanisms, including the permeability and eventually the degradation rate of the microcarriers and the diffusion through the hydrogel. The hydrogel consisted of 2-hydroxyethyl methacrylate cross-linked by ethylene glycol dimethacrylate. The microcarriers were biodegradable poly-ε-caprolactone (PCL) microspheres in which active molecules, such as levonorgestrel (LNG), were encapsulated. The hydrogels were characterized by water swelling, thermal properties, LNG diffusion through drug-free and drug-depleted hydrogel membranes and LNG release from devices with drug dispersed in the hydrogel. The PCL microspheres were observed by scanning electron microscopy; their size distribution, LNG loading and release were also investigated. The hydrogel-microsphere assemblies were characterized in terms of the distribution of the microspheres within the hydrogel, water swelling and the release of the encapsulated molecules. The developed device, due to its composite structure, has the ability to combine several release mechanisms, leading to drug release obeying zero-order kinetics for most of the time. [less ▲]

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See detailA novel formulation of inhaled doxycycline reduces allergen-induced inflammation, hyperresponsiveness and remodeling by matrix metalloproteinases and cytokines modulation in a mouse model of asthma
Guéders, Maud ULiege; Bertholet, P.; Perin, Fabienne ULiege et al

in Biochemical Pharmacology (2008), 75(2), 514-26

Background In this study, we assess the effectiveness of inhaled doxycycline, a tetracycline antibiotic displaying matrix metalloproteinases (MMP) inhibitory effects to prevent allergen-induced ... [more ▼]

Background In this study, we assess the effectiveness of inhaled doxycycline, a tetracycline antibiotic displaying matrix metalloproteinases (MMP) inhibitory effects to prevent allergen-induced inflammation, hyperresponsiveness and remodeling. MMPs play key roles in the complex cascade of events leading to asthmatic phenotype. Methods Doxycycline was administered by aerosols by the mean of a novel formulation as a complex with hydroxypropyl-gamma-cyclodextrin (HP-gamma-CD) used as an excipient. BALB/c mice (n = 16–24 in each group) were sensitized and exposed to aerosolized ovalbumin (OVA) from day 21 to 27 (short-term exposure protocol) or 5 days/odd weeks from day 22 to 96 (long-term exposure protocol). Results In the short-term exposure model, inhaled doxycycline decreased allergen-induced eosinophilic inflammation in bronchoalveolar lavage (BAL) and in peribronchial areas, as well as airway hyperresponsiveness. In lung tissue, exposure to doxycycline via inhaled route induced a fourfold increase in IL-10 levels, a twofold decrease in IL-5, IL-13 levels and diminished MMP-related proteolysis and the proportion of activated MMP-9 as compared to placebo. In the long-term exposure model, inhaled doxycycline significantly decreased the extent of glandular hyperplasia, airway wall thickening, smooth muscle hyperplasia and subepithelial collagen deposition which are well recognized features of airway remodeling. Conclusion Doxycycline administered by aerosols decreases the allergen-induced airway inflammation and hyperresponsiveness and inhibits the development of bronchial remodeling in a mouse model of asthma by modulation of cytokines production and MMP activity. [less ▲]

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See detailPhase I/IIclinical trial of local GM-CSF application in patients with cervical HPV-associated low grade squamous intraepithelial lesions
Hubert, Pascale ULiege; Doyen, Jean ULiege; Chapelle, X. et al

Conference (2007)

Background: Quantitative and functional alterations of professional antigen-presenting cells (APC) in SIL suggest that these lesions may have a diminished capacity to capture viral antigens. Moreover, GM ... [more ▼]

Background: Quantitative and functional alterations of professional antigen-presenting cells (APC) in SIL suggest that these lesions may have a diminished capacity to capture viral antigens. Moreover, GM-CSF (whose production is decreased in HPV-transformed keratinocytes) is an essential factor for the migration of APC in cervical (pre)neoplastic lesions formed in vitro and transplanted in vivo on mouse. In this study we performed a phase I/II clinical trial in order to determine whether a local application of GM-CSF on cervical low-grade squamous intraepithelial lesions (LSIL) might increase the recruitment of APC into the epithelium and indirectly the viral antigen presentation to the immune system. Methods: Fifteen patients with LSIL (10 GM-CSF and 5 placebo) were enrolled in this study. Patients received 4 GM-CSF applications (or placebo gel) and were followed during 6-7 months. APC infiltration was quantified by immunostaining with anti-CD1a mAb. Cellular immune response was evaluated by using an IFN-gamma intracellular staining on PBMC stimulated in vitro with the E7 HPV16 protein and L1 HPV16 Virus-like particles (VLP). Hybrid capture was performed to semi-quantify the viral DNA in cervical brush specimens. Results: GM-CSF applications were well tolerated in all patients. No difference in the cytological/histological and viral parameters assessed at 2 and 6 months after the last application was observed between the GM-CSF and the placebo group. An increased number of CD1a+ APC was observed in 6/10 patients treated by GM-CSF compared to 1/5 patient in the placebo group. There was an increased immune response against HPV in the GM-CSF group showed by NK and T cells producing IFN-gamma. [less ▲]

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See detailContribution of cyclodextrins in the developement of different pharmaceutical formulations of a nex matrix metalloproteinase inhibitor
Evrard, Brigitte ULiege; Bertholet, Pascal; Guéders, Maud ULiege et al

in Journal of Inclusion Phenomena and Molecular Recognition in Chemistry (2007), 57(1-4), 303-308

Ro 28-2653 is a new synthetic inhibitor of matrix metalloproteinases. The ability of these enzymes to degrade various components of the extracellular matrix seems to play a major role in tumors ... [more ▼]

Ro 28-2653 is a new synthetic inhibitor of matrix metalloproteinases. The ability of these enzymes to degrade various components of the extracellular matrix seems to play a major role in tumors progression and is potentially effective against bronchial remodeling in asthma and BPCO. Ro 28-2653 is very poorly soluble in water. This low solubility estimated at about 0.56 lg/ml in water at 25 C gives rise to difficulties in pharmaceutical formulation of oral, injectable or <br />nebulizable solutions. The purpose of our study is to prepare and to characterize inclusion complexes between Ro 28-2653 and cyclodextrins and to investigate the biopharmaceutical repercussion of the inclusion of the active substance.The complex formation was investigated by phase solubility studies. 1H-NMR spectroscopy and molecular modeling studies were carried out to elucidate the structure of the inclusion <br />complex between Ro 28-2653 and cyclodextrin. Oral, intravenous and nebulizable solutions of Ro 28-2653 were developed with cyclodextrin. The in vivo studies were performed on healthy sheep for the pharmacokinetic evaluation of the oral and intravenous formulations while the nebulization of the complex solution was studied by using an asthma model in mouse. [less ▲]

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See detailPharmacokinetic study of a new synthetic MMP inhibitor (Ro 28-2653) after IV and oral administration of cyclodextrin solutions
Piette, Marie ULiege; Evrard, Brigitte ULiege; Frankenne, Francis et al

in European Journal of Pharmaceutical Sciences (2006), 28(3), 189-195

Ro 28-2653 (5-biphenyl-4-yl-5-[4-(4-nitro-phenyl)-piperazin-1-yl]-pyrimidine-2,4,6-trione) is a new synthetic inhibitor of matrix metalloproteinases (MMPs) with a high selectivity towards MMP2, MMP9 and ... [more ▼]

Ro 28-2653 (5-biphenyl-4-yl-5-[4-(4-nitro-phenyl)-piperazin-1-yl]-pyrimidine-2,4,6-trione) is a new synthetic inhibitor of matrix metalloproteinases (MMPs) with a high selectivity towards MMP2, MMP9 and membrane type 1-MMP. It has been shown that cyclodextrins (CDs) are able to form inclusion complexes with Ro 28-2653 and to increase its aqueous solubility. The aim of this study is to demonstrate that an increase in Ro 28-2653 solubility, via ternary complex formation, can lead to an increase in the oral bioavailability of this drug. This study shows that a synergistic effect exists between hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and L-lysine. The use of this multicomponent system enabled the preparation of oral and intravenous solutions of Ro 28-2653. In vivo evaluation of the oral solution of the inclusion complex of Ro 28-2653 in comparison with a suspension of the same uncomplexed drug showed a significant (p < 0.05) increase in absolute bioavailability. The area under curve (AUC) and the peak serum concentration (C-max) were approximately 10 times higher than those obtained with the suspension, while the time (T-max) to reach C-max was reduced. Moreover, in vivo administration of Ro 28-2653 solutions highlighted some information about the pharmacokinetic behavior of Ro 28-2653: a long biologic half-life (about 15.5 h) and a small overall volume of distribution (81). (c) 2006 Elsevier B.V. All rights reserved. [less ▲]

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See detailAutomated method for the determination of a new matrix metalloproteinase inhibitor in ovine plasma and serum by coupling of restricted access material for on-line sample clean-up to liquid chromatography
Chiap, Patrice ULiege; Piette, Marie ULiege; Evrard, Brigitte ULiege et al

in Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences (2005), 817(1), 109-117

A fully automated liquid chromatographic method was developed for the determination of Ro 28-2653, a new synthetic inhibitor of matrix metalloproteinases (MMPs), in ovine serum and plasma. The method was ... [more ▼]

A fully automated liquid chromatographic method was developed for the determination of Ro 28-2653, a new synthetic inhibitor of matrix metalloproteinases (MMPs), in ovine serum and plasma. The method was based on the coupling of a pre-column packed with restricted access material, namely LiChrospher RP-8 ADS (alkyl diol silica), for sample clean-up to an analytical column containing octyl silica stationary phase. One hundred mul of biological sample, to which 2-propanol was automatically added, were injected onto the ADS pre-column, which was then washed with a washing liquid consisting of a mixture of 25 mM phosphate buffer (pH 7.0) and acetonitrile (90: 10; v/v) for 10 min. By rotation of the switching valve, the analyte was then eluted in the back-flush mode with the LC mobile phase composed of a mixture of acetonitrile and 25 mM phosphate buffer (pH 7.0) (57:43; v/v). The UV detection was performed at 395 nm. The main parameters likely to influence the sample preparation technique were investigated. The method was then validated over a concentration range from 17.5 to 1950 ng/mI, the first concentration level corresponding to the lower limit of quantitation. At this concentration level, the mean bias and the R.S.D. value for intermediate precision were -2.4% and 4.2%, respectively. (C) 2004 Elsevier B.V. All rights reserved. [less ▲]

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See detailCyclodextrins as a potential carrier in drug nebulization.
Evrard, Brigitte ULiege; Bertholet, P.; Guéders, Maud ULiege et al

in Journal of Controlled Release (2004), 96(3), 403-10

The inhalation route is widely studied for many drug applications focusing on either local or systemic distributions. One matter of concern is the solubilization of hydrophobic drugs. We have studied the ... [more ▼]

The inhalation route is widely studied for many drug applications focusing on either local or systemic distributions. One matter of concern is the solubilization of hydrophobic drugs. We have studied the feasibility of using different cyclodextrins (CDs) to elaborate pharmaceutical formulations for the inhalation route and tested the short-term toxicity of such formulations administered by inhalation to C57BL/6 mice. We have shown that HP-beta-CD, gamma-CD, as well as RAMEB aqueous solutions can undergo aerosolization and that the resulting droplet-size ranges are compatible with pulmonary deposition. In vivo, we have demonstrated that short-term exposure to inhaled HP-beta-CD, gamma-CD and RAMEB solutions are non-toxic after assessing bronchoalveolar lavage (BAL), lung and kidney histology, bronchial responsiveness to methacholine and blood urea. The only change noted is a slight increase in lymphocyte count in the BAL after HP-beta-CD and gamma-CD inhalation. We conclude that CDs are useful in significantly enhancing the solubility of apolar drugs with a view to inhalation therapy although an increase in lymphocyte counts in the BAL after CDs inhalations needs further investigations. [less ▲]

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See detailSkin compatibility of cyclodextrins and their derivatives: a comparative assessment using a corneoxenometry bioassay.
Piel, Géraldine ULiege; Moutard, S.; Uhoda, Emmanuelle ULiege et al

in European Journal of Pharmaceutics and Biopharmaceutics (2004), 57(3), 479-82

Few studies have been performed to assess the risk of skin damage by cyclodextrins (CD) and they have yielded contradictory results. The present study was conducted using the corneoxenometry bioassay on ... [more ▼]

Few studies have been performed to assess the risk of skin damage by cyclodextrins (CD) and they have yielded contradictory results. The present study was conducted using the corneoxenometry bioassay on human stratum corneum to compare the skin compatibility of CD currently used in pharmaceutical preparations (betaCD, gammaCD, Rameb, Dimeb, Trimeb, HP-betaCD and HP-gammaCD) and that of new amphiphilic CD derivatives, namely, the phospholipidyl-CD (DMPE-Dimeb and DMPE-Trimeb). All the tested CD were well tolerated by the stratum corneum at a concentration of 5%. However, inter-individual reactivity was larger for DMPE-Dimeb, suggesting a more aggressive trend for this compound. Cutaneous Index of Mildness values obtained confirm that Dimeb is able to extract some skin components and shows that DMPE-Dimeb performs similarly. [less ▲]

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See detailCyclodextrins as a potential carrier in drug nebulization
Evrard, Brigitte ULiege; Bertholet, P.; Guéders, Maud ULiege et al

in Journal of Controlled Release (2004), 96(3), 403-410

The inhalation route is widely studied for many drug applications focusing on either local or systemic distributions. One matter of concern is the solubilization of hydrophobic drugs. We have studied the ... [more ▼]

The inhalation route is widely studied for many drug applications focusing on either local or systemic distributions. One matter of concern is the solubilization of hydrophobic drugs. We have studied the feasibility of using different cyclodextrins (CDs) to elaborate pharmaceutical formulations for the inhalation route and tested the short-term toxicity of such formulations administered by inhalation to C57BL/6 mice. We have shown that HP-beta-CD, gamma-CD, as well as RAMEB aqueous solutions can undergo aerosolization and that the resulting droplet-size ranges are compatible with pulmonary deposition. In vivo, we have demonstrated that short-term exposure to inhaled HP-beta-CD, gamma-CD and RAMEB solutions are non-toxic after assessing bronchoalveolar lavage (BAL), lung and kidney histology, bronchial responsiveness to methacholine and blood urea. The only change noted is a slight increase in lymphocyte count in the BAL after HP-beta-CD and gamma-CD inhalation. We conclude that CDs are useful in significantly enhancing the solubility of apolar drugs with a view to inhalation therapy although an increase in lymphocyte counts in the BAL after CDs inhalations needs further investigations. (C) 2004 Elsevier B.V. All rights reserved. [less ▲]

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See detailDelivery of granulocyte-macrophage colony-stimulating factor in bioadhesive hydrogel stimulates migration of dendritic cells in models human papillomavirus-associated (pre)neoplastic epithelial lesions
Hubert, Pascale ULiege; Evrard, Brigitte ULiege; Maillard, Catherine ULiege et al

in Antimicrobial Agents and Chemotherapy (2004), 48(11), 4342-4348

Because of the central role of dendritic cells and/or Langerhans cells(DC/LC) in the induction of cellular immune responses, pharmacological agents that modulate the recruitment of these cells might have ... [more ▼]

Because of the central role of dendritic cells and/or Langerhans cells(DC/LC) in the induction of cellular immune responses, pharmacological agents that modulate the recruitment of these cells might have a clinical interest. The present study was designed to evaluate the capacity of several pharmaceutical formulations to topically deliver granulocyte-macrophage colony-stimulating factor (GM-CSF) on human papillomavirus (HPV)-associated genital (pre)neoplastic lesions. The formulations were evaluated for their bioactivity and for their potential to recruit DC in organotypic cultures of HPV-transformed keratinocytes. We found that a bioadhesive polycarbophil gel (Noveon) at pH 5.5 is able to maintain the bioactivity of GM-CSF at 4 or 37°C for at least 7 days, whereas a decreased activity of GM-CSF was observed when the molecule is included in other polymer gels. GM-CSF incorporated in the polycarbophil gel was also a potent factor in enhancing the colonization of DC into organotypic cultures of HPV-transformed keratinocytes since the infiltration of DC in the in vitro-formed (pre)neoplastic epithelium was very low under basal conditions and dramatically increased in the presence of GM-CSF gel. We next demonstrated that GM-CSF incorporated in polycarbophil gel induces the recruitment of human DC in a human (pre)neoplastic epithelium grafted into NOD/SCID mice. The efficacy of GM-CSF in this formulation was equivalent to that observed with liquid GM-CSF. These results suggest that GM-CSF incorporated in polycarbophil gel could play an important role in the recruitment of DC/LC in mucosal surfaces and be useful as a new immunotherapeutic approach for genital HPV-associated (pre)neoplastic lesions. [less ▲]

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See detailInfluence de la methyl-b-cyclodextrine sur la cinetique de libération de l'inuline encapsulée dans des liposomes bioadhésifs
Piel, Géraldine ULiege; Boulmedarat, Laila; Bochot, Amélie et al

Poster (2003, November 12)

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