Biopharmaceutical optimization in neglected diseases for paediatric patients by applying the provisional paediatric biopharmaceutical classification system

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Long-Circulating Hyaluronan-Based Nanohydrogels as Carriers of Hydrophobic Drugs

[EN] Nanohydrogels based on natural polymers, such as polysaccharides, are gaining interest as vehicles for therapeutic agents, as they can modify the pharmacokinetics and pharmacodynamics of the carried drugs. In this work, hyaluronan-riboflavin nanohydrogels were tested in vivo in healthy rats highlighting their lack of toxicity, even at high doses, and their different biodistribution with respect to that of native hyaluronan. They were also exploited as carriers of a hydrophobic model drug, the anti-inflammatory piroxicam, that was physically embedded within the nanohydrogels by an autoclave treatment. The nanoformulation was tested by intravenous administration showing an improvement of the pharmacokinetic parameters of the molecule. The obtained results indicate that hyaluronan-based self-assembled nanohydrogels are suitable systems for low-soluble drug administration, by increasing the dose as well as the circulation time of poorly available therapeutic agents.Financial support from University Sapienza Progetti di Ricerca: grant RP116154C2EF9AC8 and grant RM11715C1743EE89 are acknowledged. Isabel Gonzalez-Alvarez, Marta Gonzalez-Alvarez and Marival Bermejo acknowledge partial financial support to project SAF2016-78756 from MINECO (Spanish Ministry of economy, industry and competitivity). Mayte Martinez-Martínez received a grant from the Ministry of Education and Science of Spain (FPU13-01105).Di Meo, C.; Martínez Martínez, M.; Coviello, T.; Bermejo, M.; Merino Sanjuán, V.; Gonzalez-Alvarez, I.; Gonzalez-Alvarez, M.... (2018). Long-Circulating Hyaluronan-Based Nanohydrogels as Carriers of Hydrophobic Drugs. Pharmaceutics. 10(4):1-15. https://doi.org/10.3390/pharmaceutics10040213S115104Allison, D. D., & Grande-Allen, K. J. (2006). Review. Hyaluronan: A Powerful Tissue Engineering Tool. Tissue Engineering, 12(8), 2131-2140. doi:10.1089/ten.2006.12.2131Prestwich, G. D. (2008). Engineering a clinically-useful matrix for cell therapy. Organogenesis, 4(1), 42-47. doi:10.4161/org.6152Ossipov, D. A. (2010). Nanostructured hyaluronic acid-based materials for active delivery to cancer. Expert Opinion on Drug Delivery, 7(6), 681-703. doi:10.1517/17425241003730399Rao, N. V., Yoon, H. Y., Han, H. S., Ko, H., Son, S., Lee, M., … Park, J. H. (2015). Recent developments in hyaluronic acid-based nanomedicine for targeted cancer treatment. Expert Opinion on Drug Delivery, 13(2), 239-252. doi:10.1517/17425247.2016.1112374Dosio, F., Arpicco, S., Stella, B., & Fattal, E. (2016). Hyaluronic acid for anticancer drug and nucleic acid delivery. Advanced Drug Delivery Reviews, 97, 204-236. doi:10.1016/j.addr.2015.11.011Montanari, E., D’Arrigo, G., Di Meo, C., Virga, A., Coviello, T., Passariello, C., & Matricardi, P. (2014). Chasing bacteria within the cells using levofloxacin-loaded hyaluronic acid nanohydrogels. European Journal of Pharmaceutics and Biopharmaceutics, 87(3), 518-523. doi:10.1016/j.ejpb.2014.03.003Svanovsky, E., Velebny, V., Laznickova, A., & Laznicek, M. (2008). The effect of molecular weight on the biodistribution of hyaluronic acid radiolabeled with111In after intravenous administration to rats. European Journal of Drug Metabolism and Pharmacokinetics, 33(3), 149-157. doi:10.1007/bf03191112Harris, E. N., Kyosseva, S. V., Weigel, J. A., & Weigel, P. H. (2006). Expression, Processing, and Glycosaminoglycan Binding Activity of the Recombinant Human 315-kDa Hyaluronic Acid Receptor for Endocytosis (HARE). Journal of Biological Chemistry, 282(5), 2785-2797. doi:10.1074/jbc.m607787200Choi, K. Y., Min, K. H., Na, J. H., Choi, K., Kim, K., Park, J. H., … Jeong, S. Y. (2009). Self-assembled hyaluronic acid nanoparticles as a potential drug carrier for cancer therapy: synthesis, characterization, and in vivo biodistribution. Journal of Materials Chemistry, 19(24), 4102. doi:10.1039/b900456dPedrosa, S. S., Pereira, P., Correia, A., & Gama, F. M. (2017). Targetability of hyaluronic acid nanogel to cancer cells : In vitro and in vivo studies. European Journal of Pharmaceutical Sciences, 104, 102-113. doi:10.1016/j.ejps.2017.03.045Yang, C., Li, C., Zhang, P., Wu, W., & Jiang, X. (2017). Redox Responsive Hyaluronic Acid Nanogels for Treating RHAMM (CD168) Over-expressive Cancer, both Primary and Metastatic Tumors. Theranostics, 7(6), 1719-1734. doi:10.7150/thno.18340Rosso, F., Quagliariello, V., Tortora, C., Di Lazzaro, A., Barbarisi, A., & Iaffaioli, R. V. (2013). Cross-linked hyaluronic acid sub-micron particles: in vitro and in vivo biodistribution study in cancer xenograft model. Journal of Materials Science: Materials in Medicine, 24(6), 1473-1481. doi:10.1007/s10856-013-4895-4Nakai, T., Hirakura, T., Sakurai, Y., Shimoboji, T., Ishigai, M., & Akiyoshi, K. (2012). Injectable Hydrogel for Sustained Protein Release by Salt-Induced Association of Hyaluronic Acid Nanogel. Macromolecular Bioscience, 12(4), 475-483. doi:10.1002/mabi.201100352Montanari, E., Capece, S., Di Meo, C., Meringolo, M., Coviello, T., Agostinelli, E., & Matricardi, P. (2013). Hyaluronic Acid Nanohydrogels as a Useful Tool for BSAO Immobilization in the Treatment of Melanoma Cancer Cells. Macromolecular Bioscience, 13(9), 1185-1194. doi:10.1002/mabi.201300114Montanari, E., Di Meo, C., Sennato, S., Francioso, A., Marinelli, A. L., Ranzo, F., … Matricardi, P. (2017). Hyaluronan-cholesterol nanohydrogels: Characterisation and effectiveness in carrying alginate lyase. New Biotechnology, 37, 80-89. doi:10.1016/j.nbt.2016.08.004Montanari, E., De Rugeriis, M. C., Di Meo, C., Censi, R., Coviello, T., Alhaique, F., & Matricardi, P. (2015). One-step formation and sterilization of gellan and hyaluronan nanohydrogels using autoclave. Journal of Materials Science: Materials in Medicine, 26(1). doi:10.1007/s10856-014-5362-6Di Meo, C., Montanari, E., Manzi, L., Villani, C., Coviello, T., & Matricardi, P. (2015). Highly versatile nanohydrogel platform based on riboflavin-polysaccharide derivatives useful in the development of intrinsically fluorescent and cytocompatible drug carriers. Carbohydrate Polymers, 115, 502-509. doi:10.1016/j.carbpol.2014.08.107Manzi, G., Zoratto, N., Matano, S., Sabia, R., Villani, C., Coviello, T., … Di Meo, C. (2017). «Click» hyaluronan based nanohydrogels as multifunctionalizable carriers for hydrophobic drugs. Carbohydrate Polymers, 174, 706-715. doi:10.1016/j.carbpol.2017.07.003Lozoya-Agullo, I., Araújo, F., González-Álvarez, I., Merino-Sanjuán, M., González-Álvarez, M., Bermejo, M., & Sarmento, B. (2018). PLGA nanoparticles are effective to control the colonic release and absorption on ibuprofen. European Journal of Pharmaceutical Sciences, 115, 119-125. doi:10.1016/j.ejps.2017.12.009Samiei, N., Mangas-Sanjuan, V., González-Álvarez, I., Foroutan, M., Shafaati, A., Zarghi, A., & Bermejo, M. (2013). Ion-pair strategy for enabling amifostine oral absorption: Rat in situ and in vivo experiments. European Journal of Pharmaceutical Sciences, 49(4), 499-504. doi:10.1016/j.ejps.2013.04.025Wei, X., Senanayake, T. H., Bohling, A., & Vinogradov, S. V. (2014). Targeted Nanogel Conjugate for Improved Stability and Cellular Permeability of Curcumin: Synthesis, Pharmacokinetics, and Tumor Growth Inhibition. Molecular Pharmaceutics, 11(9), 3112-3122. doi:10.1021/mp500290

Ionic Hydrogel Based on Chitosan Cross-Linked with 6-Phosphogluconic Trisodium Salt as a Drug Delivery System

[EN] In this work, 6-phosphogluconic trisodium salt (6-PG(-)Na(+)) is introduced as a new aqueous and nontoxic cross-linking agent to obtain ionic hydrogels. Here, it is shown the formation of hydrogels based on chitosan cross-linked with 6-PG(-)Na(+). This formulation is obtained by ionic interaction of cationic groups of polymer with anionic groups of the cross linker. These hydrogels are nontoxic, do not cause dermal irritation, are easy to extend, and have an adequate adhesion force to be applied as polymeric film over the skin. This AWN formulation exhibits a first order release kinetic and can be applied as drug vehicle for topical administration or as wound dressing for wound healing. The primary goal of this communication is to report the identification and utility of 6-phosphogluconic trisodium salt (6-PG(-)Na(+)) as a nontoxic cross-linker applicable for cationic polymers.The authors acknowledge partial financial support to project SAF2016-78756 from MINECO (Spanish Ministry of economy, industry and competitiveness). Maria Teresa Martinez Martinez received a grant from the Ministry of Education and Science of Spain (FPU13-01105). The product was patented in Spain in 2016 by authors of this paper. Patent application 201631463.Martínez Martínez, M.; Rodríguez Berna, G.; Gonzalez-Alvarez, I.; Hernández, MJ.; Corma Canós, A.; Bermejo, M.; Merino Sanjuán, V.... (2018). Ionic Hydrogel Based on Chitosan Cross-Linked with 6-Phosphogluconic Trisodium Salt as a Drug Delivery System. Biomacromolecules. 19(4):1294-1304. https://doi.org/10.1021/acs.biomac.8b00108S1294130419

New Insights of Oral Colonic Drug Delivery Systems for Inflammatory Bowel Disease Therapy

[EN] Colonic Drug Delivery Systems (CDDS) are especially advantageous for local treatment of inflammatory bowel diseases (IBD). Site-targeted drug release allows to obtain a high drug concentration in injured tissues and less systemic adverse effects, as consequence of less/null drug absorption in small intestine. This review focused on the reported contributions in the last four years to improve the effectiveness of treatments of inflammatory bowel diseases. The work concludes that there has been an increase in the development of CDDS in which pH, specific enzymes, reactive oxygen species (ROS), or a combination of all of these triggers the release. These delivery systems demonstrated a therapeutic improvement with fewer adverse effects. Future perspectives to the treatment of this disease include the elucidation of molecular basis of IBD diseases in order to design more specific treatments, and the performance of more in vivo assays to validate the specificity and stability of the obtained systems.The authors want to thank the Spanish Government (project RTI2018-100910-B-C41 (MCUI/AEI/FEDER, UE)) and the Generalitat Valenciana (project PROMETEO/2018/024) for support. This work was also supported by the project "MODELOS IN VITRO DE EVALUACION BIOFARMACEUTICA" SAF2016-78756(AEI/FEDER, EU) funded by Agencia Estatal Investigacion and European Union, through FEDER (Fondo Europeo de Desarrollo Regional).Hernández Teruel, A.; Gonzalez-Alvarez, I.; Bermejo, M.; Merino Sanjuán, V.; Marcos Martínez, MD.; Sancenón Galarza, F.; Gonzalez-Alvarez, M.... (2020). New Insights of Oral Colonic Drug Delivery Systems for Inflammatory Bowel Disease Therapy. 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Gated Mesoporous Silica Nanocarriers for a "two-Step" Targeted System to Colonic Tissue

[EN] Colon targeted drug delivery is highly relevant not only to treat colonic local diseases but also for systemic therapies. Mesoporous silica nanoparticles (MSNs) have been demonstrated as useful systems for controlled drug release given their biocompatibility and the possibility of designing gated systems able to release cargo only upon the presence of certain stimuli. We report herein the preparation of three gated MSNs able to deliver their cargo triggered by different stimuli (redox ambient (S1), enzymatic hydrolysis (S2), and a surfactant or being in contact with cell membrane (S3)) and their performance in solution and in vitro with Caco-2 cells. Safranin O dye was used as a model drug to track cargo fate. Studies of cargo permeability in Caco-2 monolayers demonstrated that intracellular safranin O levels were significantly higher in Caco-2 monolayers when using MSNs compared to those of free dye. Internalization assays indicated that S2 nanoparticles were taken up by cells via endocytosis. S2 nanoparticles were selected for in vivo tests in rats. For in vivo assays, capsules were filled with S2 nanoparticles and coated with Eudragit FS 30 D to target colon. The enteric coated capsule containing the MSNs was able to deliver S2 nanoparticles in colon tissue (first step), and then nanoparticles were able to deliver safranin O inside the colonic cells after the enzymatic stimuli (second step). This resulted in high levels of safranin O in colonic tissue combined with low dye levels in plasma and body tissues. The results suggested that this combination of enzyme-responsive gated MSNs and enteric coated capsules may improve the absorption of drugs in colon to treat local diseases with a reduction of systemic effects.The authors acknowledge the financial support from the Spanish Government (Projects MAT2015-64139-C4-1-R, SAF2016-78756 and AGL2015-70235-C2-2-R) and the Generalitat Valenciana (Project GVA/2014/13).Gonzalez-Alvarez, M.; Coll Merino, MC.; Gonzalez-Alvarez, I.; Giménez Morales, C.; Aznar, E.; Martínez-Bisbal, M.; Lozoya Agulló, I.... (2017). Gated Mesoporous Silica Nanocarriers for a "two-Step" Targeted System to Colonic Tissue. Molecular Pharmaceutics. 14(12):4442-4453. https://doi.org/10.1021/acs.molpharmaceut.7b00565S44424453141

Profiles of Problematic Internet Use and Its Impact on Adolescents' Health-Related Quality of Life

The internet has been a breakthrough for adolescents in many ways, but its use can also become dysfunctional and problematic, leading to consequences for personal well-being. The main objective is to analyze profiles related to problematic internet use and its relationship with health-related quality of life (HRQoL). An analytical and cross-sectional study was carried out in a region of northern Spain. The sample comprised 12,285 participants. Sampling was random and representative. Mean age and standard deviation was 14.69 +/- 1.73 (11-18 years). The Spanish versions of the Problematic and Generalized Internet Use Scale (GPIUS2) and of the Health-Related Quality of Life (KIDSCREEN-27) were used. Four profiles were detected (non-problematic use, mood regulator, problematic internet use, and severe problematic use). The prevalence of these last two profiles was 18.5% and 4.9%, respectively. Problematic internet use correlated negatively and significantly with HRQoL. The severe problematic use profile presented a significant decrease in all dimensions of HRQoL. Analyses were carried out to extract a cut-off point for GPIUS2 (52 points). The results and practical implications are discussed.This research was funded by Spanish Ministry of Economy, Industry and Competitiveness, RTI2018-094212-B-I00: (CIBER-AACC); and by the International University of la Rioja, Project "Cyberpsychology (Trienio 2017-20)"

Treating multiple sclerosis with generic cladribine

Meeting AbstractEuropean Comm Treatment & Res Multiple Sclerosi

Urinary Kininogen-1 and Retinol binding protein-4 respond to Acute Kidney Injury: Predictors of patient prognosis?

Implementation of therapy for acute kidney injury (AKI) depends on successful prediction of individual patient prognosis. Clinical markers as serum creatinine (sCr) have limitations in sensitivity and early response. The aim of the study was to identify novel molecules in urine which show altered levels in response to AKI and investigate their value as predictors of recovery. Changes in the urinary proteome were here investigated in a cohort of 88 subjects (55 AKI patients and 33 healthy donors) grouped in discovery and validation independent cohorts. Patients'urine was collected at three time points: within the first 48 h after diagnosis(T1), at 7 days of follow-up(T2) and at discharge of Nephrology(T3). Differential gel electrophoresis was performed and data were confirmed by Western blot (WB), liquid chromatography/mass spectrometry (LC-MS/MS) and enzyme-linked immunosorbent assay (ELISA). Retinol binding protein 4 (RBP4) and kininogen-1 (KNG1) were found significantly altered following AKI. RBP4 increased at T1, and progressively decreased towards normalization. Maintained decrease was observed for KNG1 from T1. Individual patient response along time revealed RBP4 responds to recovery earlier than sCr. In conclusion, KNG1 and RBP4 respond to AKI. By monitoring RBP4, patient's recovery can be anticipated pointing to a role of RBP4 in prognosis evaluation.Funding: from Instituto de Salud Carlos III: FIS PI11/01401, PI13/01873, FIS IF08/3667-1, CP09/00229, PI13/00047, PI10/00624, ISCIII-RETIC REDinREN RD012/0021. FEDER funds, Comunidad de Madrid/CIFRA S2010/BMD-2378, Programa Intensificación Actividad Investigadora (ISCIII/Agencia Laín-Entralgo/CM) to AO, IDCSalud (3371/002) and Fundación Conchita Rábago de Jiménez Díaz, Proteomic Facility from Universidad Complutense de Madrid-Fundación Parque Científico de Madrid (UCM-FPCM), Spain, a member of ProteoRed-ISCIII Network member of ProteoRed- ISCIII Networ