Drug absorption through a cell monolayer: a theoretical work on a non-linear three-compartment model

The subject of analysis is a non-linear three-compartment model, widely used in pharmacological absorption studies. It has been transformed into a general form, thus leading automatically to an appropriate approximation. This made the absorption profile accessible and expressions for absorption times, apparent permeabilities and equilibrium values were given. These findings allowed a profound analysis of results from non-linear curve fits and delivered the dependencies on the systems' parameters over a wide range of values. The results were applied to an absorption experiment with multidrug transporter-affected antibiotic CNV97100 on Caco-2 cell monolayers.Comment: 21 pages, 8 figures (v4: detailed definition of the treated model - additional information about limitations

Tucumanin, a β-hydroxy-γ-lactone bistetrahydrofuranic acetogenin from Annona cherimolia, is a potent inhibitor of mitochondrial complex I

A new β-hydroxy-γ-methyl-γ-lactone bistetrahydrofuranic acetogenin, tucumanin, with the infrequent symmetrical threo/trans/threo/trans/ threo relative configuration at the tetrahydrofuran rings was isolated from Annona cherimolia (Annonaceae) seeds. The inhibitory potency on the mitochondrial complex I of acetogenins with this relative configuration (tucumanin and asimicin) was compared with that shown by the corresponding pairs with an asymmetrical threo/trans/threo/trans/erythro relative configuration (laherradurin/rolliniastatin-2, and itrabin/molvizarin). All these compounds act as selective inhibitors of mitochondrial complex 1 in the 0.18 - 1.55 nM range.Fil: Barrachina, Isabel. Universidad de Valencia; EspañaFil: Neske, Adriana. Universidad Nacional de Tucumán; ArgentinaFil: Granell, Susana. Universidad de Valencia; EspañaFil: Bermejo, Almudena. Universidad de Valencia; EspañaFil: Chahboune, Nadia. Universidad de Valencia; EspañaFil: El Aouad, Noureddine. Universidad de Valencia; EspañaFil: Alvarez, Olga. Universidad Nacional de Tucumán; ArgentinaFil: Bardon, Alicia del Valle. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto de Química del Noroeste. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia. Instituto de Química del Noroeste; Argentina. Universidad Nacional de Tucumán; ArgentinaFil: Zafra Polo, M. Carmen. Universidad de Valencia; Españ

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

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146268/1/bcp13650.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146268/2/bcp13650_am.pd

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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Acute fasting before conception affects metabolic and endocrine status without impacting follicle and oocyte development and embryo gene expression in the rabbit.

Food deprivation affects female reproduction. The goal of the present study was to elucidate in the rabbit model the effects of acute energy restriction on ovarian function (follicle development, atresia rate and in vitro oocyte maturation) and embryonic development and gene expression of some candidate genes. Serum metabolic parameters (non-esterified fatty acids (NEFA), triglycerides, glucose, insulin and leptin concentrations) and endocrine markers (oestradiol-17β and progesterone concentrations) were also studied. A control group of nulliparous does fed ad libitum and a 72-h fasted group were used. At the end of the nutritional treatment, the ovaries of half of the animals were retrieved while the other animals were re-fed and artificially inseminated to recover embryos at 84 h after insemination, during the luteal phase. At the end of fasting, increased serum NEFA and decreased leptin concentrations were observed in the fasted group, but no differences appeared in serum steroid concentrations, follicle population and atresia rate or nuclear and cytoplasmic oocyte maturation. In the luteal phase, insulin concentrations increased notably in the fasted group. The number of recovered embryos per female and the speed of embryo development were reduced in the food-deprived group. Acute fasting altered both metabolic and endocrine markers and embryo development, but follicle and oocyte development and embryo gene expression were not affected

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Among the major reasons for the success of the Internet have been the simple networking architecture and the IP interoperation layer. However, the traffic model has recently changed. More and more applications (e.g. peerto-peer, content delivery networks) target on the content that they deliver rather than on the addresses of the servers who (originally) published/hosted that content. This trend has motivated a number of content-oriented networking studies. In this paper we summarize some the most important approache

Secure Geographic Routing in Ad Hoc and Wireless Sensor Networks

Security in sensor networks is one of the most relevant research topics in resource constrained wireless devices and networks. Several attacks can be suffered in ad hoc and wireless sensor networks (WSN), which are highly susceptible to attacks, due to the limited resources of the nodes. In this paper, we propose innovative and lightweight localization techniques that allow for intrusion identification and isolation schemes and provide accurate location information. This information is used by our routing protocol which additionally incorporates a distributed trust model to prevent several routing attacks to the network. We finally evaluate our algorithms for accurate localization and for secure routing which have been implemented and tested in real ad hoc and wireless sensor networks