Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 4 uppsatser.

Glucose 1,6-bisphosphate is an important small molecule involved in the regulation of glycolysis. Four enzymes synthesize this compound. One enzyme is known to degrade it, glucose 1,6-bisphosphatase. Other groups have produced work that indicates that there are two isoforms of this enzyme, one predominant in the brain and one in the muscle. This thesis contains the work performed in attempts to isolate and characterize the muscle isoform of glucose 1,6-bisphosphatase. While this enzyme was not isolated, much was learned about it and the results from this work may help in the future identification of this enzyme.

L’objectif principal de ce travail de thèse est de développer une nouvelle formulation formant un dépôt in situ après administration parentérale pour la libération prolongée de principes actifs. Les systèmes à base de chitosane (CS) formant des hydrogels sous l’action de la chaleur corporelle ont été choisis parmi les différentes catégories de formulations injectables se solidifiant in situ pour la biocompatibilité et la biodégradabilité reconnue de ce polymère. Après une revue des différents systèmes thermo-gélifiants à base de CS et de leurs utilisations, nous nous sommes intéressés en détail aux mécanismes sur lesquels reposaient la formation des hydrogels de CS / agent gélifiant. Une étude rhéologique approfondie combinée à de la 31P-RMN a permis de mettre en évidence le rôle clé de la partie polyol de l’agent gélifiant dans cemécanisme. La troisième partie a été consacrée au développement d’un nouveau système associant le CS au glucose-1-phosphate (G1-P). Une étude des propriétés physico-chimiques et de la stabilité de ce système a mis en évidence sa gélification dans les conditions physiologiques et l’amélioration significative de sa stabilité à long terme par rapport au système standard CS / glycérophosphate. Des essais de tolérance locale souscutanée réalisés sur un modèle murin ont montré que le système est raisonnablement bien toléré. Enfin, la dernière partie, consacrée à l’étude de la libération in vitro de différents composés modèles, a démontré l’aptitude du réseau polymère de CS / G1-P à prolonger la libération des substances incorporées. / The aim of this work was to develop a new parenteral in situ forming depot (ISFD) system for the controlled delivery of drugs. Chitosan (CS)-based systems that undergo sol / gel transition upon heating at physiological temperature were selected among the different categories of ISFDs due to their well-known biocompatibility and biodegradability. After an overall review of the recent progresses on standard CS-based ISFD systems, the synergistic mechanisms underlying the temperature-induced gelation of the CS / gelling agent systems were investigated through comprehensive rheological studies completed by 31P-NMR measurements. These investigations emphasized the key role of the polyol part of the gelling agent. The next step consisted in developing a new system combining CS and glucose-1-phosphate (G1-P). The physico-chemical characteristics and storage stability of this system were investigated. The results highlighted a sol / gel transition under physiological conditions and improved storage stability compared to the standard CS / glycerophosphate system. Local tolerability studies of the hydrogels in rats showed that the system was reasonably well tolerated. Finally, the last chapter, dedicated to the study of the in vitro release behavior of several model compounds, emphasized the ability of the polymeric CS / G1-P network to sustain the release of the incorporated substances.

Diss. (sammanfattning) Uppsala : Univ., 2003. / Härtill 9 uppsatser.

Introducción: La resistencia antimicrobiana es un problema alarmante en la salud pública mundial. A mediados del 2017, la Organización Mundial de la Salud (OMS) reportó una lista de las bacterias para la búsqueda de nuevos antibióticos, incluyendo sobre todo enterobacterias. En el Perú, hubo reporte de casos de Klebsiella pneumoniae resistente a antibióticos en diferentes regiones del país. Por lo tanto, existe una necesidad de encontrar nuevos sitios diana de acción farmacológica para enfrentar esta problemática sanitaria. Objetivo: Identificar las moléculas orgánicas con capacidad de inhibición de la enzima Glucosa 1-fosfato Timidilil Transferasa (RmlA) de K. pneumoniae resistente a antibióticos utilizando la técnica de acoplamiento molecular. Materiales y métodos: Se realizó un estudio in-silico, mediante programas para acoplamiento molecular por ordenador local. La semejanza de fármacos con el sustrato natural de la enzima fue dada con programas de similaridad de ligandos, se obtuvieron datos teóricos de las interacciones entre los fármacos seleccionados con el sitio activo de la enzima. Finalmente se analizó cada ligando en función de sus energías libres. Resultados: Se analizó computacionalmente 14100 unidades farmacológicas con posible interacción con la enzima RmlA de K. pneumoniae resistente a antibióticos, según las energías libres de interacción los valores enteros están entre 96 a 103 (kcal/mol), frente al valor de acoplamiento del sustrato-enzima de -222.357 (kcal/mol). Conclusiones: Se encontraron posibles fármacos inhibidores de la enzima RmlA de K. pneumonia, es necesario continuar con la valoración y estudio de estos fármacos en estudios laboratoriales para mejorar la propuesta de inhibición enzimática basada en este trabajo de investigación computacional. / Introduction: Antimicrobial resistance is an alarming problem in global public health. In mid-2017, the World Health Organization (WHO) reported a list of bacteria for the search for new antibiotics, including especially Enterobacteriaceae. In Peru, there were reports of cases of antibiotic-resistant Klebsiella pneumoniae in different regions of the country. Therefore, there is a need to find new target sites for pharmacological action to address this health problem. Objective: Identify organic molecules with the capacity to inhibit the enzyme Glucose 1-phosphate Thymidylyl Transferase (RmlA) of antibioticresistant K. pneumoniae using the molecular docking technique. Materials and methods: An in-silico study was carried out, using programa for molecular docking by local computer. The similarity of drugs with the natural substrate of the enzyme was given with ligand similarity programs, theoretical data were obtained on the interactions between the selected drugs with the active site of the enzyme. Finally, each ligand was analyzed based on its free energies. Results: 14100 pharmacological units with possible interaction with the RmlA enzyme of antibiotic-resistant K. pneumoniae were computationally analyzed. According to the interaction free energies, the integer values are between 96 to 103 (kcal/mol), compared to the coupling value of the substrate. enzyme of -222,357 (kcal/mol). Conclusions: Possible drugs that inhibit the RmlA enzyme of K. pneumonia were found; it is necessary to continue with the evaluation and study of these drugs in laboratory studies to improve the proposal for enzyme inhibition based on this computational research work.