Publicação
New fight against tuberculosis using pharmaceutical ionic liquids
| Resumo: | Tuberculosis (TB) is to this day a disease that threatens public health, being the second major cause of infectious disease related deaths. Only in 2020, caused the death of 1.5 million people in highly populated or developing countries. The treatment of this disease involves multi-drug formulations including rifampicin as one of the prominent drugs used. This drug has a low bioavailability, and it is also hepatotoxic. However, rifampicin can be ionized, being an excellent target for the development of organic salts and ionic liquids (OSILs) based on this active pharmaceutical ingredient (Rif-OSIL). The ionization of this drug as well as the combination with highly polar counter-ions considerably increased its water solubility at least 450 times comparing to the neutral API reported value. In parallel, it is observed a reducing in the octanol/water partition coefficient as a clear indication about the improvement of the API permeability. All Rif-OSILs based on cationic or anionic approaches were characterized by 1H and 13C NMR, FTIR and elemental analysis to proof the desired chemical structures. In vivo toxicity assays were performed in zebrafish (Danio rerio) to evaluate the impacts in toxicity of the drug (Rif and Rif-OSILs) when bioavailability is increased. From these assays, both catalase and glutathione-S-transferase were inhibited by the rifampicin organic salt, but no statistically relevant oxidative damage in the form of lipid peroxidation was observed. Another problem of rifampicin involves the low action local concentration for effective treatment. Dry powders for inhalation from both original rifampicin and the most promissory Rif-OSIL were produced through Supercritical CO2-assisted Spray Drying and then they were tested in Andersen-Cascade Impactor to assess aerodynamic properties. Two protocols were used, one of which produced powders capable of reaching the alveoli, in which infection by Mycobacterium tuberculosis occurs. This work opens good perspectives to use Rif-OSILs as a sustainable and more effective therapeutic strategy for the treatment of tuberculosis. |
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| Autores principais: | Bernardes, Afonso José Reis |
| Assunto: | Rifampicin organic salt and ionic liquid tuberculosis bioavailability in vivo toxicity dry powders |
| Ano: | 2023 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade Nova de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório Institucional da UNL |
| Resumo: | Tuberculosis (TB) is to this day a disease that threatens public health, being the second major cause of infectious disease related deaths. Only in 2020, caused the death of 1.5 million people in highly populated or developing countries. The treatment of this disease involves multi-drug formulations including rifampicin as one of the prominent drugs used. This drug has a low bioavailability, and it is also hepatotoxic. However, rifampicin can be ionized, being an excellent target for the development of organic salts and ionic liquids (OSILs) based on this active pharmaceutical ingredient (Rif-OSIL). The ionization of this drug as well as the combination with highly polar counter-ions considerably increased its water solubility at least 450 times comparing to the neutral API reported value. In parallel, it is observed a reducing in the octanol/water partition coefficient as a clear indication about the improvement of the API permeability. All Rif-OSILs based on cationic or anionic approaches were characterized by 1H and 13C NMR, FTIR and elemental analysis to proof the desired chemical structures. In vivo toxicity assays were performed in zebrafish (Danio rerio) to evaluate the impacts in toxicity of the drug (Rif and Rif-OSILs) when bioavailability is increased. From these assays, both catalase and glutathione-S-transferase were inhibited by the rifampicin organic salt, but no statistically relevant oxidative damage in the form of lipid peroxidation was observed. Another problem of rifampicin involves the low action local concentration for effective treatment. Dry powders for inhalation from both original rifampicin and the most promissory Rif-OSIL were produced through Supercritical CO2-assisted Spray Drying and then they were tested in Andersen-Cascade Impactor to assess aerodynamic properties. Two protocols were used, one of which produced powders capable of reaching the alveoli, in which infection by Mycobacterium tuberculosis occurs. This work opens good perspectives to use Rif-OSILs as a sustainable and more effective therapeutic strategy for the treatment of tuberculosis. |
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