Produção e avaliação da atividade anti-inflamatória de implantes contendo anti-inflamatório não esteroidal na osteoartrite induzida em joelhos de ratos
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Data
2013
Tipo de documento
Dissertação
Título da Revista
ISSN da Revista
Título de Volume
Área do conhecimento
Ciências da Saúde
Modalidade de acesso
Acesso aberto
Editora
Autores
Cunha, Romilton Crozetta da
Orientador
Kanis, Luiz Alberto
Coorientador
Resumo
Entre as formas de tratar a osteoartrite (AO) está o uso de anti-inflamatórios não esteroidais (AINEs), sempre com a recomendação para ser usado na menor dose efetiva e no menor tempo possível. Isso por que os efeitos adversos nos sistemas gastrointestinal, cardiocirculatório e renal são bem conhecidos. O uso de sistemas diferenciados de liberação de fármacos como os dispositivos implantáveis tem propiciado alternativas para reduzir a concentração plasmática circulante e direcionar o fármaco para o local de ação, podendo reduzir assim muitos dos efeitos colaterais dos fármacos. O objetivo deste estudo foi produzir, caracterizar e avaliar a atividade anti-inflamatória de dois sistemas poliméricos implantáveis contendo diclofenaco de sódio em modelo de inflamação aguda induzida por carragenina em joelho de ratos. Foram produzidos dois dispositivos implantáveis contendo diclofenaco de sódio, o primeiro incorporado em misturas de EUDRAGIT RS 100 e PEG400, chamado de EUDPEG; e outro contendo EUDRAGIT RS 100 e PCL-T, chamado de EUDPCL-T. Os materiais foram caracterizados por microscopia ótica, análises termomecânicas e foi determinada a velocidade de liberação em meio de tampão fosfato pH 7.4. Após caracterização os dispositivos EUDPCL-T (3,0 mg de diclofenaco de sódio) e EUDPEG (3,6 mg de diclofenaco de sódio) foram implantados justa articular na região posterior dos joelhos e após 4 dias foi induzido edema de joelho pela injeção intra-articular de carragenina. Nos tempos 6 horas e no 7º dia após a indução da artrite, os animais foram anestesiados e o edema medido através da variação da circunferência do joelho, seguido de sacrifício para análise de mediadores inflamatórios, mieloperoxidade (MPO) e óxido nítrico presentes na articulação. Também foram avaliadas as lesões gástricas. Os resultados foram comparados com administração oral de 30 mg/Kg de diclofenaco de sódio. As microscopias demonstraram que o filme EUDPEG é totalmente transparente devido à solubilidade do diclofenaco na matriz polimérica e apresenta um comportamento mecânico plástico com menor capacidade de deformação. Para o filme EUDPCL-T foi observado um filme totalmente opaco associado à cristalização do diclofenaco de sódio na matriz polimérica e variação de deformação em função da tensão característica de material elastomérico. Os estudos de liberação de diclofenaco de sódio in vitro a partir dos filmes utilizados mostraram duas fases distintas de liberação, uma fase de liberação acelerada, que durou em torno de 24 horas, onde EUDPEG apresentou maior velocidade de liberação, e uma fase lenta onde ocorreu a inversão das velocidades de liberação, com filme EUDPCL-T, apresentando um aumento da quantidade liberada por tempo quando comparado com o EUDPEG. O dispositivo EUDPCL-T promoveu redução estatisticamente significativa (p<0,05) do edema e da concentração de MPO quando comparado com o grupo controle 6 horas e 7 dias após a indução do edema, enquanto o grupo que recebeu tratamento por via oral mostrou diferença significativa somente 7 dias após a indução da artrite. O dispositivo EUDPEG reduziu o edema significativamente (p<0,05) somente 7 dias após a indução da artrite, mas não foi eficaz para reduzir a concentração de MPO. No doseamento de nitratos/nitritos 6 h após a indução da artrite, somente os grupos tratados com dispositivos implantáveis EUDPEG e EUDPCL-T mostraram diferença estatisticamente significativa quando comparados com o grupo controle. Sete dias após a indução da artrite nenhum grupo que recebeu tratamento mostrou diferença estatística nos níveis de nitratos/nitrito com o grupo controle. Os resultados demonstram que a colocação do dispositivo EUDPCL-T para entrega do diclofenaco de sódio justa articular, promoveu a mesma atividade na diminuição do edema e na diminuição dos marcadores inflamatórios quando comparado com a administração por via oral, porém com doses inferiores.
Among the options to treat osteoarthritis there is the use of non-steroidal anti-inflammatory, always with the recommendation of using the least effective dose in the shortest time possible. It is suggested because the adverse effects in the gastrointestinal, cardio circulatory and renal systems are well known. The use of different systems of drug releases like implantable devices has propitiated alternatives to reduce the circulatory plasma concentration, directing the drug to the action site than reducing many of the collateral effects. The objective of this study was to characterize and evaluate the anti-inflammatory activity of two polimeric implantable devices containing diclofenac sodium in a model of induced osteoarthritis by carragenina in the knees of Wistar rats. It was produced two implantable devices containing diclofenac sodium, the first one obtained by blending of EUDAGRIT RS 100 and PEG400, called EUDPEG, and the other one containing EUDRAGRIT RS 100 and PCL-T, called EUDPCL-T. The materials were characterized by optic microscope and thermodynamic analysis (DMA) and the release mechanism determined within a phosphate buffer pH 7.4. After characterizing, the devices was implanted EUDPCL-T (3,0 mg of Sodium diclofenaco) and EUDPEG (3,6 mg of sodium diclofenaco) in the articulation in the posterior knee region and after 4 days it was induced the knee edema by the injection of carragenina. In the 6th hour and 7 days after the inducing the animals received anesthesia and the edema was measured by the variation of the knee circumference, followed by sacrifice for the analysis of the inflammatory mediators, MPO and nitric oxide within the articulation, it was also evaluated the number of gastric lesions. The optic microscopy showed that the EUDPEG film is totally transparent due to the solubility of diclofenac in the polymeric matrix and shows a mechanical plastic behavior with less capacity of deformation. For the EUDPCL-T film it was observed a totally opaque film associated with diclofenac sodium crystallization in the polymeric matrix and shows deformation variation due to tension characteristic of elastomeric material. The in vitro studies of diclofenac sodium releases by the films showed two distinct phases of release for both polymeric films, one fast release phase, which lasted 24 hours, where EUDPEG showed faster release , and one slow phase where the inversion of release speed was observed. EUDPCL-T showed a tendency of increase in quantity released by time when compared to EUDPEG. The EUDPCL-T device promoted statistically significant reduction (p<0,05) of the edema and the MPO concentration when compared to the group that didn¿t received treatment, 6 hours 7 days after the edema induction while the group that received oral treatment, showed significant difference only seven days after the osteoarthritis induction. The EUDPEG device also reduced the edema only after seven days of osteoarthritis induction but wasn¿t able to reduce the MPO concentration. When the measures of the knee circumference were taken in the 7th day after osteoarthritis induction, all the treated groups showed edema reduction when compared to the group that only received carragenina. The MPO activity was lesser in the EUDPCL-T group with a statistically significant difference when compared to the CRGN group in the sixth hour seven days later of osteoarthritis induction, while the DICL group showed difference only after seven days of osteoarthritis induction. In the nitrates/nitrites research six hours after osteoarthritis induction only the EUDPEG and EUDPCLT groups showed significant statistical difference when compared to the CRGN group, seven days after osteoarthritis induction none group showed statistical difference with the CRGN group. The results showed that the device implantation delivers the diclofenac sodium at the joint, promoted the same activity in reducing edema and inflamatory markers when compared to the oral administration, but with much inferior doses.
Among the options to treat osteoarthritis there is the use of non-steroidal anti-inflammatory, always with the recommendation of using the least effective dose in the shortest time possible. It is suggested because the adverse effects in the gastrointestinal, cardio circulatory and renal systems are well known. The use of different systems of drug releases like implantable devices has propitiated alternatives to reduce the circulatory plasma concentration, directing the drug to the action site than reducing many of the collateral effects. The objective of this study was to characterize and evaluate the anti-inflammatory activity of two polimeric implantable devices containing diclofenac sodium in a model of induced osteoarthritis by carragenina in the knees of Wistar rats. It was produced two implantable devices containing diclofenac sodium, the first one obtained by blending of EUDAGRIT RS 100 and PEG400, called EUDPEG, and the other one containing EUDRAGRIT RS 100 and PCL-T, called EUDPCL-T. The materials were characterized by optic microscope and thermodynamic analysis (DMA) and the release mechanism determined within a phosphate buffer pH 7.4. After characterizing, the devices was implanted EUDPCL-T (3,0 mg of Sodium diclofenaco) and EUDPEG (3,6 mg of sodium diclofenaco) in the articulation in the posterior knee region and after 4 days it was induced the knee edema by the injection of carragenina. In the 6th hour and 7 days after the inducing the animals received anesthesia and the edema was measured by the variation of the knee circumference, followed by sacrifice for the analysis of the inflammatory mediators, MPO and nitric oxide within the articulation, it was also evaluated the number of gastric lesions. The optic microscopy showed that the EUDPEG film is totally transparent due to the solubility of diclofenac in the polymeric matrix and shows a mechanical plastic behavior with less capacity of deformation. For the EUDPCL-T film it was observed a totally opaque film associated with diclofenac sodium crystallization in the polymeric matrix and shows deformation variation due to tension characteristic of elastomeric material. The in vitro studies of diclofenac sodium releases by the films showed two distinct phases of release for both polymeric films, one fast release phase, which lasted 24 hours, where EUDPEG showed faster release , and one slow phase where the inversion of release speed was observed. EUDPCL-T showed a tendency of increase in quantity released by time when compared to EUDPEG. The EUDPCL-T device promoted statistically significant reduction (p<0,05) of the edema and the MPO concentration when compared to the group that didn¿t received treatment, 6 hours 7 days after the edema induction while the group that received oral treatment, showed significant difference only seven days after the osteoarthritis induction. The EUDPEG device also reduced the edema only after seven days of osteoarthritis induction but wasn¿t able to reduce the MPO concentration. When the measures of the knee circumference were taken in the 7th day after osteoarthritis induction, all the treated groups showed edema reduction when compared to the group that only received carragenina. The MPO activity was lesser in the EUDPCL-T group with a statistically significant difference when compared to the CRGN group in the sixth hour seven days later of osteoarthritis induction, while the DICL group showed difference only after seven days of osteoarthritis induction. In the nitrates/nitrites research six hours after osteoarthritis induction only the EUDPEG and EUDPCLT groups showed significant statistical difference when compared to the CRGN group, seven days after osteoarthritis induction none group showed statistical difference with the CRGN group. The results showed that the device implantation delivers the diclofenac sodium at the joint, promoted the same activity in reducing edema and inflamatory markers when compared to the oral administration, but with much inferior doses.
Palavras-chave
Artrite, Osteoartrite, Agentes antiinflamatórios, Joelhos, Osteoartrite - Tratamento