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limitam o uso na terapia clínica, como agranulocitose, cardiotoxicidade e hepatotoxicidade.
oxidativo, tornando-a um fármaco mais seguro aos pacientes.
Palavras-chave: esquizofrenia, clozapina, nanossistemas, vias de estresse oxidativo.
clozapine-loaded chitosan-coated or polyethyleneglycol-coated nanocapsules (25 mg/Kg i.p.).
Keywords: schizophrenia, clozapine, nanosystems, oxidative stress pathways.
comentários gerais sobre os resultados mostrados nos manuscritos deste trabalho. No item PERSPECTIVAS, estão expostos os possíveis estudos para dar continuidade a este trabalho.
Os RL induzem o estresse oxidativo e danos em todos os tipos de moléculas biológicas e podem estar envolvidos na patologia da esquizofrenia (HALLIWELL, 2006; DIETRICH- MUSZALKA & OLAS, 2009; HALLIWELL, 2012a; 2012b). O cérebro e o SNC são propensos ao estresse oxidativo, pois estão insuficientemente equipados com sistemas de defesa antioxidante para prevenir o dano oxidativo imposto pelas doenças neurodegenerativas (HALLIWELL, 2006). Em pacientes esquizofrênicos ocorre a desregulação do metabolismo de ERO e ERN, tal processo pode ser verificado através das análises das atividades anormais das enzimas antioxidantes, além de outros biomarcadores de estresse oxidativo como a peroxidação lipídica em plasma, glóbulos vermelhos, plaquetas e/ou líquido cefalorraquidiano (REDDY & YAO, 1996; YAO et al., 1998; DIETRICH-MUSZALKA, OLAS & RABE-JABLONSKA, 2005). Tais achados tem sido associados com discinesia tardia, sintomas negativos e sinais neurológicos (LI et al., 2006). Estudos sugerem que o excesso de formação de ERO pode desempenhar um papel crucial na etiologia da esquizofrenia. A disfunção da membrana celular causada pela peroxidação lipídica pode ser secundária a uma patologia mediada por RL e pode contribuir para a sintomatologia e complicações do tratamento. Estudos realizados por meio da avaliação da atividade da enzima antioxidante SOD em plaquetas evidenciaram a indução de estresse oxidativo em pacientes esquizofrênicos, sugerindo que a supressão da atividade da SOD em pacientes com esquizofrenia está associada com maior geração de ERO e da peroxidação lipídica (DIETRICH-MUSZALKA, OLAS & RABE-JABLONSKA, 2005).
Dentre os sistemas carreadores de fármacos, os sistemas nanoparticulados, compostos que apresentam diâmetro entre 10 e 1000 nm, tem despertado atenção devido às suas vantagens como vetores, destacando-se os lipossomas e as partículas poliméricas (COUVREUR, FATAL & ANDREMONT, 1991; SOPPIMATH et al., 2001).
a Difference between BNC x CNC (p < 0.05) b Difference between BCSN x CCSN (p < 0.05) c Difference between BPEGN x CPEGN (p < 0.05) The results of several hematological parameters evaluated are shown in figures following (Figure 1, Figure 2 and Figure 3). The findings demonstrated that CZP group had significantly decreased values (p < 0.05) compared to SAL group for RBC, as well as Hb and Ht indicates the cytotoxic potential of drug (Figure 1A, 1B and 1C, respectively). The groups treated with nanossystems got better and significant results for RBC and Hb compared to CZP group. The nanocapsules coated with CS and PEG were statistically different of uncoated nanocapsules, obtaining better results for RBC. In Hb parameter coating with PEG got better performance. However, the groups that received nanocapsules showed a significant decrease in Ht. Figure 1D shows the MCV values for all treated groups were significantly different compared to SAL group, but was only BPEGN was statistically different of CZP group. Figure 1E shows values for MCH, as BNC as CPEGN and nanocapsules coated with CS were significantly different of SAL group. All treated groups nanosystems were statistically different of CZP group. Figure 1F shows values for MCHC as BNC as BCSN and BPEGN differed significantly of SAL and CZP group, already CPEGN group differ only CZP group. Finally, in Figure 1G are values for RDW where BCSN group was statistically diferent of SAL and CZP group, and BPEGN group different only CZP group. FIGURE 1 - Hematological parameters of red blood cells in Wistar rats exposed to different nanosystems treatments. In A: values for RBC; B: values for Hb; C: values for Ht; D: values for MCV; E: values for MCH; F: values for MCHC; G: values for RDW. SAL: saline solution; CZP: clozapine free; BNC: blank uncoated nanocapsules; CNC: clozapine-loaded uncoated nanocapsules; BCSN: blank chitosan-coated nanocapsules; CCSN: clozapine-loaded chitosan-coated nanocapsules; BPEGN: blank polyethyleneglycol-coated nanocapsules; CPEGN: clozapina-loaded polyethyleneglycol-coated nanocapsules. a Significantly different SAL (p < 0.05); b Significantly different CZP (p < 0.05); c Significantly different BNC and CNC (p < 0.05); d Significantly different BCSN and CCSN (p < 0.05). The values for WBC and differential leukocyte counts are shown in Figure 2. CZP group had parameters significantly decreased (p <0.05) for WBC, as well as neutrophilic, monocytic and lymphocytic series, however a significant increase was observed for eosinophilic serie (Figure 2A, Figure 2B, Figure 2C and Figure 2D, respectively). All groups treated with nanosystems got better and significant results when compared with CZP group for WBC, the nanocapsules coated CS and PEG were statistically different of uncoated nanocapsules getting better results, coat with CS was the best performance (Figure 2A). All groups treated with nanosystems were significantly different when compared to CZP group for differential count of neutrophils, the nanocapsules coated with PEG had a significant increased of neutrophilic serie and significantly different of the others and nanocapsules (Figure 2B). All treated groups, except BPEGN group, had significantly decreased values lymphocytic serie when compared with SAL group. Except CCSN group, all groups treated with nanosystems had better results than CZP group to lymphocytic serie (Figure 2C). The group that received CS-coated nanocapsules showed an increase in monocytic and basophilic series significantly higher than SAL and CZP groups, as well as differed significantly of the other nanocapsules (Figure 2D and Figure 2F). All groups were treated with nanosystems were significantly different when compared with SAL and CZP groups in eosinophilic series, CPEGN group showed an increase in eosinophilic series significantly higher compared to the other groups (Figure 2E). FIGURE 2 - Hematological parameters of white blood cells in Wistar rats exposed to different nanosystems treatments. In A: values for WBC; B: values for Neutrophils; C: values for Lymphocytes; D: values for Monocytes; E: values for Eosinophils; F: values for Basophils. SAL: saline solution; CZP: clozapine free; BNC: blank uncoated nanocapsules; CNC: clozapine-loaded uncoated nanocapsules; BCSN: blank chitosan-coated nanocapsules; CCSN: clozapine-loaded chitosan-coated nanocapsules; BPEGN: blank polyethyleneglycol-coated nanocapsules; CPEGN: clozapina-loaded polyethyleneglycol-coated nanocapsules. a Significantly different SAL (p < 0.05); b Significantly different CZP (p < 0.05); c Significantly different BNC and CNC (p < 0.05); d Significantly different BCSN and CCSN (p < 0.05). The global parameters MPV and platelet count are shown in Figure 3. All treatment groups were significantly different when compared to SAL group. The uncoated nanocápsulas, coated with CS and BPEGN groups were significantly different when compared to CZP group (Figure 3A). BNC and CCSN group were significantly different SAL and CZP groups. BCSN group showed differences only CZP group. Nanocapsules coated with CS were different of the other nanosystems (Figure 3B). FIGURE 3 - Hematological parameters of plaquets in Wistar rats exposed to different nanosystems treatments. In A: values for Plaquets; B: values for MPV. SAL: saline solution; CZP: clozapine free; BNC: blank uncoated nanocapsules; CNC: clozapine-loaded uncoated nanocapsules; BCSN: blank chitosan-coated nanocapsules; CCSN: clozapine-loaded chitosan-coated nanocapsules; BPEGN: blank polyethyleneglycol-coated nanocapsules; CPEGN: clozapina-loaded polyethyleneglycol-coated nanocapsules. a Significantly different SAL (p < 0.05); b Significantly different CZP (p < 0.05); c Significantly different BNC and CNC (p < 0.05); d Significantly different BCSN and CCSN (p < 0.05). The results for CK, CK-MB and homocysteine analysis are shown in Figure 4. The result for CK showed that there was a significant increase (p < 0.05) in all treated groups when compared with SAL group, however all groups treated with nanosystems showed a significant improvement when compared CZP group, being nanocapsules with CS-coated the best performance (Figure 4A). CK-MB there was a significant increase induced by CZP group, the groups treated with different nanosystems showed a significant improvement in the CK-MB, and groups treated with nanocapsules uncoated and CS-coated the best results (Figure 4B). The results for homocysteine there was a significant increase induced by CZP group, however when linked to the nanosystems there was a significant decrease in these levels, again the group treated with CS-coated nanocapsules had better results (Figure 4C). FIGURE 4 – Markers cardiac function in Wistar rats exposed to different nanosystems treatments. In A: values for CK; B: values for CK-MB; C: values for Homocysteine. SAL: saline solution; CZP: clozapine free; BNC: blank uncoated nanocapsules; CNC: clozapine-loaded uncoated nanocapsules; BCSN: blank chitosan-coated nanocapsules; CCSN: clozapine-loaded chitosan-coated nanocapsules; BPEGN: blank polyethyleneglycol-coated nanocapsules; CPEGN: clozapina-loaded polyethyleneglycol-coated nanocapsules. a Significantly different SAL (p < 0.05); b Significantly different CZP (p < 0.05). The results for GOT and GPT are showed in Figure 5. The result for GOT demonstrate that there was a significant increase (p < 0.05) of the parameters evaluated induced by CZP group, as well as for GPT (Figure 5A, Figure 5B, respectively). All groups treated with nanossystems showed a significant improvement in markers liver function in relation to CZP group. The group treated with CS-coated nanocapsules obtained better results. FIGURE 5 – Markers hepatic function in Wistar rats exposed to different nanosystems treatments. In A: values for GOT; B: values for GPT. SAL: saline solution; CZP: clozapine free; BNC: blank uncoated nanocapsules; CNC: clozapine-loaded uncoated nanocapsules; BCSN: blank chitosan-coated nanocapsules; CCSN: clozapine-loaded chitosan-coated nanocapsules; BPEGN: blank polyethyleneglycol-coated nanocapsules; CPEGN: clozapina-loaded polyethyleneglycol-coated nanocapsules. a Significantly different SAL (p < 0.05); b Significantly different CZP (p < 0.05). The results for the analysis of urea and creatinine are showed in Figure 6. The results of treated groups to urea is present similar to SAL and CZP group suggesting that nanoparticles systems are not nephrotoxic, with the exception of the groups treated with nano- coated with CS (Figure 6A). For creatinine results were significantly decreased compared to SAL group, as well as groups receiving uncoated nanocápsulas, coated with PEG and CCNS were significantly decreased compared CZP group (Figure 6B). FIGURE 6 – Markers renal function in Wistar rats exposed to different nanosystems treatments. In A: values for Urea; B: values for Creatinine. SAL: saline solution; CZP: clozapine free; BNC: blank uncoated nanocapsules; CNC: clozapine-loaded uncoated nanocapsules; BCSN: blank chitosan-coated nanocapsules; CCSN: clozapine-loaded chitosan-coated nanocapsules; BPEGN: blank polyethyleneglycol-coated nanocapsules; CPEGN: clozapina-loaded polyethyleneglycol-coated nanocapsules. a Significantly different SAL (p < 0.05); b Significantly different CZP (p < 0.05).
In Figure 7 are showed images of histopathological findings of heart, the histological evaluation revealed that the group receiving CZP had significant changes in organ, as heart congestion and relaxation of cells cardiac. FIGURE 7 – Histopathological analysis of heart in Wistar rats exposed to different nanosystems treatments. In A: SAL group; B: CZP group; C: BNC group; D: CNC group; E: BCSN group; F: CCSN group; G: BPEGN group; H: CPEGN group. SAL: saline solution; CZP: clozapine free; BNC: blank uncoated nanocapsules; CNC: clozapine-loaded uncoated nanocapsules; BCSN: blank chitosan-coated nanocapsules; CCSN: clozapine-loaded chitosan-coated nanocapsules; BPEGN: blank polyethyleneglycol-coated nanocapsules; CPEGN: clozapina-loaded polyethyleneglycol-coated nanocapsules. In Figure 8 are showed images of histopathological findings of the liver. The histological evaluation revealed that the group receiving CZP had significant changes in organ, as liver necrosis. FIGURE 8 – Histopathological analysis of liver in Wistar rats exposed to different nanosystems treatments. In A: SAL group; B: CZP group; C: BNC group; D: CNC group; E: BCSN group; F: CCSN group; G: BPEGN group; H: CPEGN group. SAL: saline solution; CZP: clozapine free; BNC: blank uncoated nanocapsules; CNC: clozapine-loaded uncoated nanocapsules; BCSN: blank chitosan-coated nanocapsules; CCSN: clozapine-loaded chitosan-coated nanocapsules; BPEGN: blank polyethyleneglycol-coated nanocapsules; CPEGN: clozapina-loaded polyethyleneglycol-coated nanocapsules.
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