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1.
Exp Eye Res ; 238: 109715, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37951338

RESUMO

This study aimed to examine the intraocular tolerability of the epidermal growth factor receptor antibody cetuximab, when applied intravitreally, and its effect on axial elongation. Guinea pigs aged 2-3 weeks were subjected to bilateral plano glasses and bilateral lens-induced myopization (LIM) as a single procedure for group I (n = 8) and group II (n = 8), respectively. In the animals of group III (n = 8), group IV (n = 8), and group V (n = 8), the right eyes of the animals, in addition to LIM, received four weekly intravitreal injections of cetuximab (Erbitux®) in doses of 6.25 µg, 12.5 µg, and 25 µg, respectively. As controls, the left eyes, in addition to LIM, received corresponding intraocular injections of phosphate-buffered saline. The animals underwent regular ophthalmoscopic examinations and biometry for axial length measurements. With increasing doses of cetuximab, the inter-eye difference in axial elongation (at study end, left eyes minus right eyes) were significantly the smallest in group I (0.00 ± 0.02 mm) and group II (-0.01 ± 0.02 mm), they were larger in group III (0.04 ± 0.04 mm) and group IV (0.10 ± 0.03 mm), and they were the largest in group V (0.11 ± 0.01 mm). The inter-eye difference in axial elongation enlarged (P < 0.001) with the number of injections applied. Retinal thickness at the posterior pole (right eyes) was significantly thicker in group V than in group II (P < 0.01). The density of apoptotic cells (visualized by TUNEL-staining) did not vary significantly between any of the groups (all P > 0.05). The results suggest that intravitreal injections of cetuximab in young guinea pigs with LIM resulted in a reduction in axial elongation in a dose-dependent and number of treatment-dependent manner. Intraocular toxic effects, such as intraocular inflammation, retinal thinning, or an increased density of apoptotic cells in the retina, were not observed in association with the intravitreally applied cetuximab.


Assuntos
Cristalino , Miopia , Cobaias , Animais , Miopia/metabolismo , Cetuximab/toxicidade , Cetuximab/metabolismo , Retina/metabolismo , Cristalino/metabolismo , Injeções Intraoculares , Modelos Animais de Doenças
2.
Monaldi Arch Chest Dis ; 89(3)2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31508927

RESUMO

Organizing pneumonia (OP) may be idiopathic or secondary to a variety of causes including drugs. OP and other forms of pulmonary toxicity secondary to cetuximab, however, have been described rarely. It is paramount to recognize and differentiate OP from other common conditions that cancer patients are prone to such as infection and pulmonary embolism. A 69-year-old man with colorectal cancer received ten cycles of palliative chemotherapy [FOLFIRI (5-Fluorouracil, Leucovorin, Irinotecan) and cetuximab] with clinical and radiological response. He developed dyspnea following cycle 4, then 6 weeks later presented with cough, fever, tachypnea, hypoxia, bilateral crackles and diffuse pulmonary shadows. He was started on antibiotics but his condition deteriorated further. Cultures, including blood and bronchioalveolar lavage, grew no pathogens and molecular analysis and cytology for bacteria viruses were negative. Trans-bronchial biopsy was consistent with organizing pneumonia. Treatment with corticosteroids resulted in dramatic clinical and radiological resolution with normalization of gas exchange and pulmonary function. Corticosteroids were stopped and he was restarted on FOLFIRI and remained well with no relapse over a year of follow up. Although pulmonary toxicity secondary to cetuximab is uncommon, it is important to recognize, as it may be associated with poor prognosis. To the best of our knowledge, this is the first report of OP attributed to cetuximab with histopathological evidence.


Assuntos
Antineoplásicos Imunológicos/toxicidade , Cetuximab/toxicidade , Neoplasias Colorretais/tratamento farmacológico , Pneumonia em Organização Criptogênica/induzido quimicamente , Dispneia/etiologia , Corticosteroides/administração & dosagem , Corticosteroides/uso terapêutico , Idoso , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Cetuximab/efeitos adversos , Cetuximab/uso terapêutico , Pneumonia em Organização Criptogênica/tratamento farmacológico , Pneumonia em Organização Criptogênica/patologia , Humanos , Masculino , Resultado do Tratamento
3.
Acta Cir Bras ; 33(8): 690-702, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30208131

RESUMO

PURPOSE: To evaluate the toxicity of Erbitux as well as its biosimilar APZ001 antibody (APZ001) in pre-clinical animal models including mice, rabbits and cynomolgus monkeys. METHODS: We performed analysis of normal behavior activity, autonomic and non-autonomic nervous functions, nervous-muscle functions, nervous excitability and sensorimotor functions on CD-1 mice. Subsequently, we studied that effects of APZ001 and Erbitux on respiratory system, cardiovascular system and kidney in Cynomolgus monkey models and performed local tolerance experiments on New Zealand rabbits. RESULTS: The comparisons between APZ001 and Erbitux showed no significant differences in mice autonomic nervous system, nervous muscle functions, non-autonomic nervous functions, nervous excitability and sensorimotor functions between treated and untreated group (p>0.05). APZ001 and Erbitux showed negative effect on CD-1 mice in the present of pentobarbital sodium anesthesia (p>0.05). Single administrations of high, medium or low doses of APZ001 did not lead to monkey urine volume alterations (p>0.05). In human tissues, APZ001 and Erbitux showed positive signals in endocardium, lung type II alveolar epithelial cell and surrounding vessels, but showed negative results in kidney and liver tissues. No hemolysis phenomenon and serious side-effects in vessels and muscles were observed in rabbits when administrated with APZ001 and Erbitux respectively. CONCLUSION: The safety comparisons between APZ001 antibody and Erbitux showed that these two antibodies showed highly similarities in mice, rabbits and cynomolgus monkey animal models in consideration of pharmaceutical effects, indicating APZ001 might be a suitable substitute for Erbitux.


Assuntos
Antineoplásicos Imunológicos/toxicidade , Medicamentos Biossimilares/toxicidade , Cetuximab/toxicidade , Animais , Antineoplásicos Imunológicos/administração & dosagem , Medicamentos Biossimilares/administração & dosagem , Sistema Cardiovascular/efeitos dos fármacos , Cetuximab/administração & dosagem , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Humanos , Imuno-Histoquímica , Rim/efeitos dos fármacos , Testes de Função Renal , Macaca fascicularis , Masculino , Camundongos , Modelos Animais , Sistema Nervoso/efeitos dos fármacos , Coelhos , Valores de Referência , Sistema Respiratório/efeitos dos fármacos , Fatores de Tempo
4.
Acta cir. bras ; 33(8): 690-702, Aug. 2018. tab, graf
Artigo em Inglês | LILACS | ID: biblio-949376

RESUMO

Abstract Purpose: To evaluate the toxicity of Erbitux as well as its biosimilar APZ001 antibody (APZ001) in pre-clinical animal models including mice, rabbits and cynomolgus monkeys. Methods: We performed analysis of normal behavior activity, autonomic and non-autonomic nervous functions, nervous-muscle functions, nervous excitability and sensorimotor functions on CD-1 mice. Subsequently, we studied that effects of APZ001 and Erbitux on respiratory system, cardiovascular system and kidney in Cynomolgus monkey models and performed local tolerance experiments on New Zealand rabbits. Results: The comparisons between APZ001 and Erbitux showed no significant differences in mice autonomic nervous system, nervous muscle functions, non-autonomic nervous functions, nervous excitability and sensorimotor functions between treated and untreated group (p>0.05). APZ001 and Erbitux showed negative effect on CD-1 mice in the present of pentobarbital sodium anesthesia (p>0.05). Single administrations of high, medium or low doses of APZ001 did not lead to monkey urine volume alterations (p>0.05). In human tissues, APZ001 and Erbitux showed positive signals in endocardium, lung type II alveolar epithelial cell and surrounding vessels, but showed negative results in kidney and liver tissues. No hemolysis phenomenon and serious side-effects in vessels and muscles were observed in rabbits when administrated with APZ001 and Erbitux respectively. Conclusion: The safety comparisons between APZ001 antibody and Erbitux showed that these two antibodies showed highly similarities in mice, rabbits and cynomolgus monkey animal models in consideration of pharmaceutical effects, indicating APZ001 might be a suitable substitute for Erbitux.


Assuntos
Humanos , Animais , Masculino , Feminino , Coelhos , Ratos , Medicamentos Biossimilares/toxicidade , Cetuximab/toxicidade , Antineoplásicos Imunológicos/toxicidade , Valores de Referência , Fatores de Tempo , Imuno-Histoquímica , Sistema Cardiovascular/efeitos dos fármacos , Modelos Animais , Avaliação Pré-Clínica de Medicamentos/métodos , Medicamentos Biossimilares/administração & dosagem , Cetuximab/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Rim/efeitos dos fármacos , Testes de Função Renal , Macaca fascicularis , Sistema Nervoso/efeitos dos fármacos
5.
Reprod Biomed Online ; 33(1): 102-10, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27184186

RESUMO

Epidermal growth factor receptor (EGFR) has proliferative properties in the testis. Cetuximab, an anti-EGFR, is administered together with chemotherapy to patients with various types of cancer. This studies aim was to investigate the effect of cetuximab on testicular function. Adult male mice were injected with cetuximab (10 mg/kg), cisplatin (8 mg/kg) or a combination of both, and killed one week or one month later. The doses were chosen by human equivalent dose calculation. Testicular function was evaluated by epididymal-spermatozoa total motile count and sperm motility, weights of testes and epididymides, and the level of anti-Müllerian hormone (AMH) in the serum. Immunohistochemistry was performed to examine germ cell proliferation (Ki-67), apoptosis (Terminal transferase-mediated deoxyuridine 5-triphosphate nick-end labelling), reserve (DAZL-Deleted in azoospermia-like, Promyelocytic leukaemia zinc-finger), blood vessels (CD34) and Sertoli cells (GATA-4). Administration of cetuximab alone increased testicular apoptosis and decreased epididymal-spermatozoa total motile count over time. When added to cisplatin, cetuximab exacerbated most of the recorded testicular parameters, compared with the effect of cisplatin alone, including testis and epididymis weights, epididymal-spermatozoa total motile count, AMH concentration, meiosis and apoptosis. In conclusion, cetuximab has only a mild effect on testicular reserve, but when added to cisplatin, it exacerbates cisplatin-induced testicular toxicity.


Assuntos
Cetuximab/toxicidade , Cisplatino/toxicidade , Testículo/efeitos dos fármacos , Animais , Hormônio Antimülleriano/metabolismo , Antígenos CD34/metabolismo , Antineoplásicos/uso terapêutico , Antineoplásicos/toxicidade , Apoptose , Biomarcadores/metabolismo , Cetuximab/administração & dosagem , Cisplatino/administração & dosagem , Epididimo/efeitos dos fármacos , Epididimo/metabolismo , Receptores ErbB/metabolismo , Fator de Transcrição GATA4/metabolismo , Marcação In Situ das Extremidades Cortadas , Antígeno Ki-67/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Células de Sertoli/efeitos dos fármacos , Células de Sertoli/metabolismo , Motilidade dos Espermatozoides/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Espermatozoides/metabolismo , Testículo/patologia , Testes de Toxicidade
6.
Oncotarget ; 6(11): 8788-806, 2015 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-25871395

RESUMO

Malignant gliomas remain aggressive and lethal primary brain tumors in adults. The epidermal growth factor receptor (EGFR) is frequently overexpressed in the most common malignant glioma, glioblastoma (GBM), and represents an important therapeutic target. GBM stem-like cells (GSCs) present in tumors are felt to be highly tumorigenic and responsible for tumor recurrence. Multifunctional magnetic iron-oxide nanoparticles (IONPs) can be directly imaged by magnetic resonance imaging (MRI) and designed to therapeutically target cancer cells. The targeting effects of IONPs conjugated to the EGFR inhibitor, cetuximab (cetuximab-IONPs), were determined with EGFR- and EGFRvIII-expressing human GBM neurospheres and GSCs. Transmission electron microscopy revealed cetuximab-IONP GBM cell binding and internalization. Fluorescence microscopy and Prussian blue staining showed increased uptake of cetuximab-IONPs by EGFR- as well as EGFRvIII-expressing GSCs and neurospheres in comparison to cetuximab or free IONPs. Treatment with cetuximab-IONPs resulted in a significant antitumor effect that was greater than with cetuximab alone due to more efficient, CD133-independent cellular targeting and uptake, EGFR signaling alterations, EGFR internalization, and apoptosis induction in EGFR-expressing GSCs and neurospheres. A significant increase in survival was found after cetuximab-IONP convection-enhanced delivery treatment of 3 intracranial rodent GBM models employing human EGFR-expressing GBM xenografts.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Cetuximab/farmacologia , Glioblastoma/tratamento farmacológico , Nanopartículas de Magnetita/administração & dosagem , Terapia de Alvo Molecular , Células-Tronco Neoplásicas/efeitos dos fármacos , Animais , Células Cultivadas , Cetuximab/administração & dosagem , Cetuximab/toxicidade , Portadores de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Glioblastoma/patologia , Humanos , Nanopartículas de Magnetita/toxicidade , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Proteínas de Neoplasias/análise , Neurônios/efeitos dos fármacos , Polietilenoglicóis/administração & dosagem , Esferoides Celulares , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Sci Rep ; 5: 8013, 2015 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-25622824

RESUMO

miRNA plays an important role in tumourgenesis by regulating expression of oncogenes and tumour suppressors. Thus affects cell proliferation and differentiation, apoptosis, invasion and angiogenesis. miRNAs are potential biomarkers for diagnosis, prognosis and therapies of different forms of cancer. However, relationship between response of cancer patients towards targeted therapy and the resulting modifications of the miRNA transcriptome in the context of pathway regulation is poorly understood. With ever-increasing pathways and miRNA-mRNA interaction databases, freely available mRNA and miRNA expression data in multiple cancer therapy have produced an unprecedented opportunity to decipher the role of miRNAs in early prediction of therapeutic efficacy in diseases. Efficient translation of -omics data and accumulated knowledge to clinical decision-making are of paramount scientific and public health interest. Well-structured translational algorithms are needed to bridge the gap from databases to decisions. Herein, we present a novel SMARTmiR algorithm to prospectively predict the role of miRNA as therapeutic biomarker for an anti-EGFR monoclonal antibody i.e. cetuximab treatment in colorectal cancer.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/tratamento farmacológico , MicroRNAs/metabolismo , Algoritmos , Anticorpos Monoclonais/toxicidade , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/genética , Diferenciação Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cetuximab/uso terapêutico , Cetuximab/toxicidade , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Receptores ErbB , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos
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