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.(AU)
Subject(s)
Animals , Rabbits , Rats , Cetuximab/analysis , Biosimilar Pharmaceuticals/analysis , Macaca fascicularis , Drug Evaluation, Preclinical/trendsABSTRACT
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.
Subject(s)
Humans , Animals , Male , Female , Rabbits , Rats , Biosimilar Pharmaceuticals/toxicity , Cetuximab/toxicity , Antineoplastic Agents, Immunological/toxicity , Reference Values , Time Factors , Immunohistochemistry , Cardiovascular System/drug effects , Models, Animal , Drug Evaluation, Preclinical/methods , Biosimilar Pharmaceuticals/administration & dosage , Cetuximab/administration & dosage , Antineoplastic Agents, Immunological/administration & dosage , Kidney/drug effects , Kidney Function Tests , Macaca fascicularis , Nervous System/drug effectsABSTRACT
Characterization of biological parameters is essential to assess the sanitary conditions of animal breeding, especially when it comes to closed colonies, such as this study. Data from biometrics, semiologic and hematological evaluation were compared between sex and age groups. Adult animals have become longer in stature over the years in captivity and adult females show considerably smaller and lighter than adult males. The tails of males were significantly higher in adult males. The average temperature was 38.5°C. Heart rate remained homogeneous in the three age groups of both sexes and did not vary among age groups as observed in respiratory rate (RR), which may have been due to physical restraint and anesthesia with ketamine hydrochloride. The RR was significantly higher in juvenile animals. With the exception of eosinophilia, present in adults, all hematologic findings were within normal limits. These data indicate that the condition of the captive colony closed under study, as well as the adopted management does not produce anomalous results or unsatisfactory on clinical parameters and biometric analysis.(AU)
A caracterização de parâmetros biológicos é imprescindível para avaliar as condições sanitárias de uma criação animal, principalmente quando se trata de colônias fechadas, como a do referido estudo. Assim, com o intuito de avaliar os dados fisiológicos de primatas cativos mantidos neste sistema de criação, o trabalho aqui exposto avaliou dados biométricos, semiológicos e hematológicos de um total de 72 macacos Cynomolgus (Macaca fascicularis) no período de dois anos consecutivos, visando garantir as características originais intrínseca da espécie. Os dados provenientes da biometria, avaliação semiológica e hematológica foram comparadas entre sexos e faixas etárias. Os animais adultos se tornaram de estatura menos longelínea ao longo dos anos em cativeiro e as fêmeas adultas se mostram consideravelmente menores e mais leves que os machos adultos. As caudas dos machos foram significativamente maiores nos machos adultos. A média da temperatura foi de 38.5ºC. A frequência cardíaca manteve-se homogênea nas três faixas etárias de ambos os sexos e não apresentou variação entre as faixas etárias como observado na frequência respiratória (FR), fato que pode ter sido em decorrência da contenção física e da anestesia com cloridrato de cetamina. A FR foi significativamente mais elevada em animais juvenis. Com exceção da eosinofilia, presente nos adultos, todos os resultados hematológicos estiveram dentro dos parâmetros de normalidade. Estes dados indicam que a condição de cativeiro da colônia fechada sob estudo, bem como o manejo adotado não produz resultados anômalos ou insatisfatórios sobre os parâmetros clínicos e biométricos analisados.(AU)
Subject(s)
Animals , Macaca fascicularis , Diagnosis of Health Situation , Clinical Laboratory Techniques , Biometry , Hematology , Animals, Laboratory , Models, AnimalABSTRACT
Characterization of biological parameters is essential to assess the sanitary conditions of animal breeding, especially when it comes to closed colonies, such as this study. Data from biometrics, semiologic and hematological evaluation were compared between sex and age groups. Adult animals have become longer in stature over the years in captivity and adult females show considerably smaller and lighter than adult males. The tails of males were significantly higher in adult males. The average temperature was 38.5°C. Heart rate remained homogeneous in the three age groups of both sexes and did not vary among age groups as observed in respiratory rate (RR), which may have been due to physical restraint and anesthesia with ketamine hydrochloride. The RR was significantly higher in juvenile animals. With the exception of eosinophilia, present in adults, all hematologic findings were within normal limits. These data indicate that the condition of the captive colony closed under study, as well as the adopted management does not produce anomalous results or unsatisfactory on clinical parameters and biometric analysis.
A caracterização de parâmetros biológicos é imprescindível para avaliar as condições sanitárias de uma criação animal, principalmente quando se trata de colônias fechadas, como a do referido estudo. Assim, com o intuito de avaliar os dados fisiológicos de primatas cativos mantidos neste sistema de criação, o trabalho aqui exposto avaliou dados biométricos, semiológicos e hematológicos de um total de 72 macacos Cynomolgus (Macaca fascicularis) no período de dois anos consecutivos, visando garantir as características originais intrínseca da espécie. Os dados provenientes da biometria, avaliação semiológica e hematológica foram comparadas entre sexos e faixas etárias. Os animais adultos se tornaram de estatura menos longelínea ao longo dos anos em cativeiro e as fêmeas adultas se mostram consideravelmente menores e mais leves que os machos adultos. As caudas dos machos foram significativamente maiores nos machos adultos. A média da temperatura foi de 38.5ºC. A frequência cardíaca manteve-se homogênea nas três faixas etárias de ambos os sexos e não apresentou variação entre as faixas etárias como observado na frequência respiratória (FR), fato que pode ter sido em decorrência da contenção física e da anestesia com cloridrato de cetamina. A FR foi significativamente mais elevada em animais juvenis. Com exceção da eosinofilia, presente nos adultos, todos os resultados hematológicos estiveram dentro dos parâmetros de normalidade. Estes dados indicam que a condição de cativeiro da colônia fechada sob estudo, bem como o manejo adotado não produz resultados anômalos ou insatisfatórios sobre os parâmetros clínicos e biométricos analisados.
Subject(s)
Animals , Biometry , Diagnosis of Health Situation , Hematology , Macaca fascicularis , Clinical Laboratory Techniques , Animals, Laboratory , Models, AnimalABSTRACT
The aim was to understand the anatomical features of the venous valve in Macaca fascicularis and to compare it with that of humans. The bilateral lower limbs (24 limbs from 12 animals) of Macaca fascicularis cadavers were dissected, and the femoral veins (FVs) were equally divided into distal, intermediate, and proximal sections. The external diameter of the FV in each section was measured. The venous valves were observed microscopically and stained with hematoxylin and eosin as well as trichrome. Data describing the human venous valve were collected from the current literature. No great saphenous veins were found among the 24 lower limbs from the Macaca fascicularis cadavers. The external diameters of the FVs in the distal, intermediate, and proximal sections were 3.53 ± 0.37 mm, 3.42 ± 0.55 mm, and 3.37 ± 0.54 mm, respectively. In most cases, there was one venous bivalve located in the FV approximately 0-2.71 mm below the junction of the FV and the deep femoral vein. Endothelium covered the luminal and sinusal surfaces of the leaflets. Abundant collagen fibers were found under the endothelial cells beneath the luminal surface of the leaflets. An elastin fiber network was located under the sinus endothelial surface. Smooth muscle cells in the FV extend to the edge of the valve. The venous valve of Macaca fascicularis is similar to that of humans, both morphologically and histologically. However, there is only one venous bivalve and no great saphenous vein in Macaca fascicularis.
El objetivo fue comprender las características anatómicas de la válvula venosa en Macaca fascicularis y compararla con la de los humanos. Fueron disecados bilateralmente los miembros pélvicos (24 miembros de 12 animales) de cadáveres de Macaca fascicularis; las venas femorales (VF) fueron divididas en secciones distal, media y proximal. Se midió el diámetro externo de las VFs en cada sección. Las válvulas venosas se observaron microscópicamente y se tiñeron con H-E y tricrómico. Los datos para describir la válvula venosa humana se obtuvieron desde la literatura. No se encontraron venas safenas magnas entre los 24 miembros inferiores. Los diámetros externos de las VFs en las secciones distal, media y proximal fueron 3,53±0,37 mm, 3,42 mm±0,55, y 3,37±0,54 mm, respectivamente. En la mayoría de los casos, hubo vena bivalva situada aproximadamente 0-2,71 mm debajo de la unión de la VF y la vena femoral profunda. El endotelio cubrió las superficies luminal y sinusal. Se observaron abundantes fibras de colágeno en las células endoteliales bajo la superficie luminal de las válvulas. Una red de fibras de elastina se encontró bajo la superficie del seno endotelial. Las células musculares lisas en las VFs se extiendían hasta el margen de la válvula. La válvula venosa del Macaca fascicularis es similar a la de los seres humanos, morfológica e histológicamente. Sin embargo, sólo hubo una vena bivalvular, y no se observaron venas safenas en Macaca fascicularis.