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1.
Curr Neurovasc Res ; 9(4): 233-8, 2012 Nov.
Article in English | MEDLINE | ID: mdl-22962865

ABSTRACT

The objective of this investigation was to assess the toxicological potential of nasal formulation of erythropoietin with low sialic acid content (Neuro EPO) after 28 days of intra-nasal dosing in rats besides to evaluate the immunogenicity and erythropoietic effect of the test substance. Healthy Wistar rats of both sexes were used for 28 days subacute toxicity and immunogenicity assays. Doses evaluated were 3450, 4830 and 6900 UI/kg/day. The toxicological endpoints examined included animal body weight, food consumption, hematological and biochemical patterns, antibodies determination, selected tissue weights and histopathological examination. Reversibility of toxic effects was evaluated at high dose 14 days after treatment period. Female B6D2F1 mice were used for evaluated erythropoietic effect of the nasal formulation. Hematological endpoints were examined every week during 28 days of intra-nasal dosing of 6900 UI/kg/day. Variations of hematological patterns were not observed after 28 days of intranasal dosing. A slight increase in glucose level of treated animals within the normal range was observed. This effect was not dose related and was reversible. Antibody formation was not observed in any of the test doses. Histopathological examination of organs and tissues did not reveal treatment induced changes. The administration of Neuro EPO in normocythaemic mice did not produce erythropoietic effect. These results suggest that Neuro EPO could be used as a neuroprotective agent, without significant systemic haematological side effects.


Subject(s)
Erythropoiesis/physiology , Erythropoietin/administration & dosage , N-Acetylneuraminic Acid/administration & dosage , Toxicity Tests, Acute , Administration, Intranasal , Animals , Drug Administration Schedule , Erythropoiesis/drug effects , Erythropoietin/toxicity , Female , Male , Mice , N-Acetylneuraminic Acid/toxicity , Rats , Rats, Wistar , Toxicity Tests, Acute/methods
2.
J Med Primatol ; 39(3): 177-86, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20345770

ABSTRACT

BACKGROUND: The purpose of this study is to better characterize the hematological, biochemical, respiratory, cardiovascular and electroneurophysiological parameters in young adult Cercopithecus aethiops sabaeus of both sexes. The rhesus and cynomolgus monkeys are widely used as experimental primate models. However, only few articles have been published testing toxicological effects of pharmaceuticals on African green monkey. METHODS: The present study was carried out with the recompilation of all parameters recorded before the first drug administration in five sub-chronic or chronic toxicological studies performed on 66 Cercopithecus aethiops sabaeus, born in Cuba. RESULTS: This study provides hematological, biochemical, respiratory, cardiovascular and electroneurophysiological data for both choosing animals to be included into experiments and monitoring these parameters during the study. CONCLUSIONS: We conclude that this study provides valuable integrated data for determining the health status, including electroneurophysiological parameters, data not previously reported for this species, of the African green monkey.


Subject(s)
Chlorocebus aethiops/physiology , Disease Models, Animal , Animals , Drug Evaluation, Preclinical , Evoked Potentials , Female , Male , Toxicity Tests , Vital Signs
4.
P R Health Sci J ; 27(1): 35-41, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18450231

ABSTRACT

Apoptosis seems to play an important role in cancer immunotherapy outcome. We have studied the kinetic pattern of apoptosis induction in H125 human lung carcinoma xenografts after treatment with the monoclonal antibody (MAb) anti-epidermal growth factor receptor (EGFr) IOR EGF/r3. Tumor-bearing nude mice were injected intravenously with a single 8 mg/kg dose of IOR EGF/r3 and tumor specimens were taken up to 30 days post treatment. Apoptosis was measured by morphometric analysis of the histological sections at each tumor specimen over time points. The results showed a significant apoptotic response in tumors within six days after injection of this MAb reaching a peak at 20 days post treatment. The kinetics were very broad, with apoptotic cells present over the entire time-frame. However, the time course of the apoptotic index showed a significant difference to the mitotic index. Finally, the MAb-induced apoptosis was related to tumor growth delay indicating a probable arrest of cell cycle and a corresponding inhibition of tumor progression, which was corroborated by the Ki67 and proliferating cell nuclear antigen (PCNA) biomarkers.


Subject(s)
Antibodies, Monoclonal/pharmacology , Apoptosis/drug effects , ErbB Receptors/immunology , Neoplasms/pathology , Animals , Humans , Male , Mice , Mice, Nude
5.
Cancer Immunol Immunother ; 56(11): 1701-10, 2007 Nov.
Article in English | MEDLINE | ID: mdl-17415565

ABSTRACT

Experimental evidences supporting the epidermal growth factor receptor (EGFR) as an important molecule for tumor metastasis had been accumulated. Currently, anti-EGFR monoclonal antibodies (mAbs) constitute a promising approach for the treatment of patients with metastatic tumors. However, the mechanisms associated with the potent anti-metastatic effect of these mAbs have not been completely elucidated due to the lack of appropriate syngeneic preclinical models. In this paper, we have investigated the effects of 7A7, an antibody specific to murine EGFR, on the metastatic properties of D122 murine lung carcinoma. 7A7 mAb significantly impaired metastatic spread of D122 cells in C57BL/6 mice by direct anti-proliferative and pro-apoptotic effects on tumor metastasis. 7A7 mAb capacity to inhibit EGFR activation on D122 cells could contribute to its anti-metastatic effect. In addition, 7A7 mAb was able to induce in vitro antibody-dependent cell-mediated cytotoxicity on D122 cells. Interestingly, 7A7 mAb treatment increased the number of natural killer cells, T lymphocytes and dendritic cells infiltrating the metastatic sites. More strikingly, depletion of CD8(+) and CD4(+) T cells in vivo completely abrogated the 7A7 mAb anti-metastatic activity whereas function of natural killer cells was irrelevant. This study supports an in vivo role for T cell response in the mechanism of action of anti-EGFR mAbs, suggesting the induction of an adjuvant effect.


Subject(s)
Antibodies, Monoclonal/pharmacology , Carcinoma, Lewis Lung/immunology , ErbB Receptors/immunology , Lung Neoplasms/immunology , Neoplasm Metastasis/immunology , Neoplasm Metastasis/prevention & control , T-Lymphocytes/immunology , Animals , Antineoplastic Agents/pharmacology , Carcinoma, Lewis Lung/drug therapy , Cell Line, Tumor , Cell Proliferation/drug effects , Disease Models, Animal , ErbB Receptors/antagonists & inhibitors , Lung Neoplasms/drug therapy , Mice , Mice, Inbred C57BL
6.
Immunobiology ; 210(1): 11-21, 2005.
Article in English | MEDLINE | ID: mdl-16076030

ABSTRACT

We have previously generated a murine anti-idiotype (Ab2) monoclonal antibody (mAb) to a murine Ab1 mAb, named P3, which selectively binds Neu-glycolyl (NeuGc)-sialic acid on several monosialo- and disialogangliosides, and also reacts with sulfatides and antigens expressed in human melanoma and breast tumors. This Ab2 mAb, designated as 1E10, induced anti-anti-idiotype antibodies (Ab3) in mice and cancer patients. These Ab3 generated by 1E10 mAb were characterized by bearing P3 mAb idiotopes (Ab3, Id +). But when the specificity of these Ab3 antibodies was tested, no specific humoral response against NeuGc-containing gangliosides was detected in sera from immunized mice. However, hyperimmune sera from melanoma and breast cancer patients vaccinated with this Ab2 mAb were able to react specifically with these gangliosides. The different expression of NeuGc-containing gangliosides in the normal tissues of mice and humans could explain these results. In order to demonstrate these findings in other animal species with a different NeuGc-sialic acid expression, we performed similar studies in monkeys and chickens. In monkeys, as in most mammals, NeuGc-containing gangliosides are self-antigens. In contrast, chickens, like humans, lack the expression of these antigens in normal tissues. Here we report that the antibody response against NeuGc-containing gangliosides induced by immunization with 1E10 mAb was completely different in both species. No specific antibody response against these gangliosides was detected in hyperimmune monkey sera. In contrast, a strong and specific Ab3 response against GM3(NeuGc) and GM2(NeuGc) gangliosides (Ab3, Ag+) was generated in chickens due to the administration of 1E10 mAb.


Subject(s)
Antibodies, Monoclonal/immunology , G(M2) Ganglioside/immunology , G(M3) Ganglioside/immunology , Immunization , Animals , Antibodies, Anti-Idiotypic/immunology , Antibodies, Monoclonal/metabolism , Antibody Specificity , Chickens/immunology , Flow Cytometry , Humans , Macaca/immunology , Species Specificity
7.
Eur J Pharm Sci ; 21(2-3): 261-70, 2004 Feb.
Article in English | MEDLINE | ID: mdl-14757498

ABSTRACT

The multiple-dose strategy with the monoclonal ior EGF/r3 antibody, in xenograft bearing nude mice, was supported upon the basis of its integrated pharmacokinetic-pharmacodynamic relationship, according to both the temporal (K(e0)=0.0015+/-0.000035h(-1)) and the time-independent sensitivity (C(50%)(ss), 9.23+/-0.17microg/ml; C(max,eff)(ss), 12.5microg/ml) components of its tumor growth delay action. This relationship was consistent with a sigmoidal E(max) pharmacodynamic model postulating a hypothetical effect compartment that permits us to estimate an effective steady-state concentration range (7.5-12microg/ml). Using this information we calculated both the cumulative and non-cumulative dosage regimens to compare their response patterns with respect to the control group. It follows that the differences in the estimated tumor growth inhibition ratio were statistically significant between the control group and either of the treated ones (P<0.05). The median survival time in treated mice under non-cumulative regimen (72+/-10 days), predicted an increase in this parameter as compared to the control one (55+/-6 days). Finally, using the allometric paradigm, the empiric power equation for dose scaling across mammalian species allowed the calculation of the dosage schedule for further clinical trial. The estimated maintenance dose in human (70kg) was 200mg/m(2) to be given weekly, and the corresponding loading dose was 600mg/m(2).


Subject(s)
Antibodies, Monoclonal/pharmacokinetics , ErbB Receptors/immunology , Animals , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/pharmacology , Carcinoma, Non-Small-Cell Lung/metabolism , Dose-Response Relationship, Drug , Humans , Injections, Intravenous , Lung Neoplasms/metabolism , Male , Mice , Mice, Nude , Time Factors , Xenograft Model Antitumor Assays/methods
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