The Experts below are selected from a list of 171 Experts worldwide ranked by ideXlab platform
Marize Campos Valadares - One of the best experts on this subject based on the ideXlab platform.
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Innovative strategy based on mechanisms to substitute animal testing for ocular Toxicity assessment of agrochemical formulations market in Brazil.
Toxicology in Vitro, 2020Co-Authors: Wanessa Machado Andrade, Artur Christian Garcia Da Silva, Aline Carvalho Batista, Larissa Cleres Moreira, Thaisângela Rodrigues Lopes E Silva Gomes, Marize Campos ValadaresAbstract:Abstract Considering the successful employment of alternative methods for Eye Toxicity assessment of products for regulatory purposes, and the recent advances in Brazilian legislative scenario, which adopted the UN GHS classification system for agrochemical formulations Toxicity assessment, there is an emerging demand for strategies that allow the evaluation of such products. Based on this, the present study aimed to address the applicability of a mechanistic-based defined approach for Eye Toxicity assessment of agrochemical formulations. It was investigated the opacity/permeability, depth and location of corneal injury in bovine cornea, and vascular events in chorioallantoic membrane induced for different Brazilian agrochemicals using a Sequential Testing Strategy (STS). CytoToxicity induced by the agrochemical formulations was evaluated by Short Time exposure (STE) (OECD TG 491) assay (step 1), corneal injury was investigated by standard Bovine Corneal Opacity and Permeability (BCOP) (OECD TG 437) followed by histopathological evaluation (step 2), and Hen Chorionic-allantoic Membrane test (HET-CAM) was used to evaluate vascular injury (step 3). The results demonstrated that the proposed defined approach enabled a classification corresponding UN GHS classification of agrochemical formulations while minimizing the use of live animals. Therefore, this approach may be useful for categorization of agrochemicals in Brazil according to the new regulatory scenario.
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a new corneal epithelial biomimetic 3d model for in vitro Eye Toxicity assessment development characterization and applicability
Toxicology in Vitro, 2020Co-Authors: Artur Christian Garcia Da Silva, Adrienny Rodrigues Chialchia, Elisandra Gava De Castro, Marlos R L E Silva, Diego Antonio Costa Arantes, Aline Carvalho Batista, Gregory T Kitten, Marize Campos ValadaresAbstract:Abstract In vitro Eye Toxicity assessment using reconstructed corneal epithelial models has emerged highlighting its applicability domain for Classification and Labeling of products and chemicals. However, due to bureaucratic issues, such models are not commercially available in Brazil and Latin America. In this work, we developed, characterized and evaluated the applicability of a new corneal epithelial biomimetic model using a cell lineage for in vitro Eye Toxicity assessment. The reconstructed tissue was obtained through the cultivation of HaCaT cells in an air-liquid interface, which presented morphology and biomarkers expression such as cytokeratin, CD44, and Ki-67 similar to human tissue. Furthermore, tissue viability was evaluated after exposure of the epithelial model to isolated chemicals from different Globally Harmonized System (GHS) Eye irritation categories, and it has been demonstrated to be a suitable endpoint for classification of test materials, allowing discrimination between irritant and non-irritant chemicals. Furthermore, the model showed suitability for testing “real-life mixtures”, once it identified irritant products between the analyzed Eyebrow henna samples commercially labeled as non-irritants. This reproducible and low-cost epithelial corneal model presents features very important for Brazil and South America for R&D&I with no unnecessary animal experimentation.
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Mechanistic-based non-animal assessment of Eye Toxicity: Inflammatory profile of human keratinocytes cells after exposure to Eye damage/irritant agents
Chemico-Biological Interactions, 2018Co-Authors: Artur Christian Garcia Da Silva, Adrienny Rodrigues Chialchia, Renato Ivan De Ávila, Marize Campos ValadaresAbstract:Eye Toxicity is a mandatory parameter in human risk and safety evaluation for products including chemicals, pesticides, medicines and cosmetics. Historically, this endpoint has been evaluated using the Draize rabbit Eye test, an in vivo model that was never formally validated. Due to advances in scientific knowledge, economic and ethical issues, non-animal methods based on mechanisms of Toxicity are being developed and validated for increasing the capability of these models to predict Eye Toxicity. In this study, the Cytometric Bead Array (CBA) and ELISA assays were used to evaluate the inflammatory cytokine profile produced by HaCaT human keratinocytes after exposure to chemicals with different UN GHS Eye Toxicity classifications, aiming to stablish a correlation between inflammatory endpoints and Eye Toxicity (damage/irritation) potential. As a first step, cytotoxic profile of the chemicals, including 3 non-irritants and 10 Eye toxicants (GHS Category 1, 2A and 2B), was evaluated after 24 h exposure using MTT assay and Inhibitory Concentration of 20% of cell viability (IC20) was calculated for each chemical. Then, the cells were exposed to these chemicals at IC20 for 24 h and supernatants and cell lysates were analyzed by CBA assay for quantification of the following cytokines: IL-6, IL-8, IL-10, IL-1β TNF and IL-12p70. Regarding cytoToxicity evaluation, chemicals showed different cytoToxicity profiles and data demonstrated no correlation with their UN GHS classification. Among the cytokines evaluated, IL-1β production has changed after exposure and such alterations were confirmed by quantification employing ELISA method. The higher intracellular levels of IL-1β were found in GHS Category 1 chemicals, followed by Category 2A and 2B, while non irritants did not induce such increase. Thus, these findings show that IL-1β measurement, using HaCaT model, can be a considerable biomarker to identify chemicals according to their potential in promote Eye Toxicity, differentiating damage from irritation potential.
Artur Christian Garcia Da Silva - One of the best experts on this subject based on the ideXlab platform.
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Innovative strategy based on mechanisms to substitute animal testing for ocular Toxicity assessment of agrochemical formulations market in Brazil.
Toxicology in Vitro, 2020Co-Authors: Wanessa Machado Andrade, Artur Christian Garcia Da Silva, Aline Carvalho Batista, Larissa Cleres Moreira, Thaisângela Rodrigues Lopes E Silva Gomes, Marize Campos ValadaresAbstract:Abstract Considering the successful employment of alternative methods for Eye Toxicity assessment of products for regulatory purposes, and the recent advances in Brazilian legislative scenario, which adopted the UN GHS classification system for agrochemical formulations Toxicity assessment, there is an emerging demand for strategies that allow the evaluation of such products. Based on this, the present study aimed to address the applicability of a mechanistic-based defined approach for Eye Toxicity assessment of agrochemical formulations. It was investigated the opacity/permeability, depth and location of corneal injury in bovine cornea, and vascular events in chorioallantoic membrane induced for different Brazilian agrochemicals using a Sequential Testing Strategy (STS). CytoToxicity induced by the agrochemical formulations was evaluated by Short Time exposure (STE) (OECD TG 491) assay (step 1), corneal injury was investigated by standard Bovine Corneal Opacity and Permeability (BCOP) (OECD TG 437) followed by histopathological evaluation (step 2), and Hen Chorionic-allantoic Membrane test (HET-CAM) was used to evaluate vascular injury (step 3). The results demonstrated that the proposed defined approach enabled a classification corresponding UN GHS classification of agrochemical formulations while minimizing the use of live animals. Therefore, this approach may be useful for categorization of agrochemicals in Brazil according to the new regulatory scenario.
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a new corneal epithelial biomimetic 3d model for in vitro Eye Toxicity assessment development characterization and applicability
Toxicology in Vitro, 2020Co-Authors: Artur Christian Garcia Da Silva, Adrienny Rodrigues Chialchia, Elisandra Gava De Castro, Marlos R L E Silva, Diego Antonio Costa Arantes, Aline Carvalho Batista, Gregory T Kitten, Marize Campos ValadaresAbstract:Abstract In vitro Eye Toxicity assessment using reconstructed corneal epithelial models has emerged highlighting its applicability domain for Classification and Labeling of products and chemicals. However, due to bureaucratic issues, such models are not commercially available in Brazil and Latin America. In this work, we developed, characterized and evaluated the applicability of a new corneal epithelial biomimetic model using a cell lineage for in vitro Eye Toxicity assessment. The reconstructed tissue was obtained through the cultivation of HaCaT cells in an air-liquid interface, which presented morphology and biomarkers expression such as cytokeratin, CD44, and Ki-67 similar to human tissue. Furthermore, tissue viability was evaluated after exposure of the epithelial model to isolated chemicals from different Globally Harmonized System (GHS) Eye irritation categories, and it has been demonstrated to be a suitable endpoint for classification of test materials, allowing discrimination between irritant and non-irritant chemicals. Furthermore, the model showed suitability for testing “real-life mixtures”, once it identified irritant products between the analyzed Eyebrow henna samples commercially labeled as non-irritants. This reproducible and low-cost epithelial corneal model presents features very important for Brazil and South America for R&D&I with no unnecessary animal experimentation.
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Mechanistic-based non-animal assessment of Eye Toxicity: Inflammatory profile of human keratinocytes cells after exposure to Eye damage/irritant agents
Chemico-Biological Interactions, 2018Co-Authors: Artur Christian Garcia Da Silva, Adrienny Rodrigues Chialchia, Renato Ivan De Ávila, Marize Campos ValadaresAbstract:Eye Toxicity is a mandatory parameter in human risk and safety evaluation for products including chemicals, pesticides, medicines and cosmetics. Historically, this endpoint has been evaluated using the Draize rabbit Eye test, an in vivo model that was never formally validated. Due to advances in scientific knowledge, economic and ethical issues, non-animal methods based on mechanisms of Toxicity are being developed and validated for increasing the capability of these models to predict Eye Toxicity. In this study, the Cytometric Bead Array (CBA) and ELISA assays were used to evaluate the inflammatory cytokine profile produced by HaCaT human keratinocytes after exposure to chemicals with different UN GHS Eye Toxicity classifications, aiming to stablish a correlation between inflammatory endpoints and Eye Toxicity (damage/irritation) potential. As a first step, cytotoxic profile of the chemicals, including 3 non-irritants and 10 Eye toxicants (GHS Category 1, 2A and 2B), was evaluated after 24 h exposure using MTT assay and Inhibitory Concentration of 20% of cell viability (IC20) was calculated for each chemical. Then, the cells were exposed to these chemicals at IC20 for 24 h and supernatants and cell lysates were analyzed by CBA assay for quantification of the following cytokines: IL-6, IL-8, IL-10, IL-1β TNF and IL-12p70. Regarding cytoToxicity evaluation, chemicals showed different cytoToxicity profiles and data demonstrated no correlation with their UN GHS classification. Among the cytokines evaluated, IL-1β production has changed after exposure and such alterations were confirmed by quantification employing ELISA method. The higher intracellular levels of IL-1β were found in GHS Category 1 chemicals, followed by Category 2A and 2B, while non irritants did not induce such increase. Thus, these findings show that IL-1β measurement, using HaCaT model, can be a considerable biomarker to identify chemicals according to their potential in promote Eye Toxicity, differentiating damage from irritation potential.
David Moir - One of the best experts on this subject based on the ideXlab platform.
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the international symposium on regulatory testing and animal welfare recommendations on best scientific practices for acute local skin and Eye Toxicity testing
Ilar Journal, 2002Co-Authors: Philip A Botham, Wallace A Hayes, David MoirAbstract:B reakout Group 1 addressed the current best practices and the future possibilities for acute local Toxicity testing—skin and Eye. Participants in the group (listed at the end of this report) had previously reviewed a number of key background references (also listed at the end of the report), which the group’s leaders had selected before the meeting. They were asked to consider the questions described below as part of their general discussion.
Judee Fischer - One of the best experts on this subject based on the ideXlab platform.
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ET-19A PHASE 1 STUDY EVALUATING ABT-414 WITH TEMOZOLOMIDE (TMZ) OR CONCURRENT RADIOTHERAPY (RT) AND TMZ IN GLIOBLASTOMA (GBM)
Neuro-oncology, 2014Co-Authors: Lisa Fichtel, Andrew B. Lassman, Ryan Merrell, Martin J. Van Den Bent, Priya Kumthekar, Andrew M. Scott, Michelle Pedersen, Erica Gomez, Judee FischerAbstract:BACKGROUND: Standard therapies have little effect on the poor survival rates of GBM. Abnormal epidermal growth factor receptor (EGFR) expression and signaling are common in GBM. ABT-414 is a unique antibody-drug conjugate, with a toxic payload (MMAF) targeted to active EGFR or mutant EGFRvIII, that has demonstrated high antitumor activity in preclinical GBM tumor models. METHODS: Objectives were to evaluate the safety, pharmacokinetics (PK), and the maximum tolerated dose (MTD) of ABT-414 when administered with TMZ (recurrent or unresectable GBM, Arm B) or concurrent RT and TMZ (newly diagnosed GBM, Arm A). Adverse events (AEs), PK parameters, objective response (RANO), and tumor tissue EGFR biomarkers were assessed. Dose escalation was determined by the continual reassessment method (CRM). RESULTS: As of April, 2014, 22/21 pts were treated in Arm A/B. Common treatment-emergent AEs included fatigue(n= 11/ 6, Arm A/B); blurred vision(n = 10/9); AST increase(n = 9, Arm A); and nausea(n = 7/7) Grade 3/4 AEs (≥ 2 pts) included lymphopenia(n = 3); Eye Toxicity(n = 3); brain edema, ALT, AST(n = 2 each) in Arm A and keratitis(n = 2) in Arm B. Doses from 0.5-3.2mg/kg have been explored. Dose limiting toxicities primarily affecting the Eye (keratitis) and liver occurred at multiple doses. The CRM has predicted 2.4mg/kg as the MTD in Arm A and 1.25mg/kg in Arm B. Patient samples are being evaluated for EGFR expression, amplification and EGFRvIII status. Efficacy endpoints are not yet mature in Arm A, but 4 patients in Arm B have best responses of 3 PRs and 1 CR. CONCLUSIONS: PK and safety data support doses of 2.4 and 1.25mg/kg as the predicted MTD in Arms A and B. Preliminary safety data demonstrate liver and Eye toxicities in Arm A and primarily Eye toxicities in Arm B. Updated biomarker results as they correlate with efficacy will be reported. Phase 2 studies assessing ABT-414 in GBM are planned.
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416OA PHASE 1 STUDY EVALUATING ABT-414 WITH CONCURRENT RADIOTHERAPY (RT) AND TEMOZOLOMIDE (TMZ) IN NEWLY DIAGNOSED GLIOBLASTOMA (GBM)
Annals of Oncology, 2014Co-Authors: Lisa Fichtel, Andrew B. Lassman, Ryan Merrell, Martin J. Van Den Bent, Priya Kumthekar, Andrew M. Scott, Michelle Pedersen, Erica Gomez, Judee FischerAbstract:ABSTRACT Aim: Despite standard therapy for GBM, median survival is 1-2 years. Abnormal epidermal growth factor receptor (EGFR) expression and signaling are common in GBM. ABT-414 is a unique antibody-drug conjugate, with a toxic payload (monomethylauristatin F) targeted to active EGFR or mutant EGFRvIII, that has demonstrated high antitumor activity in preclinical GBM tumor models. Methods: Objectives were to evaluate the safety, pharmacokinetics (PK), and the maximum tolerated dose (MTD) of ABT-414 when administered every 14 days with concurrent RT and TMZ in newly diagnosed GBM. Adverse events, PK parameters, objective response (RANO), and tumor tissue EGFR biomarkers were assessed. Dose escalation was determined by the exposure-adjusted continual reassessment method (EACRM). Results: As of April 9, 2014, 22 pts were treated (13/9 Male/Female, median age 58 years, range 34-79). Common treatment-emergent adverse events (TEAEs, ≥ 5 pts) included fatigue (n= 11); blurred vision (n = 10); thrombocytopenia (n = 8); AST increase (n = 9); ALT increase (n = 8); nausea (n = 7); Eye pain (n = 6); lacrimation increase (n = 6); dry Eye, headache, and constipation (n = 5 each). Grade 3/4 TEAEs (≥ 2 pts) included lymphopenia (n = 3); Eye Toxicity (n = 3); brain edema, ALT, AST (n = 2 each). Doses from 0.5 - 3.2 mg/kg have been explored. Dose limiting toxicities primarily affecting the Eye (keratitis) and liver occurred at the 2, 2.6, 3.0, and 3.2 mg/kg doses. The EACRM has predicted 2.4 mg/kg as the MTD. Confirmatory safety data are being collected. PK data from 9 subjects in the dose range of 0.5 - 3 mg/kg indicate that exposure (Cmax and AUC) of ABT‐414 appeared to be dose proportional with a half‐life of approximately 11 days. Efficacy endpoints are not yet mature. Patient samples are being evaluated for EGFR expression, amplification and EGFRvIII status to determine which marker best associates with clinical benefit. Conclusions: PK and safety data support a dose of 2.4 mg/kg as the predicted MTD. Preliminary safety data demonstrate increased liver and Eye toxicities in addition to common RT + TMZ toxicities. Further follow-up may demonstrate whether ABT-414 improves outcome. Disclosure: H.K. Gan: employee of Ludwig Institute for Cancer Research, which has licensed ABT-806; A. Lassman: Consultancy: Amgen, Celgene, Genentech, Sigma-Tau, Agenus, Roche, Stemline, Synapse, RadMD, Venture Inflections, Novartis, Kyowa Hakko Kirin, Abbott, Scientia Advisors, MSD, GSK, Able Assoc, Defined Health, Easton Assoc.; M.J. van den Bent: Consultancy: Roche, ABBVIE, Actelion, Celldex, AMGEN. Research support: Roche, ABBVIE. Speakers bureau: MSD; A. Scott: employee of Ludwig Institute for Cancer Research, which has licensed ABT-806; Consultancy and stock ownership - Life Science Pharmaceuticals; M. Pedersen, E. Gomez, J. Fischer, W. Ames, H. Xiong, M. Dudley, L. Roberts-Rapp, P.J. Ansell and K. Holen: is an AbbVie employee and may own stock; D.A. Reardon: Speaker's Bureau – Merck/Schering and Genentech/Roche; Advisory Board – Novartis; Amgen; Roche/Genentech; EMD Serono; Stemline Therapeutics; Momenta Pharmaceuticals. All other authors have declared no conflicts of interest.
Shiewmei Huang - One of the best experts on this subject based on the ideXlab platform.
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can skin Eye Toxicity be used as a biomarker for dose selection of fda approved anti egfr agents
Journal of Clinical Oncology, 2008Co-Authors: Padmaja Mummaneni, Hong Zhao, Shashi Amur, L Kenna, Felix W Frueh, N A Rahman, Shiewmei HuangAbstract:14696 Background: Epidermal growth factor receptor (EGFR) is an attractive target for anti-cancer agents, which have shown activity against various types of tumors. Skin/Eye Toxicity is a class adverse effect associated with anti-EGFR therapy. This project aims to determine whether skin/Eye Toxicity can be used as a biomarker for dose selection of anti-EGFR agents. Methods: Extract information on dose and skin/Eye Toxicity from datasets of FDA approved anti-EGFR agents; Tabulate the percentage of subjects with skin/Eye Toxicity and perform sigmoidal Emax modeling to estimate the dose associated with maximum skin/Eye Toxicity; Compare the model estimated dose and the label recommended dose; Determine the capability using skin/Eye Toxicity as a measure for dose selection for anti-EGFR agents. Results: Skin/Eye Toxicity data were obtained from all six FDA approved anti-EGFR agents. The sigmoidal Emax model fit the data from trials of Drug A, Drug B and Drug C well, and the predicted dose matched the label re...
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Can skin/Eye Toxicity be used as a biomarker for dose selection of FDA approved Anti-EGFR agents?
Journal of Clinical Oncology, 2008Co-Authors: Padmaja Mummaneni, Hong Zhao, Shashi Amur, L Kenna, Felix W Frueh, N A Rahman, Shiewmei HuangAbstract:14696 Background: Epidermal growth factor receptor (EGFR) is an attractive target for anti-cancer agents, which have shown activity against various types of tumors. Skin/Eye Toxicity is a class adverse effect associated with anti-EGFR therapy. This project aims to determine whether skin/Eye Toxicity can be used as a biomarker for dose selection of anti-EGFR agents. Methods: Extract information on dose and skin/Eye Toxicity from datasets of FDA approved anti-EGFR agents; Tabulate the percentage of subjects with skin/Eye Toxicity and perform sigmoidal Emax modeling to estimate the dose associated with maximum skin/Eye Toxicity; Compare the model estimated dose and the label recommended dose; Determine the capability using skin/Eye Toxicity as a measure for dose selection for anti-EGFR agents. Results: Skin/Eye Toxicity data were obtained from all six FDA approved anti-EGFR agents. The sigmoidal Emax model fit the data from trials of Drug A, Drug B and Drug C well, and the predicted dose matched the label re...
