The Experts below are selected from a list of 306 Experts worldwide ranked by ideXlab platform
Thomas Singer - One of the best experts on this subject based on the ideXlab platform.
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the application of 3d cell models to support drug safety assessment opportunities challenges
Advanced Drug Delivery Reviews, 2014Co-Authors: Adrian Roth, Thomas SingerAbstract:The selection of drug candidates early in development has become increasingly important to minimize the use of animals and to avoid costly failures of drugs later in development. In vitro systems to predict and assess Organ Toxicity have so far been of limited value due to difficulties in demonstrating in vivo-relevant Toxicity at a cell culture level. To overcome the limitations of single-cell type monolayer cultures and short-lived primary cell preparations, researchers have created novel 3-dimensional culture systems which appear to more closely resemble in vivo biology. These could become a key for the pharmaceutical industry in the evaluation of drug candidates. However, the value and acceptance of those new models in standard drug safety applications have yet to be demonstrated. This review aims to provide an overview of the different approaches undertaken in the field of pre-clinical safety assessment, Organ Toxicity, in particular, with an emphasis on examples and technical challenges.
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The application of 3D cell models to support drug safety assessment: opportunities & challenges.
Advanced Drug Delivery Reviews, 2013Co-Authors: Adrian Roth, Thomas SingerAbstract:The selection of drug candidates early in development has become increasingly important to minimize the use of animals and to avoid costly failures of drugs later in development. In vitro systems to predict and assess Organ Toxicity have so far been of limited value due to difficulties in demonstrating in vivo-relevant Toxicity at a cell culture level. To overcome the limitations of single-cell type monolayer cultures and short-lived primary cell preparations, researchers have created novel 3-dimensional culture systems which appear to more closely resemble in vivo biology. These could become a key for the pharmaceutical industry in the evaluation of drug candidates. However, the value and acceptance of those new models in standard drug safety applications have yet to be demonstrated. This review aims to provide an overview of the different approaches undertaken in the field of pre-clinical safety assessment, Organ Toxicity, in particular, with an emphasis on examples and technical challenges.
Adrian Roth - One of the best experts on this subject based on the ideXlab platform.
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the application of 3d cell models to support drug safety assessment opportunities challenges
Advanced Drug Delivery Reviews, 2014Co-Authors: Adrian Roth, Thomas SingerAbstract:The selection of drug candidates early in development has become increasingly important to minimize the use of animals and to avoid costly failures of drugs later in development. In vitro systems to predict and assess Organ Toxicity have so far been of limited value due to difficulties in demonstrating in vivo-relevant Toxicity at a cell culture level. To overcome the limitations of single-cell type monolayer cultures and short-lived primary cell preparations, researchers have created novel 3-dimensional culture systems which appear to more closely resemble in vivo biology. These could become a key for the pharmaceutical industry in the evaluation of drug candidates. However, the value and acceptance of those new models in standard drug safety applications have yet to be demonstrated. This review aims to provide an overview of the different approaches undertaken in the field of pre-clinical safety assessment, Organ Toxicity, in particular, with an emphasis on examples and technical challenges.
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The application of 3D cell models to support drug safety assessment: opportunities & challenges.
Advanced Drug Delivery Reviews, 2013Co-Authors: Adrian Roth, Thomas SingerAbstract:The selection of drug candidates early in development has become increasingly important to minimize the use of animals and to avoid costly failures of drugs later in development. In vitro systems to predict and assess Organ Toxicity have so far been of limited value due to difficulties in demonstrating in vivo-relevant Toxicity at a cell culture level. To overcome the limitations of single-cell type monolayer cultures and short-lived primary cell preparations, researchers have created novel 3-dimensional culture systems which appear to more closely resemble in vivo biology. These could become a key for the pharmaceutical industry in the evaluation of drug candidates. However, the value and acceptance of those new models in standard drug safety applications have yet to be demonstrated. This review aims to provide an overview of the different approaches undertaken in the field of pre-clinical safety assessment, Organ Toxicity, in particular, with an emphasis on examples and technical challenges.
John M. Frazier - One of the best experts on this subject based on the ideXlab platform.
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predictive toxicodynamics empirical mechanistic approaches
Toxicology in Vitro, 1997Co-Authors: John M. FrazierAbstract:A major objective of the toxicological sciences is to predict the in vivo toxicological consequences of human exposure to pure chemicals, complex mixtures and commercial formulations. Historically, the experimental approach to this goal has been to investigate toxicological processes in whole animal models and extrapolate the results obtained to predict human risk using various extrapolation procedures (high-dose/low-dose extrapolation, interspecies extrapolation and route-to-route extrapolation). Can in vitro methods be more widely employed in quantitative risk assessment? One major limitation to the broader application of in vitro Toxicity testing methods is the lack of validated techniques for the extrapolation of in vitro-derived toxicodynamic data to the in vivo situation. The objective of this paper is to describe some approaches to the development of techniques to extrapolate in vitro Toxicity testing data to predict in vivo toxicological responses. An empirical approach within the context of a mechanistic framework is explored. The basic hypothesis is that the in vivo response can be constructed from a cellular Toxicity factor that accounts for the cellular response and a toxicodynamic factor that relates toxicological events at the cellular level to the observable in vivo responses. A predictive paradigm to describe the in vivo acute target Organ Toxicity (hepatoToxicity) of a model chemical (cadmium) is discussed. The cellular Toxicity factor is derived from in vitro Toxicity testing studies using isolated rat hepatocytes. The toxicodynamic factor is derived through Biologically-Based Response (BBR) modelling techniques to predict target Organ Toxicity markers (i.e. plasma hepatic enzyme levels as markers for acute hepatoToxicity). The ultimate goal is to develop validated extrapolation procedures that can be applied to predicting target Organ Toxicity quantitatively in human populations based on in vitro Toxicity studies using human cellular models.
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Predictive toxicodynamics : Empirical/mechanistic approaches
Toxicology in vitro : an international journal published in association with BIBRA, 1997Co-Authors: John M. FrazierAbstract:A major objective of the toxicological sciences is to predict the in vivo toxicological consequences of human exposure to pure chemicals, complex mixtures and commercial formulations. Historically, the experimental approach to this goal has been to investigate toxicological processes in whole animal models and extrapolate the results obtained to predict human risk using various extrapolation procedures (high-dose/low-dose extrapolation, interspecies extrapolation and route-to-route extrapolation). Can in vitro methods be more widely employed in quantitative risk assessment? One major limitation to the broader application of in vitro Toxicity testing methods is the lack of validated techniques for the extrapolation of in vitro-derived toxicodynamic data to the in vivo situation. The objective of this paper is to describe some approaches to the development of techniques to extrapolate in vitro Toxicity testing data to predict in vivo toxicological responses. An empirical approach within the context of a mechanistic framework is explored. The basic hypothesis is that the in vivo response can be constructed from a cellular Toxicity factor that accounts for the cellular response and a toxicodynamic factor that relates toxicological events at the cellular level to the observable in vivo responses. A predictive paradigm to describe the in vivo acute target Organ Toxicity (hepatoToxicity) of a model chemical (cadmium) is discussed. The cellular Toxicity factor is derived from in vitro Toxicity testing studies using isolated rat hepatocytes. The toxicodynamic factor is derived through Biologically-Based Response (BBR) modelling techniques to predict target Organ Toxicity markers (i.e. plasma hepatic enzyme levels as markers for acute hepatoToxicity). The ultimate goal is to develop validated extrapolation procedures that can be applied to predicting target Organ Toxicity quantitatively in human populations based on in vitro Toxicity studies using human cellular models.
Roni Shouval - One of the best experts on this subject based on the ideXlab platform.
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Conditioning Regimen-Specific Patterns and Determinants of Acute Severe Organ Toxicity Following Allogeneic Transplantation
Biology of Blood and Marrow Transplantation, 2020Co-Authors: Joshua A. Fein, Avichai Shimoni, Ivetta Danylesko, Noga Shem-tov, Ronit Yerushalmi, Guy Chowers, Zachary Cohen, Arnon Nagler, Roni ShouvalAbstract:Background In recipients of allogeneic hematopoietic stem cell transplantation (HSCT), Organ Toxicity is a barrier to administering high-intensity conditioning. We hypothesized that determinants of acute Organ Toxicity are specific to individual regimens. We sought to characterize these toxicities, evaluate their prognostic implication, and derive predictors of severe Toxicity at the regimen level. Methods This retrospective study included adults undergoing first allogeneic HSCT at a single center between 2001 and 2014. Patients received grafts from matched sibling or unrelated donors and received any of the following regimens: Cy/TBI, Bu/Cy, Flu/Bu 12.8 mg, Flu/Bu 6.4 mg, Flu/Treosulfan 36-42 gr/m2, and Flu/Mel 100-140 mg/m2. Studied toxicities included acute kidney injury (AKI) per KDIGO definition and increases in total bilirubin, AST, ALT, and alkaline phosphatase (Alk Phos) per CTCAE grading. The incidence of toxicities from conditioning through 30-days post-HSCT was tabulated. Risk factors for severe Organ Toxicity were assessed within each regimen using multivariable logistic regressions. Results In a cohort of 707 patients, the main indications were acute leukemia (57%), myelodysplastic syndrome (13%), and aggressive lymphoma (9%). GvHD prophylaxis included methotrexate in 80% of patients, and 56% received ATG. The incidence of AKI and increased serum bilirubin in each regimen is shown in Figure 1A/B, respectively. Sinusoidal-obstructive syndrome (6% overall) accounted for only 17% of gr. ≥ 3 bilirubinemia in the entire cohort. Elevations in AST, ALT, and Alk Phos of gr ≥ 3 were not common ( Conclusion Allogeneic transplantation recipients are at high risk for acute Organ damage. We describe patterns of renal and liver Toxicity across several regimens. Determinants of acute severe Organ Toxicity, defined as those associated with short-term mortality, are regimen dependent. Our findings suggest these factors should be considered in selecting the preparative regimen. While requiring validation, the newly-defined composite endpoint of acute severe Organ Toxicity (ASOT) may be valuable in studying transplantation strategies.
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Early Organ Toxicity Following Allogeneic Hematopoietic Stem Cell Transplantation Differs By Conditioning Regimen
Blood, 2019Co-Authors: Joshua A. Fein, Avichai Shimoni, Ivetta Danylesko, Noga Shem-tov, Ronit Yerushalmi, Guy Chowers, Zachary Cohen, Arnon Nagler, Roni ShouvalAbstract:Background: In recipients of allogeneic hematopoietic stem cell transplantation (HSCT), Organ Toxicity is a barrier to administering high-intensity conditioning regimens. We hypothesized that determinants of acute Organ Toxicity are specific to individual conditioning regimens. We sought to characterize toxicities across common transplantation regimens, evaluate their prognostic implication, and derive predictors of severe Toxicity at the regimen level. Methods: This retrospective study included adults undergoing first allogeneic HSCT at a single center between the years of 2001 and 2014 (median: 2010). Patients received grafts from matched sibling or unrelated donors and were conditioned with any of the following regimens: Cyclophosphamide + TBI (Cy/TBI), Busulfan + Cyclophosphamide (Bu/Cy), Fludarabine + 12.8 mg Busulfan (Flu/Bu4), Fludarabine + 6.4 mg Busulfan (Flu/Bu2), Fludarabine + 36-42 gr/m2 Treosulfan (Flu/Treo), and Fludarabine + 100-140 mg/m2 Melphalan (Flu/Mel). Toxicities were defined by the KDIGO scale for acute kidney injury (AKI) and by the CTCAE v. 5.0 for increases in total bilirubin, AST, ALT, and alkaline phosphatase (Alk. Phos.) The incidence of toxicities from the start of conditioning through 30 days post-transplantation was tabulated by regimen. Risk factors for severe Organ Toxicity were assessed within each regimen cohort using multivariable logistic regressions. Results: In a cohort of 707 patients, the median age was 52 years. The main indications for transplantation were acute leukemia (57%), myelodysplastic syndrome (13%), and aggressive lymphoma (9%). Graft-versus-host-disease prophylaxis included methotrexate in 80% of patients, and 56% received anti-thymocyte globulin (ATG). The most common regimens were Flu/Treo (n = 160) and Bu/Cy (n = 141). As expected, patient characteristics varied between regimens. The incidence of AKI and increased serum bilirubin in each regimen is shown in Figure 1A and 1B, respectively. Sinusoidal-obstructive syndrome (6% overall) accounted for only 17% of gr. ≥ 3 bilirubinemia in the entire cohort. Elevations in AST, ALT, and Alk. Phos of gr. ≥ 3 were not common (<8%). In multivariable logistic regression, AKI gr. ≥ 2, increased bilirubin gr. ≥ 3, AST gr. ≥ 3, and Alk. Phos. gr. ≥ 2 were associated with increased 100-day mortality (p < 0.05). Acute severe Organ Toxicity (ASOT) was defined as the occurrence of any of these toxicities. ASOT had an odds ratio (OR) of 3.4 (95% CI: 2.2-5.3) for 100-day mortality. Within each regimen, we studied the relationship between ASOT and transplantation/patient characteristics (Figure 1C). Elevations in baseline bilirubin were predictive of ASOT in Cy/TBI (OR: 1.68 [1.19-2.37]), while increasing creatinine was predictive in patients conditioned with Flu/Mel (OR: 1.43 [1.09-1.88]). High-risk disease (DRI) was associated with increased risk in patients receiving Flu/Bu4 (1.26 [1.01-1.58]). In patients treated with Bu/Cy, administration of ATG increased the risk of ASOT (1.31 [1.11-1.55]). Conclusion: Allogeneic stem cell transplantation recipients are at high risk for acute Organ damage. We describe patterns of renal and liver Toxicity across several regimens. Determinants of acute severe Organ Toxicity, defined as those associated with short-term mortality, are regimen dependent. Our findings suggest that these factors should be considered when selecting the preparative regimen. While requiring validation, the newly-defined composite endpoint of acute severe Organ Toxicity (ASOT) may be valuable in studying transplantation strategies. Figure 1 Disclosures No relevant conflicts of interest to declare.
Anne Jannin - One of the best experts on this subject based on the ideXlab platform.
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the contribution of endothelial activation and injury to end Organ Toxicity following allogeneic hematopoietic stem cell transplantation
Biology of Blood and Marrow Transplantation, 2008Co-Authors: Kenneth R Cooke, Anne JanninAbstract:Over the last 25 years, allogeneic hematopoietic stem cell transplantation (HSCT) has been used increasingly as a curative treatment option for patients with hematologic and neoplastic diseases. Despite major advances in transplant immunology and improvements in supportive and critical care medicine, HSCT is still plagued by several life-threatening complications. As such, the establishment of effective therapeutic options for these complications will be crucial as increasing numbers of high-risk transplants are performed each year. This brief review will discuss the contribution of vascular endothelial cell activation and injury to inflammation and end-Organ Toxicity that occurs following allogeneic HSCT, and will highlight translational research efforts that have paved the way to the development of novel strategies to treat and prevent disease. Finally, we will discuss in detail the clinical manifestations and challenges encompassed by the syndrome of thrombotic microangiopathy following HSCT.