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Toxicology Testing (toxicology + testing)
Selected AbstractsThe Industry View on Long-Term Toxicology Testing in Drug Development of Human PharmaceuticalsBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 2000Herman Van Cauteren The 1990's have seen a general acceptance that studies with a maximal duration of 6 months in rodents are all that is required for adequate safety assessment of developmental pharmaceutical agents. However, controversy has arisen concerning the most appropriate duration for chronic toxicity testing in non-rodents. Initial suggestions that 6 months duration was sufficient have been countered by findings noted in 12-month studies that were not seen in shorter-term studies. Retrospective analysis of available data eventually lead to a subsequent ICH recommendation that studies of 9 months duration would be now acceptable. However, until recently the FDA position on this recommendation was unclear and an analysis of industry practices since the ICH recommendation was made in 1997 has shown that the 9-month guideline is not widely applied. Recent clarification by the FDA will probably result in a continued but limited use of this alternative. An industry view on the future of chronic toxicology testing in rodents and non-rodents is presented. [source] Flow cytometry peripheral blood micronucleus test in vivo: Determination of potential thresholds for aneuploidy induced by spindle poisonsENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 4 2010Zoryana Cammerer Abstract Non-DNA binding genotoxins (e.g., aneugens), unlike DNA-binding genotoxins, are theoretically expected to show thresholded concentration-effect response curves. This is a major issue in genetic toxicology testing because the identification of thresholds in vivo can provide a safety margin for exposure to a particular compound. In the current study we measured micronucleus induction by flow cytometry to determine the dose-response curves for tubulin interacting agents, a specific class of aneugens. All experiments with aneugens, which include colchicine, vinblastine, vincristine, as well as the clastogen cyclophosphamide (CP) were performed in mice to avoid the splenic elimination of micronucleated reticulocytes, which has been described in rats. Flow cytometry analysis revealed a non-linear dose-dependent increase in micronuclei frequencies for all tested aneugens, and a linear dose response curve for the clastogen, CP. To determine whether micronucleus induction at higher doses was due to chromosome loss (aneuploidy) or chromosome breakage (clastogenicity), flow sorting of the micronucleated reticulocytes and fluorescent in situ hybridization (FISH) with a mouse pan centromeric probe were performed for vinblastine, vincristine, and colchicine. Statistical evaluation of the flow cytometry and FISH data was performed to determine the threshold levels for chromosome loss in vivo. The threshold concentrations for vinblastine, vincristine, and colchicine were found at 0.35, 0.017, and 0.49 mg kg,1, respectively. Environ. Mol. Mutagen., 2010. © 2009 Wiley-Liss, Inc. [source] Relationships Between Concentrations of Cocaine and Its Hydrolysates in Peripheral Blood, Heart Blood, Vitreous Humor and UrineJOURNAL OF FORENSIC SCIENCES, Issue 2 2006Wayne C. Duer Ph.D. ABSTRACT: Cocaine is known to degrade in vivo and in vitro by several hydrolytic mechanisms. A previous study found that the initial amount of cocaine added to plasma could be accounted for by summing the molar concentrations of cocaine's hydrolysis products and the cocaine remaining after hydrolysis. The present study was undertaken to investigate whether or not relationships might exist between such molar concentration sums for different postmortem bodily fluids. Determinations of cocaine, benzoylecgonine, ecgonine methyl ester, and ecgonine were performed using liquid chromatography/mass spectrometry (LC/MS/MS) with heart blood, femoral blood, vitreous humor (VH), and urine (UR). The results demonstrate a strong correlation between blood and VH concentrations (correlation coefficients of 0.88,0.94), weak correlation between the UR and blood concentrations (correlation coefficients of 0.61,0.64), and weak correlation between UR and VH concentrations (correlation coefficient of 0.59). The results demonstrate that ecgonine is a significant hydrolysate with concentrations on the same order of magnitude as benzoylecgonine. The results are consistent with rapid distribution of the parent drug and its hydrolysates in the blood and VH. The strong correlation between the blood and VH demonstrates that VH is an important medium for toxicology testing when attempting to make a determination of cocaine intoxication. [source] The Industry View on Long-Term Toxicology Testing in Drug Development of Human PharmaceuticalsBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 2000Herman Van Cauteren The 1990's have seen a general acceptance that studies with a maximal duration of 6 months in rodents are all that is required for adequate safety assessment of developmental pharmaceutical agents. However, controversy has arisen concerning the most appropriate duration for chronic toxicity testing in non-rodents. Initial suggestions that 6 months duration was sufficient have been countered by findings noted in 12-month studies that were not seen in shorter-term studies. Retrospective analysis of available data eventually lead to a subsequent ICH recommendation that studies of 9 months duration would be now acceptable. However, until recently the FDA position on this recommendation was unclear and an analysis of industry practices since the ICH recommendation was made in 1997 has shown that the 9-month guideline is not widely applied. Recent clarification by the FDA will probably result in a continued but limited use of this alternative. An industry view on the future of chronic toxicology testing in rodents and non-rodents is presented. [source] Pluripotent plasticity of stem cells and liver repopulationCELL BIOCHEMISTRY AND FUNCTION, Issue 3 2010Luisa Gennero Abstract Different types of stem cells have a role in liver regeneration or fibrous repair during and after several liver diseases. Otherwise, the origin of hepatic and/or extra-hepatic stem cells in reactive liver repopulation is under controversy. The ability of the human body to self-repair and replace the cells and tissues of some organs is often evident. It has been estimated that complete renewal of liver tissue takes place in about a year. Replacement of lost liver tissues is accomplished by proliferation of mature hepatocytes, hepatic oval stem cells differentiation, and sinusoidal cells as support. Hepatic oval cells display a distinct phenotype and have been shown to be a bipotential progenitor of two types of epithelial cells found in the liver, hepatocytes, and bile ductular cells. In gastroenterology and hepatology, the first attempts to translate stem cell basic research into novel therapeutic strategies have been made for the treatment of several disorders, such as inflammatory bowel diseases, diabetes mellitus, celiachy, and acute or chronic hepatopaties. In the future, pluripotent plasticity of stem cells will open a variety of clinical application strategies for the treatment of tissue injuries, degenerated organs. The promise of liver stem cells lie in their potential to provide a continuous and readily available source of liver cells that can be used for gene therapy, cell transplant, bio-artificial liver-assisted devices, drug toxicology testing, and use as an in vitro model to understand the developmental biology of the liver. Copyright © 2010 John Wiley & Sons, Ltd. [source] | ||||||||||