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Organ Toxicity (organ + toxicity)
Selected AbstractsTK/TD dose,response modeling of toxicityENVIRONMETRICS, Issue 5 2007Munni Begum Abstract In environmental cancer risk assessment of a toxic chemical, the main focus is in understanding induced target organ toxicity that may in turn lead to carcinogenicity. Mathematical models based on systems of ordinary differential equations with biologically relevant parameters are tenable methods for describing the disposition of chemicals in target organs. In evaluation of a toxic chemical, dose,response assessment often addresses only toxicodynamics (TD) of the chemical, while its toxicokinetics (TK) do not enter into consideration. The primary objective of this research is to integrate both TK and TD in evaluation of toxic chemicals while performing dose,response assessment. Population models, with hierarchical setup and nonlinear predictors, for TK concentration and TD effect measures are considered. A one-compartment model with biologically relevant parameters, such as organ volume, uptake rate and excretion rate, or clearance, is used to derive the TK predictor while a two parameter Emax model is used as a predictor for TD measures. Inference of the model parameters with nonnegative and assay's Limit of Detection (LOD) constraints was carried out by Bayesian approaches using Markov Chain Monte Carlo (MCMC) techniques. Copyright © 2006 John Wiley & Sons, Ltd. [source] Allogeneic bone marrow transplantation with reduced conditioning (RC-BMT)EUROPEAN JOURNAL OF HAEMATOLOGY, Issue 2 2001Lars Vindeløv Abstract: Allogeneic bone marrow transplantation with conventional conditioning (CC-BMT) has the potential of curing various malignant and non-malignant diseases. The curative mechanisms encompass 1) stem cell support for myeloablative radio-chemotherapy, 2) the graft-versus-tumor (GVT) effect, 3) gene replacement for genetic diseases and 4) immunoablation for autoimmune diseases. CC-BMT is characterized by high intensity conditioning, the requirement of prolonged and expensive hospital treatment and a treatment related mortality (TRM) of 10,50% depending on diagnosis, disease stage, patient age and donor type. Recent preclinical and clinical progress has resulted in the emergence of new concepts and procedures that allow replacement of patient bone marrow and immune system with that of the donor by a transplant procedure with markedly reduced conditioning (RC-BMT). This type of transplant, sometimes referred to as mini-BMT, activates curative mechanisms 2,4, which for a number of diseases seems sufficient for cure. It avoids the severe organ toxicity of myeloablative radio-chemotherapy and the complications of profound neutropenia. Patients beyond the age limit of conventional BMT (50,60 yr) may therefore be candidates for this type of transplant as well as patients which because of other medical conditions or the type of disease for which the transplant is needed are poor candidates for CC-BMT. The procedure can be performed in an outpatient setting. The resulting cost reduction should contribute to making allogenic BMT more readily available. This review describes basic concepts and procedures involved in RC-BMT and summarizes preliminary results obtained with RC-BMT in different transplant centers. [source] Overproduction of reactive oxygen species in end-stage renal disease patients: A potential component of hemodialysis-associated inflammationHEMODIALYSIS INTERNATIONAL, Issue 1 2005Marion Morena Abstract During the past decade, hemodialysis (HD)-induced inflammation has been linked to the development of long-term morbidity in end-stage renal disease (ESRD) patients on regular renal replacement therapy. Because interleukins and anaphylatoxins produced during HD sessions are potent activators for nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, an example of an enzyme that is responsible for overproduction of reactive oxygen species (ROS), this may constitute a link between leukocyte activation and cell or organ toxicity. Oxidative stress, which results from an imbalance between oxidant production and antioxidant defense mechanisms, has been documented in ESRD patients using lipid and/or protein oxidative markers. Characterization of HD-induced oxidative stress has included identification of potential activators for NADPH oxidase. Uremia per se could prime phagocyte oxidative burst. HD, far from improving the oxidative status, results in an enhancement of ROS owing to hemoincompatibility of the dialysis system, hemoreactivity of the membrane, and trace amounts of endotoxins in the dialysate. In addition, the HD process is associated with an impairment in antioxidant mechanisms. The resulting oxidative stress has been implicated in long-term complications including anemia, amyloidosis, accelerated atherosclerosis, and malnutrition. Prevention of oxidative stress in HD might focus on improving the hemocompatibility of the dialysis system, supplementation of deficient patients with antioxidants, and modulation of NADPH oxidase by pharmacologic approaches. [source] Influence of subacute treatment of some plant growth regulators on serum marker enzymes and erythrocyte and tissue antioxidant defense and lipid peroxidation in ratsJOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 4 2006Ismail Celik Abstract This study aims to investigate the effects of the plant growth regulators (PGRs) (2,3,5-triiodobenzoic acid (TIBA), Naphthaleneacetic acid (NAA), and 2,4-dichlorofenoxyacetic acid (2,4-D)) on serum marker enzymes (aspartate aminotransferase (AST), alanin aminotransferase (ALT), creatine phosphokinase (CPK), and lactate dehydrogenase (LDH)), antioxidant defense systems (reduced glutathione (GSH), glutathione reductase (GR), superoxide dismutase (SOD), glutathione-S-transferase (GST), and catalase (CAT)), and lipid peroxidation content (malondialdehyde = MDA) in various tissues of rats. 50 and 100 ppm of PGRs as drinking water were administered orally to rats (Sprague,Dawley albino) ad libitum for 25 days continuously. The PGRs treatment caused different effects on the serum marker enzymes, antioxidant defense systems, and the MDA content in experimented rats compared to controls. Results showed that TIBA caused a significant decrease in serum AST activity with both the dosage whereas serum CPK was significantly increased with 100 ppm dosage of TIBA. Meanwhile, serum AST, CPK, and LDH activities were significantly increased with both dosage of NAA and 2,4-D. The lipid peroxidation end-product MDA significantly increased in the all tissues treated with both dosages of PGRs without any change in the brain and erythrocyte of rats treated with both the dosages of 2,4-D. The GSH depletion in the kidney and brain tissues of rats treated with both dosages of PGRs was found to be significant. Furthermore, the GSH depletion in the erythrocyte of rats treated with both dosages of PGRs except 50 ppm dosage of 2,4-D was significant too. Also, the GSH level in the liver was significantly depleted with 50 ppm of 2,4-D and NAA, whereas the GSH depletion in the same tissue did not significantly change with the treatment. The activity of antioxidant enzymes was also seriously affected by PGRs; SOD significantly decreased in the liver, heart, kidney, and brain of rats treated with both dosages of NAA, whereas the SOD activity in the erythrocytes, liver, and heart was either significantly decreased or not changed with two doses of 2,4-D and TIBA. Although the CAT activity significantly increased in the erythrocyte and brain of rats treated with both doses of PGRs, it was not changed in the liver, heart, and kidney. Meanwhile, the ancillary enzyme GR activity significantly increased in the brain, heart, and liver but decreased in the erythrocyte and kidney of rats treated with both doses of PGRs. The drug-metabolizing enzyme GST activity significantly increased in the heart and kidney but decreased in the brain and erythrocytes of rats treated with both dosages of PGRs. As a conclusion, the results indicate that PGRs might affect antioxidant potential enzymes, the activity of hepatic damage enzymes, and lipid peroxidation dose independently. Also, the rats resisted to oxidative stress via antioxidant mechanism but the antioxidant mechanism could not prevent the increases in lipid peroxidation in rat's tissues. These data, along with the determined changes, suggest that PGRs produced substantial systemic organ toxicity in the erythrocyte, liver, brain, heart, and kidney during the period of a 25-day subacute exposure. © 2006 Wiley Periodicals, Inc. J Biochem Mol Toxicol 20:174,182, 2006; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20134 [source] Dronedarone: A New Treatment for Atrial FibrillationJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 11 2008JAMES C. LAUGHLIN M.D. Dronedarone is a benzofuran derivative pharmacologically related to amiodarone but without the iodine moiety. It is designed for the treatment of atrial fibrillation and atrial flutter. Historically, amiodarone has proved most effective in maintaining sinus rhythm and has been used safely in patients with advanced heart failure. However, its use has been limited by cumulative and often irreversible organ toxicity, especially in younger patients. Dronedarone was developed in an effort to provide equivalent efficacy and safety with less toxicity. Dronedarone has proved efficacious without toxic or proarrhythmic effects and has minimal side effects, but remaining concerns exist regarding its use in patients with advanced heart failure. [source] Activity of the matrix metalloproteinase-9 promoter in human normal and tumor cellsJOURNAL OF CELLULAR PHYSIOLOGY, Issue 1 2004Cristina Morelli Matrix metalloproteinases (MMPs) belong to a family of proteins essential for those processes involving extracellular matrix degradation, such as embryonic development, morphogenesis, and tissue resorption and remodeling. Some members of this family play a crucial role also in tumor invasion. Most notably, MMP-9 is expressed in invasive tumors, and represents a key protein in brain tumor progression, whereas it is not expressed in adult normal tissues. The expression of the MMP-9, like other members of the family, is transcriptionally regulated. We, therefore, postulated that the MMP-9 promoter could be useful in driving selective expression of exogenous genes in tumor cells. This represents a key feature for gene therapy applications, since currently employed viral promoters induce severe organ toxicity, limiting the clinical benefits. In this study, we investigated the activity of the MMP-9 promoter in driving exogenous gene expression in human cell lines. High levels of reporter gene expression were detected in tumor derived cell lines, whereas the MMP-9 promoter activity in non-tumor cells was negligible. Furthermore, we show that tumor necrosis factor alpha (TNF,) is able to enhance considerably the MMP-9 promoter activity only in tumor cells. Since recent studies have indicated that MMP-9 enzymatic activity is detectable in the blood, it would be possible to screen potential responsive patients for a tumor gene therapy approach based on the MMP-9 promoter. Taken together these data suggest that MMP-9 promoter has the characteristics for transcritpionally targeted and inducible gene therapy applications. J. Cell. Physiol. 199: 126,133, 2004© 2003 Wiley-Liss, Inc. [source] Acute non-oliguric kidney failure and cholestatic hepatitis induced by ibuprofen and acetaminophen: a case reportACTA PAEDIATRICA, Issue 5 2009Marco Zaffanello Abstract The combined use of acetaminophen with ibuprofen has long been in clinical use because the target of action of each drug is different and they do not interfere with each other. Appropriate dosing and managing of these drugs do not likely lead to organ toxicity. However, both acetaminophen and ibuprofen can induce liver problems and acute kidney failure, respectively, if administered at high doses. We report the case of a female child, in treatment with both acetaminophen and ibuprofen, administered at therapeutic antipyretic doses in condition of volume depletion, who suffered acute kidney and liver failure. Conclusion: The combined ibuprofen and acetaminophen treatment, even if administered at therapeutic dosages and in a reduced number of doses, may be dangerous in conditions of volume depletion. [source] | ||||||||||