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Drug Safety Evaluation (drug + safety_evaluation)
Selected AbstractsApplication of Genomics in Preclinical Drug Safety EvaluationBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 6 2006Peter G. Lord Toxicologists have traditionally gathered pathological, morphological, chemical and biochemical information from in vivo studies of preclinical species in order to assess drug safety and to determine how new drugs can be safely administered to the human patient population. In recent years the emerging "-omics" technologies have been developed and integrated into preclinical studies in order to better assess drug safety by gaining information on the cellular and molecular events underlying adverse drug reactions. Genomics approaches in particular have become readily available and are being applied in several stages of drug development. The burgeoning literature on what has become known as "toxicogenomics" has for the most part highlighted successful applications of gene expression profiling in predictive toxicology, enabling decisions to be made on the developability of a compound early in the drug development process. It is also becoming apparent that toxicogenomic approaches are good starting points to develop experiments designed to gain a mechanistic insight into drug toxicities within and across species. Gene expression arrays permit the measurement of responses of essentially all the genes in the entire genome to be monitored, and knowledge of the function of the genes affected can identify the potential mechanisms to then be confirmed using conventional biochemical, toxicological and pathological approaches. As toxicologists put these technologies into practice they build up a knowledge base to better characterize toxicities at the molecular level and to make the search for much needed, novel biomarkers of toxicity more achievable. [source] Evaluation of mutagenic and antimutagenic properties of some bioactive xanthone derivatives using Vibrio harveyi testLETTERS IN APPLIED MICROBIOLOGY, Issue 3 2010Abstract Aims:, Drug safety evaluation plays an important role in the early phase of drug development, especially in the preclinical identification of compounds' biological activity. The Vibrio harveyi assay was used to assess mutagenic and antimutagenic activity of some aminoalkanolic derivatives of xanthone (1,5), which were synthesized and evaluated for their anticonvulsant and hemodynamic activities. Methods and Results:, A novel V. harveyi assay was used to assess mutagenic and antimutagenic activity of derivatives of xanthone 1,5. Two V. harveyi strains were used: BB7 (natural isolate) and BB7M (BB7 derivative containing mucA and mucB genes on a plasmid pAB91273, products of these genes enhance error-prone DNA repair). According to the results obtained, the most beneficial mutagenic and antimutagenic profiles were observed for compounds 2 and 3. A modification of the chemical structure of compound 2 by the replacement of the hydroxy group by a chloride improved considerably the antimutagenic activity of the compound. Thus, antimutagenic potency reached a maximum with the presence of tertiary amine and chloride atom in the side chain. Conclusions:, Among the newly synthesized aminoalkanolic derivatives of xanthone with potential anticonvulsant properties, there are some compounds exhibiting in vitro antimutagenic activity. In addition, it appears that the V. harveyi assay can be applied for primary mutagenicity and antimutagenicity assessment of compounds. Significance and Impact of the Study:, The obtained preliminary mutagenicity and antimutagenicity results encourage further search in the group of amino derivatives of xanthone as the potential antiepileptic drugs also presenting some antimutagenic potential. Furthermore, V. harveyi test may be a useful tool for compounds safety evaluation. [source] Magnitude of Error Introduced by Application of Heart Rate Correction Formulas to the Canine QT IntervalANNALS OF NONINVASIVE ELECTROCARDIOLOGY, Issue 4 2006Andrew King B.V.M.S. Background: Accurate detection of drug-induced QT interval changes is often confounded by concurrent heart rate changes. Application of heart rate correction formulas has been the traditional approach to account for heart rate,induced QT interval changes, and thereby identify the direct effect of the test article on cardiac repolarization. Despite numerous recent studies identifying the imprecision of these formulas they continue to be applied. Methods: Using a chronic atrioventricular dissociated His-paced canine model, heart rate correction methods were evaluated for their ability to generate a corrected QT interval independent of original heart rate. Additionally, His bundle pacing at a heart rate of 60 beats/min allowed calculation of the magnitude of error introduced by application of heart rate correction formulas. Results: Of the fixed parameter heart rate correction formulas, only Van de Water was able to predict corrected QT values independent of the original heart rate. The magnitude of error discovered by application of heart rate correction formulas varied, but in many cases was very large. Bazett's formula was associated with a mean overcorrection of 67.9 ms; Fridericia's 28.7 ms. Van de Water was the best fixed parameter formula with a mean error of 10.8 ms. As expected, group and individual corrections derived from linear regression of the HR-QT data offered improvement over the traditional formulas. Both were able to predict QTc values independent of the heart rate. However, errors of the magnitude of 10 and 6 ms, respectively, were still introduced. Conclusion: Van de Water and linear regression correction methods were superior to others in this study, but all methods generated QTc errors equal to or much greater than the magnitude of interest for drug safety evaluation. [source] Identification of Urinary Biomarkers Useful for Distinguishing a Difference in Mechanism of Toxicity in Rat Model of CholestasisBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 3 2009Kenji Ishihara To inhibit biliary secretion of bile, cyclosporine A was administered to male Sprague,Dawley rats. Obstruction of bile flow was induced by administration of 4,4,-methylene dianiline, ,-naphthylisothiocyanate or bile duct ligation. Clinical pathological and histopathological examinations were performed to confirm cholestatic injury and 1H nuclear magnetic resonance spectral data for urine samples were analysed to determine similarities and differences in profiles of metabolites using the SpotfireŽ. In cyclosporine A-treated groups, serum total bilirubin and bile acid were significantly increased but no remarkable hepatic histopathological-changes were observed. In 4,4,-methylene dianiline-, ,-naphthylisothiocyanate- and bile duct ligation-treated groups, serum alkaline phosphatase, ,-glutamyltranspeptidase and total bilirubin levels increased significantly, and hepatic histopathological-changes were observed. On urinary 1H nuclear magnetic resonance spectral analysis, area intensities derived from 0.66 to 1.90 ppm were decreased by cyclosporine A, whereas they were increased by other treatments. These metabolites were identified using the NMR suiteŽ as bile acids, branched-chain amino acids, n-butyrate, propionate, methyl malonate and valerate. These metabolites were further investigated by K-means clustering analysis. The cluster of these metabolites is considered to be altered by cholestasis. We conclude that bile acids, valine and methyl malonate have a possibility to be urinary cholestatic biomarkers, which distinguish a difference in mechanism of toxicity. 1H nuclear magnetic resonance metabonomics thus appears to be useful for determining the mechanisms of toxicity and can be front-loaded in drug safety evaluation and biomarker discovery. [source] | ||||||||||