| Autor: |
Harrington, Y. A., Korb, S. K., Cozzi, N. V., Nye, S. H., Wittenburg, A. L., Vernon, H. J., Evans, D. L., O'Connor, J. A., Lapczynski, L. H., Dahly-Vernon, A. J., Baye, J. F., Roman, R. J., Jacob, H. J. |
| Předmět: |
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| Zdroj: |
Clinical Pharmacology & Therapeutics; Feb2006, Vol. 79 Issue 2, pP82-P82, 1p |
| Abstrakt: |
Background/aims: Over 90% of drug candidates fail in clinical trials, incurring high costs to the pharmaceutical industry. To address this problem, PhysioGenix has developed a novel combinatorial breeding strategy, the PharmGenix™ panel, to capture greater genetic diversity within the rat genome and allow for preclinical drug screening. Tacrine, which causes hepatotoxicity in a small percentage of the human population, was tested to demonstrate the utility of this panel.Methods: A single dose of tacrine (35 mg/kg) was administered to each of six hybrid PharmGenix™ strains, CD-IGS and CDF strains. Rats were euthanized twenty-four hours later and serum analyzed for alanine transaminase (ALT) and aspartate transaminase (AST) levels, indicators of hepatotoxicity.Results: Tacrine did not significantly elevate ALT levels in CD-IGS or CDF, however, the PharmGenix™ panel showed significant ALT elevations in five of the six strains, ranging from 111% to 142% of control values. CD-IGS and CDF exhibited increases in AST levels of 82% and 174%, respectively, while the PharmGenix ™ rats showed much higher AST levels, ranging between 621% and 1069% of control values in four of the six strains.Conclusions: The ability to detect significant AST and ALT elevations in the PharmGenix™ panel, but not in CD-IGS or CDF, suggests a genetic component underlies the development of tacrine toxicity and may have alerted the pharmaceutical industry to toxicity currently seen in a small percentage of the human population.Clinical Pharmacology & Therapeutics (2005) 79, P82–P82; doi: 10.1016/j.clpt.2005.12.294 [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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