Emerging Safety Science Workshop Summary (2008) / Chapter Skim
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2 Investigative Toxicology: The State of the Art
2 Investigative Toxicology: The State of the Art
Pages 5-12
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From page 5... ...
Frazier also explained that, instead of asking the classic mechanistic questions that many people try to answer using toxicology, his group first tries to decide whether a particular toxicologic liability is a class-wide pharmacological phenomenon or is due to some individual, off-target liability. This is information can help in making decisions about lead optimization, and about whether to take a program forward or revert to a backup program and start over.
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From page 6... ...
Therefore, they decided to look at the different compounds, see which ones caused free r adical production, and then determine whether this superoxide production correlated with the alveolar damage. Using an in vitro model that employed an A549 lung adenocarcinoma cell line, they incubated the cells with either the compound or a control for 4 hours, exposed the cells to a hydroethidine dye, and then ran them through a flow cytometer with a 488 nm argon laser.
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From page 7... ...
The results correlated remarkably well: the candidates that generated large amounts of superoxide showed lung lesions after 10 days, whereas those that induced limited superoxide production did not show lesions. The candidate with the least superoxide production, which was selected for moving forward, failed to elicit pulmonary hemorrhaging even after a 28-day toxicology study.
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From page 8... ...
However, they hypothesized that because the target population for these drugs is adults, and adults have closed growth plates, the presence of the lesions in test animals might not be problematic. Ten-day toxicological studies in rats showed a clear dose–response relationship between the various compounds and hypertrophy in the growth plates.
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From page 9... ...
• Studies on Von Kossa–stained frozen whole-leg preparations yielded mineralization information indicating that the bone changes were limited to the area right at the growth plate, with very minimal changes in the subphyseal area. This finding had great clinical relevance because it implied that the only changes caused by the compounds were associated with an actively growing growth plate, which would not be expected in individuals much older than about age 16–17.
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From page 10... ...
Thus the group was able to conclude that the risk to the target population should be fairly limited, since those who would be given the drug would be old enough that they would have closed physes. HEART VALVE lesions The third pathology associated with the ALK5 inhibitors was heart valve lesions.
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From page 11... ...
The heart valve lesions were novel. They had very rapid onset and caused potentially irreversible functional damage, and even though they appeared only at doses much higher than clinical levels, they were considered problematic.
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From page 12... ...
Furthermore, it is important to sample the target populations cleanly, as there are multiple cell populations within every organ, and confocal imagery or laser capture microdissection (LCM) can be used to identify and isolate the individual cell populations of interest.
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