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          PAG as Biomarker for Phospholipidosis
          Amiodarone Study
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Monitoring Phospholipidosis of Drug Candidates

Monitoring PAG for the identification of phospholipidosis can be easily implemented into existing routine toxicity studies. In this example it is shown that PAG is a very sensitive biomarker for phospholipidosis. In this study two compounds were administered with a single dose to animals. Thereby two dose-groups per compound and one control group were used. Both compounds had nearly identical structures (several hundred Daltons) with the only difference shown in the figure below. Whereas compound B is a clean compound, compound A was identified as phospholipidosis inducer (with a by far lower potential compared to amiodarone). In congruence with histopathology increased PAG levels were only found for compound A, whereby the levels for the low-dosed group were increased by a factor of two and the levels of the high-dosed group were increased by a factor of four 24 hours after dosing. In addition a significant down-regulation of citrate cycle intermediates was found for the high-dosed group of compound A. Only for this group organ damages were found reconfirming the assumption that associate organ toxicity can be monitored by citrate cycle intermediates in combination with PAG.

Compound A

Compound B

Structures of two compounds (R is similar for both compound with a size of several hundred Daltons) and mean PAG levels for control animals and two dose groups per compound.




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