Detection and Mechanistic Comparison of Two Anti-Trypanosomal Diamidines in a Rat Renal Model Public Deposited

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  • March 20, 2019
Creator
  • Goldsmith, Rachel B.
    • Affiliation: School of Medicine, Department of Pathology and Laboratory Medicine
Abstract
  • There is an urgent need for new treatments for human African trypanosomiasis (HAT), a neglected parasitic disease indigenous to sub-Saharan Africa. HAT progresses in two stages; the second stage is fatal without treatment. Current treatments for both stages are toxic or difficult to administer. Pafuramidine was in phase III clinical trials for first stage HAT. In an expanded phase I trial, 7% of patients experienced severe delayed nephrotoxicity resulting in the termination of the clinical development of pafuramidine. Furamidine, the active diamidine metabolite of pafuramidine, was detected in rat kidney eight days after administration of pafuramidine, indicating it was likely the nephrotoxic agent. A second generation diamidine, CPD-0801, was shown to be highly active in first stage HAT mouse and primate models. In addition, it is the only compound that is curative in both second stage HAT mouse and primate models. While the in vivo results for CPD-0801 are exciting, it has the drawback of being structurally related to furamidine. For this molecule to proceed to clinical trial, it must be demonstrated that CPD-0801 is less likely to induce nephrotoxicity than pafuramidine. The current study determined that rat kidney exposure to CPD-0801 was 14 times less than furamidine. This discovery was a positive indication that CPD-0801 may have less potential for the delayed nephrotoxic effect. In an effort to explain this promising finding, a series of studies were designed and executed. Based on imaging and transport studies, CPD-0801 and furamidine can enter tubule cells independent of organic cation transporters 1/2, and exit possibly through multidrug and toxin extruder. Additionally, due to intracellular binding, five times more CPD-0801 was freely available for transport. While the transport data may explain the cell specificity of diamidines, binding may explain differences in accumulation and excretion. Future studies should be aimed at defining and measuring the intracellular binding of this molecule. Based on this work, CPD-0801 has improved accumulation, binding and excretion characteristics as compared to furamidine in rat kidney. These data may indicate that CPD-0801 is less likely to be nephrotoxic than furamidine. Therefore, development of CPD-0801 for second stage HAT should continue.
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  • " ... in partial fulfillment of the requirements for the degree of Doctorate in Philosophy in the Department of Pathology and Laboratory Medicine."
Advisor
  • Tidwell, Richard R.
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  • Chapel Hill, NC
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  • Open access
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