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Preliminary in vivo pharmacokinetic and pharmacodynamic evaluation of a novel calcineurin-independent inhibitor of NFAT

  • Original Article
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Transplant International

Abstract

A-285222 (A-285) is a bis-trifluoromethyl-pyrazole (BTP), a novel class of immunosuppressive agents that inhibit NFAT activity in vitro in human and non-human primate cells through a calcineurin-independent mechanism. In this preliminary study, we treated cynomolgus monkeys with different doses of A-285 for several days. Blood was collected from all animals at different times during the study. From these samples, plasma concentrations of A-285 were measured by liquid chromatography/mass spectrometry (LC/MS), and intracellular T-cell production of the cytokines IL-2, IFN-γ, and TNF-α was quantified by flow cytometry using a mitogen-stimulated whole blood assay. Marked inhibition of cytokine production occurred after administration of the first dose of A-285, and this effect was comparable to that of cyclosporine. While neurological toxic side effects were seen when the plasma concentration of A-285 exceeded 4 µg/ml, at lower plasma levels the drug was well tolerated over 2 weeks and its pharmacodynamic effects were sustained throughout this time.

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Acknowledgements

This research was supported by grants from the Max Kade Foundation, New York, N.Y., the Ralph and Marian Falk Trust, the Hedco Foundation, and Abbott Laboratories, Abbott Park, Ill.

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Authors and Affiliations

  1. Department of Cardiothoracic Surgery, Transplantation Immunology Laboratory, Stanford, California, USA

    Tudor Bîrsan, Camille Dambrin & Randall E. Morris

  2. Transplantation and Immunology Research, Novartis Pharma AG, 4002, Basle, Switzerland

    Randall E. Morris

  3. Abbott Laboratories, Abbott Park, Illinois, USA

    Wolfgang Jacobsen & Uwe Christians

  4. Department of Biopharmaceutical Sciences, School of Pharmacy, University of California, San Francisco, California, USA

    Kennan C. Marsh, Stevan W. Djuric, Karl W. Mollison & George W. Carter

Authors
  1. Tudor Bîrsan
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  2. Camille Dambrin
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  3. Kennan C. Marsh
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  4. Wolfgang Jacobsen
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  5. Stevan W. Djuric
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  6. Karl W. Mollison
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  7. Uwe Christians
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  8. George W. Carter
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  9. Randall E. Morris
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Corresponding author

Correspondence to Randall E. Morris.

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Bîrsan, T., Dambrin, C., Marsh, K.C. et al. Preliminary in vivo pharmacokinetic and pharmacodynamic evaluation of a novel calcineurin-independent inhibitor of NFAT. Transpl Int 17, 145–150 (2004). https://doi.org/10.1007/s00147-003-0676-1

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  • DOI: https://doi.org/10.1007/s00147-003-0676-1

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