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Author Notes:

Corresponding author: A. A. Ansari, 101 Woodruff Circle, Rm 2309, Dept. of Pathology and Lab Medicine, Emory University, Atlanta, GA 30322; Email: pathaaa@emory.edu; Phone: 404-712-2834; Fax: 404-712-1771

The authors would like to thank Daniel Homerick for excellent technical assistance with the HPLC-MS assay, Dr. K. George Chandy for helpful suggestions with the study, and the Yerkes National Primate Research staff for their excellent care of the animals and sample collections.

H. Wulff is an inventor on the University of California patent claiming 5-(4- phenoxybutoxy)psoralen and related compounds for the treatment of autoimmune diseases. H. Wulff further holds founder stock in a start-up company (Airmid LLC) that is developing 5-(4-phenoxybutoxy)psoralen for the treatment of multiple sclerosis and possibly of psoriasis.

Subjects:

Research Funding:

This work was supported by grants RO1 27057, IR24RR16988, RR00165, and RO1 GM076063 from the National Institutes of Health.

Keywords:

  • effector memory T-cells
  • SIV
  • PAP-1
  • K+ channel blockers

Pharmacokinetics, Toxicity, and Functional Studies of the Selective Kv1.3 Channel Blocker 5-(4-Phenoxybutoxy)Psoralen in Rhesus Macaques

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Journal Title:

Experimental Biology and Medicine

Volume:

Volume 232, Number 10

Publisher:

, Pages 1338-1354

Type of Work:

Article | Post-print: After Peer Review

Abstract:

The small molecule PAP-1 (5-(4-phenoxybutoxy)psoralen) is a selective blocker of the voltage-gated potassium channel Kv1.3 that is highly expressed in cell membranes of activated effector memory T-cells (TEM). The blockade of Kv1.3 results in membrane depolarization and inhibition of TEM cell proliferation and function. In this study, the in vitro effects of PAP-1 on rhesus macaques (RM) T cells and the in vivo toxicity and pharmacokinetics (PK) were examined in RM with the ultimate aim of utilizing PAP-1 to define the role of TEM in RM infected with simian immunodeficiency virus (SIV). Electrophysiological studies on RM T-cells revealed a Kv1.3 expression pattern similar to that in human T-cells. Thus, PAP-1 effectively suppressed RM TEM cell proliferation. Intravenously administered PAP-1 showed a half-life of 6.4 hrs and the volume of distribution suggested that it is distributed extensively into extravascular compartments. Orally administered PAP-1 was efficiently absorbed and plasma concentrations in RM undergoing a 30-day chronic dosing study indicated that PAP-1 levels that are suppressive to TEM cells in vitro can be achieved and maintained in vivo at a non-toxic dose. PAP-1 selectively inhibited TEM function in vivo as indicated by a modest reactivation of cytomegalovirus (CMV) replication. Immunization of these chronically-treated RM with the live influenza A/PR8 virus suggest that the development of an in vivo flu-specific central memory response was unaffected by PAP-1. These RM remained disease-free during the entire course of the PAP-1 study. Collectively these data provide a rational basis for future studies with PAP-1 in SIV-infected RM.

Copyright information:

© 2007 by the Society for Experimental Biology and Medicine

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