Zidampidine, an aryl phosphate derivative of AZT: in vivo pharmacokinetics, metabolism, toxicity, and anti-viral efficacy against hemorrhagic fever caused by Lassa virus.
The pharmacokinetics, metabolism, and toxicity of Zidampidine, an aryl phosphate derivative of AZT, 3'-azidothymidine-5'-[p-bromophenyl methoxyalaninyl phosphate] were investigated in CD-1 mice. Following iv injection, Zidampidine was rapidly converted to its metabolites Ala-AZT-MP and AZT. Zidampidine was not toxic to mice at doses up to 250mg/kg. We next examined the therapeutic effect of Zidampidine in CBA mice challenged with intracerebral injections of the Josiah strain of Lassa virus. Mice were treated either with vehicle or non-toxic doses of Zidampidine administered intraperitoneally 24h prior, 1h prior, and 24, 48, 72, and 96h after virus inoculation. The probability of survival following the Lassa challenge was significantly improved for Zidampidine-treated mice (Kaplan Meier, Log-Rank p value<0.0001). This pilot study provides the basis for future preclinical evaluation of Zidampidine and its potential as a new agent for the treatment of viral hemorrhagic fevers caused by Lassa virus.
Uckun
F M
FM
Drug Discovery Program, Parker Hughes Center for Clinical Immunology, 2699 Patton Road, St. Paul, MN 55113, USA. fatih_uckun@ih.org
Venkatachalam
T K
TK
Erbeck
D
D
Chen
C L
CL
Petkevich
A S
AS
Vassilev
A
A
D000818:Animals; D054306:Dideoxynucleotides; D004195:Disease Models, Animal; D005260:Female; D006868:Hydrolysis; D007835:Lassa Fever / Q000188:drug therapy*; D007836:Lassa virus / Q000187:drug effects*; D051379:Mice; D008813:Mice, Inbred ICR; D015394:Molecular Structure; D013942:Thymine Nucleotides; D013997:Time Factors; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity
C118768:3'-azido-3'-deoxythymidine-5'-(4-bromophenyl methoxyalaninyl phosphate); D054306:Dideoxynucleotides; D013942:Thymine Nucleotides; D015215:Zidovudine