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Single-dose hemodynamic toxicity and pharmacokinetics of a partial phosphorothioate anti-HIV oligonucleotide (AR177) after intravenous infusion to cynomolgus monkeys

TL Wallace, SA Bazemore, DJ Kornbrust and PA Cossum

Aronex Pharmaceuticals, Inc., The Woodlands, Texas, USA.

5' GTGGTGGGTGGGTGGGT-3' (AR177) is a 17-mer oligonucleotide with anti- human immunodeficiency virus (HIV) activity that is composed of a phosphodiester backbone and single phosphorothioate linkages at the 3' and 5' ends. A hemodynamic toxicity study was conducted in which cynomolgus monkeys were infused i.v. over a 10-minute period with single doses of 5, 20 or 50 mg AR177/kg or saline. Blood pressure, ECG, clinical chemistry, hematology, complement factors, coagulation parameters and the AR177 plasma concentration were determined. AR177 did not cause any mortality in this study, nor did it cause changes in blood pressure, ECG, clinical chemistry or hematology parameters at any dose. There was a minimal, dose-dependent increase in the levels of complement split product Bb and total hemolytic complement. There was a significant dose-dependent and reversible inhibition of coagulation with the 20- and 50-mg/kg doses that lasted up to several hours after infusion. The time course of the inhibition of coagulation closely matched the plasma levels of AR177. There was a no-effect plasma AR177 concentration vs. activated partial thromboplastin time of approximately 60 to 100 micrograms AR177/ml, above which there was prolongation of activated partial thromboplastin time. These data demonstrate that AR177 does not cause significant hemodynamic toxicity at the doses studied and that this drug could be administered as a rapid infusion without any acute, life-threatening effects at doses that produce plasma concentrations that have shown anti-HIV activity in vitro.

Volume 278, Issue 3, pp. 1306-1312, 09/01/1996
Copyright © 1996 by American Society for Pharmacology and Experimental Therapeutics




This article has been cited by other articles:


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 Toxicol SciHome page
T. L. Wallace, C. Gamba-Vitalo, K. S. Loveday, and P. A. Cossum
Acute, Multiple-Dose, and Genetic Toxicology of AR177, an Anti-HIV Oligonucleotide
Toxicol. Sci., January 1, 2000; 53(1): 63 - 70.
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 J. Pharmacol. Exp. Ther.Home page
T. L. Wallace, S. A. Bazemore, K. Holm, P. M. Markham, J. P. Shea, N. Chaudhary, and P. A. Cossum
Pharmacokinetics and Distribution of a 33P-labeled Anti-Human Immunodeficiency Virus Oligonucleotide (AR177) after Single- and Multiple-Dose Intravenous Administration to Rats
J. Pharmacol. Exp. Ther., March 1, 1997; 280(3): 1480 - 1488.
[Abstract] [Full Text]


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Copyright © 1996 by the American Society for Pharmacology and Experimental Therapeutics.