Different effect of benzylacyclouridine on the toxic and therapeutic effects of azidothymidine in mice.

Important note: Information in this article was accurate in 1991. The state of the art may have changed since the publication date.

Different effect of benzylacyclouridine on the toxic and therapeutic effects of azidothymidine in mice.

Blood. 1990 Dec 1;76(11):2216-21. Unique Identifier : AIDSLINE MED/91077426
Falcone A; Darnowski JW; Ruprecht RM; Chu SH; Brunetti I; Calabresi P; Department of Medicine, Roger Williams General Hospital, Boston,; MA.

Abstract: It has been reported that in vitro uridine (Urd) can reverse azidothymidine (AZT) cytotoxicity without decreasing anti-human immunodeficiency virus (HIV) activity. Our studies in mice have shown that daily oral doses of benzylacyclouridine (BAU), an inhibitor of Urd breakdown, also reduces AZT hematologic toxicity, presumably by elevating the plasma concentration of Urd. We now extend these murine studies and report the effect of various doses of exogenous Urd, various doses of BAU, or the combination of BAU and Urd, administered daily, on AZT-induced toxicity. In mice receiving concomitant AZT, daily doses of Urd of 1,000 to 2,000 mg/kg increase peripheral reticulocytes and slightly reduce AZT-induced hematologic toxicity. However, the range of effective doses is narrow, and higher doses of Urd (greater than 3,000 mg/kg/d) significantly enhance hematologic toxicity. At its most effective dose, (2,000 mg/kg/d), Urd produces 28% mortality. In contrast, BAU doses up to 300 mg/kg/d reduced AZT-related hematologic toxicity in a dose-dependent manner without mortality. Higher daily doses of BAU and the combination of BAU with low doses of Urd were not more effective. Studies conducted in mice infected with the Rauscher murine leukemia virus (RLV) indicate that BAU does not impair the antiretroviral effect of AZT when administered at doses that reduce AZT-induced anemia and leukopenia. These findings may be significant for the treatment of patients with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex.

Keywords: Acquired Immunodeficiency Syndrome/DRUG THERAPY Anemia/CHEMICALLY INDUCED/*PREVENTION & CONTROL Animal Dose-Response Relationship, Drug Female Kinetics Leukemia, Experimental/DRUG THERAPY Leukopenia/CHEMICALLY INDUCED/*PREVENTION & CONTROL Mice Mice, Inbred BALB C Rauscher Virus/DRUG EFFECTS Support, Non-U.S. Gov't Support, U.S. Gov't, P.H.S. Uracil/*ANALOGS & DERIVATIVES/ADMINISTRATION & DOSAGE/THERAPEUTIC USE Uridine/ADMINISTRATION & DOSAGE/BLOOD/PHARMACOLOGY Zidovudine/PHARMACOLOGY/*TOXICITY/THERAPEUTIC USE JOURNAL ARTICLE
910430
M9140660

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