Important note: Information in this article was accurate in 1990. The state of the art may have changed since the publication date.
ANTIRETROVIRAL EFFICACY, PHARMACOKINETICS, AND TOXICITY OF PHOSPHONOFORMATE IN THE FELINE LEUKEMIA VIRUS/CAT MODEL
Diss Abstr Int [B]; 50(8):3413 1990. Unique Identifier : AIDSLINE ICDB/90665051 Swenson CL; Ohio State Univ.
Abstract:
In vitro and in vivo studies of the antiretroviral efficacy, pharmacokinetics, and toxicity of phosphonoformate (PFA) were conducted using the feline leukemia virus (FeLV)/cat system as a model for acquired immunodeficiency syndrome (AIDS). FeLV infection of 3201 cells, on FeLV-negative feline lymphoma cell line, was inhibited by greater than 70% at a concentration of only 1 uM PFA and by greater than 90% at concentrations of a 64 to 256 uM PFA as evidenced by reverse transcriptase activity. FeLV infection of 81C cells, a sarcoma-positive, leukemia-negative feline fibroblast cell line, was inhibited by greater than 98% at concentrations of 256 to 512 uM PFA. PFA directly inactivated progeny virus of FL-74 cells, an FeLV-infected feline lymphoma cell line, without influencing whole virus production. Mean plasma PFA clearance was two-fold higher in young than adult cats, presumably due to enhanced bone accumulation of PFA in young cats. Mean oral bioavailability in young cats was 35%. A technique for chronic continuous intravenous infusion in young and adult cats was developed for administration of PFA. Continuous intravenous PFA administration (1,000 mg/kg/day) prevented FeLV viremia in 4 of 6 specific pathogen-free cats while 12 of 12 control cats became viremic following intravenous inoculation with FeLV. PFA treatment caused reduced weight gain, rickets-like bone lesions, and decreased plasma alkaline phosphatase, phosphorus, and calcitriol. Further investigation of PFA-induced bone lesions revealed widened growth plates, increased osteoid, failure of mineralization, and decreased mineralized area in young cats treated with PFA for 14 days. Adult cats treated with PFA for 14 days developed osteomalacia and failure of mineralization. Bone lesions in PFA-treated cats were similar to those reported for animals treated with bisphosphonates. Results of these studies indicate that PFA has significant antiretroviral activity in vitro and in vivo. PFA-induced bone lesions observed in cats suggest a need to evaluate human patients treated with PFA for metabolic bone disease. (Full text available from University Microfilms International, Ann Arbor, MI, as Order No. AAD90-02027)
Keywords: Animal Antiviral Agents/PHARMACOKINETICS/TOXICITY/*THERAPEUTIC USE Bone and Bones/METABOLISM Cat Diseases/*DRUG THERAPY/METABOLISM Cats Half-Life Leukemia/DRUG THERAPY/METABOLISM/*VETERINARY Leukemia Virus, Feline/DRUG EFFECTS/PHYSIOLOGY Osteomalacia/CHEMICALLY INDUCED Phosphonoacetic Acid/*ANALOGS & DERIVATIVES/PHARMACOKINETICS/ TOXICITY/THERAPEUTIC USE Virus Replication/DRUG EFFECTS THESIS 900630
M9060635
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Important note: Information in this article was accurate in 1990. The state of the art may have changed since the publication date.
