title: Biologic effects after a single dose of poly(I):poly(C12U) in healthy volunteers.
abstract: Poly(I):poly(C12U) (mismatched double-stranded RNA; atvogen), an interferon inducer, is active against human immunodeficiency virus in vitro. To determine the extent and duration of the biologic effects of poly(I):poly(C12U), we administered a single dose of the drug to healthy volunteers in a randomized, double-blind, placebo-controlled 2-week crossover study. We analyzed blood for alpha and gamma interferons, neopterin, 2',5'-oligoadenylate synthetase, lymphocyte surface markers, lymphocyte proliferation after exposure to soluble antigens and mitogens, and natural killer cell activity. Minimal biologic effects were observed after administration of a single 200-mg dose to four volunteers; therefore, the dose was increased to 600 mg in 10 subjects. Only neopterin levels and symptoms were greater after administration of 600 mg of poly(I):poly(C12U) than after administration of placebo (Wilcoxon signed rank sum test, P = 0.06). A definite response in 2',5'-oligoadenylate synthetase activity, however, was seen in a few subjects. Neither alpha nor gamma interferon was detectable in serum after poly(I):poly(C12U) dosing. The neopterin changes after administration of poly(I):poly(C12U) were similar at both poly(I):poly(C12U) dose levels, with an early decrease at 6 h, a peak at 1 day, and a gradual decrease toward the baseline over the following 3 days. A mild flu-like syndrome occurred in one-half of the subjects following administration of poly(I):poly(C12U) and in only one subject following administration of placebo. This syndrome resolved within 16 h after poly(I):poly(C12U) dosing. We conclude that poly(I):poly(C12U) does not induce measurable levels of interferon and causes only minimal biologic or toxic effects among those parameters measured after administration of a single dose in the 200- to 600-mg dose range in health volunteers.
authors.affiliation: Department of Medicine, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, Maryland 21205.
authors.forename: C W
authors.initials: CW
authors.lastname: Hendrix
authors.forename: J B
authors.initials: JB
authors.lastname: Margolick
authors.forename: B G
authors.initials: BG
authors.lastname: Petty
authors.forename: R B
authors.initials: RB
authors.lastname: Markham
authors.forename: L
authors.initials: L
authors.lastname: Nerhood
authors.forename: H
authors.initials: H
authors.lastname: Farzadegan
authors.forename: P O
authors.initials: PO
authors.lastname: Ts'o
authors.forename: P S
authors.initials: PS
authors.lastname: Lietman
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000187:drug effects; D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology*; D015415:Biomarkers; D001708:Biopterins / Q000031:analogs & derivatives / Q000032:analysis; D004311:Double-Blind Method; D006801:Humans; D007372:Interferons / Q000032:analysis; D007694:Killer Cells, Natural / Q000187:drug effects; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D019798:Neopterin; D009504:Neutrophils / Q000187:drug effects; D011070:Poly I-C / Q000008:administration & dosage / Q000494:pharmacology*; D011072:Poly U / Q000008:administration & dosage / Q000494:pharmacology*; D012330:RNA, Double-Stranded / Q000008:administration & dosage / Q000494:pharmacology*; D016176:T-Lymphocyte Subsets / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D015415:Biomarkers; D012330:RNA, Double-Stranded; D001708:Biopterins; D011072:Poly U; D019798:Neopterin; D007372:Interferons; C047490:poly(I).poly(c12,U); D015088:2',5'-Oligoadenylate Synthetase; D011070:Poly I-C