title: Inhibition of woodchuck hepatitis virus replication by adenine arabinoside monophosphate coupled to lactosaminated poly-L-lysine and administered by intramuscular route.
abstract: We prepared a hepatotropic conjugate, suitable for intramuscular (IM) injection, of lactosaminated poly-L-lysine with adenine arabinoside monophosphate (ara-AMP), a drug active against hepatitis B virus (HBV). We studied its organ distribution in mice and its antiviral activity in woodchucks that are carriers of woodchuck hepatitis virus (WHV). In mice, after IM administration of a conjugate tritiated in the drug moiety (5.2 micrograms/g equal to 2 micrograms/g of ara-AMP) radioactivity in liver was three times greater than in kidney, spleen, and intestine. On the contrary, after IM injection of unconjugated, tritiated, ara-AMP (5 micrograms/g) the amounts of radioactivity in liver, spleen, and kidney were similar. Unconjugated ara-AMP and the conjugate were administered IM to woodchucks for 13 days. Unconjugated ara-AMP decreased viremia at the daily dose of 5 mg/kg but was ineffective at 2.5 mg/kg. The conjugate at the daily doses of 4.2 and 7 mg/kg (equal to 1.5 and 2.5 mg/kg of ara-AMP, respectively) markedly lowered the viremia, which decreased to undetectable levels in the animals treated with the higher dose. Assuming that in HBV-infected patients the same doses will be active, then the amount of conjugate (soluble at 200 mg/mL) required by a 70-kg patient will be contained in a volume of 1.5 to 2.5 mL, compatible with the IM route. Compared with a similar ara-AMP complex with lactosaminated human albumin, currently being studied in clinical trials for the treatment of chronic type B hepatitis, which must be infused intravenously, the present conjugate might provide more patient compliance because of IM administration.
authors.affiliation: Dipartimento di Patologia sperimentale, Università di Bologna, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Fiume
authors.forename: G
authors.initials: G
authors.lastname: Di Stefano
authors.forename: C
authors.initials: C
authors.lastname: Busi
authors.forename: A
authors.initials: A
authors.lastname: Mattioli
authors.forename: M
authors.initials: M
authors.lastname: Rapicetta
authors.forename: R
authors.initials: R
authors.lastname: Giuseppetti
authors.forename: A R
authors.initials: AR
authors.lastname: Ciccaglione
authors.forename: C
authors.initials: C
authors.lastname: Argentini
mesh_terms: D000606:Amino Sugars / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004279:DNA, Viral / Q000097:blood; D004355:Drug Stability; D005260:Female; D006509:Hepatitis B / Q000188:drug therapy; D017919:Hepatitis B Virus, Woodchuck / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007262:Infusions, Intravenous; D007700:Kinetics; D008297:Male; D008392:Marmota / Q000821:virology; D051379:Mice; D011107:Polylysine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D001084:Vidarabine Phosphate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000606:Amino Sugars; D000998:Antiviral Agents; D004279:DNA, Viral; C086198:lactosaminated polylysine-adenine arabinoside monophosphate; D001084:Vidarabine Phosphate; D011107:Polylysine