Inhibition of woodchuck hepatitis virus replication by adenine arabinoside monophosphate coupled to lactosaminated poly-L-lysine and administered by intramuscular route
✍ Scribed by Prof. Luigi Fiume; Giuseppina Di Stefano; Corrado Busi; Alessandro Mattioli; Maria Rapicetta; Roberto Giuseppetti; Anna Rita Ciccaglione; Claudio Argentini
- Publisher
- John Wiley and Sons
- Year
- 1995
- Tongue
- English
- Weight
- 638 KB
- Volume
- 22
- Category
- Article
- ISSN
- 0270-9139
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✦ Synopsis
We prepared a hepatotropic conjugate, suitable for intramuscular (IM) injection, of lactosaminated poly-Llysine with adenine arabinoside monophosphate (ara-AMP), a drug active against hepatitis B virus (HBW. 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 pg/g equal to 2 pgtg 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 pg/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 mgkg. The conjugate at the daily doses of 4.2 and 7 mgkg (equal to 1.5 and 2.5 mgkg of ara-AMP, respectively) markedly lowered the viremia, which decreased to undetectable levels in the animals treated with the higher dose. Assuming that in HBVinfected 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.