Liver targeting of adenine arabinoside monophosphate (ara-AMP) by coupling to lactosaminated human serum albumin.

Abstract

Adenine arabinoside monophosphate (ara-AMP) is a potent antiviral agent against hepadnaviruses but its use in the treatment of chronic hepatitis B is hampered by severe neurotoxic side effects, which are dose dependent. In order to reduce these adverse reactions and to adopt the lysosomotropic approach to antiviral chemotherapy, ara-AMP was coupled to lactosaminated human serum albumin (L-HSA), a neoglycoprotein which specifically penetrates hepatocytes. In mice with Ectromelia virus hepatitis, ara-AMP coupled with L-HSA was selectively delivered to liver cells in which it was released in a pharmacologically active form. Moreover in woodchucks with WHV hepatitis and in patients with chronic HBV infection, coupled ara-AMP inhibited hepadnavirus replication at a dose (1.5 mg/kg/day) 3-6 times lower than the free drug. A clinical study using a 28-day period of treatment with conjugated ara-AMP at 1.5 mg/kg/day has now been started. In the first 6 patients the treatment has been completed. The conjugate inhibited virus growth without producing any side effects. L-HSA-ara-AMP conjugate must be given by intravenous infusion. New hepatotropic conjugates of ara-AMP have been recently prepared which could be administered by bolus intravenous injection or by intramuscular route. These complexes might assure a better compliance in patients with hepatitis B virus infection for a long lasting liver targeted antiviral treatment.

• Authors: L Fiume, C Busi, G Di Stefano, A Mattioli, M Torrani-Cerenzia, F Bonino, G Capra, W De Bernardi, A Ponzetto, B Lavezzo
• Journal: The Italian journal of gastroenterology (Ital J Gastroenterol) Vol. 27 Issue 4 Pg. 189-92 (May 1995) ISSN: 0392-0623 [Print] Italy
• PMID: 8520036 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amino Sugars
• Antiviral Agents
• Drug Carriers
• Serum Albumin
• lactosaminated polylysine-adenine arabinoside monophosphate
• lactosaminated serum albumin
• Vidarabine Phosphate
• Polylysine

Topics

• Amino Sugars (administration & dosage, pharmacokinetics)
• Animals
• Antiviral Agents (administration & dosage, pharmacokinetics)
• Drug Carriers
• Hepatitis B (drug therapy, virology)
• Humans
• Liver (metabolism)
• Macaca fascicularis
• Marmota
• Mice
• Polylysine (administration & dosage, analogs & derivatives, pharmacokinetics)
• Rabbits
• Rats
• Serum Albumin (metabolism)
• Vidarabine Phosphate (administration & dosage, analogs & derivatives, pharmacokinetics)