LIVER TARGETING OF ADENINE-ARABINOSIDE MONOPHOSPHATE (ARA-AMP) BY COUPLING TO LACTOSAMINATED HUMAN SERUM-ALBUMIN

Adenine arabinoside monophosphate (ara-AMP) is a potent antiviral agen t against hepadnaviruses but its use in the treatment of chronic hepat itis B is hampered by severe neurotoxic side effects, which are dose d ependent. 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 whic h specifically penetrates hepatocytes, In mice with Ectromelia virus h epatitis, ara-AMP coupled with L-HSA was selectively delivered to live r cells in which it was released in a pharmacologically active form, M oreover 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 s tudy 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 prod ucing any side effects, L-HSA-ara-AMP conjugate must be given by intra venous infusion, New hepatotropic conjugates of ara-AMP have been rece ntly prepared which could be administered by bolus intravenous injecti on or by intramuscular route, These complexes might assure a better co mpliance in patients with hepatitis B virus infection for a long lasti ng liver targeted antiviral treatment.