Liver targeting of adenine arabinoside monophosphate (ara-AMP) by coupling to lactosaminated human serum albumin.
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.
Fiume
L
L
Dipartimento di Pathologia Sperimentale, Università di Bologna, Italy.
Busi
C
C
Di Stefano
G
G
Mattioli
A
A
Torrani-Cerenzia
M
M
Bonino
F
F
Capra
G
G
De Bernardi
W
W
Ponzetto
A
A
Lavezzo
B
B
D000606:Amino Sugars / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004337:Drug Carriers; D006509:Hepatitis B / Q000188:drug therapy / Q000821:virology; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008252:Macaca fascicularis; D008392:Marmota; D051379:Mice; D011107:Polylysine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D011817:Rabbits; D051381:Rats; D012709:Serum Albumin / Q000378:metabolism; D001084:Vidarabine Phosphate / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
D000606:Amino Sugars; D000998:Antiviral Agents; D004337:Drug Carriers; D012709:Serum Albumin; C086198:lactosaminated polylysine-adenine arabinoside monophosphate; C046912:lactosaminated serum albumin; D001084:Vidarabine Phosphate; D011107:Polylysine