Fiume L, Busi C, Di Stefano G, Mattioli A, Torrani-Cerenzia M, Bonino F, Capra G, De Bernardi W, Ponzetto A, Lavezzo B
Dipartimento di Pathologia Sperimentale, Università di Bologna, Italy.
Ital J Gastroenterol. 1995 May;27(4):189-92.
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.
单磷酸阿糖腺苷（ara - AMP）是一种针对嗜肝DNA病毒的强效抗病毒药物，但其在慢性乙型肝炎治疗中的应用受到严重神经毒性副作用的阻碍，这些副作用具有剂量依赖性。为了减少这些不良反应并采用溶酶体亲和方法进行抗病毒化疗，将ara - AMP与乳糖胺化人血清白蛋白（L - HSA）偶联，L - HSA是一种能特异性穿透肝细胞的新糖蛋白。在感染痘苗病毒肝炎的小鼠中，与L - HSA偶联的ara - AMP被选择性地递送至肝细胞，并以药理活性形式释放。此外，在感染土拨鼠肝炎病毒的土拨鼠和慢性乙肝病毒感染患者中，偶联的ara - AMP抑制嗜肝DNA病毒复制的剂量（1.5毫克/千克/天）比游离药物低3至6倍。一项使用1.5毫克/千克/天的偶联ara - AMP进行为期28天治疗的临床研究现已启动。前6例患者已完成治疗。该偶联物抑制病毒生长且未产生任何副作用。L - HSA - ara - AMP偶联物必须通过静脉输注给药。最近制备了ara - AMP的新型亲肝偶联物，可通过静脉推注或肌肉注射给药。这些复合物可能确保乙肝病毒感染患者在长期的肝脏靶向抗病毒治疗中具有更好的依从性。
