Ciesla Stephanie L, Trahan Julissa, Wan W Brad, Beadle James R, Aldern Kathy A, Painter George R, Hostetler Karl Y
Department of Medicine (0676), San Diego VA Healthcare System, University of California, San Diego, 305 Stein Clinical Research Building, 9500 Gilman Drive, La Jolla, CA 92093-0676, USA.
Antiviral Res. 2003 Aug;59(3):163-71. doi: 10.1016/s0166-3542(03)00110-4.
Smallpox was eradicated by vaccination in the 1970s. However, concerns have arisen about the potential use of variola virus as a biological weapon. Most of the world's population has little residual immunity because systematic vaccination against smallpox ceased in the early 1970s. Vaccination of key elements of the population against smallpox is again being considered. However, there are now large numbers of persons who cannot be safely vaccinated with the current vaccine because of AIDS, immunosuppressive drugs, and certain common skin disorders. It would be useful to have a potent orally active drug as an alternative for these persons in case of an outbreak of smallpox. Alkoxyalkyl esters of cidofovir (CDV) have been shown to be highly active and selective against poxviruses in vitro with activities several logs greater than the activity of unmodified CDV. This is due in large part to increased cellular penetration and conversion to CDV-diphosphate, the active antiviral. In this paper, the oral pharmacokinetics of 14C-labeled hexadecyloxypropyl-cidofir (HDP-CDV), octadecyloxyethyl-cidofir (ODP-CDV), and oleyloxypropyl-cidofir (OLP-CDV) are examined and oral bioavailability and tissue distribution assessed and compared with parenteral CDV. The alkoxyalkyl CDVs are highly orally bioavailable and do not concentrate in kidney, the site of the dose-limiting toxicity of CDV. Plasma and tissue drug levels are many times greater than the in vitro EC(50s) for variola, cowpox, and vaccinia viruses. Thus, the compounds are good candidates for further development for prevention and treatment of smallpox infection and the complications of vaccination.
天花在20世纪70年代通过接种疫苗被根除。然而，人们对天花病毒可能被用作生物武器产生了担忧。由于20世纪70年代初系统性天花疫苗接种停止，世界上大多数人口几乎没有残余免疫力。针对天花对关键人群进行疫苗接种再次被考虑。然而，现在有大量人群由于艾滋病、免疫抑制药物和某些常见皮肤病而不能安全接种现有疫苗。万一天花爆发，有一种强效口服活性药物作为这些人的替代选择将很有用。西多福韦（CDV）的烷氧基烷基酯已被证明在体外对痘病毒具有高活性和选择性，其活性比未修饰的CDV高几个对数。这在很大程度上归因于细胞渗透性增加以及转化为活性抗病毒物质CDV - 二磷酸。在本文中，研究了14C标记的十六烷氧基丙基 - 西多福韦（HDP - CDV）、十八烷氧基乙基 - 西多福韦（ODP - CDV）和油氧基丙基 - 西多福韦（OLP - CDV）的口服药代动力学，并评估了口服生物利用度和组织分布，并与肠外给药的CDV进行比较。烷氧基烷基CDV具有很高的口服生物利用度，且不集中在肾脏（CDV剂量限制性毒性的部位）。血浆和组织药物水平比天花、牛痘和痘苗病毒的体外EC(50)值高许多倍。因此，这些化合物是预防和治疗天花感染及疫苗接种并发症进一步开发的良好候选药物。
