Hartmann K, Ferk G, North T W, Pedersen N C
I. Medizinische Tierklinik, München, Germany.
Antiviral Res. 1997 Sep;36(1):11-25. doi: 10.1016/s0166-3542(97)00030-2.
9-[(2R,5R-2,5-dihydro-5-phosphonomethoxy)-2-furanyl]adenine, or D4API, was tested in the feline immunodeficiency virus (FIV) infection model and found to be significantly more inhibitory in vitro than its parent compound 9-phosphonylmethoxethyl adenine (PMEA). Cytotoxicity was less than for PMEA or azidothymidine (AZT) for culture periods of 7 days, but more toxic after 10 days. D4API was rapidly absorbed by cats following subcutaneous inoculation, with a plasma half-life of less than 1 h after intravenous inoculation and between 2 and 3 h after subcutaneous injection. Peripheral blood mononuclear cells collected from cats given a single dose of D4API were refractory, however, to FIV infection in vitro for up to 24 h. Given its prolonged intracellular phase and high selectivity index, high dose D4API therapy was tested for its ability to abort an acute (i.e. 2 week) FIV infection. A divided daily dose of D4API, which was one-fourth the toxic dose and 125 times the concentration that would totally inhibit virus replication in vitro, completely abrogated the anticipated viremia and antibody responses. Unfortunately, a majority of treated/uninfected and treated/infected test cats died acutely of drug toxicity after 47 days of treatment. Toxicity in vivo mirrored what was observed in vitro, being precipitous and cumulative in nature. Toxic signs included widespread hepatic and lymphoid necrosis. A surviving treated/FIV infected cat remained healthy to day 175 when the study was terminated; antibodies appeared 2 months later than in untreated/infected cats and virus was only detectable at low levels on day 175. In contrast, untreated/infected cats were viremic and antibody positive from 3 to 4 weeks post-infection onwards. Therefore, it was possible to alter, but not abort, an early FIV infection with prolonged, high-dose D4API treatment.
9-[(2R,5R-2,5-二氢-5-膦酰甲氧基)-2-呋喃基]腺嘌呤，即D4API，在猫免疫缺陷病毒（FIV）感染模型中进行了测试，结果发现其在体外的抑制作用明显强于其母体化合物9-膦酰甲氧基乙基腺嘌呤（PMEA）。在7天的培养期内，其细胞毒性低于PMEA或叠氮胸苷（AZT），但在10天后毒性更大。猫皮下接种后，D4API能迅速被吸收，静脉接种后的血浆半衰期小于1小时，皮下注射后为2至3小时。然而，从接受单剂量D4API的猫身上采集的外周血单核细胞在体外长达24小时内对FIV感染具有抗性。鉴于其较长的细胞内期和高选择性指数，对高剂量D4API疗法中止急性（即2周）FIV感染的能力进行了测试。每日分剂量给予的D4API，其剂量为毒性剂量的四分之一，是在体外完全抑制病毒复制浓度的125倍，完全消除了预期的病毒血症和抗体反应。不幸的是，大多数接受治疗的未感染和感染测试猫在治疗47天后因药物毒性急性死亡。体内毒性反映了体外观察到的情况，具有突发性和累积性。毒性迹象包括广泛的肝脏和淋巴坏死。一只存活的接受治疗的FIV感染猫在研究终止时的第175天仍保持健康；抗体出现的时间比未治疗的感染猫晚2个月，并且在第175天时仅能检测到低水平的病毒。相比之下，未治疗的感染猫在感染后3至4周起就出现病毒血症且抗体呈阳性。因此，延长高剂量D4API治疗有可能改变早期FIV感染，但无法中止感染。
