Uckun Fatih M, Qazi Sanjive, Pendergrass Sharon, Lisowski Elizabeth, Waurzyniak Barbara, Chen Chun-Lin, Venkatachalam T K
Drug Discovery Program, Departments of Virology, Immunology, Pathology, Pharmaceutical Sciences, and Chemistry, Parker Hughes Institute, St. Paul, and Parker Hughes Center for Clinical Immunology, Roseville, Minnesota 55113, USA.
Antimicrob Agents Chemother. 2002 Nov;46(11):3428-36. doi: 10.1128/AAC.46.11.3428-3436.2002.
We have evaluated the clinical potential of stavudine-5'-(p-bromophenyl methoxyalaninyl phosphate(stampidine [STAMP]), a novel aryl phosphate derivative of stavudine, as a new anti-human immunodeficiency virus (anti-HIV) agent, by examining its acute, subacute, and chronic toxicity profile in mice as well as by testing its antiviral activity in a surrogate human peripheral blood lymphocyte (Hu-PBL)-SCID mouse model of human AIDS. STAMP was very well tolerated in BALB/c and CD-1 mice, without any detectable acute or subacute toxicity at single intraperitoneal or oral bolus doses as high as 500 mg/kg of body weight. Notably, daily administration of STAMP intraperitoneally or orally for up to 8 consecutive weeks was not associated with any detectable toxicity at cumulative dose levels as high as 6.4 g/kg. Micromolar concentrations of the active STAMP metabolite in plasma were rapidly achieved and maintained for more than 4 h after parenteral as well as oral administration of a nontoxic 100-mg/kg bolus dose of STAMP. In accordance with its favorable pharmacokinetic profile and in vitro potency, STAMP exhibited dose-dependent and potent in vivo anti-HIV activity in Hu-PBL-SCID mice against a genotypically and phenotypically nucleoside analog reverse transcriptase inhibitor (NRTI)-resistant clinical HIV type 1 (HIV-1) isolate (BR/92/019; D67N, L214F, T215D, K219Q) at nontoxic dose levels. The remarkable in vivo safety and potency of STAMP warrants the further development of this promising new antiretroviral agent for possible clinical use in patients harboring NRTI-resistant HIV-1.
我们评估了司他夫定-5'-（对溴苯基甲氧基丙氨酰磷酸酯）（司他莫定[STAMP]）的临床潜力，它是司他夫定的一种新型芳基磷酸酯衍生物，作为一种新型抗人类免疫缺陷病毒（抗HIV）药物，我们通过检测其在小鼠中的急性、亚急性和慢性毒性概况，以及在人类艾滋病的替代人类外周血淋巴细胞（Hu-PBL）-SCID小鼠模型中测试其抗病毒活性来进行评估。在BALB/c和CD-1小鼠中，STAMP耐受性良好，在高达500mg/kg体重的单次腹腔内或口服大剂量给药时，没有任何可检测到的急性或亚急性毒性。值得注意的是，连续8周每天腹腔内或口服给予STAMP，在累积剂量水平高达6.4g/kg时，没有任何可检测到的毒性。在给予无毒的100mg/kg大剂量STAMP进行肠胃外和口服给药后，血浆中活性STAMP代谢物的微摩尔浓度迅速达到并维持超过4小时。根据其良好的药代动力学特征和体外效力，STAMP在Hu-PBL-SCID小鼠中对一种基因型和表型上对核苷类似物逆转录酶抑制剂（NRTI）耐药的临床1型人类免疫缺陷病毒（HIV-1）分离株（BR/92/019；D67N、L214F、T215D、K219Q）在无毒剂量水平下表现出剂量依赖性和强效的体内抗HIV活性。STAMP显著的体内安全性和效力保证了这种有前景的新型抗逆转录病毒药物的进一步开发，以便可能用于携带NRTI耐药HIV-1的患者的临床治疗。
