Havlin K A, Kuhn J G, Craig J B, Weiss G R, Koeller J, Turner J N, Luther J S, Clark G, Bair K W, Wargin W
Department of Medicine, University of Texas Health Science Center, San Antonio 78284.
Anticancer Drugs. 1991 Aug;2(4):357-63. doi: 10.1097/00001813-199108000-00004.
The arylmethylaminopropanediols (AMAPs) are a new class of DNA intercalators. 773U82.HCl is the second of these compounds to enter clinical trial. Significant antitumor activity for 773U82.HCl was documented in a variety of murine and human tumor models. This phase I study examined a 1-, 2- and 6-hour infusion given every 28 days. Thirty-six patients received 58 courses of drug at doses ranging from 15 mg/m2 to 980 mg/m2. The dose-limiting toxicity of 773U82.HCl was hemolysis noted at 980 mg/m2. Change in color of the plasma and decreases in haptoglobin were correlated with drug concentrations of the infusate greater than or equal to 3 mg/ml. Clinically significant changes in hemoglobin levels requiring blood transfusions did not occur. Neurologic toxicity occurred at 720 mg/m2 with the most severe neurologic toxicity occurring in a patient with the highest peak plasma concentration (4.1 micrograms/ml). With an increase in duration of the infusion and amount of fluid administered, the neurologic toxicity resolved. Other toxicities included mild nausea and vomiting and a dose-related phlebitis. Pharmacokinetic studies were completed in 22 patients. The mean terminal t1/2 beta was 4.4 h with a mean apparent volume of distribution at steady state (Vdss) of 314 l/m2. The mean total body clearance was 72 l/h/m2. Peak plasma levels ranged from 0.04 to 4.14 micrograms/ml. Further studies with 773U82.HCl on this schedule at the doses studied are not recommended. Hematologic monitoring for evidence of intravascular hemolysis should be included in future studies with 773U82.HCl.
芳基甲基氨基丙二醇（AMAPs）是一类新型的DNA嵌入剂。773U82.HCl是这类化合物中第二个进入临床试验的。773U82.HCl在多种小鼠和人类肿瘤模型中显示出显著的抗肿瘤活性。这项I期研究考察了每28天进行一次的1小时、2小时和6小时静脉输注。36名患者接受了58个疗程的药物治疗，剂量范围为15mg/m²至980mg/m²。773U82.HCl的剂量限制性毒性是在980mg/m²时出现的溶血。血浆颜色改变和触珠蛋白降低与输注液中药物浓度大于或等于3mg/ml相关。未发生需要输血的具有临床意义的血红蛋白水平变化。在720mg/m²时出现神经毒性，最严重的神经毒性发生在一名血浆峰浓度最高（4.1μg/ml）的患者身上。随着输注持续时间和给药液体量的增加，神经毒性得到缓解。其他毒性包括轻度恶心、呕吐和与剂量相关的静脉炎。对22名患者完成了药代动力学研究。平均终末t1/2β为4.4小时，稳态时平均表观分布容积（Vdss）为314l/m²。平均全身清除率为72l/h/m²。血浆峰浓度范围为0.04至4.14μg/ml。不建议按照本方案对773U82.HCl进行所研究剂量的进一步研究。在未来对773U82.HCl的研究中应包括对血管内溶血证据的血液学监测。
