Willems Anja M, Bruynzeel Anne M, Kedde Marc A, van Groeningen Cees J, Bast Aalt, van der Vijgh Wim J
Department of Medical Oncology, Vrije Universiteit Medical Center, De Boelelaan 1117, BR 232, 1081 HV, Amsterdam, The Netherlands.
Cancer Chemother Pharmacol. 2006 May;57(5):678-84. doi: 10.1007/s00280-005-0083-7. Epub 2005 Sep 1.
The flavonol monohydroxyethylrutoside (monoHER) has demonstrated protection against doxorubicin-induced cardiotoxicity in in vitro and in vivo studies without affecting the antitumor effect. In the present phase I study, the possible side effects and the pharmacokinetics of monoHER were evaluated in healthy volunteers with the aim to develop a safe and feasible dose to be evaluated in cancer patients treated with doxorubicin. The study was performed as a single blind, randomized trial in healthy volunteers (age between 19 and 56 years). At each dose level, six subjects received monoHER and three placebo. MonoHER was solubilized in 100 ml dextrose 5% and administered as an i.v. infusion in 10 min. The placebo consisted of 100 ml dextrose 5%. The starting dose of monoHER was 100 mg/m(2). Dose escalation by 100% of the preceding dose took place after finishing each dose level until the protecting pharmacokinetic values for C (max) and AUC(infinity) (as observed in mice after 500 mg/kg monoHER i.p.) were reached and/or serious side effects were observed. The dose was escalated up to 1,500 mg/m(2). The mean values of C (max) and AUC(infinity) were 360+/-69.3 microM and 6.8+/-2.1 micromol min/ml, respectively. These values were comparable to the C (max) and AUC(infinity) observed under the protecting conditions in mice. No serious side effects occurred during the entire study. Thus, 1,500 mg/m(2) is a feasible and safe dose to be evaluated in a phase II study to investigate the protective properties of monoHER against doxorubicin-induced cardiotoxicity in cancer patients.
在体外和体内研究中，黄酮醇单羟乙基芦丁（单羟乙基芦丁）已证明对阿霉素诱导的心脏毒性具有保护作用，且不影响抗肿瘤效果。在本I期研究中，对健康志愿者评估了单羟乙基芦丁的可能副作用和药代动力学，目的是确定一个安全可行的剂量，用于接受阿霉素治疗的癌症患者。该研究作为一项单盲、随机试验在健康志愿者（年龄在19至56岁之间）中进行。在每个剂量水平，6名受试者接受单羟乙基芦丁，3名受试者接受安慰剂。单羟乙基芦丁溶解于100ml 5%葡萄糖溶液中，并在10分钟内静脉输注给药。安慰剂为100ml 5%葡萄糖溶液。单羟乙基芦丁的起始剂量为100mg/m²。在完成每个剂量水平后，将剂量在前一剂量基础上增加100%，直至达到C（max）和AUC（∞）的保护药代动力学值（如在小鼠腹腔注射500mg/kg单羟乙基芦丁后观察到的）和/或观察到严重副作用。剂量逐步增加至1500mg/m²。C（max）和AUC（∞）的平均值分别为360±69.3μM和6.8±2.1μmol·min/ml。这些值与在小鼠保护条件下观察到的C（max）和AUC（∞）相当。在整个研究过程中未发生严重副作用。因此，1500mg/m²是一个可行且安全的剂量，可在II期研究中评估单羟乙基芦丁对癌症患者阿霉素诱导的心脏毒性的保护特性。
