5,6-dimethylxanthenone-4-acetic acid (DMXAA), a novel antivascular agent: phase I clinical and pharmacokinetic study.
5,6-dimethylxanthenone-4-acetic acid (DMXAA), a novel antivascular agent: phase I clinical and pharmacokinetic study.
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5,6-二甲基苯乙烯-4-乙酸（DMXAA），一种新型的抗血管剂：I期临床和药代动力学研究。
DOI：
10.1038/sj.bjc.6600885
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发表时间：
2003-04-22
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
这项I期剂量递增研究的目的是确定5，6-二甲基咕吨酮乙酸（DMXAA）的毒性、最大耐受剂量、药代动力学和药效学终点。总共有46名患者接受了247次DMXAA输注，剂量范围为6至4900 mg/m2。最大耐受剂量确定为3700 mg m−2;在最高剂量水平（4900 mg m−2）下观察到尿失禁、视力障碍和焦虑等剂量限制性毒性。DMXAA的药代动力学呈剂量依赖性。峰浓度和曲线下面积分别从6 mg m−2时的4.8 μM和3.2 μM h增加到3700 mg m−2时的1290 μM和7600 μM h，而清除率在相同剂量范围内从7.4 l h−1 m−2下降到1.7 l h−1 m−2。终末半衰期为8.1±4.3 h。当剂量高达320 mg m−2时，超过99%的药物与蛋白质结合;在更高的剂量下，游离药物的百分比在4900 mg m−2时增加到最大值6.9%。在650 mg m−2及以上剂量水平下观察到5-羟色胺代谢物5-羟基吲哚乙酸呈剂量依赖性增加。在1300 mg m−2剂量下有1例未证实的部分缓解。总之，DMXAA是一种新型血管靶向药物，耐受性良好。
The purpose of this phase I, dose-escalation study was to determine the toxicity, maximum tolerated dose, pharmacokinetics, and pharmacodynamic end points of 5,6-dimethylxanthenone acetic acid (DMXAA). In all, 46 patients received a total of 247 infusions of DMXAA over 15 dose levels ranging from 6 to 4900 mg m−2. The maximum tolerated dose was established at 3700 mg m−2; dose-limiting toxicities in the form of urinary incontinence, visual disturbance, and anxiety were observed at the highest dose level (4900 mg m−2). The pharmacokinetics of DMXAA were dose dependent. Peak concentrations and area under the curve level increased from 4.8 μM and 3.2 μM h, respectively, at 6 mg m−2 to 1290 μM and 7600 μM h at 3700 mg m−2, while clearance declined from 7.4 to 1.7 l h−1 m−2 over the same dose range. The terminal half-life was 8.1±4.3 h. More than 99% of the drug was protein bound at doses up to 320 mg m−2; at higher doses the percent free drug increased to a maximum of 6.9% at 4900 mg m−2. Dose-dependent increases in the serotonin metabolite 5-hydroxyindoleacetic acid were observed at dose levels of 650 mg m−2 and above. There was one unconfirmed partial response at 1300 mg m−2. In conclusion, DMXAA is a novel vascular targeting agent and is well tolerated.
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用抗肿瘤剂5,6-二甲基二苯甲酮-4-乙酸的小鼠中肿瘤中一氧化氮合酶的持续诱导。
影响因子：
8.8
作者：
Moilanen, E;Thomsen, LL;Miles, DW;Happerfield, L;Knowles, RG;Moncada, S
通讯作者：
Moncada, S
通过与 5-羟色胺和生物还原药物联合使用，增强抗血管剂 5,6-二甲基呫吨酮-4-乙酸 (DMXAA) 的抗肿瘤作用。
影响因子：
8.8
作者：
Lash, C J;Li, A E;Rutland, M;Baguley, B C;Zwi, L J;Wilson, W R
通讯作者：
Wilson, W R
DOI：
10.1016/0360-3016(94)90292-5
发表时间：
1994-05-15
影响因子：
7
作者：
CLIFFE, S;TAYLOR, ML;WILSON, WR
通讯作者：
WILSON, WR
DOI：
10.1016/0360-3016(92)90848-c
发表时间：
1992-01-01
影响因子：
7
作者：
HILL, SA;WILLIAMS, KB;DENEKAMP, J
通讯作者：
DENEKAMP, J
影响因子：
3.4
作者：
KAYE, SB;CLAVEL, M;CAVALLI, F
通讯作者：
CAVALLI, F