医学
治疗指标
杀伤力
药代动力学
药理学
治疗效果
致死剂量
血浆浓度
丸(消化)
半数致死剂量
合成致死
毒性
药品
内科学
毒理
化学
生物
生物化学
基因
DNA修复
作者
Zaharko Ds,Grieshaber Ck,Jacqueline Plowman,Cradock Jc
出处
期刊:PubMed
日期:1986-12-01
卷期号:70 (12): 1415-21
被引量:46
摘要
Flavone acetic acid is a novel structure which exhibits an interesting spectrum of antitumor activity in preclinical studies. It has little antitumor activity in the leukemias and pronounced antitumor activity in solid tumors. Preclinical therapeutic, toxicologic, and pharmacokinetic studies are summarized and considered together to introduce the concept of a therapeutic window of effective plasma concentrations and effective exposure times in attempts to maximize therapeutic effects and minimize toxic effects. Plasma concentrations, predicted to fall from 600 to 100 micrograms/ml over 10 hours resulting from 267 mg/kg ip bolus injections in mice are curative to sc implanted colon 38. Doses of 356 mg/kg and higher cause acute lethality in many mice. Iv doses cause acute lethality in mice more frequently than ip doses, which suggests a peak toxic effect. However, iv infusions in mice, which also can be curative to colon 38, can also result in a lethal effect, although more delayed, even though the predicted plasma concentrations are much below the peak plasma concentrations that appear to be necessary for acute lethality. Plasma concentrations, 100 to 600 micrograms/ml predicted to result from single doses that are therapeutic and not acutely lethal in mice, if maintained by infusion in dogs for 28 hours or longer result in delayed lethality. We conclude that relatively high plasma concentrations (greater than 100 micrograms/ml) are needed for therapeutic activity with this antitumor agent and that lethality can result from two distinctly different causes. An acute lethality can result from an excessively high peak plasma concentration (greater than 600 micrograms/ml). A delayed lethality can result from a too-long exposure (greater than 24 hrs) at therapeutically effective plasma concentrations (100-600 micrograms/ml). We also note that unexpected kinetic differences exist among the mouse, dog, and man. Whereas usually with antitumor agents plasma clearances are proportional to body surface area, and hence faster in small species, quite the opposite is true with flavone acetic acid. Mice exhibit a slower plasma clearance relative to dogs and man.
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