Steger-Hartmann Thomas, Graham Philip B, Müller Simone, Schweinfurth Hermann
SCHERING AG, Experimental Toxicology, Berlin, Germany.
Invest Radiol. 2006 May;41(5):449-59. doi: 10.1097/01.rli.0000208223.34203.49.
Vasovist (EPIX Pharmaceuticals and Schering AG) is a newly developed blood pool contrast agent for magnetic resonance imaging with a high affinity for human albumin, making it an ideal tool for the detection of structural abnormalities such as stenosis and aneurysm. For the risk assessment of the single diagnostic use in patients, the toxicity of this compound was investigated.
Studies of acute, repeated-dose, reproductive, and developmental toxicity as well as local tolerance, immunotoxicity, and mutagenic potential were performed.
Lethality was observed in rodents after single intravenous administration at doses of at least 2 orders of magnitude higher than the anticipated human dose of 0.03 mmol/kg. The no observed adverse effect level after repeated daily administration over the course of 4 weeks to monkeys exceeded the single diagnostic dose by a factor of 3.3. The main effect of repeated dosing in both rats and monkeys was vacuolation in kidney proximal tubules without concomitant effect on kidney function. Studies into reproduction toxicity have shown no evidence of effects on fertility or perinatal and postnatal development. Signs of embryo-fetal toxicity were observed in rabbits after repeated administration of high doses. No indications of immunotoxic and mutagenic effects were observed. In local tolerance testing, Vasovist was well tolerated after intravenous administration.
Vasovist was well tolerated with reasonable safety margins between the single diagnostic dose of 0.03 mmol/kg in humans and the doses resulting in adverse effects in animal studies.
血管造影剂（EPIX制药公司和先灵公司）是一种新开发的用于磁共振成像的血池造影剂，对人白蛋白具有高亲和力，使其成为检测诸如狭窄和动脉瘤等结构异常的理想工具。为了评估其在患者单次诊断使用中的风险，对该化合物的毒性进行了研究。
进行了急性、重复给药、生殖和发育毒性以及局部耐受性、免疫毒性和致突变潜力的研究。
在啮齿动物单次静脉注射后，观察到致死性，其剂量至少比预期的人体剂量0.03 mmol/kg高2个数量级。在4周的时间内对猴子每日重复给药后的未观察到不良反应水平比单次诊断剂量高出3.3倍。在大鼠和猴子中重复给药的主要影响是肾近端小管空泡化，但对肾功能没有伴随影响。生殖毒性研究表明没有证据表明对生育力或围产期及产后发育有影响。在高剂量重复给药后，在兔子中观察到胚胎-胎儿毒性迹象。未观察到免疫毒性和致突变作用的迹象。在局部耐受性测试中，静脉注射后血管造影剂耐受性良好。
血管造影剂耐受性良好，在人类单次诊断剂量0.03 mmol/kg与动物研究中导致不良反应的剂量之间有合理的安全边际。
