静脉注射紫杉醇和西罗莫司对大鼠的急性毒性比较

IF 2.9 Q2 TOXICOLOGY

Current Research in Toxicology Pub Date : 2025-01-01 DOI:10.1016/j.crtox.2025.100248

Jing Xie , Denise Schuett , Ulrich Speck , Tobias Haase

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引用次数: 0

摘要

目的考虑到西罗莫司（雷帕霉素）作为球囊包膜外周静脉内治疗的探索，以及每日低剂量西罗莫司不良耐受性的报道，本研究的目的是研究单剂量西罗莫司在大鼠血管内与紫杉醇和对照物的潜在毒理学效应。方法将西罗莫司或紫杉醇分别以20 mg/kg的单剂量溶解于同一载体中，分别于5、14 d后处死。以经生理盐水稀释的Cremophor EL/乙醇为对照。分析对生存、血液学、器官重量、器官组织学的潜在影响。结果西罗莫司、紫杉醇和机动车单次静脉注射可引起暂时性镇静。一只用紫杉醇治疗的动物死亡，可能是由于溶剂毒性。西罗莫司、紫杉醇和对照均耐受。西罗莫司或紫杉醇治疗的动物出现暂时的血液学影响和胸腺萎缩，14天后消退。西罗莫司引起卵巢和子宫的暂时性体重减轻。雄性大鼠在西罗莫司治疗14天后出现睾丸组织学改变。值得注意的是，与紫杉醇和载药治疗相比，西罗莫司在雄性大鼠中诱导了长期的体重减轻。结论经单次大剂量静脉给药后，两种药物的耐受性相似且可接受。本研究的结果不表明安全问题，将排除西罗莫司作为一种活性成分用于球囊导管作为紫杉醇的替代品。

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Comparative acute toxicity of intravenous paclitaxel and sirolimus in rats

Aim

In view of the exploration of sirolimus (rapamycin) as balloon coating for peripheral intravasal treatment and the reports on unfavorable tolerance of daily low-dose sirolimus, the aim of the study was to investigate potential toxicological effects of a single intravascular dose of sirolimus in comparison to paclitaxel and vehicle in the rat.

Methods

Rats were treated intravenously with a single dose of 20 mg/kg sirolimus or paclitaxel dissolved in identical vehicle and sacrificed 5- or 14-days post treatment. Vehicle (Cremophor EL/Ethanol diluted with saline) treated rats served as a control. Potential effects on survival, hematology, organ weights, organ histology were analyzed.

Results

Single dose i.v. injection of sirolimus, paclitaxel and vehicle induced temporary sedation after treatment. One animal treated with paclitaxel died, probably due to solvent toxicity. Sirolimus, paclitaxel and the vehicle control were tolerated. Animals treated with sirolimus or paclitaxel showed temporary hematological effects and thymic atrophy that subsided after 14 days. Sirolimus induced a temporary weight reduction of ovaries and uterus. Male rats showed histological changes of testes at 14 days after sirolimus treatment. Notably, sirolimus induced a prolonged body weight reduction compared to paclitaxel and vehicle treatment in male rats.

Conclusion

Both substances showed similar and acceptable tolerability after high single-dose intravenous treatment. The results of this study do not indicate safety concerns that would preclude the use of sirolimus as an active ingredient on balloon catheters as an alternative to paclitaxel.

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来源期刊

Current Research in Toxicology Environmental Science-Health, Toxicology and Mutagenesis

CiteScore

4.70

自引率

3.00%

发文量

审稿时长

82 days