Four-week intravenous repeated dose toxicity study of vitacamphorae injection in rats
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ORIGINAL ARTICLE
Four-week intravenous repeated dose toxicity study of vitacamphorae injection in rats Yazhi Yuan 1 & Mei Su 2 & Jing Liu 3 & Yajing Lou 2 & Yufeng Xia 1 & Bo Zhou 3 Received: 23 September 2019 / Accepted: 10 January 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract The study was undertaken to evaluate the safety of vitacamphorae (VCP) injection in Sprague-Dawley (SD) rats. Rats were intravenously administered with VCP at the doses of 0, 5, 15, and 50 mg/kg/day (equivalent to 0, 5, 15, and 50 times the clinical equivalent dose) for 4 weeks, respectively. In addition, we also tested oxidative stress-related parameters and cytokine levels in rat serum. In the current study, intravenous administration of VCP at a dose of 50 mg/kg/day caused significant pathophysiological responses in rats. Compared with the control group, different doses of VCP exposure had no significant effect on body weight, food consumption, and clinic pathology of rats after 4 weeks of VCP administration. Rats in high-dose group (50 mg/kg/day) showed general symptoms of convulsions after VCP administration. The toxicological significance of VCP exposure in the spleen of high-dose female rats was observed, which showed a significant increase in the relative spleen weights (P < 0.01) and mild lymphocyte proliferation in splenic pathology. Furthermore, the results of oxidative stress and cytokine detection showed that the levels of antioxidant enzymes SOD increased in each administration group, but the levels of a series of pro-inflammatory cytokines IL-1β, IL-6, IL-8, IL-12, and IFN-γ also increased in these groups. Above changes caused by VCP exposure can be reversed after 4 weeks of recovery. Overall, the results showed that the no-observed-adverse-effect-level (NOAEL) of VCP injection for 4-week toxicity was 15 mg/kg/day. Keywords Vitacamphorae injection . Four-week toxicity . Oxidative stress . Pro-inflammatory cytokines
Introduction Vitacamphorae (VCP) injection is a traditional Chinese medicine injection for the treatment of circulatory and cardiac failure, especially the heart failure (HF). It has been reported that π-oxocamphor was the main chemical component of VCP injection (Liang et al. 2016) and an endogenous Yazhi Yuan and Mei Su contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00210-020-01820-6) contains supplementary material, which is available to authorized users. * Bo Zhou [email protected] 1
School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China
2
Jiangsu Carephar Pharmaceutical Co., Ltd, Nanjing 210009, China
3
Jiangsu Center for Safety Evaluation of Drugs, School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 210009, China
metabolite of camphor extracted from Cinnamomum camphora (L.) Presl (Miyazawa et al. 2001). At present, we usually synthesize π-oxocamphor through multi-step chemical reaction using camphor as raw material (Jiang et al. 2011
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