Safety Assessment of Aconitum-Derived Bulleyaconitine A: A 91-Day Oral Toxicity Study and a Tissue Accumulation Study in Rats

摘要

Background: Bulleyaconitine A（BLA） is a diterpenoid alkaloid from the rhizomes of Aconitum bulleyanum Diels and has been clinically used for chronic pain treatment in China for many years. However, the newly reported adverse events of BLA indicated that BLA still has potential safety issues. Materials and Methods: To assess the safety of BLA, analgesic tests, acute toxicity studies, repeated-dose oral toxicity studies, and tissue distribution studies after single and repeated administration of BLA were carried out. Results: Administration of 0.14 mg/kg BLA showed potent analgesic effects in both analgesic tests. In acute toxicity study, the LD50 value of BLA was calculated to be 3.4434 mg/kg. In the subchronic toxicity study, the no observed adverse effect level was 0.25 mg/kg, and the lowest observed adverse effect level was 0.5 mg/kg. The spleen, liver, and kidneys are newly identified target organs of BLA toxicity after long-term administration. Moreover, unlike a single BLA administration, repeated administration showed BLA redistribution from organs with an abundant blood supply to immune and metabolic organs. Conclusions: These results suggested that BLA itself would be nontoxic at a dosage of 0.25 mg/kg in rats and should be carefully used when combining BLA with medications that can cause spleen, liver, or kidney injury.