目的 通過SD大鼠的單次和重復(fù)靜脈給藥毒性試驗(yàn)，評(píng)價(jià)氫溴酸樟柳堿注射液的安全性。方法 單次給藥毒性試驗(yàn)采用最大耐受量法，觀察大鼠的死亡情況和毒性反應(yīng)。重復(fù)給藥毒性試驗(yàn)：將大鼠隨機(jī)分為溶媒對(duì)照組和氫溴酸樟柳堿10、50、200 mg/kg劑量組，每組30只，尾iv給藥，連續(xù)13周，停藥恢復(fù)4周。進(jìn)行各項(xiàng)毒理學(xué)指標(biāo)檢測(cè)。結(jié)果 急性毒性試驗(yàn)：氫溴酸樟柳堿注射液在364.5~504.5 mg/kg對(duì)大鼠產(chǎn)生明顯毒性，癥狀有給藥時(shí)尖叫、俯臥、后肢無力、顫抖、抽搐、驚厥、瞳孔散大、尾部發(fā)紺等，甚至造成個(gè)別動(dòng)物死亡。重復(fù)給藥毒性試驗(yàn)：50、200 mg/kg劑量組出現(xiàn)體質(zhì)量增長減緩，攝食下降，給藥后尖叫，鼻端、眼周異常分泌物增多，皮膚脫毛、結(jié)痂，耳廓潰瘍、缺損，瞳孔散大，尾部發(fā)紺，血紅蛋白（HGB）、紅細(xì)胞壓積（HCT）、Cl-濃度升高等癥狀，200 mg/kg劑量組還出現(xiàn)給藥后肌張力減退、顫抖、抽搐、呼吸困難、皮下炎性包塊等表現(xiàn)。溶媒對(duì)照組和200 mg/kg劑量組動(dòng)物注射部位均出現(xiàn)靜脈炎及靜脈周圍炎，嚴(yán)重程度無差異，停藥4周后病變減輕。結(jié)論 氫溴酸樟柳堿注射液SD大鼠靜脈單次給藥的最大耐受量（MTD）為428.8 mg/kg，約相當(dāng)于臨床劑量的2 573倍；重復(fù)給藥毒性試驗(yàn)未見明顯毒性反應(yīng)劑量（NOAEL）為10 mg/kg，約相當(dāng)于臨床劑量的60倍。

Objective To evaluate the safety of anisodine hydrobromide injection for SD rats by single and repeat administration toxicity studies. Methods In single dose toxicity study, maximum tolerance dose (MTD) method was applied to observe the death and toxic reaction of rats. In repeat doses toxicity study, rats were randomly divided into vehicle control, anisodine hydrobromide injection 10, 50 and 200 mg/kg groups, and each group had 30 rats. All animals were intravenously given vehicle or anisodine hydrobromide injection for 13 weeks followed by 4-week recovery. Toxicology parameters were determined. Results In single dose toxicity study, anisodine hydrobromide injection induced obvious toxicity in rats at 364.5-504.5 mg/kg, such as screaming during administration, face lying, muscular hypotonus of hindlimb, tremor, spasm, convulsion, mydriasis, tail cyanosis, even some rats died. In repeat doses toxicity study, following adverse effects were observed in rats at 50 and 200 mg/kg groups:body weight increasing slowly, food consumption decreasing, screaming during administration, abnormal secretions increasing at the end of nose and around eyes, depilation and scab of skin, ulcer and defect of auricle, mydriasis, tail cyanosis, HGB, HCT and Cl-increasing. At 200 mg/kg group, muscular hypotonus, tremor, spasm, dyspnea, subcutaneous inflammatory lumps were also observed. Phlebitis and periphlebitis were found at injection site in rats at both vehicle control and 200mg/kg groups, with no obvious difference between the two groups, and alleviated after 4-week recovery. Conclusion The maximum tolerance dose (MTD) of anisodine hydrobromide injection in SD rats by single dose intravenous injection was 428.8 mg/kg, about 2573 times of clinical dose. The no observed adverse effect level (NOAEL) in repeat doses toxicity study was 10 mg/kg, about 60 times of clinical dose.

四川省科技支撐項(xiàng)目（2016sz0027）