National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention, Key Laboratory of Parasite and Vector Biology, Shanghai, People's Republic of China.
Parasitol Res. 2010 Mar;106(4):775-81. doi: 10.1007/s00436-010-1748-7. Epub 2010 Feb 13.
The antinematode effect of tribendimidine (TBD) and its metabolites has been studied. A total of 107 hamsters were each infected with 250 Necator americanus third stage infective larvae (NaL3) for 25 days. In the first test, 75 hamsters were divided equally into 15 groups for determination of ED(50) and ED(90.) Among them, five groups were treated orally with TBD or its metabolite, p-(1-dimethylamino ethylimino)aniline (aminoamidine, deacylated amidantel, BAY d 9216, dADT), at single doses of 1, 2, 4, 8, and 16 mg/kg. The remaining five groups were administered with acetylated dADT (AdADT) at single oral doses of 8, 12, 18, 24, and 30 mg/kg. In the second test, 20 hamsters were equally divided into four groups. Two groups were treated intramuscularly with TBD and dADT at a single dose of 16 mg/kg, while in the remaining two groups, single intramuscular dose of AdADT 15 or 30 mg/kg was administered. In the third test, two groups of six hamsters were treated orally with terephthalaldehyde (TPAL) and terephthalic acid (TPAC) at a single dose of 1,000 mg/kg. Other 85 rats, each infected with 300 Nippostrongylus braziliensis third stage infective larvae (NbL3), were used in three tests. For determination of ED(50) and ED(90) in the first test, five groups of five rats were treated orally with TBD or dADT at single doses of 3.0, 4.2, 5.9, 8.2, and 11.5 mg/kg or 2.0, 2.9, 4.2, 6.1, and 8.8 mg/kg, respectively. In the second test, three groups of eight to nine rats were treated orally with TBD at a single 8.4-mg/kg dose (ED(90)) and AdADT 100 or 200 mg/kg, respectively. In the third test, two groups of four rats were treated orally with TPAL and TPAC at a single dose of 1,000 mg/kg. Twenty-four to 48 h post-treatment, all the feces of each hamster and rat were collected for recovery of worms expelled from the feces. Following this period, all of the animals were sacrificed, and the adult hookworm or N. braziliensis from small intestine and large intestine were recovered and counted for calculation of worm burden reduction. The results showed that the ED(50) and ED(90) for TBD, dADT, and AdADT determined in treatment of N. americanus-infected hamsters were 1.849 and 13.598, 3.922 and 54.354, as well as 20.966 and 51.633 mg/kg, respectively. In intramuscular administration of TBD and dADT at single dose of 16 mg/kg or AdADT 30 mg/kg, similar worm burden reductions of 71.4-76.3% were observed. Two other metabolites, i.e., TPAL and TPAC, exhibited no effect against N. americanus. The ED(50) and ED(90) for TBD and dADT determined in treatment of rats infected with N. braziliensis were 3.234 and 8.435, as well as 2.345 and 5.104 mg/kg. Oral administration of AdADT at a higher single dose of 100 or 200 mg/kg resulted in worm burden reductions of 11.9-46.3%, which was significantly lower than 84.5% of worm burden reduction obtained from rats treated with TBD 8.4 mg/kg. The results indicate that in oral administration, TBD exhibits slightly better effect against N. americanus in hamsters than dADT, but AdADT possesses less effect; TBD, dADT, and AdADT show promising effect in intramuscular treatment of N. americanus-infected hamsters; the effect of oral dADT against N. braziliensis in rats is somewhat better than TBD, while AdADT endorses poor effect; and TPAL and TPAC are ineffective metabolites of TBD against both species of nematodes.
本研究旨在探讨三苯双脒（TBD）及其代谢物的抗线虫作用。将 107 只仓鼠用 250 条美洲钩口线虫第三期幼虫（NaL3）感染 25 天，分为 15 组，每组 7 只，分别检测 ED50 和 ED90。第一组用 TBD 或其代谢物，对二甲氨基乙基脒（氨基脒，去乙酰化 amidantel，BAY d 9216，dADT），5 个剂量组（1、2、4、8 和 16mg/kg）进行单剂量口服治疗，另 5 个剂量组（乙酰化 dADT，AdADT），8、12、18、24 和 30mg/kg 进行单剂量口服治疗。第二组，20 只仓鼠随机分为 4 组，2 组肌肉内注射 TBD 和 dADT，剂量均为 16mg/kg，2 组肌肉内注射 AdADT，剂量分别为 15mg/kg 和 30mg/kg。第三组，6 只仓鼠分为 2 组，口服邻苯二甲醛（TPAL）和邻苯二甲酸（TPAC），剂量均为 1000mg/kg。此外，还使用 85 只大鼠，每只感染 300 条巴西牛带绦虫第三期幼虫（NbL3），进行了 3 次试验。第一组用 TBD 或 dADT，5 个剂量组（3.0、4.2、5.9、8.2 和 11.5mg/kg）和 5 个剂量组（2.0、2.9、4.2、6.1 和 8.8mg/kg），5 只大鼠口服，确定 ED50 和 ED90。第二组，3 组 8-9 只大鼠口服 TBD，剂量为 8.4mg/kg（ED90），AdADT 剂量分别为 100mg/kg 和 200mg/kg。第三组，2 组 4 只大鼠口服 TPAL 和 TPAC，剂量均为 1000mg/kg。治疗后 24-48 小时，收集每组仓鼠和大鼠的所有粪便，以回收从粪便中排出的线虫。在此期间，所有动物均被处死，从小肠和大肠中回收成年钩虫或巴西牛带绦虫，并计算虫体负荷减少量。结果表明，在感染美洲钩口线虫的仓鼠中，TBD、dADT 和 AdADT 的 ED50 和 ED90 分别为 1.849 和 13.598、3.922 和 54.354 以及 20.966 和 51.633mg/kg。在感染美洲钩口线虫的仓鼠中，肌肉内注射 TBD 和 dADT 剂量为 16mg/kg 或 AdADT 剂量为 30mg/kg，均可获得 71.4%-76.3%的相似虫体负荷减少率。另外两种代谢物，邻苯二甲醛（TPAL）和邻苯二甲酸（TPAC）对美洲钩口线虫没有作用。在感染巴西牛带绦虫的大鼠中，TBD 和 dADT 的 ED50 和 ED90 分别为 3.234 和 8.435、2.345 和 5.104mg/kg。AdADT 高剂量 100mg/kg 和 200mg/kg 口服给药，线虫负荷减少率分别为 11.9%-46.3%，显著低于 TBD 剂量为 8.4mg/kg 时的 84.5%线虫负荷减少率。结果表明，口服 TBD 对感染美洲钩口线虫的仓鼠的疗效略优于 dADT，但 AdADT 的疗效较差；TBD、dADT 和 AdADT 对感染美洲钩口线虫的仓鼠肌肉内治疗具有良好的疗效；口服 dADT 对感染巴西牛带绦虫的大鼠的疗效稍好于 TBD，而 AdADT 的疗效较差；邻苯二甲醛（TPAL）和邻苯二甲酸（TPAC）是 TBD 对这两种线虫的无效代谢物。
