Mitsui Yoshinori
Department of Parasitology, Institute of Tropical Medicine, Nagasaki University , 1-12-4 Sakamoto, Nagasaki 852-8523, Japan.
Trop Med Health. 2014 Jun;42(2):87-92. doi: 10.2149/tmh.2013-28. Epub 2014 Apr 3.
It has been demonstrated that continuous exposure to amodiaquine (AQ) alone elicits in vitro antischistosomal activities at concentrations of 1-10 μg/ml. However, orally administered drugs reach a peak blood concentration within one or two hours and then gradually decrease. The blood concentration does not remain at a constant level over several days as in vitro concentration of continuous drug exposure. In vitro activities by one day exposure to AQ better reflect the actual antischistosomal activities after oral administration than those elicited by continuous exposure. The objective of the present study is to compare the antischistosomal potential of one-day exposure to AQ with that to praziquantel (PZQ), a current antischistosomal drug. Schistosoma mansoni adult worm pairs were incubated with 0 (control), 1, 2, 5 and 10 μg/ml AQ as well as 0.01, 0.02, 0.05 and 0.1 μg/ml PZQ for the first day, and were subsequently incubated in drug-free media for a period of 14 days. The one-day exposure to AQ significantly reduced the daily egg output of the worm pairs at 1-10 μg/ml. The inhibitory effect on egg production continued at 5 and 10 μg/ml but proved temporary at 1 and 2 μg/ml. Furthermore, AQ-induced specific morphological alterations (severe swelling and/or localization of hemozoin) were observed in the worms at 5 and 10 μg/ml. The AQ-specific appearance of the male worms gradually faded during subsequent incubation in drug-free media, although the female worms showed elongation. Meanwhile, PZQ inhibited the egg output of adult worm pairs at concentrations of 0.01-0.1 μg/ml during exposure. The inhibitory effect on egg production continued at 0.05 and 0.1 μg/ml but proved temporary at 0.01 and 0.02 μg/ml. Furthermore, PZQ induced a visible contraction and shortening of the male and female worms at 0.05 and 0.1 μg/ml during exposure, but the PZQ-specific alterations quickly disappeared during subsequent incubation in drug-free media. To our knowledge, this is the first report showing that one-day exposure to AQ inhibits the egg production of adult worm pairs at 1-10 μg/ml and induces specific morphological alterations in the worms at 5 and 10 μg/ml. The present findings have important implications for the evaluation of the therapeutic effects of both AQ monotherapy and combination therapy with artesunate on schistosomiasis in clinical field trials.
已证明，单独持续暴露于阿莫地喹（AQ）时，在浓度为1-10μg/ml时会引发体外抗血吸虫活性。然而，口服给药的药物在一两个小时内达到血药浓度峰值，然后逐渐下降。血药浓度不会像体外持续药物暴露浓度那样在数天内保持恒定水平。与持续暴露引发的活性相比，一天暴露于AQ的体外活性更能反映口服给药后的实际抗血吸虫活性。本研究的目的是比较一天暴露于AQ与当前抗血吸虫药物吡喹酮（PZQ）的抗血吸虫潜力。将曼氏血吸虫成虫配对物在第一天与0（对照）、1、2、5和10μg/ml的AQ以及0.01、0.02、0.05和0.1μg/ml的PZQ一起孵育，随后在无药物培养基中孵育14天。一天暴露于1-10μg/ml的AQ可显著降低成虫配对物的每日产卵量。在5和10μg/ml时对产卵的抑制作用持续存在，但在1和2μg/ml时被证明是暂时的。此外，在5和10μg/ml时在虫体中观察到AQ诱导的特定形态学改变（严重肿胀和/或疟原虫色素的定位）。在随后无药物培养基孵育期间，雄虫的AQ特异性外观逐渐消失，尽管雌虫出现伸长。同时，在暴露期间，PZQ在浓度为0.01-0.1μg/ml时抑制成虫配对物的产卵。在0.05和0.1μg/ml时对产卵的抑制作用持续存在，但在0.01和0.02μg/ml时被证明是暂时的。此外，在暴露期间，PZQ在0.05和0.1μg/ml时诱导雄虫和雌虫明显收缩和缩短，但在随后无药物培养基孵育期间，PZQ特异性改变迅速消失。据我们所知，这是第一份报告表明一天暴露于1-10μg/ml的AQ可抑制成虫配对物的产卵，并在5和10μg/ml时在虫体中诱导特定形态学改变。本研究结果对在临床现场试验中评估AQ单药治疗和青蒿琥酯联合治疗血吸虫病的治疗效果具有重要意义。
