Antimalarial activities of gedunin and 7-methoxygedunin and synergistic activity with dillapiol
Antimalarial activities of gedunin and 7-methoxygedunin and synergistic activity with dillapiol
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DOI：
10.1111/j.1744-7348.2003.tb00279.x
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发表时间：
2003-01-01
影响因子：
2.6
通讯作者：
Arnason, JT
中科院分区：
文献类型：
--
作者：
Omar, S;Godard, K;Arnason, JT
研究了苦楝科植物香柏木中的Gedunin对感染伯氏疟原虫的CD-1小鼠的体内抗疟作用。当以50 mg/kg/d的剂量连续4天口服给药时，gedunin能够将寄生虫血症水平抑制44%。然而，在0-100 mg/kg（-1）天（-1）剂量范围内未观察到明显的剂量-反应效应。Sprague-Dawley大鼠的初步药代动力学显示吸收较差。然而，50 mg kg（-1）day（-1）gedunin与25 mg kg（-1）day（-1）dillapiol（一种细胞色素P450抑制剂）的二元治疗使小鼠的寄生虫血症清除率增加至75%。当与25 mg kg（-1）day（-1）dillapiol联合给药时，在0-50 mg kg（-1）day（-1）gedunin剂量范围内观察到明显的剂量反应。此外，7-甲氧基gedumn，一种比gedunin更稳定的半合成衍生物，在50 mg/kg（-1）/天（-1）时可将小鼠体内的水平抑制67%。当以该剂量与25 mg kg（-1）day（-1）dillapiol联合给药时，清除率增加至80%。这些结果证明了基于gedunin的抗疟药物和植物药的潜在疗效以及联合治疗的价值。
Gedunin from Cedrela odorata (Mellaceae), a potent in vitro antimalarial agent, was investigated for its in vivo efficacy in CD-1 mice infected with Plasmodium berghei. When orally administered at 50 mg kg(-1) day(-1) for 4 days, gedunin was able to suppress the parasitaemia level by 44%. However, no clear dose-response effects were observed in the 0-100 mg kg(-1) day(-1) dose range. Preliminary pharmacokinetics in Sprague-Dawley rats showed poor absorption. However, a binary treatment of 50 mg kg(-1) day(-1) gedunin with 25 mg kg(-1) day(-1) dillapiol, a cytochrome P450 inhibitor, increased parasitaemia clearance in mice to 75%. A clear dose-response was observed in the 0-50 mg kg(-1) day(-1) gedunin dose range when administration was combined with 25 mg kg(-1) day(-1) dillapiol. In addition, 7-methoxygedumn, a semi-synthetic derivative which is more stable to degradation than gedunin, suppressed the level in mice by 67% at 50 mg kg(-1) day(-1). When administered at this dose in combination with 25 mg kg(-1) day(-1) dillapiol, clearance increased to 80%. These results demonstrate the potential efficacy of antimalarial drugs and phytomedicines based on gedunin and the value of the combination therapy.