Antimalarial activities of gedunin and 7‐methoxygedunin and synergistic activity with dillapiol

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<jats:title>Summary</jats:title><jats:p>Gedunin from <jats:italic>Cedrela odorata</jats:italic> (Meliaceae), a potent <jats:italic>in vitro</jats:italic> antimalarial agent, was investigated for its <jats:italic>in vivo</jats:italic> efficacy in CD‐1 mice infected with <jats:italic>Plasmodium berghei</jats:italic>. 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‐methoxygedunin, 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 potentialefficacy of antimalarial drugs and phytomedicines based on gedunin and the value of the combination therapy.</jats:p>

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