Xylopic acid-amodiaquine and xylopic acid-artesunate combinations are effective in managing malaria in Plasmodium berghei-infected mice

BACKGROUND: Evidence of Plasmodium resistance to some of the current anti-malarial agents makes it imperative to search for newer and effective drugs to combat malaria. Therefore, this study evaluated whether the co-administrations of xylopic acid-amodiaquine and xylopic acid-artesunate combinations will produce a synergistic anti-malarial effect. METHODS: Antiplasmodial effect of xylopic acid (XA: 3, 10, 30, 100, 150 mg kg(−1)), artesunate (ART: 1, 2, 4, 8, 16 mg kg(−1)), and amodiaquine (AQ: 1.25, 2.5, 5, 10, 20 mg kg(−1)) were evaluated in Plasmodium berghei (strain ANKA)-infected mice to determine respective ED(50)s. Artemether/lumefantrine was used as the positive control. XA/ART and XA/AQ were subsequently administered in a fixed-dose combination of their ED(50)s (1:1) and the combination fractions of their ED(50)s (1/2, 1/4, 1/8, 1/16, and 1/32) to determine the experimental ED(50)s (Z(exp)). An isobologram was constructed to determine the nature of the interaction between XA/ART, and XA/AQ combinations by comparing Z(exp) with the theoretical ED(50) (Z(add)). Bodyweight and 30-day survival post-treatment were additionally recorded. RESULTS: ED(50)s for XA, ART, and AQ were 9.0 ± 3.2, 1.61 ± 0.6, and 3.1 ± 0.8 mg kg(−1), respectively. The Z(add), Z(exp,) and interaction index for XA/ART co-administration was 5.3 ± 2.61, 1.98 ± 0.25, and 0.37, respectively while that of XA/AQ were 6.05 ± 2.0, 1.69 ± 0.42, and 0.28, respectively. The Z(exp) for both combination therapies lay significantly (p < 0.001) below the additive isoboles showing XA acts synergistically with both ART and AQ in clearing the parasites. High doses of XA/ART combination significantly (p < 0.05) increased the survival days of infected mice with a mean hazard ratio of 0.40 while all the XA/AQ combination doses showed a significant (p < 0.05) increase in the survival days of infected mice with a mean hazard ratio of 0.27 similar to AL. Both XA/ART and XA/AQ combined treatments significantly (p < 0.05) reduced weight loss. CONCLUSION: Xylopic acid co-administration with either artesunate or amodiaquine produces a synergistic anti-plasmodial effect in mice infected with P. berghei.