Xylopic Acid-Amodiaquine and Xylopic Acid-Artesunate Combinations are Effective in Managing Malaria in Plasmodium Berghei-infected Mice.

Abstract

Background: Evidence of plasmodium resistance to some of the current antimalarial 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 synergistic antimalarial 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 ANKA-infected mice to determine respective ED50s. Artemether/lumefantrine (AL: 1.14/6.9) p.o. was used as the positive control. XA/ART and XA/AQ were subsequently administered in a fixed-dose combination of their ED50s (1:1) and the combination fractions of their ED50s (1/2, 1/4, 1/8, 1/16, and 1/32) to determine the experimental ED50s (Zexp). An isobologram was constructed to determine the nature of the interaction between XA/ART, and XA/AQ combinations by comparing Zexp with the theoretical ED50 (Zadd). Body weight and 30-day survival post-treatment were additionally recorded. Results: ED50s for XA, ART, and AQ were 9.0 ± 3.2, 1.61 ± 0.6, and 3.1 ± 0.8 mg kg-1 respectively. The Zadd, Zexp 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 Zexp 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 Plasmodium berghei ANKA.