Evaluation of the efficacy of xylopic acid — artesunate, and xylopic acid —amodiaquine co-administration in plasmodium berghei malaria mouse model

Abstract

Evidence of Plasmodium resistance to some of the current antimalarial agents makes it imperative to search for newer, and effective drugs to combat this challenge, and combination therapy remains key in the quest to address this problem. Therefore, this study evaluated the interaction that exist when xylopic acid-artesunate and xylopic acid-amodiaquine are co-administered in managing malaria in mice. 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 mice infected with Plasmodium berghei ANKA and treated for 5 days with the respective drugs p.o. Using iterative curve-fitting of the log-dose responses, the respective ED50s for the three compounds were determined. XA and ART, and XA and AQ were subsequently administered in a fixed-dose combination of their ED50s (1:1) along with the combination fractions of (1/2, 1/4, 1/8, 1/16, and 1/32) to get the experimental ED50S (Zexp). An isobologram was constructed to determine the nature of interaction between xylopic acid —artesunate, and xylopic acid —amodiaquine combinations by comparing Zexp with the theoretical ED50 (Zadd). Also, the treatments ability to relieve other signs of malaria such as weight loss and pyrexia were assessed. All animals were continuously observed further after treatment in a 30-day survival test. ED50s for xylopic acid, artesunate, and amodiaquine were 9.0±3.2, 1.61±0.6, and 3.1±0.8 mg/kg. The Zadd and Zexp for xylopic acid and artesunate co-administration (XA—ART) was 5.3±2.61 and 1.98±0.25, respectively, with an interaction index of 0.37. The xylopic acid and amodiaquine combination therapy (XA—AQ) gave Zadd and Zexp of 6.05±2.0 and 1.69±0.42, respectively, with an interaction index of 0.28. The Zexp for both combination therapies lied significantly (p<0.001) below the additive isoboles showing that xylopic acid acts synergistically with both artesunate and amodiaquine in clearing the parasites. XA/AQ and the high dose XA/ART combination significantly (p<0.05) increased the survival days of infected mice and also reduced their weight loss.