Isobolographic analysis of co‑administration of two plant‑derived antiplasmodial drug candidates, cryptolepine and xylopic acid, in Plasmodium berghei

Abstract

Background: Increasing resistance to current anti-malarial therapies requires a renewed effort in searching for alternative therapies to combat this challenge, and combination therapy is the preferred approach to address this. The present study confirms the anti-plasmodial effects of two compounds, cryptolepine and xylopic acid and the relation‑ ship that exists in their combined administration determined. Methods: Anti-plasmodial effect of cryptolepine (CYP) (3, 10, 30 mg kg−1) and xylopic acid (XA) (3, 10, 30 mg kg−1) was evaluated in Plasmodium berghei-infected male mice after a 6-day drug treatment. The respective doses which produced 50% chemosuppression ­(ED50) was determined by iterative fitting of the log-dose responses of both drugs. CYP and XA were then co-administered in a fixed dose combination of their ­ED50s (1:1) as well as different fractions of these combinations (1/2, 1/4, 1/8, 1/16 and 1/32) to find the experimental E­ D50 ­(Zexp). The nature of interaction between cryptolepine and xylopic acid was determined by constructing an isobologram to compare the Z ­ exp with the theoretical ­ED50 ­(Zadd). Additionally, the effect of cryptolepine/xylopic acid co-administration on vital organs asso‑ ciated with malarial parasiticidal action was assessed. Results: The ­Zadd and ­Zexp were determined to be 12.75 ± 0.33 and 2.60 ± 0.41, respectively, with an interaction index of 0.2041. The ­Zexp was significantly (P < 0.001) below the additive isobole indicating that co-administration of cryptolepine and xylopic acid yielded a synergistic anti-plasmodial effect. This observed synergistic antiplasmodial effect did not have any significant deleterious effect on the kidney, liver and spleen. However, the testis were affected at high doses. Conclusion: The co-administration of cryptolepine and xylopic acid produces synergistic anti-malarial effect with minimal toxicity.