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

Abstract

BackgroundIncreasing 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 relationship that exists in their combined administration determined.MethodsAnti-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 ED50 (Zexp). The nature of interaction between cryptolepine and xylopic acid was determined by constructing an isobologram to compare the Zexp with the theoretical ED50 (Zadd). Additionally, the effect of cryptolepine/xylopic acid co-administration on vital organs associated with malarial parasiticidal action was assessed.ResultsThe 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.ConclusionThe co-administration of cryptolepine and xylopic acid produces synergistic anti-malarial effect with minimal toxicity.

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

“…Although the XA monotherapy experiment did not significantly prevent weight loss, the combination therapy with ART and AQ showed significant reduction in weight loss in the 10.6 mg/kg and 12.1 mg/kg combination doses. This observation correlates with other studies where a combination of xylopic acid and cryptolepine prevented a loss in body weight in mice infected with P. berghei ANKA (12,16).…”

“…Compared to a recent study by Ameyaw et al (12), combining xylopic acid and artesunate gave a higher supra-additivity and synergistic interaction than xylopic acid and cryptolepine combination, probably, due to the high synergistic property of artesunate (25)(26)(27). Nevertheless,…”

“…Xylopic acid, extracted from the unripe fruits of Xylopia aethiopica has been examined previously to have antiplasmodial, anti-inflammatory, antipyretic (11), and analgesic (15) properties. Also, it has been recently reported to act synergistically when combined with other plant-derived antiplasmodial compounds such as cryptolepine (12). artesunate are administered together, the Zexp was significantly below the line of additivity ("additive" isobole) and the Zadd, which means the two drugs have a synergistic anti-plasmodial effect.…”

“…The observed increased antiplasmodial activity of XA/ART combination could also be attributed to the two drugs interacting with several targets in the parasite. XA inhibits plasmodium dehydrogenase (28), an enzyme which catalyzes the reduction of pyruvate to lactate, crucial for energy production, whilst artemisinin derivatives are believed to undergo reductive activation of the peroxide group in the presence of ferrous ion which is released upon hemoglobin digestion within the food vacuole of the parasite (12,29). This forms a carbon-centered radical which alkylates vital parasite proteins such as heme and membrane-associated parasite proteins (30,31).…”

“…Artesunate, amodiaquine, and xylopic acid have all been shown to be effective in combination therapies as demonstrated by Ameyaw and colleagues on the synergistic effect of xylopic acid in combination with cryptolepine in clearing malaria parasites in a malaria experimental model (12). Similarly, the antimalarial activity of amodiaquine and artesunate was enhanced when combined with lopinavir/ritonavir (13).…”