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

Silas Acheampong Osei; Robert Peter Biney; Ernest Obese; Mary Atta-Panyi Agbenyeku; Isaac Yaw Attah; Elvis Ofori Ameyaw; Johnson Nyarko Boampong

doi:10.1186/s12936-021-03658-6

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

Malar J. 2021 Feb 25;20(1):113. doi: 10.1186/s12936-021-03658-6.

Authors

Silas Acheampong Osei^{1

2}, Robert Peter Biney^{2

3}, Ernest Obese^{2

3}, Mary Atta-Panyi Agbenyeku¹, Isaac Yaw Attah^{1

2}, Elvis Ofori Ameyaw^{4

5}, Johnson Nyarko Boampong^{1

2}

Affiliations

¹ Department of Biomedical Sciences, School of Allied Health Sciences, University of Cape Coast, Cape Coast, Ghana.
² School of Pharmacy and Pharmaceutical Sciences, University of Cape Coast, Cape Coast, Ghana.
³ Department of Pharmacology, School of Medical Sciences, University of Cape Coast, Cape Coast, Ghana.
⁴ Department of Biomedical Sciences, School of Allied Health Sciences, University of Cape Coast, Cape Coast, Ghana. elvisameyaw@gmail.com.
⁵ School of Pharmacy and Pharmaceutical Sciences, University of Cape Coast, Cape Coast, Ghana. elvisameyaw@gmail.com.

Abstract

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 ED₅₀s. Artemether/lumefantrine 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 (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 ED₅₀ (Z_add). Bodyweight 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 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.

Keywords: Amodiaquine; Antimalarial drugs; Artesunate; Combination therapies; Isobolographic analysis; Plasmodium berghei; Synergism; Xylopic acid.

MeSH terms

Amodiaquine / therapeutic use*
Animals
Antimalarials / therapeutic use*
Artesunate / therapeutic use*
Diterpenes, Kaurane / therapeutic use*
Dose-Response Relationship, Drug
Drug Combinations
Female
Malaria / drug therapy*
Mice
Mice, Inbred ICR
Plasmodium berghei / drug effects

Substances

Antimalarials
Diterpenes, Kaurane
Drug Combinations
xylopic acid
Amodiaquine
Artesunate