Repurposing Dihydroartemisinin-Piperaquine-Doxycycline as an Antimalarial Drug: A Study in Plasmodium berghei-Infected Mice

Udeme Owunari Georgewill, Elias Adikwu


Artemisinin-based combination (ACT) therapy is the mainstay for malaria treatment. However, Plasmodium parasite with decreased susceptibility to ACT has emerged. Hence, it is imperative to discover new drugs or explore new drug combinations that can decrease Plasmodium parasite resistance. This study assessed the antiplasmodial activity of dihydroartemisinin-piperaquine- doxycycline (D-P-DX) on mice infected with Plasmodium berghei. Swiss albino mice (25-30g) of both sexes inoculated with 1x107 Plasmodium berghei intraperitoneally were used. The mice were randomly grouped and orally treated with DX (2.2 mg/kg), D-P (1.71/13.7 mg/kg) and D-P-DX daily in curative, suppressive and prophylactic studies. The negative and the positive controls were treated daily with normal saline (0.2mL) and chloroquine (CQ) (10mg/kg), respectively. After treatment, blood samples were assessed for percentage parasitemia, hematological and lipid parameters. Also, the mice were observed for mean survival time. D-P, DX, and D-P-DX produced significant decreases in percentage parasitemia at p<0.05, p<0.01 and p<0.001, respectively when compared to negative control. In the curative study, D-P, DX, and D-P-DX produced 64.9%, 71.1%, and 93.6% parasitemia inhibitions when compared to 70.0% inhibition produced by CQ. Plasmodium berghei -induced alterations in packed cell volume, white blood cells, red blood cells, hemoglobin, high-density lipoprotein cholesterol, total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels were significantly restored by DX (p<0.05) and D-P (p<0.01) and D-P-DX (p<0.001) when compared to the negative control. D-P-DX showed significant antiplasmodial activity against Plasmodium berghei- infected mice. It may be clinically useful for the treatment of malaria.


artemisinins; doxycycline; malaria; repurposing; resistance

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Amaratunga C, Lim P, Suon S, Sreng, S, Mao S, Sopha C et al. (2016). Dihydroartemisininpiperaquine resistance in Plasmodium falciparum malaria in Cambodia: A multisite prospective cohort study. Lancet Infect Dis. 16, 357.

Amato D.R, Lim P, Miotto O, Amaratunga C, Dek D, Pearson R.D et al. (2017) Genetic markers associated with dihydroartemisininpiperaquine failure in Plasmodium falciparum malaria in Cambodia: A genotype-phenotype association study. Lancet Infect Dis. 17, 164173

Basco, L K, & Le Bras J. (1993). Activity in vitro of doxycycline against multidrug-resistant Plasmodium falciparum. Transaction of Royal Society of Tropical Medicine and Hygiene. 87:469470

Beeson JG, Drew DR, Boyle MJ, Feng G, Fowkes FJ, Richards JS et al. (2016) Merozoite surface proteins in red blood cell invasion, immunity and vaccines against malaria. FEMS Microbiology Review. 40(3):343372.

Desai M, Hill J, Fernandes S, Walker P, Pell C, Gutman J et al. (2018). Prevention of malaria in pregnancy. Lancet Infectious Disease. 18, 119132.

Gaillard T, Madamet M, & Pradines B. (2015). Tetracyclines in malaria. Malarial Journal. 14, 445 ;1-10.

Griffith KS, Lewis LS, Mali S, & Parise ME. (2007) Treatment of malaria in the United States: a systematic review. Journal of American Medical Association. 297:22642277

Hiben MG, Sibhat GG, Fanta BS, Gebrezgi HD, & Tesema SB (2016). Evaluation of Senna singueana leaf extract as an alternative or adjuvant therapy for malaria. Journal of Traditional and Complimentary Medicine. 6:112-117

Joseph AO, & Samson OT (2020) Antiplasmodial Efficacy of Anacardium occidentale in Albino Mice Infected with Plasmodium berghei. Journal of Family Medicine and Disease Prevention. 6:123;1-6

Kakuru A, Jagannathan P, Muhindo M.K, Natureeba P, Awori, P, Nakalembe M, et al., (2016) Dihydroartemisinin-Piperaquine for the Prevention of Malaria in Pregnancy. New England Journal of Medicine. 374, 928939.

Knight DJ, & Peters W. (1980). The antimalarial action of N-Benzyl oxydihydrotriazines and the studies on its mode of action. Annals of Tropical Medicine and Parasitology. 74: 393-404.

Leang R, Barrette A, Bouth DM, Menard D, Abdur R, Duong S et al., (2013). Efficacy of dihydroartemisinin-piperaquine for treatment of uncomplicated Plasmodium falciparum and Plasmodium vivax in Cambodia, 2008 to 2010. Antimicrobial Agents Chemotherapy. 57, 818826.

McEvoy G. (2008). AHFS Drug Information. Bethesda, MD: American Society of Health-System Pharmacists, Inc; 2008.

Mekonnen LB. (2015). In vivo antimalarial activity of the crude root and fruit extracts of Croton macrostachyus (Euphorbiaceae) against Plasmodium berghei in mice. Journal of Traditional and Complimentary Medicine. 5:168e173

Meshnick SR. (1994) The mode of action of antimalarial endoperoxides. Transaction of Royal Society of Tropical Medicine and Hygiene 88:131-2.

Nardos A, & Makonnen E (2017). In vivo antiplasmodial activity and toxicological assessment of hydroethanolic crude extract of Ajuga remota. Malarial Journal. 16:25; 1-8

Nosten F, & White NJ. (2007) Artemisinin-based combination treatment of falciparum malaria. American Journal of Tropical Medicine and Hygiene. 77, 181192

Peters W. (1967). Rational methods in the search for antimalarial drugs. Transaction of Royal Society of Tropical Medicine and Hygiene. 61: 400-410.

Prapunwattana P, OSullivan WJ, & Yuthavong Y. (1988). Depression of Plasmodium falciparum dihydroorotate dehydrogenase activity in in vitroculture by tetracycline. Molecular and Biochemical Parasitology. 27:11924.

Ryley JF, & Peters W. (1970) The antimalarial activity of some quinolone esters. Annals of Tropical Medicine and Parasitology. 84: 209-222.

Satish PVV, Kumari DS, & Sunita K, (2017) Antiplasmodial efficacy of Calotropis gigantean (L.) against Plasmodium falciparum (3D7 strain) and Plasmodium berghei (ANKA). Journal of Vector Borne Disease. 54(3):215-225

Saunders D. L, Vanachayangkul P, & Lon C. (2014) DihydroartemisininPiperaquine Failure in Cambodia. New England Journal of Medicine. 371, 484485

Somsak V, Damkaew A, & Onrak P. (2018) Antimalarial activity of kaempferol and its combination with chloroquine in Plasmodium berghei infection in mice. Journal of Pathology. 2018:1-7.

Tan KR, Magill AJ, Parise ME, & Arguin PM, (2011). Doxycycline for Malaria Chemoprophylaxis and Treatment: Report from the CDC Expert Meeting on Malaria Chemoprophylaxis, Hygiene. 5; 84(4): 517531.

Trning J. Piperaquine, Bioanalysis (2007) Drug Metabolism and Pharmacokinetics. Gteborg, Sweden: Institute of Neuroscience and Physiology, Department of Pharmacology, The Sahlgrenska Academy at Gteborg University

Tayler NM, De Jess R, Spadafora R, Coronado LM, R, & Spadafora C (2020) Antiplasmodial activity of Cocos nucifera leaves in Plasmodium berghei-infected mice. Journal of Parasitic Disease 44, 305313.

Visser BJ, Wieten RW, Nagel IM. & Grobusch MP (2013) Serum lipids and lipoproteins in malaria - a systematic review and meta-analysis. Malarail Journal. 12, 442, 1-16

WHO. World Malaria Report 2016. Geneva: World Health Organization; 2016

Yavo W, Faye B, Kuete T, Djohan V, Oga SA, Kassi RR et al. (2011). Multicentric assessment of the efficacy and tolerability of dihydroartemisinin-piperaquine compared to artemether-lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria in Sub-Saharan Africa. Malarial Journal. 2011; 10:198.

Yeo AE, Edstein MD, Shanks GD, & Rieckmann KH (1997). Potentiation of the antimalarial activity of atovaquone by doxycycline against Plasmodium falciparum in vitro. Parasitology Research. 83:48991.



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Biology, Medicine, & Natural Product Chemistry
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