Evaluation of the inhibitory effect of ivermectin on the growth of Babesia and The ileria parasites in vitro and in vivo

Batiha, Gaber El-Saber and Beshbishy, Amani Magdy and Tayebwa, Dickson Stuart and Adeyemi, O. S. and Yokoyama, Naoaki and Igarashi, Ikuo (2019) Evaluation of the inhibitory effect of ivermectin on the growth of Babesia and The ileria parasites in vitro and in vivo. Tropical Medicineand Health, 47 (42). pp. 1-12.

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Abstract

Background:Treatment is the principle way to control and eliminate piroplasmosis. The search for newchemotherapy againstBabesiaandTheileriahas become increasingly urgent due to parasite resistance to currentdrugs. Ivermectin (IVM) was the world’s first endectocide, capable of killing a wide variety of parasites and vectors,both inside and outside the body. It is currently authorized to treat onchocerciasis, lymphatic filariasis,strongyloidiasis, and scabies. The current study documented the efficacy of IVM on the growth ofBabesiaandTheileriain vitro and in vivo.Methods:The fluorescence-based assay was used for evaluating the inhibitory effect of IVM on fourBabesiaspecies, includingB.bovis,B.bigemina,B.divergens,B.caballi, andTheileria equi, the combination with diminazeneaceturate (DA), clofazimine (CF), and atovaquone (AQ) on in vitro cultures, and on the multiplication of aB.microti-infected mouse model. The cytotoxicity of compounds was tested on Madin–Darby bovine kidney (MDBK), mouseembryonic fibroblast (NIH/3 T3), and human foreskin fibroblast (HFF) cell lines.Results:The half-maximal inhibitory concentration (IC50) values determined for IVM againstB.bovis,B.bigemina,B.divergens,B.caballi,andT.equiwere 53.3 ± 4.8, 98.6 ± 5.7, 30.1 ± 2.2, 43.7 ± 3.7, and 90.1 ± 8.1μM, respectively. Toxicityassays on MDBK, NIH/3 T3, and HFF cell lines showed that IVM affected the viability of cells with a half-maximaleffective concentration (EC50) of 138.9 ± 4.9, 283.8 ± 3.6, and 287.5 ± 7.6μM, respectively. In the in vivo experiment, IVM,when administered intraperitoneally at 4 mg/kg, significantly (p< 0.05) inhibited the growth ofB.microtiin mice by63%. Furthermore, combination therapies of IVM–DA, IVM–AQ, and IVM–CF at a half dose reduced the peakparasitemia ofB.microtiby 83.7%, 76.5%, and 74.4%, respectively. Moreover, this study confirmed the absence ofB.microtiDNA in groups treated with combination chemotherapy of IVM + DA and IVM + AQ 49 days after infection.Conclusions:These findings suggest that IVM has the potential to be an alternative remedy for treating piroplasmosis.

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