The effect of ivermectin alone and in combination with cobicistat or elacridar in experimental Schistosoma mansoni infection in mice

Belén Vicente,Juliane Chaccour,Julio López-Abán,Antonio Muro,Juan Hernández-Goenaga,Patricia Nicolas,Carlos Chaccour,Pedro Fernández-Soto

doi:10.1038/s41598-021-84009-y

Abstract

Schistosoma mansoni is less susceptible to the antiparasitic drug ivermectin than other helminths. By inhibiting the P-glycoprotein or cytochrome P450 3A in mice host or parasites in a murine model, we aimed at increasing the sensitivity of S. mansoni to the drug and thus preventing infection. We assigned 124 BALB/c mice to no treatment, treatment with ivermectin only or a combination of ivermectin with either cobicistat or elacridar once daily for three days before infecting them with 150 S. mansoni cercariae each. The assignment was done by batches without an explicit randomization code. Toxicity was monitored. At eight weeks post-infection, mice were euthanized. We determined number of eggs in intestine and liver, adult worms in portal and mesenteric veins. Disease was assessed by counting granulomas/cm2 of liver and studying organ weight indices and total weight. IgG levels in serum were also considered. No difference between groups treated with ivermectin only or in combination with cobicistat or elacridar compared with untreated, infected controls. Most mice treated with ivermectin and elacridar suffered severe neurological toxicity. In conclusion, systemic treatment with ivermectin, even in the presence of pharmacological inhibition of P-glycoprotein or cytochrome P450 3A, did not result in effective prophylaxis for S. mansoni infection in an experimental murine model.

Highlights

Progress in the control or elimination of schistosomiasis must be approached from different angles: accurate, fast and cheap diagnosis; affordable, safe and effective treatment; and well-established prevention and control strategies
In the mouse model of schistosome infection, adult worm load can be reduced by very high doses of ivermectin[9], as it appears that Schistosoma mansoni is much less susceptible to ivermectin than other helminths[10]
We found no differences between the infected groups previously treated with ivermectin (G3 Iv), ivermectin + cobicistat (G4 Iv-Co) or untreated (G2 Inf)

Summary

Introduction

Progress in the control or elimination of schistosomiasis must be approached from different angles: accurate, fast and cheap diagnosis; affordable, safe and effective treatment; and well-established prevention and control strategies. In the mouse model of schistosome infection, adult worm load can be reduced by very high doses of ivermectin[9], as it appears that Schistosoma mansoni is much less susceptible to ivermectin than other helminths[10]. It is unknown whether S. mansoni cercariae differ in sensitivity to ivermectin, to date no study has described a prophylactic model. The objective of this work was to evaluate the capacity of ivermectin alone and in combination with elacridar or cobicistat to prevent S. mansoni infection in an experimental model using BALB/c mice

Objectives

Methods

Results

Discussion

Conclusion