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

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.

Considering ivermectin for treatment of schistosomiasis

“…Likewise, despite the pronounced effect on worm motility, there was no reduction of worm burden in infected mice following gavage treatment of 25 mg/kg ivermectin in 2 days, starting 6 weeks postinfection (Ryan et al 2023 ). A failure of prophylaxis attempts (1 mg/kg delivered by gavage in three successive days before infection) was observed in infected mice (Vicente et al ( 2021 ). In contrast, there was a slight (but statistically significant) reduction in worm burden, destructive changes (mainly in female worms), decreased liver inflammation, and an increase in the quantity of dead ova in mice that were treated with 25 mg ivermectin/kg by gavage, in two consecutive days starting 6 weeks PI (Taman et al 2014 ).…”

Programmed cell death pathways as targets for developing antifilarial drugs: Lessons from the recent findings

“…[116][117][118] Interestingly, IVM has exhibited better efficacy against all the developmental stages of the parasites responsible for schistosomiasis. [119][120][121] F I G U R E 1 Schematic representation of the potential efficacy of different chemotherapeutics across the developmental stages of filarial parasites reside in the human host (Wuchereria bancrofti and Onchocerca volvulus), bovine host (Setaria cervi) and rodent host (Acanthocheilonema viteae). elegans.…”

“…On the other hand, ALB, when used in combination with praziquantel and nitazode, targets larval forms of Schistosoma mansoni and eggs of Schistosoma japonicum , Schistosoma haematobium and S. mansoni 116–118 . Interestingly, IVM has exhibited better efficacy against all the developmental stages of the parasites responsible for schistosomiasis 119–121 …”

Xenobiotic-Metabolizing Enzymes in Trematodes

“…By contrast, the treatment of murine schistosomiasis with P-glycoprotein inhibitors does not improve the therapeutic effect against schistosomes. In particular, systemic treatment with ivermectin, even in the presence of the pharmacological inhibition of P-glycoprotein or cytochrome P450 3A, does not result in effective prophylaxis of S. mansoni infection in an experimental murine model [ 77 ].…”