Safety of oral administration of high doses of ivermectin by means of biocompatible polyelectrolytes formulation

Abstract

The FDA-approved drug ivermectin is applied for treatments of onchocerciasis and lymphatic filariasis. The anticancer and anti-viral activities have been demonstrated stressing possibilities for the drug repurposing and therefore new information on high dosage safety is on demand. We analyzed in vivo tissue responses for high doses of ivermectin using Corydoras fish as animal model. We made intestinal histology and hematologic assays after oral administration of ivermectin transported with polyelectrolytes formulation. Histology showed any apparent damage of intestinal tissues at 0.22-170 mg of ivermectin/kg body weight. Immunofluorescence evidenced delocalization of Myosin-Vb at enterocytes only for the higher dose. Hematology parameters showed random variations after 7 days from administration, but a later apparent recover after 14 and 21 days. The study evaluated the potential of high doses of oral administration of ivermectin formulation, which could be an alternative with benefits in high compliance therapies.

Intravenous veterinary ivermectin in a COVID-19 patient causing neurotoxicity

“…Most of the safety and pharmacokinetic data on oral administered ivermectin are from doses of 0.15–0.20 mg/kg. In an animal study by Rafael et al doses of ivermectin in the range of 0.22–0.86 mg/kg were not harmful to intestinal tissue and blood cells in general [17] .…”

Cubosomal lipid nanoassemblies with pH-sensitive shells created by biopolymer complexes: A synchrotron SAXS study

“…The structural changes established by SAXS suggested that the biopolymers were successfully incorporated to the cubosomal lipid structures, rendering the obtained nanoparticles pH-responsive vehicles. Both biopolymers have been incorporated in different types of nanoparticles [44,54,57]. However, they built-up a promising new nanostructured material in association with lipid-based cubosomes by tailoring liquid crystalline structure and poly-charged shells, which can render stronger interaction and deeper penetration in the mucosal layers of intestine.…”

“…The described pH-responsiveness, related to the structural features of the biopolymertailored cubosomes, may represent important advantages for the development of colloidal vehicles for biomedical applications where pH variation plays an important role. Previously, the combination of CHarg and ALG in the production of micro and nanoparticles as drug delivery systems has shown great potential for in vivo oral administration [54,[56][57][58][59]. Indeed, the gastrointestinal tract presents extreme pH variation to which drug delivery devices can be developed to respond in a manner to provide localized, optimized, and prolonged delivery of the carried bioactives.…”

“…A recent SAXS study has shown that lipids associated with the polysaccharide chitosan can assemble into certain cubic phases depending on the lipid/polymer mass ratio and the degree of hydration [55]. Moreover, the association of chitosan and chitosan-N-arginine with alginate, another polysaccharide with advantageous characteristics, allowed the production of pH-sensitive nanoparticles as drug delivery systems for the anthelmintic drugs ivermectin, mebendazole and praziquantel [56][57][58][59]. Indeed, chitosan and alginate are oppositely charged polyelectrolytes in aqueous medium, which renders the association of both macromolecules pH-dependent [54].…”

High compliance and effective treatment of fish endoparasitic infections with oral drug delivery nanobioparticles: Safety of intestinal tissue and blood parameters

“…One hundred and eighty adult specimens of C. schwartzi, bought from a commercial provider, were employed in similar conditions as described in our previous studies (Madrid et al, 2021;Mathews et al, 2018;Patta et al, 2020). The fish were divided into three aquariums with 15 L of dechlorinated water, previously conditioned to adequate water conditions for the species, with a constant temperature of 28°C using thermostat systems (Hopar Aquarium Heater H-606 150W), constant pH 6.8 and adjusted physicochemical parameters (Seachem Prime water conditioner), and submitted to constant filtration and aeration (Aquatech FE25 Filtration System) with the water flow rate adjusted to 250 L/h.…”