Abstract
Introduction
SARS-CoV-2 replication in cell cultures has been shown to be inhibited by ivermectin. However, ivermectin’s low aqueous solubility and bioavailability hinders its application in COVID-19 treatment. Also, it has been suggested that best outcomes for this medication can be achieved via direct administration to the lung.
Objectives
This study aimed at evaluating the safety of a novel ivermectin inhalable formulation in rats as a pre-clinical step.
Methods
Hydroxy propyl-β-cyclodextrin (HP-β-CD) was used to formulate readily soluble ivermectin lyophilized powder. Adult male rats were used to test lung toxicity for ivermectin-HP-β-CD formulations in doses of 0.05, 0.1, 0.2, 0.4 and 0.8 mg/kg for 3 successive days.
Results
The X-ray diffraction for lyophilized ivermectin-HP-β-CD revealed its amorphous structure that increased drug aqueous solubility 127-fold and was rapidly dissolved within 5 s in saline. Pulmonary administration of ivermectin-HP-β-CD in doses of 0.2, 0.4 and 0.8 mg/kg showed dose-dependent increase in levels of TNF-α, IL-6, IL-13 and ICAM-1 as well as gene expression of MCP-1, protein expression of PIII-NP and serum levels of SP-D paralleled by reduction in IL-10. Moreover, lungs treated with ivermectin (0.2 mg/kg) revealed mild histopathological alterations, while severe pulmonary damage was seen in rats treated with ivermectin at doses of 0.4 and 0.8 mg/kg. However, ivermectin-HP-β-CD formulation administered in doses of 0.05 and 0.1 mg/kg revealed safety profiles.
Conclusion
The safety of inhaled ivermectin-HP-β-CD formulation is dose-dependent. Nevertheless, use of low doses (0.05 and 0.1 mg/kg) could be considered as a possible therapeutic regimen in COVID-19 cases.
【저자키워드】 COVID-19, Ivermectin, Safety, Toxicity, pulmonary delivery, 【초록키워드】 Treatment, Gene Expression, IL-6, lung, ICAM-1, outcome, pulmonary, Bioavailability, Cell culture, low dose, therapeutic, male, Inhaled, MCP-1, Mild, IL-10, medication, SARS-CoV-2 replication, TNF-α, IL-13, administration, dose, COVID-19 cases, regimen, X-ray diffraction, Serum level, profiles, protein expression, pulmonary damage, Administered, objective, Result, shown, was used, inhibited, treated, were used, suggested, increase in, dose-dependent, histopathological, reduction in, alterations, pre-clinical step, 【제목키워드】 Treatment, Tolerance, Inhaled,