Abstract: www.nature.com/scientificreports OPEN Nebulized ivermectin for COVID‑19 and other respiratory diseases, a proof of concept, dose‑ranging study in rats Carlos Chaccour1,2,3*, Gloria Abizanda4,5, Ángel Irigoyen‑Barrio6,7, Aina Casellas1,8, Azucena Aldaz5,6, Fernando Martínez‑Galán6, Felix Hammann9 & Ana Gloria Gil6,7 Ivermectin is a widely used antiparasitic drug with known efficacy against several single-strain RNA viruses. Recent data shows significant reduction of SARS-CoV-2 replication in vitro by ivermectin concentrations not achievable with safe doses orally. Inhaled therapy has been used with success for other antiparasitics. An ethanol-based ivermectin formulation was administered once to 14 rats using a nebulizer capable of delivering particles with alveolar deposition. Rats were randomly assigned into three target dosing groups, lower dose (80–90 mg/kg), higher dose (110–140 mg/kg) or ethanol vehicle only. A toxicology profile including behavioral and weight monitoring, full blood count, biochemistry, necropsy and histological examination of the lungs was conducted. The pharmacokinetic profile of ivermectin in plasma and lungs was determined in all animals. There were no relevant changes in behavior or body weight. There was a delayed elevation in muscle enzymes compatible with rhabdomyolysis, that was also seen in the control group and has been attributed to the ethanol dose which was up to 11 g/kg in some animals. There were no histological anomalies in the lungs of any rat. Male animals received a higher ivermectin dose adjusted by adipose weight and reached higher plasma concentrations than females in the same dosing group (mean ­Cmax 86.2 ng/ml vs. 26.2 ng/ ml in the lower dose group and 152 ng/ml vs. 51.8 ng/ml in the higher dose group). All subjects had detectable ivermectin concentrations in the lungs at seven days post intervention, up to 524.3 ng/g for high-dose male and 27.3 ng/g for low-dose females. nebulized ivermectin can reach pharmacodynamic concentrations in the lung tissue of rats, additional experiments are required to assess the safety of this formulation in larger animals. As of August 19, 2020, there have been more than 22 million COVID-19 cases causing over 785,000 deaths worldwide. In the absence of a vaccine, numerous efforts are ongoing to develop drug-based strategies to prevent, treat or reduce the transmission of the virus. Data on several drug regimens suggest lack of efficacy for lopinavirritonavir1, hydroxychloroquine as p ­ rophylaxis2 or even harmfulness such as high-dose hydroxychloroquine for ­prophylaxis3 while ­remdesivir4 and ­dexamethasone5 seem to improve patients’ outcome. Ivermectin is a widely used antiparasitic drug with known efficacy against several single-strain RNA viruses including ­Dengue6, ­Zika7 and other v­ iruses8. The effect on flaviviruses could be explained by a reduction of the viral penetration into the nucleus via an effect on the host´s importin alpha/beta19, inhibition of the viral ­helicase8 or yet to be described mechanisms. Caly et al. showed a significant reduction of SARS-CoV-2 replication after incubating Vero cells, a cell line derived from African Green Monkey kidney epithelial cells, for 48 h with ivermectin concentrations not readily attainable in vivo10. Yet, these findings stirred widespread interest and together with a preprint report of 1 ISGlobal, Hospital Clínic - Universitat de Barcelona, Rosello 132, 5ª 2ª, 08036 Barcelona, Spain. 2Ifakara Health..