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Nebulized ivermectin for COVID-19 and other respiratory diseases, a proof of concept, dose-ranging study in rats

Chaccour et al., Scientific Reports, doi:10.1038/s41598-020-74084-y
Oct 2020  
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Study showing that nebulized ivermectin can reach pharmacodynamic concentrations in the lung tissue of rats. Authors note that additional experiments are required to assess the safety of this formulation in larger animals.
Ivermectin, better known for antiparasitic activity, is a broad spectrum antiviral with activity against many viruses including H7N7 Götz, Dengue Tay, Wagstaff, HIV-1 Wagstaff, Simian virus 40 Wagstaff (B), Zika Barrows, Yang, West Nile Yang, Yellow Fever Mastrangelo, Varghese, Japanese encephalitis Mastrangelo, Chikungunya Varghese, Semliki Forest virus Varghese, Human papillomavirus Li, Epstein-Barr Li, BK Polyomavirus Bennett, and Sindbis virus Varghese.
Ivermectin is an inhibitor of importin-α/β-dependent nuclear import of viral proteins Götz, Kosyna, Wagstaff, Wagstaff (B), a SARS-CoV-2 3CLpro inhibitor Mody, binds to glycan sites on the SARS-CoV-2 spike protein preventing interaction with blood and epithelial cells and inhibiting hemagglutination Boschi, exhibits dose-dependent inhibition of lung injury Abd-Elmawla, Ma, may inhibit SARS-CoV-2 induced formation of fibrin clots resistant to degradation Vottero, shows protection against inflammation, cytokine storm, and mortality in an LPS mouse model of severe infection/inflammation that shares key pathological features of severe COVID-19 DiNicolantonio, Zhang, may be beneficial in severe COVID-19 by binding IGF1 to inhibit the promotion of inflammation, fibrosis, and cell proliferation that leads to lung damage Zhao, may minimize SARS-CoV-2 induced cardiac damage Liu, Liu (B), has immunomodulatory Munson and anti-inflammatory DiNicolantonio (B), Yan properties, and has an extensive and very positive safety profile Descotes.
6 studies investigate novel formulations of ivermectin for improved efficacy Albariqi, Albariqi (B), Chaccour, Errecalde, Mansour, Saha (B)
Chaccour et al., 13 Oct 2020, peer-reviewed, 8 authors.
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Nebulized ivermectin for COVID-19 and other respiratory diseases, a proof of concept, dose-ranging study in rats
Carlos Chaccour, Gloria Abizanda, Ángel Irigoyen-Barrio, Aina Casellas, Azucena Aldaz, Fernando Martínez-Galán, Felix Hammann, Ana Gloria Gil
Scientific Reports, doi:10.1038/s41598-020-74084-y
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 C max 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 lopinavirritonavir 1 , hydroxychloroquine as prophylaxis 2 or even harmfulness such as high-dose hydroxychloroquine for prophylaxis 3 while remdesivir 4 and dexamethasone 5 seem to improve patients' outcome. Ivermectin is a widely used antiparasitic drug with known efficacy against several single-strain RNA viruses including Dengue 6 , Zika 7 and other viruses 8 . 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/beta1 9 , inhibition of the viral helicase 8 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 vivo 10 .
Author contributions Competing interests The authors declare no competing interests.
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