Hydroxychloroquine as an aerosol might markedly reduce and even prevent severe clinical symptoms after SARS-CoV-2 infection

Klimke, A.; Hefner, Gudrun; Will, B.; Voss, Ursula

doi:10.1016/j.mehy.2020.109783

Cited by 55 publications

(44 citation statements)

References 29 publications

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“…While there is no commercially available aerosolized formulation of HCQ, a recent empirical study of inhaled HCQ aerosols at 4 mg per day over one week found it was well tolerated without significant adverse events (14). This further supports the rationale of applying inhalable liposomal HCQ with direct lung targeting in COVID-19 infection/disease prevention and treatment.…”

Section: Discussionmentioning

confidence: 64%

A Strategy to Treat COVID-19 Disease with Targeted Delivery of Inhalable Liposomal Hydroxychloroquine: A Non-clinical Pharmacokinetic Study

Tai¹,

Wu²,

et al. 2020

Preprint

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly identified pathogen causing coronavirus disease 2019 (COVID-19) pandemic. Hydroxychloroquine (HCQ), an antimalarial and anti-inflammatory drug, has been shown to inhibit SARS-CoV-2 infection in vitro and tested in clinical studies. However, lung concentration (6.7 μg/mL) to predict the in vivo antiviral efficacy might not be achievable with the currently proposed oral dosing regimen. Further, a high cumulative doses of HCQ may raise concerns of systemic toxicity, including cardiotoxicity. Here, we described a non-clinical study to investigate the pharmacokinetics of a novel formulation of liposomal HCQ administrated by intratracheal (IT) instillation in Sprague-Dawley (SD) rats which achieved 129.4 μg/g (Cmax) in the lung. Compared to unformulated HCQ administered intravenous (IV), liposomal HCQ with normalized dose showed higher (~30-fold) lung exposure, longer (~2.5-fold) half-life in lung, but lower blood exposure with ~20% of Cmax and 74% of AUC and lower heart exposure with 24% of Cmax and 58% of AUC. In conclusion, the pharmacokinetics results in an animal model demonstrate the proof of concept that inhalable liposomal HCQ may provide clinical benefit and serve as a potential treatment for COVID-19.

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Section: Discussionmentioning

confidence: 64%

A Strategy to Treat COVID-19 Disease with Targeted Delivery of Inhalable Liposomal Hydroxychloroquine: A Non-clinical Pharmacokinetic Study

Tai¹,

Wu²,

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…There are several common adverse effects associated with this medication including diarrhea, vomiting, and peripheral neuropathy 91 . Fenoterol has already been recommended to reduce severe pulmonary symptoms of COVID-19 patients 92 . Doxi uridine has been suggested as a possible SARS-CoV-2 inhibitor based on similarities with active antivirals already tested by arti cial intelligence 93 .…”

Section: Resultsmentioning

confidence: 99%

Bisindolylmaleimide IX: A novel anti-SARS-CoV2 agent targeting viral main protease 3CLpro demonstrated by virtual screening and in vitro assays

Gupta

Maciorowski

Zak

et al. 2020

Preprint

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The emergence of SARS/MERS drug-resistant COVID-19 with high transmission and mortality has recently been declared a pandemic. Like all coronaviruses, SARS-CoV-2 is a relatively large virus consisting of several enzymes with essential functions within its proteome. Here, we focused on repurposing approved and investigational drugs by identifying potential drugs that are predicted to effectively inhibit critical enzymes. We targeted seven proteins with enzymatic activities known to be essential at different stages of the virus life cycle; PLpro, 3CLpro, RdRP, Helicase, ExoN, NendoU, and 2’-O-MT. For virtual screening, the energy minimization of a crystal structure of the modeled protein was carried out using the Protein Preparation Wizard1. Following active site selection based on data mining and COACH predictions, we performed a high-throughput virtual screen of drugs (n=5903) that are approved by worldwide regulatory bodies. The screening was performed against viral targets using three sequential docking modes (i.e. HTVS, SP, and XP). Our in-silico virtual screening identified ~290 potential drugs based on the criteria of energy, docking parameters, ligand, and binding site strain and score. Drugs specific to each target protein were further analyzed for binding free energy perturbation by molecular mechanics (prime MM-GBSA) and pruning the hits to the top 32 candidates. Top lead from each target pool was further subjected to molecular dynamics simulation using the Desmond module. Herein we report the evaluation of in-vitro efficacy of selected hit drug molecules on SARS-CoV-2 virus inhibition. Among eight molecules included in our evaluation, we found the micromolar inhibitor of protein kinase C isoforms, Bisindolylmaleimide IX (BIM IX), as the most potent inhibitor of SARS-CoV-2 in-vitro. Further, in-silico predicted target validation through enzymatic assays confirmed its interaction with 3CLpro to be the target. Therefore, our data support advancing BIM IX for clinical evaluation as a potential treatment for COVID-19. This is the first study that has showcased the possibility of using bisindolylmaleimide IX to treat COVID-19 through this pipeline.

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“…A small nonrandom clinical trial in France showed that HCQ combined with azithromycin has a significant therapeutic effect (Gautret et al, 2020), and it has been reported that CQ can effectively inhibit the deterioration of new coronary pneumonia, improve lung imaging performance, promote viral reversion and shorten the time of disease onset (Gao et al, 2020). It has been hypothesized that HCQ aerosols can be inhaled early in infection, allowing for the sufficient therapeutic effects on alveolar epithelial cells while avoiding the adverse effects of large oral doses (Klimke et al, 2020). However, it has also been reported that the combination of HCQ and azithromycin in 11 patients with severe 2019-nCoV infection has not achieved a positive clinical effect (Molina et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Chloroquine and hydroxychloroquine as ACE2 blockers to inhibit viropexis of 2019-nCoV Spike pseudotyped virus

Wang

Han

et al. 2020

Preprint

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The pandemic coronavirus COVID-19 affected global health from the end of 2019 to 2020 and may challenge global health in the future. There have been reports of Chloroquine (CQ) and Hydroxychloroquine (HCQ) used in clinical treatment. In our study, we used CCK-8 stain, flow cytometry and immunofluorescent stain to evaluated the toxicity and autophagy of CQ and HCQ respectively on ACE2 high expressed HEK293T cells (ACE2 hi cells). We further analysied the binding character of CQ and HCQ to ACE2 by molecular docking, surface plasmon resonance (SPR) assays and molecule docking, COVID-19 spike pseudotype virus was also taken to investigate the suppression viropexis effect of CQ and HCQ. Results showed that HCQ is slightly more toxic to ACE2 hi cells than CQ, both CQ and HCQ could bind to ACE2, and they also exhibit equivalent suppression effect for the entrance of COVID-19 Spike pseudotype virus into ACE2 hi cells. Our finding provides a theoretical and experimental basis for the clinical treatment of CQ and HCQ for COVID-19.

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Hydroxychloroquine as an aerosol might markedly reduce and even prevent severe clinical symptoms after SARS-CoV-2 infection

Cited by 55 publications

References 29 publications

A Strategy to Treat COVID-19 Disease with Targeted Delivery of Inhalable Liposomal Hydroxychloroquine: A Non-clinical Pharmacokinetic Study

A Strategy to Treat COVID-19 Disease with Targeted Delivery of Inhalable Liposomal Hydroxychloroquine: A Non-clinical Pharmacokinetic Study

Bisindolylmaleimide IX: A novel anti-SARS-CoV2 agent targeting viral main protease 3CLpro demonstrated by virtual screening and in vitro assays

Chloroquine and hydroxychloroquine as ACE2 blockers to inhibit viropexis of 2019-nCoV Spike pseudotyped virus

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