Potential new treatment strategies for COVID-19: is there a role for bromhexine as add-on therapy?

Depfenhart, Markus; Villiers, Danielle de; Lemperle, Gottfried; Meyer, Markus; Somma, Salvatore Di

doi:10.1007/s11739-020-02383-3

Cited by 70 publications

(54 citation statements)

References 76 publications

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“…Ambroxol had low activity in the NCATS single-dose experiments, supporting our hypothesis that ambroxol’s beneficial effect is not related to direct antiviral activity. 64 Both bromhexine 65 and ambroxol 66 induce autophagy in vitro . Although the different cell systems in which these drugs were tested might influence the experimental results, ambroxol was measured to be at least twice as potent as bromhexine at clinically relevant concentrations.…”

Section: Resultsmentioning

confidence: 99%

Virtual and In Vitro Antiviral Screening Revive Therapeutic Drugs for COVID-19

Bocci

Bradfute

et al. 2020

ACS Pharmacol. Transl. Sci.

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The urgent need for a cure for early phase COVID-19 infected patients critically underlines drug repositioning strategies able to efficiently identify new and reliable treatments by merging computational, experimental, and pharmacokinetic expertise. Here we report new potential therapeutics for COVID-19 identified with a combined virtual and experimental screening strategy and selected among already approved drugs. We used hydroxychloroquine (HCQ), one of the most studied drugs in current clinical trials, as a reference template to screen for structural similarity against a library of almost 4000 approved drugs. The top-ranked drugs, based on structural similarity to HCQ, were selected for in vitro antiviral assessment. Among the selected drugs, both zuclopenthixol and nebivolol efficiently block SARS-CoV-2 infection with EC 50 values in the low micromolar range, as confirmed by independent experiments. The anti-SARS-CoV-2 potential of ambroxol, amodiaquine, and its active metabolite ( N -monodesethyl amodiaquine) is also discussed. In trying to understand the “hydroxychloroquine” mechanism of action, both p K a and the HCQ aromatic core may play a role. Further, we show that the amodiaquine metabolite and, to a lesser extent, zuclopenthixol and nebivolol are active in a SARS-CoV-2 titer reduction assay. Given the need for improved efficacy and safety, we propose zuclopenthixol, nebivolol, and amodiaquine as potential candidates for clinical trials against the early phase of the SARS-CoV-2 infection and discuss their potential use as adjuvant to the current (i.e., remdesivir and favipiravir) COVID-19 therapeutics.

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Section: Resultsmentioning

confidence: 99%

Virtual and In Vitro Antiviral Screening Revive Therapeutic Drugs for COVID-19

Bocci

Bradfute

et al. 2020

ACS Pharmacol. Transl. Sci.

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“…1, another TMPRSS2 inhibitor with a greater distribution capacity into the lung tissue is bromhexine hydrochloride. 9,10 It is an old over-the-counter medication that has been used for several decades as a mucolytic agent. The current study, an open-label, randomized clinical trial, examined the efficacy of early start of oral bromhexine, in the intensive care unit (ICU) admission, rate of mechanical ventilation, and mortality in patients with COVID-19 pneumonia.…”

Section: Outcome Measuresmentioning

confidence: 99%

Effect of bromhexine on clinical outcomes and mortality in COVID-19 patients: A randomized clinical trial

et al. 2020

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Introduction: Bromhexine is a potential therapeutic option in COVID-19, but no data from a randomized clinical trial has been available. The present study aimed to evaluate the efficacy of bromhexine in intensive care unit (ICU) admission, mechanical ventilation, and mortality in patients with COVID-19. Methods: An open-label randomized clinical trial study was performed in Tabriz, North-West of Iran. They were randomized to either the treatment with the bromhexine group or the control group, in a 1:1 ratio with 39 patients in each arm. Standard therapy was used in both groups and those patients in the treatment group received oral bromhexine 8 mg three times a day additionally. The primary outcome was a decrease in the rate of ICU admissions, intubation/mechanical ventilation, and mortality. Results: A total of 78 patients with similar demographic and disease characteristics were enrolled. There was a significant reduction in ICU admissions (2 out of 39 vs. 11 out of 39, P = 0.006), intubation (1 out of 39 vs. 9 out of 39, P = 0.007) and death (0 vs. 5, P = 0.027) in the bromhexine treated group compared to the standard group. No patients were withdrawn from the study because of adverse effects. Conclusion: The early administration of oral bromhexine reduces the ICU transfer, intubation, and the mortality rate in patients with COVID-19. This affordable medication can easily be administered everywhere with a huge positive impact(s) on public health and the world economy. Altogether, the verification of our results on a larger scale and different medical centers is strongly recommended. Trial Registration: IRCT202003117046797N4; https://irct.ir/trial/46969.

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“…Electro micrographs of multiple virions attacking the cell membrane ( i ), viral genome expression subsuming all functions of the cell to form thousands of virion copies within inclusion vesicles ( ii ) and finally release of multiple virions by fusion of inclusion packaging vesicles with the cell surface plasma membrane of the infected host cell ( iii ). Original composite figure adapted in parts from Depfenhart et al [ 7 ] Kupferschmidt and Cohen [ 8 ] and Mason [ 9 ]. Scale bar: 1000 nm…”

Section: Figurementioning

confidence: 99%

Development of a Clinical MALDI-ToF Mass Spectrometry Assay for SARS-CoV-2: Rational Design and Multi-Disciplinary Team Work

et al. 2020

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The COVID-19 pandemic caused by the SARS-CoV-2 coronavirus has stretched national testing capacities to breaking points in almost all countries of the world. The need to rapidly screen vast numbers of a country’s population in order to control the spread of the infection is paramount. However, the logistical requirement for reagent supply (and associated cost) of RT-PCR based testing (the current front-line test) have been hugely problematic. Mass spectrometry-based methods using swab and gargle samples have been reported with promise, but have not approached the task from a systematic analysis of the entire diagnostic process. Here, the pipeline from sample processing, the biological characteristics of the pathogen in human biofluid, the downstream bio- and physical-chemistry and the all-important data processing with clinical interpretation and reporting, are carefully compiled into a single high-throughput and reproducible rapid process. Utilizing MALDI-ToF mass spectrometric detection to viral envelope glycoproteins in a systems biology-multidisciplinary team approach, we have achieved a multifaceted clinical MALDI ToF MS screening test, primarily (but not limited to) SARS-CoV-2, with direct application to other future epidemics/pandemics that may arise. The clinical information generated not only includes SARS-CoV-2 coronavirus detection–(Spike protein fragments S1, S2b, S2a peaks), but other respiratory viral infections detected as well as an assessment of generalised oral upper respiratory immune response (elevated total Ig light chain peak) and a measure of the viral immune response (elevated intensity of IgA heavy chain peak). The advantages of the method include; (1) ease of sampling, (2) speed of analysis, and much reduced cost of testing. These features reveal the diagnostic utility of MALDI-ToF mass spectrometry as a powerful and economically attractive global solution

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Potential new treatment strategies for COVID-19: is there a role for bromhexine as add-on therapy?

Cited by 70 publications

References 76 publications

Virtual and In Vitro Antiviral Screening Revive Therapeutic Drugs for COVID-19

Virtual and In Vitro Antiviral Screening Revive Therapeutic Drugs for COVID-19

Effect of bromhexine on clinical outcomes and mortality in COVID-19 patients: A randomized clinical trial

Development of a Clinical MALDI-ToF Mass Spectrometry Assay for SARS-CoV-2: Rational Design and Multi-Disciplinary Team Work

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