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In Silico |
Sgrignani et al., Frontiers in Molecular Biosciences, doi:10.3389/fmolb.2021.666626 (Peer Reviewed) |
Computational Identification of a Putative Allosteric Binding Pocket in TMPRSS2 |
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In SIlico study of TMPRSS2 inhibition by camostat, nafamostat, and bromhexine, suggesting allosteric binding for bromhexine, compared to camostat and nafamostat which bind to the active site of TMPRSS2 forming covalent adducts. |
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In Silico
In Silico
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| Sgrignani et al., Frontiers in Molecular Biosciences, doi:10.3389/fmolb.2021.666626 (Peer Reviewed) |
| Computational Identification of a Putative Allosteric Binding Pocket in TMPRSS2 |
In SIlico study of TMPRSS2 inhibition by camostat, nafamostat, and bromhexine, suggesting allosteric binding for bromhexine, compared to camostat and nafamostat which bind to the active site of TMPRSS2 forming covalent adducts.
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Sgrignani et al., 4/30/2021, peer-reviewed, 2 authors.
In Silico studies are an important part of preclinical research, however results may be very different in vivo.
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Late |
Tolouian et al., J. Investig. Med., doi:10.1136/jim-2020-001747 (Peer Reviewed) |
death, ↓76.0%, p=0.43 |
Effect of bromhexine in hospitalized patients with COVID-19 |
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Small RCT with 100 patients, 48 with bromhexine added to SOC, showing slower viral- conversion but lower mortality and greater clinical improvement with bromhexine (not statistically significant with few deaths and very high recovery). Th.. |
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Late treatment study
Late treatment study
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| Tolouian et al., J. Investig. Med., doi:10.1136/jim-2020-001747 (Peer Reviewed) |
| Effect of bromhexine in hospitalized patients with COVID-19 |
Small RCT with 100 patients, 48 with bromhexine added to SOC, showing slower viral- conversion but lower mortality and greater clinical improvement with bromhexine (not statistically significant with few deaths and very high recovery). The very large difference between unadjusted and adjusted results is due to much higher risk for patients with renal disease and the much higher prevalence of renal disease in the bromhexine group.The study also shows 90% of patients in the control group had BMI>=30 compared to 0% in the treatment group, suggesting a possible problem with randomization. Due to the imbalance between groups, results were adjusted for BMI>30, smoking, and renal disease.11 patients were lost to followup in the treatment group compared to zero in the control group, perhaps in part due to faster recovery in the treatment group. 9 patients were excluded from the treatment group because they did not want to take bromhexine after discharge. Therefore up to 29% of treatment patients may have been excluded because they recovered quickly.
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risk of death, 76.0% lower, RR 0.24, p = 0.43, treatment 48, control 52, Table 3, adjusted, RR approximated with OR.
risk of no improvement, 75.9% lower, RR 0.24, p = 0.43, treatment 48, control 52, Table 2, adjusted, RR approximated with OR.
risk of COVID-19 case, 74.5% higher, RR 1.75, p = 0.02, treatment 29 of 48 (60.4%), control 18 of 52 (34.6%), mid-recovery day 7.
Tolouian et al., 3/15/2021, Randomized Controlled Trial, Iran, Middle East, peer-reviewed, 7 authors.
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PrEP |
Mikhaylov et al., medRxiv, doi:10.1101/2021.03.03.21252855 (Preprint) |
hosp., ↓80.0%, p=0.49 |
Bromhexine Hydrochloride Prophylaxis of COVID-19 for Medical Personnel: A Randomized Open-Label Study |
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Small prophylaxis RCT with 25 treatment and 25 control health care worker, showing lower PCR+, symptomatic cases, and hospitalization with treatment, although not statistically significant with the small sample size. |
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Pre-Exposure Prophylaxis study
Pre-Exposure Prophylaxis study
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| Mikhaylov et al., medRxiv, doi:10.1101/2021.03.03.21252855 (Preprint) |
| Bromhexine Hydrochloride Prophylaxis of COVID-19 for Medical Personnel: A Randomized Open-Label Study |
Small prophylaxis RCT with 25 treatment and 25 control health care worker, showing lower PCR+, symptomatic cases, and hospitalization with treatment, although not statistically significant with the small sample size.
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risk of hospitalization, 80.0% lower, RR 0.20, p = 0.49, treatment 0 of 25 (0.0%), control 2 of 25 (8.0%), continuity correction due to zero event.
risk of symptomatic case, 90.9% lower, RR 0.09, p = 0.05, treatment 0 of 25 (0.0%), control 5 of 25 (20.0%), continuity correction due to zero event.
risk of no virological cure, 71.4% lower, RR 0.29, p = 0.14, treatment 2 of 25 (8.0%), control 7 of 25 (28.0%).
Mikhaylov et al., 3/8/2021, Randomized Controlled Trial, Russia, Europe, preprint, 8 authors.
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In Vitro |
Carpinteiro et al., Journal of Biological Chemistry, doi:10.1016/j.jbc.2021.100701 (Peer Reviewed) (In Vitro) |
in vitro |
Inhibition of acid sphingomyelinase by ambroxol prevents SARS-CoV-2 entry into epithelial cells |
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In Vitro study showing that ambroxol (a metabolite of bromhexine) inhibits SARS-CoV-2 infection. |
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In Vitro
In Vitro
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| Carpinteiro et al., Journal of Biological Chemistry, doi:10.1016/j.jbc.2021.100701 (Peer Reviewed) (In Vitro) |
| Inhibition of acid sphingomyelinase by ambroxol prevents SARS-CoV-2 entry into epithelial cells |
In Vitro study showing that ambroxol (a metabolite of bromhexine) inhibits SARS-CoV-2 infection.
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Carpinteiro et al., 1/31/2021, peer-reviewed, 10 authors.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
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Review |
Al-Kuraishy et al., Current Medical and Drug Research (Review) (Preprint) |
review |
The potential role of Bromhexine in the management of COVID-19: Decipher and a real game-changer |
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Review article noting that bromhexine is a TMPRSS2 inhibitor with greater effect in lung tissue and attenuates the entry and proliferation of SARS‐CoV‐2. |
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Review
Review
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| Al-Kuraishy et al., Current Medical and Drug Research (Review) (Preprint) |
| The potential role of Bromhexine in the management of COVID-19: Decipher and a real game-changer |
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Review article noting that bromhexine is a TMPRSS2 inhibitor with greater effect in lung tissue and attenuates the entry and proliferation of SARS‐CoV‐2.
Al-Kuraishy et al., 12/31/2020, preprint, 5 authors.
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Late |
Mareev et al., Кардиология, doi:10.18087/cardio.2020.11.n1440 (Peer Reviewed) |
no disch., ↓38.8%, p=0.02 |
Results of Open-Label non-Randomized Comparative Clinical Trial: “BromhexIne and Spironolactone for CoronаvirUs Infection requiring hospiTalization (BISCUIT) |
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Prospective 103 PCR+ patients in Russia, 33 treated with bromexhine+spironolactone. The odds ratio of having a positive PCR or hospitalization for ≥10 days was 0.07 [0.008–0.61] with treatment. Dosing was bromhexine 8mg 4 times daily, sp.. |
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Late treatment study
Late treatment study
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| Mareev et al., Кардиология, doi:10.18087/cardio.2020.11.n1440 (Peer Reviewed) |
| Results of Open-Label non-Randomized Comparative Clinical Trial: “BromhexIne and Spironolactone for CoronаvirUs Infection requiring hospiTalization (BISCUIT) |
Prospective 103 PCR+ patients in Russia, 33 treated with bromexhine+spironolactone. The odds ratio of having a positive PCR or hospitalization for ≥10 days was 0.07 [0.008–0.61] with treatment. Dosing was bromhexine 8mg 4 times daily, spironolactone 25-50 mg/day for 10 days.
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risk of PCR+ on day 10 and hospitalization > 10 days, 38.8% lower, RR 0.61, p = 0.02, treatment 14 of 24 (58.3%), control 20 of 21 (95.2%), OR converted to RR.
risk of no virological cure, 87.4% lower, RR 0.13, p = 0.08, treatment 0 of 17 (0.0%), control 3 of 13 (23.1%), continuity correction due to zero event, day 10.
Mareev et al., 12/3/2020, Randomized Controlled Trial, Russia, Europe, peer-reviewed, 20 authors.
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Early |
Li et al., Clinical and Translational Science, doi:10.1111/cts.12881 (Peer Reviewed) |
no disch., ↓75.0%, p=0.11 |
Bromhexine Hydrochloride Tablets for the Treatment of Moderate COVID‐19: An Open‐Label Randomized Controlled Pilot Study |
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Tiny RCT with 12 bromhexine and 6 control patients showing non-statistically significant improvements in chest CT, need for oxygen therapy, and discharge rate within 20 days. Authors recommend a larger scale trial. |
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Early treatment study
Early treatment study
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| Li et al., Clinical and Translational Science, doi:10.1111/cts.12881 (Peer Reviewed) |
| Bromhexine Hydrochloride Tablets for the Treatment of Moderate COVID‐19: An Open‐Label Randomized Controlled Pilot Study |
Tiny RCT with 12 bromhexine and 6 control patients showing non-statistically significant improvements in chest CT, need for oxygen therapy, and discharge rate within 20 days. Authors recommend a larger scale trial.
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risk of no hospital discharge, 75.0% lower, RR 0.25, p = 0.11, treatment 2 of 12 (16.7%), control 4 of 6 (66.7%).
risk of oxygen therapy, 50.0% lower, RR 0.50, p = 0.57, treatment 2 of 12 (16.7%), control 2 of 6 (33.3%).
recovery time, 3.2% higher, relative time 1.03, treatment 12, control 6.
Li et al., 9/3/2020, Randomized Controlled Trial, China, Asia, peer-reviewed, 10 authors.
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Early |
Ansarin et al., Bioimpacts, doi:10.34172/bi.2020.27 (Peer Reviewed) |
death, ↓90.9%, p=0.05 |
Effect of bromhexine on clinical outcomes and mortality in COVID-19 patients: A randomized clinical trial |
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RCT with 39 bromhexine and 39 control patients showing lower mortality, intubation, and ICU admission with treatment. The treatment group received bromhexine hydrochloride 8 mg three times a day for two weeks. All patients received SOC in.. |
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Early treatment study
Early treatment study
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| Ansarin et al., Bioimpacts, doi:10.34172/bi.2020.27 (Peer Reviewed) |
| Effect of bromhexine on clinical outcomes and mortality in COVID-19 patients: A randomized clinical trial |
RCT with 39 bromhexine and 39 control patients showing lower mortality, intubation, and ICU admission with treatment. The treatment group received bromhexine hydrochloride 8 mg three times a day for two weeks. All patients received SOC including HCQ.
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risk of death, 90.9% lower, RR 0.09, p = 0.05, treatment 0 of 39 (0.0%), control 5 of 39 (12.8%), continuity correction due to zero event.
risk of mechanical ventilation, 88.9% lower, RR 0.11, p = 0.01, treatment 1 of 39 (2.6%), control 9 of 39 (23.1%).
risk of ICU admission, 81.8% lower, RR 0.18, p = 0.01, treatment 2 of 39 (5.1%), control 11 of 39 (28.2%).
Ansarin et al., 7/19/2020, Randomized Controlled Trial, Iran, Middle East, peer-reviewed, 11 authors.
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Theory |
Depfenhart et al., Internal and Emergency Medicine, doi:10.1007/s11739-020-02383-3 (Peer Reviewed) (Theory) |
theory |
Potential new treatment strategies for COVID-19: is there a role for bromhexine as add-on therapy? |
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Proposal to use bromhexine to inhibit TMPRSS2-specific viral entry for prophylaxis and treatment of COVID-19. |
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Theory
Theory
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| Depfenhart et al., Internal and Emergency Medicine, doi:10.1007/s11739-020-02383-3 (Peer Reviewed) (Theory) |
| Potential new treatment strategies for COVID-19: is there a role for bromhexine as add-on therapy? |
Proposal to use bromhexine to inhibit TMPRSS2-specific viral entry for prophylaxis and treatment of COVID-19.
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Depfenhart et al., 5/26/2020, peer-reviewed.
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Theory |
Habtemariam et al., Pharmacol. Res., doi:10.1016/j.phrs.2020.104853 (Peer Reviewed) (Theory) |
theory |
Possible use of the mucolytic drug, bromhexine hydrochloride, as a prophylactic agent against SARS-CoV-2 infection based on its action on the Transmembrane Serine Protease 2 |
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Note on the potential use of bromhexine hydrochloride for prophylaxis of SARS-CoV-2, based on the role of TMPRSS2 in SARS-CoV-2 infection, and the TMPRSS2 inhibition of bromhexine hydrochloride. |
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Theory
Theory
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| Habtemariam et al., Pharmacol. Res., doi:10.1016/j.phrs.2020.104853 (Peer Reviewed) (Theory) |
| Possible use of the mucolytic drug, bromhexine hydrochloride, as a prophylactic agent against SARS-CoV-2 infection based on its action on the Transmembrane Serine Protease 2 |
Note on the potential use of bromhexine hydrochloride for prophylaxis of SARS-CoV-2, based on the role of TMPRSS2 in SARS-CoV-2 infection, and the TMPRSS2 inhibition of bromhexine hydrochloride.
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Habtemariam et al., 4/30/2020, peer-reviewed, 6 authors.
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Review |
Maggio et al., Pharmacol Res., doi:10.1016/j.phrs.2020.104837 (Review) (Peer Reviewed) |
review |
Repurposing the mucolytic cough suppressant and TMPRSS2 protease inhibitor bromhexine for the prevention and management of SARS-CoV-2 infection |
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Proposal to use bromhexine for prophylaxis and treatment of COVID-19 based on TMPRSS2 inhibition, widespread clinical use, and supporting pharmacokinetic and safety data. |
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Review
Review
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| Maggio et al., Pharmacol Res., doi:10.1016/j.phrs.2020.104837 (Review) (Peer Reviewed) |
| Repurposing the mucolytic cough suppressant and TMPRSS2 protease inhibitor bromhexine for the prevention and management of SARS-CoV-2 infection |
Proposal to use bromhexine for prophylaxis and treatment of COVID-19 based on TMPRSS2 inhibition, widespread clinical use, and supporting pharmacokinetic and safety data.
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Maggio et al., 4/22/2020, peer-reviewed, 2 authors.
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In Vitro |
Hoffman et al., Cell, doi:10.1016/j.cell.2020.02.052 (Peer Reviewed) (In Vitro) |
in vitro |
SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibito |
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In Vitro study showing that SARS-CoV-2 uses ACE2 for entry and TMPRSS2 for S protein priming, and that TMPRSS2 inhibitor camostat blocked entry and may be an effective treaetment. |
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In Vitro
In Vitro
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| Hoffman et al., Cell, doi:10.1016/j.cell.2020.02.052 (Peer Reviewed) (In Vitro) |
| SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibito |
In Vitro study showing that SARS-CoV-2 uses ACE2 for entry and TMPRSS2 for S protein priming, and that TMPRSS2 inhibitor camostat blocked entry and may be an effective treaetment.
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Hoffman et al., 3/5/2020, peer-reviewed, 13 authors.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
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