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Journal of Molecular Graphics &... Jul 2022Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects the host cells through interaction of its spike protein with human angiotensin-converting enzyme 2...
Inhibitory mechanism of Ambroxol and Bromhexine Hydrochlorides as potent blockers of molecular interaction between SARS-CoV-2 spike protein and human angiotensin-converting Enzyme-2.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects the host cells through interaction of its spike protein with human angiotensin-converting enzyme 2 (hACE-2). High binding affinity between the viral spike protein and host cells hACE-2 receptor has been reported to enhance the viral infection. Thus, the disruption of this molecular interaction will lead to reduction in viral infectivity. This study, therefore, aimed to analyze the inhibitory potentials of two mucolytic drugs; Ambroxol hydrochlorides (AMB) and Bromhexine hydrochlorides (BHH), to serve as potent blockers of these molecular interactions and alters the binding affinity/efficiency between the proteins employing computational techniques. The study examined the effects of binding of each drug at the receptor binding domain (RBD) of the spike protein and the exopeptidase site of hACE-2 on the binding affinity (ΔG) and molecular interactions between the two proteins. Binding affinity revealed that the binding of the two drugs at the RBD-ACE-2 site does not alter the binding affinity and molecular interaction between the proteins. However, the binding of AMB (-56.931 kcal/mol) and BHH (-46.354 kcal/mol) at the exopeptidase site of hACE-2, significantly reduced the binding affinities between the proteins compared to the unbound, ACE-2-RBD complex (-64.856 kcal/mol). The result further showed the two compounds have good affinity at the hACE-2 site, inferring they might be potent inhibitors of hACE-2. Residue interaction networks analysis further revealed the binding of the two drugs at the exopeptidase site of hACE-2 reduced the number of interacting amino residues, subsequently leading to loss of interactions between the two proteins, with BHH showing better reduction in the molecular interaction and binding affinity than AMB. The result of the structural analyses additionally, revealed that the binding of the drugs considerably influences the dynamic of the complexes when compared to the unbound complex. The findings from this study suggest the binding of the two drugs at the exopeptidase site reduces the binding effectiveness of the proteins than their binding at the RBD site, and consequently might inhibit viral attachment and entry.
Topics: Ambroxol; Angiotensin-Converting Enzyme 2; Angiotensins; Bromhexine; Humans; Protein Binding; SARS-CoV-2; Spike Glycoprotein, Coronavirus; COVID-19 Drug Treatment
PubMed: 35487151
DOI: 10.1016/j.jmgm.2022.108201 -
BioImpacts : BI 2020Bromhexine 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...
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. 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. 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, = 0.006), intubation (1 out of 39 vs. 9 out of 39, = 0.007) and death (0 vs. 5, = 0.027) in the bromhexine treated group compared to the standard group. No patients were withdrawn from the study because of adverse effects. 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. IRCT202003117046797N4; https://irct.ir/trial/46969.
PubMed: 32983936
DOI: 10.34172/bi.2020.27 -
Journal of Research in Medical Sciences... 2020Paraquat (PQ) poisoning is characterized by rapidly progressive acute poisoning with high mortality and no specific antidote. Although some clinical studies have been... (Review)
Review
BACKGROUND
Paraquat (PQ) poisoning is characterized by rapidly progressive acute poisoning with high mortality and no specific antidote. Although some clinical studies have been conducted to investigate the benefits of high-dose ambroxol as an adjuvant treatment for PQ poisoning, the efficacy is controversial.
MATERIALS AND METHODS
After searching for relevant articles in English and Chinese databases from 1978 to 2019 according to the keywords (paraquat poisoning/methy viologen/gramoxone, and ambroxol/mucosolvan/Bromhexine), we found seven articles that met our inclusion and exclusion criteria. A meta-analysis was performed using fixed-effects model and random-effects model according to the value in Stata software (version 15.0). Four outcome indicators (hospital mortality, partial pressure of oxygen (PaO), oxygenation index (PaO/FiO), and survival time of the deceased patients) were of interest to us.
RESULTS
The meta-analysis showed that adjuvant treatment with high doses of ambroxol increased PaO (weighted mean difference [WMD] = 13.73 [mmHg], 95% confidence interval [CI]: 8.68-18.79, = 11.80, < 0.001), PaO/FiO (WMD = 38.81 [mmHg], 95% CI: 29.85-47.76, = 8.49, = 0.000), and survival time of the deceased patients (WMD = 2.58 [], 95% CI: 0.97-4.18, = 3.15, = 0.002) compared with usual treatment. Treatment with high doses of ambroxol also appeared to reduce the hospital mortality (relative risk = 0.69, 95% CI: 0.55-0.86, Z = 3.25, = 0.001).
CONCLUSION
This study found that high-dose ambroxol is an effective therapy for PQ poisoning and may reduce the in-hospital mortality.
PubMed: 33088304
DOI: 10.4103/jrms.JRMS_484_19 -
Frontiers in Bioscience (Landmark... Jan 2022To evaluate the effect of 0.2% ambroxol eye drop on tear secretion and corneal healing on a rabbit dry eye model, and to delineate potential underlying mechanisms.
OBJECTIVE
To evaluate the effect of 0.2% ambroxol eye drop on tear secretion and corneal healing on a rabbit dry eye model, and to delineate potential underlying mechanisms.
MATERIALS AND METHOD
A mixed mechanism dry eye model was created using 12 healthy New Zealand rabbits by excision of the main lacrimal glands, Harderian gland and nictitating membrane. Establishment of the model was confirmed by the decrease of Schirmer I and increase of corneal fluorescein staining scores. Two weeks after model creation, the rabbits were randomly and evenly divided into NaCl, 0.1% sodium hyaluronate and 0.2% ambroxol groups. Each group was administered the respective eye drops 4 times a day for four weeks. The Schirmer I test and corneal fluorescein staining were performed at two and four weeks. After four weeks of treatment, the animals were sacrificed and the conjunctiva and eyelid specimens collected. Inflammatory factors IL-8, TNF-α, and goblet cell specific mucin MUC5AC were measured by ELISA while the lid meibomian gland was evaluated by oil red O staining.
RESULTS
Compared with the baseline, 2 weeks after the surgery, Schirmer I test value decreased significantly (20.35 ± 5.18 mm/5 min vs 13.95 ± 4.64 mm/5 min, < 0.01), and the fluorescein staining score increased significantly (0.5 ± 0.6 vs 5.5 ± 1.4, 0.01). After four weeks of treatment, compared with the NaCl and sodium hyaluronate groups, tear secretion in ambroxol group increased significantly ( < 0.01), while the corneal fluorescence staining score decreased significantly ( < 0.01). In the conjunctival tissue, significant decrease was seen in TNF-α ( < 0.01) and IL-8 [ (unilateral) < 0.05] concentrations in ambroxol group, and significant increase in MUC5AC concentration ( < 0.01) in ambroxol group as well. The lipid content in the lid meibomian glands appeared increased after the administration of ambroxol.
CONCLUSION
The present rabbit dry eye model study demonstrated potentials of topically administered 0.2% ambroxol in stimulating tear and mucin secretion, inhibiting ocular surface inflammation, promoting corneal healing, and possibly augmenting meibomian gland lipid production.
Topics: Animals; Rabbits; Ambroxol; Cornea; Dry Eye Syndromes; Meibomian Glands; Tears
PubMed: 35090309
DOI: 10.31083/j.fbl2701004 -
Brazilian Journal of Microbiology :... 2017Fungi is a well-known model used to study drug metabolism and its production in in vitro condition. We aim to screen the most efficient strain of Cunninghamella sp....
Fungi is a well-known model used to study drug metabolism and its production in in vitro condition. We aim to screen the most efficient strain of Cunninghamella sp. among C. elegans, C. echinulata and C. blakesleeana for bromhexine metabolites production. We characterized the metabolites produced using various analytical tools and compared them with mammalian metabolites in Rat liver microsomes (RLM). The metabolites were collected by two-stage fermentation of bromhexine with different strains of Cunninghamella sp. followed by extraction. Analysis was done by thin layer chromatography, high performance thin layer chromatography, Fourier transform infrared spectroscopy, high performance liquid chromatography and Liquid chromatography-mass spectrometry. The role of Cytochrome P3A4 (CYP3A4) enzymes in bromhexine metabolism was studied. Fungal incubates were spiked with reference standard - clarithromycin to confirm the role of CYP3A4 enzyme in bromhexine metabolism. Three metabolites appeared at 4.7, 5.5 and 6.4min retention time in HPLC. Metabolites produced by C. elegans and RLM were concluded to be similar based on their retention time, peak area and peak response of 30.05%, 21.06%, 1.34%, and 47.66% of three metabolites and bromhexine in HPLC. The role of CYP3A4 enzyme in metabolism of bromhexine and the presence of these enzymes in Cunninghamella species was confirmed due to absence of peaks at 4.7, 5.4 and 6.7min when RLM were incubated with a CYP3A4 enzyme inhibitor - clarithromycin.
Topics: Animals; Biotransformation; Bromhexine; Chromatography, High Pressure Liquid; Chromatography, Thin Layer; Cunninghamella; Cytochrome P-450 CYP3A; Mass Spectrometry; Microsomes; Rats; Spectroscopy, Fourier Transform Infrared
PubMed: 27988088
DOI: 10.1016/j.bjm.2016.11.003 -
Japanese Journal of Pharmacology Oct 1985Effects of bromhexine and pilocarpine on the secretions of submaxillary saliva in dogs and of tears in rabbits were investigated including their effects on lysozyme...
Effects of bromhexine and pilocarpine on the secretions of submaxillary saliva in dogs and of tears in rabbits were investigated including their effects on lysozyme activity in an attempt to elucidate the efficacy of bromhexine on Sjögren's syndrome. Pilocarpine (0.3 mg/kg, p.o.) significantly increased spontaneous salivary flow rate, but bromhexine (20 and 40 mg/kg, p.o.) had almost no influence on spontaneous salivary flow rate. Pilocarpine increased total protein, saccharide, lysozyme and IgA secretions in saliva under electrical stimulation of the chorda tympani. Bromhexine did more markedly increase total lysozyme and IgA secretions in saliva, with minor increases in total protein and saccharide secretions. Pilocarpine (0.4 mg/kg, i.v.) had almost no influence on lysozyme concentration in tears, whereas it markedly increased tear secretion volume leading to an increase in total lysozyme secretion. On the other hand, bromhexine (4 and 8 mg/kg, i.v.) significantly increased both lysozyme concentration and total lysozyme secretion in tears from 50 min after injection, without influencing tear secretion volume. From these findings, it is suggested that bromhexine may work effectively on Sjögren's syndrome by acting to accelerate the secretions of lysozyme and IgA in saliva and tears, which are known to have antiinflammatory and bacteriocidal effects.
Topics: Animals; Bromhexine; Dogs; Male; Muramidase; Pilocarpine; Proteins; Saliva; Salivation; Tears; Time Factors
PubMed: 4087569
DOI: 10.1254/jjp.39.241 -
Internal and Emergency Medicine Aug 2020Of huge importance now is to provide a fast, cost-effective, safe, and immediately available pharmaceutical solution to curb the rapid global spread of SARS-CoV-2.... (Review)
Review
Of huge importance now is to provide a fast, cost-effective, safe, and immediately available pharmaceutical solution to curb the rapid global spread of SARS-CoV-2. Recent publications on SARS-CoV-2 have brought attention to the possible benefit of chloroquine in the treatment of patients infected by SARS-CoV-2. Whether chloroquine can treat SARS-CoV-2 alone and also work as a prophylactic is doubtful. An effective prophylactic medication to prevent viral entry has to contain, at least, either a protease inhibitor or a competitive virus ACE2-binding inhibitor. Using bromhexine at a dosage that selectively inhibits TMPRSS2 and, in so doing, inhibits TMPRSS2-specific viral entry is likely to be effective against SARS-CoV-2. We propose the use of bromhexine as a prophylactic and treatment. We encourage the scientific community to assess bromhexine clinically as a prophylactic and curative treatment. If proven to be effective, this would allow a rapid, accessible, and cost-effective application worldwide.
Topics: Betacoronavirus; Bromhexine; COVID-19; Coronavirus Infections; Expectorants; Humans; Pandemics; Pneumonia, Viral; SARS-CoV-2; Serine Endopeptidases; Virus Internalization
PubMed: 32458206
DOI: 10.1007/s11739-020-02383-3 -
Frontiers in Molecular Biosciences 2021Camostat, nafamostat, and bromhexine are inhibitors of the transmembrane serine protease TMPRSS2. The inhibition of TMPRSS2 has been shown to prevent the viral infection...
Camostat, nafamostat, and bromhexine are inhibitors of the transmembrane serine protease TMPRSS2. The inhibition of TMPRSS2 has been shown to prevent the viral infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other viruses. However, while camostat and nafamostat inhibit TMPRSS2 by forming a covalent adduct, the mode of action of bromhexine remains unclear. TMPRSS2 is autocatalytically activated from its inactive form, zymogen, through a proteolytic cleavage that promotes the binding of Ile256 to a putative allosteric pocket (A-pocket). Computer simulations, reported here, indicate that Ile256 binding induces a conformational change in the catalytic site, thus providing the atomistic rationale to the activation process of the enzyme. Furthermore, computational docking and molecular dynamics simulations indicate that bromhexine competes with the N-terminal Ile256 for the same binding site, making it a potential allosteric inhibitor. Taken together, these findings provide the atomistic basis for the development of more selective and potent TMPRSS2 inhibitors.
PubMed: 33996911
DOI: 10.3389/fmolb.2021.666626 -
The Cochrane Database of Systematic... Jul 2015Bronchiectasis is a chronic respiratory disease characterised by abnormal dilatation of the bronchi, and presents typically with a chronic productive cough (or chronic... (Review)
Review
BACKGROUND
Bronchiectasis is a chronic respiratory disease characterised by abnormal dilatation of the bronchi, and presents typically with a chronic productive cough (or chronic wet cough in children) and recurrent infective exacerbations. It significantly impacts daily activities and quality of life, and can lead to recurrent hospitalisations, severe lung function impairment, respiratory failure and even death.
OBJECTIVES
To provide an overview of the efficacy and safety of interventions for adults and children with bronchiectasis from Cochrane reviews.To identify gaps in the evidence base that will inform recommendations for new research and reviews, and to summarise information on reported outcomes and make recommendations for the reporting of standard outcomes in future trials and reviews.
METHODS
We included Cochrane reviews of non-cystic fibrosis (CF) bronchiectasis. We searched the Cochrane Database of Systematic Reviews. The search is current to 11 February 2015. We also identified trials that were potentially eligible for, but not currently included in, published reviews to make recommendations for new Cochrane reviews. We assessed the quality of included reviews using the AMSTAR criteria. We presented an evidence synthesis of data from reviews alongside an evidence map of clinical trials and guideline data. The primary outcomes were exacerbations, lung function and quality of life.
MAIN RESULTS
We included 21 reviews but extracted data from, and rated the quality of, only nine reviews that reported results for people with bronchiectasis alone. Of the reviews with no usable data, two reviews included studies with mixed clinical populations where data were not reported separately for people with bronchiectasis and 10 reviews did not contain any trials. Of the 40 studies included across the nine reviews, three (number of participants nine to 34) included children. The studies ranged from single session to year-long studies. Each review included from one to 11 trials and 28 (70%) trials in the overview included 40 or fewer participants. The total number of participants included in reviews ranged from 40 to 1040. The age range of adult participants was from 36 to 73 years and children ranged from six to 16 years. The proportion of male participants ranged from 21% to 72%. Where reported, mean baseline forced expiratory volume in one second (FEV1) ranged from 1.17 L to 1.66 L and from 47% to 88% predicted. Most of the reviews had search dates older than two years.We have summarised the published evidence as outlined in Cochrane reviews, but it was not possible to draw definitive conclusions. There was inconclusive evidence on the use of long-term antibiotics and nebulised hypertonic saline for reducing exacerbation frequency and evidence that human deoxyribonuclease (RhDNase) increases exacerbation frequency. Improvements in lung function were reported for inhaled corticosteroids (ICS) though this was small and not clinically relevant. Evidence of benefit for hyperosmolar agents and mucolytics was inconclusive. There was limited evidence of improvements in quality of life with airway clearance techniques and physical therapy but evidence of benefit for hyperosmolar agents was inconclusive. Secondary outcomes were not clearly reported in all trials in the included reviews. Improvements in dyspnoea, wheeze and cough-free days were reported for small trials of ICS and LABA (long-acting beta2-agonsts)/ICS and cough reduction was also reported for a small bromhexine trial. Reduction in sputum production was reported for long-term antibiotics and airway clearance techniques but evidence of benefit for hyperosmolar agents was inconclusive.Adverse events were included as outcomes in seven reviews. The review of long-term (four weeks to one year) prophylactic courses of antibiotics reported significantly more cases of wheeze (Peto odd ratio (OR) 8.56, 95% confidence intervals (CI) 1.63 to 44.93), dyspnoea (12 versus three, P value = 0.01) and chest pain (seven versus zero, P value = 0.01) from the same trial (74 participants) but no differences in occurrence of diarrhoea, rash or number of withdrawals. In the review of mucolytics versus placebo, relevant outcomes were not reported for erdosteine comparisons and no significant adverse effects were reported for bromhexine, though adverse events were associated with RhDNase (OR 28.19, 95% CI 3.77 to 210.85, 1 study). Of the remaining five reviews, adverse events were not reported in the single trials included in the ICS review or the physical therapy review and the impact of adverse events in the single trial included in the inhaled LABA/ICS combination versus ICS review were unclear. The reviews of short-term courses of antibiotics and inhaled hyperosmolar agents reported no significant differences in occurrence of adverse events. Fewer admissions to hospital were reported for long-term antibiotics, but this outcome was not reported in all reviews. No reviews reported differences in mortality, but again this outcome was not included in all reviews.We did not explicitly include antibiotic resistance as an outcome in the review, but this was unclear in the Cochrane reviews and evidence from other trials should be considered.We rated all reviews as high quality (AMSTAR), though opportunities for improved reporting (e.g. summary of findings and GRADE evaluation of the evidence) were identified for inclusion in future updates of the reviews. However, the majority of trials were not high quality and confidence in the effects of treatments, therefore, requires additional evidence from larger and more methodologically robust trials. We evaluated the overall coverage of important topics in bronchiectasis by mapping the quality of the current evidence base against published guidelines and identifying high priority areas for new research on; use of short-course and long-term antibiotics, ICS and oral corticosteroids, inhaled hyperosmolars, mucolytics, and use of airway clearance techniques.
AUTHORS' CONCLUSIONS
This overview clearly points to significant opportunities for further research aimed at improving outcomes for people with bronchiectasis. We have highlighted important endpoints for studies (particularly exacerbations, quality of life and lung function), and areas of clinical practice that are in most urgent need of evidence-based support (including long-term antibiotics, ICSs and mucolytics).As the evidence is confined to small trials of short duration, it is not currently possible to assess the balance between the benefits and potential harms of treatments for bronchiectasis.
Topics: Adrenal Cortex Hormones; Adult; Anti-Bacterial Agents; Bronchiectasis; Child; Deoxyribonucleases; Expectorants; Humans; Nebulizers and Vaporizers; Review Literature as Topic; Saline Solution, Hypertonic
PubMed: 26171905
DOI: 10.1002/14651858.CD010337.pub2 -
EClinicalMedicine Apr 2024Repurposed drugs with host-directed antiviral and immunomodulatory properties have shown promise in the treatment of COVID-19, but few trials have studied combinations...
Early treatment with fluvoxamine, bromhexine, cyproheptadine, and niclosamide to prevent clinical deterioration in patients with symptomatic COVID-19: a randomized clinical trial.
BACKGROUND
Repurposed drugs with host-directed antiviral and immunomodulatory properties have shown promise in the treatment of COVID-19, but few trials have studied combinations of these agents. The aim of this trial was to assess the effectiveness of affordable, widely available, repurposed drugs used in combination for treatment of COVID-19, which may be particularly relevant to low-resource countries.
METHODS
We conducted an open-label, randomized, outpatient, controlled trial in Thailand from October 1, 2021, to June 21, 2022, to assess whether early treatment within 48-h of symptoms onset with combinations of fluvoxamine, bromhexine, cyproheptadine, and niclosamide, given to adults with confirmed mild SARS-CoV-2 infection, can prevent 28-day clinical deterioration compared to standard care. Participants were randomly assigned to receive treatment with fluvoxamine alone, fluvoxamine + bromhexine, fluvoxamine + cyproheptadine, niclosamide + bromhexine, or standard care. The primary outcome measured was clinical deterioration within 9, 14, or 28 days using a 6-point ordinal scale. This trial is registered with ClinicalTrials.gov (NCT05087381).
FINDINGS
Among 1900 recruited, a total of 995 participants completed the trial. No participants had clinical deterioration by day 9, 14, or 28 days among those treated with fluvoxamine plus bromhexine (0%), fluvoxamine plus cyproheptadine (0%), or niclosamide plus bromhexine (0%). Nine participants (5.6%) in the fluvoxamine arm had clinical deterioration by day 28, requiring low-flow oxygen. In contrast, most standard care arm participants had clinical deterioration by 9, 14, and 28 days. By day 9, 32.7% (110) of patients in the standard care arm had been hospitalized without requiring supplemental oxygen but needing ongoing medical care. By day 28, this percentage increased to 37.5% (21). Additionally, 20.8% (70) of patients in the standard care arm required low-flow oxygen by day 9, and 12.5% (16) needed non-invasive or mechanical ventilation by day 28. All treated groups significantly differed from the standard care group by days 9, 14, and 28 (p < 0.0001). Also, by day 28, the three 2-drug treatments were significantly better than the fluvoxamine arm (p < 0.0001). No deaths occurred in any study group. Compared to standard care, participants treated with the combination agents had significantly decreased viral loads as early as day 3 of treatment (p < 0.0001), decreased levels of serum cytokines interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β) as early as day 5 of treatment, and interleukin-8 (IL-8) by day 7 of treatment (p < 0.0001) and lower incidence of post-acute sequelae of COVID-19 (PASC) symptoms (p < 0.0001). 23 serious adverse events occurred in the standard care arm, while only 1 serious adverse event was reported in the fluvoxamine arm, and zero serious adverse events occurred in the other arms.
INTERPRETATION
Early treatment with these combinations among outpatients diagnosed with COVID-19 was associated with lower likelihood of clinical deterioration, and with significant and rapid reduction in the viral load and serum cytokines, and with lower burden of PASC symptoms. When started very soon after symptom onset, these repurposed drugs have high potential to prevent clinical deterioration and death in vaccinated and unvaccinated COVID-19 patients.
FUNDING
Ped Thai Su Phai (Thai Ducks Fighting Danger) social giver group.
PubMed: 38516100
DOI: 10.1016/j.eclinm.2024.102517