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Medicine Sep 2020Bromhexine hydrochloride tablets may be effective in the treatment of Coronavirus disease 2019 (COVID-19) in children. This study will further evaluate the efficacy and...
BACKGROUND
Bromhexine hydrochloride tablets may be effective in the treatment of Coronavirus disease 2019 (COVID-19) in children. This study will further evaluate the efficacy and safety of bromhexine hydrochloride tablets in the treatment of COVID-19 in children.
METHODS
The following electronic databases will be searched, with all relevant randomized controlled trials (RCTs) up to August 2020 to be included: PubMed, Embase, Web of Science, the Cochrane Library, China National Knowledge Infrastructure (CNKI), the Chongqing VIP China Science and Technology Database (VIP), Wanfang, the Technology Periodical Database, and the Chinese Biomedical Literature Database (CBM). As well as the above, Baidu, the International Clinical Trials Registry Platform (ICTRP), Google Scholar, and the Chinese Clinical Trial Registry (ChiCTR) will also be searched to obtain more comprehensive data. Besides, the references of the included literature will also be traced to supplement our search results and to obtain all relevant literature.
RESULTS
This systematic review will evaluate the current status of bromhexine hydrochloride in the treatment of COVID-19 in children, to evaluate its efficacy and safety.
CONCLUSION
This study will provide the latest evidence for evaluating the efficacy and safety of bromhexine hydrochloride in the treatment of COVID-19 in children.
PROSPERO REGISTRATION NUMBER
CRD42020199805.
ETHICS AND DISSEMINATION
The private information of individuals will not be published. This systematic review will also not involve endangering participant rights. Ethical approval is not available. The results may be published in peer-reviewed journals or disseminated at relevant conferences.
Topics: Betacoronavirus; Bromhexine; COVID-19; Child; Coronavirus Infections; Expectorants; Humans; Meta-Analysis as Topic; Pandemics; Pneumonia, Viral; Research Design; SARS-CoV-2; Systematic Reviews as Topic; Treatment Outcome
PubMed: 32925756
DOI: 10.1097/MD.0000000000022114 -
Human Molecular Genetics Jul 2022Cognitive impairment is a common non-motor complication of Parkinson's disease (PD). Glucocerebrosidase gene (GBA1) variants are found in 10-15% of PD cases and are...
Cognitive impairment is a common non-motor complication of Parkinson's disease (PD). Glucocerebrosidase gene (GBA1) variants are found in 10-15% of PD cases and are numerically the most important risk factor for PD and dementia with Lewy bodies. Accumulation of α-synuclein and tau pathology is thought to underlie cognitive impairment in PD and likely involves cholinergic as well as dopaminergic neurons. Neural crest stem cells were isolated from both PD patients with the common heterozygous N370S GBA1 mutation and normal subjects without GBA1 mutations. The stem cells were used to generate a cholinergic neuronal cell model. The effects of the GBA1 variant on glucocerebrosidase (GCase) protein and activity, and cathepsin D, tau and α-synuclein protein levels in cholinergic neurons were examined. Ambroxol, a GCase chaperone, was used to investigate whether GCase enhancement was able to reverse the effects of the GBA1 variant on cholinergic neurons. Significant reductions in GCase protein and activity, as well as in cathepsin D levels, were found in GBA1 mutant (N370S/WT) cholinergic neurons. Both tau and α-synuclein levels were significantly increased in GBA1 mutant (N370S/WT) cholinergic neurons. Ambroxol significantly enhanced GCase activity and decreased both tau and α-synuclein levels in cholinergic neurons. GBA1 mutations interfere with the metabolism of α-synuclein and tau proteins and induce higher levels of α-synuclein and tau proteins in cholinergic neurons. The GCase pathway provides a potential therapeutic target for neurodegenerative disorders related to pathological α-synuclein or tau accumulation.
Topics: Ambroxol; Cathepsin D; Cells, Cultured; Cholinergic Agents; Glucosylceramidase; Humans; Mutation; Parkinson Disease; alpha-Synuclein; tau Proteins
PubMed: 35179198
DOI: 10.1093/hmg/ddac038 -
JAMA Network Open Jun 2023
Topics: Humans; Ambroxol; Gaucher Disease; Glucosylceramidase; Mutation
PubMed: 37342045
DOI: 10.1001/jamanetworkopen.2023.19336 -
Journal of Virology Apr 2021Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) infects cells through interaction of its spike protein (SARS2-S) with angiotensin-converting enzyme...
Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) infects cells through interaction of its spike protein (SARS2-S) with angiotensin-converting enzyme 2 (ACE2) and activation by proteases, in particular transmembrane protease serine 2 (TMPRSS2). Viruses can also spread through fusion of infected with uninfected cells. We compared the requirements of ACE2 expression, proteolytic activation, and sensitivity to inhibitors for SARS2-S-mediated and SARS-CoV-S (SARS1-S)-mediated cell-cell fusion. SARS2-S-driven fusion was moderately increased by TMPRSS2 and strongly by ACE2, while SARS1-S-driven fusion was strongly increased by TMPRSS2 and less so by ACE2 expression. In contrast to that of SARS1-S, SARS2-S-mediated cell-cell fusion was efficiently activated by batimastat-sensitive metalloproteases. Mutation of the S1/S2 proteolytic cleavage site reduced effector cell-target cell fusion when ACE2 or TMPRSS2 was limiting and rendered SARS2-S-driven cell-cell fusion more dependent on TMPRSS2. When both ACE2 and TMPRSS2 were abundant, initial target cell-effector cell fusion was unaltered compared to that of wild-type (wt) SARS2-S, but syncytia remained smaller. Mutation of the S2 cleavage (S2') site specifically abrogated activation by TMPRSS2 for both cell-cell fusion and SARS2-S-driven pseudoparticle entry but still allowed for activation by metalloproteases for cell-cell fusion and by cathepsins for particle entry. Finally, we found that the TMPRSS2 inhibitor bromhexine, unlike the inhibitor camostat, was unable to reduce TMPRSS2-activated cell-cell fusion by SARS1-S and SARS2-S. Paradoxically, bromhexine enhanced cell-cell fusion in the presence of TMPRSS2, while its metabolite ambroxol exhibited inhibitory activity under some conditions. On Calu-3 lung cells, ambroxol weakly inhibited SARS2-S-driven lentiviral pseudoparticle entry, and both substances exhibited a dose-dependent trend toward weak inhibition of authentic SARS-CoV-2. Cell-cell fusion allows viruses to infect neighboring cells without the need to produce free virus and contributes to tissue damage by creating virus-infected syncytia. Our results demonstrate that the S2' cleavage site is essential for activation by TMPRSS2 and unravel important differences between SARS-CoV and SARS-CoV-2, among those, greater dependence of SARS-CoV-2 on ACE2 expression and activation by metalloproteases for cell-cell fusion. Bromhexine, reportedly an inhibitor of TMPRSS2, is currently being tested in clinical trials against coronavirus disease 2019. Our results indicate that bromhexine enhances fusion under some conditions. We therefore caution against the use of bromhexine in high dosages until its effects on SARS-CoV-2 spike activation are better understood. The related compound ambroxol, which similarly to bromhexine is clinically used as an expectorant, did not exhibit activating effects on cell-cell fusion. Both compounds exhibited weak inhibitory activity against SARS-CoV-2 infection at high concentrations, which might be clinically attainable for ambroxol.
Topics: Ambroxol; Amino Acid Substitution; Angiotensin-Converting Enzyme 2; Bromhexine; COVID-19; Cell Line; Humans; Mutation, Missense; Proteolysis; Severe acute respiratory syndrome-related coronavirus; SARS-CoV-2; Serine Endopeptidases; Severe Acute Respiratory Syndrome; Spike Glycoprotein, Coronavirus; Virus Internalization
PubMed: 33608407
DOI: 10.1128/JVI.00002-21 -
British Medical Journal Aug 1965
Topics: Actinomycetales; Agriculture; Ambroxol; Antigens; Farmer's Lung; Humans; Serologic Tests
PubMed: 14314458
DOI: 10.1136/bmj.2.5457.359-f -
European Review For Medical and... Nov 2020This paper presents a newborn (G2P2, gestational age of 39+6 weeks, birth weight of 3,200 g, with normal fetal amniotic fluid) with suspected coronavirus disease 2019...
OBJECTIVE
This paper presents a newborn (G2P2, gestational age of 39+6 weeks, birth weight of 3,200 g, with normal fetal amniotic fluid) with suspected coronavirus disease 2019 (COVID-19) admitted to our hospital on February 10, 2020, at the birth age of 16 hours and 34 minutes. The Apgar scores at 1 and 5 min were 9 and 10 points, respectively.
PATIENTS AND METHODS
The mother of the newborn was exposed to a patient with COVID-19 five days before delivery. The newborn had nausea and vomiting after birth, with feeding intolerance, and full enteral feeding was given on the 6th day after birth. The newborn was in good general condition during the period of hospitalization.
RESULTS
The two 2019-nCoV nucleic acid tests of the newborn were negative on the 5th and 7th days after birth. On the 1st and 8th days after birth, typical pulmonary lesions were detected in the newborn by chest CT. Our study supports that chest imaging examination should be actively performed in the newborn even with a negative 2019-nCoV nucleic acid test in cases where a pregnant woman is exposed to a patient with COVID-19 or is confirmed with 2019-nCoV infection.
CONCLUSIONS
For newborns with typical pulmonary lesions, strict quarantine measures are suggested if the possibility of COVID-19 cannot be excluded.
Topics: Ambroxol; Anti-Bacterial Agents; Ascorbic Acid; Breast Feeding; C-Reactive Protein; COVID-19; COVID-19 Nucleic Acid Testing; Expectorants; Female; Humans; Infant, Newborn; Lung; Male; Maternal Exposure; Nausea; Parenteral Nutrition; Pregnancy; Pregnancy Complications, Infectious; Serum Amyloid A Protein; Tomography, X-Ray Computed; Vitamins; Vomiting
PubMed: 33275274
DOI: 10.26355/eurrev_202011_23859 -
Respiratory Medicine Apr 1998Reactive free oxygen radicals are known to play an important role in the pathogenesis of various lung diseases such as idiopathic pulmonary fibrosis (IPF), adult... (Review)
Review
Reactive free oxygen radicals are known to play an important role in the pathogenesis of various lung diseases such as idiopathic pulmonary fibrosis (IPF), adult respiratory distress syndrome (ARDS) or cystic fibrosis (CF). They can originate from endogenous processes or can be part of exogenous exposures (e.g. ozone, cigarette smoke, asbestos fibres). Consequently, therapeutic enhancement of anti-oxidant defence mechanisms in these lung disorders seems a rational approach. In this regard, N-acetyl-L-cysteine (NAC) and ambroxol have both been frequently investigated. Because of its SH group, NAC scavenges H2O2 (hydrogen peroxide), .OH (hydroxol radical), and HOCl (hypochlorous acid). Furthermore, NAC can easily be deacetylated to cysteine, an important precursor of cellular glutathione synthesis, and thus stimulate the cellular glutathione system. This is most evident in pulmonary diseases characterized by low glutathione levels and high oxidant production by inflammatory cells (e.g. in IPF and ARDS). NAC is an effective drug in the treatment of paracetamol intoxication and may even be protective against side-effects of mutagenic agents. In addition NAC reduces cellular production of pro-inflammatory mediators (e.g. TNF-alpha, IL-1). Also, ambroxol [trans-4-(2-amino-3,5-dibromobenzylamino)-cyclohexane hydrochloride] scavenges oxidants (e.g. .OH, HOCl). Moreover, ambroxol reduces bronchial hyperreactivity, and it is known to stimulate cellular surfactant production. In addition, ambroxol has anti-inflammatory properties owing to its inhibitory effect on the production of cellular cytokines and arachidonic acid metabolites. For both substances effective anti-oxidant and anti-inflammatory function has been validated when used in micromolar concentrations. These levels are attainable in vivo in humans. This paper gives an up-to-date overview about the current knowledge of the hypothesis that oxidant-induced cellular damage underlies the pathogenesis of many human pulmonary diseases, and it discusses the feasibility of anti-oxidant augmentation therapy to the lung by using NAC or ambroxol.
Topics: Acetylcysteine; Ambroxol; Animals; Expectorants; Free Radical Scavengers; Humans; Lung; Lung Diseases
PubMed: 9659525
DOI: 10.1016/s0954-6111(98)90506-6 -
International Journal of Molecular... Feb 2023We report synthesis of a novel 1,2,3,4-tetrahydroquinazoline derivative, named 2-(6,8-dibromo-3-(4-hydroxycyclohexyl)-1,2,3,4-tetrahydroquinazolin-2-yl)phenol (), which...
We report synthesis of a novel 1,2,3,4-tetrahydroquinazoline derivative, named 2-(6,8-dibromo-3-(4-hydroxycyclohexyl)-1,2,3,4-tetrahydroquinazolin-2-yl)phenol (), which was obtained from the hydrochloride of 4-((2-amino-3,5-dibromobenzyl)amino)cyclohexan-1-ol (ambroxol hydrochloride) and salicylaldehyde in EtOH. The resulting compound was produced in the form of colorless crystals of the composition ∙0.5EtOH. The formation of the single product was confirmed by the IR and H spectroscopy, single-crystal and powder X-ray diffraction, and elemental analysis. The molecule of contains a chiral tertiary carbon of the 1,2,3,4-tetrahydropyrimidine fragment and the crystal structure of ∙0.5EtOH is a racemate. Optical properties of ∙0.5EtOH were revealed by UV-vis spectroscopy in MeOH and it was established that the compound absorbs exclusively in the UV region up to about 350 nm. ∙0.5EtOH in MeOH exhibits dual emission and the emission spectra contains bands at about 340 and 446 nm upon excitation at 300 and 360 nm, respectively. The DFT calculations were performed to verify the structure as well as electronic and optical properties of . ADMET properties of the -isomer of were evaluated using the SwissADME, BOILED-Egg, and ProTox-II tools. As evidenced from the blue dot position in the BOILED-Egg plot, both human blood-brain barrier penetration and gastrointestinal absorption properties are positive with the positive PGP effect on the molecule. Molecular docking was applied to examine the influence of the structures of both -isomer and -isomer of on a series of the SARS-CoV-2 proteins. According to the docking analysis results, both isomers of were found to be active against all the applied SARS-CoV-2 proteins with the best binding affinities with Papain-like protease (PLpro) and nonstructural protein 3 (Nsp3_range 207-379-AMP). Ligand efficiency scores for both isomers of inside the binding sites of the applied proteins were also revealed and compared with the initial ligands. Molecular dynamics simulations were also applied to evaluate the stability of complexes of both isomers with Papain-like protease (PLpro) and nonstructural protein 3 (Nsp3_range 207-379-AMP). The complex of the -isomer with Papain-like protease (PLpro) was found to be highly unstable, while the other complexes are stable.
Topics: Humans; Ambroxol; COVID-19; Molecular Docking Simulation; SARS-CoV-2; Quinazolines; Coronavirus Papain-Like Proteases
PubMed: 36902093
DOI: 10.3390/ijms24054660 -
Informatics in Medicine Unlocked 2021Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has been responsible for the cause of global pandemic Covid-19 and to date, there is no effective treatment...
Structural insights and inhibition mechanism of TMPRSS2 by experimentally known inhibitors Camostat mesylate, Nafamostat and Bromhexine hydrochloride to control SARS-coronavirus-2: A molecular modeling approach.
Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has been responsible for the cause of global pandemic Covid-19 and to date, there is no effective treatment available. The spike 'S' protein of SARS-CoV-2 and ACE2 of the host cell are being targeted to design new drugs to control Covid-19. Similarly, a transmembrane serine protease, TMPRSS2 of the host cell plays a significant role in the proteolytic cleavage of viral 'S' protein helpful for the priming of ACE2 receptors and viral entry into human cells. However, three-dimensional structural information and the inhibition mechanism of TMPRSS2 is yet to be explored experimentally. Hence, we have used a molecular dynamics (MD) simulated homology model of TMPRSS2 to study the inhibition mechanism of experimentally known inhibitors Camostat mesylate, Nafamostat and Bromhexine hydrochloride (BHH) using molecular modeling techniques. Prior to docking, all three inhibitors were geometry optimized by semi-empirical quantum chemical RM1 method. Molecular docking analysis revealed that Camostat mesylate and its structural analogue Nafamostat interact strongly with residues His296 and Ser441 present in the catalytic triad of TMPRSS2, whereas BHH binds with Ala386 along with other residues. Comparative molecular dynamics simulations revealed the stable behavior of all the docked complexes. MM-PBSA calculations also revealed the stronger binding of Camostat mesylate to TMPRSS2 active site residues as compared to Nafamostat and BHH. Thus, this structural information could be useful to understand the mechanistic approach of TMPRSS2 inhibition, which may be helpful to design new lead compounds to prevent the entry of SARS-Coronavirus 2 in human cells.
PubMed: 34075338
DOI: 10.1016/j.imu.2021.100597 -
CNS Neuroscience & Therapeutics 2008For almost three decades ambroxol has been used in the therapy of airway diseases. In 2002, ambroxol lozenges were marketed for the treatment of sore throat making use... (Review)
Review
For almost three decades ambroxol has been used in the therapy of airway diseases. In 2002, ambroxol lozenges were marketed for the treatment of sore throat making use of its local anesthetic effect. Detailed investigations of ambroxol with modern pharmacological methods yielded additional interesting results: ambroxol has been found to have profound effects on neuronal voltage-gated Na(+), as well as Ca(2+) channels, and to effectively reduce chronic inflammatory and neuropathic pain in rodents. The question was raised whether ambroxol affects the central nervous system (CNS) directly, or whether its effects can be explained solely by a peripheral action. This issue was addressed by re-examining pharmacokinetics, as well as toxicology of ambroxol. It has been concluded that even at the highest clinically used doses ambroxol does not have significant direct effects on the CNS. At clinically relevant plasma concentrations ambroxol either does not penetrate blood-brain barrier, or its brain levels are too low to cause relevant effects. The analgesic effects of ambroxol by either systemic administration to animals, or by topical application in humans can be explained by ambroxol-induced blockade of ion channels in peripheral neurons.
Topics: Ambroxol; Animals; Central Nervous System; Central Nervous System Agents; Humans
PubMed: 18482096
DOI: 10.1111/j.1527-3458.2007.00032.x