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1.
Int J Pharm ; 625: 122057, 2022 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-35908632

RESUMO

Different crystal forms of active pharmaceutical ingredients (APIs) may display variations in physicochemical properties. During the drug development process, the definitive purpose is to maintain homogeneous quality in a single crystalline form. Hence, it is important to evaluate and understand the properties of each crystal form of APIs in pharmaceutics. In this study, forms 0, Ⅰ, Ⅱ, III of bromhexine hydrochloride, and form S of bromhexine were characterized by the commonly used methods X-ray powder diffraction, thermogravimetry-differential thermal analysis, and single crystal structure X-ray diffraction. Additionally, X-ray absorption fine structure spectroscopy (XAFS), a seldom used method in the pharmaceutics discipline was also applied to explore the chemical environment of bromine atoms in forms 0, Ⅰ, Ⅱ and S as well as chloride ions in forms 0 to Ⅱ. The XAFS spectra of each form were different from each of the other forms which indicated the chemical environment around target elements in the crystal polymorphs were distinct. Then, we measured the commercial bromhexine hydrochloride tablets with XAFS measurement and found that XAFS could distinguish the crystal form in the tablets. Hence, we demonstrated that XAFS measurements would be applicable as one of the methods for the direct detection of APIs in the tablets.


Assuntos
Bromoexina , Difração de Pó , Análise Espectral , Comprimidos/química , Difração de Raios X , Raios X
2.
Molecules ; 27(13)2022 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-35807327

RESUMO

We develop an electrochemical sensor for the determination of bromhexine hydrochloride (BHC), a widely use mucolytic drug. The sensor is prepared by electrodeposition of cobalt oxides (CoOx) on a glassy carbon electrode modified with carboxylated single-walled carbon nanotubes (SWCNT). A synergistic effect between CoOx and SWCNT is observed, leading to a significant improvement in the BHC electrooxidation current. Based on cyclic voltammetry studies at varying scan rates, we conclude that the electrochemical oxidation of BHC is under mixed diffusion-adsorption control. The proposed sensor allows the amperometric determination of BHC in a linear range of 10-500 µM with a low applied voltage of 0.75 V. The designed sensor provides reproducible measurements, is not affected by common interfering substances, and shows excellent performance for the analysis of BHC in pharmaceutical preparations.


Assuntos
Bromoexina , Nanotubos de Carbono , Cobalto/química , Técnicas Eletroquímicas , Eletrodos , Galvanoplastia , Nanotubos de Carbono/química , Óxidos/química
3.
Vopr Virusol ; 67(2): 126-132, 2022 05 05.
Artigo em Russo | MEDLINE | ID: mdl-35521985

RESUMO

COVID-19 (novel coronavirus disease 2019), caused by the SARS-CoV-2 virus, has various clinical manifestations and several pathogenic pathways. Although several therapeutic options have been used to control COVID-19, none of these medications have been proven to be a definitive cure. Transmembrane serine protease 2 (TMPRSS2) is a protease that has a key role in the entry of SARS-CoV-2 into host cells. Following the binding of the viral spike (S) protein to the angiotensin-converting enzyme 2 (ACE2) receptors of the host cells, TMPRSS2 processes and activates the S protein on the epithelial cells. As a result, the membranes of the virus and host cell fuse. Bromhexine is a specific TMPRSS2 inhibitor that potentially inhibits the infectivity cycle of SARS-CoV-2. Moreover, several clinical trials are evaluating the efficacy of bromhexine in COVID-19 patients. The findings of these studies have shown that bromhexine is effective in improving the clinical outcomes of COVID-19 and has prophylactic effects by inhibiting TMPRSS2 and viral penetration into the host cells. Bromhexine alone cannot cure all of the symptoms of SARS-CoV-2 infection. However, it could be an effective addition to control and prevent the disease progression along with other drugs that are used to treat COVID-19. Further studies are required to investigate the efficacy of bromhexine in COVID-19.


Assuntos
Bromoexina , COVID-19 , Bromoexina/farmacologia , COVID-19/tratamento farmacológico , Humanos , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/metabolismo , Internalização do Vírus
4.
J Mol Graph Model ; 114: 108201, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35487151

RESUMO

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 (ΔGbind) 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.


Assuntos
Ambroxol , Bromoexina , COVID-19 , Enzima de Conversão de Angiotensina 2 , Angiotensinas/metabolismo , COVID-19/tratamento farmacológico , Humanos , Ligação Proteica , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/química
5.
Ann Pharm Fr ; 80(5): 687-696, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34968477

RESUMO

New validated Spectroscopic methods were developed to assay Bromhexine Hydrochloride and its active metabolite Ambroxol Hydrochloride separately in pure form and pharmaceutical formulations. The spectrophotometric assay (method I) shows complex formation between each of the drugs and Eosin Y at 540nm at pH 3.6 and 3.4mL of 4×10-4M Eosin for Bromhexine and Ambroxol. The Spectrofluorimetric assay (method II) depends on quenching eosin native fluorescence by the studied drugs, which measured at 540nm after excitation at 302nm. The spectrophotometric absorbance-concentration plot is rectilinear over the ranges (1.0-5.0) and (1.0-10.0) µg/mL for bromhexine and ambroxol with LOD of 0.31 and 0.14µg/mL and LOQ of 0.94 and 0.42µg/mL for the two drugs respectively. The fluorometric-concentration plot is linear along the range (1.0-5.0) µg/mL and (1-10) µg/mL for the two drugs respectively with LOD of 0.13µg/mL and 0.22µg/mL and LOQ of 0.4µg/mL and 0.65µg/mL for the two drugs, respectively. Developed assays have been validated in agreement with ICH recommendations and they were used in the analysis of commercial drug formulations containing the two mucolytic drugs and the results were matching with those obtained by the comparison method.


Assuntos
Ambroxol , Bromoexina , Ambroxol/análise , Bromoexina/análise , Amarelo de Eosina-(YS) , Expectorantes/análise , Espectrofotometria/métodos
6.
BMJ Open ; 11(8): e045190, 2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34344672

RESUMO

INTRODUCTION: SARS-CoV-2 infection in Mexico has caused ~2.7 million confirmed cases; around 20%-25% of health workers will be infected by the virus at their workplace, with approximately 4.4% of mortality. High infectivity of SARS-CoV-2 is related with cell entry mechanism, through the ACE receptor. SARS-CoV-2 requires transmembrane protease serine 2 to cleave its spike glycoprotein and ensure fusion of host cell and virus membrane. We propose studying prophylactic treatment with hydroxychloroquine (HCQ) and bromhexine (BHH), which have been shown to be effective in preventing SARS-CoV-2 infection progression when administered in early stages. The aim of this study is to assess the efficacy of HCQ and BHH as prophylactic treatments for SARS-CoV-2 infection in healthy health workers exposed to the virus. METHODS AND ANALYSIS: Double-blind randomised clinical trial, with parallel allocation at a 1:1 ratio with placebo, of low doses of HCQ plus BHH, for 60 days. Study groups will be defined as follows: (1) HCQ 200 mg/day+BHH 8 mg/8 hours versus (2) HCQ placebo plus BHH placebo. Primary endpoint will be efficacy of both interventions for the prevention of SARS-CoV-2 infection, determined by the risk ratio of infected personnel and the absolute risk. At least a 16% reduction in absolute risk is expected between the intervention and placebo groups; a minimum of 20% infection is expected in the placebo group. The sample size calculation estimated a total of 214 patients assigned: two groups of 107 participants each. ETHICS AND DISSEMINATION: This protocol has been approved by the local Medical Ethics Committee (National Institute of Rehabilitation 'Luis Guillermo Ibarra Ibarra', approval number INRLGII/25/20) and by the Federal Commission for Protection against Sanitary Risks (COFEPRIS, approval number 203 300 410A0058/2020). The results of the study will be submitted for publication in peer-reviewed journals and disseminated through conferences. TRIAL REGISTRATION NUMBER: NCT04340349.


Assuntos
Bromoexina , COVID-19 , COVID-19/tratamento farmacológico , Método Duplo-Cego , Humanos , Hidroxicloroquina/uso terapêutico , México , SARS-CoV-2 , Resultado do Tratamento
7.
Arch Pharm (Weinheim) ; 354(10): e2100131, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34131945

RESUMO

A gradient elution high-performance liquid chromatographic method with a diode array detector is introduced for the first time for the simultaneous estimation of three drugs, namely, oxytetracycline hydrochloride (OXT), lidocaine (LDC), and bromhexine hydrochloride (BRH), in a veterinary formulation (OxyClear® solution) that contains many interfering additives. The method used a C-8 column. The chromatographic eluting solution included acidified water (0.1% trifluoroacetic acid in water) and acetonitrile at a 1-ml/min flow rate and 254 nm as a nominated detection wavelength. The chromatographic process was assessed in terms of linearity, precision, accuracy, LOD, and LOQ. OXT, LDC, and BRH were linear in the range of 1-60, 5-100, and 1-60 µg/ml, respectively. The three drugs were determined successfully without the interference of three excipients having UV absorbances. Furthermore, the purities of the peaks of the three drugs were confirmed by comparing the UV spectra of investigated peaks to the UV reference spectra in Clarke's Analysis of Drugs and Poisons. The greenness value of the method was 0.69 with a faint green-colored pictogram using the AGREE tool. These merits recommend the application of the planned method in QC laboratories for purity testing and concentration assays for the pure drugs and commercial formulations.


Assuntos
Bromoexina/análise , Cromatografia Líquida de Alta Pressão/métodos , Lidocaína/análise , Oxitetraciclina/análise , Anestésicos Locais/análise , Antibacterianos/análise , Cromatografia Líquida de Alta Pressão/veterinária , Combinação de Medicamentos , Excipientes/química , Expectorantes/análise , Limite de Detecção , Reprodutibilidade dos Testes , Drogas Veterinárias/análise
8.
Yakugaku Zasshi ; 141(4): 599-610, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-33790125

RESUMO

Elneopa NF No. 1 and No. 2 infusions are total parenteral nutrition solutions packaged in four-chambered infusion bags. They have been used as home parenteral nutrition, with various drugs injected into the infusion bags, for treating patient symptoms. In this study, we investigated the stability of six drugs, including famotidine, scopolamine butylbromide, furosemide, bromhexine hydrochloride, betamethasone sodium phosphate, and metoclopramide hydrochloride in the infusion bags under dark conditions at 4℃ for 7 days. Additionally, we developed a high-performance liquid chromatography method to determine drug concentrations in the infusions. The concentrations of injected famotidine, scopolamine butylbromide, and betamethasone sodium phosphate remained unchanged when the four chambers of Elneopa NF No. 1 and No. 2 were opened and the infusions were mixed. Their respective concentrations in the upper and lower chambers also remained unchanged. The concentration of furosemide in the upper chamber of the No. 1 infusion bag decreased after 5 days, although no change was observed in the other chambers and the mixed infusions with the four chambers opened. The concentration of bromhexine hydrochloride slightly decreased in the upper chambers (approximately 3%) after the co-infusion but decreased significantly in the other chambers and the mixed infusions with the four chambers opened. The concentration of metoclopramide hydrochloride significantly decreased in the upper chambers after the co-infusion; however, no change in concentration was observed in the other chambers and the mixed infusion with the four chambers opened. The results of this study provide useful information on home-based parenteral nutrition.


Assuntos
Betametasona/análogos & derivados , Bromoexina , Brometo de Butilescopolamônio , Embalagem de Medicamentos , Famotidina , Furosemida , Metoclopramida , Soluções de Nutrição Parenteral/análise , Nutrição Parenteral Total no Domicílio , Betametasona/análise , Bromoexina/análise , Brometo de Butilescopolamônio/análise , Estabilidade de Medicamentos , Famotidina/análise , Furosemida/análise , Metoclopramida/análise
9.
PLoS One ; 16(3): e0248132, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33705495

RESUMO

BACKGROUND: COVID-19 is a rapidly spreading disease that has caused extensive burden to individuals, families, countries, and the world. Effective treatments of COVID-19 are urgently needed. This is the second edition of a living systematic review of randomized clinical trials assessing the effects of all treatment interventions for participants in all age groups with COVID-19. METHODS AND FINDINGS: We planned to conduct aggregate data meta-analyses, trial sequential analyses, network meta-analysis, and individual patient data meta-analyses. Our systematic review was based on PRISMA and Cochrane guidelines, and our eight-step procedure for better validation of clinical significance of meta-analysis results. We performed both fixed-effect and random-effects meta-analyses. Primary outcomes were all-cause mortality and serious adverse events. Secondary outcomes were admission to intensive care, mechanical ventilation, renal replacement therapy, quality of life, and non-serious adverse events. According to the number of outcome comparisons, we adjusted our threshold for significance to p = 0.033. We used GRADE to assess the certainty of evidence. We searched relevant databases and websites for published and unpublished trials until November 2, 2020. Two reviewers independently extracted data and assessed trial methodology. We included 82 randomized clinical trials enrolling a total of 40,249 participants. 81 out of 82 trials were at overall high risk of bias. Meta-analyses showed no evidence of a difference between corticosteroids versus control on all-cause mortality (risk ratio [RR] 0.89; 95% confidence interval [CI] 0.79 to 1.00; p = 0.05; I2 = 23.1%; eight trials; very low certainty), on serious adverse events (RR 0.89; 95% CI 0.80 to 0.99; p = 0.04; I2 = 39.1%; eight trials; very low certainty), and on mechanical ventilation (RR 0.86; 95% CI 0.55 to 1.33; p = 0.49; I2 = 55.3%; two trials; very low certainty). The fixed-effect meta-analyses showed indications of beneficial effects. Trial sequential analyses showed that the required information size for all three analyses was not reached. Meta-analysis (RR 0.93; 95% CI 0.82 to 1.07; p = 0.31; I2 = 0%; four trials; moderate certainty) and trial sequential analysis (boundary for futility crossed) showed that we could reject that remdesivir versus control reduced the risk of death by 20%. Meta-analysis (RR 0.82; 95% CI 0.68 to 1.00; p = 0.05; I2 = 38.9%; four trials; very low certainty) and trial sequential analysis (required information size not reached) showed no evidence of difference between remdesivir versus control on serious adverse events. Fixed-effect meta-analysis showed indications of a beneficial effect of remdesivir on serious adverse events. Meta-analysis (RR 0.40; 95% CI 0.19 to 0.87; p = 0.02; I2 = 0%; two trials; very low certainty) showed evidence of a beneficial effect of intravenous immunoglobulin versus control on all-cause mortality, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm or reject realistic intervention effects. Meta-analysis (RR 0.63; 95% CI 0.35 to 1.14; p = 0.12; I2 = 77.4%; five trials; very low certainty) and trial sequential analysis (required information size not reached) showed no evidence of a difference between tocilizumab versus control on serious adverse events. Fixed-effect meta-analysis showed indications of a beneficial effect of tocilizumab on serious adverse events. Meta-analysis (RR 0.70; 95% CI 0.51 to 0.96; p = 0.02; I2 = 0%; three trials; very low certainty) showed evidence of a beneficial effect of tocilizumab versus control on mechanical ventilation, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm of reject realistic intervention effects. Meta-analysis (RR 0.32; 95% CI 0.15 to 0.69; p < 0.00; I2 = 0%; two trials; very low certainty) showed evidence of a beneficial effect of bromhexine versus standard care on non-serious adverse events, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm or reject realistic intervention effects. Meta-analyses and trial sequential analyses (boundary for futility crossed) showed that we could reject that hydroxychloroquine versus control reduced the risk of death and serious adverse events by 20%. Meta-analyses and trial sequential analyses (boundary for futility crossed) showed that we could reject that lopinavir-ritonavir versus control reduced the risk of death, serious adverse events, and mechanical ventilation by 20%. All remaining outcome comparisons showed that we did not have enough information to confirm or reject realistic intervention effects. Nine single trials showed statistically significant results on our outcomes, but were underpowered to confirm or reject realistic intervention effects. Due to lack of data, it was not relevant to perform network meta-analysis or possible to perform individual patient data meta-analyses. CONCLUSIONS: No evidence-based treatment for COVID-19 currently exists. Very low certainty evidence indicates that corticosteroids might reduce the risk of death, serious adverse events, and mechanical ventilation; that remdesivir might reduce the risk of serious adverse events; that intravenous immunoglobin might reduce the risk of death and serious adverse events; that tocilizumab might reduce the risk of serious adverse events and mechanical ventilation; and that bromhexine might reduce the risk of non-serious adverse events. More trials with low risks of bias and random errors are urgently needed. This review will continuously inform best practice in treatment and clinical research of COVID-19. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020178787.


Assuntos
COVID-19/terapia , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Corticosteroides/uso terapêutico , Alanina/análogos & derivados , Alanina/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antivirais/uso terapêutico , Bromoexina/uso terapêutico , COVID-19/tratamento farmacológico , COVID-19/mortalidade , Ensaios Clínicos como Assunto , Expectorantes/uso terapêutico , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Respiração Artificial , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/isolamento & purificação , Resultado do Tratamento
10.
J Chromatogr Sci ; 59(5): 425-431, 2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33532822

RESUMO

Two simple, sensitive and validated chromatographic methods were developed for quantitative determination of bromhexine hydrochloride (BHX) in presence of its major impurities, impurity B (IMB) and impurity C (IMC), as specified by British Pharmacopoeia. First method (I) was high-performance thin layer chromatography-densitometry at which the chromatographic separation was performed using silica gel plates and developing system consisted of hexane:acetone:ammonia solution (9:0.5:0.08, by volume) with ultraviolet scanning at 240 nm and linearity was achieved in the ranges of 0.40-10.00, 0.20-2.00 and 0.20-2.00 µg/band of BHX, IMB and IMC, respectively. Also, second chromatographic method (II) was high-performance liquid chromatography (HPLC) where the separation was carried out on C18 column at isocratic mode at flow rate 1.5 mL/min. The mobile phase consisted of methanol:water (90:10, v/v) adjusted to pH 2.5 with O-phosphoric acid and temperature was adjusted to 40°C. The scanning wavelength was 240 nm. The chromatographic run time was 6 min. Linearity of this method was achieved in the ranges of 4.00-40.00, 0.20-10.00 and 0.50-10.00 µg/mL for BHX, IMB and IMC, respectively. The validation of these chromatographic methods was made according to International Conference on Harmonization guidelines. These methods were successfully applied for determination of BHX in its pharmaceutical formulation. Also, statistical comparison was attained between the developed methods and the reported HPLC method using Student's t-test and F-test, and the obtained results showed that there was not any significant difference between them concerning with accuracy and precision.


Assuntos
Bromoexina/análise , Bromoexina/química , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia em Camada Delgada/métodos , Contaminação de Medicamentos , Limite de Detecção , Modelos Lineares , Reprodutibilidade dos Testes , Comprimidos
11.
J Virol ; 95(9)2021 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-33608407

RESUMO

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.IMPORTANCE 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.


Assuntos
COVID-19/metabolismo , Vírus da SARS/metabolismo , SARS-CoV-2/metabolismo , Síndrome Respiratória Aguda Grave/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Internalização do Vírus , Ambroxol/farmacologia , Substituição de Aminoácidos , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Bromoexina/farmacologia , COVID-19/genética , Linhagem Celular , Humanos , Mutação de Sentido Incorreto , Proteólise/efeitos dos fármacos , Vírus da SARS/genética , SARS-CoV-2/genética , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Síndrome Respiratória Aguda Grave/genética , Glicoproteína da Espícula de Coronavírus/genética
13.
BMC Complement Med Ther ; 20(1): 380, 2020 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-33357221

RESUMO

BACKGROUND: Rhinoviruses and influenza viruses cause millions of acute respiratory infections annually. Symptoms of mild acute respiratory infections are commonly treated with over-the-counter products like ambroxol, bromhexine, and N-acetyl cysteine, as well as of thyme and pelargonium extracts today. Because the direct antiviral activity of these over-the-counter products has not been studied in a systematic way, the current study aimed to compare their inhibitory effect against rhinovirus and influenza virus replication in an in vitro setting. METHODS: The cytotoxicity of ambroxol, bromhexine, and N-acetyl cysteine, as well as of thyme and pelargonium extracts was analyzed in Madin Darby canine kidney (MDCK) and HeLa Ohio cells. The antiviral effect of these over-the-counter products was compared by analyzing the dose-dependent inhibition (i) of rhinovirus A2- and B14-induced cytopathic effect in HeLa Ohio cells and (ii) of influenza virus A/Hong Kong/68 (subtype H3N2)- and A/Jena/8178/09 (subtype H1N1, pandemic)-induced cytopathic effect in MDCK cells at non-cytotoxic concentrations. To get insights into the mechanism of action of pelargonium extract against influenza virus, we performed time-of-addition assays as well as hemagglutination and neuraminidase inhibition assays. RESULTS: N-acetyl cysteine, thyme and pelargonium extract showed no or only marginal cytotoxicity in MDCK and HeLa Ohio cells in the tested concentration range. The 50% cytotoxic concentration of ambroxol and bromhexine was 51.85 and 61.24 µM, respectively. No anti-rhinoviral activity was detected at non-cytotoxic concentrations in this in vitro study setting. Ambroxol, bromhexine, and N-acetyl cysteine inhibited the influenza virus-induced cytopathic effect in MDCK cells no or less than 50%. In contrast, a dose-dependent anti-influenza virus activity of thyme and pelargonium extracts was demonstrated. The time-of addition assays revealed an inhibition of early and late steps of influenza virus replication by pelargonium extract whereas zanamivir acted on late steps only. The proven block of viral neuraminidase activity might explain the inhibition of influenza virus replication when added after viral adsorption. CONCLUSION: The study results indicate a distinct inhibition of influenza A virus replication by thyme and pelargonium extract which might contribute to the beneficial effects of these plant extracts on acute respiratory infections symptoms.


Assuntos
Vírus da Influenza A/efeitos dos fármacos , Pelargonium , Extratos Vegetais/uso terapêutico , Infecções Respiratórias/tratamento farmacológico , Rhinovirus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Acetilcisteína , Ambroxol , Animais , Bromoexina , Cães , Células HeLa , Humanos , Células Madin Darby de Rim Canino , Testes de Sensibilidade Microbiana , Fitoterapia , Extratos Vegetais/farmacologia , Thymus (Planta) , Testes de Toxicidade
14.
Kardiologiia ; 60(8): 4-15, 2020 Sep 07.
Artigo em Russo | MEDLINE | ID: mdl-33155953

RESUMO

The article focuses on effective treatment of the novel coronavirus infection (COVID-19) at early stages and substantiates the requirement for antiviral therapy and for decreasing the viral load to prevent the infection progression. The absence of a specific antiviral therapy for the SARS-CoV-2 virus is stated. The authors analyzed results of early randomized studies using lopinavir/ritonavir, remdesivir, and favipiravir in COVID-19 and their potential for the treatment of novel coronavirus infection. Among the drugs blocking the virus entry into cells, the greatest attention was paid to the antimalaria drugs, chloroquine and hydroxychloroquine. The article addresses in detail ineffectiveness and potential danger of hydroxychloroquine, which demonstrated neither a decrease in the time of clinical recovery nor any improvement of prognosis for patients with COVID-19. The major objective was substantiating a possible use of bromhexine, a mucolytic and anticough drug, which can inhibit transmembrane serin protease 2 required for entry of the SARS-CoV-2 virus into cells. Spironolactone may have a similar feature. Due to its antiandrogenic effects, spironolactone can inhibit X-chromosome-related synthesis of ACE-2 receptors and activation of transmembrane serin protease 2. In addition to slowing the virus entry into cells, spironolactone decreases severity of fibrosis in different organs, including the lungs. The major part of the article addresses clinical examples of managing patients with COVID-19 at the University Clinic of the Medical Research and Educational Centre of the M. V. Lomonosov Moscow State University, including successful treatment with schemes containing bromhexine and spironolactone. In conclusion, the authors described the design of a randomized, prospective BISCUIT study performed at the University Clinic of the M. V. Lomonosov Moscow State University with an objective of evaluating the efficacy of this scheme.


Assuntos
Bromoexina , Infecções por Coronavirus , Pandemias , Pneumonia Viral , Espironolactona , Betacoronavirus , Bromoexina/uso terapêutico , COVID-19 , Infecções por Coronavirus/tratamento farmacológico , Hospitalização , Humanos , Moscou , Pneumonia Viral/tratamento farmacológico , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , SARS-CoV-2 , Espironolactona/uso terapêutico
15.
Clin Transl Sci ; 13(6): 1096-1102, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32881359

RESUMO

This open-label randomized controlled pilot study aimed to test the study feasibility of bromhexine hydrochloride (BRH) tablets for the treatment of mild or moderate coronavirus disease 2019 (COVID-19) and to explore its clinical efficacy and safety. Patients with mild or moderate COVID-19 were randomly divided into the BRH group or the control group at a 2:1 ratio. Routine treatment according to China's Novel Coronavirus Pneumonia Diagnosis and Treatment Plan was performed in both groups, whereas patients in the BRH group were additionally given oral BRH (32 mg t.i.d.) for 14 consecutive days. The efficacy and safety of BRH were evaluated. A total of 18 patients with moderate COVID-19 were randomized into the BRH group (n = 12) or the control group (n = 6). There were suggestions of BRH advantage over placebo in improved chest computed tomography, need for oxygen therapy, and discharge rate within 20 days. However, none of these findings were statistically significant. BRH tablets may potentially have a beneficial effect in patients with COVID-19, especially for those with lung or hepatic injury. A further definitive large-scale clinical trial is feasible and necessary.


Assuntos
Bromoexina/uso terapêutico , COVID-19/tratamento farmacológico , SARS-CoV-2 , Adulto , Bromoexina/efeitos adversos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Comprimidos
16.
Medicine (Baltimore) ; 99(37): e22114, 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32925756

RESUMO

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.


Assuntos
Bromoexina/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Betacoronavirus , COVID-19 , Criança , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/fisiopatologia , Expectorantes/farmacologia , Humanos , Metanálise como Assunto , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/fisiopatologia , Projetos de Pesquisa , SARS-CoV-2 , Revisões Sistemáticas como Assunto , Resultado do Tratamento
17.
Curr Drug Metab ; 21(7): 548-561, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32651960

RESUMO

BACKGROUND: Painful peripheral neuropathy is a dose-limiting adverse effect of the antitumor drug oxaliplatin. The main symptoms of neuropathy: tactile allodynia and cold hyperalgesia, appear in more than 80% of patients on oxaliplatin therapy and are due to the overexpression of neuronal sodium channels (Navs) and neuroinflammation. OBJECTIVE: This study assessed antiallodynic and antihyperalgesic properties of two repurposed drugs with antiinflammatory and Nav-blocking properties (bromhexine and its pharmacologically active metabolite - ambroxol) in a mouse model of neuropathic pain induced by oxaliplatin. Using molecular docking techniques, we predicted targets implicated in the observed in vivo activity of bromhexine. METHODS: Oxaliplatin (a single intraperitoneal dose of 10 mg/kg) induced tactile allodynia and cold hyperalgesia in CD-1 mice and the effectiveness of single-dose or repeated-dose bromhexine and ambroxol to attenuate pain hypersensitivity was assessed in von Frey and cold plate tests. Additionally, Veber analysis and molecular docking experiments of bromhexine on mouse (m) and human (h) Nav1.6-1.9 were carried out. RESULTS: At the corresponding doses, ambroxol was more effective than bromhexine as an antiallodynic agent. However, at the dose of 150 mg/kg, ambroxol induced motor impairments in mice. Repeated-dose bromhexine and ambroxol partially attenuated the development of late-phase tactile allodynia in oxaliplatin-treated mice. Only 7-day administration of bromhexine attenuated the development of late-phase cold hyperalgesia. Bromhexine was predicted to be a strong inhibitor of mNav1.6, mNav1.7, mNav1.9, and hNav1.7-hNav1.9. CONCLUSION: The conversion of bromhexine to other than ambroxol active metabolites should be considered when interpreting some of its in vivo effects. Nav-blocking properties of bromhexine (and previously also predicted for ambroxol) might underlie its ability to attenuate pain caused by oxaliplatin.


Assuntos
Analgésicos/uso terapêutico , Antineoplásicos , Bromoexina/uso terapêutico , Hiperalgesia/tratamento farmacológico , Neuralgia/tratamento farmacológico , Oxaliplatina , Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêutico , Analgésicos/química , Analgésicos/farmacologia , Animais , Bromoexina/química , Bromoexina/farmacologia , Temperatura Baixa/efeitos adversos , Reposicionamento de Medicamentos , Humanos , Hiperalgesia/induzido quimicamente , Masculino , Camundongos , Simulação de Acoplamento Molecular , Neuralgia/induzido quimicamente , Tato , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Canais de Sódio Disparados por Voltagem/química
18.
Med Hypotheses ; 144: 110020, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32590326

RESUMO

Pulmonary surfactant is considered to be one of the soaps. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the other enveloped viruses become very weak against surfactant. The SARS virus binds to angiotensin-converting enzyme (ACE2) receptor and causes pneumonia. In the lung, the ACE2 receptor sits on the top of lung cells known as alveolar epithelial type II (AE2) cells. These cells play an important role in producing surfactant. Pulmonary surfactant is believed to regulate the alveolar surface tension in mammalian lungs. To our knowledge, AE2 cells are believed to act as immunoregulatory cells; however, pulmonary surfactant itself has not been believed to act as a defender against the enveloped viruses. This study hypothesises that pulmonary surfactant may be a strong defender of enveloped viruses. Therefore, old coronaviruses merely cause pneumonia. On the contrary, new SARS-CoV-2 can suppress the production of surfactant that binds to the ACE2 of AE2 cells. The coronavirus can survive in the lung tissue because of the exhaustion of pulmonary surfactant.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/prevenção & controle , COVID-19/fisiopatologia , Pneumonia Viral/fisiopatologia , Surfactantes Pulmonares/uso terapêutico , SARS-CoV-2 , Ambroxol/uso terapêutico , Bromoexina/uso terapêutico , COVID-19/tratamento farmacológico , Ensaios Clínicos como Assunto , Cristalografia por Raios X , Humanos , Modelos Teóricos , Fagocitose , Pregnenodionas/uso terapêutico , Alvéolos Pulmonares/metabolismo , Tensão Superficial , Tensoativos
19.
Int J Mol Med ; 46(2): 467-488, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32468014

RESUMO

The major impact produced by the severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) focused many researchers attention to find treatments that can suppress transmission or ameliorate the disease. Despite the very fast and large flow of scientific data on possible treatment solutions, none have yet demonstrated unequivocal clinical utility against coronavirus disease 2019 (COVID­19). This work represents an exhaustive and critical review of all available data on potential treatments for COVID­19, highlighting their mechanistic characteristics and the strategy development rationale. Drug repurposing, also known as drug repositioning, and target based methods are the most used strategies to advance therapeutic solutions into clinical practice. Current in silico, in vitro and in vivo evidence regarding proposed treatments are summarized providing strong support for future research efforts.


Assuntos
Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos , Pneumonia Viral/tratamento farmacológico , Internalização do Vírus/efeitos dos fármacos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/classificação , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Enzima de Conversão de Angiotensina 2 , Betacoronavirus/patogenicidade , Betacoronavirus/fisiologia , Bromoexina/farmacologia , Bromoexina/uso terapêutico , COVID-19 , Clorpromazina/farmacologia , Clorpromazina/uso terapêutico , Ensaios Clínicos como Assunto/métodos , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/mortalidade , Diminazena/farmacologia , Diminazena/uso terapêutico , Reposicionamento de Medicamentos/métodos , Reposicionamento de Medicamentos/normas , Reposicionamento de Medicamentos/tendências , Ésteres , Gabexato/análogos & derivados , Gabexato/farmacologia , Gabexato/uso terapêutico , Guanidinas , Humanos , Pandemias , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Peptidil Dipeptidase A/uso terapêutico , Pneumonia Viral/epidemiologia , Pneumonia Viral/mortalidade , Receptor Tipo 1 de Angiotensina/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/uso terapêutico , SARS-CoV-2 , Transdução de Sinais/efeitos dos fármacos
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