RESUMEN
The respiratory tract is commonly affected in multisystem disorders. Although many drugs have been developed to target various components of these diseases, there is still a need for effective treatments that can address both respiratory and non-respiratory symptoms. Bromhexine and ambroxol are mucolytic agents with a good safety profile that are widely used to treat respiratory conditions. These compounds seem to present several unresolved questions when carrying out their therapeutic effects, suggesting that they may not merely improve mucociliary clearance. These assumptions have provided the basis for researchers to investigate the specific characteristics of bromhexine and ambroxol. This has led to the emergence of several repositionings for this compound. Accordingly, these compounds have also shown potential benefits in the treatment of various extrapulmonary disorders, including neurological disorders, and inflammatory bowel disease. We gathered findings from relevant studies published in English between 1970 and December 2023 by searching databases including PubMed, Google Scholar, Scopus, Embase, and the Cochrane Library. Our findings revealed that most of the research on extrapulmonary uses has been conducted at the preclinical level. Accordingly, more clinical studies are needed to determine the effectiveness of bromhexine and ambroxol in these conditions. This article provides an overview of the potential extrapulmonary applications of bromhexine and ambroxol and discusses the potential advantages of using these drugs in multisystem disorders.
Asunto(s)
Ambroxol , Bromhexina , Expectorantes , Ambroxol/farmacología , Humanos , Bromhexina/farmacología , Expectorantes/farmacología , Expectorantes/uso terapéutico , Animales , Pulmón/efectos de los fármacos , Pulmón/metabolismoRESUMEN
A long-term stability study using high performance liquid chromatography (HPLC) revealed an unidentified impurity in the bromhexine hydrochloride injection, which was employed as a mucolytic agent. Investigations into stress degradation and elemental impurities revealed one of the elemental impurities Fe3+ in this injection as the primary generator of these impurities. This impurity, named N-carboxymethyl bromhexine, was a product formed during drug-excipient interaction between bromhexine and tartaric acid with Fe3+. The structure of the impurity was identified through ultra-high-performance liquid chromatography with diode array detector (UHPLC-DAD), liquid chromatograph mass spectrometer (LC-MS). Further, the formation mechanism of the impurity was discussed. Overall, this study elucidates the cause, origin, and mechanism of an unknown impurity in bromhexine hydrochloride injection, providing a basis for quality control for bromhexine hydrochloride injections and drug products containing both amine and tartaric acid.
Asunto(s)
Bromhexina , Contaminación de Medicamentos , Excipientes , Bromhexina/química , Bromhexina/análisis , Cromatografía Líquida de Alta Presión/métodos , Excipientes/química , Excipientes/análisis , Tartratos/química , Tartratos/análisis , Espectrometría de Masas/métodos , Estabilidad de Medicamentos , Control de CalidadRESUMEN
The current study aimed to investigate the pharmacokinetics of bromhexine hydrochloride in broilers after single intravenous (IV) and oral (PO) administration at 2.5 mg/kg body weight (BW). The trial adopted a randomized, parallel-controlled design, where 20 twelve-wk-old broilers were randomly assigned to either the PO or IV group. Blood samples were collected at predetermined time points, and plasma was further separated for analysis. The bromhexine hydrochloride concentrations in plasma samples were determined using an ultra-performance liquid chromatography-tandem quadrupole mass spectrometry (UPLC-MS/MS) method. Noncompartmental analysis (NCA) using Phoenix software was conducted to analyze the concentration versus time data of bromhexine hydrochloride in every chicken. Subsequently, the main pharmacokinetic parameters between the 2 groups were statistically analyzed using SPSS software. Results from NCA revealed that after oral administration at 2.5 mg/kg BW, bromhexine hydrochloride exhibited slow absorption, reaching an average peak concentration of 32.72 ng/mL at 1.78 h. However, incomplete absorption was observed, with an absolute bioavailability of only 20.06% ± 10.84%. Additionally, bromhexine hydrochloride displayed wide distribution, with a steady-state distribution volume (VSS) of 22.55 ± 13.45 L/kg, and slow elimination, with a clearance (Cl) of 1.52 ± 0.38 L/h/kg. Furthermore, gender effects were assessed on the pharmacokinetics of bromhexine hydrochloride in broilers, revealing better absorption in male broilers compared to females. This disparity may be attributed to the faster blood flow and richer blood volume typically found in male broilers.
Asunto(s)
Bromhexina , Pollos , Animales , Masculino , Administración Oral , Femenino , Bromhexina/farmacocinética , Bromhexina/administración & dosificación , Inyecciones Intravenosas/veterinaria , Espectrometría de Masas en Tándem/veterinaria , Distribución Aleatoria , Disponibilidad Biológica , Administración Intravenosa/veterinariaRESUMEN
Bromhexine and ambroxol are among the mucolytic drugs most widely used to treat acute and chronic respiratory diseases. Entering the municipal wastewater and undergoing transformations during disinfection with active chlorine, these compounds can produce nitrogen- and bromine-containing disinfection by-products (DBPs) that are dangerous for aquatic ecosystems. In the present study, primary and deep degradation products of ambroxol and bromhexine obtained in model aquatic chlorination experiments were studied via the combination of high-performance liquid and gas chromatography with high-resolution mass spectrometry. It was shown that at the initial stages, the reactions of cyclization, hydroxylation, chlorination, electrophilic ipso-substitution of bromine atoms with chlorine, and oxidative N-dealkylation occur. Along with known metabolites, a number of novel primary DBPs were tentatively identified based on their elemental compositions and tandem mass spectra. Deep degradation of bromhexine and ambroxol gives twenty-four identified volatile and semi-volatile compounds of six classes, among which trihalomethanes account for more than 50%. The specific class of bromhexine- and ambroxol-related DBPs are bromine-containing haloanilines. Seven of them, including methoxy derivatives, were first discovered in the present study. One more novel class of DBPs associated with bromhexine and ambroxol is represented by halogenated indazoles formed through dealkylation of the primary transformation products containing pyrazoline or tetrahydropyrimidine cycle in their structure.
Asunto(s)
Ambroxol , Bromhexina , Expectorantes , Halogenación , Contaminantes Químicos del Agua , Ambroxol/química , Bromhexina/química , Expectorantes/química , Contaminantes Químicos del Agua/química , Purificación del Agua/métodos , Cloro/químicaRESUMEN
Introducción y objetivo Desde su aparición en diciembre de 2019, la enfermedad por coronavirus causada por el síndrome respiratorio agudo severo coronavirus2 se ha convertido en una emergencia mundial, propagándose rápidamente por todo el mundo. En respuesta a la derivación temprana de estos pacientes a centros de salud ambulatorios, decidimos buscar tratamientos más eficaces en las primeras etapas de su derivación. Este estudio tiene como objetivo prevenir tanto la progresión como el deterioro de las condiciones físicas de los pacientes con COVID-19, reducir la tasa de derivaciones y mitigar los riesgos de hospitalización y de muerte. Material y métodos Realizado en el Centro Terapéutico Dibaj, ciudad de Hamadan, Irán, un ensayo controlado aleatorizado doble ciego abarcó 225 pacientes con COVID-19 de abril a septiembre de 2022. Se obtuvo la aprobación ética de la Universidad de Ciencias Médicas de Hamadan (Aprobación n.° IR.UMSHA .REC.1400.957), con el protocolo registrado en el Registro Iraní de Ensayos Clínicos (Registro n.° IRCT20220302054167N1). Los pacientes cumplieron con el diagnóstico de COVID-19 a través de la presentación de síntomas y la confirmación por PCR, excluyendo aquellos con antecedentes de vacunas y afectación de órganos. Los pacientes con una saturación de oxígeno superior al 92% se asignaron a tres grupos: el grupoA recibió N-acetilcisteína, el grupoB recibió bromhexina y el grupoC recibió atención estándar. Los seguimientos de los niveles de oxígeno, los síntomas y las necesidades de hospitalización se realizaron los días7 y 14, con pacientes hospitalizados monitorizados durante un mes después de la hospitalización. Resultados El estudio encontró que tanto la N-acetilcisteína como la bromhexina pueden reducir efectivamente las tasas de hospitalización y la mortalidad y acortar la duración de la hospitalización... (AU)
Introduction and aim Since its emergence in December 2019, the coronavirus disease caused by the severe acute respiratory syndrome coronavirus2 has become a global emergency, spreading rapidly worldwide. In response to the early referral of these patients to outpatient health centers, we decided to seek more effective treatments in the early stages of their referral. This study aims to prevent both the progression and deterioration of the physical conditions of COVID-19 patients, reduce the rate of referrals, and mitigate the risks of hospitalization and death. Material and methods Conducted at Dibaj Therapeutic Center, Hamadan City, Iran, a double-blind randomized controlled trial encompassed 225 COVID-19 patients from April to September 2022. Ethical approval was obtained from Hamadan University of Medical Sciences (Approval No.: IR.UMSHA.REC.1400.957), with the protocol registered in the Iranian Registry of Clinical Trials (Registration No.: IRCT20220302054167N1). In this study, we included patients who tested positive for COVID-19 PCR and were symptomatic, excluding those who were pregnant or had received a COVID-19 vaccine. Patients with oxygen saturation above 92% were allocated to three groups: GroupA received N-acetylcysteine, GroupB received Bromhexine, and GroupC received standard care. Follow-ups on oxygen levels, symptoms, and hospitalization needs were conducted on days 7 and 14, with hospitalized patients monitored for one month post-hospitalization. Results The study found that both N-acetylcysteine and Bromhexine can effectively reduce hospitalization rates and mortality and shorten the duration of hospitalization. The third visit of patients who received N-acetylcysteine showed an increase of 1.33% in oxygen saturation compared to their first visit, and in patients who received Bromhexine, this increase was 1.19%. The mortality rate was 9.33% in the control group and zero in both groups of patients who received medication... (AU)
Asunto(s)
Humanos , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , /tratamiento farmacológico , Infecciones por Coronavirus , Acetilcisteína/farmacología , Bromhexina/farmacologíaRESUMEN
Introducción y objetivo Desde su aparición en diciembre de 2019, la enfermedad por coronavirus causada por el síndrome respiratorio agudo severo coronavirus2 se ha convertido en una emergencia mundial, propagándose rápidamente por todo el mundo. En respuesta a la derivación temprana de estos pacientes a centros de salud ambulatorios, decidimos buscar tratamientos más eficaces en las primeras etapas de su derivación. Este estudio tiene como objetivo prevenir tanto la progresión como el deterioro de las condiciones físicas de los pacientes con COVID-19, reducir la tasa de derivaciones y mitigar los riesgos de hospitalización y de muerte. Material y métodos Realizado en el Centro Terapéutico Dibaj, ciudad de Hamadan, Irán, un ensayo controlado aleatorizado doble ciego abarcó 225 pacientes con COVID-19 de abril a septiembre de 2022. Se obtuvo la aprobación ética de la Universidad de Ciencias Médicas de Hamadan (Aprobación n.° IR.UMSHA .REC.1400.957), con el protocolo registrado en el Registro Iraní de Ensayos Clínicos (Registro n.° IRCT20220302054167N1). Los pacientes cumplieron con el diagnóstico de COVID-19 a través de la presentación de síntomas y la confirmación por PCR, excluyendo aquellos con antecedentes de vacunas y afectación de órganos. Los pacientes con una saturación de oxígeno superior al 92% se asignaron a tres grupos: el grupoA recibió N-acetilcisteína, el grupoB recibió bromhexina y el grupoC recibió atención estándar. Los seguimientos de los niveles de oxígeno, los síntomas y las necesidades de hospitalización se realizaron los días7 y 14, con pacientes hospitalizados monitorizados durante un mes después de la hospitalización. Resultados El estudio encontró que tanto la N-acetilcisteína como la bromhexina pueden reducir efectivamente las tasas de hospitalización y la mortalidad y acortar la duración de la hospitalización... (AU)
Introduction and aim Since its emergence in December 2019, the coronavirus disease caused by the severe acute respiratory syndrome coronavirus2 has become a global emergency, spreading rapidly worldwide. In response to the early referral of these patients to outpatient health centers, we decided to seek more effective treatments in the early stages of their referral. This study aims to prevent both the progression and deterioration of the physical conditions of COVID-19 patients, reduce the rate of referrals, and mitigate the risks of hospitalization and death. Material and methods Conducted at Dibaj Therapeutic Center, Hamadan City, Iran, a double-blind randomized controlled trial encompassed 225 COVID-19 patients from April to September 2022. Ethical approval was obtained from Hamadan University of Medical Sciences (Approval No.: IR.UMSHA.REC.1400.957), with the protocol registered in the Iranian Registry of Clinical Trials (Registration No.: IRCT20220302054167N1). In this study, we included patients who tested positive for COVID-19 PCR and were symptomatic, excluding those who were pregnant or had received a COVID-19 vaccine. Patients with oxygen saturation above 92% were allocated to three groups: GroupA received N-acetylcysteine, GroupB received Bromhexine, and GroupC received standard care. Follow-ups on oxygen levels, symptoms, and hospitalization needs were conducted on days 7 and 14, with hospitalized patients monitored for one month post-hospitalization. Results The study found that both N-acetylcysteine and Bromhexine can effectively reduce hospitalization rates and mortality and shorten the duration of hospitalization. The third visit of patients who received N-acetylcysteine showed an increase of 1.33% in oxygen saturation compared to their first visit, and in patients who received Bromhexine, this increase was 1.19%. The mortality rate was 9.33% in the control group and zero in both groups of patients who received medication... (AU)
Asunto(s)
Humanos , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , /tratamiento farmacológico , Infecciones por Coronavirus , Acetilcisteína/farmacología , Bromhexina/farmacologíaRESUMEN
INTRODUCTION AND AIM: Since its emergence in December 2019, the coronavirus disease caused by the severe acute respiratory syndrome coronavirus 2 has become a global emergency, spreading rapidly worldwide. In response to the early referral of these patients to outpatient health centers, we decided to seek more effective treatments in the early stages of their referral. This study aims to prevent both the progression and deterioration of the physical conditions of COVID-19 patients, reduce the rate of referrals, and mitigate the risks of hospitalization and death. MATERIAL AND METHODS: Conducted at Dibaj Therapeutic Center, Hamadan City, Iran, a double-blind randomized controlled trial encompassed 225 COVID-19 patients from April to September 2022. Ethical approval was obtained from Hamadan University of Medical Sciences (Approval No.: IR.UMSHA.REC.1400.957), with the protocol registered in the Iranian Registry of Clinical Trials (Registration No. : IRCT20220302054167N1). In this study, we included patients who tested positive for COVID-19- PCR and were symptomatic, excluding those who were pregnant or had received a COVID-19 vaccine. Patients with oxygen saturation above 92% were allocated to three groups: Group A received N-acetylcysteine, Group B received Bromhexine, and Group C received standard care. Follow-ups on oxygen levels, symptoms, and hospitalization needs were conducted on days 7 and 14, with hospitalized patients monitored for one month post-hospitalization. RESULTS: The study found that both N-acetylcysteine and Bromhexine can effectively reduce hospitalization rates and mortality and shorten the duration of hospitalization. The third visit of patients who received N-acetylcysteine showed an increase of 1.33% in oxygen saturation compared to their first visit, and in patients who received Bromhexine, this increase was 1.19%. The mortality rate was 9.33% in the control group and zero in both groups of patients who received medication. CONCLUSION: In conclusion, the results of this study indicate that NAC and bromhexine may be effective in the treatment of patients with positive COVID-19, with a lower hospitalization rate, shorter hospitalization, faster recovery time, and reduced mortality compared to the control group.
Asunto(s)
Bromhexina , COVID-19 , Humanos , Acetilcisteína/uso terapéutico , Pacientes Ambulatorios , Vacunas contra la COVID-19 , Irán , Resultado del Tratamiento , HospitalizaciónRESUMEN
Pseudomonas aeruginosa is an opportunistic pathogen prone to developing drug-resistance and is a major cause of infection for burn patients and patients suffering from cystic fibrosis or are hospitalized in intensive care units. One of the virulence factors of this bacterium is the lipase enzyme that degrades the extracellular matrix of the host tissue and promotes invasion. Bromhexine is a mucolytic drug and has recently been reported to function as a competitive inhibitor of lipase with an IC50 value of 49 µM. In the present study, an attempt was made to identify stronger inhibitors from the ChEMBL database of bioactive compounds, as compared to the reference compound Bromhexine. Following docking and MD simulations, four hit compounds (N1-N4) were selected that showed promising binding modes and low RMSD values indicative of stable protein-ligand complexes. From subsequent binding pose metadynamics (BPMD) simulations, two of these (N2 and N4) stood out as more potent than Bromhexine, displaying stable interactions with residues in the catalytic site of the enzyme. Biological investigations were performed for all four compounds. Among them, the same two hit compounds were found to be the most effective binders with IC50 values of 22.1 and 27.5 µM, respectively; i.e. roughly twice as efficient as the reference Bromhexine. Taken together, our results show that these hits can be promising new candidates to use as leads for the development of drugs targeting the P. aeruginosa lipase enzyme.Communicated by Ramaswamy H. Sarma.
Asunto(s)
Bromhexina , Pseudomonas aeruginosa , Humanos , Lipasa , Simulación del Acoplamiento Molecular , Inhibidores Enzimáticos/farmacología , Simulación de Dinámica MolecularRESUMEN
AIM: To evaluate the efficacy and safety of a combination drug containing ambroxol, guaifenesin, and levosalbutamol, oral solution, versus Ascoril Expectorant, syrup (combination of bromhexine, guaifenesin, and salbutamol) in the treatment of productive cough in adult patients with acute bronchitis. MATERIALS AND METHODS: This open-label, randomized, phase III study included patients with acute bronchitis who had a productive cough with difficulty in sputum expectoration. 244 patients were randomized in a 1:1 ratio and received 10 mL of the study drug or reference drug 3 times daily for 2 weeks. After 7 and 14 days of treatment, the physician evaluated patient's subjective complaints and the efficacy of therapy. The primary endpoint was the proportion of patients with high and very high efficacy. RESULTS: The primary endpoint was reached by 70 (0.5738) patients in the study drug group and 54 (0.4426) in the reference drug group (p=0.04). The intergroup difference was 0.1311 [95% confidence interval: 0.0057; 0.2566]. The lower limit of the 95% confidence interval was above zero, which confirms the superiority of therapy with the study drug over therapy with Ascoril Expectorant. The proportion of patients with a 1-point total score reduction and with complete resolution of all symptoms according to the Modified Cough Relief and Sputum Expectoration Questionnaire after 7 and 14 days was numerically higher in the study drug group versus the reference drug group. There were no statistically significant differences between the groups in the incidence of adverse events. CONCLUSION: The efficacy of a new combination drug containing ambroxol, guaifenesin, and levosalbutamol in the treatment of productive cough in adult patients with acute bronchitis is superior to the efficacy of Ascoril Expectorant. The safety profiles of the study drug and the reference drug were comparable.
Asunto(s)
Ambroxol , Bromhexina , Bronquitis , Guaifenesina , Humanos , Adulto , Guaifenesina/efectos adversos , Tos/tratamiento farmacológico , Tos/etiología , Ambroxol/efectos adversos , Expectorantes/efectos adversos , Albuterol/efectos adversos , Resultado del Tratamiento , Bronquitis/diagnóstico , Bronquitis/tratamiento farmacológico , Bronquitis/inducido químicamente , Bromhexina/efectos adversos , Levalbuterol/uso terapéutico , Combinación de Medicamentos , Enfermedad AgudaRESUMEN
Ambroxol hydrochloride (AMB) and bromhexine hydrochloride (BRO) are classic expectorants and bronchosecretolytic pharmaceuticals. In 2022, both AMB and BRO were recommended by medical emergency department of China to alleviate cough and expectoration for symptoms caused by COVID-19. The reaction characteristics and mechanism of AMB/BRO with chlorine disinfectant in the disinfection process were investigated in this study. The reaction of chlorine with AMB/BRO were well described by a second-order kinetics model, first-order in both AMB/BRO and chlorine. The second order rate reaction constant of AMB and BRO with chlorine at pH 7.0 were 1.15 × 102 M-1s-1 and 2.03 × 102 M-1s-1, respectively. During chlorination, a new class of aromatic nitrogenous disinfection by-products (DBPs) including 2-chloro-4, 6-dibromoaniline and 2, 4, 6-tribromoaniline were identified as the intermediate aromatic DBPs by gas chromatography-mass spectrometry. The effect of chlorine dosage, pH, and contact time on the formation of 2-chloro-4, 6-dibromoaniline and 2, 4, 6-tribromoaniline were evaluated. In addition, it was found that bromine in AMB/BRO were vital bromine source to greatly promote the formation of classic brominated DBPs, with the highest Br-THMs yields of 23.8% and 37.8%, respectively. This study inspired that bromine in brominated organic compounds may be an important bromine source of brominated DBPs.
Asunto(s)
Ambroxol , Bromhexina , COVID-19 , Desinfectantes , Contaminantes Químicos del Agua , Purificación del Agua , Humanos , Desinfección/métodos , Halogenación , Expectorantes , Bromo/química , Cloro/química , Purificación del Agua/métodos , Desinfectantes/análisis , Halógenos , Cloruros , Contaminantes Químicos del Agua/químicaRESUMEN
Itching is an unpleasant sensation on the skin that could negatively impact the quality of life. Over the years, many non-pharmacological and pharmacological approaches have been introduced to mitigate this burdensome condition; However, the effectiveness of these methods remains questioned. Bromhexine, derived from the Adhatoda vasica plant, is a safe drug with minimal side effects. It has been widely used in managing respiratory symptoms over the years. The results of our study revealed that bromhexine has the potential to alleviate acute itch induced by Compound 48/80, a known mast cell destabilizer. According to our findings, bromhexine exerts its antipruritic effects primarily by inhibiting the Transmembrane Protein Serine Protease 2 (TMPRSS2) and, to a lesser extent, by decreasing the activation of the Kynurenine Pathway (KP). We further investigated the KP involvement by administrating 1-Methyl Tryptophan (1-MT), a known indoleamine-2,3-dioxygenase (IDO) inhibitor. 1-MT was found to be effective in reducing the itch itself. Moreover, co-administration of bromhexine and 1-MT resulted in synergistic antipruritic effects, suggesting that KP plays a role in acute itch. To conclude, we have presented for the first time a repositioning of bromhexine as a treatment for acute itch. In addition, we addressed the involvement of TMPRSS2 and KP in this process.
Asunto(s)
Bromhexina , Quinurenina , Ratones , Animales , Quinurenina/metabolismo , Antipruriginosos , Calidad de Vida , Prurito/tratamiento farmacológico , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismoRESUMEN
In this work, two chromatographic methods are developed and validated for the determination of enrofloxacin and bromhexine (BRM) HCl in the presence of two of their specified impurities, ciprofloxacin and BRM impurity C. The suggested chromatographic methods included the use of thin layer chromatography (TLC-densitometry) and high-performance liquid chromatography (HPLC). In case of TLC-densitometry, good separation was achieved by using mobile phase of n.butanol:acetone:water:glacial acetic acid:triethylamine (10:3:1:0.5:0.5, by volume) on silica gel stationary phase at 254-nm detection. The developed HPLC method used BDS HYPERSIL C18 column with a mobile phase of water:acetonitrile:methanol:triflouroacetic acid. A linear gradient elution of 75-10%, 20-50% and 5-40% for water, acetonitrile and methanol, respectively, was applied in 13 min at a flow rate of 1.5 mL min-1. These methods were sufficient to separate the four substances simultaneously, and they are validated as per International Conference on Harmonization guidelines.
Asunto(s)
Cromatografía Líquida de Alta Presión , Cromatografía en Capa Delgada/métodos , Cromatografía Líquida de Alta Presión/métodos , Bromhexina/química , Bromhexina/aislamiento & purificación , Enrofloxacina/química , Enrofloxacina/aislamiento & purificaciónRESUMEN
BACKGROUND: Bromhexine is a potent inhibitor of transmembrane serine protease 2 and appears to have an antiviral effect in controlling influenza and parainfluenza infection; however, its efficacy in COVID-19 is controversial. METHODS: A group of hospitalized patients with confirmed COVID-19 pneumonia were randomized using 1:1 allocation to either standard treatment lopinavir/ritonavir and interferon beta-1a or bromhexine 8 mg four times a day in addition to standard therapy. The primary outcome was clinical improvement within 28 days, and the secondary outcome measures were time to hospital discharge, all-cause mortality, duration of mechanical ventilation, the temporal trend in 2019-nCoV reverse transcription-polymerase chain reaction positivity and the frequency of adverse drug events within 28 days from the start of medication. RESULTS: A total of 111 patients were enrolled in this randomized clinical trial and data from 100 patients (48 patients in the treatment arm and 52 patients in the control arm) were analyzed. There was no significant difference in the primary outcome of this study, which was clinical improvement. There was no significant difference in the average time to hospital discharge between the two arms. There were also no differences observed in the mean intensive care unit stay, frequency of intermittent mandatory ventilation, duration of supplemental oxygenation or risk of death by day 28 noted between the two arms. CONCLUSION: Bromhexine is not an effective treatment for hospitalized patients with COVID-19. The potential prevention benefits of bromhexine in asymptomatic postexposure or with mild infection managed in the community remain to be determined.
Asunto(s)
Bromhexina , COVID-19 , Humanos , SARS-CoV-2 , Bromhexina/uso terapéutico , Resultado del Tratamiento , Alta del PacienteRESUMEN
In March 2020, the World Health Organization (WHO) declared COVID-19 a pandemic, and the spike protein has been reported to be an important drug target for anti-COVID-19 treatment. As such, in this study, we successfully developed a novel electrochemical receptor biosensor by immobilizing the SARS-CoV-2 spike protein and using AuNPs-HRP as an electrochemical signal amplification system. Moreover, the time-current method was used to quantify seven antiviral drug compounds, such as arbidol and chloroquine diphosphate. The results show that the spike protein and the drugs are linearly correlated within a certain concentration range and that the detection sensitivity of the sensor is extremely high. In the low concentration range of linear response, the kinetics of receptor-ligand interactions are similar to that of an enzymatic reaction. Among the investigated drug molecules, bromhexine exhibits the smallest Ka value, and thus, is most sensitively detected by the sensor. Hydroxychloroquine exhibits the largest Ka value. Molecular docking simulations of the spike protein with six small-molecule drugs show that residues of this protein, such as Asp, Trp, Asn, and Gln, form hydrogen bonds with the -OH or -NH2 groups on the branched chains of small-molecule drugs. The electrochemical receptor biosensor can directly quantify the interaction between the spike protein and drugs such as abidor and hydroxychloroquine and perform kinetic studies with a limit of detection 3.3 × 10-20 mol/L, which provides a new research method and idea for receptor-ligand interactions and pharmacodynamic evaluation.
Asunto(s)
Bromhexina , COVID-19 , Nanopartículas del Metal , Humanos , Glicoproteína de la Espiga del Coronavirus/química , Hidroxicloroquina/farmacología , SARS-CoV-2 , Simulación del Acoplamiento Molecular , Cinética , Ligandos , Oro , Antivirales/farmacologíaRESUMEN
Tetracyclines are frequently employed in animal husbandry. Bromhexine is a mucolytic drug that improves the efficacy of tetracyclines. It has been reported that residues of tetracyclines in milk may have negative effects on humans. Two versatile and accurate methods were developed for concurrent analysis of oxytetracycline (OTC) and bromhexine (BR) residues in spiked milk samples. Sample preparation was carefully considered for extraction and cleanup using the ecofriendly chemicals acetic acid, 0.1 N EDTA and ethanol or methanol. The first method was a TLC-densitometric method in which TLC plates previously treated with 10% EDTA (pH 9 with 40% sodium hydroxide) were used as a stationary phase. A solvent mixture of methanol : methylene chloride : 2% aqueous acetic acid (8 : 2 : 0.5, by volume) was the developing system, and detection was carried out at 254 nm. Metformin was used as the internal standard, and linearity was achieved in the ranges of 0.2-10 and 0.04-2 µg per band for OTC and BR, respectively. The second method was a RP-HPLC method; separation was performed on a C18 column using an isocratic mixture of ethanol : 7.5% aqueous acetic acid (70 : 30, v/v). Separation was achieved within 10 minutes, and linearity was proven in the ranges of 0.05-50 and 0.05-30 µg mL-1 for OTC and BR, respectively. Diclofenac sodium was used as an internal standard. The proposed methods were validated in accordance with the FDA Center for Veterinary Medicine guidelines. Moreover, the performance and health and environmental impacts of the methods were evaluated using several greenness metrics, namely, the National Environmental Methods Index (NEMI), modified NEMI, Green Analytical Procedure Index (GAPI), Analytical Eco-Scale and Analytical GREEnness (AGREE) metric approaches. All the obtained results proved the validity of the developed methods concerning its performance and ecological effects. The methods can be used to investigate the presence of OTC residues in various marketed milk samples to maintain public health.
Asunto(s)
Bromhexina , Oxitetraciclina , Humanos , Animales , Oxitetraciclina/análisis , Leche/química , Bromhexina/análisis , Metanol/análisis , Ácido Edético/análisis , Tetraciclinas/análisis , Antibacterianos/análisis , Etanol/análisisRESUMEN
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, â , â ¡, 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, â , â ¡ and S as well as chloride ions in forms 0 to â ¡. 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.
Asunto(s)
Bromhexina , Difracción de Polvo , Análisis Espectral , Comprimidos/química , Difracción de Rayos X , Rayos XRESUMEN
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.
Asunto(s)
Bromhexina , Nanotubos de Carbono , Cobalto/química , Técnicas Electroquímicas , Electrodos , Galvanoplastia , Nanotubos de Carbono/química , Óxidos/químicaRESUMEN
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.
Asunto(s)
Bromhexina , Tratamiento Farmacológico de COVID-19 , Bromhexina/farmacología , Humanos , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus/metabolismo , Internalización del VirusRESUMEN
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.
Asunto(s)
Ambroxol , Bromhexina , Tratamiento Farmacológico de COVID-19 , Enzima Convertidora de Angiotensina 2 , Angiotensinas/metabolismo , Humanos , Unión Proteica , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus/químicaRESUMEN
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.