-
JAMA Neurology Apr 2020Mutations of the glucocerebrosidase gene, GBA1 (OMIM 606463), are the most important risk factor for Parkinson disease (PD). In vitro and in vivo studies have reported... (Clinical Trial)
Clinical Trial
IMPORTANCE
Mutations of the glucocerebrosidase gene, GBA1 (OMIM 606463), are the most important risk factor for Parkinson disease (PD). In vitro and in vivo studies have reported that ambroxol increases β-glucocerebrosidase (GCase) enzyme activity and reduces α-synuclein levels. These observations support a potential role for ambroxol therapy in modifying a relevant pathogenetic pathway in PD.
OBJECTIVE
To assess safety, tolerability, cerebrospinal fluid (CSF) penetration, and target engagement of ambroxol therapy with GCase in patients with PD with and without GBA1 mutations.
INTERVENTIONS
An escalating dose of oral ambroxol to 1.26 g per day.
DESIGN, SETTING, AND PARTICIPANTS
This single-center open-label noncontrolled clinical trial was conducted between January 11, 2017, and April 25, 2018, at the Leonard Wolfson Experimental Neuroscience Centre, a dedicated clinical research facility and part of the University College London Queen Square Institute of Neurology in London, United Kingdom. Participants were recruited from established databases at the Royal Free London Hospital and National Hospital for Neurology and Neurosurgery in London. Twenty-four patients with moderate PD were evaluated for eligibility, and 23 entered the study. Of those, 18 patients completed the study; 1 patient was excluded (failed lumbar puncture), and 4 patients withdrew (predominantly lumbar puncture-related complications). All data analyses were performed from November 1 to December 14, 2018.
MAIN OUTCOMES AND MEASURES
Primary outcomes at 186 days were the detection of ambroxol in the CSF and a change in CSF GCase activity.
RESULTS
Of the 18 participants (15 men [83.3%]; mean [SD] age, 60.2 [9.7] years) who completed the study, 17 (8 with GBA1 mutations and 9 without GBA1 mutations) were included in the primary analysis. Between days 0 and 186, a 156-ng/mL increase in the level of ambroxol in CSF (lower 95% confidence limit, 129 ng/mL; P < .001) was observed. The CSF GCase activity decreased by 19% (0.059 nmol/mL per hour; 95% CI, -0.115 to -0.002; P = .04). The ambroxol therapy was well tolerated, with no serious adverse events. An increase of 50 pg/mL (13%) in the CSF α-synuclein concentration (95% CI, 14-87; P = .01) and an increase of 88 ng/mol (35%) in the CSF GCase protein levels (95% CI, 40-137; P = .002) were observed. Mean (SD) scores on part 3 of the Movement Disorders Society Unified Parkinson Disease Rating Scale decreased (ie, improved) by 6.8 (7.1) points (95% CI, -10.4 to -3.1; P = .001). These changes were observed in patients with and without GBA1 mutations.
CONCLUSIONS AND RELEVANCE
The study results suggest that ambroxol therapy was safe and well tolerated; CSF penetration and target engagement of ambroxol were achieved, and CSF α-synuclein levels were increased. Placebo-controlled clinical trials are needed to examine whether ambroxol therapy is associated with changes in the natural progression of PD.
TRIAL REGISTRATION
ClinicalTrials.gov identifier: NCT02941822; EudraCT identifier: 2015-002571-24.
Topics: Aged; Ambroxol; Glucosylceramidase; Humans; Male; Middle Aged; Mutation; Parkinson Disease; Treatment Outcome
PubMed: 31930374
DOI: 10.1001/jamaneurol.2019.4611 -
Turkish Journal of Medical Sciences Dec 2021Currently there is not an effective antiviral treatment for COVID-19, but a large number of drugs have been evaluated since the beginning of the pandemic, and many of... (Review)
Review
BACKGROUND/AIM
Currently there is not an effective antiviral treatment for COVID-19, but a large number of drugs have been evaluated since the beginning of the pandemic, and many of them have been used for the treatment of COVID-19 despite the preliminary or conflicting results of the clinical trials. We aimed to review and summarize all of the current knowledge on the antivirals for COVID-19
RESULTS
There are 2 main drug groups for SARS-CoV-2: agents that target proteins or RNA of the virus or interfere with proteins or biological processes in the host that support the virus. The main drug groups include inhibitors of viral entry into the human cell (convalescent plasma, monoclonal antibodies, nanobodies, mini proteins, human soluble ACE-2, camostat, dutasteride, proxalutamide, bromhexin, hydroxychloroquine, umifenovir nitazoxanid, niclosamide, lactoferrin), inhibitors of viral proteases (lopinavir/ritonavir, PF-07321332, PF-07304814, GC376), inhibitors of viral RNA (remdesivir, favipiravir, molnupiravir, AT-527, merimepodib, PTC299), inhibitors of host proteins supporting virus (plitidepsin, fluvoxamine, ivermectin), and agents supporting host natural immunity (Interferons).
CONCLUSION
When taking into account the results of all the available laboratory and clinical trials on the subject, monoclonal antibodies seem to be the most effective treatment for COVID-19 at the moment, and high-titer convalescent plasma also could be effective when administered during the early phase of the disease. As lopinavir/ritonavir, hydroxychloroquine, merimepodib, and umifenovir were found to be ineffective in RCTs, they should not be used. Additional studies are needed to define the role of remdesivir, favipiravir, interferons, ivermectin, dutasteride, proxulutamide, fluvoxamine, bromhexine, nitazoxanide, and niclosamid in the treatment of COVID-19. Finally, the results of phase trials are waited to learn whether or not the newer agents such as molnupiravir, PF-07321332, PF-07304814, plitidepsin and AT-527 are effective in the treatment of COVID-19.
Topics: Antiviral Agents; COVID-19; Humans; Immunization, Passive; Pandemics; SARS-CoV-2; COVID-19 Serotherapy; COVID-19 Drug Treatment
PubMed: 34391321
DOI: 10.3906/sag-2106-250 -
Journal of Molecular Structure Jun 2021Bromhexine is an expectorant drug repurposing as a TMPRSS2 inhibitor, which has also been proposed for potential treatment in COVID-19 infection. Multicomponent crystal...
Bromhexine is an expectorant drug repurposing as a TMPRSS2 inhibitor, which has also been proposed for potential treatment in COVID-19 infection. Multicomponent crystal strategy has been applied in bromhexine to improve its poor solubility, which limits its bioavailability and efficacy. A new bromhexine crystal and its fumarate salt crystal have been successfully obtained by slow evaporation technique. Both compounds have been characterized by X-ray single-crystal diffraction, TGA and FT-IR spectroscopy. Hirshfeld surface analysis has been carried out to further quantify the patterns of intermolecular interactions. Compared with bromhexine, the multicomponent crystal with pharmaceutically acceptable conformer of fumaric acid shows improved thermal stability and solubility in water.
PubMed: 36536618
DOI: 10.1016/j.molstruc.2021.130154 -
Maedica Mar 2020Irrational prescribing results produce a negative impact on health and economy of both individuals and society, leading to wastage of resources and widespread health...
Irrational prescribing results produce a negative impact on health and economy of both individuals and society, leading to wastage of resources and widespread health hazards. Outpatients with mild, moderate, and severe COPD were included. Several parameters were noted: patient's age and gender, outpatient (OPD) ID number, date of admission, occupation, h/o smoking, alcohol consumption, etc, disease condition details (duration, gradation as mild, moderate and severe, and co-existing diseases), prescribed medication details (dose, frequency, route of administration, and duration). Drug selection was assessed as per GOLD guidelines, the severity of disease was categorized according to the same guidelines, and medication efficacy was evaluated by treatment outcome according to the modified MRC dyspnoea scale. Inhalation route (36.95%) was the most preferred route of drug administration in this study, followed by the parenteral route (34.34%), and enteral route (28.71%). Adherence to GOLD 2015: All patients (n=400) were categorized to Gold stages I to IV based on the severity of COPD. Amongst these patients, 11 were in stage I, 146 in stage II, 184 in stage III, and 59 in stage IV. The majority of subjects received fixed-dose combination therapy: levocetirizine + montelukast (77%) and least bromhexine + guaiphenesin + terbutaline + menthol (18%). Dyspnoea status was graded from 0 to 4 according to the modified MRC dyspnea scale. Out of the 400 patients, 18 had grade 0, 44 grade 1, 156 grade 2, 133 grade 3, and 49 grade 4. Overall, data from this analysis suggest that adherence to GOLD guidelines does not have a perceivable impact on symptom prevalence, exacerbation rate or lung function. Male sex, asthma and severe co-morbidities as a cerebrovascular insult could be associated with a risk for frequent exacerbations.
PubMed: 32419859
DOI: 10.26574/maedica.2020.15.1.37 -
European Respiratory Review : An... Mar 2021Effective therapeutic interventions for the treatment and prevention of coronavirus disease 2019 (COVID-19) are urgently needed. A systematic review was conducted to...
Effective therapeutic interventions for the treatment and prevention of coronavirus disease 2019 (COVID-19) are urgently needed. A systematic review was conducted to identify clinical trials of pharmacological interventions for COVID-19 published between 1 December 2019 and 14 October 2020. Data regarding efficacy of interventions, in terms of mortality, hospitalisation and need for ventilation, were extracted from identified studies and synthesised qualitatively. In total, 42 clinical trials were included. Interventions assessed included antiviral, mucolytic, antimalarial, anti-inflammatory and immunomodulatory therapies. Some reductions in mortality, hospitalisation and need for ventilation were seen with interferons and remdesivir, particularly when administered early, and with the mucolytic drug, bromhexine. Most studies of lopinavir/ritonavir and hydroxychloroquine did not show significant efficacy over standard care/placebo. Dexamethasone significantly reduced mortality, hospitalisation and need for ventilation standard care, particularly in patients with severe disease. Evidence for other classes of interventions was limited. Many trials had a moderate-to-high risk of bias, particularly in terms of blinding; most were short-term and some included low patient numbers.This review highlights the need for well-designed clinical trials of therapeutic interventions for COVID-19 to increase the quality of available evidence. It also emphasises the importance of tailoring interventions to disease stage and severity for maximum efficacy.
Topics: Antiviral Agents; COVID-19; Clinical Trials as Topic; Hospitalization; Host-Pathogen Interactions; Humans; Immunization, Passive; Respiration, Artificial; SARS-CoV-2; Severity of Illness Index; Treatment Outcome; COVID-19 Drug Treatment; COVID-19 Serotherapy
PubMed: 33731328
DOI: 10.1183/16000617.0384-2020 -
JAMA Network Open Jun 2023Ambroxol was identified as an enhancer of stability and residual activity of several misfolded glucocerebrosidase variants in 2009.
IMPORTANCE
Ambroxol was identified as an enhancer of stability and residual activity of several misfolded glucocerebrosidase variants in 2009.
OBJECTIVES
To assess hematologic and visceral outcomes, biomarker changes, and safety of ambroxol therapy for patients with Gaucher disease (GD) without disease-specific treatment.
DESIGN, SETTING, AND PARTICIPANTS
Patients with GD who could not afford enzyme replacement therapy were enrolled and received oral ambroxol from May 6, 2015, to November 9, 2022, at Xinhua Hospital, affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China. Thirty-two patients with GD (29 with GD type 1, 2 with GD type 3, and 1 with GD intermediate types 2-3) were enrolled. Of those, 28 patients were followed up for longer than 6 months; 4 were excluded due to loss of follow-up. Data analyses were performed from May 2015 to November 2022.
INTERVENTION
An escalating dose of oral ambroxol (mean [SD] dose, 12.7 [3.9] mg/kg/d).
MAIN OUTCOMES AND MEASURES
Patients with GD receiving ambroxol were followed up in a genetic metabolism center. Biomarkers of chitotriosidase activity and glucosylsphingosine level, liver and spleen volumes, and hematologic parameters were measured at baseline and various time points throughout the ambroxol treatment.
RESULTS
A total of 28 patients (mean [SD] age, 16.9 [15.3] years; 15 male patients [53.6%]) received ambroxol for a mean (SD) duration of 2.6 (1.7) years. Two patients with severe symptoms at baseline experienced deterioration of hematologic parameters and biomarkers and were deemed nonresponders; clinical response was observed in the other 26 patients. After 2.6 years of ambroxol treatment, the mean (SD) hemoglobin concentration improved from 10.4 (1.7) to 11.9 (1.7) g/dL (mean [SD], 1.6 [1.7] g/dL; 95% CI, 0.8-2.3 g/dL; P < .001), and the mean (SD) platelet count improved from 69 (25) to 78 (30) × 103/µL (mean [SD], 9 [22] × 103/µL; 95% CI, -2 to 19 × 103/µL; P = .09). The mean (SD) spleen volume decreased from 17.47 (7.18) to 12.31 (4.71) multiples of normal (MN) (mean [SD], -5.16 [5.44] MN; 95% CI, -10.19 to -0.13; P = .04), and the mean (SD) liver volume decreased from 1.90 (0.44) to 1.50 (0.53) MN (mean [SD], -0.39 [0.42] MN; 95% CI, -0.75 to -0.04; P = .03). Biomarker median percentage changes from baseline were -43.1% for chitotriosidase activity (from 14 598 [range, 3849-29 628] to 8312 [range, 1831-16 842] nmol/mL/h; z = -3.413; P = .001) and -34.1% for glucosylsphingosine level (from 251.3 [range, 73.6-944.2] to 165.7 [range, 21.3-764.8] ng/mL; z = -2.756; P = .006). Patients were divided into subgroups according to age when initiating treatment; those who received treatment at a younger age (mean [SD] age, 6.3 [2.7] years) experienced more rapid improvements: hemoglobin concentration increased by 16.5% (from 10.3 [1.5] to 12.0 [1.5] g/dL; mean [SD] change, 1.6 [1.6] g/dL; 95% CI, 0.7-2.5 g/dL; P = .002), and platelet count increased by 12.0% (from 75 [24] to 84 [33] × 103/µL; mean [SD] change, 9 [26] × 103/µL; 95% CI, -5 to 24 × 103/µL; P = .17); whereas chitotriosidase activity decreased by 64.0% (from 15 710 [range, 4092-28 422] to 5658 [range, 1146-16 843] nmol/mL/h; z = -2.803; P = .005), and glucosylsphingosine level decreased by 47.3% (from 248.5 [range, 122.8-674.9] to 131.0 [range, 41.1-448.5] ng/mL; z = -2.385; P = .02). Three of the 28 patients experienced mild and transient adverse events.
CONCLUSIONS AND RELEVANCE
In this case series of ambroxol repurposing among patients with GD, long-term treatment with ambroxol was safe and associated with patient improvement. Improvements in hematologic parameters, visceral volumes, and plasma biomarkers were larger among patients with relatively mild symptoms of GD and patients who received initial treatment at younger ages.
Topics: Humans; Male; Adolescent; Child; Child, Preschool; Gaucher Disease; Ambroxol; China; Biomarkers; Hemoglobins
PubMed: 37342037
DOI: 10.1001/jamanetworkopen.2023.19364 -
European Review For Medical and... Jun 2023Evidence for the mucolytic and expectorant efficacy of intravenous (IV) N-acetylcysteine (NAC) is limited. This study aimed to evaluate in a large, multicenter,... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Evidence for the mucolytic and expectorant efficacy of intravenous (IV) N-acetylcysteine (NAC) is limited. This study aimed to evaluate in a large, multicenter, randomized, controlled, subject, and rater-blinded study whether IV NAC is superior to placebo and non-inferior to ambroxol in improving sputum viscosity and expectoration difficulty.
PATIENTS AND METHODS
A total of 333 hospitalized subjects from 28 centers in China with respiratory disease (such as acute bronchitis, chronic bronchitis and exacerbations, emphysema, mucoviscidosis, and bronchiectasis) and abnormal mucus secretion were randomly allocated in a 1:1:1 ratio to receive NAC 600 mg, ambroxol hydrochloride 30 mg, or placebo as an IV infusion twice daily for 7 days. Mucolytic and expectorant efficacy was assessed by ordinal categorical 4-point scales and analyzed by stratified and modified Mann-Whitney U statistics.
RESULTS
NAC showed consistent and statistically significant superiority to placebo and non-inferiority to ambroxol in change from baseline to day 7 in both sputum viscosity scores [mean (SD) difference 0.24 (0.763), p<0.001 vs. placebo] and expectoration difficulty score [mean (SD) difference 0.29 (0.783), p=0.002 vs. placebo]. Safety findings confirm the good tolerability profile of IV NAC reported from previous small studies, and no new safety concerns were identified.
CONCLUSIONS
This is the first large, robust study of the efficacy of IV NAC in respiratory diseases with abnormal mucus secretion. It provides new evidence for IV NAC administration in this indication in clinical situations where the IV route is preferred.
Topics: Humans; Acetylcysteine; Expectorants; Ambroxol; Respiration Disorders; Mucus; Double-Blind Method
PubMed: 37318485
DOI: 10.26355/eurrev_202306_32628 -
Frontiers in Bioscience (Landmark... Jan 2022To evaluate the effect of 0.2% ambroxol eye drop on tear secretion and corneal healing on a rabbit dry eye model, and to delineate potential underlying mechanisms.
OBJECTIVE
To evaluate the effect of 0.2% ambroxol eye drop on tear secretion and corneal healing on a rabbit dry eye model, and to delineate potential underlying mechanisms.
MATERIALS AND METHOD
A mixed mechanism dry eye model was created using 12 healthy New Zealand rabbits by excision of the main lacrimal glands, Harderian gland and nictitating membrane. Establishment of the model was confirmed by the decrease of Schirmer I and increase of corneal fluorescein staining scores. Two weeks after model creation, the rabbits were randomly and evenly divided into NaCl, 0.1% sodium hyaluronate and 0.2% ambroxol groups. Each group was administered the respective eye drops 4 times a day for four weeks. The Schirmer I test and corneal fluorescein staining were performed at two and four weeks. After four weeks of treatment, the animals were sacrificed and the conjunctiva and eyelid specimens collected. Inflammatory factors IL-8, TNF-α, and goblet cell specific mucin MUC5AC were measured by ELISA while the lid meibomian gland was evaluated by oil red O staining.
RESULTS
Compared with the baseline, 2 weeks after the surgery, Schirmer I test value decreased significantly (20.35 ± 5.18 mm/5 min vs 13.95 ± 4.64 mm/5 min, < 0.01), and the fluorescein staining score increased significantly (0.5 ± 0.6 vs 5.5 ± 1.4, 0.01). After four weeks of treatment, compared with the NaCl and sodium hyaluronate groups, tear secretion in ambroxol group increased significantly ( < 0.01), while the corneal fluorescence staining score decreased significantly ( < 0.01). In the conjunctival tissue, significant decrease was seen in TNF-α ( < 0.01) and IL-8 [ (unilateral) < 0.05] concentrations in ambroxol group, and significant increase in MUC5AC concentration ( < 0.01) in ambroxol group as well. The lipid content in the lid meibomian glands appeared increased after the administration of ambroxol.
CONCLUSION
The present rabbit dry eye model study demonstrated potentials of topically administered 0.2% ambroxol in stimulating tear and mucin secretion, inhibiting ocular surface inflammation, promoting corneal healing, and possibly augmenting meibomian gland lipid production.
Topics: Animals; Rabbits; Ambroxol; Cornea; Dry Eye Syndromes; Meibomian Glands; Tears
PubMed: 35090309
DOI: 10.31083/j.fbl2701004 -
Journal of Research in Medical Sciences... 2020Paraquat (PQ) poisoning is characterized by rapidly progressive acute poisoning with high mortality and no specific antidote. Although some clinical studies have been... (Review)
Review
BACKGROUND
Paraquat (PQ) poisoning is characterized by rapidly progressive acute poisoning with high mortality and no specific antidote. Although some clinical studies have been conducted to investigate the benefits of high-dose ambroxol as an adjuvant treatment for PQ poisoning, the efficacy is controversial.
MATERIALS AND METHODS
After searching for relevant articles in English and Chinese databases from 1978 to 2019 according to the keywords (paraquat poisoning/methy viologen/gramoxone, and ambroxol/mucosolvan/Bromhexine), we found seven articles that met our inclusion and exclusion criteria. A meta-analysis was performed using fixed-effects model and random-effects model according to the value in Stata software (version 15.0). Four outcome indicators (hospital mortality, partial pressure of oxygen (PaO), oxygenation index (PaO/FiO), and survival time of the deceased patients) were of interest to us.
RESULTS
The meta-analysis showed that adjuvant treatment with high doses of ambroxol increased PaO (weighted mean difference [WMD] = 13.73 [mmHg], 95% confidence interval [CI]: 8.68-18.79, = 11.80, < 0.001), PaO/FiO (WMD = 38.81 [mmHg], 95% CI: 29.85-47.76, = 8.49, = 0.000), and survival time of the deceased patients (WMD = 2.58 [], 95% CI: 0.97-4.18, = 3.15, = 0.002) compared with usual treatment. Treatment with high doses of ambroxol also appeared to reduce the hospital mortality (relative risk = 0.69, 95% CI: 0.55-0.86, Z = 3.25, = 0.001).
CONCLUSION
This study found that high-dose ambroxol is an effective therapy for PQ poisoning and may reduce the in-hospital mortality.
PubMed: 33088304
DOI: 10.4103/jrms.JRMS_484_19 -
Frontiers in Molecular Biosciences 2021Camostat, nafamostat, and bromhexine are inhibitors of the transmembrane serine protease TMPRSS2. The inhibition of TMPRSS2 has been shown to prevent the viral infection...
Camostat, nafamostat, and bromhexine are inhibitors of the transmembrane serine protease TMPRSS2. The inhibition of TMPRSS2 has been shown to prevent the viral infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other viruses. However, while camostat and nafamostat inhibit TMPRSS2 by forming a covalent adduct, the mode of action of bromhexine remains unclear. TMPRSS2 is autocatalytically activated from its inactive form, zymogen, through a proteolytic cleavage that promotes the binding of Ile256 to a putative allosteric pocket (A-pocket). Computer simulations, reported here, indicate that Ile256 binding induces a conformational change in the catalytic site, thus providing the atomistic rationale to the activation process of the enzyme. Furthermore, computational docking and molecular dynamics simulations indicate that bromhexine competes with the N-terminal Ile256 for the same binding site, making it a potential allosteric inhibitor. Taken together, these findings provide the atomistic basis for the development of more selective and potent TMPRSS2 inhibitors.
PubMed: 33996911
DOI: 10.3389/fmolb.2021.666626