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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 -
BMC Neurology Feb 2019Currently there are no disease-modifying treatments for Parkinson's disease dementia (PDD), a condition linked to aggregation of the protein α-synuclein in subcortical... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Currently there are no disease-modifying treatments for Parkinson's disease dementia (PDD), a condition linked to aggregation of the protein α-synuclein in subcortical and cortical brain areas. One of the leading genetic risk factors for Parkinson's disease is being a carrier in the gene for β-Glucocerebrosidase (GCase; gene name GBA1). Studies in cell culture and animal models have shown that raising the levels of GCase can decrease levels of α-synuclein. Ambroxol is a pharmacological chaperone for GCase and is able to raise the levels of GCase and could therefore be a disease-modifying treatment for PDD. The aims of this trial are to determine if Ambroxol is safe and well-tolerated by individuals with PDD and if Ambroxol affects cognitive, biochemical, and neuroimaging measures.
METHODS
This is a phase II, single-centre, double-blind, randomized placebo-controlled trial involving 75 individuals with mild to moderate PDD. Participants will be randomized into Ambroxol high-dose (1050 mg/day), low-dose (525 mg/day), or placebo treatment arms. Assessments will be undertaken at baseline, 6-months, and 12-months follow up times. Primary outcome measures will be the Alzheimer's disease Assessment Scale-cognitive subscale (ADAS-Cog) and the ADCS Clinician's Global Impression of Change (CGIC). Secondary measures will include the Parkinson's disease Cognitive Rating Scale, Clinical Dementia Rating, Trail Making Test, Stroop Test, Unified Parkinson's disease Rating Scale, Purdue Pegboard, Timed Up and Go, and gait kinematics. Markers of neurodegeneration will include MRI and CSF measures. Pharmacokinetics and pharmacodynamics of Ambroxol will be examined through plasma levels during dose titration phase and evaluation of GCase activity in lymphocytes.
DISCUSSION
If found effective and safe, Ambroxol will be one of the first disease-modifying treatments for PDD.
TRIAL REGISTRATION
ClinicalTrials.gov NCT02914366, 26 Sep 2016/retrospectively registered.
Topics: Aged; Ambroxol; Brain; Dementia; Double-Blind Method; Female; Humans; Male; Middle Aged; Parkinson Disease; Research Design
PubMed: 30738426
DOI: 10.1186/s12883-019-1252-3 -
Indian Journal of Pharmacology 2015A 53-year-old woman visited her physician complaining of acute breathlessness and productive cough. Her medications included budesonide and formoterol for asthma,...
A 53-year-old woman visited her physician complaining of acute breathlessness and productive cough. Her medications included budesonide and formoterol for asthma, fixed-dose combination aspirin 150 mg + clopidogrel 75 mg + atorvastatin 20 mg for ischemic heart disease. History revealed that she had allergic rhinitis and was hypersensitive to penicillins. The patient was prescribed acebrophylline (ABP). Six hours after ABP therapy she presented with generalized urticarial lesions, swelling of hands, feet, lips and face, suggestive of angioedema. ABP was stopped immediately, and the patient was treated symptomatically. This case was categorized as probable as per standard causality assessment scale.
Topics: Ambroxol; Angioedema; Asthma; Bronchitis; Bronchodilator Agents; Female; Humans; Middle Aged; Theophylline; Treatment Outcome
PubMed: 25878387
DOI: 10.4103/0253-7613.153435 -
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 -
Multidisciplinary Respiratory Medicine 2017Since its introduction to the market in 1963, bromhexine, an over-the-counter drug, has been investigated for its activity in animal models and in humans with diverse... (Review)
Review
Since its introduction to the market in 1963, bromhexine, an over-the-counter drug, has been investigated for its activity in animal models and in humans with diverse respiratory conditions. Bromhexine is a derivate of the plant used in some countries for the treatment of various respiratory diseases. Bromhexine has been found to enhance the secretion of various mucus components by modifying the physicochemical characteristics of mucus. These changes, in turn, increase mucociliary clearance and reduce cough. Principal clinical research studies were primarily developed in an era when stringent methodological approaches and good clinical practices were not developed yet. Clinical studies were conducted mainly in patients with chronic bronchitis and in patients with various respiratory diseases, and demonstrated the efficacy of bromhexine in improving respiratory symptoms. Furthermore, the co-administration of antibiotics with bromhexine amplified the actions of the antibiotic. Although the clinical evidence shows only modest but positive results, bromhexine is indicated for its mucoactive activity. Larger trials with adequate methodology are required to identify when treatment with bromhexine can improve clinical outcomes.
PubMed: 28331610
DOI: 10.1186/s40248-017-0088-1 -
Expert Opinion on Drug Metabolism &... Mar 2019Major unmet needs remain for improved antibiotic treatment in lung infections. While development of new antibiotics is needed to overcome resistance, other approaches to... (Review)
Review
Major unmet needs remain for improved antibiotic treatment in lung infections. While development of new antibiotics is needed to overcome resistance, other approaches to optimize therapy using existing agents are also attractive. Ambroxol induces lung autophagy at human-relevant doses and improves lung levels of several approved antibiotics. Areas covered: This review discusses preclinical and clinical studies of the effects of ambroxol (and its prodrug precursor bromhexine) co-treatment upon levels of antibiotics in lung tissue, sputum, and bronchoalveolar lavage fluid. Expert opinion: Ambroxol co-treatment is associated with significant increases in lung tissue and airway surface fluid levels of a range of antibiotics including beta lactams, glycopeptides, macrolides, nitrofurans, and rifamycins. In most cases, the increased levels are only modest and are insufficient to overcome high-level resistance against that same antibiotic class, and so co-treatment with ambroxol is unlikely to alter clinical outcomes. Additionally, for most antibiotics there is no evidence that outcomes in non-resistant disease are improved by higher drug levels, and there is limited efficacy of co-treatment of antibiotics with ambroxol for most pathogens. The two cases where ambroxol may improve therapy are rifampin-sensitive tuberculosis and non-tuberculous mycobacterial infection, and vancomycin sensitive methicillin resistant Staphylococcus aureus pneumonia.
Topics: Ambroxol; Animals; Anti-Bacterial Agents; Bacterial Infections; Bromhexine; Drug Resistance, Bacterial; Expectorants; Humans; Lung; Lung Diseases; Tissue Distribution
PubMed: 30721101
DOI: 10.1080/17425255.2019.1578748 -
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 -
Clinical Medicine Insights. Ear, Nose... 2019Upper and lower respiratory tract infections are common conditions for which medical advice is sought, and their management relies on the use of prescription and... (Review)
Review
BACKGROUND
Upper and lower respiratory tract infections are common conditions for which medical advice is sought, and their management relies on the use of prescription and over-the-counter (OTC) medicines. Ambroxol, bromhexine, carbocysteine, erdosteine, -acetyl cysteine (NAC), and sobrerol are mucoactive agents for which clinical trials have been conducted, have been awarded well-established status by regulatory authorities, and are available as OTC or prescription products.
OBJECTIVE
To briefly review the evidence-based efficacy and safety of these substances in the therapy of upper respiratory airways infections.
METHODS
We conducted searches in MEDLINE and other databases for clinical trials and reviews done on the efficacy and safety of ambroxol, bromhexine, carbocysteine, erdosteine, NAC, and sobrerol.
RESULTS
Clinical trials have shown that these mucolytics have an important place in the relief of cough symptoms by easing the elimination of mucus. All drugs have shown comparable efficacy in the symptomatic treatment of productive cough, with some shared characteristics and some specific features.
CONCLUSIONS AND RELEVANCE
All mucolytics reviewed have a good safety profile, although some precautions should be taken when using ambroxol and bromhexine, and the use of NAC and carbocysteine should be monitored in special patient groups. Overall, however, the available evidence from randomised, controlled, and observational trials, as well as pragmatic, real-life experience, suggests that these products are useful in the therapy of upper respiratory airways infections, including bronchitis, sinusitis, and rhinosinusitis.
PubMed: 30670922
DOI: 10.1177/1179550618821930 -
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