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BMC Neurology May 2024To date, no disease modifying therapies are available for Parkinson's disease (PD). Since PD is the second most prevalent neurodegenerative disorder, there is a high... (Randomized Controlled Trial)
Randomized Controlled Trial
Study protocol of the GRoningen early-PD Ambroxol treatment (GREAT) trial: a randomized, double-blind, placebo-controlled, single center trial with ambroxol in Parkinson patients with a GBA mutation.
BACKGROUND
To date, no disease modifying therapies are available for Parkinson's disease (PD). Since PD is the second most prevalent neurodegenerative disorder, there is a high demand for such therapies. Both environmental and genetic risk factors play an important role in the etiology and progression of PD. The most common genetic risk factor for PD is a mutation in the GBA1(GBA)-gene, encoding the lysosomal enzyme glucocerebrosidase (GCase). The mucolytic ambroxol is a repurposed drug, which has shown the property to upregulate GCase activity in-vitro and in-vivo. Ambroxol therefore has the potency to become a disease modifying therapy in PD, which was the reason to design this randomized controlled trial with ambroxol in PD patients.
METHODS
This trial is a single-center, double-blind, randomized, placebo-controlled study, including 80 PD patients with a GBA mutation, receiving either ambroxol 1800 mg/day or placebo for 48 weeks. The primary outcome measure is the Unified Parkinson's Disease Rating Scale motor subscore (part III) of the Movement Disorder Society (MDS-UPDRSIII) in the practically defined off-state at 60 weeks (after a 12-week washout period). Secondary outcomes include a 3,4-dihydroxy-6-18F-fluoro-I-phenylalanine ([F]FDOPA) PET-scan of the brain, Magnetic Resonance Imaging (with resting state f-MRI and Diffusion Tensor Imaging), GCase activity, both intra- and extracellularly, sphingolipid profiles in plasma, Montreal Cognitive Assessment (MoCA), quality of life (QoL) measured by the Parkinson's Disease Questionnaire (PDQ-39) and the Non-Motor Symptom Scale (NMSS) questionnaire.
DISCUSSION
Ambroxol up to 1200 mg/day has shown effects on human cerebrospinal fluid endpoints, which supports at least passage of the blood-brain-barrier. The dose titration in this trial up to 1800 mg/day will reveal if this dose level is safe and also effective in modifying the course of the disease.
TRIAL REGISTRATION
NCT05830396. Registration date: March 20, 2023.
Topics: Humans; Ambroxol; Parkinson Disease; Glucosylceramidase; Double-Blind Method; Mutation; Male; Female; Aged; Middle Aged; Treatment Outcome; Expectorants; Adult
PubMed: 38693511
DOI: 10.1186/s12883-024-03629-9 -
Molecular Genetics & Genomic Medicine Apr 2024Gaucher disease (GD) is a lysosomal storage disorder caused by a deficiency in the GBA1-encoded enzyme, β-glucocerebrosidase. Enzyme replacement therapy is ineffective... (Review)
Review
Gaucher disease (GD) is a lysosomal storage disorder caused by a deficiency in the GBA1-encoded enzyme, β-glucocerebrosidase. Enzyme replacement therapy is ineffective for neuronopathic Gaucher disease (nGD). High-dose ambroxol has been administered as an alternative treatment for a group of patients with nGD. However, little is known about the clinical indication and the long-term outcome of patients after ambroxol therapy. We herein report a case of a female patient who presented with a progressive disease of GD type 2 from 11 months of age and had the pathogenic variants of p.L483P (formerly defined as p.L444P) and p.R502H (p.R463H) in GBA1. A combined treatment of imiglucerase with ambroxol started improving the patient's motor activity in 1 week, while it kept the long-lasting effect of preventing the deteriorating phenotype for 30 months. A literature review identified 40 patients with nGD, who had received high-dose ambroxol therapy. More than 65% of these patients favorably responded to the molecular chaperone therapy, irrespective of p.L483P homozygous, heterozygous or the other genotypes. These results highlight the long-lasting effect of ambroxol-based chaperone therapy for patients with an expanding spectrum of mutations in GBA1.
Topics: Humans; Female; Gaucher Disease; Ambroxol; Lysosomal Storage Diseases; Combined Modality Therapy; Molecular Chaperones
PubMed: 38553911
DOI: 10.1002/mgg3.2427 -
EClinicalMedicine Apr 2024Repurposed drugs with host-directed antiviral and immunomodulatory properties have shown promise in the treatment of COVID-19, but few trials have studied combinations...
Early treatment with fluvoxamine, bromhexine, cyproheptadine, and niclosamide to prevent clinical deterioration in patients with symptomatic COVID-19: a randomized clinical trial.
BACKGROUND
Repurposed drugs with host-directed antiviral and immunomodulatory properties have shown promise in the treatment of COVID-19, but few trials have studied combinations of these agents. The aim of this trial was to assess the effectiveness of affordable, widely available, repurposed drugs used in combination for treatment of COVID-19, which may be particularly relevant to low-resource countries.
METHODS
We conducted an open-label, randomized, outpatient, controlled trial in Thailand from October 1, 2021, to June 21, 2022, to assess whether early treatment within 48-h of symptoms onset with combinations of fluvoxamine, bromhexine, cyproheptadine, and niclosamide, given to adults with confirmed mild SARS-CoV-2 infection, can prevent 28-day clinical deterioration compared to standard care. Participants were randomly assigned to receive treatment with fluvoxamine alone, fluvoxamine + bromhexine, fluvoxamine + cyproheptadine, niclosamide + bromhexine, or standard care. The primary outcome measured was clinical deterioration within 9, 14, or 28 days using a 6-point ordinal scale. This trial is registered with ClinicalTrials.gov (NCT05087381).
FINDINGS
Among 1900 recruited, a total of 995 participants completed the trial. No participants had clinical deterioration by day 9, 14, or 28 days among those treated with fluvoxamine plus bromhexine (0%), fluvoxamine plus cyproheptadine (0%), or niclosamide plus bromhexine (0%). Nine participants (5.6%) in the fluvoxamine arm had clinical deterioration by day 28, requiring low-flow oxygen. In contrast, most standard care arm participants had clinical deterioration by 9, 14, and 28 days. By day 9, 32.7% (110) of patients in the standard care arm had been hospitalized without requiring supplemental oxygen but needing ongoing medical care. By day 28, this percentage increased to 37.5% (21). Additionally, 20.8% (70) of patients in the standard care arm required low-flow oxygen by day 9, and 12.5% (16) needed non-invasive or mechanical ventilation by day 28. All treated groups significantly differed from the standard care group by days 9, 14, and 28 (p < 0.0001). Also, by day 28, the three 2-drug treatments were significantly better than the fluvoxamine arm (p < 0.0001). No deaths occurred in any study group. Compared to standard care, participants treated with the combination agents had significantly decreased viral loads as early as day 3 of treatment (p < 0.0001), decreased levels of serum cytokines interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β) as early as day 5 of treatment, and interleukin-8 (IL-8) by day 7 of treatment (p < 0.0001) and lower incidence of post-acute sequelae of COVID-19 (PASC) symptoms (p < 0.0001). 23 serious adverse events occurred in the standard care arm, while only 1 serious adverse event was reported in the fluvoxamine arm, and zero serious adverse events occurred in the other arms.
INTERPRETATION
Early treatment with these combinations among outpatients diagnosed with COVID-19 was associated with lower likelihood of clinical deterioration, and with significant and rapid reduction in the viral load and serum cytokines, and with lower burden of PASC symptoms. When started very soon after symptom onset, these repurposed drugs have high potential to prevent clinical deterioration and death in vaccinated and unvaccinated COVID-19 patients.
FUNDING
Ped Thai Su Phai (Thai Ducks Fighting Danger) social giver group.
PubMed: 38516100
DOI: 10.1016/j.eclinm.2024.102517 -
European Review For Medical and... Feb 2024Clinical pharmacists identified contraindications in two cases concerning the co-administration of cefoperazone and ambroxol hydrochloride injection, prompting a...
BACKGROUND
Clinical pharmacists identified contraindications in two cases concerning the co-administration of cefoperazone and ambroxol hydrochloride injection, prompting a thorough investigation.
CASE PRESENTATION
Clinically, two cases of contraindications for the co-administration of cefoperazone and ambroxol hydrochloride injection were discovered. After the intervention and analysis by clinical pharmacists, the possible reason could be the precipitation of free alkali due to the immediate administration of ambroxol after the infusion of cefoperazone. Clinical pharmacists suggested avoiding the co-administration of the two and recommended flushing the intravenous lines with 5% glucose injection or 0.9% sodium chloride injection during intravenous infusion to prevent direct drug interaction causing precipitation, thereby reducing the occurrence of adverse events. No adverse events occurred after the intervention, and no harm was caused to the patients.
CONCLUSIONS
The co-administration of cefoperazone and ambroxol hydrochloride injection can lead to the precipitation of free alkali, posing a risk of adverse events. Clinical pharmacists' intervention could prevent this interaction. This practice has been shown to be effective, with no subsequent adverse events reported.
Topics: Humans; Pharmacists; Cefoperazone; Ambroxol; Contraindications; Alkalies
PubMed: 38436193
DOI: 10.26355/eurrev_202402_35490 -
Brazilian Journal of Veterinary Medicine 2024Respiratory diseases considerably affect equine athletes, being the second most common cause of poor performance. Among these diseases, fungal pneumonia in horses,...
Respiratory diseases considerably affect equine athletes, being the second most common cause of poor performance. Among these diseases, fungal pneumonia in horses, caused specifically by spp., is relatively rare but potentially fatal. Fungal pneumonia typically affects horses exposed to fungal elements due to environmental factors, immunosuppression, or previous debilitating illnesses. Treatment is complex, with minimal success due to late diagnosis and serious concomitant underlying diseases. The choice of medication depends on the site of infection, the fungal species involved, and financial considerations. This report describes a case of pulmonary aspergillosis diagnosed in a 10-year-old castrated Quarter Horse. Transtracheal lavage revealed fungal elements characteristic of . Treatment with dexamethasone, bromhexine hydrochloride, and itraconazole led to a successful recovery. The diagnosis of equine aspergillosis is challenging because its clinical signs overlap with other respiratory diseases. Fungal infections like aspergillosis are gaining attention in the equine health scene. Early and accurate diagnosis is crucial to avoid unnecessary use of antibiotics and prevent antimicrobial resistance. Furthermore, veterinarians and horse handlers must be aware of the risks of spreading aspergillosis to humans, emphasizing preventative measures and respiratory protection.
PubMed: 38282831
DOI: 10.29374/2527-2179.bjvm004723 -
BMC Chemistry Jan 2024Bromhexine (BR), guaiafenesin (GUF) and salbutamol (SAL) are formulated as Ventocough syrup® (with and without sugar), labeled to contain propyl paraben and sodium...
Bromhexine (BR), guaiafenesin (GUF) and salbutamol (SAL) are formulated as Ventocough syrup® (with and without sugar), labeled to contain propyl paraben and sodium benzoate as inactive ingredients. They are used to make coughing more productive and easier. A crucial element and a major issue in the pharmaceutical industry is the control of organic related impurities to obtain safe and effective treatment. Guaiacol (GUL) is reported to be GUF related impurity that was proved to be extremely toxic (toxic rating class 5), and its use should be banned. In this work, In-Silico study and ADMET estimation were conducted to predict GUL pharmacokinetic properties and its toxicity profile. Additionally, two chromatographic methods were conducted to analyze the studied components along with GUF impurity in the presence of the labeled dosage form excipients. The In-Silico study assured that GUL has oral rat acute toxicity and it is considered to be skin sensitizer. On the other hand, the developed TLC- densitometeric method depended on using a mobile phase mixture of hexane: methylene chloride: triethylamine (5.0:6.0:0.3, by volume) as a developing system. UV-Scanning was performed immediately at 275 nm for SAL, GUF and GUL, while scanning at 310 nm was used for scanning BR. Linearity was established in the ranges of 0.25-4.0, 0.25-4.0, 0.5-8.0 and 0.1-1.6 µg/band for BR, SAL, GUF and GUL, respectively. In the developed HPLC method, separation was performed on X-Bridge® C column (250 × 4.6 mm, 5 μm) using a solvent mixture of 0.05M disodium hydrogen phosphate pH 3 with aqueous phosphoric acid: methanol (containing 0.3%, v/v triethylamine) (40:60, v/v). Detection was done at 225 nm and separation was achieved within 10 min. Linearity was proved in the range of 2-50 µg/mL for the proposed drugs. Validation of the developed methods was done and all the calculated parameters were within the acceptable limits recommended by ICH guidelines. After that, methods were used to examine the potency of the selected marketed dosage forms and concentrations of all drugs were within the acceptable limits. Additionally, complete separation between the studied drugs and the additives were observed. The developed methods can be used during routine quality control analysis of the proposed drugs when the required issues concern on sensitivity, selectivity and analysis time.
PubMed: 38281055
DOI: 10.1186/s13065-024-01122-5 -
Scientific Reports Dec 2023Chronic obstructive pulmonary disease (COPD) is a severe condition that leads to premature mortality and places a significant financial burden on healthcare systems. An... (Meta-Analysis)
Meta-Analysis
Chronic obstructive pulmonary disease (COPD) is a severe condition that leads to premature mortality and places a significant financial burden on healthcare systems. An adjunctive therapy in COPD includes the simultaneous administration of astragalus injection and ambroxol hydrochloride. Despite its widespread use, the effectiveness of this combined approach in COPD treatment has not been systematically evaluated. Thus, we conducted a systematic review and meta-analysis to assess the efficacy of combining astragalus injection with ambroxol hydrochloride as an adjuvant treatment for COPD. Six electronic databases were used to search for relevant randomized controlled trials, and data analysis was conducted using Review Manager 5.4. A total of 14 randomized controlled trials were included, involving 1070 patients who met the criteria. The results of the meta-analysis indicated that the combination of astragalus injection with ambroxol hydrochloride as an adjuvant treatment can improve various clinical parameters in patients with COPD compared to conventional treatment alone. These parameters include the clinical effective rate (OR = 5.44, 95% CI 3.51-8.43, I = 0%), partial pressure of oxygen in artery (MD = 1.12, 95% CI 0.87-1.36, I = 5%), partial pressure of carbon dioxide in artery (MD = - 1.43, 95% CI - 1.65 to - 1.21, I = 0%), forced expiratory volume in one second (MD = 0.30, 95% CI 0.18-0.42, I = 0%), percentage of forced expiratory volume in one second (MD = 16.18, 95% CI 12.60-19.76, I = 82%), forced vital capacity (MD = 0.33, 95% CI 0.21-0.45, I = 36%), hemoglobin (MD = - 16.17, 95% CI - 20.84 to - 11.51, I = 29%), and the ratio of forced expiratory volume in one second to forced vital capacity (MD = 2.51, 95% CI - 0.05 to 5.06, I = 0%). The combination of astragalus injection and ambroxol hydrochloride could be a selection of COPD patients as an adjuvant treatment. However, further validation is required to evaluate the effectiveness of combining astragalus injection and ambroxol hydrochloride as an adjunctive treatment for patients with COPD.
Topics: Humans; Ambroxol; Quality of Life; Pulmonary Disease, Chronic Obstructive
PubMed: 38087032
DOI: 10.1038/s41598-023-49421-6 -
International Journal of Molecular... Nov 2023Ambroxol (ABX), a frequently prescribed secretolytic agent which enhances the ciliary beat frequency (CBF) and ciliary bend angle (CBA, an index of amplitude) by 30%,...
Ambroxol-Enhanced Frequency and Amplitude of Beating Cilia Controlled by a Voltage-Gated Ca Channel, Cav1.2, via pH Increase and [Cl] Decrease in the Lung Airway Epithelial Cells of Mice.
Ambroxol (ABX), a frequently prescribed secretolytic agent which enhances the ciliary beat frequency (CBF) and ciliary bend angle (CBA, an index of amplitude) by 30%, activates a voltage-dependent Ca channel (Ca1.2) and a small transient Ca release in the ciliated lung airway epithelial cells (c-LAECs) of mice. The activation of Ca1.2 alone enhanced the CBF and CBA by 20%, mediated by a pH increase and a [Cl] decrease in the c-LAECs. The increase in pH, which was induced by the activation of the Na-HCO cotransporter (NBC), enhanced the CBF (by 30%) and CBA (by 15-20%), and a decrease in [Cl], which was induced by the Cl release via anoctamine 1 (ANO1), enhanced the CBA (by 10-15%). While a Ca-free solution or nifedipine (an inhibitor of Ca1.2) inhibited 70% of the CBF and CBA enhancement using ABX, Ca1.2 enhanced most of the CBF and CBA increases using ABX. The activation of the Ca1.2 existing in the cilia stimulates the NBC to increase pH and ANO1 to decrease the [Cl] in the c-LAECs. In conclusion, the pH increase and the [Cl] decrease enhanced the CBF and CBA in the ABX-stimulated c-LAECs.
Topics: Animals; Mice; Ambroxol; Calcium; Cells, Cultured; Cilia; Epithelial Cells; Hydrogen-Ion Concentration; Lung; Mice, Inbred CBA
PubMed: 38069298
DOI: 10.3390/ijms242316976 -
Pharmaceutical Research Dec 2023Orodispersible tablets (orally disintegrating tablets, ODTs) have been used in pharmacotherapy for over 20 years since they overcome the problems with swallowing solid...
PURPOSE
Orodispersible tablets (orally disintegrating tablets, ODTs) have been used in pharmacotherapy for over 20 years since they overcome the problems with swallowing solid dosage forms. The successful formula manufactured by direct compression shall ensure acceptable mechanical strength and short disintegration time. Our research aimed to develop ODTs containing bromhexine hydrochloride suitable for registration in accordance with EMA requirements.
METHODS
We examined the performance of five multifunctional co-processed excipients, i.e., F-Melt® C, F-Melt® M, Ludiflash®, Pharmaburst® 500 and Prosolv® ODT G2 as well as self-prepared physical blend of directly compressible excipients. We tested powder flow, true density, compaction characteristics and tableting speed sensitivity.
RESULTS
The manufacturability studies confirmed that all the co-processed excipients are very effective as the ODT formula constituents. We noticed superior properties of both F-Melt's®, expressed by good mechanical strength of tablets and short disintegration time. Ludiflash® showed excellent performance due to low works of plastic deformation, elastic recovery and ejection. However, the tablets released less than 30% of the drug. Also, the self-prepared blend of excipients was found sufficient for ODT application and successfully transferred to production scale. Outcome of the scale-up trial revealed that the tablets complied with compendial requirements for orodispersible tablets.
CONCLUSIONS
We proved that the active ingredient cannot be absorbed in oral cavity and its dissolution profiles in media representing upper part of gastrointestinal tract are similar to marketed immediate release drug product. In our opinion, the developed formula is suitable for registration within the well-established use procedure without necessity of bioequivalence testing.
Topics: Excipients; Drug Compounding; Administration, Oral; Solubility; Tablets
PubMed: 37726407
DOI: 10.1007/s11095-023-03605-x -
Chemical & Pharmaceutical Bulletin 2023Polymorphic crystals of ambroxol, forms I and II, and form A ambroxol hydrochloride crystals were characterized with bromine K-edge X-ray absorption near-edge structure...
Polymorphic crystals of ambroxol, forms I and II, and form A ambroxol hydrochloride crystals were characterized with bromine K-edge X-ray absorption near-edge structure (XANES) spectroscopy and single-crystal X-ray structure analysis. The XANES spectra had unique shapes depending on the crystal forms. Refined single-crystal structures revealed different interatomic interactions around bromine atoms, such as C-H…Br and N-H…Br hydrogen bonds, Br…O halogen bonds, and N-H…π interactions. Differences in these weak interactions could affect the electronic states of the bromines, resulting in differences in the XANES spectra. The results demonstrated that weak non-conventional interatomic interactions could alter the shape of XANES spectra. Hence, the spectra could be used for evaluating polymorphs of active pharmaceutical ingredients.
Topics: X-Rays; Bromine; Ambroxol; X-Ray Absorption Spectroscopy; Hydrochloric Acid
PubMed: 37661380
DOI: 10.1248/cpb.c23-00392