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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 -
JAMA Network Open Jun 2023
Topics: Humans; Ambroxol; Gaucher Disease; Glucosylceramidase; Mutation
PubMed: 37342045
DOI: 10.1001/jamanetworkopen.2023.19336 -
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 -
Italian Journal of Pediatrics Jul 2023To examine the clinical impact of bronchoscope alveolar lavage (BAL) combination with budesonide, ambroxol + budesonide, or acetylcysteine + budesonide in the...
BACKGROUND
To examine the clinical impact of bronchoscope alveolar lavage (BAL) combination with budesonide, ambroxol + budesonide, or acetylcysteine + budesonide in the treatment of refractory Mycoplasma pneumoniae pneumonia (RMPP).
METHODS
Eighty-two RMPP patients admitted to Pediatrics at The First People's Hospital of Zhengzhou were retrospectively evaluated between August 2016 and August 2019. All patients were administered BAL in addition to intravenous Azithromycin, expectoration, and nebulizer inhalation. The medications added to the BLA separated the patients into the Budesonide group, Ambroxol + budesonide group, and acetylcysteine + budesonide group. Analyzed were the variations in laboratory examination indices, improvement in lung imaging, overall effective rate, and adverse responses in the three groups.
RESULTS
The laboratory test indices of patients in all three groups improved significantly relative to pre-treatment levels, and the results were statistically significant. After therapy, there were no significant differences between the three groups in terms of white blood cell (WBC), C-reactive protein (CRP), or erythrocyte sedimentation rate (ESR). Serum lactate dehydrogenase (LDH) and serum ferritin (SF) varied significantly across the three groups (P < 0.05). In the acetylcysteine + budesonide group, the absorption rate of lung imaging lesions and clinical efficacy were superior to those of the other two groups. There were no significant differences between the three groups in the occurrence of adverse events (P > 0.05).
CONCLUSIONS
BLA-coupled acetylcysteine + budesonide was superior to the other two groups in enhancing the effectiveness of RMPP in children, which might increase lung opacity absorption and minimize lung inflammation.
Topics: Child; Humans; Mycoplasma pneumoniae; Acetylcysteine; Retrospective Studies; Budesonide; Ambroxol; Pneumonia, Mycoplasma
PubMed: 37422684
DOI: 10.1186/s13052-023-01491-y -
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 -
BMC Microbiology Jun 2023Emergence of multi-drug resistant Pseudomonas aeruginosa, coupled with the pathogen's versatile virulence factors, lead to high morbidity and mortality rates. The...
BACKGROUND
Emergence of multi-drug resistant Pseudomonas aeruginosa, coupled with the pathogen's versatile virulence factors, lead to high morbidity and mortality rates. The current study investigated the potential association between the antibiotic resistance and the production of virulence factors among P. aeruginosa clinical isolates collected from Alexandria Main University Hospital in Egypt. We also evaluated the potential of the phenotypic detection of virulence factors to reflect virulence as detected by virulence genes presence. The role of alginate in the formation of biofilms and the effect of ambroxol, a mucolytic agent, on the inhibition of biofilm formation were investigated.
RESULTS
A multi-drug resistant phenotype was detected among 79.8% of the isolates. The most predominant virulence factor was biofilm formation (89.4%), while DNase was least detected (10.6%). Pigment production was significantly associated with ceftazidime susceptibility, phospholipase C production was significantly linked to sensitivity to cefepime, and DNase production was significantly associated with intermediate resistance to meropenem. Among the tested virulence genes, lasB and algD showed the highest prevalence rates (93.3% and 91.3%, respectively), while toxA and plcN were the least detected ones (46.2% and 53.8%, respectively). Significant association of toxA with ceftazidime susceptibility, exoS with ceftazidime and aztreonam susceptibility, and plcH with piperacillin-tazobactam susceptibility was observed. There was a significant correlation between alkaline protease production and the detection of algD, lasB, exoS, plcH and plcN; pigment production and the presence of algD, lasB, toxA and exoS; and gelatinase production and the existence of lasB, exoS and plcH. Ambroxol showed a high anti-biofilm activity (5% to 92%). Quantitative reverse transcriptase polymerase chain reaction showed that alginate was not an essential matrix component in P. aeruginosa biofilms.
CONCLUSIONS
High virulence coupled with the isolates' multi-drug resistance to commonly used antimicrobials would increase morbidity and mortality rates among P. aeruginosa infections. Ambroxol that displayed anti-biofilm action could be suggested as an alternative treatment option, yet in vivo studies are required to confirm these findings. We recommend active surveillance of antimicrobial resistance and virulence determinant prevalence for better understanding of coregulatory mechanisms.
Topics: Humans; Virulence Factors; Anti-Bacterial Agents; Pseudomonas aeruginosa; Ceftazidime; Prevalence; Egypt; Ambroxol; Pseudomonas Infections; Drug Resistance, Bacterial; Microbial Sensitivity Tests
PubMed: 37270502
DOI: 10.1186/s12866-023-02897-8 -
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 -
European Review For Medical and... Jun 2023This work aimed to explore the therapeutic effect of micropump intravenous infusion of ambroxol hydrochloride (AH) on respiratory distress syndrome (RDS) in premature... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
This work aimed to explore the therapeutic effect of micropump intravenous infusion of ambroxol hydrochloride (AH) on respiratory distress syndrome (RDS) in premature infants.
PATIENTS AND METHODS
56 premature infants from 28 to 34 weeks were recruited for analysis in this work. According to the treatment methods, they were randomly divided into two groups, with 28 patients in each group. Patients in the experimental group were given intravenous AH by micropump, while those in the control group inhaled atomized AH. The therapeutic effects were evaluated by comparing the data after treatment.
RESULTS
The results showed that the serum 8-iso-PGP2α level in the experimental group was 166.32 ± 49.52, which was substantially inferior to that in the control group (183.32 ± 52.54), p < 0.05. In the experimental group, PaO2, SaO2, and PaO2/FiO2 were 95.88 ± 12.82 mmHg, 95.86 ± 2.27%, and 346.81 ± 51.93 mmHg, respectively, after 7 days of treatment. Compared with the control group (88.21 ± 12.82 mmHg, 93.18 ± 3.13%, and 266.83 ± 48.09 mmHg), the difference was statistically significant, p < 0.05. The oxygen duration, respiratory distress relief time, and length of stay were 95.12 ± 12.53 h, 4.4 ± 0.6 d, and 19.84 ± 2.8 d, respectively, in the experimental group, while they were 145.92 ± 13.85 h, 6.9 ± 0.9 d, and 28.42 ± 3.7 d, respectively, in the control group, showing great differences (p < 0.05).
CONCLUSIONS
Micropump infusion of AH in the treatment of premature RDS patients was more conducive to efficacy. It can alleviate the clinical symptoms of children with RDS, improve their blood gas indicators, relieve and repair the damage to alveolar epithelial cell lipids in children with RDS, and ultimately improve the therapeutic effect, which can be used for the clinical treatment of premature RDS.
Topics: Infant, Newborn; Infant; Female; Child; Humans; Ambroxol; Infusions, Intravenous; Infant, Premature; Respiratory Distress Syndrome, Newborn; Premature Birth
PubMed: 37318484
DOI: 10.26355/eurrev_202306_32627 -
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