Effects of N-Acetylcysteine combined with Ambroxol Hydrochloride on clinical symptoms, CRP, and PCT in children with pneumonia.

OBJECTIVE: This study investigated the effects of N-Acetylcysteine (NAC) combined with Ambroxol Hydrochloride (AH) on clinical symptoms, C-Reactive Protein (CRP), and Procalcitonin (PCT) levels in children with pneumonia. METHODS: A total of 98 children with pneumonia were assigned to the control group and observation group by random number table method. NAC was administered to the observation group and AH was given to the control group. The therapeutic effect was observed, the disappearance time of clinical symptoms and levels of inflammatory factors, lung function parameters, blood gas analysis parameters, and immunoglobulin were measured. The incidence of adverse reactions was statistically analyzed. RESULTS: A higher effective rate was observed in the observation group than in the control group (p < 0.05). Antipyretic time, cough disappearance time, and lung rale disappearance time in the observation group were shorter than those in the control group (p < 0.05). After treatment, CRP and PCT were lower (p < 0.05), FVC, FEV1, and FEV1/FVC were higher, PaCO2 was lower, PaO2 and SaO2 were higher, and IgA, IgG, IgM, and C3 were higher in the observation group than those in the control group (p < 0.05). The incidence of adverse reactions between the two groups was not significantly different (p > 0.05). CONCLUSION: NAC combined with AH is effective in the treatment of pediatric pneumonia by effectively alleviating clinical symptoms, reducing inflammatory factors, and improving lung function and immune function.

Clinical and preclinical insights into high-dose ambroxol therapy for Gaucher disease type 2 and 3: A comprehensive systematic review.

RATIONALE: Gaucher disease (GD), an autosomal recessive lysosomal storage disease, results from GBA1 variants causing glucocerebrosidase (GCase) deficiency. While enzyme replacement therapy (ERT) helps with systemic symptoms, neurological complications in GD2 and GD3 persist due to the blood-brain-barrier (BBB) limiting ERT efficacy. Ambroxol, a BBB-permeable chaperone, enhances GCase activity. Our review explores high-dose ambroxol's therapeutic potential, both preclinical and clinical, in GD2 and GD3. METHODS: PubMed was searched for studies published before March 2023, including clinical, animal, and in vitro studies focusing on the effect of high-dose ambroxol in GD2 and GD3. A narrative synthesis was performed. RESULTS: Nine in vitro, three animal, and eight clinical studies were included, demonstrating varied responses to ambroxol across diverse outcome measures. In vitro and animal studies demonstrated reduced endoplasmatic reticulum stress due to the relocation of GCase from the ER to the lysosomes. In vitro cell lines exhibited varying degrees of increased GCase activity. Clinical trials observed reduced lyso-GL1 levels in plasma (41-89%) and cerebrospinal fluid (CSF) (26-97%), alongside increased GCase activity in GD3 patients. Ambroxol exhibited varying effects on neurological outcomes and development. No severe adverse events were reported. CONCLUSION: High-dose ambroxol shows promise in managing neurological manifestations in GD3, albeit with uncertainties resulting from genetic heterogeneity and variable response. Further clinical trials, are essential for elucidating dosage-response relationships and refining treatment outcomes and strategies for neuronopathic GD.

Beyond the lungs: Exploring diverse applications of bromhexine and ambroxol.

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.

Molecular mechanisms of the ambroxol action in Gaucher disease and GBA1 mutation-associated Parkinson disease.

Glucocerebrosidase (GCase), encoded by the GBA1 gene, is one of the lysosomal enzymes responsible for hydrolyzing the glycosphingolipids. Deficiency in GCase activity (in patients with two defective alleles of GBA1) leads to glucosylceramide storage in lysosomes which in turn results in the development of the Gaucher diseases, a lysosomal storage disorder, while a heterozygous state may be correlated with the GBA1 mutation-associated Parkinson disease. One of the proposed forms of therapy for these two conditions is the use of pharmacological chaperones which work by facilitating the achievement of the correct conformation of abnormally folded enzymes. Several compounds with chaperone activities against GCase have already been tested, one of which turned out to be ambroxol. Studies conducted on the action of this compound have indeed indicated its effectiveness in increasing GCase levels and activity. However, some data have begun to question its activity as a chaperone against certain GCase variants. Then, a number of articles appeared pointing to other mechanisms of action of ambroxol, which may also contribute to the improvement of patients' condition. This paper summarizes the biological mechanisms of action of ambroxol in Gaucher disease and GBA1 mutation-associated Parkinson disease, focused on its activity as a chaperone, modulator of ERAD pathways, inducer of autophagy, and pain reliever in cellular and animal models as well as in patients. The effects of these activities on the reduction of disease markers and symptoms in patients are also discussed. Consideration of all the properties of ambroxol can help in the appropriate choice of therapy and the determination of the effective drug dose.

Mucolytic Drugs Ambroxol and Bromhexine: Transformation under Aqueous Chlorination Conditions.

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.

Cost-effectiveness of ambroxol in the treatment of Gaucher disease type 2.

Objective: Our aim was to compare the costs and efficacy of ambroxol in combination with imiglucerase with the costs and efficacy of imiglucerase only in the treatment of Gaucher disease type 2 (GD2) in the socio-economic settings of the Republic of Serbia, an upper-middle-income European economy. Methods: The perspective of the Serbian Republic Health Insurance Fund was chosen for this study, and the time horizon was 6 years. The main outcomes of the study were quality-adjusted life years gained with ambroxol + imiglucerase and comparator, and direct costs of treatment. The study was conducted through the generation and simulation of the Markov chain model. The model results were obtained after Monte Carlo microsimulation of a sample with 1,000 virtual patients. Results: Treatment with ambroxol in combination with imiglucerase was cost-effective when compared with imiglucerase only and was associated with positive values of net monetary benefit regardless of the onset of the disease. Such beneficial result for ambroxol and imiglucerase combination is primarily driven by the low cost of ambroxol and its considerable clinical effectiveness in slowing the progression of neural complications of GD2. Conclusion: If ambroxol and imiglucerase are used in combination for the treatment of GD2, it is more cost-effective than using imiglucerase alone.

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 ([18F]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.

Rapid and long-lasting efficacy of high-dose ambroxol therapy for neuronopathic Gaucher disease: A case report and literature review.

Gaucher disease (GD) is a lysosomal storage disorder caused by a deficiency in the GBA1-encoded enzyme, ß-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.

Exploring the efficacy and safety of Ambroxol in Gaucher disease: an overview of clinical studies.

Gaucher disease (GD) is mainly caused by glucocerebrosidase (GCase) enzyme deficiency due to genetic variations in the GBA1 gene leading to the toxic accumulation of sphingolipids in various organs, which causes symptoms such as anemia, thrombocytopenia, hepatosplenomegaly, and neurological manifestations. GD is clinically classified into the non-neuronopathic type 1, and the acute and chronic neuronopathic forms, types 2 and 3, respectively. In addition to the current approved GD medications, the repurposing of Ambroxol (ABX) has emerged as a prospective enzyme enhancement therapy option showing its potential to enhance mutated GCase activity and reduce glucosylceramide accumulation in GD-affected tissues of different GBA1 genotypes. The variability in response to ABX varies across different variants, highlighting the diversity in patients' therapeutic outcomes. Its oral availability and safety profile make it an attractive option, particularly for patients with neurological manifestations. Clinical trials are essential to explore further ABX's potential as a therapeutic medication for GD to encourage pharmaceutical companies' investment in its development. This review highlights the potential of ABX as a pharmacological chaperone therapy for GD and stresses the importance of addressing response variability in clinical studies to improve the management of this rare and complex disorder.

The use of Ambroxol for the treatment of Gaucher disease: A systematic review.

Gaucher disease (GD) is a heterogeneous condition requiring tailored treatment approaches. The aim of this systematic review was to synthesise and evaluate current evidence pertaining to the use of Ambroxol for the treatment of GD. Published and unpublished literature databases, conference proceedings and the reference lists of included studies were searched until 23 November 2023. A narrative synthesis was performed. Database search and risk of bias assessment were performed independently by two reviewers. Twenty-one studies (182 patients) were included. The evidence was low in quality. Variable responses to Ambroxol were observed. Response rates were 36% and 55% in two studies reporting on type 1 GD. One study found a 22% response rate in type 2 GD, whereas another study found 29% of patients with type 3 GD reported neurological improvements. No severe adverse events were reported in the literature, with mild and reversible side effects reported. Varying response rates are to be expected (29%-100%) when treating neurological manifestations. Varying degrees of symptomatic improvement for the treatment of GD were noted in the literature. Multidisciplinary team input and clinical judgement are advised to provide personalized treatment of this complex and multi-faceted condition.

Meta-analysis of the efficacy of budesonide and ambroxol hydrochloride inhalation in children with pneumonia and their effects on inflammatory response.

Childhood pneumonia, often caused by acute upper respiratory tract infections or bronchitis, is one of the leading causes of mortality in children. Nebulized inhalation, as a low-risk treatment method, has garnered significant attention. However, its effectiveness and safety remain controversial. In this study, a systematic review of relevant literature on the use of budesonide (BUD) and ambroxol hydrochloride (AMB) inhalation in the treatment of childhood pneumonia was conducted, and a total of 10 articles were included. The meta-analysis revealed an odds ratio (OR) of 1.61 and an I2 value of 0.00 % for the effectiveness of combined BUD and AMB inhalation therapy in children with pneumonia, indicating no heterogeneity among the studies in terms of effectiveness. The OR values for BUD or AMB inhalation in alleviating cough, lung auscultation abnormalities, respiratory distress, body temperature, and cyanosis of the lips in children with pneumonia all favored the combined BUD therapy, showing significant relief of the aforementioned symptoms. However, due to variations in drug dosage and administration methods, high heterogeneity was observed. This study suggested that combined BUD and AMB inhalation therapy has better efficacy in treating childhood pneumonia, and BUD combined with AMB inhalation is more effective in alleviating symptoms such as cough, lung auscultation abnormalities, respiratory distress, normalizing body temperature, and reducing cyanosis of the lips. Nevertheless, further validation is required due to the limited sample size and substantial heterogeneity in the included studies. To sum up, this study provides the first analysis of the efficacy and inflammatory response of BUD and AMB inhalation in children with pneumonia. Future research should aim to verify and clarify these findings, considering the limitations of the existing studies in terms of sample size and heterogeneity.

Characterization of Ambroxol and Its Hydrochloride Salt Crystals by Bromine K-Edge X-Ray Absorption Near-Edge Structure Spectroscopy and X-Ray Crystal Structure Analysis.

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.

Novel Drug Targets and Emerging Pharmacotherapies in Neuropathic Pain.

Neuropathic pain is a debilitating condition characterized by abnormal signaling within the nervous system, resulting in persistent and often intense sensations of pain. It can arise from various causes, including traumatic nerve injury, neuropathy, and certain diseases. We present an overview of current and emerging pharmacotherapies for neuropathic pain, focusing on novel drug targets and potential therapeutic agents. Current pharmacotherapies, including tricyclic antidepressants, gabapentinoids, and serotonin norepinephrine re-uptake inhibitors, are discussed, as are emerging treatments, such as ambroxol, cannabidiol, and N-acetyl-L-cysteine. Additionally, the article highlights the need for further research in this field to identify new targets and develop more effective and targeted therapies for neuropathic pain management.

Structural and dynamics insights into the GBA variants associated with Parkinson's disease.

The GBA1 gene encodes for the lysosomal enzyme glucocerebrosidase (GCase), which maintains glycosphingolipid homeostasis and regulates the autophagy process. Genomic variants of GBA1 are associated with Goucher disease; however, several heterozygous variants of GBA (E326K, T369M, N370S, L444P) are frequent high-risk factors for Parkinson's disease (PD). The underlying mechanism of these variants has been revealed through functional and patient-centered research, but the structural and dynamical aspects of these variants have not yet been thoroughly investigated. In the current study, we used a thorough computational method to pinpoint the structural changes that GBA underwent because of genomic variants and drug binding mechanisms. According to our findings, PD-linked nsSNP variants of GBA showed structural variation and abnormal dynamics when compared to wild-typ. The docking analysis demonstrated that the mutants E326K, N370S, and L444P have higher binding affinities for Ambroxol. Root means square deviation (RMSD), Root mean square fluctuation analysis (RMSF), and MM-GBSA analysis confirmed that the Ambroxol are more stable in the binding site of N370S and L444P, and that their binding affinities are stronger as compared to the wild-type and T369M variants of GBA. The evaluation of hydrogen bonds and the calculation of the free binding energy provided additional evidence in favor of this conclusion. When docked with Ambroxol, GBA demonstrated an increase in binding affinity and catalytic activity. Understanding the therapeutic efficacy and potential against the aforementioned changes in the GBA will be beneficial in order to use more efficient methods for developing novel drugs.Communicated by Ramaswamy H. Sarma.

Prevalence of different virulence factors and their association with antimicrobial resistance among Pseudomonas aeruginosa clinical isolates from Egypt.

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.

The ANeED study - ambroxol in new and early dementia with Lewy bodies (DLB): protocol for a phase IIa multicentre, randomised, double-blinded and placebo-controlled trial.

Background: Currently, there are no disease-modifying pharmacological treatment options for dementia with Lewy bodies (DLB). The hallmark of DLB is pathological alpha-synuclein (aS) deposition. There are growing amounts of data suggesting that reduced aS clearance is caused by failure in endolysosomal and authophagic pathways, as well as and glucocerebrosidase (GCase) dysfunction and mutations in the GCase gene (GBA). The population's studies demonstrated that the incidence of GBA mutations is higher among Parkinson's disease (PD) patients, and carriers of such mutations have a higher risk of developing PD. The incidence of GBA mutations is even higher in DLB and a genome-wide association study (GWAS) confirmed the correlation between GBA mutations and DLB. In vivo experiments have shown that ambroxol (ABX) may increase GCase activity and GCase levels and therefore enhance aS autophagy-lysosome degradation pathways. Moreover, there is an emerging hypothesis that ABX may have an effect as a DLB modifying drug. The aims of the study "Ambroxol in new and early Dementia with Lewy Bodies (ANeED) are to investigate the tolerability, safety and effects of ABX in patients with DLB. Methods: This is a multicentre, phase IIa, double-blinded, randomised and placebo-controlled clinical trial, using a parallel arm design for 18 months' follow-up. The allocation ratio is 1:1 (treatment:placebo). Discussion: The ANeED study is an ongoing clinical drug trial with ABX. The unique, but not fully understood mechanism of ABX on the enhancement of lysosomal aS clearance may be promising as a possible modifying treatment in DLB. Trial Registration: The clinical trial is registered in the international trials register - clinicaltrials.com (NCT0458825) and nationally at the Current Research Information System in Norway (CRISTIN 2235504).

Evaluation of safety and efficacy of inhaled ambroxol in hospitalized adult patients with mucopurulent sputum and expectoration difficulty.

Background: Ambroxol is a widely used mucoactive drug in sputum clearance of respiratory diseases taken orally and by injection. However, there is a paucity of evidence for inhaled ambroxol in sputum clearance. Methods: This study performed a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial at 19 centers in China. Hospitalized adult patients with mucopurulent sputum and expectoration difficulty were recruited. Patients were randomized by 1:1 to receive inhalation of either ambroxol hydrochloride solution 3 mL (22.5 mg) + 0.9% sodium chloride 3 mL or 0.9% sodium chloride 6 mL twice daily for 5 days, with an interval of more than 6 h. The primary efficacy endpoint was the absolute change in the sputum property score after treatment compared to the baseline in the intention-to-treat population. Results: Between 10 April 2018 and 23 November 2020, 316 patients were recruited and assessed for eligibility, of whom 138 who received inhaled ambroxol and 134 who received a placebo were included. Patients who received inhaled ambroxol had a significantly greater decrease in the sputum property score compared with patients who received inhalation of placebo (difference: -0.29; 95% CI: -0.53 to -0.05; p = 0.0215). Compared with the placebo, inhaled ambroxol also significantly reduced more expectoration volume in 24 h (difference: -0.18; 95% CI: -0.34 to -0.03; p = 0.0166). There was no significant difference in the proportion of adverse events between the two groups, and no deaths were reported. Discussion: In hospitalized adult patients with mucopurulent sputum and expectoration difficulty, inhaled ambroxol was safe and effective for sputum clearance compared with a placebo. Clinical trial registration: [https://www.chictr.org.cn/showproj.html?proj=184677], Chinese Clinical Trial Registry [ChiCTR2200066348].

Baicalin/ambroxol hydrochloride combined dry powder inhalation formulation targeting lung delivery for treatment of idiopathic pulmonary fibrosis: Fabrication, characterization, pharmacokinetics, and pharmacodynamics.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and often fatal lung disease caused by multiple factors. Currently, safe, and effective drugs for the treatment of IPF have been extremely scarce. Baicalin (BA) is used to treat pulmonary fibrosis, IPF, chronic obstructive pulmonary disease, and other lung diseases. Ambroxol hydrochloride (AH), a respiratory tract lubricant and expectorant, is often used to treat chronic respiratory diseases, such as bronchial asthma, emphysema, tuberculosis, and cough. The combination of BA and AH can relieve cough and phlegm, improve lung function, and potentially treat IPF and its symptoms. However, given the extremely low solubility of BA, its bioavailability for oral absorptions is also low. AH, on the other hand, has been associated with certain side effects, such as gastrointestinal tract and acute allergic reactions, which limit its applicability. Therefore, an efficient drug delivery system is urgently needed to address the mentioned problems. This study combined BA and AH as model drugs with L-leucine (L-leu) as the excipient to prepare BA/AH dry powder inhalations (BA/AH DPIs) using the co-spray drying method. We the performed modern pharmaceutical evaluation, which includes particle size, differential scanning calorimetry analysis, X-ray diffraction, scanning electron microscope, hygroscopicity, in vitro aerodynamic analysis, pharmacokinetics, and pharmacodynamics. Notably, BA/AH DPIs were found to be advantageous over BA and AH in treating IPF and had better efficacy in improving lung function than did the positive drug pirfenidone. The BA/AH DPI is a promising preparation for the treatment of IPF given its lung targeting, rapid efficacy, and high lung bioavailability.

[Evaluation of the efficacy and safety of a combination drug containing ambroxol, guaifenesin, and levosalbutamol versus a fixed-dose combination of bromhexine/guaifenesin/salbutamol in the treatment of productive cough in adult patients with acute bronchitis].

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.

Repurposing the mucolytic agent ambroxol for treatment of sub-acute and chronic ischaemic stroke.

Ambroxol is a well-known mucolytic expectorant, which has gained much attention in amyotrophic lateral sclerosis, Parkinson's and Gaucher's disease. A specific focus has been placed on ambroxol's glucocerebrosidase-stimulating activity, on grounds that the point mutation of the gba1 gene, which codes for this enzyme, is a risk factor for developing Parkinson's disease. However, ambroxol has been attributed other characteristics, such as the potent inhibition of sodium channels, modification of calcium homeostasis, anti-inflammatory effects and modifications of oxygen radical scavengers. We hypothesized that ambroxol could have a direct impact on neuronal rescue if administered directly after ischaemic stroke induction. We longitudinally evaluated 53 rats using magnetic resonance imaging to examine stroke volume, oedema, white matter integrity, resting state functional MRI and behaviour for 1 month after ischemic stroke onset. For closer mechanistic insights, we evaluated tissue metabolomics of different brain regions in a subgroup of animals using ex vivo nuclear magnetic resonance spectroscopy. Ambroxol-treated animals presented reduced stroke volumes, reduced cytotoxic oedema, reduced white matter degeneration, reduced necrosis, improved behavioural outcomes and complex changes in functional brain connectivity. Nuclear magnetic resonance spectroscopy tissue metabolomic data at 24 h post-stroke proposes several metabolites that are capable of minimizing post-ischaemic damage and that presented prominent shifts during ambroxol treatment in comparison to controls. Taking everything together, we propose that ambroxol catalyzes recovery in energy metabolism, cellular homeostasis, membrane repair mechanisms and redox balance. One week of ambroxol administration following stroke onset reduced ischaemic stroke severity and improved functional outcome in the subacute phase followed by reduced necrosis in the chronic stroke phase.