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.

Interventions for the treatment of persistent post-COVID-19 olfactory dysfunction.

BACKGROUND: Olfactory dysfunction is an early and sensitive marker of COVID-19 infection. Although self-limiting in the majority of cases, when hyposmia or anosmia persists it can have a profound effect on quality of life. Little guidance exists on the treatment of post-COVID-19 olfactory dysfunction, however several strategies have been proposed from the evidence relating to the treatment of post-viral anosmia (such as medication or olfactory training). OBJECTIVES: To assess the effects (benefits and harms) of interventions that have been used, or proposed, to treat persisting olfactory dysfunction due to COVID-19 infection. A secondary objective is to keep the evidence up-to-date, using a living systematic review approach.  SEARCH METHODS: The Cochrane ENT Information Specialist searched the Cochrane COVID-19 Study Register; Cochrane ENT Register; CENTRAL; Ovid MEDLINE; Ovid Embase; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished studies. The date of the search was 16 December 2020. SELECTION CRITERIA: Randomised controlled trials including participants who had symptoms of olfactory disturbance following COVID-19 infection. Only individuals who had symptoms for at least four weeks were included in this review. Studies compared any intervention with no treatment or placebo. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. Primary outcomes were the recovery of sense of smell, disease-related quality of life and serious adverse effects. Secondary outcomes were the change in sense of smell, general quality of life, prevalence of parosmia and other adverse effects (including nosebleeds/bloody discharge). We used GRADE to assess the certainty of the evidence for each outcome. MAIN RESULTS: We included one study with 18 participants, which compared the use of a 15-day course of oral steroids combined with nasal irrigation (consisting of an intranasal steroid/mucolytic/decongestant solution) with no intervention. Psychophysical testing was used to assess olfactory function at baseline, 20 and 40 days. Systemic corticosteroids plus intranasal steroid/mucolytic/decongestant compared to no intervention Recovery of sense of smell was assessed after 40 days (25 days after cessation of treatment) using the Connecticut Chemosensory Clinical Research Center (CCCRC) score. This tool has a range of 0 to 100, and a score of ≥ 90 represents normal olfactory function. The evidence is very uncertain about the effect of this intervention on recovery of the sense of smell at one to three months (5/9 participants in the intervention group scored ≥ 90 compared to 0/9 in the control group; risk ratio (RR) 11.00, 95% confidence interval (CI) 0.70 to 173.66; 1 study; 18 participants; very low-certainty evidence). Change in sense of smell was assessed using the CCCRC score at 40 days. This study reported an improvement in sense of smell in the intervention group from baseline (median improvement in CCCRC score 60, interquartile range (IQR) 40) compared to the control group (median improvement in CCCRC score 30, IQR 25) (1 study; 18 participants; very low-certainty evidence). Serious adverse events andother adverse events were not identified in any participants of this study; however, it is unclear how these outcomes were assessed and recorded (1 study; 18 participants; very low-certainty evidence). AUTHORS' CONCLUSIONS: There is very limited evidence available on the efficacy and harms of treatments for persistent olfactory dysfunction following COVID-19 infection. However, we have identified other ongoing trials in this area. As this is a living systematic review we will update the data regularly, as new results become available. For this (first) version of the living review we identified only one study with a small sample size, which assessed systemic steroids and nasal irrigation (intranasal steroid/mucolytic/decongestant). However, the evidence regarding the benefits and harms from this intervention to treat persistent post-COVID-19 olfactory dysfunction is very uncertain.

Anti-inflammatory, expectorant, and antitussive properties of Kyeongok-go in ICR mice.

CONTEXT: Kyeongok-go (KOG) is a traditional mixed herb preparation consisting of Panax ginseng CA Meyer (Araliaceae), Poria cocos Wolf (Polyporaceae), Rehmannia glutinosa (Gaertner) Liboschitz ex Steudel (Orobanchaceae), and honey. Various pharmacological effects of KOG are reported, but the efficacy on respiratory diseases has not been evaluated. OBJECTIVE: The anti-inflammatory, expectorant, and antitussive properties of KOG were examined using animal models of respiratory diseases. MATERIALS AND METHODS: KOG (100, 200, and 400 mg/kg) was orally administered to ICR mice (n = 8) once a day for 11 days. Anti-inflammatory effects of vehicle, xylene, KOG and DEXA (1 mg/kg) were determined by monitoring edoema and redness of treated ears, and measuring the relative and absolute weight of each ear. Expectorant properties of vehicle, KOG and AM (250 mg/kg) were evaluated by observing body surface redness, and the amount of mucous secreted by the trachea. The antitussive potential of vehicle, NH4OH, KOG and TB (50 mg/kg) was evaluated by monitoring changes in the number of coughs (for 6 min). RESULTS: KOG (400 mg/kg) treated mice showed 31.29% and 30.72% (p < 0.01) decreases in the relative and absolute weights of each ear relative to xylene control mice, 39.06% increases (p < 0.01) in TLF OD values relative to intact vehicle control mice, and 59.53% decrease (p < 0.01) in coughing compared to NH4OH control mice. Dose-dependent changes were observed in all experimental models. CONCLUSIONS: KOG may be a potential therapeutic agent for the treatment of various respiratory diseases, particularly those caused by environmental toxins.

Topical Ambroxol 20% for the Treatment of Classical Trigeminal Neuralgia - A New Option? Initial Clinical Case Observations.

BACKGROUND: Trigeminal neuralgia is difficult to treat and shows upregulation of sodium channels. The expectorant ambroxol acts as a strong local anesthetic, about 40 times stronger than lidocaine. It preferentially inhibits the channel subtype Nav 1.8, expressed especially in nociceptive C-fibers. It seemed reasonable to try ambroxol for the treatment with neuropathic facial pain unresponsive to other standard options. MATERIAL AND METHODS: Medical records of patients suffering from classical trigeminal neuralgia (n = 5) and successful pain reduction following topical ambroxol 20% cream in addition to standard treatment are reported. RESULTS: All patients reported pain attacks with pain intensity between 4 and 10 NRS (numeric pain scale). In all cases they could be triggered, 3 patients reported additional spontaneous pain. Attacks were reduced in all 5 patients. Pain reduction achieved following ambroxol 20% cream was 2-8 points (NRS) earliest within 15-30 minutes and lasted for 4-6 hours mostly. This was reproducible in all cases; in one case pain was eliminated after 1 week. No patient reported side effects or skin changes; oral medication was reduced in 2 patients. CONCLUSION: For the first time, a clinically significant pain relief following topical ambroxol 20% cream in patients with trigeminal neuralgia is reported. In view of the positive side effect profile, topical ambroxol for patients with such a highly impaired quality of life should be investigated further as a matter of urgency.

Intraluminal therapy for Helicobacter pylori infection.

BACKGROUND AND AIM: Several strategies have been proposed to increase the eradication rate of Helicobacter pylori. However, the widespread increasing resistance rates to current multiple-dose oral antibiotic therapies call for alternative therapeutic approaches. We aim to develop a novel intraluminal therapy for H. pylori infection (ILTHPI). METHODS: From April 2017 to December 2017, 100 H. pylori-infected treatment-naïve patients with upper abdominal pain or discomfort underwent endoscopic examinations and concomitant ILTHPI, which comprised the control of intragastric pH, the irrigation of gastric mucosal surface with a mucolytic agent, and the application of single-dose medicaments containing antibiotic powders. The safety profiles while conducting ILTHPI and adverse events after ILTHPI were evaluated. The success of eradication was assessed based on the result of the 13 C-urea breath test 6 weeks after ILTHPI. In addition, a patient with successful ILTHPI was reconfirmed by a negative H. pylori stool antigen test four to 6 months after ILTHPI to exclude short-term recurrence. RESULTS: All the 100 enrolled patients completed the ILTHPI with good safety profiles and mild adverse events (6%). Five patients dropped out, and 51 of 95 patients (53.7%) achieved successful eradication immediately after endoscopic examinations. All 51 patients revealed negative stool H. pylori antigen tests four to 6 months after successful ILTHPI. No short-term recurrence was observed. CONCLUSIONS: We have developed a novel therapeutic approach. With the ILTHPI, H. pylori can be eradicated immediately by administrating a single-dose regimen while conducting an endoscopic examination. CLINICAL TRIALS NUMBER: NCT03124420.

COMPARISON OF ISOFLURANE GAS VERSUS A GUAIFENESIN, KETAMINE, AND MEDETOMIDINE CONSTANT-RATE INFUSION FOR MAINTENANCE ANESTHESIA IN AMERICAN BLACK BEARS (URSUS AMERICANUS).

Published anesthetic protocols for captive and free-ranging bears are limited to injectable inductions with maintenance via inhalants or additional injectable boluses. Though common in other species, intravenous (IV) continuous-rate infusions (CRI) using guaifenesin combinations have not been evaluated in ursids. This study evaluated the use of a CRI compared to an inhalant for maintenance anesthesia. Seven healthy American black bears (Ursus americanus) were anesthetized in a crossover design with two different anesthetic maintenance protocols. Bears were immobilized with ketamine (2.02 ± 0.14 mg/kg) and medetomidine (0.04 ± 0.003 mg/kg) for both protocols. The anesthetic maintenance control protocol consisted of isoflurane gas (ISO) started at 2% delivered by endotracheal tube; the experimental protocol consisted of guaifenesin, medetomidine, ketamine (GMK) IV CRI started at 50 mg/kg/hr guaifenesin, 0.01 mg/kg/hr medetomidine, and 1 mg/kg/hr ketamine. Induction and recovery parameters including time to first effect, recumbency, and hands on; duration of maintenance protocol; and time from reversals administered to head up, standing on all four feet, no ataxia, and to fully recovered were recorded and compared between protocols. Heart rate, respiratory rate, rectal temperature, blood pressure, end tidal carbon dioxide, and hemoglobin oxygen saturation were recorded at 5-min intervals and compared between protocols. Venous blood gases were obtained at the start, middle, and end of the maintenance anesthesia and compared between protocols. All bears exhibited hypertension with mild respiratory acidosis throughout procedures. Measured physiologic parameters did not differ significantly between the isoflurane and the GMK CRI maintenance protocols, with the exception of higher endpoint (ISO) pCO2 measurements. No adverse events were recorded with either protocol, and adequate depth of anesthesia was maintained with both protocols. GMK CRI provides a safe, effective, and more portable alternative to inhalant anesthetics for maintenance anesthesia in bears in captivity or in the field.

The therapeutic efficacy of high-dose ambroxol and the nursing effects in the treatment of severe pneumonia.

To observe and analyze the therapeutic efficacy of high-dose ambroxol in the treatment of severe pneumonia, as well as summarize the nursing methods. A total of 180 patients diagnosed with severe pneumonia and treated at our hospital who were enrolled. The patients were divided into a control group and are search group, with 90 patients in each group. Of those, patients in the research group were treated with high-doses ambroxol, while small-dose ambroxol was administered to patients in the control group. The therapeutic efficacy was compared between both groups. Meanwhile, predictive nursing regimens were applied on patients in the research group, while routine nursing care was given to patients in the control group. The nursing satisfaction was compared between both groups. By comparing the pulmonary function indicators, Comparison of procalcitonin (PCT) and C-reactive protein (CRP) results showed that all indicators of the research group were obviously better than those of the control group (p<0.05). The time of infection control, ICU stay and hospital stay of the research group were significantly less than those of the control group (p<0.05). Moreover, the overall nursing satisfaction of the research group was significantly higher than that of the control group (p<0.05).Application of high-dose ambroxol and scientific nursing methods could significantly improve the therapeutic efficacy in the treatment of severe pneumonia and gain favorable nursing satisfaction.

Impact of PEGylation on the mucolytic activity of recombinant human deoxyribonuclease I in cystic fibrosis sputum.

Highly viscous mucus and its impaired clearance characterize the lungs of patients with cystic fibrosis (CF). Pulmonary secretions of patients with CF display increased concentrations of high molecular weight components such as DNA and actin. Recombinant human deoxyribonuclease I (rhDNase) delivered by inhalation cleaves DNA filaments contained in respiratory secretions and thins them. However, rapid clearance of rhDNase from the lungs implies a daily administration and thereby a high therapy burden and a reduced patient compliance. A PEGylated version of rhDNase could sustain the presence of the protein within the lungs and reduce its administration frequency. Here, we evaluated the enzymatic activity of rhDNase conjugated to a two-arm 40 kDa polyethylene glycol (PEG40) in CF sputa. Rheology data indicated that both rhDNase and PEG40-rhDNase presented similar mucolytic activity in CF sputa, independently of the purulence of the sputum samples as well as of their DNA, actin and ions contents. The macroscopic appearance of the samples correlated with the DNA content of the sputa: the more purulent the sample, the higher the DNA concentration. Finally, quantification of the enzymes in CF sputa following rheology measurement suggests that PEGylation largely increases the stability of rhDNase in CF respiratory secretions, since 24-fold more PEG40-rhDNase than rhDNase was recovered from the samples. The present results are considered positive and provide support to the continuation of the research on a long acting version of rhDNase to treat CF lung disease.

Use of N-acetylcysteine plus simethicone to improve mucosal visibility during upper GI endoscopy: a double-blind, randomized controlled trial.

BACKGROUND AND AIM: Upper GI endoscopy (UGE) is essential for the diagnosis of gastrointestinal diseases. Mucus and bubbles may decrease mucosal visibility. The use of mucolytics could improve visualization. Our aim was to determine whether premedication with simethicone or simethicone plus N-acetylcysteine is effective in improving visibility during UGE. METHODS: This was a randomized, double-blinded, placebo-controlled trial with 2 control groups: no intervention and water 100 mL (W); and 3 intervention groups: simethicone 200 mg (S); S + N-acetylcysteine (NAC) 500 mg (S+NAC500); and S + NAC 1000 mg (S+NAC1000). The solution was ingested 20 minutes before UGE. Gastric visibility was evaluated in 4 segments with a previously described scale. A score of less than 7 points was defined as adequate visibility (AV). Water volume was used to improve visibility, and adverse reactions were evaluated as a secondary outcome. Multiple group comparison was performed using non-parametric one-way analysis of variance (ANOVA). RESULTS: Two hundred thirty patients were included in the study, 68% female, mean age 49 years. The most common indication for UGE was epigastric pain/dyspepsia (33%). AV was more frequent in the S+NAC500 and S+NAC1000 groups (65% and 67%) compared with no intervention (44%, P = .044) and water (41%, P = .022). The gastric total visibility scale (TVS) was significantly better in the S+NAC500 and S+NAC1000 groups compared with water (P = .03 and P = .008). Simethicone was not different from no intervention and water. S+NAC1000 required less water volume to improve visibility. No adverse reactions from the study drugs were observed. CONCLUSIONS: Premedication with S+NAC500 and S+NAC1000 improves visibility during UGE. The use of simethicone did not show improvements in gastric visibility. TVS was worse in patients using water alone. (Clinical trial registration number: NCT 01653171.).

Erdosteine: Drug exhibiting polypharmacy for the treatment of respiratory diseases.

Mucoactive drugs are commonly used in the treatment of acute respiratory tract diseases, such as lower and acute respiratory infection and chronic bronchitis (CB) or chronic obstructive pulmonary disease (COPD) in which an increased mucus secretion is one of main clinical features. Indeed these drugs are designed to promote secretion clearance and to specifically alter the viscoelastic properties of mucus, restoring an effective mucociliary clearance and reducing broncho-obstructive symptoms. In association with mucolytics, these patients frequently also receive antibiotics to reduce the bacterial load, thus decreasing the release of infectious and pro-inflammatory products. Erdosteine is one of the most used mucoactive agents for the treatment of several respiratory diseases where the overlap of bacterial infection is frequent. Although the effectiveness in the reducing mucus in acute and chronic respiratory disease has been demonstrated for others mucolytic, some of them when given in combination with an antibiotic therapy, could reduce the antibiotic efficacy in some situation. Differently, erdosteine potentiates the antibiotic effect when given in combination with antibiotics. We have reviewed the literature available on both clinical and in vitro studies that have investigated this effect of erdosteine on the effect of antibiotics when used as combined therapy.

A randomized, open-label, crossover study evaluating bioequivalence of two N-acetylcysteine 2% oral solution formulations in healthy subjects
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OBJECTIVE: N-acetylcysteine is a mucolytic agent used to treat bronchopulmonary diseases associated with airway mucus hypersecretion. The bioequivalence of a new oral N-acetylcysteine 2% formulation was evaluated relative to an appropriate reference product. MATERIALS AND METHODS: This open-label, randomized, crossover study assessed the bioequivalence of a new N-acetylcysteine 2% oral solution compared to an approved reference N-acetylcysteine 2% oral solution in healthy subjects in terms of pharmacokinetics, including area under the plasma concentration vs. time curve of N-acetylcysteine plasma concentrations from time 0 to the last measurable sampling time point and the maximum postdose concentration. Bioequivalence was concluded if the 90% confidence intervals for the ratio of the geometric means of the two pharmacokinetic parameters with baseline correction were entirely within the range of 80 - 125%. RESULTS: 46 participants were randomized. The ratios of the geometric means for the test vs. reference treatment, with baseline correction, were 1.0961 (90% confidence interval: 1.0228, 1.1746) for area under the plasma concentration curve of test N-acetylcysteine plasma concentrations and 1.0938 (90% confidence interval: 1.0142, 1.1796) for maximum postdose concentration; both were within the predefined range to demonstrate bioequivalence. Most treatment-emergent adverse events were mild or moderate and not considered study drug related. CONCLUSION: The new N-acetylcysteine 2% oral solution was found to be bioequivalent to the marketed reference formulation. Treatments were generally safe and well tolerated.
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Pharmacokinetics and safety of salbutamol/ambroxol fixed-dose combination granules in healthy Chinese subjects
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OBJECTIVES: The aim of the study was to investigate the pharmacokinetics and tolerability of salbutamol/ambroxol fixed-dose combination granules following single and multiple dosing in healthy Chinese subjects. MATERIALS AND METHODS: This was a randomized, open-label, two-period, one-sequence study (n = 12). Each subject received a single oral dose in period 1 and multiple doses in period 2. Plasma concentrations of these two components were determined using a validated LC-MS/MS method. Adverse events (AEs) were documented throughout the study. Investigators evaluated AEs in terms of frequency, duration, intensity, seriousness, outcome, and relationship to study drugs. RESULTS: Following single dosing, Cmax values were 8.07 ± 1.31 ng/mL and 25.7 ± 6.5 ng/mL for salbutamol and ambroxol, respectively. The corresponding T1/2 values were 8.15 ± 3.13 hours and 9.31 ± 2.27 hours, respectively. Moreover, no statistical differences in the pharmacokinetics of salbutamol and ambroxol in subjects receiving single or multiple dosage were observed. Single- and multiple-dose oral administration of fixed-dose combination granules were safe and well tolerated in healthy Chinese subjects. Drug hypersensitivity syndrome did not occur during our study. CONCLUSION: The pharmacokinetics of salbutamol and ambroxol in the fixed-dose combination granules were not affected by dosing duration, and gender differences seemed to have no effect on the pharmacokinetics of salbutamol and ambroxol after a single dose and multiple doses of the medication.
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Investigation of a potential drug-drug interaction between salbutamol and ambroxol and bioequivalence of a new fixed-dose combination containing these two drugs in healthy Chinese subjects.

OBJECTIVES: The aims of the study were to investigate the potential drug-drug interaction between salbutamol and ambroxol, the bioequivalence of the new fixed-dose combination containing salbutamol and ambroxol compared with co-administration of the two separate formulations, and to describe the safety and tolerability of the fixed-dose combination formulation in healthy Chinese volunteers. MATERIALS AND METHODS: An open-label, single-dose, four-treatment, four-period crossover study for evaluation of drug-drug interaction and bioequivalence (n = 24) was performed. Each participant received salbutamol 4 mg, ambroxol 15 mg, salbutamol 4 mg co-administered with ambroxol 15 mg or fixed-dose combination formulation (salbutamol 4 mg and ambroxol 15 mg). Plasma concentrations of two analytes were determined with the use of validated LC-MS/MS method. Safety and tolerability were assessed by recording adverse events. RESULTS: Co-administration of salbutamol and ambroxol was not associated with a significant influence on single salbutamol or ambroxol pharmacokinetics. After statistical comparisons of log-transformed Cmax and AUC of salbutamol and ambroxol between fixed-dose combination and concomitant treatments, all 90% confidence intervals of geometric mean ratios were within the predefined equivalence range of 80 - 125%. No serious adverse events were reported, and all treatments were safe and well tolerated in Chinese healthy subjects. CONCLUSION: There were no significant drug-drug pharmacokinetic interactions between salbutamol and ambroxol after oral administration. The new formulation was bioequivalent to the co-administration of two drugs in separate dosage forms.
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Observational study on the dispensing of cough syrups to children with acute cough by community pharmacists in France.

BACKGROUND: Over-the-counter medicines may be proposed by pharmacists for children with acute cough. Study objectives were to describe the sociodemographic profile of children who were proposed a cough syrup by a pharmacist, the nature of the cough and type(s) of cough syrup proposed and to assess the evolution of the cough, tolerance and satisfaction with treatment. METHODS: Observational, prospective, longitudinal, multicentre study with 157 pharmacies in France. Children who were proposed a cough syrup by a pharmacist were recruited. Questionnaires were completed by the pharmacists and/or parents at inclusion and by the parents after 5 days of treatment. RESULTS: Four hundred fourteen children were included (mean age: 6.0±2.9 years); 45.9% had a dry and 43.3% a productive cough. 30.4% were proposed an allopathic antitussive syrup, 28.3% an allopathic expectorant syrup and 23.7% a homeopathic syrup. Children with a dry cough were more likely to be given an allopathic antitussive (55.2%) or homeopathic (28.2%) syrup. Children with a productive cough or cough of several days duration were more likely to be given an allopathic expectorant syrup (70.1%). Cough disappearance was more frequent with homeopathic syrups compared to allopathic expectorants (P=0.002), or allopathic antitussives (P=0.042). Adverse events were most common with allopathic antitussive syrups (18.7%) (P<0.001). Two-thirds of parents were satisfied with the treatment their child received. CONCLUSIONS: Pharmacists play an important role in the management of acute cough in children. Homeopathic cough syrups may have an interest in terms of public health.

Management of Non-Cystic Fibrosis Bronchiectasis.

OBJECTIVE: The purpose of this report is to describe the case of a 43-year-old male with asthma who was hospitalized for an exacerbation of non-cystic fibrosis bronchiectasis (NCFB), a chronic lung disease that is characterized by dilation of the airways, persistent cough, chronic sputum production, and recurrent respiratory infections. He was treated with oral and inhaled antibiotics, inhaled bronchodilators, and aggressive airway-clearance techniques including nebulized 7% sodium chloride, flutter valve, and high-frequency chest wall oscillation. SETTINGS: Community pharmacy, nursing facility pharmacy, consultant pharmacy practice. PRACTICE CONSIDERATIONS: As the number of patients diagnosed with NCFB continues to increase, it is crucial to recognize that specific guidance for management of NCFB is warranted, as treatment responses differ from cystic fibrosis bronchiectasis or chronic obstructive pulmonary disease. CONCLUSION: It is important for pharmacists to understand the pharmacologic and nonpharmacologic treatments for NCFB to better assist physicians and patients and improve therapeutic outcomes.

Effect of erdosteine on the rate and duration of COPD exacerbations: the RESTORE study.

Oxidative stress contributes to chronic obstructive pulmonary disease (COPD) exacerbations and antioxidants can decrease exacerbation rates, although we lack data about the effect of such drugs on exacerbation duration.The RESTORE (Reducing Exacerbations and Symptoms by Treatment with ORal Erdosteine in COPD) study was a prospective randomised, double-blind, placebo-controlled study, enrolling patients aged 40-80 years with Global Initiative for Chronic Obstructive Lung Disease stage II/III. Patients received erdosteine 300 mg twice daily or placebo added to usual COPD therapy for 12 months. The primary outcome was the number of acute exacerbations during the study.In the pre-specified intention-to-treat population of 445 patients (74% male; mean age 64.8 years, forced expiratory volume in 1 s 51.8% predicted) erdosteine reduced the exacerbation rate by 19.4% (0.91 versus 1.13 exacerbations·patient-1·year-1 for erdosteine and placebo, respectively; p=0.01), due to an effect on mild events; the reduction in the rate of mild exacerbations was 57.1% (0.23 versus 0.54 exacerbations·patient-1·year-1 for erdosteine and placebo, respectively; p=0.002). No significant difference was observed in the rate of moderate and severe exacerbations (0.68 versus 0.59 exacerbations·patient-1·year-1 for erdosteine and placebo, respectively; p=0.054) despite a trend in favour of the comparison group. Erdosteine decreased the exacerbation duration irrespective of event severity by 24.6% (9.55 versus 12.63 days for erdosteine and placebo, respectively; p=0.023). Erdosteine significantly improved subject and physician subjective severity scores (p=0.022 and p=0.048, respectively), and reduced the use of reliever medication (p<0.001), but did not affect the St George's Respiratory Questionnaire score or the time to first exacerbation.In patients with COPD, erdosteine can reduce both the rate and duration of exacerbations. The percentage of patients with adverse events was similar in both the placebo and erdosteine treatment groups.

Ambroxol effects in glucocerebrosidase and α-synuclein transgenic mice.

OBJECTIVE: Gaucher disease is caused by mutations in the glucocerebrosidase 1 gene that result in deficiency of the lysosomal enzyme glucocerebrosidase. Both homozygous and heterozygous glucocerebrosidase 1 mutations confer an increased risk for developing Parkinson disease. Current estimates indicate that 10 to 25% of Parkinson patients carry glucocerebrosidase 1 mutations. Ambroxol is a small molecule chaperone that has been shown to increase glucocerebrosidase activity in vitro. This study investigated the effect of ambroxol treatment on glucocerebrosidase activity and on α-synuclein and phosphorylated α-synuclein protein levels in mice. METHODS: Mice were treated with ambroxol for 12 days. After the treatment, glucocerebrosidase activity was measured in the mouse brain lysates. The brain lysates were also analyzed for α-synuclein and phosphorylated α-synuclein protein levels. RESULTS: Ambroxol treatment resulted in increased brain glucocerebrosidase activity in (1) wild-type mice, (2) transgenic mice expressing the heterozygous L444P mutation in the murine glucocerebrosidase 1 gene, and (3) transgenic mice overexpressing human α-synuclein. Furthermore, in the mice overexpressing human α-synuclein, ambroxol treatment decreased both α-synuclein and phosphorylated α-synuclein protein levels. INTERPRETATION: Our work supports the proposition that ambroxol should be further investigated as a potential novel disease-modifying therapy for treatment of Parkinson disease and neuronopathic Gaucher disease to increase glucocerebrosidase activity and decrease α-synuclein and phosphorylated α-synuclein protein levels. Ann Neurol 2016;80:766-775.

Bifunctional Drugs for the Treatment of Respiratory Diseases.

Over the last decade, there has been a steady increase in the use of fixed dose combinations for the treatment of a range of diseases, including cancer, AIDS, tuberculosis and other infectious diseases. It is now evident that patients with asthma or chronic obstructive pulmonary disease (COPD) can also benefit from the use of fixed dose combinations, including combinations of a long-acting ß2-agonist (LABA) and an inhaled corticosteroid (ICS), and combinations of LABAs and long-acting muscarinic receptor antagonists (LAMAs). There are now also "triple inhaler" fixed dose combinations (containing a LABA, LAMA and ICS) under development and already being made available in clinical practice, with the first such triple combination having been approved in India. The use of combinations containing drugs with complementary pharmacological actions in the treatment of patients with asthma or COPD has led to the discovery and development of drugs having two different primary pharmacological actions in the same molecule that we have called "bifunctional drugs". In this review we have discussed the state of the art of bifunctional drugs that can be categorized as bifunctional bronchodilators, bifunctional bronchodilator/anti-inflammatory drugs, bifunctional anti-inflammatory drugs and bifunctional mucolytic and anti-inflammatory drugs.

Effects and mechanisms of ambroxol inhalation (Mucosolvan®) in the treatment of neonatal pneumonia.

Neonatal pneumonia is the leading cause of mortality in children aged <5 years. Ambroxol (Mucosolvan®) is a mucolytic and secretolytic drug and belongs to the group of expectorants with anti-oxidative and anti-inflammatory effects. The purpose of the present study was to observe the effects and mechanisms of Mucosolvan ® inhalation on neonatal pneumonia. Between January 2014 and October 2015, a total of 80 newborns with pneumonia were randomly divided into control and observation groups. While the patients in the control group were treated with conventional treatment only, those patients in the observation group were treated with Mucosolvan® in addition to the conventional treatment. The lung function index and serum inflammatory mediators were measured before and after treatment on days 1, 3 and 7. In the observation group, there was a significant increase in the lung function index as compared to the control group. Also, there was a significant decrease observed in the expression of inflammatory factors which in turn activated NF-κB pathway and cell apoptosis. The above findings had shown that Mucosolvan® improved lung function and exhibited good inflammatory response. In addition, we found that Mucosolvan® inhibited cell apoptosis and NF-κB pathway activation and effectively improved pulmonary functions.

Consensus Document on Home Nebulization for Maintenance Treatment of Obstructive Airway Diseases: A Joint Initiative by the National Allergy Asthma Bronchitis Institute (NAABI) and Chest Research Foundation (CRF).

Recent years have seen an increase in the use of nebulizers for delivering maintenance therapy in obstructive airway diseases (OADs) such as asthma and chronic obstructive pulmonary disease (COPD). The probable factors associated with this increase at home are: convenience of drug delivery, technological advances making the nebulizer equipment more efficient and portable, increase in the prevalence of OADs and the ageing population which may impact the optimal use of handheld inhalers such as pressurized metered dose inhalers (pMDIs) and dry powder inhalers (DPIs). Although there is increase in the use of maintenance therapy with nebulization, there has been no such increase in the evidence base available for the appropriate use of nebulizers. The last international guidelines were published in 2001. Hence there is a need to address this knowledge gap especially with the widespread use of home nebulization in India. With this objective, we organized a consensus meeting to address certain critical questions pertaining to the use of nebulizers for maintenance treatment in OADs. This article presents the findings of the consensus panel on the use of maintenance treatment of OADs with nebulization at home.