Beatrice Ragnoli

Ambroxol in the 21st century: pharmacological and clinical update

Background: Belonging to the group of expectorants, ambroxol is an active substance with a long history that influences parameters considered to be the basis for the physiological production and the transport of the bronchial mucus. Therefore, ambroxols indication is ‘secretolytic therapy in acute and chronic bronchopulmonary diseases associated with abnormal mucus secretion and impaired mucus transport’. Objective: The aim of this review is to evaluate the pharmacological and clinical data on the mucokinetic compound ambroxol. Methods: The existing database that covers > 40 years of pharmacological research and clinical development was analysed. Only studies with adequate study design were evaluated. Conclusion: Ambroxol is shown to exert several activities: i) secretolytic activity (i.e., promotes mucus clearance, facilitates expectoration, and eases productive cough); ii) anti-inflammatory and antioxidant activity; and iii) a local anaesthetic effect through sodium channel blocking at the level of the cell membrane. The reduction on chronic obstructive pulmonary disease exacerbations is consistent and clinically relevant. The anaesthetic effect is a new pharmacological action that could be beneficial in the management of acute respiratory tract infections. The efficacy and safety of ambroxol is well established.

Usefulness of Exhaled Nitric Oxide and Sputum Eosinophils in the Long-term Control of Eosinophilic Asthma

BACKGROUND The aim of the present study was to treat unstable asthma according to exhaled nitric oxide (eNO) and induced-sputum eosinophils (sEos) levels to assess if this strategy is better than the conventional approach based on symptoms and function to achieve asthma control. METHODS Fourteen patients with mild-to-moderate persistent asthma (6 men, 8 women) were recruited. During the recruitment visit, the patients, previously treated for asthma following Global Initiative for Asthma recommendations, underwent clinical evaluation and pulmonary function tests (PFTs). Then, after 4 weeks of washout from inhaled antiinflammatory treatment, the patients underwent a basal visit performing PFTs, challenge test to methacholine, and determination of eNO and sEos counts. These procedures were repeated after 3, 6, and 12 months while the patients were treated with inhaled steroids in a stepwise fashion according to eNO and sEos values. RESULTS At the end of the study, a significant decrease in eNO and sEos was observed (57.2 +/- 32.8 parts per billion [ppb] vs 22.1 +/- 10.8 ppb, p < 0.01; and 27.1 +/- 27.1% vs 3.7 +/- 3.5%, p < 0.01, respectively). A close correlation (r2 = 0.41, p < 0.01) between the percentage change of eNO and sEos was observed only after 6 months. Patients treated according to the levels of these inflammatory markers had fewer symptoms and fewer exacerbations compared to those the year before when they were conventionally treated. CONCLUSIONS Our results show the usefulness of eNO and sEos for titrating treatment in asthmatic patients in order to achieve better long-term control of the disease. The eNO decrease reflects adequately the reduction of sEos only after 6 months.

Exhaled Nitric Oxide as a Biomarker in COPD and Related Comorbidities

Chronic Obstructive Pulmonary Disease (COPD) is defined as a disease characterized by persistent, progressive airflow limitation. Recent studies have underlined that COPD is correlated to many systemic manifestations, probably due to an underlying pattern of systemic inflammation. In COPD fractional exhaled Nitric Oxide (FeNO) levels are related to smoking habits and disease severity, showing a positive relationship with respiratory functional parameters. Moreover FeNO is increased in patients with COPD exacerbation, compared with stable ones. In alpha-1 antitrypsin deficiency, a possible cause of COPD, FeNO levels may be monitored to early detect a disease progression. FeNO measurements may be useful in clinical setting to identify the level of airway inflammation, per se and in relation to comorbidities, such as pulmonary arterial hypertension and cardiovascular diseases, either in basal conditions or during treatment. Finally, some systemic inflammatory diseases, such as psoriasis, have been associated with higher FeNO levels and potentially with an increased risk of developing COPD. In these systemic inflammatory diseases, FeNO monitoring may be a useful biomarker for early diagnosis of COPD development.

The combined impact of exhaled nitric oxide and sputum eosinophils monitoring in asthma treatment: a prospective cohort study

BACKGROUND Inhaled corticosteroids (ICS) treatment for asthma control is generally focused on lung function and symptoms, but inadequately correlated with airway inflammation. OBJECTIVE To compare asthma control in a group of patients whose treatment was based on fraction of exhaled nitric oxide (FENO) and sputum eosinophils (intervention group) with a group in whom treatment was based on clinical score (control group). Study design and primary outcome: Randomized parallel-group longitudinal 24-month study including 5 visits every 6 months. A combination of asthma exacerbation rate and symptom score at 24 months was the primary outcome. PARTICIPANTS Fourteen patients with eosinophilic asthma per group were included. RESULTS In the intervention group, exacerbation rate/patient/year was reduced at 12 months (0.82) (-73%) and, to a greater extent at 24 months (0.5) (-84%) compared with baseline (3.21, p<0.01). In the control group, a significant reduction in exacerbation rate/patient/year was only observed between month 12 (3.0) and 24 (2.0, -33%, p<0.01). At 24 months, exacerbation rate was lower (-75%) in the intervention (0.5) than in the control group (2.0, p<0.05). Compared with baseline, mean symptom scores at 24 months were reduced in both groups (intervention group: -72%; control group: - 60%), but were lower in the intervention (8.1±1.0, p<0.05; -27%) than in the control group (11±2.6). ICS dose gradually increased in both groups throughout the study, with no between-group differences. CONCLUSION Compared with conventional strategy, longitudinal monitoring of FENO and sputum eosinophils improves eosinophilic asthma control in terms of reduced symptoms and exacerbations without additional increase e in ICS treatment.

Values in Elderly People for Exhaled Nitric Oxide Study.

Ageing population is constantly increasing due to rising life expectancy; consequently, the percentage of the elderly patients with asthma is increasing, as well. Fractional exhaled nitric oxide (FeNO) is a biomarker of lung inflammation, and currently it is widely used in clinical practice for asthma diagnosis and monitoring. Yet, there are no data about normal values of FeNO in patients of more than 65 years of age with normal lung function. The aim of this study was to establish adult FeNO reference values for subjects older than 65 years, according to the international guidelines. FeNO was measured in 303 healthy, nonsmoking adults more than 65 years of age, with normal spirometry values measured using the online single-breath technique. The results were analyzed by chemiluminescent detection. The FeNO levels obtained range from 5.00 to 29.9 ppb, with a mean value of 12.48 ± 2.80 ppb. A significant association of FeNO levels with age (p < 0.05) was observed. There was no difference in FeNO values between men and women unlike what was observed in younger patients. FeNO levels in healthy controls over 65 years of age are influenced by age as in younger adults. However, there is no difference in FeNO values in male and female seniors, in contrast with what was found in younger adults in other studies. These data can be useful for the clinician to interpret the values of FeNO assessed during clinical practice.

LONG-TERM ADJUSTMENT OF STABLE ASTHMA TREATMENT WITH FRACTIONAL EXHALED NITRIC OXIDE AND SPUTUM EOSINOPHILS

Current approaches to control asthma do not involve direct assessment of airway inflammation. The aim of this study is to assess whether the therapeutic adjustments of steroid treatment according to a stepwise algorithm based on sputum Eosinophils (sEos) and fractioned exhaled Nitric Oxide (FeNO) were effective in maintaining the stability of a group of stable asthmatic patients during a twelvemonth follow-up. Fourteen asthmatic patients, treated for asthma according to a previously published protocol, were enrolled in the study. The patients underwent clinical evaluation, pulmonary function tests, measuring of airway hyperresponsiveness to methacholine, and determination of FeNO and sEos at visit 1. These procedures were repeated after 6 and 12 months (Visits 2 and 3, respectively). Symptoms score gradually improved during the study (p=0.008), no changes were observed in the frequency of clinical asthma exacerbations or in airway hyperresponsiveness to methacholine. At the end of the study both sEos and FeNO were significantly improved (p=0.011 and p=0.003, respectively) and at visit 3 the median steroid dose was reduced (p=0.039) in accordance with the improving of symptoms score, FeNO and sEos values. A direct relationship was observed between the difference of FeNO values and the difference of sEos registered between visits 1 and 2 (r2=609, p0.001) and between visits 2 and 3 (r2=646, p<0.001). In conclusion, long-term titration of asthma inhaled steroid treatment based on sEos and FeNO values was able to provide long-term clinical stability and improvement to the asthmatic patients studied, without significant increases in the steroid dose.

Acute respiratory distress following intravenous injection of trichloroethylene

Trichloroethylene (TCE) is an industrial solvent, quite popular as a drug of addiction, that can be obtained legally and easily. Its narcotic effects begin with a state of mild rapture and continue with central nervous system depression (1–2). We report a case of acute and insidious interstitial pneumonia evolving into acute respiratory distress syndrome (ARDS) following intravenous self-injection of TCE, which, after mechanical ventilation and the infusion of N-acetylcysteine (NAC), had a favourable outcome.