INTRODUCTION: Studies indicate that chronic treatment with mucoactive drugs may reduce COPD exacerbation rates. This real-world, multicenter, prospective, observational study aimed to determine the effect of long-term mucoactive treatment on exacerbations in patients with COPD in the Czech Republic. METHODS: 452 adult patients on the Czech Multicenter Research Database of COPD with post-bronchodilator FEV1 ≤ 60% of predicted value received standard of care and were followed up for 5 years. For the first 24 months, 81 patients received regular thiol-based mucoactive drugs (77 erdosteine, 4 N-acetylcysteine) at the discretion of the treating physician and 371 patients had no mucoactive treatment (control group). Erdosteine was fully reimbursed, and NAC was partially reimbursed for COPD patients. The annual number/rate of COPD exacerbations over 5 years was monitored. RESULTS: Patients receiving mucoactive treatment for 24 months had a significantly larger reduction from baseline in all exacerbations compared to the control group (- 0.61 vs - 0.18, p = 0.026; - 0.54 vs - 0.09, p = 0.007; - 0.55 vs 0.04, p = 0.005; - 0.67 vs 0.13, p = 0.002; - 0.53 vs 0.10, p = 0.019 in the first to fifth year, respectively). The reduction in moderate exacerbations was also significantly larger in those receiving mucoactive treatment versus no mucoactive treatment. The exacerbation rate was reduced to a greater extent in the subgroups with cough or with stage 3‒4 COPD who received mucoactive treatment but was independent of the use of inhaled corticosteroids (ICS). CONCLUSION: Mucoactive treatment for two years reduced the number of COPD exacerbations (all, moderate) over five years of follow-up. The reduction in exacerbations was more pronounced in patients with cough or with stage 3‒4 COPD but was independent of the use of ICS.

• Keywords
• Chronic obstructive pulmonary disease, Cough, Erdosteine, Exacerbations, Mucoactive,
• MeSH
• Acetylcysteine * therapeutic use   MeSH
• Time Factors MeSH
• Pulmonary Disease, Chronic Obstructive * drug therapy   physiopathology   diagnosis   MeSH
• Expectorants * therapeutic use   MeSH
• Middle Aged MeSH
• Humans MeSH
• Follow-Up Studies MeSH
• Disease Progression MeSH
• Prospective Studies MeSH
• Aged MeSH
• Forced Expiratory Volume MeSH
• Treatment Outcome MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Observational Study MeSH
• Geographicals
• Czech Republic MeSH
• Names of Substances
• Acetylcysteine * MeSH
• Expectorants * MeSH

PURPOSE: Chronic obstructive pulmonary disease (COPD) is a prevalent and preventable condition that typically worsens over time. Acute exacerbations of COPD significantly impact disease progression, underscoring the importance of prevention efforts. This observational study aimed to achieve two main objectives: (1) identify patients at risk of exacerbations using an ensemble of clustering algorithms, and (2) classify patients into distinct clusters based on disease severity. METHODS: Data from portable medical devices were analyzed post-hoc using hyperparameter optimization with Self-Organizing Maps (SOM), Density-Based Spatial Clustering of Applications with Noise (DBSCAN), Isolation Forest, and Support Vector Machine (SVM) algorithms, to detect flare-ups. Principal Component Analysis (PCA) followed by KMeans clustering was applied to categorize patients by severity. RESULTS: 25 patients were included within the study population, data from 17 patients had the required reliability. Five patients were identified in the highest deterioration group, with one clinically confirmed exacerbation accurately detected by our ensemble algorithm. Then, PCA and KMeans clustering grouped patients into three clusters based on severity: Cluster 0 started with the least severe characteristics but experienced decline, Cluster 1 consistently showed the most severe characteristics, and Cluster 2 showed slight improvement. CONCLUSION: Our approach effectively identified patients at risk of exacerbations and classified them by disease severity. Although promising, the approach would need to be verified on a larger sample with a larger number of recorded clinically verified exacerbations.

• Keywords
• COPD, Clustering, Data analysis, Machine learning,
• Publication type
• Journal Article MeSH

The combination of aminophylline and salbutamol is frequently used in clinical practice in the treatment of obstructive lung diseases. While the side effects (including arrhythmias) of the individual bronchodilator drugs were well described previously, the side effects of combined treatment are almost unknown. We aimed to study the arrhythmogenic potential of combined aminophylline and salbutamol treatment in vitro. For this purpose, we used the established atomic force microscopy (AFM) model coupled with cardiac organoids derived from human pluripotent stem cells (hPSC-CMs). We focused on the chronotropic, inotropic, and arrhythmogenic effects of salbutamol alone and aminophylline and salbutamol combined treatment. We used a method based on heart rate/beat rate variability (HRV/BRV) analysis to detect arrhythmic events in the hPSC-CM based AFM recordings. Salbutamol and aminophylline had a synergistic chronotropic and inotropic effect compared to the effects of monotherapy. Our main finding was that salbutamol reduced the arrhythmogenic effect of aminophylline, most likely mediated by endothelial nitric oxide synthase activated by beta-2 adrenergic receptors. These findings were replicated and confirmed using hPSC-CM derived from two cell lines (CCTL4 and CCTL12). Data suggest that salbutamol as an add-on therapy may not only deliver a bronchodilator effect but also increase the cardiovascular safety of aminophylline, as salbutamol reduces its arrhythmogenic potential.

• Keywords
• Aminophylline, Arrhythmogenic effects, Atomic force microscopy, iPSC, Biomechanical properties, Cardiomyocytes, Drug cardiotoxicity, HESC, Pulmonary drug screening, Salbutamol,
• MeSH
• Albuterol * pharmacology   MeSH
• Aminophylline * pharmacology   MeSH
• Bronchodilator Agents pharmacology   MeSH
• Cell Line MeSH
• Myocytes, Cardiac drug effects   metabolism   MeSH
• Humans MeSH
• Microscopy, Atomic Force MeSH
• Pluripotent Stem Cells drug effects   cytology   MeSH
• Arrhythmias, Cardiac * drug therapy   MeSH
• Heart Rate drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Albuterol * MeSH
• Aminophylline * MeSH
• Bronchodilator Agents MeSH

BACKGROUND AND OBJECTIVE: Theophylline has been used for decades in human medicine for its psychostimulant, anti-inflammatory, and bronchodilator effects. Historically, in pulmonary medicine, theophylline has been used in the treatment of obstructive pulmonary diseases such as bronchial asthma (BA) or chronic obstructive pulmonary disease (COPD). This review aims to determine whether theophylline still has its place in the therapy of obstructive pulmonary diseases or whether we can even extend its use to other diagnoses such as atropine-resistant cardiac arrests, apnea of prematurity, or others. Moreover, we also aim to determine if there is a rationale for using low-dose theophylline due to its immunomodulatory and anti-inflammatory effect, or if the future of methylxanthines lies in newly synthesized derivates of theophylline such as bamifylline, or doxofylline. METHODS: The narrative review is based on a literature search of the articles indexed in the PubMed database in 2023. We searched the database since the year 2009 using the MeSH terms "theophylline", "aminophylline", and "methylxanthines" and we included original articles in the English language. KEY CONTENT AND FINDINGS: Theophylline has a number of adverse drug reactions (ADRs), the most serious of which is its effect on the cardiovascular system. It can cause severe arrhythmias or even cardiac arrest when overdosed. On the other hand, there is still a substantial amount of its applications in current clinical practice. CONCLUSIONS: There is considerable controversy associated with its use in current medicine, which can be attributed both to its narrow therapeutic range and its mentioned cardiotoxic effect. Herein, we summarize the current state-of-art of theophylline and its use in human medicine.

• Keywords
• Theophylline, aminophylline, bronchial asthma (BA), chronic obstructive pulmonary disease (COPD), methylxanthines,
• Publication type
• Journal Article MeSH
• Review MeSH

INTRODUCTION: Recently, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) has published an update on the Global Strategy for Prevention, Diagnosis and Management of COPD, introducing a new classification of chronic obstructive pulmonary disease (COPD). Our aim was to assess the prognostic value of the new GOLD classification system in comparison with the previous GOLD classification systems (GOLD stages I-IV and GOLD groups A-D) and the BODE index. METHODS: We used the data of 784 patients with COPD from the Czech Multicenter Research Database of COPD. Patient survival was analyzed with the use of Kaplan-Meier estimate and Cox model of proportional risks. ROC analysis and area under curve (AUC) were used for comparison of GOLD classifications and BODE index. The analyses were performed with the use of software R (version 4.2.0). RESULTS: We analyzed data of 782 patients with complete data on GOLD classifications. The study population comprised 72.9% of men, 89.1% current or former smokers, with a mean age of 66.6 years, a mean BMI of 27.4 and a mean FEV1 44.9% of predicted. Probability of 5-year survival differed by GOLD classification. Application of the 2023 GOLD classification showed increased risk of death in group B (HR 1.82, 95% CI 1.14-2.92; p = 0.013) and in group E (HR 2.48, 95% CI 1.54-3.99; p˂0.001). The ROC analysis showed that the overall prognostic value of the 2023 GOLD classification was similarly weak to previous A-D GOLD classification schemes (AUCs 0.557-0.576) and was lower compared to the GOLD 1-4 system (AUC 0.614) and even lower when compared to the BODE index (AUC 0.715). CONCLUSION: We concluded that the new GOLD classification system has poor prognostic properties and that specific prediction tools (eg, the BODE index) should be used for mortality risk assessment.

• Keywords
• COPD, GOLD classification, mortality, prognosis,
• MeSH
• Pulmonary Disease, Chronic Obstructive * diagnosis   therapy   MeSH
• Risk Assessment MeSH
• Humans MeSH
• Prognosis MeSH
• Disease Progression MeSH
• Proportional Hazards Models MeSH
• Aged MeSH
• Severity of Illness Index MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Aged MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH

Background: Adherence to inhaled medication constitutes a major problem in patients with chronic obstructive pulmonary disease (COPD) globally. However, large studies evaluating adherence in its entirety and capturing a large variety of potentially associated factors are still lacking. Objective: To study both elementary types of adherence to chronic inhaled COPD medication in "real-life" COPD patients and to assess relationships with a wide-ranging spectrum of clinical parameters. Methods: Data from the Czech Multicentre Research Database (CMRD) of COPD, an observational prospective study, were used. Overall adherence (OA) was evaluated with Morisky Medication Adherence Scale (©MMAS-4) and adherence to an application technique (A-ApplT) with the Five Steps Assessment. Mann-Whitney U test, Spearman's correlation, and logistic regression were used to explore relationships between variables. Results: Data of 546 participants (69.6% of all patients from the CMRD) were analyzed. Two-thirds self-reported optimal OA, but only less than one-third demonstrated A-ApplT without any error. OA did not correlate with A-ApplT. Next, better OA was associated with higher education, a higher number of inhalers, a lower rate of exacerbations, poorer lung function, higher degree of upper respiratory tract symptoms (SNOT-22), absence of depressive symptoms, ex-smoking status, regular mouthwash after inhaled corticosteroids (ICS), and flu vaccination. By contrast, better A-ApplT was associated with a lower number of inhalers, better lung function, and regular mouthwash after ICS. Independent predictors of nonoptimal OA included lower degree of education, absence of flu vaccination, anemia, depression, and peptic ulcer history, whereas independent predictors of lower A-ApplT were lower education, absence of regular mouthwash after ICS, and higher COPD Assessment Test score. Conclusions: Parameters associated with OA and A-ApplT differ, and those associated with both adherence domains are sometimes associated inversely. Based on this finding, we understand these as two separate constructs with an overlap.

• Keywords
• COPD, adherence, application technique, compliance, inhalation systems,
• Publication type
• Journal Article MeSH

INTRODUCTION: The concept of phenotyping emerged, reflecting specific clinical, pulmonary and extrapulmonary features of each particular chronic obstructive pulmonary disease (COPD) case. Our aim was to analyze prognostic utility of: "Czech" COPD phenotypes and their most frequent combinations, "Spanish" phenotypes and Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages + groups in relation to long-term mortality risk. METHODS: Data were extracted from the Czech Multicenter Research Database (CMRD) of COPD. Kaplan-Meier (KM) estimates (at 60 months from inclusion) were used for mortality assessment. Survival rates were calculated for the six elementary "Czech" phenotypes and their most frequent and relevant combinations, "Spanish" phenotypes, GOLD grades and groups. Statistically significant differences were tested by Log Rank test. An analysis of factors underlying mortality risk (the role of confounders) has been assessed with the use of classification and regression tree (CART) analysis. Basic factors showing significant differences between deceased and living patients were entered into the CART model. This showed six different risk groups, the differences in risk were tested by a Log Rank test. RESULTS: The cohort (n=720) was 73.1% men, with a mean age of 66.6 years and mean FEV1 44.4% pred. KM estimates showed bronchiectases/COPD overlap (HR 1.425, p=0.045), frequent exacerbator (HR 1.58, p<0.001), cachexia (HR 2.262, p<0.001) and emphysematous (HR 1.786, p=0.015) phenotypes associated with higher mortality risk. Co-presence of multiple phenotypes in a single patient had additive effect on risk; combination of emphysema, cachexia and frequent exacerbations translated into poorest prognosis (HR 3.075; p<0.001). Of the "Spanish" phenotypes, AE CB and AE non-CB were associated with greater risk of mortality (HR 1.787 and 2.001; both p=0.001). FEV1% pred., cachexia and chronic heart failure in patient history were the major underlying factors determining mortality risk in our cohort. CONCLUSION: Certain phenotypes ("Czech" or "Spanish") of COPD are associated with higher risk of death. Co-presence of multiple phenotypes (emphysematous plus cachectic plus frequent exacerbator) in a single individual was associated with amplified risk of mortality.

• Keywords
• chronic obstructive pulmonary disease; COPD, classification and regression tree; CART, cluster, mortality, phenotypes,
• MeSH
• Bronchitis, Chronic * MeSH
• Pulmonary Disease, Chronic Obstructive * diagnosis   MeSH
• Phenotype MeSH
• Humans MeSH
• Disease Progression MeSH
• Prospective Studies MeSH
• Aged MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Geographicals
• Spain MeSH

Cardiac side effects of some pulmonary drugs are observed in clinical practice. Aminophylline, a methylxanthine bronchodilator with documented proarrhythmic action, may serve as an example. Data on the action of aminophylline on cardiac cell electrophysiology and contractility are not available. Hence, this study was focused on the analysis of changes in the beat rate and contraction force of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) and HL-1 cardiomyocytes in the presence of increasing concentrations of aminophylline (10 µM-10 mM in hPSC-CM and 8-512 µM in HL-1 cardiomyocytes). Basic biomedical parameters, namely, the beat rate (BR) and contraction force, were assessed in hPSC-CMs using an atomic force microscope (AFM). The beat rate changes under aminophylline were also examined on the HL-1 cardiac muscle cell line via a multielectrode array (MEA). Additionally, calcium imaging was used to evaluate the effect of aminophylline on intracellular Ca2+ dynamics in HL-1 cardiomyocytes. The BR was significantly increased after the application of aminophylline both in hPSC-CMs (with 10 mM aminophylline) and in HL-1 cardiomyocytes (with 256 and 512 µM aminophylline) in comparison with controls. A significant increase in the contraction force was also observed in hPSC-CMs with 10 µM aminophylline (a similar trend was visible at higher concentrations as well). We demonstrated that all aminophylline concentrations significantly increased the frequency of rhythm irregularities (extreme interbeat intervals) both in hPSC-CMs and HL-1 cells. The occurrence of the calcium sparks in HL-1 cardiomyocytes was significantly increased with the presence of 512 µM aminophylline. We conclude that the observed aberrant cardiomyocyte response to aminophylline suggests an arrhythmogenic potential of the drug. The acquired data represent a missing link between the arrhythmic events related to the aminophylline/theophylline treatment in clinical practice and describe cellular mechanisms of methylxanthine arrhythmogenesis. An AFM combined with hPSC-CMs may serve as a robust platform for direct drug effect screening.

• Keywords
• IPSC, aminophylline, arrhythmogenic effects, atomic force microscopy, cardiomyocytes, drug cardiotoxicity, hESC, methylxanthines,
• Publication type
• Journal Article MeSH