Roflumilast tópico y oral en dermatología. Una revisión narrativa / Topical and Oral Roflumilast in Dermatology: A Narrative Review

Roflumilast es un inhibidor de la fosfodiesterasa-4 aprobado de forma oral para la prevención de exacerbaciones en pacientes con enfermedad pulmonar obstructiva crónica y fenotipo de bronquitis crónica. En dermatología, el roflumilast tópico está aprobado por la Food and Drug Administration en psoriasis en placas y dermatitis seborreica leve/moderada. En cuanto a su uso fuera de indicación, hemos encontrado un ensayo clínico que avala la utilidad del roflumilast oral en psoriasis, así como pequeñas series de casos o casos clínicos aislados en hidradenitis supurativa, aftosis oral recurrente, eccema numular, liquen plano y enfermedad de Behçet. Su perfil de seguridad es favorable, similar al del apremilast, y su coste es considerablemente inferior a los de los fármacos de nueva generación, o incluso al de algunos inmunosupresores clásicos. Presentamos una revisión de roflumilast tópico y oral, en términos de farmacocinética y farmacodinámica, efectos adversos, usos dermatológicos aprobados y fuera de indicación. Roflumilast es un agente prometedor en dermatología.(AU)

Oral roflumilast is a phosphodiesterase-4 inhibitor approved for the prevention of exacerbations of chronic obstructive pulmonary disease and chronic bronchitis. In dermatology, topical roflumilast is authorized by the US Food and Drug Administration for the treatment of plaque psoriasis and mild to moderate seborrheic dermatitis. Several studies have described the off-label use of roflumilast in dermatology, including a randomized controlled trial showing its usefulness in the treatment of psoriasis; case reports and small series have also reported successful outcomes in hidradenitis suppurativa, recurrent oral aphthosis, nummular eczema, lichen planus, and Behçet disease. Roflumilast has a favorable safety profile, similar to that of apremilast, and it is considerably cheaper than new generation drugs and even some conventional immunosuppressants. We review the pharmacokinetics and pharmacodynamics of topical and oral roflumilast and discuss potential adverse effects and both approved and off-label uses in dermatology. Roflumilast is a promising agent to consider.(AU)

[Translated aticle] Topical and Oral Roflumilast in Dermatology: A Narrative Review / Roflumilast tópico y oral endermatología. Una revisión narrativa

Roflumilast es un inhibidor de la fosfodiesterasa-4 aprobado de forma oral para la prevención de exacerbaciones en pacientes con enfermedad pulmonar obstructiva crónica y fenotipo de bronquitis crónica. En dermatología, el roflumilast tópico está aprobado por la Food and Drug Administration en psoriasis en placas y dermatitis seborreica leve/moderada. En cuanto a su uso fuera de indicación, hemos encontrado un ensayo clínico que avala la utilidad del roflumilast oral en psoriasis, así como pequeñas series de casos o casos clínicos aislados en hidradenitis supurativa, aftosis oral recurrente, eccema numular, liquen plano y enfermedad de Behçet. Su perfil de seguridad es favorable, similar al del apremilast, y su coste es considerablemente inferior a los de los fármacos de nueva generación, o incluso al de algunos inmunosupresores clásicos. Presentamos una revisión de roflumilast tópico y oral, en términos de farmacocinética y farmacodinámica, efectos adversos, usos dermatológicos aprobados y fuera de indicación. Roflumilast es un agente prometedor en dermatología.(AU)

Oral roflumilast is a phosphodiesterase-4 inhibitor approved for the prevention of exacerbations of chronic obstructive pulmonary disease and chronic bronchitis. In dermatology, topical roflumilast is authorized by the US Food and Drug Administration for the treatment of plaque psoriasis and mild to moderate seborrheic dermatitis. Several studies have described the off-label use of roflumilast in dermatology, including a randomized controlled trial showing its usefulness in the treatment of psoriasis; case reports and small series have also reported successful outcomes in hidradenitis suppurativa, recurrent oral aphthosis, nummular eczema, lichen planus, and Behçet disease. Roflumilast has a favorable safety profile, similar to that of apremilast, and it is considerably cheaper than new generation drugs and even some conventional immunosuppressants. We review the pharmacokinetics and pharmacodynamics of topical and oral roflumilast and discuss potential adverse effects and both approved and off-label uses in dermatology. Roflumilast is a promising agent to consider.(AU)

COPD in People with HIV: Epidemiology, Pathogenesis, Management, and Prevention Strategies.

Chronic obstructive pulmonary disease (COPD) is a progressive respiratory disorder characterized by airflow limitation and persistent respiratory symptoms. People with HIV (PWH) are particularly vulnerable to COPD development; PWH have demonstrated both higher rates of COPD and an earlier and more rapid decline in lung function than their seronegative counterparts, even after accounting for differences in cigarette smoking. Factors contributing to this HIV-associated difference include chronic immune activation and inflammation, accelerated aging, a predilection for pulmonary infections, alterations in the lung microbiome, and the interplay between HIV and inhalational toxins. In this review, we discuss what is known about the epidemiology and pathobiology of COPD among PWH and outline screening, diagnostic, prevention, and treatment strategies.

Opportunities to improve asthma and COPD prevention and care: insights from the patient journey obtained through focus groups.

BACKGROUND: The healthcare experiences of patients hold valuable insights for improving the quality of services related to their well-being. We therefore invited and explored the perspectives of patients living with asthma and chronic obstructive pulmonary disease (COPD) on their interaction with the systems supporting health, in order to identify opportunities to improve services to prevent, treat and manage these conditions. METHODS: Two virtual focus groups were held in August 2021, one for adult asthma and one for COPD, to learn of patients' experiences receiving care for these conditions in the Vancouver Coastal Health (VCH) region of British Columbia. Participants were recruited through online postings or their clinician. We discussed the care pathway for each condition and invited participants to share their experiences of the past 5 years, specifically their reflections on the process, including feelings, points of praise and frustration, and opportunities for improvement in this context. Composite patient journey maps were developed for each condition to reflect the experiences shared. Audio recordings of the focus groups were transcribed and used in qualitative data analysis. RESULTS: Thematic analysis revealed the following as possible areas for improvement: low public awareness of asthma and COPD and associated risk factors, non-standardised diagnosis pathways that delay diagnosis, and inconsistency in delivering valued aspects of care such as supports for self-management, trust-inspiring acute care, empowering patient communication and timely access to care. CONCLUSION: We successfully used focus groups to generate composite journey maps of the experiences of patients living with asthma (n=8) and COPD (n=9) to identify features that these patients consider important for improving the healthcare system for asthma and COPD in VCH. Health professionals, decision makers and patient advocates in VCH and beyond can consider these insights when evaluating, and planning changes to, current practices and policies in service delivery.

Keratin 15 protects against cigarette smoke-induced epithelial mesenchymal transformation by MMP-9.

BACKGROUND: Chronic obstructive pulmonary disease (COPD), a chronic inflammatory lung disease, is a leading cause of morbidity and mortality worldwide. Prolonged cigarette smoking (CS) that causes irreversible airway remodeling and significantly reduces lung function is a major risk factor for COPD. Keratin15+ (Krt15+) cells with the potential of self-renewal and differentiation properties have been implicated in the maintenance, proliferation, and differentiation of airway basal cells; however, the role of Krt15 in COPD is not clear. METHODS: Krt15 knockout (Krt15-/-) and wild-type (WT) mice of C57BL/6 background were exposed to CS for six months to establish COPD models. Krt15-CrePGR;Rosa26-LSL-tdTomato mice were used to trace the fate of the Krt15+ cells. Hematoxylin and eosin (H&E) and Masson stainings were performed to assess histopathology and fibrosis, respectively. Furthermore, lentivirus-delivered short hairpin RNA (shRNA) was used to knock down KRT15 in human bronchial epithelial (HBE) cells stimulated with cigarette smoke extract (CSE). The protein expression was assessed using western blot, immunohistochemistry, and enzyme-linked immunosorbent assay. RESULTS: Krt15-/- CS mice developed severe inflammatory cell infiltration, airway remodeling, and emphysema. Moreover, Krt15 knockout aggravated CS-induced secretion of matrix metalloproteinase-9 (MMP-9) and epithelial-mesenchymal transformation (EMT), which was reversed by SB-3CT, an MMP-9 inhibitor. Consistent with this finding, KRT15 knockdown promoted MMP-9 expression and EMT progression in vitro. Furthermore, Krt15+ cells gradually increased in the bronchial epithelial cells and were transformed into alveolar type II (AT2) cells. CONCLUSION: Krt15 regulates the EMT process by promoting MMP-9 expression and protects the lung tissue from CS-induced injury, inflammatory infiltration, and apoptosis. Furthermore, Krt15+ cells transformed into AT2 cells to protect alveoli. These results suggest Krt15 as a potential therapeutic target for COPD.

Chronic Obstructive Pulmonary Disease Series Part 4: Identifying, Managing, and Preventing Exacerbations.

Chronic obstructive pulmonary disease (COPD) remains a leading cause of death in the United States, with exacerbations significantly contributing to overall morbidity, mortality, and health care costs. The purpose of this review is to discuss the recognition, treatment, and prevention of COPD exacerbations, with an emphasis on the role that pharmacists can have of ensuring appropriate treatment of acute exacerbations and preventing future exacerbations.

Lifestyle practices that reduce seasonal PM2.5 exposure and their impact on COPD.

Particulate matter (PM) is a major air pollutant that has led to global health concerns and can cause and exacerbate chronic obstructive pulmonary disease (COPD). We asked patients with COPD to complete a detailed questionnaire about their lifestyle practices to reduce PM2.5 exposure and analyzed the relationship between ambient PM2.5 concentrations and lifestyle practices. We prospectively enrolled 104 COPD patients from four hospitals in different areas of Korea. They completed detailed questionnaires twice (at enrollment and the end of the study) and Internet of Things-based sensors were installed in their homes to continuously measure PM2.5 for 1 year. The relationship between PM2.5 concentrations, lifestyle practices, and COPD exacerbations were analyzed in each season. The PM2.5 concentration was higher outdoors than indoors in all seasons except summer, and the difference was largest in winter. The six lifestyle practices that significantly lowered the annual indoor PM2.5 concentration compared with the outdoors. The higher the economic status and educational level of patients, the lower the indoor PM2.5 concentration. Some lifestyle practices were associated with reduced small airway resistance, presented as R5-R20 determined by impulse oscillometry, and scores of the St. George's Respiratory Questionnaire. Some lifestyle practices are associated with reduced indoor PM2.5 concentrations and can even affect clinical outcomes, including small airway resistance and quality of life of COPD patients.

Protective effect of oleo-gum resin of Commiphora wightii against elastase-induced chronic obstructive pulmonary disease-linked lung inflammation and emphysema: Isolation and identification of key bioactive phytoconstituent.

ETHNOPHARMACOLOGICAL RELEVANCE: Oleo-gum resin of Commiphora wightii (Arnott) Bhandari of family Burseraceae, commonly known as 'guggul', is a well known Ayurvedic drug used traditionally to treat various disorders including respiratory ailments. However, role of C. wightii in chronic obstructive pulmonary disease (COPD) is not known. AIM: The present work was designed to investigate the protective potential of standardized C. wightii extract/and its fractions against elastase-induced COPD-linked lung inflammation and to identify key bioactive constituent(s). MATERIAL AND METHODS: C. wightii oleo-gum resin extract was prepared using Soxhlet extraction technique and the resultant extract was standardized on basis of guggulsterone content using HPLC. The extract was partitioned by different solvents in increasing order of polarity. Standardized extract/its partitioned fractions were orally administered to male BALB/c mice 1 h prior to intra-tracheal instillation of elastase (1U/mouse). Anti-inflammatory effect was evaluated by analyzing inflammatory cells and myeloperoxidase activity in lungs. The various fraction(s) were subjected to column chromatography to isolate bioactive compound. Isolated compound was identified using 1H and 13C-NMR and analyzed for assessment of several inflammatory mediators using techniques like ELISA, PCR, and gelatin zymography. RESULTS: C. wightii extract attenuated elastase-induced lung inflammation in dose-dependent manner and Ethyl acetate fraction (EAF) provided maximum protection. EAF was subjected to column chromatography followed by assessment of bioactivity of each sub-fraction, ultimately leading towards isolation of two compounds i.e. C1 and C2. C1 seems to be the key active principle of C. wightii, as it displayed significant anti-inflammatory activity against elastase induced lung inflammation while C2 largely remains ineffective. C1 was identified as mixture of E- and Z-guggulsterone (GS). Reduction in the elastase induced lung inflammation by GS was associated with downregulation of expression of several COPD linked pro-inflammatory factors such as IL-6/TNF-α/IL-1ß/KC/MIP-2/MCP-1/G-CSF as well as normalization of redox imbalance as indicated by levels of ROS/MDA/protein carbonyl/nitrite/GSH etc. Further, 21 days prolonged administration of GS (10 mg/kg b.wt; once daily) protected against elastase-induced emphysema by mitigating expression/activity of MMP-2/-9 and increasing TIMP-1 expression. CONCLUSION: Overall, guggulsterone seems to be the key bioactive constituent responsible for exerting beneficial effects of C. wightii against COPD.

Effect of the Lipoxin Receptor Agonist BML-111 on Cigarette Smoke Extract-Induced Macrophage Polarization and Inflammation in RAW264.7 Cells.

Background: Macrophages are known to play a crucial role in the chronic inflammation associated with Chronic Obstructive Pulmonary Disease (COPD). BML-111, acting as a lipoxin A4 (LXA4) receptor agonist, has shown to be effective in protecting against COPD. However, the precise mechanism by which BML-111 exerts its protective effect remains unclear. Methods: In order to establish a cell model of inflammation, cigarette smoke extract (CSE) was used on the RAW264.7 cell line. Afterwards, an Enzyme-linked immunosorbent assay (ELISA) kit was employed to measure concentrations of tumor necrosis factor-α (TNF-α), interleukin-1beta (IL-1ß), interleukin-18 (IL-18), and interleukin-10 (IL-10) in the cell supernatants of the RAW264.7 cells.In this study, we examined the markers of macrophage polarization using two methods: quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis. Additionally, we detected the expression of Notch-1 and Hes-1 through Western blotting. Results: BML-111 effectively suppressed the expression of pro-inflammatory cytokines TNF-α, IL-1ß, and IL-18, as well as inflammasome factors NLRP3 and Caspase-1, while simultaneously up-regulating the expression of the anti-inflammatory cytokine IL-10 induced by CSE. Moreover, BML-111 reduced the expression of iNOS, which is associated with M1 macrophage polarization, and increased the expression of Arg-1, which is associated with M2 phenotype. Additionally, BML-111 downregulated the expression of Hes-1 and the ratio of activated Notch-1 to Notch-1 induced by CSE. The effect of BML-111 on inflammation and macrophage polarization was reversed upon administration of the Notch-1 signaling pathway agonist Jagged1. Conclusion: BML-111 has the potential to suppress inflammation and modulate M1/M2 macrophage polarization in RAW264.7 cells. The underlying mechanism may involve the Notch-1 signaling pathway.

Intervención farmacéutica en el manejo de inhaladores con pacientes EPOC citados para una espirometría en un centro de salud / Pharmaceutical intervention in the usage of inhalers with COPD patients that have an appointment in a health center to do an spirometry

Antecedentes: el uso de los inhaladores es algo complejo, con este trabajo en pacientes con EPOC debido a su complejidad, lo que se pretende es que tras la intervención de un farmacéutico se garanti-ce el uso adecuado de dichos medicamentos con el fin de mejorar la calidad de vida.Métodos: se citaba a los pacientes para la realiza-ción de una espirometría por parte de la enfermera y por otro lado la farmacéutica en una consulta valoraba el uso de los inhaladores y realizaba los test de adherencia y calidad de vida. A los tres meses los pacientes acudían a la segunda visita y la farmacéutica repetía el mismo el proceso para detectar los posibles cambios tras la intervención.Resultados: en aquellos pacientes que acudieron a las dos visitas se observó que había cambios estadísticamente significativos entre las puntuacio-nes de adherencia en la primera visita respecto a la segunda. La media de puntuaciones es mayor en la segunda visita (49,09) respecto a la primera (46,45), diferencia significativa con una p<0,05. La calidad de vida era igual en ambas visitas y la media de errores en el uso de inhaladores en la segunda visi-ta (1,773) se reduce de forma significativa respecto a la media de errores en la primera visita (4,727).Conclusiones: la intervención de un farmacéutico en un equipo multidisciplinar para el seguimiento de pacientes EPOC ha resultado beneficiosa para dichos pacientes, sobre todo en cuanto al manejo de los inhaladores y la adherencia al tratamiento. (AU)

Background: the usage of inhalers is something complex. This work with COPD patients pretends that, after the pharmacist intervention, the correct usage of these drugs is guaranteed so as to im-prove the quality of life. Methods: the nurse set a date to do an spirometry to the patients. On the other hand, the pharmacist assessed the usage of the inhalers and carried out the adherence and quality of life tests. Three months after, the patients came back to the con-sultation and the pharmacist repeated the same procedure to detect any possible change after the intervention.Results: on those patients that attended both ap-pointments, it was seen that there were statistically significant changes between the adherence punc-tuation regarding both appointments. The average of punctuation is higher in the second appointment (49.09) in respect to the first one (46.45), this is a significant difference with a p<0.05. The quality of life was the same in both appointments and the errors average in the usage of inhalators in the second appointment decreased (1773) significantly in respect to the errors average in the first appoint-ment (4727).Conclusion: the intervention of a pharmacist in a multidisciplinary team to the following of COPD pa-tients is advantageous to these patients, mainly in relation to the usage of inhalers and the adherence to treatment. (AU)

Azithromycin ameliorated cigarette smoke-induced airway epithelial barrier dysfunction by activating Nrf2/GCL/GSH signaling pathway.

BACKGROUND: Airway epithelium is the first barrier against environmental insults, and epithelial barrier dysfunction caused by cigarette smoke (CS) is particularly relevant to chronic obstructive pulmonary disease (COPD) progression. Our study was to determine whether Azithromycin (AZI) ameliorates CS-induced airway epithelial barrier dysfunction and the underlying mechanisms. METHODS: Primary bronchial epithelial cells (PBECs), human bronchial epithelial cells (HBECs), Sprague Dawley rats and nuclear factor erythroid 2-related factor 2 (Nrf2)-/- mice were pretreated with AZI and subsequently exposed to CS. Transepithelial electronic resistance (TEER), junction proteins as well as pro-inflammatory cytokines and apoptosis markers were examined to assess epithelial barrier dysfunction. Metabolomics study was applied to explore the underlying mechanism of AZI. RESULTS: CS-induced TEER decline and intercellular junction destruction, accompanied with inflammatory response and cell apoptosis in PBECs were restored by AZI dose-dependently, which were also observed in CS-exposed rats. Mechanistically, GSH metabolism pathway was identified as the top differentially impacted pathway and AZI treatment upregulated the activities of glutamate cysteine ligase (GCL) and the contents of metabolites in GSH metabolic pathway. Furthermore, AZI apparently reversed CS-induced Nrf2 suppression, and similar effects on airway epithelial barrier dysfunction were also found for Nrf2 agonist tert-butylhydroquinone and vitamin C. Finally, deletion of Nrf2 in both HBECs and C57BL/6N mice aggravated CS-induced GSH metabolism imbalance to disrupt airway epithelial barrier and partially deprived the effects of AZI. CONCLUSION: These findings suggest that the clinical benefits of AZI for COPD management are related with the protection of CS-induced airway epithelial barrier dysfunction via activating Nrf2/GCL/GSH pathway, providing potential therapeutic strategies for COPD.

Prevention of Re-Hospitalization for Acute Exacerbations: Perspectives of People with Chronic Obstructive Pulmonary Disease: A Qualitative Study.

Purpose: Current guidelines for prevention of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) reflect clinical understanding of the causes of exacerbations but with a limited recognition of person-specific contributing factors. As part of a randomized trial of a person-centered intervention aiming to promote self-determination, we describe personal perspectives of those with chronic obstructive pulmonary disease (COPD) on what they saw as the causes and best ways to stay well and prevent rehospitalization after an AECOPD. Patients and Methods: Twelve participants (mean age 69.3 years, six female, six male; eight New Zealand European, two Maori, one Pacific, and one other) were interviewed about their experiences of staying well and out of hospital. Data were collected via individual semi-structured interviews one year following an index hospital admission for AECOPD and focused on the participants' views and experiences of their health condition, their beliefs about staying well, and the causes of and factors preventing further exacerbations and hospitalizations. Data were analyzed using constructivist grounded theory methods. Results: Three main themes were identified that described participants' views on what helped or hindered them to stay well and out of hospital: 1) Being Positive: The importance of having a positive mindset; 2) Being Proactive: Practical steps to reduce the risk of, and consequences from, episodes of AECOPD; and 3) Being in Control: Feeling in command of one's life and health. Each of these was affected by Being Connected: The influence of significant others, particularly close family. Conclusion: This research expands our understanding of how patients manage COPD and adds patient perspectives to current knowledge on how to prevent recurrent AECOPD. Programs which promote self-efficacy and positivity would be beneficial additions to AECOPD prevention strategies, as could the inclusion of family or significant others in wellbeing plans.

Bronchitis, COPD, and pneumonia after viral endemic of patients with leprosy on Sorok Island in South Korea.

Viral respiratory diseases (VRDs) cause lung inflammation and inflammatory cytokine production. We study whether dapsone is responsible for its observed preventive treatment effects of the sustained viral RNA interferon response. Around 2008 and 2012, Korea's Dementia Management Act stipulated drastic changes in the administration of dementia medication by medical staff. Participants were randomized and we compared leprosy patients with VRDs after prescribing dapsone as a standard treatment from 2005 to 2019. Significance was evaluated based on the dapsone-prescribed (+) subgroup and the dapsone-unprescribed (-) subgroup of the VRD diagnosed (+) and VRD undiagnosed (-) subgroup. We analyzed VRD ( +)/(- with dapsone (+)/(-) group and used a T-test, and designed the equation of acetylation with dapsone and acetylcholine (AA) equation. The 6394 VRD participants who received the dapsone intervention compared to the 3255 VRD participants in the control group demonstrated at T2 VRD (+) dapsone (-) (mean (M) = 224.80, SD = 97.50): T3 VRD (-) dapsone (+) (M = 110.87, SD = 103.80), proving that VRD is low when dapsone is taken and high when it is not taken. The t value is 3.10, and the p value is 0.004395 (significant at p < 0.05). After an increase in VRDs peaked in 2009, bronchitis, COPD, and pneumonia surged in 2013. The AA equation was strongly negatively correlated with the prevalence of bronchitis and chronic obstructive pulmonary disease (COPD): with bronchitis, r(15) = -0.823189, p = 0.005519, and with COPD, r(15) = -0.8161, p = 0.000207 (significant at p < 0.05). Dapsone treated both bronchitis and COPD. This study provides theoretical clinical data to limit acetylcholine excess during the VRD pandemic for bronchitis, COPD, and pneumonia.

The Impact of the Danish National Smoking Ban From 2007 on the Incidence of Eight Smoking-related Diseases: A Nationwide Register-based Interrupted Time Series Analysis.

BACKGROUND: Previous research has documented the effect of comprehensive smoking bans on preventing various adverse health outcomes in the years post-ban. In 2007, Denmark implemented a national smoking ban that prohibited indoor smoking in workplaces and public settings, although only partial restrictions applied in specific premises such as small bars, one-person offices, and in psychiatric units. We tested the hypothesis that the implementation of the national smoking ban was associated with a decrease in incidence of smoking-related morbidity in the Danish population compared to the pre-ban period. METHODS: Interrupted time series analyses including the entire Danish population (≥30 years) was conducted. Information of hospitalizations and cause-specific mortality due to acute myocardial infarction, heart failure, hemorrhagic stroke, ischemic stroke, chronic obstructive pulmonary disease, cancer in bronchus and lung, cancer in lip, mouth, oral cavity, and pharynx, and bladder cancer were obtained from population-based registers. Poisson regression models accounting for seasonal variations and secular trends quantified immediate changes in incidence rates occurring at the time of the smoking ban as well as changes in the post-ban trend compared to pre-ban levels. RESULTS: Overall, we observed no consistent declines in incidence of cardiovascular diseases, chronic obstructive pulmonary disease, or the specific types of cancer in the post-ban period compared with the pre-ban period. CONCLUSION: No consistent reduction in incidence of smoking-related diseases was observed after the smoking ban was introduced in Denmark. This probably reflects that the Danish smoking ban included several exemptions, resulting in a less comprehensive ban compared to those introduced in other countries. IMPLICATIONS: In this study, we found that the Danish national smoking ban from 2007 did not consistently reduced the incidence of eight smoking-related outcomes in the post-ban period compared to pre-ban levels. We argue that due to the exemptions in the smoking ban, which for example allowed smoking in specific premises of the care and nursing sector, in one-person offices, and small bars, the ban was not sufficiently comprehensive to influence smoking behavior and thereof the incidence of smoking-related morbidity. Our findings highlight the importance of introducing comprehensive legislative measures to yield largest health benefits at a population level.