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OBJECTIVE: Our objective was to test the hypothesis, in a double-blind, placebo-controlled study that vipoglanstat, an inhibitor of microsomal prostaglandin E synthase-1 (mPGES-1) which decreases prostaglandin E2 (PGE2) and increases prostacyclin biosynthesis, improves RP. METHODS: Patients with systemic sclerosis (SSc) and ≥7 RP attacks during the last screening week prior to a baseline visit were randomised to four weeks treatment with vipoglanstat 120 mg or placebo. A daily electronic diary captured RP attacks (duration and pain) and Raynaud's Condition Score, with change in RP attacks/week as primary end point. Cold challenge assessments were performed at baseline and end of treatment. Exploratory endpoints included patients' and physicians' global impression of change, Assessment of Scleroderma-associated Raynaud's Phenomenon questionnaire, mPGES-1 activity, and urinary excretion of arachidonic acid metabolites. RESULTS: Sixty-nine subjects received vipoglanstat (n = 33) or placebo (n = 36). Mean weekly number of RP attacks (baseline; vipoglanstat 14.4[SD 6.7], placebo 18.2[12.6]) decreased by 3.4[95% CI -5.8;-1.0] and 4.2[-6.5;-2.0] attacks per week (p= 0.628) respectively. All patient reported outcomes improved, with no difference between the groups. Mean change in recovery of peripheral blood flow after cold challenge did not differ between the study groups. Vipoglanstat fully inhibited mPGES-1, resulting in 57% reduction of PGE2 and 50% increase of prostacyclin metabolites in urine. Vipoglanstat was safe and well tolerated. CONCLUSION: Although vipoglanstat was safe, and well tolerated in a dose achieving full inhibition of mPGES-1, it was ineffective in SSc-related RP. Further development and evaluation of vipoglanstat will therefore be in other diseases where mPGES-1 plays a pathogenetic role.
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OBJECTIVE: Our main aim was to investigate the effect of a single oral dose of C21, a selective angiotensin II type 2 receptor agonist, on cold-induced vasoconstriction in SSc-related RP. METHODS: This was a phase IIa, randomized, double-blind, cross-over, single-dose, placebo-controlled, single-centre study. Twelve female patients with SSc (median age 58.5 years, median duration of RP 19.0 years) attended on four occasions: screening, treatment visits 1 and 2 (separated by 3-7 days) and follow-up. At the first treatment visit, patients were randomized to receive either a single oral dose of C21 (200 mg) or placebo, then the opposite treatment on the second visit. Forty min after each treatment, each patient underwent a standard hand cold challenge. The primary end point was the area under the curve (AUC) for rewarming for each finger (eight fingers) over 15 min. Secondary end points included the maximum finger temperature after rewarming (MAX). Statistical analyses were performed by multiplicative ANCOVA models. RESULTS: For all eight fingers combined, mean AUC for rewarming was higher after treatment with C21 than after placebo (geometric mean 20â046°C*s vs 19â558°C*s), but not significantly (P = 0.380) and MAX (at 15 min) was also higher (geometric mean 23.5°C vs 22.5°C; P = 0.036). C21 was well tolerated. CONCLUSION: Despite the small trial size, a signal emerged suggesting that even in patients with established SSc, C21 may confer benefit for RP and deserves further investigation. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT04388176.
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Doença de Raynaud , Escleroderma Sistêmico , Humanos , Feminino , Pessoa de Meia-Idade , Receptor Tipo 2 de Angiotensina/uso terapêutico , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/tratamento farmacológico , Escleroderma Sistêmico/diagnóstico , Dedos , Temperatura Corporal , Doença de Raynaud/etiologia , Doença de Raynaud/complicaçõesRESUMO
Substantial evidence supports the involvement of the renin-angiotensin system in pulmonary hypertension (PH), and the angiotensin II type 2 receptor (AT2R) is known to exert tissue protective actions. The effect of the selective AT2R agonist C21 (also known as Compound 21 or buloxibutid) was evaluated in the rat Sugen-hypoxia PH model. After a single injection of Sugen 5416 and hypoxia for 21 days, C21 (2 or 20 mg/kg) or vehicle was administered perorally twice daily from Day 21 to Day 55. On Day 56, hemodynamic assessments were performed, and lung and heart tissue were prepared for quantification of cardiac and vascular remodeling and fibrosis. Treatment with C21 20 mg/kg improved cardiac output and stroke volume and decreased right ventricular hypertrophy (all p < 0.05). Treatment with C21 2 mg/kg significantly decreased vessel wall and muscular layer thickness and increased the luminal opening in vessels >100 µm (all p < 0.05). There were no significant differences between the two C21 doses on any parameter, and post hoc analyses comparing the merged C21 groups with the vehicle group showed that C21 treatment reduced vascular remodeling (reduced endothelial proliferation and thickening of the vascular wall) in vessels of all sizes; moreover, the diastolic pulmonary artery pressure and right ventricular pressure were reduced along with reduction of right ventricular hypertrophy. Sugen 5416 and hypoxia increased pulmonary collagen deposition, which was counteracted by C21 20 mg/kg. In conclusion, the effects of C21 on vascular remodeling, hemodynamic alterations, and fibrosis suggest that AT2R agonists may have a role in Group 1 and 3 PH treatment.
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Hipertensão Pulmonar , Ratos , Animais , Hipertensão Pulmonar/tratamento farmacológico , Hipertrofia Ventricular Direita , Receptor Tipo 2 de Angiotensina/agonistas , Remodelação Vascular , Fibrose , Hipóxia/complicações , Hipóxia/tratamento farmacológicoRESUMO
Interstitial lung disease (ILD) encompasses a heterogeneous group of more than 200 conditions, of which primarily idiopathic pulmonary fibrosis (IPF), idiopathic nonspecific interstitial pneumonia, hypersensitivity pneumonitis, ILD associated with autoimmune diseases and sarcoidosis may present a progressive fibrosing (PF) phenotype. Despite different aetiology and histopathological patterns, the PF-ILDs have similarities regarding disease mechanisms with self-sustaining fibrosis, which suggests that the diseases may share common pathogenetic pathways. Previous studies show an enhanced activation of serotonergic signaling in pulmonary fibrosis, and the serotonin (5-HT)2 receptors have been implicated to have important roles in observed profibrotic actions. Our research findings in support by others, demonstrate antifibrotic effects with 5-HT2B receptor antagonists, alleviating several key events common for the fibrotic diseases such as myofibroblast differentiation and connective tissue deposition. In this review, we will address the potential role of 5-HT and in particular the 5-HT2B receptors in three PF-ILDs: ILD associated with systemic sclerosis (SSc-ILD), ILD associated with rheumatoid arthritis (RA-ILD) and IPF. Highlighting the converging pathways in these diseases discloses the 5-HT2B receptor as a potential disease target for PF-ILDs, which today have an urgent unmet need for therapeutic strategies.
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Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/patologia , Doenças Pulmonares Intersticiais/metabolismo , Doenças Pulmonares Intersticiais/patologia , Receptor 5-HT2B de Serotonina/metabolismo , Animais , Humanos , Fibrose Pulmonar Idiopática/imunologia , Inflamação/patologia , Doenças Pulmonares Intersticiais/imunologia , Modelos Biológicos , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologiaRESUMO
OBJECTIVES: Previous studies on firefighters indicate an increased risk of cancer although findings regarding which cancer sites are in excess have been inconsistent. The aim of this study was to investigate the cancer incidence among Swedish firefighters. METHODS: This updated cohort study included 1080 men who worked at least 1 year as a firefighter in the city of Stockholm, Sweden during 1931-1983. First-time diagnoses of cancer were identified through the Swedish Cancer Registry from 1958 until 2012. Employment as a firefighter was determined from the annual fire station enrolment records. Standardized incidence ratios were calculated using the Stockholm population as reference. RESULTS: Firefighters in Stockholm had a low overall risk of cancer (SIR = 0.81 95% CI 0.71-0.91). However, firefighters were at an increased risk of stomach cancer (SIR = 1.89 95% CI 1.25-2.75). Firefighters had significantly low risks for prostate cancer (SIR = 0.68 95% CI 0.52-0.87) and malignant melanoma of the skin (SIR = 0.30 95% CI 0.06-0.88). There was a statistically significant trend of increasing overall risk of cancer with increasing employment duration, although there was still no excess of cancer overall in any of the categories of employment duration. CONCLUSION: Stockholm firefighters had an increased risk of stomach cancer but a low overall risk of cancer. The trend of increasing overall risk of cancer with increasing employment duration could potentially be related to the carcinogenic exposures at work.
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Bombeiros/estatística & dados numéricos , Neoplasias/epidemiologia , Neoplasias Gástricas/epidemiologia , Adulto , Idoso , Estudos de Coortes , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Exposição Ocupacional/efeitos adversos , Suécia/epidemiologiaRESUMO
We investigated regional air trapping on computed tomography in current smokers with normal spirometry. It was hypothesised that presence of regional air trapping may indicate a specific manifestation of smoking-related changes.40 current smokers, 40 patients with chronic obstructive pulmonary disease (COPD), and 40 healthy never- smokers underwent computed tomography scans. Regional air trapping was assessed on end-expiratory scans and emphysema, micronodules and bronchial wall thickening on inspiratory scans. The ratio of expiratory and inspiratory mean lung attenuation (E/I) was calculated as a measure of static (fixed) air trapping.Regional air trapping was present in 63% of current smokers, in 45% of never smokers and in 8% of COPD patients (p<0.001). Current smokers with and without regional air trapping had E/I ratio of 0.81 and 0.91, respectively (p<0.001). Forced expiratory volume in 1â s (FEV1) was significantly higher and emphysema less frequent in current smokers with regional air trapping.Current smokers with regional air trapping had higher FEV1 and less emphysema on computed tomography. In contrast, current smokers without regional air trapping resembled COPD. Our results highlight heterogeneity among smokers with normal spirometry and may contribute to early detection of smoking related structural changes in the lungs.
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Pulmão/diagnóstico por imagem , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Enfisema Pulmonar/diagnóstico por imagem , Fumar/fisiopatologia , Idoso , Ar , Líquido da Lavagem Broncoalveolar/citologia , Broncoscopia , Estudos de Casos e Controles , Feminino , Volume Expiratório Forçado , Capacidade Residual Funcional , Humanos , Modelos Lineares , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Variações Dependentes do Observador , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Espirometria , Suécia , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Smokers have increased cell concentration in the lower respiratory tract indicating a chronic inflammatory state, which in some individuals may lead to development of chronic obstructive pulmonary disease (COPD). Computer tomography (CT) imaging provides means of quantifying pulmonary structure and early signs of disease. We investigated whether lung density on high resolution CT differs between smokers and never-smokers and if this were associated to intensity of inflammation. METHODS: Forty smoking volunteers with normal pulmonary function, 40 healthy never-smokers and 40 patients with COPD of GOLD stage I-II, were included. Mean lung attenuation and percentage of pixels in the lung with attenuation between -750 and -900 HU (percentage higher density spectrum (%HDS)) were calculated on inspiratory CT-scans. Markers of systemic inflammation in blood and cell counts in bronchoalveolar lavage (BAL) fluid were recorded. RESULTS: Lung density expressed as %HDS was increased in smokers (44.0 ± 5.8%) compared to both never-smokers (38.3 ± 5.8%) and patients with COPD (39.1 ± 5.8%), (p < 0.001, for both). Females had denser lungs than males, which was dependent on body height. Cell concentration in BAL were correlated to lung density in smokers (r = 0.50, p < 0.001). CONCLUSIONS: Lung density on CT is associated with cell concentration in BAL in smokers and may mirror an inflammatory response in the lung. Gender difference in lung density is dependent on height. In COPD with emphysema, loss of lung tissue may counterbalance the expected increase in density due to inflammation. The findings may help to interpret high resolution CT in the context of smoking and gender and highlight the heterogeneity of structural changes in COPD.
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Pulmão/diagnóstico por imagem , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Caracteres Sexuais , Fumar/patologia , Tomografia Computadorizada por Raios X/normas , Idoso , Feminino , Volume Expiratório Forçado/fisiologia , Humanos , Inflamação/diagnóstico , Inflamação/epidemiologia , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Fumar/epidemiologiaRESUMO
Background: Timely treatment of acute allergic reactions (AARs) is important to minimize reaction severity. Corticosteroid tablets dissolved in water are commonly used in mainstay treatment. A new oral film that dissolves on the tongue provides a faster and less cumbersome alternative to tablets for corticosteroid administration during AARs. This study evaluated patients' preferences for attributes related to administration mode of corticosteroids in AARs. Methods: A web-based survey was sent to a sample from the adult Swedish population (≥18 years) with experience of corticosteroid treatment for AAR. We assessed the willingness to pay (WTP) for attributes related to corticosteroid treatment by applying a discrete choice experiment (DCE) approach. DCE attributes were administration mode, time to symptom relief, and price. The WTP for each attribute was derived using the attribute's coefficient in a logistic regression analysis. We specified a forced choice (FC) and an unforced choice (UC) model. In the FC model, the respondents chose between 2 hypothetical treatments and in the UC model, between any of 2 hypothetical treatments and their current treatment. Results: The final study population included 348 subjects, of which 80% were women. All the evaluated DCE attributes were significant predictors for the treatment choice (p<.001). In the FC model, the incremental WTP for an oral film compared with tablets was 409 Swedish kronor (SEK [≈36.7]), with no other factors considered. In the UC model, the incremental WTP for the oral film compared with tablets was 574 SEK (≈51.7). After considering the value of the respondents' current treatment, the WTP for the oral film decreased to 336 SEK (≈30.3). The total WTP was reduced by 17 SEK (≈1.5) per minute of shorter time to symptom relief. Subgroup analyses showed that people with circulatory symptoms and experience of swallowing difficulties related to allergy medication had higher WTP for the oral film than the average respondent. Conclusion: The findings show a substantial economic benefit of the oral film vs tablets for patients with AARs in Sweden. This result remained also after compensation for the full value of the patients' current treatment.
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Background: Acute allergic reactions (AARs) occur shortly after exposure to an allergen, and the severity is on a continuum. Systemic corticosteroids (CS) are mainstay treatment of moderate to severe AARs, whereas those at risk of the most severe AARs (ie, anaphylaxis) are also recommended prescription of epinephrine autoinjectors. There is limited research on the impact of AARs not fulfilling the criteria for anaphylaxis. We have characterized a sample with a history of moderate to severe AARs and evaluated their self-reported disease burden (ie, daily life impact, anxiety, and treatment impediments). Methods: Survey study of adults with experience of AARs treated with CS. Participants recruited from a web-based panel and using social media were asked to complete a questionnaire related to their allergy and experience of AARs. The results were summarized for the whole sample and across subgroups with and without prescription of epinephrine. Results: The final study sample included 387 participants (80% women, mean age 41), of which 129 (33%) had at some point been prescribed epinephrine. The most common symptoms were respiratory (80%) and skin (78%) manifestations, and the mean (standard deviation, SD) self-rated severity score (scale from 0 [very mild] to 10 [very severe]) of the most recent AAR was 6.1 (2.0). More than 80% had experience of AARs interrupting daily activities and 50% of AARs that had limited work/studies or participation in leisure activities. Most of the respondents reported some degree of anxiety related to AARs and 43% had feared for their lives. Moreover, difficulties swallowing allergy medicine at an AAR was experienced by 26% and not having the medicine available when needed by 66%. Participants with prescription of epinephrine experienced more severe AARs than those without such prescription (mean [SD] severity 6.8 [2.1] vs 5.8 [1.8], p < 0.0001); however, also those without epinephrine prescription reported considerable anxiety and impact on daily life and to a similar degree as those with prescription. Conclusions: In this sample, subjects with experience of AARs treated with CS showed a considerable disease burden with anxiety and interruption on daily life, as well as problems related to access to, and swallowing of, medication. Although respondents with epinephrine prescription had more severe disease, a high disease burden was also evident among those without epinephrine. The study increases the knowledge of people with moderate to severe AARs, a patient population that has previously been underrepresented in the research literature.
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BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by inflammation and remodeling of the lungs. This results in alterations in extracellular matrix (ECM) and structural changes leading to airflow obstruction. We studied the expression of tenascin-C (Tn-C) and alpha smooth muscle actin (α-SMA), which act as a marker of myofibroblasts, in large airways from COPD patients. Our aim was to elucidate whether this expression correlated with smoking or with disease development. METHODS: Bronchoscopy was performed on 20 COPD patients (mean age 56 years; range 39-61; FEV1/FVC < 70% and FEV1 median 53% (range 33-69) of predicted). Age and smoking matched smokers (S) without COPD (n = 13) and age matched non-smokers (NS) (n = 14) served as controls. Bronchial mucosal biopsies were analyzed by immunohistochemistry. The distribution of Tn-C expression was assessed and graded in three levels, and the number of spindle shaped cells staining positive for α-SMA were counted. RESULTS: Biopsies from COPD patients had more (P < 0.001) Tn-C expression than the two control groups. A significantly (P < 0.05) increased number of spindle shaped cells expressing α-SMA was observed in COPD patients compared with the controls. Smokers and nonsmokers did not differ in this respect. The expression of Tn-C correlated positively (P < 0.001) to the number of α-SMA positive cells. CONCLUSIONS: We demonstrate increased expression of Tn-C and α-SMA positive cells in the large airways in COPD. This was not associated to smoking per se, but to the presence of airway obstruction. Our findings add new information regarding remodeling characteristics and highlight the large airways as a potential site for airways obstruction in COPD.
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Actinas/análise , Brônquios/química , Doença Pulmonar Obstrutiva Crônica/metabolismo , Mucosa Respiratória/química , Tenascina/análise , Adulto , Análise de Variância , Biópsia , Brônquios/fisiopatologia , Broncoscopia , Estudos de Casos e Controles , Desmina/análise , Feminino , Volume Expiratório Forçado , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Razão de Chances , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Fumar/efeitos adversos , Suécia , Regulação para Cima , Vimentina/análise , Capacidade VitalRESUMO
OBJECTIVE: The link and interplay between different airway exposures and rheumatoid arthritis (RA) risk are unclear. This study was undertaken to determine whether respiratory disease is associated with development of RA, and specifically to examine this relationship by RA serostatus and smoking exposure. METHODS: Using data from the Epidemiological Investigation of Rheumatoid Arthritis study, this analysis included 1,631 incident RA cases and 3,283 matched controls recruited from 2006 to 2016. Linking these individuals to the National Patient Register provided information on past acute or chronic, upper or lower respiratory disease diagnoses. For each disease group, we estimated adjusted odds ratios (ORadj ) with 95% confidence intervals (95% CI) for RA, using logistic regression models adjusted for age, sex, residential area, body mass index, and education both overall and stratified by anti-citrullinated protein antibody (ACPA)/rheumatoid factor (RF) status and by smoking status. RESULTS: Respiratory disease diagnoses were associated with risk of RA, with an ORadj of 1.2 for acute upper respiratory disease (95% CI 0.8-1.7), 1.4 for chronic upper respiratory disease (95% CI 1.1-1.9), 2.4 for acute lower respiratory disease (95% CI 1.5-3.6), and 1.6 for chronic lower respiratory disease (95% CI 1.5-3.6). These associations were present irrespective of RF or ACPA status, though the association was somewhat stronger for ACPA/RF-positive than ACPA/RF-negative RA. The association between any respiratory disease and RA was stronger for nonsmokers (ORadj 2.1 [95% CI 1.5-2.9]) than for smokers (ORadj 1.2 [95% CI 0.9-1.5]). CONCLUSION: Respiratory diseases increase the risk for both seropositive and seronegative RA, but only among nonsmokers. These findings raise the hypothesis that smoking and airway disease are associated with RA development through partly different mechanisms.
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Artrite Reumatoide/epidemiologia , Asma/epidemiologia , Doenças Pulmonares Intersticiais/epidemiologia , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Infecções Respiratórias/epidemiologia , Doença Aguda , Adulto , Idoso , Anticorpos Antiproteína Citrulinada/imunologia , Artrite Reumatoide/imunologia , Doença Crônica , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Doenças Respiratórias/epidemiologia , Fator Reumatoide/imunologia , Fatores de Risco , Fumar , Suécia/epidemiologiaRESUMO
BACKGROUND: COVID-19 morbidity and mortality remains high and the need for safe and effective drugs continues despite vaccines. METHODS: Double-blind, placebo-controlled, multi-centre, randomised, parallel group phase 2 trial to evaluate safety and efficacy of oral angiotensin II type 2 receptor agonist C21 in hospitalized patients with COVID-19 and CRP ≥ 50-150 mg/L conducted at eight sites in India (NCT04452435). Patients were randomly assigned 100 mg C21 bid or placebo for 7 days in addition to standard of care. Primary endpoint: reduction in CRP. The study period was 21 July to 13 October 2020. FINDINGS: 106 patients were randomised and included in the analysis (51 C21, 55 placebo). There was no significant group difference in reduction of CRP, 81% and 78% in the C21 and placebo groups, respectively, with a treatment effect ratio of 0.85 [90% CI 0.57, 1.26]. In a secondary analysis in patients requiring supplemental oxygen at randomisation, CRP was reduced in the C21 group compared to placebo. At the end of the 7-day treatment, 37 (72.5%) and 30 (54.5%) of the patients did not require supplemental oxygen in the C21 and placebo group, respectively (OR 2.20 [90% CI 1.12, 4.41]). A post hoc analysis showed that at day 14, the proportion of patients not requiring supplemental oxygen was 98% and 80% in the C21 group compared to placebo (OR 12.5 [90% CI 2.9, 126]). Fewer patients required mechanical ventilation (one C21 patient; four placebo patients), and C21 was associated with a numerical reduction in the mortality rate (one vs three in the C21 and placebo group, respectively). Treatment with C21 was safe and well tolerated. INTERPRETATION: Among hospitalised patients with COVID-19 receiving C21 for 7 days there was no reduction in CRP compared to placebo. However, a post-hoc analysis indicated a marked reduction of requirement for oxygen at day 14. The day 14 results from this study justify further evaluation in a Phase 3 study and such a trial is currently underway. FUNDING: Vicore Pharma AB and LifeArc, UK.
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BACKGROUND: External agents, especially metal and wood dust, are believed to be risk factors for development of idiopathic pulmonary fibrosis (IPF). The aim of this case-control study was to investigate which occupational exposure types are associated with development of severe pulmonary fibrosis (PF), and especially IPF. METHODS: An extensive postal questionnaire including 30 specific items regarding occupational exposure was completed by 181 patients with severe PF and respiratory failure reported to the Swedish Oxygen Register, among whom 140 were judged as having IPF. The questionnaire was also completed by 757 control subjects. We stratified data for age, sex and smoking and calculated odds ratios (ORs). RESULTS: We found increased risk for IPF in men with exposure to birch dust (OR 2.7, 95% confidence interval (95% CI) 1.30-5.65) and hardwood dust (OR 2.7, 95% CI 1.14-6.52). Men also had slightly increased ORs associated with birds. We did not find any increased risk in association with metal dust exposure. CONCLUSION: Exposure for birch and hardwood dust may contribute to the risk for IPF in men.
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Poeira , Metais/efeitos adversos , Doenças Profissionais/etiologia , Exposição Ocupacional/efeitos adversos , Fibrose Pulmonar/etiologia , Madeira/efeitos adversos , Estudos de Casos e Controles , Poeira/análise , Feminino , Humanos , Masculino , Doenças Profissionais/epidemiologia , Exposição Ocupacional/estatística & dados numéricos , Fibrose Pulmonar/epidemiologia , Fatores de Risco , Fatores Sexuais , Suécia/epidemiologia , Fatores de TempoRESUMO
BACKGROUND: Chemoattractant receptor-homologous molecule expressed on T helper type 2 (Th2) cell (CRTh2) receptor antagonists is being investigated for asthma. OBJECTIVES: The aim of this study was to assess the effects of the CRTh2 receptor antagonist, AZD1981 (with/without inhaled corticosteroids [ICSs]), on lung function and asthma control. PATIENTS AND METHODS: Adults aged 18-60 years were enrolled in two randomized, placebo-controlled, parallel-group trials (protocol number: D9830C00003 [study 1, n=209] and protocol number: D9830C00004 [study 2, n=510]). In study 1, patients with stable asthma (forced expiratory volume in 1 second [FEV1]: 65%-110%) were withdrawn from ICS (<400 µg/d) and randomized to AZD1981 1,000 mg twice daily (bid) or placebo. In study 2, patients with uncontrolled asthma (FEV1: 40%-85%) despite ICS therapy (≥500 µg/d) were randomized to 50 mg, 400 mg, or 1,000 mg bid AZD1981 or placebo. The primary efficacy variable for both trials was the change in morning peak expiratory flow after 4 weeks of treatment. Secondary variables included Asthma Control Questionnaire (ACQ-5) scores, FEV1 assessments, safety, and tolerability. In study 2, efficacy was also assessed according to atopic status. RESULTS: Following 4 weeks of treatment, there was a nonsignificant increase in morning peak expiratory flow on AZD1981 1,000 mg bid (9.5 L/min vs placebo, P=0.086 [study 1] and 12 L/min vs placebo, P=0.16 [study 2]). In study 2, all doses of AZD1981 provided significant improvements in ACQ-5 scores (0.26-0.3 units vs placebo, P=0.010-0.022); however, there was no dose-response relationship. Improved ACQ-5 scores and FEV1 were observed in the majority of atopic patients treated with AZD1981. AZD1981 was well tolerated across treatment groups. CONCLUSION: Further research may be warranted in atopic patients to fully evaluate the clinical efficacy of AZD1981.
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Acetatos/farmacologia , Acetatos/uso terapêutico , Asma/tratamento farmacológico , Indóis/farmacologia , Indóis/uso terapêutico , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Acetatos/administração & dosagem , Administração Oral , Adolescente , Adulto , Método Duplo-Cego , Feminino , Humanos , Indóis/administração & dosagem , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Smoking is the major risk factor for the development of Chronic Obstructive Pulmonary Disease (COPD), but epidemiological data suggest that other etiological factors may also be involved. Chlamydia pneumoniae (Cpn) is an established cause of acute and chronic upper and lower respiratory tract infections. Data obtained from in vitro and in vivo studies indicate that Cpn infection can be involved in the development of both small airways disease and emphysema, the two major components of COPD. The aim of this study was to investigate the possible association between chronic Cpn infection and COPD. The study population was comprised of 199 consecutive patients who underwent bronchoscopy due to longstanding airway symptoms and for whom spirometry and serum samples for serology were available. Acute and convalescent sera were analysed for specific IgG and IgA Cpn antibodies using microimmunofluorescence. Chronic Cpn infection, defined as persistent elevated titres of IgA > or = 1/64, was present in 85 patients. Chronic infection was associated with smoking and higher age, but no gender difference was observed. Thirty patients had COPD, defined as FEV1/FVC < 70% without any features of asthma. Patients with COPD were older than those without, and there was no association with gender in this group. A statistically significant association, remaining after correction for smoking, was observed between chronic Cpn infection and COPD, and there was a trend for decreasing lung function with increasing antibody titres. The results suggest that chronic Cpn infection may be an independent risk factor for the development of COPD.
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Infecções por Chlamydophila/complicações , Chlamydophila pneumoniae , Doença Pulmonar Obstrutiva Crônica/microbiologia , Doença Aguda , Adulto , Fatores Etários , Idoso , Anticorpos Antibacterianos/sangue , Infecções por Chlamydophila/fisiopatologia , Chlamydophila pneumoniae/imunologia , Doença Crônica , Feminino , Volume Expiratório Forçado , Humanos , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Fatores de Risco , Fumar/efeitos adversos , Capacidade VitalRESUMO
Formoterol is a long-acting beta2-agonist with a rapid onset of effect in patients with chronic obstructive pulmonary disease (COPD), making it potentially suitable for both maintenance and as-needed bronchodilator treatment. To evaluate the efficacy and tolerability of maintenance formoterol in patients with COPD and to compare the effects of additional formoterol as needed with terbutaline. In this 6-month, double-blind study, 657 patients with COPD (40 years, forced expiratory volume in 1s [FEV1] 40-70% predicted normal) were randomized to formoterol 9 microg twice daily (bid) plus terbutaline 0.5 mg as needed (FORM bid), formoterol 9 microg bid plus formoterol 4.5 microg as needed (FORM bid+prn), or placebo bid plus terbutaline 0.5 mg as needed (placebo), all administered via Turbuhaler. Primary efficacy variables were FEV1 and the sum of breathlessness and chest tightness scores combined symptom score. Formoterol significantly (P<0.01) increased FEV(1) compared with placebo: FORM bid 6.5% (95% CI: 2.5, 10.7%); FORM bid+prn 11.8% (95% CI: 7.7, 16.2%). Combined symptom score decreased significantly in both formoterol groups compared with placebo: FORM bid -0.27 (95% CI: -0.49, -0.06; P=0.012); FORM bid+prn -0.32 (95% CI: -0.53, -0.11; P=0.0026). Similar significant (P<0.05) improvements were seen in both formoterol groups for morning peak expiratory flow, cough and sleep scores, and reliever use. In this study, formoterol 9 microg bid via Turbuhaler as maintenance therapy, with either formoterol or terbutaline as rescue medication, provided sustained improvements in lung function and COPD symptoms. Both formoterol regimens were well tolerated with no differences in adverse events or electrocardiogram profiles.
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Agonistas Adrenérgicos beta/uso terapêutico , Etanolaminas/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Corticosteroides/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Fumarato de Formoterol , Humanos , Pulmão/efeitos dos fármacos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Nebulizadores e Vaporizadores , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/psicologia , Qualidade de Vida , Terbutalina/uso terapêutico , Resultado do TratamentoRESUMO
OBJECTIVE: To investigate risk factors for acute coronary syndrome (ACS) in patients with new-onset rheumatoid arthritis (RA). METHODS: We performed a nested case-control study of patients with incident RA included in the Epidemiological Investigation of RA study. Cases with ACS were identified using Swedish national health registers and matched with up to 5 controls without ACS, based on incidence density-based sampling. Information on potential exposures (clinical disease activity, serologic features, genetic markers, comorbidities, pharmacotherapies, and sick leave) was collected from medical charts and register-based sources. RESULTS: We identified 138 cases and 624 controls. Smoking, history of myocardial infarction, and >50 days of sick leave the year following RA onset were associated with an increased risk of ACS. Area under the curve measurements of C-reactive protein level, erythrocyte sedimentation rate, Disease Activity Score in 28 joints (DAS28), and global health in the upper tertile during the first year and the complete followup period were both strongly associated with an increased risk of ACS. Treatment with disease-modifying antirheumatic drugs did not alter the ACS risk, nor did the presence of rheumatoid factor (RF) or shared epitope alleles, whereas high anti-citrullinated protein antibody (ACPA) levels were borderline significantly associated with ACS risk. CONCLUSION: In this study of risk factors for ACS in incident RA, clinical markers of inflammatory activity, disease activity, and total number of days of sick leave and disability pension during the first year following RA onset were identified as ACS risk factors. We found no association with RF, which was previously linked to cardiovascular disease risk in RA, but there was a borderline significant association with high ACPA levels.
Assuntos
Síndrome Coronariana Aguda/epidemiologia , Síndrome Coronariana Aguda/etiologia , Artrite Reumatoide/complicações , Síndrome Coronariana Aguda/sangue , Adulto , Idoso , Antirreumáticos/uso terapêutico , Artrite Reumatoide/sangue , Artrite Reumatoide/tratamento farmacológico , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Fator Reumatoide/sangue , Fatores de RiscoRESUMO
OBJECTIVE: Assessment of patient preferences for attributes of asthma treatments. METHODS: Two hundred ninety-eight patients (age range, 18 to 60 years) from 15 centers in Sweden completed a questionnaire concerning their asthma, and ranked 18 alternative treatments using conjoint analysis. Patients were receiving treatment with either inhaled corticosteroids (ICS) and short-acting bronchodilator (n = 123) or ICS and long-acting bronchodilator (separate inhalers, n = 87; combination inhaler, n = 88). Attributes analyzed were maintenance treatment, additional reliever, time to onset and duration of reliever, number of symptom-free days (SFDs) per month, and out-of-pocket cost per month. RESULTS: Conjoint analysis showed that the most important aspect of treatment was SFD. Forty percent of the patients had Assuntos
Antiasmáticos/uso terapêutico
, Asma/tratamento farmacológico
, Satisfação do Paciente
, Administração por Inalação
, Adolescente
, Corticosteroides/uso terapêutico
, Adulto
, Antiasmáticos/economia
, Broncodilatadores/uso terapêutico
, Custos de Medicamentos
, Feminino
, Humanos
, Masculino
, Pessoa de Meia-Idade
, Nebulizadores e Vaporizadores
, Inquéritos e Questionários
RESUMO
OBJECTIVES: To estimate the effects of smoking, gender and occupational exposure on the risk of developing severe pulmonary fibrosis (PF), including dose-response and interaction effects. METHODS: National case-control study of 171 patients (cases) who had started a long-term oxygen therapy for PF in Sweden between February 1997 and April 2000, and 719 random control participants from the general population. Of these cases, 137 had probable idiopathic PF (IPF). The ORs for smoking, gender and occupational exposure were estimated using Mantel-Haenszel analysis and conditional logistic regression, controlling for age and year of diagnosis. RESULTS: The adverse effect of smoking was amplified by male gender and occupational exposure, OR 4.6 (95% CI 2.1 to 10.3) for PF, and OR 3.0 (1.3 to 6.5) for IPF, compared with in non-exposed women. Higher cumulative smoking exposure was linearly associated with increased risks. Compared with smoking less than 10 pack-years, smoking ≥20 pack-years was associated with increased risk of PF and IPF, OR 2.6 (1.4 to 4.9) and OR 2.5 (1.3 to 5.0), respectively. CONCLUSIONS: Smoking has a dose-related association with increased risk of severe PF. Men with a history of smoking and occupational exposure is a particular risk group for developing severe PF.