RESUMEN
Exhaled breath contains numerous volatile organic compounds (VOCs) known to be related to lung disease like asthma. Its collection is non-invasive, simple to perform and therefore an attractive method for the use even in young children. We analysed breath in children of the multicenter All Age Asthma Cohort (ALLIANCE) to evaluate if 'breathomics' have the potential to phenotype patients with asthma and wheeze, and to identify extrinsic risk factors for underlying disease mechanisms. A breath sample was collected from 142 children (asthma: 51, pre-school wheezers: 55, healthy controls: 36) and analysed using gas chromatography-mass spectrometry (GC/MS). Children were diagnosed according to Global Initiative for Asthma guidelines and comprehensively examined each year over up to seven years. Forty children repeated the breath collection after 24 or 48 months. Most breath VOCs differing between groups reflect the exposome of the children. We observed lower levels of lifestyle-related VOCs and higher levels of the environmental pollutants, especially naphthalene, in children with asthma or wheeze. Naphthalene was also higher in symptomatic patients and in wheezers with recent inhaled corticosteroid use. No relationships with lung function or TH2 inflammation were detected. Increased levels of naphthalene in asthmatics and wheezers and the relationship to disease severity could indicate a role of environmental or indoor air pollution for the development or progress of asthma. Breath VOCs might help to elucidate the role of the exposome for the development of asthma. The study was registered at ClinicalTrials.gov (NCT02496468).
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Dermatitis Atópica , Microbiota , Dermatitis Atópica/tratamiento farmacológico , Humanos , Inflamación , Poaceae , Polen , PielRESUMEN
Chronic obstructive pulmonary disease (COPD) primarily affects the lungs; however, cardiovascular conditions are among the most common extrapulmonary comorbidities. Besides shared risk factors such as cigarette smoking, pathophysiological connections between the lung and the heart have been identified as mediators of reduced cardiac output. Recent research has focused on hyperinflation of the lung as a pulmonary cause for heart dysfunction. Hyperinflation is a typical lung abnormality seen in COPD; it is characterized by increased residual volume, intrathoracic gas volume, and total lung capacity while vital capacity is decreased. The degree of hyperinflation with airway obstruction is inversely related to left ventricular filling, stroke volume, and cardiac output. The underlying mechanisms are assumed to be compression of the pulmonary veins and thus reduced preload of the left heart as well as decreased pulmonary microvascular blood flow due to compression of the pulmonary vasculature. Treatment with a dual bronchodilator antagonizes this detrimental lung-heart unbalance effectively: Pulmonary blood flow, left ventricular end-diastolic volume, and stroke volume increase in COPD patients without cardiac abnormalities. Similar effects, yet less pronounced, were reported with single bronchodilator therapy. Future work needs to investigate whether these promising findings can be reproduced in COPD patients with cardiovascular diseases.
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Broncodilatadores , Enfermedad Pulmonar Obstructiva Crónica , Volumen Sistólico , Corazón/fisiopatología , Humanos , Pruebas de Función RespiratoriaRESUMEN
INTRODUCTION: Chronic lung allograft dysfunction with its clinical correlative of bronchiolitis obliterans syndrome (BOS) remains the major limiting factor for long-term graft survival. Currently there are no established methods for the early diagnosis or prediction of BOS. To assess the feasibility of breath collection as a non-invasive tool and the potential of breath volatile organic compounds (VOC) for the early detection of BOS, we compared the breath VOC composition between transplant patients without and different stages of BOS. METHODS: 75 outpatients (25 BOS stage 0, 25 BOS stage 1 + 2, 25 BOS stage 3) after bilateral lung transplantation were included. Exclusion criteria were active smoking, oxygen therapy and acute infection. Patients inhaled room air through a VOC and sterile filter and exhaled into an aluminum reservoir tube. Breath was loaded directly onto Tenax® TA adsorption tubes and was subsequently analyzed by gas-chromatography/mass-spectrometry. RESULTS: The three groups were age and gender matched, but differed with respect to time since transplantation, the spectrum of underlying disease, and treatment regimes. Relative to patients without BOS, BOS stage 3 patients showed a larger number of different VOCs, and more pronounced differences in the level of VOCs as compared to BOS stage 1 + 2 patients. Logistic regression analysis found no differences between controls and BOS 1 + 2, but four VOCs (heptane, isopropyl-myristate, ethyl-acetate, ionone) with a significant contribution to the discrimination between controls and BOS stage 3. A combination of these four VOCs separated these groups with an area under the curve of 0.87. CONCLUSION: Breath sample collection using our reservoir sampler in the clinical environment was feasible. Our results suggest that breath VOCs can discriminate severe BOS. However, convincing evidence for VOCs with a potential to detect early onset BOS is lacking.
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Aloinjertos/fisiopatología , Pruebas Respiratorias/métodos , Trasplante de Pulmón , Receptores de Trasplantes , Compuestos Orgánicos Volátiles/análisis , Factores de Confusión Epidemiológicos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Fumar/efectos adversosRESUMEN
BACKGROUND: Subcutaneous allergen immunotherapy with grass pollen allergoids has been proven to be effective and safe in the treatment of patients with allergic rhinoconjunctivitis. Based on the extensive cross-reactivity among Pooideae species, it has been suggested that grass pollen extracts could be prepared from a single species, rather than from a multiple species mixture. OBJECTIVE: To find the optimal dose of a Phleum pratense (P. pratense) allergoid preparation and compare its efficacy and safety to a 6-grass pollen allergoid preparation. METHODS: In this double-blind, placebo-controlled study (EudraCT: 2011-000674-58), three doses of P. pratense allergoid (1800 therapeutic units (TU), standard-dose 6000 TU and 18 000 TU) were compared with placebo and the marketed 6-grass pollen allergoid (6000 TU). In a pre-seasonal dosing regimen, 102 patients were randomized to five treatment groups and received nine subcutaneous injections. The primary efficacy endpoint was the change in weal size (late-phase reaction [LPR]) in response to the intracutaneous testing (ICT) before and after treatment, comparing the active allergoids to placebo. Secondary outcomes were the change in Total Nasal Symptom Score (TNSS) assessed in the allergen exposure chamber (AEC), the changes in P. pratense-serum-specific IgG4 and the incidence of adverse events (AEs). RESULTS: All three doses of the P. pratense and the 6-grass pollen allergoid preparations were significantly superior to placebo for the primary outcome, whereas there were no significant differences in the change in TNSS. Compared to the standard-dose, the high-dose of P. pratense did not produce any additional significant benefit, but showed a slight increase in AEs. Yet this increase in AEs was lower than for the 6-grass pollen preparation. CONCLUSIONS & CLINICAL RELEVANCE: The standard-dose of the new P. pratense allergoid was comparable to the marketed 6-grass pollen preparation at equal dose for the parameters measured.
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Alérgenos/inmunología , Relación Dosis-Respuesta Inmunológica , Phleum/efectos adversos , Extractos Vegetales/inmunología , Polen/inmunología , Rinitis Alérgica Estacional/inmunología , Rinitis Alérgica Estacional/terapia , Adolescente , Adulto , Anciano , Alergoides , Desensibilización Inmunológica/efectos adversos , Desensibilización Inmunológica/métodos , Femenino , Alemania , Humanos , Inmunoglobulina E/inmunología , Inmunoglobulina G/inmunología , Masculino , Persona de Mediana Edad , Extractos Vegetales/administración & dosificación , Rinitis Alérgica Estacional/diagnóstico , Inmunoterapia Sublingual , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Allergen exposure chambers (AECs) are clinical facilities allowing for controlled exposure of subjects to allergens in an enclosed environment. AECs have contributed towards characterizing the pathophysiology of respiratory allergic diseases and the pharmacological properties of new therapies. In addition, they are complementary to and offer some advantages over traditional multicentre field trials for evaluation of novel therapeutics. To date, AEC studies conducted have been monocentric and have followed protocols unique to each centre. Because there are technical differences among AECs, it may be necessary to define parameters to standardize the AECs so that studies may be extrapolated for driving basic immunological research and for marketing authorization purposes by regulatory authorities. METHODS: For this task force initiative of the European Academy of Allergy and Clinical Immunology (EAACI), experts from academia and regulatory agencies met with chamber operators to list technical, clinical and regulatory unmet needs as well as the prerequisites for clinical validation. RESULTS: The latter covered the validation process, standardization of challenges and outcomes, intra- and interchamber variability and reproducibility, in addition to comparability with field trials and specifics of paediatric trials and regulatory issues. CONCLUSION: This EAACI Position Paper aims to harmonize current concepts in AECs and to project unmet needs with the intent to enhance progress towards use of these facilities in determining safety and efficacy of new therapeutics in the future.
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Alérgenos/inmunología , Desensibilización Inmunológica/métodos , Ambiente Controlado , Exposición por Inhalación , Desensibilización Inmunológica/normas , Desensibilización Inmunológica/tendencias , Política de Salud , Humanos , Hipersensibilidad/inmunología , Hipersensibilidad/terapia , Exposición por Inhalación/efectos adversos , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: Efficacy testing of immunotherapy in field studies is often hampered by variation of airborne allergens. Standardized allergen exposure in challenge chamber settings might be an alternative. Therefore, we developed a universal technique to create an atmosphere loaded with allergen particles of adjustable size from aqueous solutions of licensed allergen extracts. OBJECTIVE: The aim of this study was to apply this technique and test the safety and efficacy of challenges with house dust mite (HDM) allergen in the Fraunhofer allergen challenge chamber. METHODS: Aerosol particles carrying HDM allergen were produced by spray-drying of an aqueous solution containing HDM allergen and lactose. In a monocenter, placebo-controlled, single-blind, dose-escalation pilot study, 18 subjects with perennial allergic rhinitis and sensitization to HDM were exposed to HDM allergen for 4 h at either 250, 500, 1000 SQE/m3 or lactose alone (0 SQE/m3 ) 7 days apart. The dose of 500 SQE/m³ was repeated to investigate reproducibility. Total nasal symptom score (TNSS) was the primary endpoint. RESULTS: Exposure to HDM increased TNSS (mean ± SD) to 3.4 ± 1.8, 3.3 ± 2.1, and 3.6 ± 2.0 at 250, 500 and 1000 SQE/m3 , respectively, while lactose alone did not change TNSS (0.7 ± 0.6). The results were reproducible at 500 SQE/m3 . Pulmonary function and adverse event frequency did not change with escalation of allergen dose. CONCLUSION: This HDM allergen particle generation is safe, specific and reproducible and can therefore be used for efficacy testing of immunotherapy and for basic clinical research.
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Antígenos Dermatofagoides/inmunología , Inmunización , Pyroglyphidae/inmunología , Adulto , Animales , Antígenos Dermatofagoides/administración & dosificación , Antígenos Dermatofagoides/efectos adversos , Desensibilización Inmunológica , Espiración , Femenino , Humanos , Inmunización/métodos , Inmunoglobulina E/inmunología , Masculino , Persona de Mediana Edad , Mucosa Nasal/inmunología , Mucosa Nasal/metabolismo , Óxido Nítrico/metabolismo , Pruebas de Función Respiratoria , Rinitis Alérgica/diagnóstico , Rinitis Alérgica/inmunología , Rinitis Alérgica/terapia , Factores de Riesgo , Adulto JovenRESUMEN
Due to its high sensitivity, compact size and low cost ion mobility spectrometry (IMS) has the potential to become a point-of-care breath analyzer. Therefore, we developed a prototype of a compact, closed gas loop IMS with gas chromatographic (GC) pre-separation and high resolving power of R = 90. In this study, we evaluated the performance of this GC-IMS under clinical conditions in a COPD study to find correlations between VOCs (10 ppbv to 1 ppmv) and COPD. Furthermore, in order to investigate possible correlations between ultra-low concentrated breath VOCs (0.1 pptv to 1 ppbv) and COPD, a modified mass spectrometer (MS) with atmospheric pressure chemical ionization (APCI) and GC pre-separation (GC-APCI-MS) was used. The GC-IMS has been used in 58 subjects (21 smokers with moderate COPD, 12 ex-smokers with COPD, 16 healthy smokers and 9 non-smokers). GC-APCI-MS data were available for 94 subjects (21 smokers with moderate COPD, 25 ex-smokers with COPD, 25 healthy smokers and 23 non-smokers). For 44 subjects, a comparison between GC-IMS and GC-APCI-MS data could be performed. Due to service intervals, subject availability and corrupt data, patient numbers were different for GC-APCI-MS and GC-IMS measurements. Using GC-IMS, three VOCs have been found showing a significant difference between healthy controls and patients with COPD. In the GC-APCI-MS data, we only observed one distinctive VOC, which has been identified as 2-pentanone. This proof-of-principle study shows the potential of our high-resolution GC-IMS in the clinical environment. Due to different linear dynamic response ranges, the data of GC-IMS and GC-APCI-MS were only comparable to a limited extent.
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Pruebas Respiratorias/métodos , Cromatografía de Gases/métodos , Espectrometría de Masas/métodos , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Compuestos Orgánicos Volátiles/análisis , Adulto , Anciano , Espiración , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sistemas de Atención de Punto , Adulto JovenRESUMEN
There is increasing evidence that breath volatile organic compounds (VOC) have the potential to support the diagnosis and management of inflammatory diseases such as COPD. In this study we used a novel breath sampling device to search for COPD related VOCs. We included a large number of healthy controls and patients with mild to moderate COPD, recruited subjects at two different sites and carefully controlled for smoking. 222 subjects were recruited in Hannover and Marburg, and inhaled cleaned room air before exhaling into a stainless steel reservoir under exhalation flow control. Breath samples (2.5 l) were continuously drawn onto two Tenax(®) TA adsorption tubes and analyzed in Hannover using thermal desorption-gas chromatography-mass spectrometry (TD-GC-MS). Data of 134 identified VOCs from 190 subjects (52 healthy non-smokers, 52 COPD ex-smokers, 49 healthy smokers, 37 smokers with COPD) were included into the analysis. Active smokers could be clearly discriminated by higher values for combustion products and smoking related VOCs correlated with exhaled carbon monoxide (CO), indicating the validity of our data. Subjects from the study sites could be discriminated even after exclusion of cleaning related VOCs. Linear discriminant analysis correctly classified 89.4% of COPD patients in the non/ex-smoking group (cross validation (CV): 85.6%), and 82.6% of COPD patients in the actively smoking group (CV: 77.9%). We extensively characterized 134 breath VOCs and provide evidence for 14 COPD related VOCs of which 10 have not been reported before. Our results show that, for the utilization of breath VOCs for diagnosis and disease management of COPD, not only the known effects of smoking but also site specific differences need to be considered. We detected novel COPD related breath VOCs that now need to be tested in longitudinal studies for reproducibility, response to treatment and changes in disease severity.
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Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Fumar/fisiopatología , Compuestos Orgánicos Volátiles/análisis , Adulto , Anciano , Líquidos Corporales/química , Pruebas Respiratorias/métodos , Espiración , Cromatografía de Gases y Espectrometría de Masas/métodos , Humanos , Masculino , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Reproducibilidad de los Resultados , Adulto JovenRESUMEN
Segmental endotoxin challenge with lipopolysaccharide (LPS) can be used as a pharmacodynamic model to safely induce a transient airway inflammation in the peripheral lung of healthy subjects and to test the anti-inflammatory efficacy of investigational new drugs. In contrast to whole lung LPS challenge only a fraction of the dose is required that can be precisely administered to a specific lung region and a vehicle challenged segment as an intra-subject control can be included. The aim of this study was to assess the intra- and inter-individual variability of the response to segmental LPS challenge for the appropriate design and power calculation of future clinical trials. Two cohorts with 10 subjects each underwent two segmental LPS challenges within five weeks. The inflammatory response was evaluated in bronchoalveolar lavage (BAL) fluid at 6 (cohort 1) and 24 h (cohort 2) both in the LPS and in a vehicle challenged segment, as well as in plasma for up to 26 h post LPS challenge. While the cytokine response was more pronounced at 6 h, the influx of neutrophils and monocytes dominated at 24 h; e.g. neutrophils increased from a median (inter-quartile range, IQR) of 0.14 (0.16) and 0.09 (0.08)x10(4) cells/mL BAL fluid at baseline to 10.2 (17.1) and 19.3 (15.9)x10(4) cells/mL 24 h after the two separate challenges. The within-subject variability was higher than the between-subject variability for most of the markers. However, sample size estimations based on the variability of outcome variables found lower or equal numbers with cross-over designs compared to parallel group designs for cellular markers at 24 h and cytokine variables at 6 h. The segmental LPS challenge model was safe. Future study designs have to balance between burden to the study subjects (4 versus 2 bronchoscopies), variability (within-versus between-subject), and the desired outcome variable (cells versus chemo/cytokine).
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Endotoxinas/toxicidad , Lipopolisacáridos/toxicidad , Neumonía/inducido químicamente , Neumonía/patología , Adulto , Biomarcadores/sangre , Líquido del Lavado Bronquioalveolar , Broncoscopía , Quimiocinas/sangre , Estudios de Cohortes , Citocinas/sangre , Femenino , Voluntarios Sanos , Humanos , Masculino , Monocitos/efectos de los fármacos , Neutrófilos/efectos de los fármacos , Reproducibilidad de los Resultados , Pruebas de Función RespiratoriaRESUMEN
BACKGROUND: The ozone challenge model can be used to assess the efficacy of anti-inflammatory compounds in early phases of clinical drug development. PUR118, a calcium salt based formulation engineered in the iSPERSE(TM) dry powder delivery technology, is a novel anti-inflammatory drug for COPD. Here we evaluated the efficacy and safety of three doses of PUR118 in attenuating ozone-induced airway inflammation in healthy volunteers. METHODS: In a single-blind, phase 1B proof of concept study, 24 subjects were enrolled to sequentially receive three doses of PUR118 (5.5 mg, n = 18; 11.0 mg, n = 18; 2.8 mg, n = 16). Each dose was inhaled 3 times (1, 13, 25 h, preceded by 2 puffs salbutamol) before the ozone exposure (250 ppb, 3 h intermittent exercise). Sputum was induced 3 h after the end of exposure. RESULTS: Sputum neutrophils, sputum CD14+ cells, as well as concentrations of IL1B, IL6, IL8, MMP9, and TNFA in sputum supernatant significantly increased after ozone exposure (n = 24). The percentage of sputum neutrophils (n = 12 who completed all treatments) did not change following treatment with different doses of PUR118. The high dose treatment group (n = 16) showed a decrease in the percentage and number of sputum macrophages (p ≤ 0.05) as well as a decrease in blood neutrophils (p = 0.04), and an increase in blood CD14 + cells (p = 0.04) compared to baseline. All dosages of PUR118 were safe and well tolerated. CONCLUSION: Ozone challenge resulted in the expected and significant increase of sputum inflammatory parameters. Treatment with multiple rising doses of PUR118 was safe and three applications within 25 h prior to the ozone challenge had small effects on ozone-induced airway inflammation. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01690949. Registered 12 September 2012.
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Compuestos de Calcio/administración & dosificación , Compuestos de Calcio/farmacología , Inflamación/prevención & control , Lactatos/administración & dosificación , Lactatos/farmacología , Ozono/efectos adversos , Sistema Respiratorio/efectos de los fármacos , Administración por Inhalación , Adulto , Antiinflamatorios/administración & dosificación , Antiinflamatorios/efectos adversos , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Biomarcadores/metabolismo , Compuestos de Calcio/efectos adversos , Compuestos de Calcio/uso terapéutico , Femenino , Humanos , Inflamación/inducido químicamente , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Lactatos/efectos adversos , Lactatos/uso terapéutico , Receptores de Lipopolisacáridos/inmunología , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Masculino , Metaloproteinasa 9 de la Matriz/metabolismo , Persona de Mediana Edad , Neutrófilos/efectos de los fármacos , Método Simple Ciego , Factor de Necrosis Tumoral alfa/metabolismo , Adulto JovenRESUMEN
BACKGROUND: Genomewide association studies identified ORMDL3 as a plausible asthma candidate gene. ORMDL proteins regulate sphingolipid metabolism and ceramide homeostasis and participate in lymphocyte activation and eosinophil recruitment. Strong sequence homology between the three ORMDL genes and ORMDL protein conservation among different species suggest that they may have shared functions. We hypothesized that if single nucleotide polymorphisms (SNPs) in ORMDL3 alter its gene expression and play a role in asthma, variants in ORMDL1 and ORMDL2 might also be associated with asthma. METHODS: Asthma associations of 44 genotyped SNPs were determined in at least 1303 subjects (651 asthmatics). ORMDL expression was evaluated in peripheral blood mononuclear cells (PBMC) from 55 subjects (eight asthmatics) before and after allergen stimulation, and in blood (n = 60, 5 asthmatics). Allele-specific cis-effects on ORMDL expression were assessed. Interactions between human ORMDL proteins were determined in living cells. RESULTS: Sixteen SNPs in all three ORMDLs were associated with asthma (14 in ORMDL3). Baseline expression of ORMDL1 (P = 1.7 × 10(-6) ) and ORMDL2 (P = 4.9 × 10(-5) ) was significantly higher in PBMC from asthmatics, while induction of ORMDLs upon stimulation was stronger in nonasthmatics. Disease-associated alleles (rs8079416, rs4795405, rs3902920) alter ORMDL3 expression. ORMDL proteins formed homo- and heterooligomers and displayed similar patterns of interaction with SERCA2 and SPT1. CONCLUSIONS: Polymorphisms in ORMDL genes are associated with asthma. Asthmatics exhibit increased ORMDL levels, suggesting that ORMDLs contribute to asthma. Formation of heterooligomers and similar interaction patterns with proteins involved in calcium homeostasis and sphingolipid metabolism could indicate shared biological roles of ORMDLs, influencing airway remodeling and hyperresponsiveness.
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Asma/genética , Regulación de la Expresión Génica , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Proteínas de la Membrana/genética , Mutación , Factores de Edad , Alelos , Asma/inmunología , Asma/metabolismo , Estudios de Casos y Controles , Mapeo Cromosómico , Epistasis Genética , Femenino , Genotipo , Humanos , Desequilibrio de Ligamiento , Masculino , Proteínas de la Membrana/metabolismo , Familia de Multigenes , Oportunidad Relativa , Polimorfismo de Nucleótido Simple , Unión ProteicaRESUMEN
BACKGROUND: Tiotropium is generally well tolerated; however, there has been debate whether antimuscarinics, particularly tiotropium administered via Respimat(®) Soft Mist(™) Inhaler, may induce cardiac arrhythmias in a vulnerable subpopulation with cardiovascular comorbidity. The aim of this study was to provide evidence of the cardiac safety of tiotropium maintenance therapy. METHODS: Combined analysis of Holter electrocardiogram (ECG) data from clinical trials of tiotropium in chronic obstructive pulmonary disease (COPD). Trials in the Boehringer Ingelheim clinical trials database conducted between 2003 and 2012, involving tiotropium HandiHaler(®) 18 µg and/or tiotropium Respimat(®) (1.25-, 2.5-, 5.0- and 10-µg doses) were reviewed. All trials involving Holter-ECG monitoring during this period were included in the analysis. Men and women aged ≥ 40 years with a smoking history of ≥ 10 pack-years, and a clinical diagnosis of COPD were included. Holter ECGs were evaluated for heart rate (HR), supraventricular premature beats (SVPBs), ventricular premature beats (VPBs) and pauses. Quantitative and categorical end-points were derived for each of the Holter monitoring days. RESULTS: Four trials (n = 727) were included in the analysis. Respimat(®) (1.25-10 µg) or HandiHaler(®) (18 µg) was not associated with changes in HR, SVPBs, VPBs and pauses compared with placebo or the pretreatment baseline period. In terms of cardiac arrhythmia end-points, there was no evidence for an exposure-effect relationship. CONCLUSIONS: In this analysis, tiotropium maintenance therapy administered using Respimat(®) (1.25-10 µg) or HandiHaler(®) (18 µg) once daily for periods of up to 48 weeks was well tolerated with no increased risk of cardiac arrhythmia in patients with COPD.
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Corazón/efectos de los fármacos , Seguridad del Paciente , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como Asunto , Bromuro de Tiotropio/efectos adversos , Adulto , Anciano , Electrocardiografía/estadística & datos numéricos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Antagonistas Muscarínicos/efectos adversos , Bromuro de Tiotropio/farmacología , Bromuro de Tiotropio/uso terapéuticoRESUMEN
The aim of the study was to characterize pharmacokinetics of tiotropium solution 5 µg compared to powder 18 µg and assess dose-dependency of tiotropium solution pharmacodynamics in comparison to placebo. In total 154 patients with chronic obstructive pulmonary disease (COPD) were included in this multicenter, randomized, double-blind within-solution (1.25, 2.5, 5 µg, and placebo), and open-label powder 18 µg, crossover study, including 4-week treatment periods. Primary end points were peak plasma concentration (Cmax,ss ), and area under the plasma concentration-time profile (AUC0-6h,ss ), both at steady state. The pharmacodynamic response was assessed by serial spirometry (forced expiratory volume in 1 second/forced vital capacity). Safety was evaluated as adverse events and by electrocardiogram/Holter. Tiotropium was rapidly absorbed with a median tmax,ss of 5-7 minutes postdosing for both devices. The gMean ratio of solution 5 µg over powder 18 µg was 81% (90% confidence interval, 73-89%) for Cmax,ss and 76% (70-82%) for AUC0-6h,ss , indicating that bioequivalence was not established. Dose ordering for bronchodilation was observed. Powder 18 µg and solution 5 µg were most effective, providing comparable bronchodilation. All treatments were well tolerated with no apparent relation to dose or device. Comparable bronchodilator efficacy to powder18 µg at lower systemic exposure supports tiotropium solution 5 µg for maintenance treatment of COPD.
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Broncodilatadores/farmacocinética , Antagonistas Colinérgicos/farmacocinética , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Derivados de Escopolamina/farmacocinética , Anciano , Broncodilatadores/administración & dosificación , Broncodilatadores/efectos adversos , Antagonistas Colinérgicos/administración & dosificación , Antagonistas Colinérgicos/efectos adversos , Estudios Cruzados , Método Doble Ciego , Femenino , Volumen Espiratorio Forzado , Humanos , Masculino , Persona de Mediana Edad , Polvos , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Derivados de Escopolamina/administración & dosificación , Derivados de Escopolamina/efectos adversos , Soluciones , Bromuro de Tiotropio , Resultado del TratamientoAsunto(s)
Alérgenos/inmunología , Ácidos Araquidónicos/metabolismo , Asma/inmunología , Líquido del Lavado Bronquioalveolar/química , Moduladores de Receptores de Cannabinoides/metabolismo , Alcamidas Poliinsaturadas/metabolismo , Receptor Cannabinoide CB2/metabolismo , Adulto , Asma/metabolismo , Pruebas de Provocación Bronquial , Líquido del Lavado Bronquioalveolar/inmunología , Endocannabinoides , Humanos , Inflamación/inmunología , Inflamación/metabolismo , Persona de Mediana Edad , Adulto JovenRESUMEN
Prediction of lung innate immune responses is critical for developing new drugs. Well-established immune modulators like lipopolysaccharides (LPS) can elicit a wide range of immunological effects. They are involved in acute lung diseases such as infections or chronic airway diseases such as COPD. LPS has a strong adjuvant activity, but its pyrogenicity has precluded therapeutic use. The bacterial lipopeptide MALP-2 and its synthetic derivative BPPcysMPEG are better tolerated. We have compared the effects of LPS and BPPcysMPEG on the innate immune response in human precision-cut lung slices. Cytokine responses were quantified by ELISA, Luminex, and Meso Scale Discovery technology. The initial response to LPS and BPPcysMPEG was marked by coordinated and significant release of the mediators IL-1ß, MIP-1ß, and IL-10 in viable PCLS. Stimulation of lung tissue with BPPcysMPEG, however, induced a differential response. While LPS upregulated IFN-γ, BPPcysMPEG did not. This traces back to their signaling pathways via TLR4 and TLR2/6. The calculated exposure doses selected for LPS covered ranges occurring in clinical studies with human beings. Correlation of obtained data with data from human BAL fluid after segmental provocation with endotoxin showed highly comparable effects, resulting in a coefficient of correlation >0.9. Furthermore, we were interested in modulating the response to LPS. Using dexamethasone as an immunosuppressive drug for anti-inflammatory therapy, we found a significant reduction of GM-CSF, IL-1ß, and IFN-γ. The PCLS-model offers the unique opportunity to test the efficacy and toxicity of biological agents intended for use by inhalation in a complex setting in humans.
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Citocinas/inmunología , Inmunidad Innata/inmunología , Factores Inmunológicos/inmunología , Pulmón/inmunología , Adulto , Antiinflamatorios/inmunología , Quimiocina CCL4/inmunología , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Humanos , Interferón gamma/inmunología , Interleucina-10/inmunología , Interleucina-1beta/inmunología , Lipopéptidos/inmunología , Lipopolisacáridos/inmunología , Masculino , Polietilenglicoles , Receptores Toll-Like/inmunologíaRESUMEN
BACKGROUND: Efficacy testing of drugs in seasonal allergic rhinitis (SAR) is often disturbed by seasonal variations of environmental allergens, and assessment of onset and duration of action is hardly possible under natural conditions. Allergen provocation in an environmental challenge chamber (ECC) can be of added value in this respect. However, the specificity, sensitivity, and reproducibility of outcome measures under both settings are unclear. OBJECTIVE: The aim of this study was to investigate and compare the diagnostic value (specificity, sensitivity, and reproducibility) of clinical end-points and biomarkers both following allergen provocation in an ECC and under natural conditions. METHODS: Sixty adult patients with SAR to grass and 60 healthy subjects were exposed twice to grass pollen in an ECC and observed twice during the pollen season. Symptoms, nasal flow, as well as exhaled and nasal nitric oxide (NO) were investigated. RESULTS: The total nasal symptom score (TNSS) in the ECC had the best reproducibility (intraclass correlation coefficient ICC=0.86) and sensitivity/specificity [area under receiver operating characteristic curve (AUC)=0.99] of all measures. Symptoms in season also had good sensitivity/specificity but were far less reproducible. Nasal flow in the ECC had good sensitivity/specificity but reproducibility was limited. NO measurements showed good reproducibility but sensitivity/specificity were limited, except for exhaled NO in season (AUC=0.75). CONCLUSION: The high reproducibility and sensitivity/specificity in the ECC suggests that TNSS is a valuable outcome measure. While exhaled NO can be considered to monitor airway inflammation, nasal NO appears to be unspecific.
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Biomarcadores/análisis , Óxido Nítrico/análisis , Poaceae/inmunología , Polen/inmunología , Rinitis Alérgica Estacional/diagnóstico , Adolescente , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
UNLABELLED: Antihistamines and nasal decongestants are well-established therapeutics in allergic rhinitis. However, no data are available which directly compare the effect size of the single substances with their combination in a single study including placebo (PLA) treatment. OBJECTIVE: The aim of this study was to evaluate the effect of a combination of cetirizine (CET) and pseudoephedrine (PSE) and to compare it to treatment with CET or PSE alone and to PLA during grass pollen allergen challenge in an environmental challenge chamber (ECC). MATERIAL AND METHODS: In a randomized, double-blind, placebo-controlled, four-way crossover study the effect of a combination of 10 mg CET with 120 mg PSE (CET + PSE) versus CET or PSE alone or PLA on symptoms, nasal flow, and nasal secretions was investigated in 49 patients with intermittent allergic rhinitis. Subjects underwent four 6-h pollen exposures in an ECC with administration of the drugs after 2 h. RESULTS: The induction of nasal symptoms, nasal secretion and nasal obstruction (measured as nasal flow) during the first 2 h of pollen exposure was highly reproducible at the 4 consecutive exposures. The symptom of nasal obstruction was significantly reduced after treatment with CET + PSE compared to the treatment with CET or PSE alone or PLA (p < 0.0001). Furthermore, the combination treatment significantly reduced the total nasal symptom score (TNSS) and visual analogue scale score (VAS) compared to the single treatments or PLA. Nasal flow was significantly increased after treatment with CET + PSE and PSE and nasal secretions were significantly reduced by CET + PSE and CET without significant additional improvement of the combination therapy. CONCLUSION: The combination treatment with CET and PSE is more effective than treatment with single substances in subjects with allergic rhinitis.
Asunto(s)
Cetirizina/uso terapéutico , Antagonistas de los Receptores Histamínicos H1 no Sedantes/uso terapéutico , Seudoefedrina/uso terapéutico , Rinitis Alérgica Estacional/tratamiento farmacológico , Adulto , Cetirizina/administración & dosificación , Estudios Cruzados , Método Doble Ciego , Combinación de Medicamentos , Sinergismo Farmacológico , Femenino , Antagonistas de los Receptores Histamínicos H1 no Sedantes/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Descongestionantes Nasales/administración & dosificación , Descongestionantes Nasales/uso terapéutico , Obstrucción Nasal/tratamiento farmacológico , Obstrucción Nasal/etiología , Polen/inmunología , Seudoefedrina/administración & dosificación , Rinitis Alérgica Estacional/inmunología , Adulto JovenRESUMEN
BACKGROUND AND OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is one of the most common causes of chronic morbidity and mortality. The "Burden of Obstructive Lung Disease" (BOLD) initiative was established as an international study collecting data about the prevalence of COPD. The Medical University of Hanover took part in this study collecting data representative for Germany. METHODS: 683 individuals aged = 40 years from the city and region of Hannover were included in the study. On the basis of standardized questionnaires data were collected on general health, physical and mental capability, smoking habits and occupational exposure to dust. All participants performed spirometry before and after inhalation of salbutamol. RESULTS: The prevalence of COPD, GOLD (Global Health Initiative on Obstructive Lung Disease) severity stage = I, was 13.2% (GOLD stage I: 7.4%; GOLD stage II: 5.0%, GOLD stage III or IV: 0.8%). There was a marked increase of the prevalence of COPD depending on age and smoking habits. The percentage of active smokers in the sample was 20.6 %. Among younger participants the percentage of female smokers was noticeable higher than in older subjects. Although clinical symptoms of COPD, GOLD stage = III correlated with disease severity, only persons with COPD reported reduced physical capability. CONCLUSION: COPD is a highly prevalent disease. With regard to the increasing life expectancy and the change of smoking habits of the population, a further increase of morbidity and mortality due to COPD must be expected, especially in women.
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Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Fumar/epidemiología , Adulto , Factores de Edad , Anciano , Femenino , Alemania/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Calidad de Vida , Índice de Severidad de la Enfermedad , Factores Sexuales , EspirometríaRESUMEN
Pneumococcal infections (pneumonia, otitis media, sinusitis, meningitis) are common and usually involve toddlers and the elderly. Currently, two pneumococcal vaccines are in clinical use. The older vaccine consists of pure capsular polysaccharides from 23 pneumococcal serotypes and induces only a limited B-cell response because polysaccharides are poor antigens that stimulate mainly B-cells. In 2000, a vaccination program with a novel 7-valent pneumococcal conjugate vaccine was launched in the U.S. The conjugation of capsular polysaccharides with a highly immunogenic diphtheria toxoid protein induces both a T cell and B cell response that results in specific humoral and mucosal immunity. Since children are the main reservoir of pneumococci, the 7-valent conjugate vaccine seems to eradicate the respective pneumococcal serotypes within the population, as demonstrated by recent US data. Pronounced herd immunity resulted in a decrease in invasive pneumococcal diseases in vaccinees and non-vaccinees as well as in a reduction of antibiotic resistance rates. However, recent data suggest a replacement of vaccine-serotypes by non-vaccine serotypes, which conquer the ecological niche created by the vaccine. In order to encounter this problem a 13-valent conjugated vaccine is currently under development.