RESUMEN
BACKGROUND: The budesonide/formoterol combination is successfully used for fast relief of asthma symptoms in addition to its use as maintenance therapy. The temporarily increased corticosteroid dose during increasing inhaler use for symptom relief is likely to suppress any temporary increase in airway inflammation and may mitigate or prevent asthma exacerbations. The relative contribution of the budesonide and formoterol components to the improved asthma control is unclear. METHODS: The acute protective effect of inhaled budesonide was tested in a model of temporarily increased airway inflammation with repeated indirect airway challenges, mimicking an acute asthma exacerbation. A randomised, double-blind, cross-over study design was used. Asthmatic patients (n = 17, mean FEV1 95% of predicted) who previously demonstrated a > or = 30% fall in forced expiratory volume in 1 second (FEV1) after inhaling adenosine 5'-monophosphate (AMP), were challenged on four consecutive test days, with the same dose of AMP (at 09:00, 12:00 and 16:00 hours). Within 1 minute of the maximal AMP-induced bronchoconstriction at 09:00 hours, the patients inhaled one dose of either budesonide/formoterol (160/4.5 microg), formoterol (4.5 microg), salbutamol (2 x 100 microg) or placebo. The protective effects of the randomised treatments were assessed by serial lung function measurements over the test day. RESULTS: In the AMP provocations at 3 and 7 hours after inhalation, the budesonide/formoterol combination provided a greater protective effect against AMP-induced bronchoconstriction compared with formoterol alone, salbutamol and placebo. In addition all three active treatments significantly increased FEV1 within 3 minutes of administration, at a time when inhaled AMP had induced the 30% fall in FEV1. CONCLUSIONS: A single dose of budesonide/formoterol provided a greater protective effect against inhaled AMP-induced bronchoconstriction than formoterol alone, both at 3 and at 7 hours after inhalation. The acute protection against subsequent bronchoconstrictor stimuli such as inhaled AMP and the rapid reversal of airway obstruction supports the use of budesonide/formoterol for both relief and prevention in the treatment of asthma.
Asunto(s)
Agonistas Adrenérgicos beta/uso terapéutico , Albuterol/uso terapéutico , Asma/tratamiento farmacológico , Broncoconstricción/efectos de los fármacos , Broncodilatadores/uso terapéutico , Budesonida/uso terapéutico , Etanolaminas/uso terapéutico , Glucocorticoides/uso terapéutico , Adenosina Monofosfato/administración & dosificación , Administración por Inhalación , Agonistas Adrenérgicos beta/administración & dosificación , Adulto , Albuterol/administración & dosificación , Asma/fisiopatología , Pruebas de Provocación Bronquial , Broncoconstrictores/administración & dosificación , Broncodilatadores/administración & dosificación , Budesonida/administración & dosificación , Estudios Cruzados , Método Doble Ciego , Combinación de Medicamentos , Etanolaminas/administración & dosificación , Femenino , Volumen Espiratorio Forzado , Fumarato de Formoterol , Glucocorticoides/administración & dosificación , Humanos , Masculino , Flujo Espiratorio Medio Máximo , Persona de Mediana Edad , Países Bajos , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
Systemic corticosteroids and additional short-acting beta2-agonists are commonly used in exacerbations of chronic obstructive pulmonary disease (COPD). In this double-blind study, the combination of a high-dose inhaled corticosteroid with a rapid-onset long-acting beta2-agonist was evaluated in the treatment of out-patient COPD exacerbations. The primary aim was to compare 14-day treatment effects of budesonide/formoterol to placebo on sputum eosinophils and, secondarily, on other indices of inflammation, forced expiratory flow in one second (FEV(1)), symptoms, health status, and adverse events. Forty-five patients not using steroids (37 male, 21/24 current/ex smoker, median packyears 38, age 65 years, FEV(1) 61% predicted), experiencing a COPD exacerbation, were treated at home with budesonide/formoterol (320/9 microg 4 times daily), prednisolone (30 mg daily), or placebo for 14 days. Sputum eosinophils were significantly reduced by budesonide/formoterol (-57%) compared to placebo (+24%) (p = 0.01). Budesonide/formoterol reduced total symptom scores significantly (p = 0.01) compared to placebo. The increase in FEV(1) by 2 weeks of treatment with budesonide/formoterol (125 ml) was not significantly different from that of placebo (43 ml) (p = 0.07). Budesonide/ formoterol treatment did not suppress morning serum cortisol compared to placebo (-16%; p = 0.50). In conclusion, budesonide/formoterol reduces sputum eosinophils and improves symptoms in the treatment of out-patient COPD exacerbations.
Asunto(s)
Antiinflamatorios/uso terapéutico , Broncodilatadores/uso terapéutico , Budesonida/uso terapéutico , Etanolaminas/uso terapéutico , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Administración por Inhalación , Administración Oral , Anciano , Método Doble Ciego , Combinación de Medicamentos , Eosinófilos/efectos de los fármacos , Eosinófilos/metabolismo , Femenino , Fumarato de Formoterol , Humanos , Masculino , Persona de Mediana Edad , Prednisolona/administración & dosificación , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Pruebas de Función Respiratoria , Esputo/química , Resultado del TratamientoRESUMEN
AIMS: Budesonide, unlike fluticasone propionate, undergoes fatty acid esterification in the lungs, and there is a need to characterize fully the distribution and fate of the two drugs after inhalation in humans. METHODS: This open-label, randomized study was performed in adults undergoing whole lung or lobar resection resulting from lung cancer. Patients were given single 1000-mug doses of both budesonide and fluticasone propionate via dry powder inhalers before surgery. Tissue samples from peripheral and central lung, an ex vivo bronchial brush sample and intercostal muscle, together with plasma samples, were taken during surgery and analysed by liquid chromatography plus tandem mass spectrometry. RESULTS: Lung tissue samples were obtained from 22 patients at surgery, 1-43 h after drug dosing. Budesonide was detectable from earliest sampling in central and peripheral lung tissue up to 10 h (in six of 22 samples), fluticasone propionate up to 22 h after inhalation (in 16 of 22 samples), and budesonide oleate up to 43 h after inhalation (in 21 of 22 samples). Budesonide, but not fluticasone propionate, was detected in intercostal muscle for up to 10 h after inhalation. Bronchial brush samples showed the presence of fluticasone propionate for up to 18 h, suggesting the presence of undissolved drug powder particles in the airway lumen. CONCLUSION: Sustained retention of esterified budesonide in the lungs supports the prolonged duration of action of budesonide and suitability for once-daily administration.
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Androstadienos/administración & dosificación , Budesonida/administración & dosificación , Esterificación/efectos de los fármacos , Neoplasias Pulmonares/tratamiento farmacológico , Administración por Inhalación , Adulto , Anciano , Androstadienos/metabolismo , Budesonida/metabolismo , Femenino , Fluticasona , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
RATIONALE: Limited information is available on repeatability of inflammatory parameters in whole induced sputum samples from patients with COPD. OBJECTIVES: To study short-term and long-term repeatability in induced sputum samples in 22 patients with moderate to severe, stable COPD (mean age 64 yr, mean FEV(1) 1.91 L=65% of predicted). Samples were collected on 71 occasions twice within 1 to 7 days (mean 3.8 days) and on 12 occasions twice with an interval of 3 months while clinically stable. Cell differentials, markers of neutrophilic and eosinophilic inflammation, respiratory membrane permeability and size-selective permeation were assessed. FINDINGS: Parameters of permeability and of size-selective permeation, % eosinophils and % neutrophils showed the best short-term repeatability with intra-class correlation coefficients (Ri) of 0.61 to 0.90, followed by total cell count (TCC) with Ri of 0.52. Repeatability of soluble cell activation markers was less satisfactory (Ri 0.34 to 0.52). Mean short-term within-patient variability for TCC and permeability was approximately 2-fold and for cell activation markers 3-fold; mean between-patients variability was twice as high. Inducing sputum slightly enhanced eosinophil numbers and % neutrophils and decreased % macrophages in successive IS samples. Long-term repeatability was comparable to short-term repeatability but variability increased. CONCLUSIONS: Repeatability of parameters assessed in whole sputum is similar as reported previously for sputum plugs. In COPD an induced sputum procedure has a minor pro-inflammatory effect. The current data facilitates power calculations but also indicates that studies using inflammatory markers in sputum may easily be underpowered.
Asunto(s)
Proteína Catiónica del Eosinófilo/metabolismo , Inflamación/metabolismo , Interleucina-8/metabolismo , Peroxidasa/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Esputo/química , Adulto , Anciano , Biomarcadores/metabolismo , Recuento de Células , Permeabilidad de la Membrana Celular , Ensayo de Inmunoadsorción Enzimática , Eosinófilos/patología , Femenino , Estudios de Seguimiento , Humanos , Inflamación/patología , Masculino , Persona de Mediana Edad , Neutrófilos/patología , Pronóstico , Enfermedad Pulmonar Obstructiva Crónica/patología , Mucosa Respiratoria/metabolismo , Esputo/citologíaRESUMEN
Inhalers containing corticosteroids and long-acting beta2-agonists are becoming increasingly important in asthma management. A rapid effect is important to patients, particularly during exacerbations. We compared the onset of bronchodilation and patient-perceived relief from dyspnoea following single-inhaler budesonide/formoterol or salmeterol/fluticasone in a model of acute bronchoconstriction. A randomised, double-blind, double-dummy, single-dose, crossover study included 27 outpatients with asthma (mean age 35 years; mean FEV1 90% predicted normal). Immediately following methacholine-induced bronchoconstriction (fall in FEV1 > or = 30%), patients inhaled budesonide/formoterol (160/4.5 microg, 1 or 2 inhalations; Symbicort Turbuhaler), salmeterol/fluticasone (50/250 microg; Seretide Diskus) or placebo on 4 study days. Lung function and Borg score were assessed for 30 min. During methacholine-induced provocation (final mean FEV1 62.5% of baseline), mean Borg score increased 10-fold (from 0.3 to 3.0 units). Hereafter, mean FEV1 at 3 min improved significantly more after budesonide/formoterol 1 and 2 inhalations (37 and 38%, respectively) than after salmeterol/fluticasone (23%; P < 0.001) or placebo (10%; P < 0.001). Median recovery times to 85% of baseline FEV1 were shorter for budesonide/formoterol (1 or 2 inhalations: 3.3 and 2.8 min, respectively) than salmeterol/fluticasone (8.9 min; P < 0.001) and placebo (> 30 min). One min after budesonide/formoterol, dyspnoea was significantly reduced (Borg score -0.86 units, both doses) compared with salmeterol/fluticasone (-0.55 units; P < 0.05) and placebo (-0.23 units; P < 0.001). Budesonide/formoterol provides immediate bronchodilation, faster than salmeterol/fluticasone, which patients can feel during acute methacholine-induced bronchoconstriction.