RESUMEN
AIM: Although early discontinuation of treatment in new users of inhaled corticosteroids (ICS) has been widely discussed, the reasons for stopping have not been investigated in depth. We aimed to describe reasons for discontinuation from a patient's perspective in relation to their experience of symptoms at the time of the investigation. METHODS: A cross-sectional study among new users that discontinued ICS use in the Netherlands was performed. Patients were interviewed by telephone, aiming to identify the symptoms for which they were prescribed ICS, the reasons for discontinuing treatment and the respiratory symptoms patients still experienced at the time of the survey. In addition, automated dispensing records of all patients were retrieved. RESULTS: From 287 eligible patients, 230 (80.1%) were interviewed. Only 22 patients (9.6%) mentioned asthma as the reason for a first ICS prescription. A decrease in symptoms was the main reason for discontinuation (45%). Thirty patients (13%) reported clinically significant residual symptoms. These patients reported more seasonal variation of symptoms and were more often prescribed short-acting beta(2)-agonists. CONCLUSIONS: The majority of patients mentioned a wide range of symptoms and conditions, other than asthma or chronic obstructive pulmonary disease, as the reason for the start of ICS therapy. Most of these conditions may be expected to be of short duration. Not surprisingly a decrease in symptoms was the main, and justifiable, reason for discontinuing ICS. However, a non-negligible proportion of patients reported residual symptoms that suggest the need of continued ICS use. Physicians and pharmacists could cooperate in identifying those patients for which ICS are really indicated and motivate them to continue the use of ICS.
Asunto(s)
Corticoesteroides/administración & dosificación , Antiasmáticos/administración & dosificación , Cooperación del Paciente/estadística & datos numéricos , Receptores Adrenérgicos beta 2/administración & dosificación , Enfermedades Respiratorias/tratamiento farmacológico , Administración por Inhalación , Estudios Transversales , Femenino , Adhesión a Directriz , Humanos , Masculino , Persona de Mediana Edad , Países Bajos , Cooperación del Paciente/psicología , Guías de Práctica Clínica como Asunto , Relaciones Profesional-Paciente , Encuestas y CuestionariosRESUMEN
Modification of membrane receptor makeup is one of the most efficient ways to control input-output signals but is usually achieved by expressing DNA or RNA-encoded proteins or by using other genome-editing methods, which can be technically challenging and produce unwanted side effects. Here we develop and validate a nanodelivery approach to transfer in vitro synthesized, functional membrane receptors into the plasma membrane of living cells. Using ß2-adrenergic receptor (ß2AR), a prototypical G-protein coupled receptor, as an example, we demonstrated efficient incorporation of a full-length ß2AR into a variety of mammalian cells, which imparts pharmacologic control over cellular signaling and affects cellular phenotype in an ex-vivo wound-healing model. Our approach for nanodelivery of functional membrane receptors expands the current toolkit for DNA and RNA-free manipulation of cellular function. We expect this approach to be readily applicable to the synthesis and nanodelivery of other types of GPCRs and membrane receptors, opening new doors for therapeutic development at the intersection between synthetic biology and nanomedicine.
Asunto(s)
Membrana Celular/efectos de los fármacos , Nanopartículas/química , Receptores Adrenérgicos beta 2/química , Receptores Citoplasmáticos y Nucleares/administración & dosificación , Membrana Celular/química , ADN/química , Humanos , Nanomedicina/tendencias , Nanopartículas/administración & dosificación , Fenotipo , ARN/química , Receptores Adrenérgicos beta 2/administración & dosificación , Receptores Citoplasmáticos y Nucleares/química , Biología Sintética/tendencias , Cicatrización de Heridas/efectos de los fármacosRESUMEN
The beta(2) adrenoreceptor is a large molecule of some 413 amino acids. The duration of stimulation of this receptor depends on where and for how long a beta(2) adrenergic drug attaches itself to the beta(2) adrenoreceptor. beta(2) adrenergic drugs have been used for over 5,000 years, but only recently have we had the advantage of adrenergic drugs specific to the beta(2) adrenoreceptor. The short-acting beta(2) adrenergic drugs most frequently used include albuterol, pirbuterol, and levalbuterol. Levalbuterol, the R enantiomer of albuterol, has been described by some as a more effective bronchodilator than racemic albuterol, because it contains none of the S enantiomer. Some contend that the S isomer has pro-inflammatory properties. The 2 long-acting beta(2) adrenergic drugs are salmeterol and formoterol. These drugs have a duration of 12 h and reportedly improve forced expiratory volume in the first second, quality of life, and symptoms. Some recent reports indicate that these drugs are associated with higher mortality, but several authors have registered the opinion that it is not the bronchodilator that should be questioned, but instead that the fault lies in the patient recruitment in those studies. Regardless, if these long-acting drugs are effective for a given patient, it would seem inadvisable to withdraw them, given the current state of evidence. Arformoterol tartrate, the R enantiomer of formoterol, was approved by the U.S. Food and Drug Administration in October 2006; it is available as a nebulizer solution, to be administered every 12 h. Several other long-acting R isomers and RR isomers are in the approval pipeline.
Asunto(s)
Agonistas Adrenérgicos beta/farmacocinética , Broncodilatadores/farmacocinética , Receptores Adrenérgicos beta 2/administración & dosificación , Administración por Inhalación , Agonistas Adrenérgicos beta/administración & dosificación , Agonistas Adrenérgicos beta/química , Broncodilatadores/administración & dosificación , Broncodilatadores/química , Humanos , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Receptores Adrenérgicos beta 2/química , Estados UnidosRESUMEN
beta-Adrenergic agonists accelerate the clearance of alveolar fluid by increasing the expression and activity of epithelial solute transport proteins such as amiloride-sensitive epithelial Na(+) channels (ENaC) and Na,K-ATPases. Here we report that adenoviral-mediated overexpression of a human beta(2)-adrenergic receptor (beta(2)AR) cDNA increases beta(2)AR mRNA, membrane-bound receptor protein expression, and receptor function (procaterol-induced cAMP production) in human lung epithelial cells (A549). Receptor overexpression was associated with increased catecholamine (procaterol)-responsive active Na(+) transport and increased abundance of Na,K-ATPases in the basolateral cell membrane. beta(2)AR gene transfer to the alveolar epithelium of normal rats improved membrane-bound beta(2)AR expression and function and increased levels of ENaC (alpha subunit) abundance and Na,K-ATPases activity in apical and basolateral cell membrane fractions isolated from the peripheral lung, respectively. Alveolar fluid clearance (AFC), an index of active Na(+) transport, in beta(2)AR overexpressing rats was up to 100% greater than sham-infected controls and rats infected with an adenovirus that expresses no cDNA. The addition of the beta(2)AR-specific agonist procaterol to beta(2)AR overexpressing lungs did not increase AFC further. AFC in beta(2)AR overexpressing lungs from adrenalectomized or propranolol-treated rats revealed clearance rates that were the same or less than normal, untreated, sham-infected controls. These experiments indicate that alveolar beta(2)AR overexpression improves beta(2)AR function and maximally upregulates beta-agonist-responsive active Na(+) transport by improving responsiveness to endogenous catecholamines. These studies suggest that upregulation of beta(2)AR function may someday prove useful for the treatment of pulmonary edema.
Asunto(s)
Catecolaminas/metabolismo , Células Epiteliales/metabolismo , Depuración Mucociliar/fisiología , Alveolos Pulmonares/metabolismo , Receptores Adrenérgicos beta 2/biosíntesis , Adenoviridae/genética , Animales , Proteínas Portadoras/metabolismo , Catecolaminas/farmacología , Línea Celular , Membrana Celular/química , Membrana Celular/metabolismo , ADN Complementario/administración & dosificación , ADN Complementario/genética , Células Epiteliales/citología , Células Epiteliales/efectos de los fármacos , Canales Epiteliales de Sodio , Transferencia de Gen Horizontal , Humanos , Transporte Iónico/efectos de los fármacos , Pulmón/citología , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Masculino , Procaterol/farmacología , Alveolos Pulmonares/citología , Alveolos Pulmonares/efectos de los fármacos , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores Adrenérgicos beta 2/administración & dosificación , Receptores Adrenérgicos beta 2/genética , Sodio/metabolismo , Canales de Sodio/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/metabolismoRESUMEN
Chronic inflammation and smooth muscle dysfunction are consistent features of asthma, and are responsible for disease progression and airway remodelling. The development of chronic airway inflammation depends upon the recruitment and activation of inflammatory cells and the subsequent release of inflammatory mediators, including cytokines. Cellular and histological evaluation of drugs with anti-inflammatory activity, such as inhaled corticosteroids (ICSs), is achieved by analysing samples of lung tissue or biological fluids, obtained by techniques such as bronchial biopsy, bronchoalveolar lavage and sputum induction. These provide valuable information on the inflammatory processes occurring in the lung, although not all are equal in value. The beneficial effects of ICSs in asthma treatment are a consequence of their potent and broad anti-inflammatory properties. Furthermore, there have been promising results indicating that ICSs can reverse some of the structural changes that contribute to airway remodelling. Long-acting beta2-agonists (LABAs) added to ICSs provide greater clinical efficacy than ICSs alone, suggesting the possibility of complementary activity on the pathophysiological mechanisms of asthma: inflammation and smooth muscle dysfunction. Leukotrienes play a part in the pathogenesis of asthma. Leukotriene receptor antagonists (LTRAs) directly inhibit bronchoconstriction and may have some anti-inflammatory effects, although the extent to which inhibiting one set of inflammatory mediators attenuates the inflammatory response is questionable. In concert with their effect on a broad variety of inflammatory mediators and cells, treatment with ICSs (including ICSs and LABAs) results in superior control of the pathophysiology of asthma and superior clinical efficacy as assessed by the greater improvements in pulmonary function and overall control of asthma compared with LTRAs.
Asunto(s)
Administración por Inhalación , Corticoesteroides/uso terapéutico , Agonistas de Receptores Adrenérgicos beta 2 , Asma/tratamiento farmacológico , Asma/fisiopatología , Preparaciones de Acción Retardada/uso terapéutico , Antagonistas de Leucotrieno/uso terapéutico , Receptores Adrenérgicos beta 2/uso terapéutico , Corticoesteroides/administración & dosificación , Preparaciones de Acción Retardada/administración & dosificación , Quimioterapia Combinada , Humanos , Antagonistas de Leucotrieno/administración & dosificación , Nebulizadores y Vaporizadores , Receptores Adrenérgicos beta 2/administración & dosificaciónRESUMEN
BACKGROUND: Beta-adrenergic receptor system has a major role in cardiac contraction. If the receptor can be increased by gene transfection by means of intracoronary infusion of beta 2-adrenergic receptor to the hearts in which the receptor is down-regulated, this maneuver may improve the cardiac function and may be applied as one therapeutic approach during cardiopulmonary bypass or percutaneous cardiopulmonary support. METHODS AND RESULTS: The beta 2-adrenergic receptor complementary DNA was transfected in vivo to the normal rat heart by intracoronary infusion by means of a hemagglutinating virus of Japan liposome method, and the transfected heart was transplanted into the abdomen of another rat. Four days after transfection, the sarcolemma of the cardiomyocytes was well labeled by immunohistochemical labeling. Expression of beta-adrenergic receptor in the heart was approximately 4 times greater than that in control hearts (134 +/- 42 vs 33 +/- 4 fmol/mg protein) according to a ligand binding assay. The cardiac response of the transfected heart to isoproterenol was shown to be enhanced in a Langendorff perfusion system: after isoproterenol, developed pressure and maximal derivative of the left ventricle were greater than in the control heart (200 +/- 12 vs 174 +/- 6 mm Hg and 4110 +/- 130 vs 3491 +/- 255 mm Hg/sec), and the minimal derivative of the left ventricle was markedly smaller (-3040 +/- 267 vs -2528 +/- 131 mm Hg/sec). CONCLUSIONS: These results indicate that expression of beta 2-adrenergic receptor was approximately 4 times greater than in normal rat hearts by gene transfection using a hemagglutinating virus of Japan liposome method, and the transfected hearts demonstrated marked enhancements in cardiac response to beta-agonist, suggesting that transfer of this gene by intracoronary infusion has potential as a novel approach to enhance cardiac function.
Asunto(s)
Agonistas Adrenérgicos beta/farmacología , Expresión Génica , Corazón/efectos de los fármacos , Isoproterenol/farmacología , Miocardio/metabolismo , Receptores Adrenérgicos beta 2/genética , Transfección , Animales , ADN Complementario/genética , Corazón/virología , Trasplante de Corazón , Inyecciones Intraarteriales , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptores Adrenérgicos beta 2/administración & dosificación , Receptores Adrenérgicos beta 2/biosíntesis , Respirovirus/genética , Sarcolema/efectos de los fármacos , Sarcolema/metabolismo , Presión Ventricular/efectos de los fármacosRESUMEN
The purpose of this analysis was to examine the effect of long-acting beta(2)-adrenoceptor agonists (LABAs) on the asthma exacerbation rate in pediatric patients. Randomized controlled trials (RCT) that included the use of LABAs to treat symptoms of pediatric asthma in children on inhaled corticosteroids, that reported asthma exacerbation rates, and that were published as full papers in peer-reviewed journals were retrieved from a search of the medical literature. Eight studies were identified that fulfilled these criteria. An exacerbation was defined as deterioration in a patient's asthma requiring a change in prescribed medication or not defined but reported as an asthma exacerbation or an asthma-related hospitalization. Analysis of data from the eight studies revealed no apparent protection from an asthma exacerbation among children on a LABA compared to patients on comparator treatment. The relative risk of an asthma exacerbation for LABA compared to placebo or short-acting beta(2)-adrenoceptor agonist (SABA) ranged from 0.95-1.86. The relative risk of hospitalization for asthma in patients treated with LABAs with regular maintenance with ICS ranged from 3.3-21.6 in the three studies that reported asthma-related hospitalizations. The lack of evidence for the control of asthma exacerbations in children regularly using a LABA should bring into question its general use as add-on therapy. Studies should be designed to directly explore the implications of these observations in pediatric patients.
Asunto(s)
Corticoesteroides/administración & dosificación , Asma/tratamiento farmacológico , Receptores Adrenérgicos beta 2/administración & dosificación , Administración por Inhalación , Adolescente , Asma/fisiopatología , Niño , Preescolar , Progresión de la Enfermedad , Quimioterapia Combinada , Hospitalización , Humanos , Efecto Placebo , Ensayos Clínicos Controlados Aleatorios como Asunto , Medición de Riesgo , Resultado del TratamientoRESUMEN
Viozan (sibenadet HCl, AR-C68397AA) is a novel dual D2 dopamine receptor, beta2-adrenoceptor agonist that has been investigated for efficacy in alleviating the symptoms of chronic obstructive pulmonary disease (COPD). The slowly progressive nature of this disease means that patients will require ongoing therapeutic management for many years, or even decades. With such long-term treatment, the safety profile of new agents will be of paramount importance. As part of the large-scale assessment of sibenadet, a 12-month safety study has been conducted. Following completion of a 2-week baseline period, 435 adults with stable, symptomatic, smoking-related COPD were randomized to receive either 500 microg sibenadet or placebo delivered via pressurized metered dose inhaler (pMDI), three times daily for 52 weeks. Sibenadet therapy was generally well tolerated, with the only notable differences seen in the incidence of tremor and taste of treatment (16.9% vs. 4.1% and 14.5% vs. 4.1% in the sibenadet and placebo groups respectively). There were a total of 79 patients with serious adverse events (SAEs), 43 (14.8%) in the sibenadet pMDI group and 36 (24.8%) in the placebo group. No clinically significant abnormal laboratory values or overall differences between treatment groups were noted. Similarly, there were no clinically significant differences between the two treatment groups for cardiac variables, or in vital signs. The secondary variables showed no notable differences with respect to lung function, exacerbations or health-related quality of life. Due to the effective beta2-agonist properties, patients in the sibenadet group did, however, report reduced rescue medication usage at all timepoints. While the results of this study show that, overall, sibenadet therapy was well tolerated, the lack of sustained benefit reported in large-scale clinical efficacy studies means that sibenadet development will not be continued.
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 2 , Broncodilatadores/administración & dosificación , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Receptores de Dopamina D2/agonistas , Tiazoles/administración & dosificación , Administración por Inhalación , Adulto , Anciano , Anciano de 80 o más Años , Broncodilatadores/efectos adversos , Método Doble Ciego , Femenino , Volumen Espiratorio Forzado/fisiología , Humanos , Cuidados a Largo Plazo , Masculino , Inhaladores de Dosis Medida , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Calidad de Vida , Receptores Adrenérgicos beta 2/administración & dosificación , Receptores de Dopamina D2/administración & dosificación , Fumar/efectos adversos , Fumar/fisiopatología , Tiazoles/efectos adversos , Resultado del TratamientoRESUMEN
Viozan, (Sibenadet HCl, AR-C68397AA) is a dual D2 dopamine receptor, beta2-adrenoceptor agonist that combines bronchodilator activity with the sensory afferent modulating effects associated with D2-receptor agonism. Investigation in animal models of key chronic obstructive pulmonary disease (COPD) symptoms has demonstrated that sibenadet effectively inhibits sensory nerve activity, thereby reducing reflex cough, mucus production and tachypnoea. The results of the early clinical evaluation of this novel agent are reported. An initial proof of concept study (Study 1) aimed to determine the clinical potential of this novel agent by assessing the effects of three doses of sibenadet therapy relative to placebo, with two commonly used bronchodilators, intended to provide a benchmark against which sibenadet activity could be judged. In all, 701 patients were randomized to one of three sibenadet dose groups (400, 600 or 1000 microg ex valve), salbutamol 200 microg, ipratropium bromide (IB) 40 microg or placebo, all three times daily via pressurized metered dose inhaler (pMDI) for 4 weeks. Once the results of Study 1 had been evaluated, a dose-ranging, study (Study 2) involving 872 patients randomized to receive sibenadet (45, 270, or 495 microg ex actuator), or placebo all three times daily via pMDI, for 6 weeks commenced. Both studies were preceded by a 2-week baseline phase and followed by a 2-week follow up period.The primary efficacy variable identified changes in key COPD symptoms over the treatment period (compared with baseline data) as determined by the novel Breathlessness, Cough and Sputum Scale (BCSS). In addition, data on lung function, health-related quality of life and adverse events were collected. Patients receiving sibenadet therapy three times daily exhibited statistically significantly greater improvements in BCSS total score than those receiving placebo or bronchodilator therapy alone. A clear dose-response was evident in Study 2. Symptom improvement in this study was also accompanied by improved lung function and health-related quality of life. Sibenadet therapy was well tolerated with an adverse events profile comparable to current bronchodilator therapy. These data were viewed as extremely encouraging, warranting further, large-scale clinical investigation.
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 2 , Broncodilatadores/administración & dosificación , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Receptores de Dopamina D2/agonistas , Tiazoles/administración & dosificación , Administración por Inhalación , Anciano , Broncodilatadores/efectos adversos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Volumen Espiratorio Forzado/efectos de los fármacos , Humanos , Masculino , Inhaladores de Dosis Medida , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Calidad de Vida , Receptores Adrenérgicos beta 2/administración & dosificación , Tiazoles/efectos adversos , Resultado del Tratamiento , Capacidad Vital/efectos de los fármacosRESUMEN
Viozan (sibenadet HCl, AR-C68397AA) is a novel dual D2 dopamine receptor, beta2-adrenoceptor agonist, developed specifically to treat the key symptoms of chronic obstructive pulmonary disease (COPD), breathlessness, cough and sputum. The dual sensory nerve modulation and bronchodilator effects of sibenadet have been demonstrated in initial dose-ranging studies of patients with COPD and large-scale clinical evaluation has now been completed. Sibenadet efficacy was determined by assessing symptomatic changes, as defined by the novel assessment tool, the Breathlessness, Cough and Sputum Scale (BCSS). The findings of two placebo-controlled studies are reported. These multicentre, double-blind, placebo-controlled studies recruited over 2000 patients with stable COPD, randomized to receive sibenadet (500 microg) or placebo, pressurized metered-dose inhaler (pMDI) (three times daily) for a period of 12 or 26 weeks. Diary cards were completed daily by patients throughout the study to record BCSS scores, peak expiratory flow (PEF), study drug and rescue bronchodilator usage, changes in concomitant medication and adverse events. The primary endpoints were defined as change from baseline to the final 4 weeks of the treatment period in mean BCSS total score, and forced expiratory volume in one second (FEV1) measured 1 hour after administration of the final dose of study drug and expressed as a percentage of the predicted FEV1. In addition, clinic assessments were made to determine changes in pulmonary function, health-related quality of life, perception of treatment efficacy and adverse events. Despite initial improvements in mean daily BCSS total scores in patients receiving sibenadet, the difference in the change from baseline to the final 4 weeks of the treatment period between the two treatment groups was neither statistically significant, nor considered to be of clinical importance. Although marked bronchodilator activity was seen early on with sibenadet treatment, the duration of effect diminished as the studies progressed. Sibenadet use was not associated with any safety concerns. These studies, utilizing the novel BCSS, have clearly illustrated that, despite initial symptomatic improvement with sibenadet therapy, this clinical benefit was not sustained over the course of the study.
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 2 , Broncodilatadores/administración & dosificación , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Receptores de Dopamina D2/agonistas , Tiazoles/administración & dosificación , Administración por Inhalación , Adulto , Anciano , Anciano de 80 o más Años , Broncodilatadores/efectos adversos , Método Doble Ciego , Femenino , Volumen Espiratorio Forzado/efectos de los fármacos , Humanos , Masculino , Inhaladores de Dosis Medida , Persona de Mediana Edad , Satisfacción del Paciente , Ápice del Flujo Espiratorio/efectos de los fármacos , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Calidad de Vida , Receptores Adrenérgicos beta 2/administración & dosificación , Receptores de Dopamina D2/administración & dosificación , Tiazoles/efectos adversos , Resultado del TratamientoRESUMEN
The need to manage the key symptoms of chronic obstructive pulmonary disease (COPD) (breathlessness, cough and sputum) is an important treatment objective. Viozan (sibenadet HCl, AR-C68397AA) is a novel dual D2 dopamine receptor, beta2-adrenoceptor agonist, which combines conventional bronchodilatory activity with the sensory nerve modulation afforded by dopamine agonism. The efficacy of this agent in relieving patient symptoms has been determined in a series of large-scale clinical studies; the results of a 3-month, placebo-controlled multi-centre study are reported. Effect on patient symptoms was determined using a novel patient-reported assessment instrument, the Breathlessness, Cough and Sputum Scale (BCSS). Patients with smoking-related COPD were required to complete a 2-week baseline period before being randomized to one of three treatment groups; sibenadet (500 microg three times daily) plus placebo (twice daily); salmeterol (50 microg twice daily) plus placebo (three times daily); placebo (twice daily) plus a second placebo (three times daily). All treatments were delivered via pressurized metered dose inhaler (pMDI) for 12 weeks. From enrolment, patients were required to complete daily diary cards to record symptoms of breathlessness, cough and sputum, medication use and adverse events. The primary outcome measure was the difference between the mean BCSS total score measured over the baseline period and the mean BCSS total score in the final 4 weeks of the treatment period. Secondary measures included assessment of lung function, rescue medication use, exacerbations, health-related quality of life, opinion of efficacy and safety. Although an initial reduction in BCSS total score (indicating symptom improvement) was seen with sibenadet therapy, this effect was not maintained for the study duration. Salmeterol therapy, however, resulted in a sustained reduction in BCSS total score. No notable benefit over placebo was seen in lung function, exacerbations or health-related quality of life with either active treatment. While the results of this study failed to demonstrate sustained efficacy with sibenadet therapy, they do indicate the value of symptom assessment in the clinical evaluation of new drugs for the treatment of COPD.
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 2 , Broncodilatadores/administración & dosificación , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Receptores de Dopamina D2/agonistas , Tiazoles/administración & dosificación , Administración por Inhalación , Adulto , Anciano , Anciano de 80 o más Años , Broncodilatadores/efectos adversos , Tos/tratamiento farmacológico , Método Doble Ciego , Disnea/tratamiento farmacológico , Femenino , Volumen Espiratorio Forzado/efectos de los fármacos , Humanos , Masculino , Inhaladores de Dosis Medida , Persona de Mediana Edad , Calidad de Vida , Receptores Adrenérgicos beta 2/administración & dosificación , Receptores de Dopamina D2/administración & dosificación , Esputo/efectos de los fármacos , Análisis de Supervivencia , Tiazoles/efectos adversos , Resultado del Tratamiento , Capacidad Vital/efectos de los fármacosRESUMEN
Asthma causes a substantial burden of morbidity and mortality, affecting 300 million people worldwide - a figure predicted to increase to 400 million by 2025. Despite the availability of a variety of treatment options and detailed treatment guidelines, many patients with asthma, and in particular those with severe persistent asthma, remain inadequately controlled. Approximately 50-80% of severe asthma has an allergic component, with immunoglobulin E (IgE) playing a role in the underlying allergic inflammatory cascade. Omalizumab is a humanised monoclonal anti-IgE antibody that targets IgE and partially inhibits the inflammatory cascade. Clinical trials have demonstrated that omalizumab added to standard asthma therapy reduces exacerbations and emergency visits with concomitant improvements in asthma control and quality of life in patients with moderate-to-severe and severe persistent allergic (IgE-mediated) asthma. Add-on omalizumab is indicated for the treatment of patients with inadequately controlled moderate-to-severe (US label) and severe (EU label) persistent allergic asthma despite treatment with high-dose inhaled corticosteroids (and in the EU, high-dose inhaled corticosteroids plus a long-acting beta2-agonist). Within this highly-targeted patient population, analyses have been unable to identify pre-treatment clinical characteristics that are predictive of a greater response to omalizumab. In contrast, assessment of response to omalizumab following 16 weeks of treatment appears to be reliably judged by physicians in clinical trial settings and may be a feasible means of selecting patients who should continue treatment.
Asunto(s)
Antiasmáticos/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Asma/tratamiento farmacológico , Agonistas de Receptores Adrenérgicos beta 2 , Antiasmáticos/administración & dosificación , Anticuerpos Antiidiotipos , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Asma/complicaciones , Quimioterapia Combinada , Humanos , Antagonistas de Leucotrieno/administración & dosificación , Omalizumab , Receptores Adrenérgicos beta 2/administración & dosificaciónRESUMEN
While the guinea pig has been the preferred choice for use as a model of allergic bronchial asthma in the evaluation of anti-asthmatic drugs, it has been shown that antigen-induced bronchoconstriction in guinea pigs is attenuated by epinephrine released from the adrenal gland. In order to investigate the possible influence of the adrenal gland on the effects of antiexudative and bronchodilative drugs on antigen-induced airway responses, we examined the inhibitory effects of procaterol, a selective beta(2)-adrenoceptor agonist, on antigen-induced airway microvascular leakage and bronchoconstriction in adrenalectomized guinea pigs and compared them with the drug's effects in sham-operated animals. Guinea pigs sensitized passively with anti-ovalbumin (OA) guinea-pig serum were adrenalectomized or sham-operated under urethane anesthesia and examined 30 min after surgery in the following experiments. (1) Animals were intravenously administered Evans blue dye to quantify airway plasma exudation, and then OA was inhaled for 10 min while measuring pulmonary inflation pressure, a parameter of bronchoconstriction. Procaterol (1, 3, 10, or 30 microg/kg) or saline (control) was administered into the airways 10 min prior to OA inhalation. The amount of extravasated Evans blue dye in the airways was calculated. (2) Venous blood samples were collected during OA or saline inhalation and plasma catecholamine levels were compared. In control animals, OA-induced increases in both the amount of Evans blue dye and in pulmonary inflation pressure were markedly greater in adrenalectomized animals than in sham-operated animals. Procaterol dose-dependently inhibited OA-induced airway microvascular leakage and bronchoconstriction, and its effects were more potent in adrenalectomized animals (significant at 1 microg/kg and higher) than in sham-operated animals (significant at 10 microg/kg and higher). Although the plasma concentration of epinephrine during OA inhalation was approximately 3 times higher than that during saline inhalation in sham-operated animals, no difference was seen in adrenalectomized animals. In conclusion, while procaterol essentially possesses pronounced inhibitory effects on antigen-induced airway microvascular leakage and bronchoconstriction in guinea pigs, the effects are considerably masked by epinephrine released from the adrenal gland.
Asunto(s)
Glándulas Suprarrenales/metabolismo , Antígenos/efectos adversos , Broncoconstricción/fisiología , Exudados y Transudados/metabolismo , Microcirculación/metabolismo , Procaterol/farmacocinética , Glándulas Suprarrenales/fisiopatología , Glándulas Suprarrenales/cirugía , Adrenalectomía , Agonistas de Receptores Adrenérgicos beta 2 , Animales , Antígenos/administración & dosificación , Antígenos/inmunología , Broncoconstricción/efectos de los fármacos , Broncoconstricción/inmunología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Epinefrina/sangre , Azul de Evans/administración & dosificación , Exudados y Transudados/efectos de los fármacos , Exudados y Transudados/inmunología , Cobayas , Pulmón/irrigación sanguínea , Pulmón/efectos de los fármacos , Pulmón/fisiopatología , Masculino , Microcirculación/efectos de los fármacos , Microcirculación/fisiopatología , Ovalbúmina/efectos adversos , Ovalbúmina/antagonistas & inhibidores , Ovalbúmina/inmunología , Procaterol/administración & dosificación , Receptores Adrenérgicos beta 2/administración & dosificaciónRESUMEN
OBJECTIVE: To test the potential of gene transfer approaches to enhance cardiac chronotropy in a porcine system as a model of the human heart. METHODS: Plasmids encoding either the human beta(2) adrenergic receptor or control constructs were injected into the right atria of native Yorkshire pig hearts. Percutaneous electrophysiological recording catheters equipped with 33 gauge circular injection needles were positioned in the mid-lateral right atrium. At the site of the earliest atrial potential the circular injection needles were rotated into the myocardium and the beta(2) adrenergic receptor (n = 6) or control plasmid constructs (n = 5) were injected. RESULTS: Injection of the beta(2) adrenergic receptor construct significantly enhanced chronotropy compared with control injections. The average (SD) heart rate of the pigs was 108 (16) beats/min before injection. Two days after injection with control plasmids the heart rate was 127 (25) beats/min (NS compared with preinjection rates). After injection with plasmid encoding the beta(2) adrenergic receptor the heart rate increased by 50% to 163 (33) beats/min (p < 0.05 compared with preinjection and postinjection control rates). CONCLUSIONS: The present studies showed in a large animal model that local targeting of gene expression may be a feasible modality to regulate cardiac pacemaking activity. In addition, these investigations provide an experimental basis for developing future clinical gene transfer approaches to upregulate heart rate and modulate cardiac conduction.