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1.
PLoS One ; 10(10): e0138122, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26465600

RESUMEN

We propose two strategies to improve the quality of tractography results computed from diffusion weighted magnetic resonance imaging (DW-MRI) data. Both methods are based on the same PDE framework, defined in the coupled space of positions and orientations, associated with a stochastic process describing the enhancement of elongated structures while preserving crossing structures. In the first method we use the enhancement PDE for contextual regularization of a fiber orientation distribution (FOD) that is obtained on individual voxels from high angular resolution diffusion imaging (HARDI) data via constrained spherical deconvolution (CSD). Thereby we improve the FOD as input for subsequent tractography. Secondly, we introduce the fiber to bundle coherence (FBC), a measure for quantification of fiber alignment. The FBC is computed from a tractography result using the same PDE framework and provides a criterion for removing the spurious fibers. We validate the proposed combination of CSD and enhancement on phantom data and on human data, acquired with different scanning protocols. On the phantom data we find that PDE enhancements improve both local metrics and global metrics of tractography results, compared to CSD without enhancements. On the human data we show that the enhancements allow for a better reconstruction of crossing fiber bundles and they reduce the variability of the tractography output with respect to the acquisition parameters. Finally, we show that both the enhancement of the FODs and the use of the FBC measure on the tractography improve the stability with respect to different stochastic realizations of probabilistic tractography. This is shown in a clinical application: the reconstruction of the optic radiation for epilepsy surgery planning.


Asunto(s)
Imagen de Difusión por Resonancia Magnética/métodos , Imagen de Difusión Tensora/métodos , Epilepsia/cirugía , Algoritmos , Encéfalo/patología , Simulación por Computador , Epilepsia/patología , Reacciones Falso Positivas , Humanos , Interpretación de Imagen Asistida por Computador/métodos , Procesamiento de Imagen Asistido por Computador , Modelos Estadísticos , Reconocimiento de Normas Patrones Automatizadas/métodos , Fantasmas de Imagen , Probabilidad , Procesos Estocásticos , Sustancia Blanca/patología
2.
Eur Respir J ; 37(3): 541-52, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-20650997

RESUMEN

The aim of the present study was to determine whether systemic sensitisation and chronic aeroallergen challenge in macaques replicate the classical and emerging immunology and molecular pathology of human asthma. Macaques were immunised and periodically challenged over 2 yrs with house dust mite allergen. At key time-points, serum, bronchoalveolar lavage (BAL) and bronchial biopsies were assayed for genes, proteins and lymphocyte subpopulations relevant to clinical asthma. Immunisation and periodic airway challenge induced changes in immunoglobulin E, airway physiology and eosinophilia consistent with chronic, dual-phase asthma. Sensitisation increased interleukin (IL)-1ß and -6 concentrations in serum, and IL-13 expression in BAL cells. Airway challenge increased: early expression of IL-5, -6, -13 and -19, and eotaxin; and variable late-phase expression of IL-4, -5 and -13, and thymus- and activation-regulated chemokine in BAL cells. CD4+ lymphocytes comprised 30% of the CD3+ cells in BAL, increasing to 50% in the late phase. Natural killer T-cells represented <3% of the CD3+ cells. Corticosteroid treatment reduced serum histamine levels, percentage of CD4+ cells and monocyte-derived chemokine expression, while increasing CD3+ and CD8+ cells in BAL. Sensitisation and periodic aeroallergen challenge of cynomolgus macaques results in physiological, cellular, molecular and protein phenotypes, and therapeutic responses observed in human asthma, providing a model system useful in target and biomarker discovery, and translational asthma research.


Asunto(s)
Corticoesteroides/farmacología , Asma/patología , Alérgenos , Animales , Biomarcadores/metabolismo , Lavado Broncoalveolar , Modelos Animales de Enfermedad , Citometría de Flujo/métodos , Regulación de la Expresión Génica , Humanos , Inmunoglobulina E/metabolismo , Células Asesinas Naturales/citología , Pulmón/fisiología , Linfocitos/citología , Macaca , Ácaros , Esteroides
3.
Alaska Med ; 49(2 Suppl): 85-8, 2007.
Artículo en Inglés | MEDLINE | ID: mdl-17929613

RESUMEN

BACKGROUND: The term Naturally Occurring Retirement Communities (NORCs) has been used since the 1980s. NORCs are defined as communities where people remain or move to when they retire. NORCs develop 'naturally', meaning that seniors tend to remain or move there when they retire, although the residences and physical environment were not constructed for a senior population. The term, Healthy-NORC, has been introduced and is associated with healthy aging. OBJECTIVES/METHODS: We describe how demographic trends will facilitate a dramatic growth in NORCs. Acknowledging the 'Determinants of Health' model, we suggest that some determinants impact people differently at different ages. We also suggest that more attention be focused on the impact of physical/social environments on health, and that some determinants of health are particularly relevant for seniors. We argue that NORCs exist on a spectrum, from NORC to H-NORC, and that health benefits for seniors increase as NORCs adopt additional characteristics associated with improved senior health. We also illustrate H-NORC research methods and policy options for local governments. RESULTS/CONCLUSION: Compared to the provision of additional medical and social services, H-NORCs represent a low-cost approach to facilitating healthy aging. Municipal governments can promote healthy aging and should pursue policies that will stimulate H-NORC development.


Asunto(s)
Envejecimiento , Servicios de Salud Comunitaria , Servicios de Salud para Ancianos , Estado de Salud , Jubilación , Factores de Edad , Anciano , Anciano de 80 o más Años , Demografía , Femenino , Política de Salud , Humanos , Gobierno Local , Masculino , Factores Socioeconómicos , Estados Unidos
4.
JAMA ; 286(23): 2956-67, 2001 Dec 19.
Artículo en Inglés | MEDLINE | ID: mdl-11743836

RESUMEN

CONTEXT: Seasonal allergic rhinitis is a common IgE-mediated disorder that produces troublesome symptoms. A recombinant humanized monoclonal anti-IgE antibody (omalizumab) forms complexes with free IgE, blocking its interaction with mast cells and basophils and lowering free IgE levels in the circulation. OBJECTIVE: To assess the efficacy and safety of omalizumab for prophylaxis of symptoms in patients with seasonal allergic rhinitis. DESIGN: Randomized, double-blind, dose-ranging, placebo-controlled trial conducted from July 25 through November 21, 1997. SETTING: Twenty-five outpatient centers throughout the United States. PATIENTS: Five hundred thirty-six patients aged 12 to 75 years with at least a 2-year history of moderate to severe ragweed-induced seasonal allergic rhinitis and a baseline IgE level between 30 and 700 IU/mL. INTERVENTIONS: Patients were randomly assigned to receive omalizumab, 50 mg (n = 137), 150 mg (n = 134), or 300 mg (n = 129), or placebo (n = 136) subcutaneously just prior to ragweed season and repeated during the pollen season every 3 weeks in patients with baseline IgE levels of 151 to 700 IU/mL (4 total treatments) and every 4 weeks in patients with baseline IgE levels of 30 to 150 IU/mL (3 total treatments). MAIN OUTCOME MEASURES: Self-assessed daily nasal symptom severity scores (range, 0-3), rescue antihistamine use, and rhinitis-specific quality of life during the 12 weeks from the start of treatment. RESULTS: Nasal symptom severity scores were significantly lower in patients who received 300 mg of omalizumab than in those who received placebo (least squares means, 0.75 vs 0.98, respectively; P =.002). A significant association was observed between IgE reduction and nasal symptoms and rescue antihistamine use. Rhinitis-specific quality of life scores were consistently better in patients who received 300 mg of omalizumab than in those who received lower dosages or placebo and did not decline during peak season. The frequency of adverse events was not significantly different among the omalizumab and placebo groups. CONCLUSION: Omalizumab decreased serum free IgE levels and provided clinical benefit in a dose-dependent fashion in patients with seasonal allergic rhinitis.


Asunto(s)
Antialérgicos/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Rinitis Alérgica Estacional/tratamiento farmacológico , Adolescente , Adulto , Anciano , Antialérgicos/administración & dosificación , Antialérgicos/efectos adversos , Anticuerpos Antiidiotipos , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Inmunoglobulina E/sangre , Masculino , Persona de Mediana Edad , Omalizumab , Calidad de Vida , Rinitis Alérgica Estacional/inmunología , Rinitis Alérgica Estacional/prevención & control
5.
Monaldi Arch Chest Dis ; 56(6): 514-20, 2001 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-11980283

RESUMEN

A highly specific monoclonal antibody binding IgE (anti-IgE/omalizumab) has made it possible to determine the immunopathogenetic role that this reaginic antibody plays in human allergic disease. It is clear from recently completed studies that IgE is essential to the full generation of early and late asthmatic responses in human bronchoprovocation trials. Importantly, anti-IgE treatment of severe asthma disease significantly improves symptoms and reduces exacerbation episodes. Elevated serum levels of IgE are prominent in the clinical presentation of allergic bronchopulmonary mycoses and IgE-mediated Type I hypersensitivity reactions are of fundamental importance to the immunopathogenesis of allergic bronchopulmonary aspergillosis. Although the role of IgE in mediating immunity to helminth parasites is considerably less clear, it is safe to conclude that the overall balance of evidence does not support a primary role for IgE in host protection with regard to schistosomiasis and strongyloidiasis.


Asunto(s)
Anticuerpos Antiidiotipos/uso terapéutico , Aspergilosis Broncopulmonar Alérgica/tratamiento farmacológico , Asma/tratamiento farmacológico , Inmunoglobulina E/uso terapéutico , Enfermedades Pulmonares Parasitarias/tratamiento farmacológico , Anticuerpos Monoclonales/uso terapéutico , Aspergilosis Broncopulmonar Alérgica/inmunología , Asma/inmunología , Relación Dosis-Respuesta Inmunológica , Humanos , Enfermedades Pulmonares Parasitarias/inmunología
6.
Immunopharmacology ; 48(3): 307-10, 2000 Jul 25.
Artículo en Inglés | MEDLINE | ID: mdl-10960673

RESUMEN

The causal role of immunoglobulin E (IgE) in triggering the cascade of biochemical events leading to allergic disease is well established. Treatments that selectively inhibit IgE activity are a logical approach in managing the allergic response. One such strategy utilizes rhuMAb-E25, a recombinant humanized IgG(1) monoclonal anti-IgE antibody, which binds to IgE. This anti-IgE antibody binds at the same epitope site of IgE that binds to FcvarepsilonRI and is thus non-anaphylactogenic. By binding to IgE and removing it via immune complex formation, the pool of IgE available to interact with mast cells and basophils is thereby reduced and the allergic response is attenuated. The clinical safety and efficacy of rhuMAb-E25 demonstrated in phase II studies of allergic asthma will be outlined.


Asunto(s)
Alérgenos/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Hipersensibilidad/tratamiento farmacológico , Inmunoglobulina E/sangre , Inmunoterapia/métodos , Alérgenos/farmacología , Animales , Anticuerpos Monoclonales/farmacología , Humanos , Inmunoglobulina E/efectos de los fármacos
7.
N Engl J Med ; 341(26): 1966-73, 1999 Dec 23.
Artículo en Inglés | MEDLINE | ID: mdl-10607813

RESUMEN

BACKGROUND: Immune responses mediated by IgE are important in the pathogenesis of allergic asthma. A recombinant humanized monoclonal antibody (rhuMAb-E25) forms complexes with free IgE and blocks its interaction with mast cells and basophils. We studied the efficacy of rhuMab-E25 as a treatment for moderate-to-severe allergic asthma. METHODS: After a 4-week run-in period, we randomly assigned 317 subjects (age range, 11 to 50 years) who required inhaled or oral corticosteroids (or both) to receive either placebo or one of two regimens of rhuMAB-E25: high-dose rhuMAb-E25 (5.8 microg per kilogram of body weight per nanogram of IgE per milliliter or low-dose rhuMAb-E25 (2.5 microg per kilogram per nanogram of IgE per milliliter) intravenously on days 0 (half a dose), 4 (half a dose), and 7 (full dose) and then once every 2 weeks thereafter for 20 weeks. For the first 12 weeks of the study, the subjects continued the regimen of corticosteroids they had received before enrollment. During the following eight weeks, the doses of corticosteroids were tapered in an effort to discontinue this therapy. The primary outcome measure was an improvement in the asthma symptom score at 12 weeks, according to a 7-point scale, in which a score of 1 indicated no symptoms and a score of 7 the most severe symptoms. RESULTS: A total of 106 subjects were assigned to receive a high dose of rhuMAb-E25, 106 were assigned to receive a low dose, and 105 were assigned to receive placebo. At base line, the mean asthma symptom score was 4.0. After 12 weeks of therapy, the mean (+/-SE) scores were 2.8+/-0.1 in the high-dose group (P=0.008) and 2.8+/-0.1 in the low-dose group (P=0.005), as compared with 3.8+/-0.1 in the placebo group. At 20 weeks, the mean scores were 2.7+/-0.1 in both the high-dose group (P=0.048) and the low-dose group (P=0.14), as compared with 2.9+/-0.1 in the placebo group. More subjects in the two rhuMAb-E25 groups were able to decrease or discontinue their use of corticosteroids than in the placebo group, but only some of the differences were significant. After 20 weeks, serum free IgE concentrations decreased by a mean of more than 95 percent in both rhuMAb-E25 groups. The therapy was well tolerated. After 20 weeks, none of the subjects had antibodies against rhuMAb-E25. CONCLUSIONS: A recombinant humanized monoclonal antibody directed against IgE has potential as a treatment for subjects with moderate or severe allergic asthma.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Asma/terapia , Inmunoglobulina E/inmunología , Administración por Inhalación , Administración Oral , Adolescente , Agonistas Adrenérgicos beta/uso terapéutico , Adulto , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Asma/tratamiento farmacológico , Asma/inmunología , Niño , Método Doble Ciego , Femenino , Volumen Espiratorio Forzado , Glucocorticoides/uso terapéutico , Humanos , Inmunoglobulina E/sangre , Masculino , Persona de Mediana Edad , Ápice del Flujo Espiratorio , Calidad de Vida
8.
Am J Med Genet ; 87(1): 17-22, 1999 Nov 05.
Artículo en Inglés | MEDLINE | ID: mdl-10528241

RESUMEN

Interstitial deletions in the terminal region of chromosome 6 are rare. We describe three new cases with subtle interstitial deletions in the q24-q26 region of the long arm of chromosome 6. The karyotypes were analyzed at a 550 band level. Patient1 is a 9-month-old boy with an interstitial deletion, del(6)(q24.2q25.1), developmental delay, low birth weight, hypotonia, heart murmur, respiratory distress, craniofacial and genital anomalies. This is the first report of a case with deletion del(6)(q24.2q25.1). Patient 2 is a 17-year-old young man with an interstitial deletion del(6)(q25.1q25.3), developmental delay, short stature, mental retardation, autism, head, face, chest, hand and feet anomalies and a history of seizures. For the first time autism was described as a manifestation in 6q deletions. Patient 3 is baby boy with a de novo interstitial deletion, del(6)(q25.1q26), anomalies of the brain, genital organs, limbs and feet. This is the first report of a case with deletion, del(6)(q25.1q26). In all three patients, fluorescence in situ hybridization (FISH) using chromosome 6 painting probe ruled out an insertion. The ESR (6q25.1) and TBP (6q27) probes were used to confirm the breakpoints. Since TBP signal is present in all cases, it confirmed an interstitial deletion proximal to this probe. Patient 1 has a deletion of the ESR locus; Patient 2 and 3 have signals for the ESR locus on both chromosomes 6. Therefore the deletion in Patients 2 and 3 are between ESR and TBP loci distal to that of Patient 1. FISH validated the deletion breakpoints assessed by conventional cytogenetics.


Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 6/genética , Anomalías Múltiples/genética , Adolescente , Adulto , Preescolar , Femenino , Humanos , Hibridación Fluorescente in Situ , Lactante , Recién Nacido , Discapacidad Intelectual/genética , Cariotipificación , Masculino
9.
AJR Am J Roentgenol ; 173(1): 53-8, 1999 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-10397099

RESUMEN

OBJECTIVE: In a multicenter study, we evaluated the relationships between the extent and severity of bronchiectasis on CT and clinical symptoms, spirometric abnormality, and sputum characteristics. SUBJECTS AND METHODS: The study population included 261 patients with symptomatic, physiologically significant bronchiectasis, who were enrolled in another study evaluating the clinical efficacy of deoxyribonudease in treatment of bronchiectasis. Patients with cystic fibrosis, allergic bronchopulmonary aspergillosis, and fungal or mycobacterial infection were excluded. In addition to high-resolution CT scanning, all patients underwent clinical evaluation, spirometry, and sputum culture. CT features scored by consensus of two observers included the extent of bronchiectasis, type of bronchiectasis (cylindric, varicose, or cystic), extent of mucoid impaction, and degree of bronchial wall thickening. RESULTS: Scores for the severity and extent of bronchiectasis correlated with the forced expiratory volume in 1 sec (FEV1) (r = -.362, p < .0001) and with the forced vital capacity (FVC) (r = -.362, p < .0001). Scores for bronchial wall thickening correlated with the FEV1 (r = -.367, p < .0001) and FVC (r = -.239, p < .001). Patients with cystic bronchiectasis were significantly more likely to grow Pseudomonas from their sputa and to have purulent sputa than were patients with cylindric or varicose bronchiectasis. Patients with cystic bronchiectasis had significantly lower FEV1 and FVC values than did patients with cylindric or varicose bronchiectasis. CONCLUSION: In this patient population, we found weak but significant correlations between the degree of morphologic abnormality on CT and the extent of physiologic impairment. Cystic bronchiectasis was associated with sputum purulence and with the growth of Pseudomonas. CT classification of the type of bronchiectasis may be useful as an index of severity of disease.


Asunto(s)
Bronquiectasia/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Bronquios/patología , Bronquiectasia/diagnóstico , Bronquiectasia/etiología , Femenino , Volumen Espiratorio Forzado , Humanos , Pulmón/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Espirometría , Esputo/microbiología , Capacidad Vital
10.
Int Arch Allergy Immunol ; 118(2-4): 112-5, 1999.
Artículo en Inglés | MEDLINE | ID: mdl-10224354

RESUMEN

Monoclonal antibodies are potentially useful therapeutic agents in a variety of immunologically mediated diseases, since they offer the theoretical advantage of selectively targeting the mediators of the immuno-pathogenesis. It has been well established that IgE antibody synthesized by the immune system plays a pivotal role in the cascade of biochemical events leading to the allergic reaction. The aim of these studies was to eliminate IgE with a monoclonal antibody as the approach for treatment of atopic disease. To this end, a murine monoclonal antibody (MAE11) directed against IgE was identified which had all of the properties necessary to interfere with IgE responses. To avoid the problems of antigenicity associated with chronic administration of murine antibodies MAE11 was humanized. The best of several humanized variants, version 25 (rhuMAb-E25), was selected for clinical trials in allergic asthma and seasonal allergic rhinitis. In a series of phase I safety studies, rhuMAb-E25, by single or multidose administrations, was shown to be very well tolerated. Phase II studies were then designed to determine whether elimination of serum IgE, as a result of rhuMAb-E25 administration, had a significant impact on allergic symptoms. Results of these clinical trials establish the involvement of IgE in the pathophysiology of rhinitis and asthma and suggest a novel treatment for allergic disease.


Asunto(s)
Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Hipersensibilidad/tratamiento farmacológico , Hipersensibilidad/inmunología , Inmunoglobulina E/inmunología , Animales , Ensayos Clínicos como Asunto , Humanos , Inmunoterapia , Ratones
12.
Curr Opin Pulm Med ; 5(1): 76-80, 1999 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-10813254

RESUMEN

Immunoglobulin-E (IgE) is believed to be the central effector antibody reacting to allergen in patients with allergic asthma. Clinical manifestations of allergic asthma result from the release of chemical mediators from mast cells and basophils on exposure to allergen. A humanized murine monoclonal antibody to IgE, rhuMAb-E25, recognizes the specific Fc epsilon3 portion of circulating IgE that binds to the high-affinity IgE receptor, Fc epsilonRI. In clinical studies, single and multiple doses of subcutaneous and intravenous rhuMAb-E25 have been shown to reproducibly reduce the serum free IgE concentrations in a dose-dependent manner. Clinical trials conducted in aeroallergen bronchoprovocation laboratories demonstrated that decreasing circulating IgE resulted in significant attenuation of the early and late asthmatic responses. Studies completed in moderate to severe allergic asthmatics have extended the safety and efficacy of rhuMAb-E25. Significant improvements in asthma symptoms, meaningful reductions in corticosteroid agents while decreasing reliance on bronchodilator rescue drugs, decreased asthma exacerbations, and improved quality of life have been documented. Because of the remarkable protein engineering and the humanization technology now available, rhuMAb-E25 therapy has elicited no antibody responses and has been safely administered to atopic subjects. rhuMAb-E25 as a novel monoclonal antibody, the first to be applied to lung diseases, holds promise for the control of many IgE-mediated diseases.


Asunto(s)
Alérgenos/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Asma/terapia , Inmunoglobulina E/inmunología , Animales , Niño , Ensayos Clínicos como Asunto , Humanos , Ratones
13.
Chest ; 114(4): 988-92, 1998 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-9792566

RESUMEN

STUDY OBJECTIVES: The peak inspiratory flow rates (PIFRs) generated by cystic fibrosis (CF) and COPD patients through a range of clinically relevant resistances have not yet been reported (to our knowledge). The objectives of this study were to (1) explore a relevant range of resistive loads and address whether patients with stable CF and COPD can generate the PIFR sufficient to disperse dry-powder inhalants (DPI) and (2) determine whether the optimal inspiratory flow rate effective for delivery of aerosolized pharmacologic therapeutic agents can be attained with a comfort rating acceptable to subjects. DESIGN: Prospective, controlled, subject-blinded study. SETTING: Pulmonary function laboratory at the VA Palo Alto Health Care System. PATIENTS OR PARTICIPANTS: Thirty-six subjects, including 12 healthy volunteers, 12 subjects with CF, and 12 subjects with COPD were studied. MEASUREMENTS: Studies of dynamic lung function and PIFR without and with varying resistances were obtained at a single laboratory visit. RESULTS: Dynamic lung function and PIFR varied inversely with the resistive load for all patient groups and did not correlate with the disease severity, as indicated by FEV1 of percent predicted. The average subjective comfort rating for any given resistive load was similar for subjects with CF and COPD. CONCLUSIONS: These results support the conclusion that subjects with stable CF and COPD of varying severity can comfortably generate the necessary flow rates to operate new and currently available DPIs over a wide range of inspiratory resistances.


Asunto(s)
Fibrosis Quística/fisiopatología , Enfermedades Pulmonares Obstructivas/fisiopatología , Pulmón/fisiopatología , Adolescente , Adulto , Anciano , Resistencia de las Vías Respiratorias , Femenino , Volumen Espiratorio Forzado , Humanos , Capacidad Inspiratoria , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Índice de Severidad de la Enfermedad
15.
Chest ; 113(5): 1329-34, 1998 May.
Artículo en Inglés | MEDLINE | ID: mdl-9596315

RESUMEN

STUDY OBJECTIVE: To study the safety and efficacy of aerosolized recombinant human DNase I in the treatment of idiopathic bronchiectasis. DESIGN: Double-blind, randomized, placebo-controlled, multicenter study. POPULATIONS: Three hundred forty-nine adult outpatients in stable condition with idiopathic bronchiectasis from 23 centers in North America, Great Britain, and Ireland. INTERVENTIONS AND MEASUREMENTS: Study patients received aerosolized rhDNase or placebo twice daily for 24 weeks. Primary end points were incidence of pulmonary exacerbations and mean percent change in FEV1 from baseline over the treatment period. RESULTS: Pulmonary exacerbations were more frequent and FEV1 decline was greater in patients who received rhDNase compared with placebo during this 24-week trial. CONCLUSIONS: rhDNase was ineffective and potentially harmful in this group of adult outpatients in stable condition with idiopathic bronchiectasis. This contrasts with previously published results that demonstrated efficacy of rhDNase in patients with cystic fibrosis bronchiectasis.


Asunto(s)
Bronquiectasia/tratamiento farmacológico , Desoxirribonucleasa I/administración & dosificación , Expectorantes/administración & dosificación , Administración por Inhalación , Aerosoles , Desoxirribonucleasa I/efectos adversos , Desoxirribonucleasa I/uso terapéutico , Método Doble Ciego , Esquema de Medicación , Expectorantes/efectos adversos , Expectorantes/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/uso terapéutico , Espirometría , Factores de Tiempo , Insuficiencia del Tratamiento
16.
J Allergy Clin Immunol ; 100(1): 110-21, 1997 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-9257795

RESUMEN

BACKGROUND: Increased serum levels of antigen-specific IgE are often associated with allergic respiratory disorders. RhuMAb-E25, a recombinant humanized monoclonal antibody, decreases free serum IgE by forming biologically inactive immune complexes with free IgE. OBJECTIVE: We hypothesized that rhuMAb-E25 would decrease total serum IgE and reduce symptoms. METHODS: Two hundred forty subjects were enrolled into five groups to determine the safety, tolerance, and efficacy of repeated administration of rhuMAb-E25 in adults with ragweed-induced allergic rhinitis and to explore the pharmacodynamic relationship of rhuMAb-E25 and IgE. One hundred eighty-one subjects received an initial intravenous loading dose (day 0, 1 month before ragweed season), followed by administration of rhuMAb-E25 (in mg/kg body weight) of 0.15 mg/kg subcutaneously, 0.15 mg/kg intravenously, or 0.5 mg/kg intravenously on days 7, 14, 28, 42, 56, 70, and 84. A subcutaneous placebo group and an intravenous placebo group were included. The total evaluation time included the 84-day treatment period, followed by a 42-day observation period. RESULTS: Adverse events were mild, and no differences were observed in the rates between the three active and two placebo treatment groups. Ragweed-specific IgE levels correlated with symptom scores. RhuMAb-E25 decreased serum free IgE levels in a dose- and baseline IgE-dependent fashion. However, only 11 subjects had IgE levels that were suppressed to undetectable levels (< or = 24 ng/ml), a sample too small to demonstrate significant differences and clinical efficacy. Thus the case for efficacy was not proven. Nonetheless, the study confirms that it is safe to repeatedly administer rhuMAb-E25 over a period of months. CONCLUSIONS: Because rhuMAb-E25 decreased serum free IgE in a dose-dependent fashion and because symptom scores correlated with antigen-specific IgE levels, the results suggest that if given in adequate doses, rhuMAb-E25 should be an effective therapy for allergic diseases.


Asunto(s)
Anticuerpos Antiidiotipos/uso terapéutico , Anticuerpos Monoclonales/farmacología , Inmunoglobulina E/inmunología , Proteínas Recombinantes de Fusión/inmunología , Proteínas Recombinantes de Fusión/uso terapéutico , Rinitis Alérgica Estacional/etiología , Rinitis Alérgica Estacional/terapia , Adolescente , Adulto , Anciano , Animales , Anticuerpos Antiidiotipos/efectos adversos , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacocinética , Especificidad de Anticuerpos , Demografía , Método Doble Ciego , Femenino , Humanos , Inmunización Pasiva/efectos adversos , Masculino , Ratones , Persona de Mediana Edad , Poaceae/inmunología , Polen/inmunología , Proteínas Recombinantes de Fusión/efectos adversos , Rinitis Alérgica Estacional/inmunología , Índice de Severidad de la Enfermedad , Pruebas Cutáneas , Volumetría
17.
Am J Respir Crit Care Med ; 155(6): 1828-34, 1997 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-9196082

RESUMEN

A humanized murine monoclonal antibody directed to the Fc epsilonR1-binding domain of human IgE (rhuMAb-E25) has been shown to inhibit the binding of IgE to mast cells without provoking mast cell activation. To examine the effects of neutralizing IgE on allergic airway responses, we assessed the effects of 9 wk of treatment with rhuMAb-E25 in a parallel group, randomized, double-blind, placebo-controlled study of 19 allergic asthmatic subjects. We found that treatment with rhuMAb-E25 reduced serum IgE, increased the dose of allergen needed to provoke an early asthmatic response, reduced the mean maximal fall in FEV1 during the early response (30 +/- 10% at baseline to 18.8 +/- 8%, versus 33 +/- 8% at baseline to 34 +/- 4% after placebo; p = 0.01), and reduced the mean maximal fall in FEV1 during the late response (24 +/- 20% at baseline to 9 +/- 10% versus 20 +/- 17% at baseline to 18 +/- 17% after placebo; p = 0.047). We conclude that an anti-IgE monoclonal antibody, which inhibits binding of IgE to its receptor, suppresses the early- and late-phase responses to inhaled allergen in allergic asthmatic subjects. Targeting IgE with rhuMAb-E25 might be a useful treatment for allergic asthma.


Asunto(s)
Alérgenos/inmunología , Anticuerpos Monoclonales/uso terapéutico , Asma/terapia , Hipersensibilidad Tardía/terapia , Hipersensibilidad Inmediata/terapia , Inmunoglobulina E/inmunología , Administración por Inhalación , Adulto , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Asma/fisiopatología , Bronquios/inmunología , Pruebas de Provocación Bronquial , Recuento de Células , Método Doble Ciego , Humanos , Hipersensibilidad Tardía/fisiopatología , Hipersensibilidad Inmediata/fisiopatología , Pulmón/fisiopatología , Pruebas de Función Respiratoria , Pruebas Cutáneas , Esputo/citología
18.
Am J Respir Crit Care Med ; 155(6): 1835-40, 1997 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-9196083

RESUMEN

Inhaled allergens, acting through IgE-dependent mechanisms, are important triggers of asthma symptoms and inducers of airway hyperresponsiveness and airway inflammation. The effect of anti-IgE recombinant humanized monoclonal antibody-E25 (rhuMAb-E25) on the provocation concentration of allergen causing a 15% fall in FEV1 (allergen PC15) during the allergen-induced early asthmatic response (EAR) was assessed in a multicenter, randomized, double-blind, parallel group study. Ten of 11 allergic asthmatic subjects randomized to receive intravenous rhuMAb-E25, 2 mg/kg on study day 0 and 1 mg/kg on Days 7, 14, 28, 42, 56, and 70 completed the study; nine received intravenous placebo. The allergen PC15 was measured on Days -1, 27, 55, and 77 and methacholine PC20 on Days -2, 42, and 76. rhuMAb-25 was well tolerated and only one patient (active group) was withdrawn because of a generalized urticarial rash after the first dose. Compared with baseline values (Day -1), the median allergen PC15 on Days 27, 55, and 77 were increased by 2.3, 2.2, and 2.7 doubling doses (delta log PC15/0.3) respectively with rhuMAb-E25 and -0.3, +0.1, and -0.8 doubling doses with placebo (p < or = 0.002). Methacholine PC20 improved slightly after rhuMAb-E25, this change becoming statistically significant on Day 76 (p < 0.05); no change was observed in the placebo group. Mean serum-free IgE fell by 89% after rhuMAb-E25 while there was no significant change after placebo. The inhibitory effects of rhuMAb-E25 on allergen-induced EAR suggest that it may be an effective, novel antiallergic treatment for asthma.


Asunto(s)
Alérgenos/inmunología , Anticuerpos Monoclonales/uso terapéutico , Asma/inmunología , Asma/terapia , Hipersensibilidad Inmediata/inmunología , Hipersensibilidad Inmediata/terapia , Inmunoglobulina E/inmunología , Adulto , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/análisis , Método Doble Ciego , Femenino , Humanos , Inmunoglobulina E/análisis , Masculino , Cloruro de Metacolina , Persona de Mediana Edad
19.
Pediatr Pulmonol ; 20(2): 63-70, 1995 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-8570304

RESUMEN

We examined the relationship of pulmonary infection and inflammation in cystic fibrosis (CF) by performing 31 bronchoalveolar lavages (BAL) in 14 young children with minimal lung disease from CF. While 10 of the 14 patients had elevated polymorphonuclear leukocyte (PMN) counts initially, only 4 had bacteria generally regarded as pathogenic in the recovered BAL fluid. Three of these 4 and 6 of the others had follow-up bronchoscopies at 6 months intervals. PMN counts remained normal for only one patient. However, pathogenic bacteria were recovered during the repeat BALs only in those patients who were colonized initially. Proinflammatory cytokines and proteinases were generally elevated, and interleukin-8 (IL-8) concentration correlated inversely with oxygen saturation (SaO2). No complications of the procedure occurred. We conclude that BAL identifies inflammation and the presence of bacteria in the lower airway at an early stage of the disease. This information may be used to guide therapy in patients too young or otherwise unable to produce sputum. These data also suggest that inflammation is present early in the course of CF lung disease before colonization and infection of the lungs with potentially pathogenic bacteria occurs. Since inflammation appears to be the earliest detectable evidence of lung disease in CF, monitoring of inflammation with BAL may serve as a useful marker of clinical benefits from new treatments in patients with minimal lung disease.


Asunto(s)
Fibrosis Quística/complicaciones , Neumonía Bacteriana/complicaciones , Bacterias/aislamiento & purificación , Lavado Broncoalveolar , Líquido del Lavado Bronquioalveolar/microbiología , Niño , Preescolar , Fibrosis Quística/metabolismo , Citocinas/metabolismo , Endopeptidasas/metabolismo , Femenino , Estudios de Seguimiento , Humanos , Lactante , Inflamación/etiología , Inflamación/metabolismo , Recuento de Leucocitos , Masculino , Neumonía Bacteriana/microbiología
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