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1.
J Immunol ; 206(11): 2714-2724, 2021 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-34011519

RESUMEN

Human type 2 cytotoxic T (Tc2) cells are enriched in severe eosinophilic asthma and can contribute to airway eosinophilia. PGD2 and its receptor PGD2 receptor 2 (DP2) play important roles in Tc2 cell activation, including migration, cytokine production, and survival. In this study, we revealed novel, to our knowledge, functions of the PGD2/DP2 axis in Tc2 cells to induce tissue-remodeling effects and IgE-independent PGD2 autocrine production. PGD2 upregulated the expression of tissue-remodeling genes in Tc2 cells that enhanced the fibroblast proliferation and protein production required for tissue repair and myofibroblast differentiation. PGD2 stimulated Tc2 cells to produce PGD2 using the routine PGD2 synthesis pathway, which also contributed to TCR-dependent PGD2 production in Tc2 cells. Using fevipiprant, a specific DP2 antagonist, we demonstrated that competitive inhibition of DP2 not only completely blocked the cell migration, adhesion, proinflammatory cytokine production, and survival of Tc2 cells triggered by PGD2 but also attenuated the tissue-remodeling effects and autocrine/paracrine PGD2 production in Tc2 induced by PGD2 and other stimulators. These findings further confirmed the anti-inflammatory effect of fevipiprant and provided a better understanding of the role of Tc2 cells in the pathogenesis of asthma.


Asunto(s)
Ácidos Indolacéticos/farmacología , Inflamación/tratamiento farmacológico , Prostaglandina D2/antagonistas & inhibidores , Piridinas/farmacología , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Linfocitos T Citotóxicos/efectos de los fármacos , Células Cultivadas , Técnicas de Cocultivo , Humanos , Inflamación/inmunología , Prostaglandina D2/biosíntesis , Receptores Inmunológicos/inmunología , Receptores de Prostaglandina/inmunología , Linfocitos T Citotóxicos/inmunología
2.
Respir Res ; 22(1): 262, 2021 Oct 07.
Artículo en Inglés | MEDLINE | ID: mdl-34620168

RESUMEN

BACKGROUND: Prostaglandin D2 (PGD2) signaling via prostaglandin D2 receptor 2 (DP2) contributes to atopic and non-atopic asthma. Inhibiting DP2 has shown therapeutic benefit in certain subsets of asthma patients, improving eosinophilic airway inflammation. PGD2 metabolites prolong the inflammatory response in asthmatic patients via DP2 signaling. The role of PGD2 metabolites on eosinophil and ILC2 activity is not fully understood. METHODS: Eosinophils and ILC2s were isolated from peripheral blood of atopic asthmatic patients. Eosinophil shape change, ILC2 migration and IL-5/IL-13 cytokine secretion were measured after stimulation with seven PGD2 metabolites in presence or absence of the selective DP2 antagonist fevipiprant. RESULTS: Selected metabolites induced eosinophil shape change with similar nanomolar potencies except for 9α,11ß-PGF2. Maximal values in forward scatter of eosinophils were comparable between metabolites. ILC2s migrated dose-dependently in the presence of selected metabolites except for 9α,11ß-PGF2 with EC50 values ranging from 17.4 to 91.7 nM. Compared to PGD2, the absolute cell migration was enhanced in the presence of Δ12-PGD2, 15-deoxy-Δ12,14-PGD2, PGJ2, Δ12-PGJ2 and 15-deoxy-Δ12,14-PGJ2. ILC2 cytokine production was dose dependent as well but with an average sixfold reduced potency compared to cell migration (IL-5 range 108.1 to 526.9 nM, IL-13 range: 125.2 to 788.3 nM). Compared to PGD2, the absolute cytokine secretion was reduced in the presence of most metabolites. Fevipiprant dose-dependently inhibited eosinophil shape change, ILC2 migration and ILC2 cytokine secretion with (sub)-nanomolar potencies. CONCLUSION: Prostaglandin D2 metabolites initiate ILC2 migration and IL-5 and IL-13 cytokine secretion in a DP2 dependent manner. Our data indicate that metabolites may be important for in vivo eosinophil activation and ILC2 migration and to a lesser extent for ILC2 cytokine secretion.


Asunto(s)
Asma/tratamiento farmacológico , Eosinófilos/efectos de los fármacos , Linfocitos/efectos de los fármacos , Prostaglandina D2/farmacología , Receptores Inmunológicos/agonistas , Receptores de Prostaglandina/agonistas , Adolescente , Adulto , Anciano , Asma/inmunología , Asma/metabolismo , Movimiento Celular/efectos de los fármacos , Forma de la Célula/efectos de los fármacos , Células Cultivadas , Eosinófilos/inmunología , Eosinófilos/metabolismo , Femenino , Humanos , Ácidos Indolacéticos/farmacología , Interleucina-13/metabolismo , Interleucina-5/metabolismo , Linfocitos/inmunología , Linfocitos/metabolismo , Masculino , Persona de Mediana Edad , Antagonistas de Prostaglandina/farmacología , Prostaglandina D2/análogos & derivados , Piridinas/farmacología , Receptores Inmunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Transducción de Señal , Adulto Joven
3.
Drug Metab Dispos ; 48(10): 917-924, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32739890

RESUMEN

This drug-drug interaction study determined the effect of cyclosporine, an inhibitor of organic anion transporting polypeptide (OATP) 1B3 and P-gp, on the pharmacokinetics (PK) of fevipiprant, an oral, highly selective, competitive antagonist of the prostaglandin D2 receptor 2 and a substrate of the two transporters. The concomitant administration of an intravenous microdose of stable isotope-labeled fevipiprant provided the absolute bioavailability of fevipiprant as well as mechanistic insights into its PK and sensitivity to drug interactions. Liquid chromatography-mass spectrometry/mass spectrometry was used to measure plasma and urine concentrations. Geometric mean ratios [90% confidence interval (CI)] for oral fevipiprant with or without cyclosporine were 3.02 (2.38, 3.82) for C max, 2.50 (2.17, 2.88) for AUClast, and 2.35 (1.99, 2.77) for AUCinf The geometric mean ratios (90% CI) for fevipiprant intravenous microdose with or without cyclosporine were 1.04 (0.86, 1.25) for C max, 2.04 (1.83, 2.28) for AUClast, and 1.95 (1.76, 2.16) for AUCinf The absolute bioavailability for fevipiprant was approximately 0.3 to 0.4 in the absence and 0.5 in the presence of cyclosporine. The intravenous microdose allowed differentiation between systemic and presystemic effects of cyclosporine on fevipiprant, demonstrating a small (approximately 1.2-fold) presystemic effect of cyclosporine and a larger (approximately twofold) effect on systemic elimination of fevipiprant. Uptake by OATP1B3 appears to be the rate-limiting step in the hepatic elimination of fevipiprant, whereas P-gp does not have a relevant effect on oral absorption. SIGNIFICANCE STATEMENT: The drug interaction investigated here with cyclosporine, an inhibitor of several drug transporters, provides a refined quantitative understanding of the role of active transport processes in liver and intestine for the absorption and elimination of fevipiprant as well as the basis to assess the need for dose adjustment in the presence of transporter inhibitors. The applied intravenous microdose approach presents a strategy to maximize learnings from a trial, limit the number and duration of clinical trials, and enhance mechanistic drug-drug interaction understanding.


Asunto(s)
Ciclosporina/farmacocinética , Ácidos Indolacéticos/farmacocinética , Piridinas/farmacocinética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Administración Intravenosa , Administración Oral , Adolescente , Adulto , Área Bajo la Curva , Disponibilidad Biológica , Estudios Cruzados , Ciclosporina/administración & dosificación , Interacciones Farmacológicas , Femenino , Voluntarios Sanos , Humanos , Ácidos Indolacéticos/administración & dosificación , Masculino , Persona de Mediana Edad , Piridinas/administración & dosificación , Miembro 1B3 de la Familia de los Transportadores de Solutos de Aniones Orgánicos/metabolismo , Adulto Joven
4.
Cytokine ; 125: 154857, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31557636

RESUMEN

Rhinovirus (RV) infections are a major cause of exacerbations in patients with asthma. Experimental RV challenges can provide insight into the pathophysiology of viral exacerbations. Previous reports, investigating mild or moderate asthma patients, have shown an upregulation in type 2 inflammation post RV infection, however, studies specifically involving asthma patients taking inhaled corticosteroids have concentrated on symptoms and lung function, rather than the inflammatory response. Eleven moderate asthma patients were inoculated with RV. Cold symptoms and asthma control were assessed at baseline and post infection. Nasal epithelial lining fluid and bronchial alveolar lavage (BAL) fluid were collected at baseline and 4 days post infection for assessment of inflammatory proteins. Patients suffered increased cold symptoms and decreased asthma control within 7 days of infection. Antiviral mechanisms were induced following inoculation, with increases in interferon -α, ß, γ and λ, as well as CXCL10 and CXCL11. Type 2 inflammatory cytokines were also significantly elevated post RV infection in both nasal and bronchial samples. In BAL, epithelial derived IL-25 and IL-33 levels strongly correlated with Th2 cytokines, IL-4, IL-5 and IL-13. We show how experimental rhinovirus challenge regulates lung and nasal biomarkers in asthma patients taking inhaled corticosteroids. These biomarkers could be used to evaluate the effects of novel drugs for asthma.


Asunto(s)
Corticoesteroides/uso terapéutico , Asma/metabolismo , Interleucina-17/metabolismo , Interleucina-33/metabolismo , Rhinovirus/inmunología , Adolescente , Adulto , Anciano , Asma/inmunología , Asma/fisiopatología , Asma/virología , Biomarcadores/metabolismo , Líquido del Lavado Bronquioalveolar/virología , Quimiocina CXCL10/metabolismo , Quimiocina CXCL11/metabolismo , Femenino , Humanos , Inflamación/inmunología , Inflamación/metabolismo , Interferón-alfa/metabolismo , Interferón beta/metabolismo , Interferón gamma/metabolismo , Interferones/metabolismo , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Interleucina-5/metabolismo , Masculino , Persona de Mediana Edad , Adulto Joven , Interferón lambda
5.
Allergy ; 74(1): 141-151, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-29974963

RESUMEN

BACKGROUND: Omalizumab, a humanized recombinant monoclonal anti-IgE antibody, proved to be effective in patients with chronic spontaneous urticaria (CSU), including severe and treatment-refractory CSU. Here, we report omalizumab's effect on gene expression in skin biopsies from CSU patients enrolled in a double-blind, placebo-controlled study. METHODS: Chronic spontaneous urticaria patients (18-75 years) were randomized to either 300 mg omalizumab (n = 20) or placebo (n = 10) administered s.c. every 4 weeks for 12 weeks (NCT01599637). Lesional and nonlesional skin biopsies were collected from the same area of consenting patients and assessed at baseline and on Day 85 compared with skin biopsies from the same area of 10 untreated healthy volunteers (HVs). Gene expression data were generated using Affymetrix HG-U133Plus2.0 microarrays. Statistical analyses were performed using R packages. RESULTS: At baseline, 63 transcripts were differentially expressed between lesional and nonlesional skin. Two-thirds of these lesional signatures were also differentially expressed between lesional and HV skin. Upon treatment with omalizumab, >75% of lesional signatures changed to reflect nonlesional skin expression levels (different vs placebo, P < 0.01). Transcripts upregulated in lesional skin (vs nonlesional and/or HV skin) suggested increased mast cell/leukocyte infiltration (FCER1G, C3AR1, CD93, S100A8, and S100A9), increased oxidative stress, vascularization (CYR61), and skin repair events (KRT6A, KRT16). Lesional signatures were not modulated by treatment in nonresponders (defined based on UAS7 longitudinal changes ≥16). CONCLUSION: Omalizumab, in treatment responders, reverted transcriptional signatures associated with CSU lesion phenotype to reflect nonlesional/HV expression levels; this is consistent with observed omalizumab-mediated clinical improvement observed in patients with CSU.


Asunto(s)
Urticaria Crónica/tratamiento farmacológico , Omalizumab/farmacología , Transcriptoma/efectos de los fármacos , Adolescente , Adulto , Anciano , Antialérgicos/farmacología , Biopsia , Urticaria Crónica/genética , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Omalizumab/uso terapéutico , Piel/patología , Resultado del Tratamiento , Adulto Joven
6.
Respir Res ; 19(1): 189, 2018 Sep 29.
Artículo en Inglés | MEDLINE | ID: mdl-30268119

RESUMEN

Asthma is characterised by chronic airway inflammation, airway obstruction and hyper-responsiveness. The inflammatory cascade in asthma comprises a complex interplay of genetic factors, the airway epithelium, and dysregulation of the immune response.Prostaglandin D2 (PGD2) is a lipid mediator, predominantly released from mast cells, but also by other immune cells such as TH2 cells and dendritic cells, which plays a significant role in the pathophysiology of asthma. PGD2 mainly exerts its biological functions via two G-protein-coupled receptors, the PGD2 receptor 1 (DP1) and 2 (DP2). The DP2 receptor is mainly expressed by the key cells involved in type 2 immune responses, including TH2 cells, type 2 innate lymphoid cells and eosinophils. The DP2 receptor pathway is a novel and important therapeutic target for asthma, because increased PGD2 production induces significant inflammatory cell chemotaxis and degranulation via its interaction with the DP2 receptor. This interaction has serious consequences in the pulmonary milieu, including the release of pro-inflammatory cytokines and harmful cationic proteases, leading to tissue remodelling, mucus production, structural damage, and compromised lung function. This review will discuss the importance of the DP2 receptor pathway and the current understanding of its role in asthma.


Asunto(s)
Antiasmáticos/administración & dosificación , Antiasmáticos/metabolismo , Asma/tratamiento farmacológico , Asma/metabolismo , Receptores Inmunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Asma/inmunología , Humanos , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Inflamación/metabolismo , Mediadores de Inflamación/antagonistas & inhibidores , Mediadores de Inflamación/inmunología , Mediadores de Inflamación/metabolismo , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/metabolismo , Receptores Inmunológicos/antagonistas & inhibidores , Receptores Inmunológicos/inmunología , Receptores de Prostaglandina/antagonistas & inhibidores , Receptores de Prostaglandina/inmunología , Transducción de Señal/fisiología
7.
Drug Metab Dispos ; 45(7): 817-825, 2017 07.
Artículo en Inglés | MEDLINE | ID: mdl-28442499

RESUMEN

Fevipiprant is a novel oral prostaglandin D2 receptor 2 (DP2; also known as CRTh2) antagonist, which is currently in development for the treatment of severe asthma and atopic dermatitis. We investigated the absorption, distribution, metabolism, and excretion properties of fevipiprant in healthy subjects after a single 200-mg oral dose of [14C]-radiolabeled fevipiprant. Fevipiprant and metabolites were analyzed by liquid chromatography coupled to tandem mass spectrometry and radioactivity measurements, and mechanistic in vitro studies were performed to investigate clearance pathways and covalent plasma protein binding. Biotransformation of fevipiprant involved predominantly an inactive acyl glucuronide (AG) metabolite, which was detected in plasma and excreta, representing 28% of excreted drug-related material. The AG metabolite was found to covalently bind to human plasma proteins, likely albumin; however, in vitro covalent binding to liver protein was negligible. Excretion was predominantly as unchanged fevipiprant in urine and feces, indicating clearance by renal and possibly biliary excretion. Fevipiprant was found to be a substrate of transporters organic anion transporter 3 (OAT3; renal uptake), multidrug resistance gene 1 (MDR1; possible biliary excretion), and organic anion-transporting polypeptide 1B3 (OATP1B3; hepatic uptake). Elimination of fevipiprant occurs via glucuronidation by several uridine 5'-diphospho glucuronosyltransferase (UGT) enzymes as well as direct excretion. These parallel elimination pathways result in a low risk of major drug-drug interactions or pharmacogenetic/ethnic variability for this compound.


Asunto(s)
Hepatocitos/metabolismo , Ácidos Indolacéticos/farmacocinética , Microsomas Hepáticos/metabolismo , Piridinas/farmacocinética , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Administración Oral , Adolescente , Adulto , Biotransformación , Heces/química , Voluntarios Sanos , Humanos , Técnicas In Vitro , Ácidos Indolacéticos/sangre , Ácidos Indolacéticos/orina , Masculino , Tasa de Depuración Metabólica , Metaboloma , Persona de Mediana Edad , Unión Proteica , Piridinas/sangre , Piridinas/orina , Eliminación Renal , Distribución Tisular , Adulto Joven
8.
Pulm Pharmacol Ther ; 39: 54-63, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-27354118

RESUMEN

BACKGROUND: There is an unmet medical need for allergic asthma patients who are uncontrolled on conventional therapies. The aim of this study was to collect efficacy and safety data for QAW039, an oral chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTh2) receptor antagonist, for the treatment of asthma. METHODS: This was an exploratory phase II, double-blind, randomized, placebo-controlled multi-center study. Patients with mild-to-moderate uncontrolled allergic asthma (N = 170) were either without or weaned off inhaled corticosteroids (ICS) and long-acting ß-agonists (LABA) and randomized (1:1) to QAW039 (500 mg once daily) or to placebo for 28 days. RESULTS: Overall, 157 patients completed the study. There were no significant differences between QAW039 and placebo for trough forced expiratory volume in 1 s (FEV1) or Asthma control questionnaire (ACQ) in the total population. Subgroup analyses demonstrated that patients with a FEV1 <70% of predicted at baseline treated with QAW039 had significant improvement compared with placebo in trough FEV1 (QAW039- Placebo [Δ] = 207 mL; 90% confidence interval [CI]: 96, 319; P = 0.002) and ACQ7 (Δ = -0.41; 90%CI: -0.69, -0.13; P = 0.009). QAW039 reached a mean maximum concentration (Cmax) of 3440 ng/mL on day 28 at a median Tmax of 1 h (range 0.5-4 h). Most adverse events (AEs) were mild/moderate and balanced between both groups, with no serious AEs. CONCLUSIONS: In the general study population, no improvement in lung function was observed with QAW039. However, a subgroup analysis revealed that patients with greater severity of airflow limitation (FEV1 < 70%) had improved lung function and asthma control when treated with QAW039. QAW039 also demonstrated a favorable safety profile. TRIALS REGISTRATION: ClinicalTrials.govNCT01253603.


Asunto(s)
Antiasmáticos/uso terapéutico , Asma/tratamiento farmacológico , Ácidos Indolacéticos/uso terapéutico , Piridinas/uso terapéutico , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Administración Oral , Adulto , Antiasmáticos/efectos adversos , Antiasmáticos/farmacocinética , Asma/fisiopatología , Método Doble Ciego , Femenino , Volumen Espiratorio Forzado , Humanos , Ácidos Indolacéticos/efectos adversos , Ácidos Indolacéticos/farmacocinética , Masculino , Persona de Mediana Edad , Piridinas/efectos adversos , Piridinas/farmacocinética , Resultado del Tratamiento
9.
J Allergy Clin Immunol ; 136(1): 96-103.e9, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-26044854

RESUMEN

BACKGROUND: It has frequently been speculated that pruritus and skin lesions develop after topical exposure to aeroallergens in sensitized patients with atopic dermatitis (AD). OBJECTIVE: We sought to study cutaneous reactions to grass pollen in adult patients with AD with accompanying clear IgE sensitization to grass allergen in an environmental challenge chamber using a monocenter, double-blind, placebo-controlled study design. METHODS: Subjects were challenged on 2 consecutive days with either 4000 pollen grains/m(3) of Dactylis glomerata pollen or clean air. The severity of AD was assessed at each study visit up to 5 days after challenge by (objective) scoring of AD (SCORAD). Additionally, air-exposed and non-air-exposed skin areas were each scored using local SCORAD scoring and investigator global assessments. Levels of a series of serum cytokines and chemokines were determined by using a Luminex-based immunoassay. The primary end point of the study was the change in objective SCORAD scores between prechallenge and postchallenge values. RESULTS: Exposure to grass pollen induced a significant worsening of AD. A pronounced eczema flare-up of air-exposed rather than covered skin areas occurred. In grass pollen-exposed subjects a significantly higher increase in CCL17, CCL22, and IL-4 serum levels was observed. CONCLUSIONS: This study demonstrates that controlled exposure to airborne allergens of patients with a so-called extrinsic IgE-mediated form of AD induced a worsening of cutaneous symptoms.


Asunto(s)
Dermatitis Atópica/inmunología , Eccema/inmunología , Prurito/inmunología , Adulto , Alérgenos/efectos adversos , Alérgenos/inmunología , Cámaras de Exposición Atmosférica/efectos adversos , Quimiocina CCL17/sangre , Quimiocina CCL22/sangre , Dactylis , Progresión de la Enfermedad , Exposición a Riesgos Ambientales/efectos adversos , Femenino , Humanos , Inmunoglobulina E/sangre , Interleucina-4/sangre , Masculino , Polen/inmunología , Adulto Joven
10.
Eur Respir J ; 46(5): 1308-21, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26357963

RESUMEN

U-BIOPRED is a European Union consortium of 20 academic institutions, 11 pharmaceutical companies and six patient organisations with the objective of improving the understanding of asthma disease mechanisms using a systems biology approach.This cross-sectional assessment of adults with severe asthma, mild/moderate asthma and healthy controls from 11 European countries consisted of analyses of patient-reported outcomes, lung function, blood and airway inflammatory measurements.Patients with severe asthma (nonsmokers, n=311; smokers/ex-smokers, n=110) had more symptoms and exacerbations compared to patients with mild/moderate disease (n=88) (2.5 exacerbations versus 0.4 in the preceding 12 months; p<0.001), with worse quality of life, and higher levels of anxiety and depression. They also had a higher incidence of nasal polyps and gastro-oesophageal reflux with lower lung function. Sputum eosinophil count was higher in severe asthma compared to mild/moderate asthma (median count 2.99% versus 1.05%; p=0.004) despite treatment with higher doses of inhaled and/or oral corticosteroids.Consistent with other severe asthma cohorts, U-BIOPRED is characterised by poor symptom control, increased comorbidity and airway inflammation, despite high levels of treatment. It is well suited to identify asthma phenotypes using the array of "omic" datasets that are at the core of this systems medicine approach.


Asunto(s)
Corticoesteroides/administración & dosificación , Antiasmáticos/administración & dosificación , Asma/complicaciones , Fumar/efectos adversos , Adulto , Ansiedad/epidemiología , Asma/tratamiento farmacológico , Asma/epidemiología , Estudios de Casos y Controles , Comorbilidad , Estudios Transversales , Depresión/epidemiología , Europa (Continente) , Femenino , Reflujo Gastroesofágico/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Óxido Nítrico/análisis , Estudios Prospectivos , Calidad de Vida , Índice de Severidad de la Enfermedad , Fumar/epidemiología , Espirometría , Encuestas y Cuestionarios , Biología de Sistemas
13.
Pulm Pharmacol Ther ; 28(2): 149-53, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24657236

RESUMEN

BACKGROUND: When first approved in the European Union (EU), the omalizumab dosing table had upper bodyweight and IgE limits of 150 kg and 700 IU/mL, respectively. In this study, we assessed the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of omalizumab in patients with IgE/bodyweight combinations above those in the original dosing table. METHODS: A multicentre, open-label, parallel-group study assessed the safety, PK and PD of omalizumab in 32 patients with mild-to-moderate allergic (IgE-mediated) asthma. Patients received two subcutaneous injections of omalizumab at one of three dosage levels (450, 525, or 600 mg), chosen according to baseline IgE (300-2000 IU/mL) and bodyweight (40-150 kg), with a 14-day interval between injections. RESULTS: Overall, 69 adverse events (AEs), none of them serious, were reported by 26 (81.3%) patients. Analysis of laboratory measurements, vital signs and ECG data revealed no adverse findings of clinical relevance. The PK profile was consistent with previous data for lower doses. Mean maximum decrease of free IgE from screening was ≥99% for all three doses, and mean free IgE concentrations remained <25 ng/mL for at least 2 weeks after the second dose. The reductions in free IgE were consistent with levels previously associated with clinical improvements. CONCLUSIONS: The safety and PK/PD findings from this study are consistent with previous data, and supported the extension of the omalizumab dosing table to include those patients with higher IgE/bodyweight combinations. Clinical trial registry and registration number: clinicaltrials.gov (NCT00546143).


Asunto(s)
Antiasmáticos/administración & dosificación , Anticuerpos Antiidiotipos/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , Asma/tratamiento farmacológico , Inmunoglobulina E/inmunología , Adolescente , Adulto , Antiasmáticos/efectos adversos , Antiasmáticos/farmacocinética , Anticuerpos Antiidiotipos/efectos adversos , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/farmacocinética , Asma/inmunología , Peso Corporal , Relación Dosis-Respuesta a Droga , Humanos , Persona de Mediana Edad , Omalizumab , Selección de Paciente , Adulto Joven
14.
Int Arch Allergy Immunol ; 160(1): 102-10, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-22948442

RESUMEN

BACKGROUND: Omalizumab has been shown to suppress responses to inhaled allergens in allergic asthma patients with pretreatment immunoglobulin E (IgE) ≤700 IU/ml. To extend current dosing tables, we evaluated the potential of high omalizumab doses to block allergen-induced bronchoconstriction in patients with higher IgE levels. METHODS: Asthmatic adults (18-65 years; body weight 40-150 kg) were divided into groups according to screening IgE (group 1: 30-300 IU/ml; group 2: 700-2,000 IU/ml) and randomized 2:1 to omalizumab/placebo every 2 or 4 weeks for 12-14 weeks. Allergen bronchoprovocation (ABP) testing was performed before treatment and at weeks 8 and 16. The primary efficacy endpoint, the early-phase allergic response (EAR), was defined as the maximum percentage drop in forced expiratory volume in 1 s during the first 30 min after ABP. Serum free IgE was determined as a pharmacodynamic endpoint, and the exhaled fractional concentration of nitric oxide (FE(NO)) was an exploratory endpoint. RESULTS: Fifty patients were included in the study. Omalizumab improved EAR; at week 8, EAR was 23.1% for placebo, 9.3% in group 1 (p = 0.018 versus placebo) and 5.6% in group 2 (p < 0.001). At week 16, EAR was 20%, 11.8% (p = 0.087) and 5.1% (p < 0.001), respectively. Free IgE decreased in groups 1 and 2 and remained <50 ng/ml in all patients during weeks 6-16. Omalizumab completely suppressed FE(NO) increases after ABP in both groups. CONCLUSIONS: Omalizumab blocked early asthmatic responses over a broad range of IgE/body weight combinations. Extending the dosing tables enables omalizumab to benefit a wider range of patients.


Asunto(s)
Antiasmáticos/uso terapéutico , Anticuerpos Antiidiotipos/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Asma/tratamiento farmacológico , Adolescente , Adulto , Anciano , Antiasmáticos/administración & dosificación , Anticuerpos Antiidiotipos/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , Asma/fisiopatología , Asma/prevención & control , Pruebas de Provocación Bronquial , Broncoconstricción/efectos de los fármacos , Método Doble Ciego , Femenino , Volumen Espiratorio Forzado/efectos de los fármacos , Humanos , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Masculino , Persona de Mediana Edad , Omalizumab , Resultado del Tratamiento , Adulto Joven
15.
Respir Res ; 13: 8, 2012 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-22296755

RESUMEN

BACKGROUND: Allergen-containing subpollen particles (SPP) are released from whole plant pollen upon contact with water or even high humidity. Because of their size SPP can preferentially reach the lower airways where they come into contact with surfactant protein (SP)-D. The aim of the present study was to investigate the influence of SP-D in a complex three-dimensional human epithelial airway model, which simulates the most important barrier functions of the epithelial airway. The uptake of SPP as well as the secretion of pro-inflammatory cytokines was investigated. METHODS: SPP were isolated from timothy grass and subsequently fluorescently labeled. A human epithelial airway model was built by using human Type II-pneumocyte like cells (A549 cells), human monocyte derived macrophages as well as human monocyte derived dendritic cells. The epithelial cell model was incubated with SPP in the presence and absence of surfactant protein D. Particle uptake was evaluated by confocal microscopy and advanced computer-controlled analysis. Finally, human primary CD4+ T-Cells were added to the epithelial airway model and soluble mediators were measured by enzyme linked immunosorbent assay or bead array. RESULTS: SPP were taken up by epithelial cells, macrophages, and dendritic cells. This uptake coincided with secretion of pro-inflammatory cytokines and chemokines. SP-D modulated the uptake of SPP in a cell type specific way (e.g. increased number of macrophages and epithelial cells, which participated in allergen particle uptake) and led to a decreased secretion of pro-inflammatory cytokines. CONCLUSION: These results display a possible mechanism of how SP-D can modulate the inflammatory response to inhaled allergen.


Asunto(s)
Células Epiteliales Alveolares/metabolismo , Asma/metabolismo , Inflamación/metabolismo , Proteína D Asociada a Surfactante Pulmonar/metabolismo , Alérgenos/inmunología , Alérgenos/metabolismo , Células Epiteliales Alveolares/inmunología , Animales , Asma/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Línea Celular , Técnicas de Cocultivo , Citocinas/inmunología , Citocinas/metabolismo , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Células Epiteliales/inmunología , Células Epiteliales/metabolismo , Humanos , Inflamación/inmunología , Macrófagos/inmunología , Macrófagos/metabolismo , Phleum/inmunología , Phleum/metabolismo , Polen/inmunología , Polen/metabolismo , Proteína D Asociada a Surfactante Pulmonar/inmunología , Ratas
16.
Respir Res ; 12: 29, 2011 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-21396106

RESUMEN

BACKGROUND: Pulmonary surfactant protein D (SP-D) is considered as a candidate biomarker for the functional integrity of the lung and for disease progression, which can be detected in serum. The origin of SP-D in serum and how serum concentrations are related to pulmonary concentrations under inflammatory conditions is still unclear. METHODS: In a cross-sectional study comprising non-smokers (n=10), young--(n=10), elderly smokers (n=20), and smokers with COPD (n=20) we simultaneously analysed pulmonary and serum SP-D levels with regard to pulmonary function, exercise, repeatability and its quaternary structure by native gel electrophoresis. Statistical comparisons were conducted by ANOVA and post-hoc testing for multiple comparisons; repeatability was assessed by Bland-Altman analysis. RESULTS: In COPD, median (IQR) pulmonary SP-D levels were lower (129(68) ng/ml) compared to smokers (young: 299(190), elderly: 296(158) ng/ml; p<0.01) and non-smokers (967(708) ng/ml; p<0.001). The opposite was observed in serum, with higher concentrations in COPD (140(89) ng/ml) as compared to non-smokers (76(47) ng/ml; p<0.01). SP-D levels were reproducible and correlated with the degree of airway obstruction in all smokers. In addition, smoking lead to disruption of the quaternary structure. CONCLUSIONS: Pulmonary and serum SP-D levels are stable markers influenced by smoking and related to airflow obstruction and disease state. Smaller subunits of pulmonary SP-D and the rapid increase of serum SP-D levels in COPD due to exercise support the translocation hypothesis and its use as a COPD biomarker. TRIAL REGISTRATION: no interventional trial.


Asunto(s)
Pulmón/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/sangre , Proteína D Asociada a Surfactante Pulmonar/sangre , Fumar/sangre , Adulto , Anciano , Análisis de Varianza , Biomarcadores/sangre , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/citología , Colorimetría , Estudios Transversales , Prueba de Esfuerzo , Femenino , Volumen Espiratorio Forzado , Alemania , Humanos , Pulmón/fisiopatología , Masculino , Persona de Mediana Edad , Oxidación-Reducción , Valor Predictivo de las Pruebas , Estructura Cuaternaria de Proteína , Enfermedad Pulmonar Obstructiva Crónica/etiología , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Proteína D Asociada a Surfactante Pulmonar/química , Reproducibilidad de los Resultados , Índice de Severidad de la Enfermedad , Fumar/efectos adversos , Capacidad Vital , Adulto Joven
17.
Respir Res ; 11: 83, 2010 Jun 22.
Artículo en Inglés | MEDLINE | ID: mdl-20569420

RESUMEN

BACKGROUND: Allergen-containing subpollen particles (SPP) are released from whole plant pollen upon contact with water or even high humidity. Because of their size SPP can preferentially reach the lower airways where they come into contact with surfactant protein (SP)-D. Our previous work demonstrated that SP-D increases the uptake of SPP by alveolar macrophages. In the present study, we investigated the uptake of SPP in human primary epithelial cells and the potential modulation by SP-D. The patho-physiological consequence was evaluated by measurement of pro-inflammatory mediators. METHODS: SPP were isolated from timothy grass and subsequently fluorescently labelled. Human primary bronchial epithelial cells were incubated with SPP or polystyrene particles (PP) in the presence and absence of surfactant protein D. In addition, different sizes and surface charges of the PP were studied. Particle uptake was evaluated by flow cytometry and confocal microscopy. Soluble mediators were measured by enzyme linked immunosorbent assay or bead array. RESULTS: SPP were taken up by primary epithelial cells in a dose dependent manner. This uptake was coincided with secretion of Interleukin (IL)-8. SP-D increased the fraction of bronchial epithelial cells that bound SPP but not the fraction of cells that internalized SPP. SPP-induced secretion of IL-8 was further increased by SP-D. PP were bound and internalized by epithelial cells but this was not modulated by SP-D. CONCLUSIONS: Epithelial cells bind and internalize SPP and PP which leads to increased IL-8 secretion. SP-D promotes attachment of SPP to epithelial cells and may thus be involved in the inflammatory response to inhaled allergen.


Asunto(s)
Antígenos de Plantas/metabolismo , Bronquios/metabolismo , Células Epiteliales/metabolismo , Phleum/inmunología , Proteínas de Plantas/metabolismo , Polen/metabolismo , Proteína D Asociada a Surfactante Pulmonar/metabolismo , Animales , Transporte Biológico , Bronquios/inmunología , Línea Celular Tumoral , Ensayo de Inmunoadsorción Enzimática , Células Epiteliales/inmunología , Citometría de Flujo , Humanos , Mediadores de Inflamación/metabolismo , Interleucina-8/metabolismo , Microscopía Confocal , Tamaño de la Partícula , Proteínas de Plantas/inmunología , Polen/inmunología , Ratas , Proteínas Recombinantes/metabolismo , Propiedades de Superficie , Factores de Tiempo
18.
Exp Lung Res ; 36(9): 522-30, 2010 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-20815657

RESUMEN

Pollen starch granules (PSGs) are allergen particles that get into contact with pulmonary surfactant and phagocytes in the terminal airways. In this study, the effects of surfactant protein D (SP-D) on the interaction of PSGs with phagocytes and on the pulmonary clearance of PSGs were determined. Fluorescently labeled PSGs were incubated in vitro with murine lung macrophages or dendritic cells (DCs) ± recombinant rat SP-D (rrSP-D). In addition, the effect of SP-D on uptake of PSGs by lung macrophages and DCs was studied in vivo. Furthermore, PSGs were instilled in Balb/c mice and the effects of SP-D on total lung clearance were assessed by optical imaging. SP-D treatment increased the number of PSG-positive macrophages and DCs in vitro. Furthermore, SP-D accelerated uptake/binding by alveolar macrophages and reduced the number of PSG-positive tissue macrophages and DCs at 24 hours. However, SP-D did not affect total lung clearance of PSGs and it did not enhance the T-cell proliferation induced by PSG-positive DCs. In conclusion, SP-D increased PSG-positive cells in vitro and accelerated PSG binding/uptake in vivo. The observed effects were limited to cellular clearance mechanisms and did not affect the total clearance of PSGs from the lung.


Asunto(s)
Alérgenos/metabolismo , Pulmón/efectos de los fármacos , Depuración Mucociliar/efectos de los fármacos , Polen/metabolismo , Proteína D Asociada a Surfactante Pulmonar/farmacología , Almidón/metabolismo , Alérgenos/inmunología , Animales , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Femenino , Citometría de Flujo , Pulmón/inmunología , Pulmón/metabolismo , Ratones , Ratones Endogámicos BALB C , Microscopía Fluorescente , Fagocitosis/efectos de los fármacos , Fagocitosis/inmunología , Polen/inmunología , Ratas , Proteínas Recombinantes , Almidón/inmunología , Linfocitos T/citología , Linfocitos T/efectos de los fármacos
19.
Respir Res ; 10: 90, 2009 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-19793393

RESUMEN

BACKGROUND: Pulmonary surfactant reduces surface tension and is present at the air-liquid interface in the alveoli where inhaled nanoparticles preferentially deposit. We investigated the effect of titanium dioxide (TiO(2)) nanosized particles (NSP) and microsized particles (MSP) on biophysical surfactant function after direct particle contact and after surface area cycling in vitro. In addition, TiO(2) effects on surfactant ultrastructure were visualized. METHODS: A natural porcine surfactant preparation was incubated with increasing concentrations (50-500 microg/ml) of TiO(2) NSP or MSP, respectively. Biophysical surfactant function was measured in a pulsating bubble surfactometer before and after surface area cycling. Furthermore, surfactant ultrastructure was evaluated with a transmission electron microscope. RESULTS: TiO(2) NSP, but not MSP, induced a surfactant dysfunction. For TiO(2) NSP, adsorption surface tension (gammaads) increased in a dose-dependent manner from 28.2 + or - 2.3 mN/m to 33.2 + or - 2.3 mN/m (p < 0.01), and surface tension at minimum bubble size (gammamin) slightly increased from 4.8 + or - 0.5 mN/m up to 8.4 + or - 1.3 mN/m (p < 0.01) at high TiO(2) NSP concentrations. Presence of NSP during surface area cycling caused large and significant increases in both gammaads (63.6 + or - 0.4 mN/m) and gammamin (21.1 + or - 0.4 mN/m). Interestingly, TiO(2) NSP induced aberrations in the surfactant ultrastructure. Lamellar body like structures were deformed and decreased in size. In addition, unilamellar vesicles were formed. Particle aggregates were found between single lamellae. CONCLUSION: TiO(2) nanosized particles can alter the structure and function of pulmonary surfactant. Particle size and surface area respectively play a critical role for the biophysical surfactant response in the lung.


Asunto(s)
Nanopartículas , Alveolos Pulmonares/efectos de los fármacos , Proteínas Asociadas a Surfactante Pulmonar/efectos de los fármacos , Titanio/farmacología , Animales , Relación Dosis-Respuesta a Droga , Femenino , Exposición por Inhalación , Microscopía Electrónica de Transmisión , Tamaño de la Partícula , Alveolos Pulmonares/diagnóstico por imagen , Alveolos Pulmonares/metabolismo , Proteínas Asociadas a Surfactante Pulmonar/metabolismo , Proteínas Asociadas a Surfactante Pulmonar/ultraestructura , Cuarzo/farmacología , Ratas , Ratas Wistar , Tensión Superficial , Porcinos , Ultrasonografía
20.
Int Arch Allergy Immunol ; 149(4): 333-42, 2009.
Artículo en Inglés | MEDLINE | ID: mdl-19295237

RESUMEN

BACKGROUND: There is increasing interest in testing surfactant preparations for asthma therapy. Previously, Curosurf was demonstrated to increase inflammation in allergic asthmatics. So far, little is known about the immunomodulatory effects of therapeutic surfactants, in particular concerning the interaction of surfactant components with eosinophils as key effector cells of the allergic airway inflammation. The aim of the present study was to determine the effect of different therapeutic surfactants on cellular functions of eosinophils. METHODS: Eosinophils were isolated from peripheral blood of atopic volunteers and incubated with the natural animal-derived surfactants Curosurf or Alveofact or the synthetic recombinant human surfactant Venticute at different concentrations for up to 42 h. RESULTS: Curosurf and Venticute modulated the viability of eosinophils. While incubation with Curosurf increased the number of necrotic eosinophils after 1, 20 and 42 h, Venticute increased the number of apoptotic and necrotic cells after 1 h, but there were no differences compared with control cells at later time points. All surfactant preparations increased the levels of eosinophil cationic protein after 20 h and, in addition, Curosurf enhanced eosinophil cationic protein release after 42 h. The supernatant of eosinophils induced chemotaxis against autologous eosinophils, and the presence of Curosurf, but not Alveofact or Venticute, augmented the chemotactic effect. Chemotaxis was partly blocked by inhibition of eotaxin but not by inhibition of leukotrienes or platelet-activating factor. CONCLUSIONS: Therapeutic surfactants differ in their effects on eosinophil viability and the accompanying release of inflammatory mediators and chemotactic signals. Proinflammatory effects were most pronounced for the natural surfactant Curosurf.


Asunto(s)
Productos Biológicos/farmacología , Eosinófilos/efectos de los fármacos , Factores Inmunológicos/farmacología , Macrófagos Alveolares/efectos de los fármacos , Fosfolípidos/farmacología , Surfactantes Pulmonares/farmacología , Proteínas Recombinantes/farmacología , Apoptosis/efectos de los fármacos , Apoptosis/inmunología , Asma/inmunología , Benzoquinonas/farmacología , Degranulación de la Célula/efectos de los fármacos , Degranulación de la Célula/inmunología , Supervivencia Celular/efectos de los fármacos , Quimiocina CCL11/inmunología , Quimiotaxis/efectos de los fármacos , Quimiotaxis/inmunología , Proteína Catiónica del Eosinófilo/metabolismo , Eosinófilos/inmunología , Humanos , Mediadores de Inflamación/inmunología , Lactamas Macrocíclicas/farmacología , Macrófagos Alveolares/inmunología , Rifabutina/análogos & derivados
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